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The series Topics in Heterocyclic Chemistry presents critical reviews on

“Heterocyclic Compounds” within topic related volumes dealing with all aspects
such as synthesis, reaction mechanisms, structure complexity, properties, reactivity,
stability, fundamental and theoretical studies, biology, biomedical studies, pharma-
cological aspects, applications in material sciences etc. Metabolism is also included
which provides information useful in designing pharmacologically active agents.
Pathways involving destruction of heterocyclic ring are also dealt with so that
synthesis of specifically functionalized non-heterocyclic molecules can be designed.
Overall scope is to cover topics dealing with most of the areas of current trends in
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The individual volumes of Topics in Heterocyclic Chemistry are thematic.
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vii
.
Preface
Synthetic sophistication has increased to an impressive level in the past two

centuries. Ongoing development of novel synthetic concepts and methodologies
has opened up the way to the construction of many complex and challenging
synthetic targets. However, in spite of its scientific merits and its profound influ-
ence on the progress of organic chemistry, it has become clear that much of the
present synthetic methodology does not meet the conditions set to future purposes.
Increasingly, severe economic and environmental constraints force the synthetic
community to think about novel procedures and synthetic concepts to optimize
efficiency.
Robotics and combinatorial techniques allow chemists to synthesize single
libraries that contain more compounds than ever before. Especially, medicinal
chemists but also chemists active in the catalysis area have embraced this efficient
new synthesis tool. Moreover, advances in molecular biology and genomics con-
tinue to improve our understanding of biological processes and to suggest new
approaches to deal with inadequately or untreated diseases that afflict mankind.
Despite all the progress in both molecular biology/genomics and combinatorial
chemistry methods, it is generally recognized that the number of pharmaceutically
relevant hits is not directly proportional to the number of compounds screened.
Both structural diversity and complexity in a collection of molecules are essential
to address.
Ideally, a synthesis starts from readily available building blocks and proceeds
fast and in one simple, safe, environmentally acceptable, and resource-effective
operation in quantitative yield. Inspired by Nature, the construction of complex
molecules by performing multiple steps in a single operation is receiving consid-
erable attention. Such processes, in which several bonds are formed in one se-
quence without isolating the intermediates, are commonly referred to as tandem
reactions. An important subclass of tandem reactions is the multicomponent
reactions (MCRs). These are defined as one-pot processes that combine at least
three easily accessible components to form a single product, which incorporates
essentially all the atoms of the starting materials. MCRs are highly flexible,
ix
x Preface
(chemo)-selective, convergent, and atom-efficient processes of high exploratory

power (EN) that minimize solvent consumption and maximize atom efficiency.
Many MCRs are well suited for the construction of heterocyclic cores. MCR-based
processes therefore contribute to a sustainable use of resources and form the perfect
basis for modular reaction sequences composed of simple reactions that achieve in
a minimal number of steps a high degree of both complexity and diversity for
a targeted set of scaffolds. As a consequence, the design of novel MCRs and
their exploration as tools in especially heterocyclic chemistry receive growing
international attention. Novel MCRs are applied in combinatorial and medicinal
chemistry but also in catalysis and more traditional natural product syntheses.
These and other topics are at the heart of this Volume of Topics in Heterocyclic
Chemistry, which is entirely devoted to MCRs in the synthesis of heterocycles.
This collection of major contributions from established scientists will certainly
stimulate discussions and further development in this field of chemistry. I hope that
you enjoy it.
VU University, Amsterdam Romano V.A. Orru & Eelco Ruijter

July 2010
Contents
Multicomponent Syntheses of Macrocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Géraldine Masson, Luc Neuville, Carine Bughin, Aude Fayol, and Jieping Zhu
Palladium-Copper Catalyzed Alkyne Activation as an Entry

to Multicomponent Syntheses of Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Thomas J.J. Müller
Multicomponent Reaction Design Strategies: Towards Scaffold

and Stereochemical Diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Rachel Scheffelaar, Eelco Ruijter, and Romano V.A. Orru
Recent Developments in Reissert-Type Multicomponent Reactions . . . . . 127

Nicola Kielland and Rodolfo Lavilla
Microwave Irradiation and Multicomponent Reactions . . . . . . . . . . . . . . . . . . 169

Jitender B. Bariwal, Jalpa C. Trivedi, and Erik V. Van der Eycken
Applications of MCR-Derived Heterocycles in Drug Discovery . . . . . . . . . . 231

Irini Akritopoulou-Zanze and Stevan W. Djuric
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
xi
Top Heterocycl Chem (2010) 25: 1–24
DOI: 10.1007/7081_2010_47
Published online: 9 July 2010
Multicomponent Syntheses of Macrocycles
Géraldine Masson, Luc Neuville, Carine Bughin, Aude Fayol,

and Jieping Zhu
Abstract How to access efficiently the macrocyclic structure remained to be a

challenging synthetic topic. Although many elegant approaches/reactions have
been developed, construction of diverse collection of macrocycles is still elusive.
This chapter summarized the recently emerged research area dealing with multi-
component synthesis of macrocycles, with particular emphasis on the approach
named “multiple multicomponent reaction using two bifunctional building blocks”.
Keywords Isocyanide Macrocycle Macrocyclization Macrocylopeptide

Multicomponent reaction Multicomponent reaction Oxazole Passerin-3CR
Staudinger reaction Ugi 4CR
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2 Macrocyclization Involving In Situ Generated (Activated) Functional Groups . . . . . . . . . . . . . . 5
3 Multiple Multicomponent Macrocyclization Using
Two Bifunctional Building Blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4 Sequential Multiple Multicomponent Macrocyclization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
1 Introduction
Macrocycles, by virtue of their widespread occurrence in nature and their intrinsic

three-dimensional structures, play an important role in chemistry and biology
and are medicinally relevant [1–4]. Indeed various important drugs, such as
G. Masson, L. Neuville, C. Bughin, A. Fayol, and J. Zhu (*)

Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 91198
Gif-sur-Yvette Cedex, France
e-mail: zhu@icsn.cnrs-gif.fr
2 G. Masson et al.
cyclosporine, macrolides (erythromycin) and the vancomycin family glycopep-

tides, contain macrocyclic element. For example, vancomycin (1, Fig. 1), a tris-
macrocyclic natural product, has been used for more than quarter a century as an
antibiotic of last resort for the treatment of infections due to methicillin-resistant
Staphylococcus aureus and other gram-positive organisms in patients allergic to
b-lactam antibiotics [5–8]. Furthermore, turning linear molecules into macrocyclic
structures is an important tool to manipulate the properties of compounds. Indeed,
bioactive linear peptides can exist in a myriad of different conformations, very few
of which are able to bind to their receptor [9–12]. Cyclization is a common
approach to force peptides adopting bioactive conformations and to assess the
important structural and dynamic properties of peptides [13]. In addition, cyclopep-
tides are much more resistant to in vivo enzymatic degradation than their linear
counterpart. Apart from pharmaceutical applications, macrocycles have also found
wide application in polymers [14], supramolecular chemistry [15–17], and nano-
materials [18].
Macrocycles and their formation, in general, have been the subjects of a mani-
fold of publications and books (selected references: [19–25]). To address the
synthesis of macrocyclic natural products or any designed macrocycles with spe-
cific purpose, ring closure is naturally the key step that will determine the efficacy
of the overall synthetic strategy. Not surprisingly, the challenging problem of
macrocyclization has attracted attention of synthetic chemists and provided impetus
for the development of new technologies. Traditionally, two classes of reactions,
namely, uni-molecular reaction ((1), Scheme 1) and cyclodimerization of two
bifunctional monomers ((2), Scheme 1) have been successfully developed and
applied in the synthesis of natural products as well as non-natural molecules (for
examples of cyclodimerization, see: [26–28]). As oligomerization is one of the
major side reactions that influence the efficiency of any given macrocyclization
OH NH2 OH OH
Me O OH
Me O
O
O
Cl
O O
C D E
Cl
HO OH
H O H O H O
O N N N NH2CH3
N N
O H O H
NH CH3
O
OOC A
NH2 CH3
B
OHOH
HO 1 Vancomycin
Fig. 1 Structure of vancomycin

Multicomponent Syntheses of Macrocycles 3
Scheme 1 Cyclization and

cyclodimerization eq 1
X Y FG
2 3
X Y X* Y*
+ eq 2
Y X Y* X*
2 4
Scheme 2 Linear sequence a

to cyclodimers X 5 YP X* YP
c
X Y Y* XP′
2 b Y XP*
6 7
d,e X* Y f X* Y*
Y* X Y* X*
8 4
reaction; high-dilution conditions are generally applied to achieve the desired ring
closure.
Although the head-to-tail dimerization of bifunctional monomers is applicable
only to C2-symmetric macrocyclic core and is very sensitive to substrate structures
and reaction conditions because of the competitive oligomerization/polymerization,
it is nevertheless inherently more efficient than the alternative stepwise process.
Thus, to synthesize macrocycle 4 from monomer 2 by stepwise process, the func-
tional groups in monomer 2 are required to be selectively protected to afford 5
and 6 before cross-coupling (Scheme 2). Macrocyclization of 8, obtained by the
removal of the protecting group P and P0 from 7, would then provide the cyclodimer
4. The advantage of this stepwise process is that oligomerization is impossible in
the initial coupling reaction (5þ6) and could potentially be avoided in the macro-
cyclization step by performing the cyclization under high-dilution conditions.
Nevertheless, five linear steps are required to elaborate the macrocycle 4 from 2,
in contrast to the one-step cyclodimerization strategy.
A third, though far less studied possibility, is the one-step synthesis of macro-
cycles by a multicomponent reaction (MCR). MCR is a process in which three or
more reactants are combined in a single reaction vessel to produce a product that
incorporates substantial portions of all the components [29]. They have, by defini-
tion, sustainable chemistry and are inherently (a) chemo- and regioselective, a
prerequisite for a successful MCR since at least three reactive functional groups
are involved and they have to react in an ordered and selective fashion; (b) atom-
economic [30] since most of them involve addition rather than substitution reactions.
4 G. Masson et al.
Indeed, addition reactions are susceptible to generate new reactive functionalities

essential for the multicomponent domino process, whereas substitution reactions
consume the functional groups; (c) step-efficient and cost-effective since they create
at least two chemical bonds in one operation [31]; (d) convergent and efficient in
generating molecular complexity and diversity [32]; (e) cost-effective since they
reduce significantly waste production by minimizing the number of costly end-
of-pipe treatment by decreasing the number of synthetic steps; (f) operationally
simple since most of the MCRs are performed under mild reaction conditions and in
some cases even proceed spontaneously in the absence of external reagent. The past
15 years have witnessed the development of many elegant MCRs allowing the facile
access to a diverse collection of chemical compounds, with particular attention
being paid to heterocycles (for reviews, see: [33–52]).
In contrast to the formidable development on the multicomponent synthesis of
heterocycles, there were only sporadic reports on the multicomponent synthesis of
macrocycles before 2005. There are roughly three options to synthesize macro-
cycles by way of MCRs as illustrated in Scheme 3 using four-component reaction:
(a) assembly of all components to produce a given scaffold with the concurrent
generation of two new cross-reactive functional groups that subsequently cyclize to
a macrocycle (1); (b) two components are polyfunctionalized such that after
assembly of all the inputs (A, B, C, and D), the remaining two functional groups
X and Y can interact to produce a macrocycle (2); (c) Multiple multicomponent
macrocyclization using two bifunctional building blocks proposed by Wessjohann
(3) (for excellent reviews, see: [53, 54]).
The development of multicomponent synthesis of macrocycles is highly chal-
lenging. To facilitate the discussion, we use the transformation shown in (1) of
Scheme 3 to illustrate the inherent difficulties associated with this approach.
To make this approach successful, the fate of intermediate 9 ((1), Scheme 3) is a
X *X
A + B + C +D ABCD ABCD eq 1
Y Y*
9 10
X Y X *X
A + B + C + D ABCD ABCD eq 2
Y Y*
9 10
X X X* X X* X*
+
A+B A+B A*B* A*B* A*B* eq 3
Y + Y Y* Y Y* Y*
Scheme 3 Synthesis of macrocycles by multicomponent reactions

key issue. Indeed, in addition to the desired macrocyclization leading to 10, the
intermediate 9 can undergo the dimerization leading to 11, which in turn can either
cyclize to afford cyclodimer 12 or continuing the intermoleculaire process to
produce trimer 13 and higher oligomers. Consequently, the constraints on the
multicomponent synthesis of 10 from four inputs A, B, C, and D are as follows:
(a) concentration dilemma. The desired macrocycle 10 is produced by an initial
multicomponent, followed by a subsequent unimolecular, events. The former
process (MCRs) is accelerated (and often a prerequisite) when the reaction is
performed at high concentration (usually higher than 0.5 M), while the macrocy-
clization generally needed to be carried out under high-dilution conditions in order
to disfavor the dimerization/oligomerization process. Consequently, concentration
has to be carefully balanced such that it will allow the formation of multicomponent
adduct 9 with reasonable kinetics and at the same time discourage any intermolec-
ular processes from 9. In an ideal case, kc [9] should also be faster than km[A][B][C]
[D] in order to avoid the accumulation of the intermediate 9, reducing therefore the
rate of the dimerization process (kd [9][9]); (b) entropic factor. The activation
energy for a ring closure can be lowered by the preorganization of the two reacting
termini into close proximity before the actual cyclization step. Naturally, the energy
for bringing the reaction centers together and restraining their motion has to be paid
for in the preorganizing steps. The forces responsible for favoring one conformation
over another are namely covalent bonds, hydrogen bonding, and steric and elec-
tronic interactions of different nature – such as electrostatic interactions, repulsive
forces, and polarization or charge transfer [55]. The interplay of these factors
of different strengths and to different degrees contributes to the conformation of
molecules and, hence as well, to preorganize reactive centers (conformation-
directed macrocyclization, see: [56]). In target-oriented synthesis, more subtle
structural elements have to be considered in order to preorganize the linear sub-
strate into a folded conformer conducive to ring closure. However, in diversity-
oriented synthesis wherein the molecular framework is not imperatively fixed on a
certain structure, matching building blocks can then be designed to assemble a
macrocycle (Scheme 4).
2 Macrocyclization Involving In Situ Generated (Activated)

Functional Groups
The Ugi four-component reaction (4CR) produced a-acetamidoamide by simply

stirring a methanol solution of an aldehyde, an amine, a carboxylic acid and an
isocyanide [57, 58]. The Mumm rearrangement (step 5, Scheme 5), being irrevers-
ible, drives the reaction towards the formation of the Ugi adduct in good to
excellent yield under extremely mild conditions.
The Ugi 4CR provides a linear peptide-like adduct. However, it provides an ideal
starting point to reach cyclic compound. A conceptually simple approach consisted of
6 G. Masson et al.
A + B + C + D
Km
*X X *X Y*
Kc Kd
ABCD ABCD ABCD ABCD
Y* Y Y X
10 9 Kc′ 11
*X Y* Ko
ABCD ABCD
*X Y*
*Y X*
ABCD ABCD
12
*Y X
Oligomers
X*
ABCD
Y 13
Scheme 4 Multicomponent synthesis of macrocycles: potential competitive reaction pathways
O R1
MeOH
R1CHO + R2NH2 + R3COOH + R4NC NHR4
R3 N
R2 O
step 1 H2O step 5
O R2 R2 O R4
H R2 HN R3COO NH
R1 N N
R3 O O
R2 step 2 step 3 R1 step 4 R1
R1 H N
R4 N
R4
H+
Scheme 5 The Ugi four-component reaction
O COOBn
CHO MeOH COOBn O
HOOC COOBn NC 0-65°C O N
+ NO2 +
N NH O N
NH2 H
12 h, 85% O2 N
NO2
15 16 14
Scheme 6 Three-component four-center Ugi reaction to b-lactam
tethering two out of four inputs and to perform the Ugi three-component/four-center
condensation. In Scheme 6 is shown a one-pot three-component synthesis of the
medicinally important b-lactame 14 by simply mixing a b-amino acid 15, an
aldehyde and an isonitrile. In this example, amine and carboxylic acid were tethered
together in the form of b-amino acid. The reaction proceeded according to Ugi
mechanism leading to a cyclic imidate intermediate 16, which upon an intramolecular
peptide
peptide
O
NH
H2N peptide COOH + R1CHO + R4NC N
O
R1 O
R1 O
N
R R4HN
H+ 4
17 18 19
Scheme 7 Synthesis of macrocycles by Ugi reaction using peptidic amino acid as a key
component
H
N O
O O O Et3N, DMF H
H H H * N
+ N N 65h, rt
H3N N N N Ph
N OH
H H 33% (dr = 1/1) MeS
O O 20 O SMe O OO NH
Ph
–
CF3COO + HN O O
O NC O
NH
H N
H
21
Scheme 8 Synthesis of cyclohexapeptide by Ugi reaction
transacylation, afforded the observed cyclic product ([59]; for earlier works, see
[60, 61]).
Applying the same principle using peptidic amino acid 17 as starting material,
one might expect the formation of macrocyclic peptide 19 via the intermediate 18
(Scheme 7).
Indeed, the first example of macrocyclization based on Ugi reaction was reported
in 1979 from the group of Failli et al. [62]. Reaction of a TFA salt of H-Ala-Phe-Val-
Gly-Leu-Met-OH (20), isobutyraldehyde and cyclohexyl isocyanide afforded the
cyclohexapeptide 21 as a mixture of two separable diastereoisomers in 33% overall
yield. Slow addition of 20 to the reaction mixture was applied to achieve the
pseudodilution in order to minimize the oligomerization (Scheme 8).
The utility of this elegant macrocyclization technology remained unexploited for
more than 20 years probably due to the low yield and limited application scope of
this reaction described in this seminal paper. In fact, when a tripeptide H-gly-gly-
gly-OH was submitted to the same reaction conditions, a cyclohexapeptide result-
ing from the cyclodimerization was formed instead of the expected cyclotripeptide.
Wessjohann and coworkers reported in 2008, a concise synthesis of cyclic RGD
pentapeptoids by three consecutive Ugi-4CR including one for macrocyclization
[63]. Thus, reaction of 23, obtained from 22 in two steps, with formaldehyde and
tert-butyl isocyanide in methanol afforded, after global deprotection under acidic
conditions, the pentapeptoid 24 in 33% yield in four steps (Scheme 9).
Yudin and coworkers reported in 2010, a variation of this reaction using a
secondary amine-terminated peptide 25 and an amphoteric amino aldehyde 26 as
8 G. Masson et al.
O O
H H
N O O
MeO N N
HO N
O O O O
O O O O
CbzHN NH a) LiOH, THF-H2O, 0°C H2N NH
N N
O b) 10% Pd/C, H2, MeOH O
Dmb Dmb
N N
22 HN NHpmc 23 HN NHpmc
O
H H
N N OH
N N
O O O
O
a) tBuNC, HCHO, MeOH
NH
N
b) TAF, CH2Cl2, rt O O Dmb = 2,4-dimethoxybenzyl
33% over 4 steps from 22
pmc = 2,2,5,7,8-Pentamethyl-chromane-6-sulfonyl
NH
24 HN NH2
Scheme 9 Synthesis of cyclopentapeptide by Ugi reaction
peptide
peptide
RHN peptide COOH O
NR
25
+ O NR
HN HN eq 1
R2HN O
R2NC N N
O R
R1 26
R1 H+ 2 O
R1
27 28
NHR
R3COOH n R1
MeOH, rt O R3 R H
R1-CHO + R4NC NR R3 N N
n N R4 eq 2
O
RHN R1 O R2 O
n NHR2 N
R
H+ 2
Scheme 10 Synthesis of macrocycles using amphoteric amino aldehyde
reaction partners [64]. The basic principle is outlined in Scheme 10. Thus, the
reaction of 25, aziridine aldehyde 26 and tert-butyl isocyanide should afford, via
intermediate 27, the cyclopeptide 28. In Failli’s original contribution, the macro-
cyclization is a transannular process. However, in Yudin’s proposal the key ring
forming process is trigged by nucleophilic addition of the aziridine nitrogen, which
is positioned exocyclic to the electrophilic imidate function ((1), Scheme 10). This
latter process was thought to be kinetically favored because of the less encumbered
trajectory of attack, increasing consequently the efficiency of the macrocyclization.
The rational behind this approach is reminiscent of the “Split-Ugi” reaction developed
for the selective functionalization of 1,n-diamines ((2), Scheme 10) [65].
O
O
H TFE, rt N
N TBSO NH
HO NH NC C 0.2 M
+ +
4h, 83% H * O
TBSO O t
N
HN dr > 20/1 BuHNOC
O
29 30
31
S
S H
H BocHN N
BocHN N NH
NH
TFE, rt O t
O t
HN O O O Bu
HN O O O Bu C 0.2 M
O O NH
O O NH 9h, 77%
dr > 20/1 N
H +
N OH TBSO N
+ HN
32 NC
H t
TBSO CONH Bu
29 O 33
Scheme 11 Synthesis of macrocycles using amphoteric amino aldehyde: examples
Indeed, this MCR worked extremely well by simply stirring the three compo-
nents in trifluoroethanol (TFE) at room temperature. Interestingly, no high-dilution
conditions were required for the above transformation. Authors prepared 12-, 15-
and 18-membered macrocycles and even nine-membered medium-sized cycles in
excellent yields with diastereoselectivities. Two examples were depicted in
Scheme 11. Thus, stirring a TFE solution of aziridine aldehyde 29, dipeptide 30
and tert-butyl isocyanide at room temperature for 4 h afforded a nine-membered
cycle 31 in 83% yield. Similarly, a 18-membered cyclopeptide 33 was obtained in
77% yield by the reaction of 29, pentapeptide 32 and tert-butyl isocyanide. In both
examples, the cyclic compounds 31 and 33 were formed with high diastereoselec-
tivities (dr > 20/1). This is intriguing, as Ugi reaction provided generally low to
moderate stereoselection when chiral substrates was used as inputs ([66–72]; for
enantioselective isocyanide-based MCRs, see: [73–80]).
The presence of an aziridine in a macrocyclic ring system provided a handle
for further functionalization via facile nucleophilic ring opening of the strained
three-membered ring. Authors demonstrated this possibility by a late-stage, site-
specific attachment of a fluorescent tag onto a macrocyclopeptide (Scheme 12).
Thus coupling of 7-mercapto-4-methylcoumarin with cyclopeptide 36, obtained
by three-component reaction of serine-derived aziridine aldehyde 34, tert-butyl
isocyanide and pentapeptide 35, afforded the conjugate 37 in 77% yield. Other
nucleophiles such as thiols, thioacids and imides worked equally well for this ring-
opening reaction.
In all above examples, macrocyclization of peptidic amino acids by Ugi reaction
is the expected transformation, while cyclodimerization is considered to be unde-
sired. Against this notion, Wessjohann and coworkers designed a tethered amino
acid having such a backbone that head-to-tail cyclization was impossible because
of the conformational constraint [81]. Thus, a twofold Ugi reaction of C-3 amino
10 G. Masson et al.
H
H N
H N NH
N NH TFE, rt O
+ O C 0.2 M HN O O
HN O O Ph O O NH
34 O Ph O O NH 8h, 76%
dr > 20 / 1 N
NC OH N
HN
H CONHt Bu
35 36
Ph H
N NH
O
O O O
O O NH
HS O S HN O
O
CH2Cl2, NEt3, t BuHNOC N N
H
rt, C 0.3 M, 77%
37
Scheme 12 Ring opening of aziridine
O
COOH
N
MeOH O NHt Bu
t
38 + BuHN O
rt NH
NH2 NC HCHO
O
39, 33%
Scheme 13 Synthesis of cyclodimers by a double Ugi reaction
substituted lithocholic acid derivative 38, formaldehyde and tert-butyl isocyanide

in methanol afforded the cyclodimer 39 in 33% yield. The reaction has to be
performed under high-dilution conditions (syringe pump addition). Under these
conditions, a cyclotrimer was also isolated in 12% yield, together with a trace
amount of tetramer. Note that the extended, rigid steroid backbone inhibited folding
of the molecule and thus making the head-to-tail cyclization of 38 impossible. This
design principle fit into the concept of unidirectional multiple multicomponent
macrocyclization using two bifunctional building blocks (MiBs) as proposed by
Wessjohann (vide supra) (Scheme 13).
An MCR allows build up of a scaffold with multitude of substituents. One highly
rewarding approach in devising novel MCRs involved the incorporation of paired
functional groups into the starting materials that can subsequently react intramo-
lecularly after all components have been assembled. In this context, Paulvannan
and coworkers reported an elegant synthesis of bridged tricyclic compounds by the
combination of Ugi 4CR and intramolecular Diels–Alder reaction (IMDA) [82].
Key to this process is the incorporation of a diene and a dienophile in two of the four
COOEt
O
H2N NC MeOH, O
COOEt
CHO + + + HOOC 36 h, r.t. H N
O
N
40 41 42 43 O
COOEt
44, 89% (dr = 92 / 8)
O
H
N N O
O
45
Scheme 14 Synthesis of heterocycles by Ugi reaction
components of the Ugi reaction. As shown in Scheme 14, stirring a methanol

solution of furaldehyde (40), benzylamine (41), benzyl isonitrile (42) and ethyl
fumarate (43) at room temperature for 36 h provided the cycloadduct (44) in 89%
yield (dr = 92/8). The initially formed Ugi adduct 45, though isolable, underwent
intramolecular [4+2] cycloaddition to afford the observed heterocycle [83].
On the basis of the same principle, we developed a three-component synthesis of
macrocycles starting from azido amide (46), aldehyde (47) and a-isocyanoaceta-
mide (48) (the a-isocyanoacetamides are easily available, see: [84–86]) bearing a
terminal triple bond (Scheme 11) [87]. The sequence is initiated by a nucleophilic
addition of isonitrile carbon to the in situ generated imine 50 led to the nitrilium
intermediate 51, which was in turn trapped by the amide oxygen to afford oxazole
52 (selected examples: [88–94]). The oxazole 52, although isolable, was in situ
converted to macrocycle 51 by an intramolecular [3+2] cycloaddition upon addition
of CuI and diisopropylethylamine (DIPEA). In this MCR, the azido and alkyne
functions were not directly involved in the three-component construction of oxa-
zole, but reacted intramolecularly leading to macrocycle once the oxazole (52) was
built up. The reaction created five chemical bonds with concurrent formation of one
macrocycle, one oxazole and one triazole (Scheme 15).
By simply changing the position of the azido and the alkyne functions, macro-
cycles with different ring connectivity can be obtained by the same three-component
reaction. Thus, the reaction of hept-6-ynal (53), morpholine and N-(4-azidobutyl)-
N-benzyl-2-isocyano-3-phenylpropanamide (54) afforded macrocycle 55 in 40%
yield. Structurally, 55 differ from 52 by the presence of an exo-substituted amino
function (Scheme 16).
3 Multiple Multicomponent Macrocyclization Using

Two Bifunctional Building Blocks
The Ugi four-component reaction is currently the most investigated MCRs in

both target-oriented [95] as well as diversity-oriented synthesis of compound
libraries (for reviews, see: [33–52]). As one of the rare truly and highly versatile
12 G. Masson et al.
Ph
n-C6H13CHO O N
O Ph N
H 47 N N
N toluene, NH4Cl, 80°C
N +
O N
then THF, CuI, DIPEA, rt
CN 45% O
46 N n-C6H13
N3 Me N
R N
48 49
Ph
Ph
O Ph
n-C6H13 N O N
O Ph N N3
n-C6H13 N
+ N + N
N3 N
O
R O
N3 n-C6H13
MeN N
N
50 51 52 Ph
Scheme 15 Tandem Ugi-[3þ2] cycloaddition to macrocycle
N N
OHC N
N3 toluene, NH4Cl
53 80°C
+ O then THF, CuI
NH O
CN DIPEA, rt N
O N N
40% O N
Ph
Ph Ph Ph
54 55
Scheme 16 Structural diversity of macrocycles by tandem Ugi-[3þ2] cycloaddition process
four-component reaction, it is also the most exploited one in developing multicom-

ponent macrocyclizations. As outlined in the Sect. 2, it is possible to synthesize
macrocycles by a single Ugi-based reaction when two out of four inputs are tethered
into a single, conformationally biased building block. A drawback of this approach
is that one of the diversity elements is lost as a consequence of using a bifunctional
building block. To overcome this drawback, Wessjohann advanced a concept of
“multiple multicomponent macrocyclization using two bifunctional building
blocks”. The basic principle rely on the use of bifunctional building blocks with
the same functionality on either side that, after multiple MCRs, leads to bidirec-
tional macrocycles. These “symmetric” bifunctional building blocks can be synthe-
sized in a more straightforward manner than the unsymmetrical ones and problems
of functional group incompatibility are avoided (for uni-directional MiBs, see
Scheme 13). In his approach, two different symmetric bifunctional building blocks
are required and the minimum number of MCRs forming the macrocycle is two.
FG1 FG3 FG3 FG3

FG1 FG2
56
Ugi
Ugi
Ugi
FG2 1st Ugi 2nd Ugi eq 1
FG4 FG4 FG4
57 58 59
2nd Ugi
FG3 FG3 i
56 FG4 Ug
FG1 FG2
FG3 FG4 FG4
U
U
gi
gi
FG3
Ugi
FG1 FG2 FG1 FG2
Ugi
Ugi
FG3 eq 2
gi
3rd Ugi 4th Ugi

U
gi
gi
U
U
60 61 62
Scheme 17 Synthesis of macrocycles by multiple multicomponent reactions including bifunctional

building blocks (MiBs)
Using Ugi-4CR as prototypical reaction, a possible reaction leading to twofold

and fourfold cyclic adduct is shown in Scheme 17. The first Ugi adduct 58 could
react further with FG1 and FG2 to afford the cyclic product 59 ((1), Scheme 17).
Alternatively, the adduct 58 can react with a second equivalent of a bifunctional
substrate 56, FG1 and FG2 to provide twofold linear Ugi adduct 60, which could be
further transformed to fourfold Ugi cyclic adduct 62 via intermediate 61. The
formation of higher-order oligomers/cyclic oligomers could be competitive making
this reaction quite difficult to control. However, it is expected that the overall
reaction outcome could in principle be governed by the three-dimensional structure
of the bifunctional inputs 56 and 57.
To favor the one desired macrocycle, the use of relatively rigid, umbrella-shaped
or kinked bifunctional building blocks results often the conformational preorgani-
zation of cyclization precursor, generated in situ by the first MCR, leading prefer-
entially to one particular macrocycle. The length of the spacers that link the two
bifunctional inputs play also the decisive role on whether cyclodimer, cyclotrimers
or higher cyclooligomers to be produced. In practice, high-dilution or pseudodilu-
tion conditions achieved by slow addition of at least one input is generally used to
disfavor the nonproductive oligomerization process.
A unique feature of the MiBs is that the macrocycles produced in this way has no
C2-symmetry axis if an asymmetric linker was used in one (or both) of the
bifunctional substrate(s). Thus, although the MiBs product looks, at the first glance,
like repetitive homodimeric macrocycles, they are in fact non-repetitive, in sharp
contrast to the cyclodimerization discussed in (2) of Scheme 1. A complication of
using asymmetric bifunctional substrates as reaction partners in MiBs is the high
tendency to generate both the head-to-head (H-H) and head-to-tail (H-T) macro-
cycles (Scheme18). Thus, first MCR could produce two regioisomeric cyclization
precursor 63 and 64, which could then undergo a second ring-closing MCR to
14 G. Masson et al.
X X
X
X 1st MCR
+A+B
Y Y
Y Y
63 64
A+B 2nd MCR A+B
65 66
Scheme 18 Formation of possible head-to head and head-to-tail cyclodimers
a b c
OHC CHO OHC CHO OHC CHO
R3COOH R3COOH R2NH2 R2NH2 R2NH2 R2NH2

R1CHO R4NC R4NC R4NC R4NC R3COOH R3COOH
Bifunctional
R2NH2 substrates H2N NH2 HOOC COOH CN NC
R3COOH
d e f
R4NC H2N NH2 H2N NH2 HOOC COOH
R1CHO R1CHO R1CHO R1CHO R1CHO R1CHO

R4NC R4NC R3COOH R3COOH R2NH2 R2NH2
HOOC COOH CN NC CN NC
Scheme 19 Ugi-4CR in MiBs: six random combinations
provide the H-H and H-T cyclodimers 65 and 66, respectively. Unless there were
significant steric and electronic biases, both 65 and 66 would be produced in a
nonselective manner.
Another characteristic feature of MiBs is that the number of the components
remained the same when any given MCR was “transformed” into a multiple MCR.
Using Ugi-4CR as an example, there are six different random combinations to
perform the MiBs, each of them will produce a macrocycle with different ring
connectivities (Scheme 19).
Using steroid as supporting scaffold, the reaction of diamine 67, diisocyanide 68
(both being derived from lithocholic acid), acetic acid and formaldehyde afforded
the macrocycle 69a in 58% yield as a mixture of head-to-tail and head-to head
cyclic dimers ((1), Scheme 20; for the sake of clarity, only the head-to-tail regioi-
somer was shown) [96–98]. On the other hand, the reaction of diacid 70, diisocya-
nide 68, isopropylamine and formaldehyde afforded the steroid-peptoid conjugate
NH2 O N
H H O
OH O R O
H H MeOH, 25°C H H H
+ NH
H2N N
H O H H H
67 O
H R R
NC H
H HN
H H
CN 69a R = H, 58%
H 68 69b R = i Pr, 28%
O
O
N
OH H
H R O
H H
H H H
NH2 MeOH, 25°C N NH
N + H
H 70 O H H
O O
H
H R O N
HO O NC H
O
H R
H H HN
CN 71a R = H, 50%
H 68 71b R = i Pr, 14%
Scheme 20 Double Ugi-4CR to cyclic dimer
71a in 50% yield ((2), Scheme 20). It is interesting to note that the diamine/
diisocyanide combination provide a macrocycle with an exo-amide bond, while
the diacid/diisocyanide combination afforded a macrocycle with an additional
endo-amide bond. These two examples demonstrated nicely the power of MiB
approach in the generation of molecular diversities.
Aldehydes other than formaldehyde can also be used leading to macrocycles as a
mixture of all four possible diastereomers (69b, 71b, Scheme 20). The intrinsic lack
of diastereoselectivity of Ugi reaction provided nevertheless an opportunity for
chemists to generate libraries of all diastereoisomers by one single operation, a
factor that could be exploited in medicinal chemistry.
By carefully designing the structure of bifunctional substrates, Wessjohann
developed a fourfold Ugi-4CR for the syntheses of large ring-size macrocycles.
Thus, the reaction of diamine 67, cyclopropane-1,1-dicarboxylic acid (72), isopro-
pylamine and formaldehyde afforded 48-membered macrocycle 73 in 49% yield
(Scheme 21). It is appropriate to note herein that a yield of 49% corresponds to an
approximately 96% calculated yield for each individual bond-forming process,
including the macrocyclization step.
An impressive threefold Ugi reaction using carefully designed trifunctional
building blocks has been subsequently developed by Wessjohann (Scheme 22).
This reaction unified eight components (74, 75, three equivalents each of formal-
dehyde and isopropylamine) via twelve reactions including two macrocyclization
steps in a one-pot fashion to produce hemicryptophane 76 in 44% yield [99, 100].
16 G. Masson et al.
O
N
H H
N
H H O
NH2 HN
H H O
O N
H H MeOH, 25°C
N O O
H2N 67
H + NH2 49% H
O NH
O O O H H
N
HO OH H H H
O N
72 H H 73
Scheme 21 Four-fold Ugi-4CR to macrocycles
O OMe O OMe
MeO O MeO O MeO O MeO O
+ –
Bu4N O2C MeOH O
+
Bu4N–O2C 74 CO2–NBu4+ O N
44% O
N
+ N
NC O
O NH2
+ O HN
O
H H HN
N NH
N
CN NC
75 76
Scheme 22 Synthesis of hemicryptophane by threefold Ugi
This approach should be highly useful in the rapid synthesis of supramolecular

receptors because of its efficient and diversity-oriented nature.
Passerini 3CR (P-3CR )has also been used for the syntheses of macrocycles
using the same MiBs concept. Shown in Scheme 23 was an example of oxidative
double P-3CR using diacid and diol as bifunctional substrates. Simply heating a
THF solution of N-Boc glutamic acid (77), triethylene glycol (78) and tert-butyl
isocyanide in the presence of IBX afforded the macrolide 79 in 59% yield (1) [101].
In this reaction, triethylene glycol (78) was oxidized in situ to the unstable dialde-
hyde 80 which then participated in the double P-3CR [102]. By applying the same
oxidative conditions, the diisocyanide/latent dialdehyde combination afforded the
macrocycle 82 in 33% yield (2). Once again, it is interesting to note that the reaction
shown in (1) afforded a macrocycle with two exo-amide bonds, while that shown in
(2) provided a macrocycle with two endo-amide bonds.
We have published, in 2003, a twofold four-component (ABC2) synthesis of
m-cyclophane 85 based on the three-component synthesis of 5-aminooxazole
developed earlier in this laboratory (for selected examples,see: [88–94]). Thus,
the reaction of a diamine (83), a bis a-isocyanoacetamide (84) and two equivalents
HOOC COOH BocHN

NC IBX, THF
77 NHBoc +
O O O O
40°C, 59% O O eq 1
*
O OH NH * O O HN
HO O
78 79
O O
O O
80
N N N N
CN 81 NC HN NH
IBX, THF O O
eq 2
O OH 40°C, 33% O O
HO O O * * O
78 O O
BocHN COOH BocHN NHBoc

82
Scheme 23 Oxidative double P-3CR to macrolides
NH2 NH2 * NH HN *
83
C6H13CHO + C6H13CHO MeOH, Reflux
O N N O
0.1 M, 52%
O NC NC O N N
N N
O O
O 84 O 85 two diastereomers
N NH2 N N
H H
C6H13CHO
O N O N
NC N N
N
O O O
O
N N
A O O B
Scheme 24 Four-component (ABC2) synthesis of m-cyclophane
of heptaldehyde afforded the cyclophane 85 in 52% yield (Scheme 24) [103]. In this
MCR, one macrocycle imbedded with two heterocycles was produced via the
creation of six chemical bonds and water was the only by-product generated. The
18 G. Masson et al.
reaction proceeded through a three-component construction of oxazole A followed

by its subsequent reaction with a second equivalent of aldehyde to provide the
observed product. Amazingly, the reaction performed at 0.1 M furnished cyclo-
phane 85 in higher yield than that carried out at 0.01 M under otherwise identical
conditions. That the multicomponent macrocyclization can be performed at such a
high concentration is unique. Several factors could account for this observation: (a)
the actual concentration of cyclization precusor A, generated by three-component
reaction, is much lower than the concentration of the starting materials (0.1 M); (b)
the in situ build-in oxazole ring in the cyclization precursor could potentially reduce
the conformational mobility of the molecule, facilitating thus the desired head-to-
tail cyclization [104–107].
Control experiment indicated that template effect (in the presence of different
metal salts) [108] was not operating for this transformation. The presence of NH
function in 86 that could potentially form a H-bond with oxazole ring, thus
preorganizing the cyclization precursor [109], was not an obligation. Indeed,
compound 86 (R = H) and 87 (R = Et, Fig. 2) was obtained in essentially identical
yield. Aliphatic diamines are suitable substrates, as cyclophane 88 and 89 can be
prepared in reasonable yield. It is interesting to note that a 47% yield of 89 meant
88% yield per chemical bond created, including the macrocyclization step.
The cyclophanes having two oxazoles could also serve as a useful chemical
platform for the generation of new structures by taking advantage of the rich
chemistry of oxazole. One such example is shown in Scheme 2. Hydrolysis of 85
under mild acidic conditions (THF-H2O, TFA) afforded the corresponding macro-
cyclic amide in over 85% yield (Scheme 25). All the six possible diastereomers
were readily separated and identified by LC/MS. It is interesting to note that the
retention time of these diastereomers was significantly different ranging from 2.2
to 26.3 min (column: Symmetry C-18, gradient H2O/MeCN = 2/3, then MeCN)
indicating the different hydrophobicity of these diastereoisomers.
The Mibs concept is, of course, not restricted to isocyanide-based MCRs.
Wessjohann recently demonstrated that multiple Staudinger reaction is highly
effective for the construction of marcocycles [110]. Thus, the reaction of diamine
83, dialdehyde 91 and acylchloride 92 in the presence of triethylamine afforded
macrocycle 93 incorporating four b-lactam units in 82% yield. The cis-stereo-
chemistry of all the four-membered rings was established based on the coupling
S S
MeOOC COOMe
O
N N NH HN NH HN
R R
O N N O O N N O O N N O
N N N
N N N
O O
O 86 R = H, 45% O O O
88 43% 89 47%
87 R = Et, 42%
Fig. 2 Examples of Four-component (ABC2) synthesis of m-cyclophanes

NH HN
NH HN
THF-TFA-H2O (8/2 /1)
O NH HN O
O N N O 85%
O O
N N N N
O O
85 O 90 O
Scheme 25 Revealing the peptidic backbone by the hydrolysis of 5-aminooxazole unit
MeO OMe
O N N O
O O
91 O Et3N
+
O
NH2 NH2 Cl
92 N N
O O
83 MeO OMe
93, 82%
Scheme 26 Multiple Staudinger reaction
constant of the two vicinal protons (around 4.6 Hz). This is not unexpected
assuming that the four-membered lactam ring was produced by a [2þ2] cycloaddi-
tion. Experimentally, acyl chloride was added after the macrocyclic oligoimine was
preformed, so the staudinger reaction was actually not involved in the ring-closure
step. Nevertheless, the formation of cyclic oligoimine is a dynamic process and
usually macrocycles with different ring sizes coexisted. Wessjohann and coworkers
have provided convincing evidence to show that the subsequent [2þ2] cycloaddi-
tion could shift the equilibrium of these oligoimines to provide one major stable
macrocycle after the Staudinger reaction. Using Ugi reaction to freeze imine
exchange in dynamic libraries as a tool to access templated macrocycles has also
been developed from the same group [111] (Scheme 26).
4 Sequential Multiple Multicomponent Macrocyclization
Most of the known synthetic receptors, such as cryptands, cyclophanes, and cages,
are homo-oligomeric structures, although more complex and unconventional topol-
ogies, such as interlocked and knotted molecules have recently proved their
20 G. Masson et al.
potential as prototypical molecular devices. It is fair to say that the conceptual

advance in supramolecular chemistry is closely related to our ability to synthesize
tailor-made macrocycles. Indeed, to further exploit the potential of these three-
dimensional large molecules in molecular recognition processes, an even more
efficient approach capable of producing genuine nonsymmetric cryptands and
other types of macromulticycles with varied molecular topologies is highly
demanding. Towards this end, an elegant synthetic strategy named sequential
MiBs has been advanced and developed by the group of Wessjohann [112].
A generic presentation of double MiBs for the synthesis of cryptand is shown in
Scheme 27. Thus, the first MiB followed by deprotection would produce a bis-
functionalized macrocycle 94 that would be engaged in a second MiB with another
bis-functionalized substrate to afford the nonsymmetric cryptand 95. With the
combination shown in scheme 27, the bridgehead core of the cryptands are tertiary
amides arising from the first double Ugi-4CR-based macrocyclization. Since there
were four components taking part in the Ugi reaction, six different combinations of
bifunctional building blocks are possible (cf scheme 19). Accordingly, up to 36
permutations leading to 36 topologically different macrocycles could be realized by
repeating just two macrocyclization steps in a sequential manner. Thus, the acces-
sible diversity of nonsymmetric cryptands is truly remarkable by applying this
approach. One such example is depicted in Scheme 28. Thus, the reaction of diacid
96, diisocyanide 97, formaldehyde and tert-butyl glycine (98) afforded, after
removal of tert-butyl ester, the macrocycle 99. The second MiB of macrocyclic
H2N COOP
COOH
RCHO
COOH
CN
a) Ugi-MiB
step 1
b) N-deprotection
COOH
CN
RCHO
COOH
H2N COOP
94
RNH2
COOH
CN
RCHO
Ugi-MiB
step 2
RNH2
CN
COOH
RCHO
95
Scheme 27 Synthesis of nonsymmetric cryptand by two consecutive MiBs

O COOH
O
O O N
O O O HN
HO O OH
96 a) MeOH, rt
+ HCHO O
b) TFA
NC O
CN
H2N
OBut O HN
N
97 98 O
O COOH
O 99
N
O O NH
NH2 O
HCHO N
O HN
N
N N O
CN NC
N
81 O HN
N
O
O O HN
N
O 100
Scheme 28 Sequential MiBs to nonsymmetric cryptands
diacid 99, diisocyanide 81, isopropylamine and formaldehyde provided the non-
symmetric cryptand 100. No purification of intermediate was required for this
three-step sequence and macrocycle 100 was obtained in 36% yield form diacid
96. This is impressive, considering that 16 chemical bonds were formed in these
reactions including two macrocyclizations.
The synthesis of clam-shaped macrobicycles and Igloo-shaped macrotetracycles
were also detailed in this full paper.
5 Conclusion
Recent years have witnessed the remarkable progress in the development of MCRs
and their applications in the total synthesis of natural products and designed
molecules with specific biological properties. However, multicomponent synthesis
of macrocycles is still in its infancy because of the intrinsic difficulties associated
with the development of such an approach. Although total synthesis of macrocyclic
22 G. Masson et al.
natural products featuring a key multicomponent macrocyclization step has yet to

be developed, the utilities and the power of this approach, especially the MiBs
approach developed by the group of Wessjohann, for the synthesis of designed
macrocyclic libraries have already been amply demonstrated. Only those methods
leading to macrocycles via covalent bond formation were discussed in this chapter,
it is nevertheless appropriate to point out that the multicomponent synthesis of
macrocycles via the reversible interactions such as imine formation, boronate
formation, metal–ligand interaction etc, can also be successfully used for the
construction of macrocycles and cages (for recent examples, see: [113, 114]). It is
expected that research in this field could be highly rewarding and could play a
pivatol role in the future development of functional macrocycles for applications in
medicine, in supramolecular chemistry and as nanomaterials.
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DOI: 10.1007/7081_2010_43
Published online: 24 June 2010
Palladium-Copper Catalyzed Alkyne Activation

as an Entry to Multicomponent Syntheses
of Heterocycles
Thomas J.J. Müller
Abstract Alkynones and chalcones are of paramount importance in heterocyclic

chemistry as three-carbon building blocks. In a very efficient manner, they can be
easily generated by palladium-copper catalyzed reactions: ynones are formed from acid
chlorides and terminal alkynes, and chalcones are synthesized in the sense
of a coupling-isomerization (CI) sequence from (hetero)aryl halides and propargyl
alcohols. Mild reaction conditions now open entries to sequential and consecutive
transformations to heterocycles, such as furans, 3-halo furans, pyrroles, pyrazoles,
substituted and annelated pyridines, annelated thiopyranones, pyridimines, meridia-
nins, benzoheteroazepines and tetrahydro-b-carbolines, by consecutive coupling-
cyclocondensation or CI-cyclocondensation sequences, as new diversity oriented
routes to heterocycles. Domino reactions based upon the coupling-isomerization reac-
tion (CIR) have been probed in the synthesis of antiparasital 2-substituted quinoline
derivatives and highly luminescent spiro-benzofuranones and spiro-indolones.
Keywords Alkenones Alkynones Allenes Cross-coupling Domino Reactions

Multicomponent Reactions Palladium Catalysis
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2 Alkyne Activation by Cross-Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2.1 The Coupling-Addition Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2.2 The Coupling-Isomerization Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
T.J.J. Müller
Institut für Organische Chemie und Makromolekulare Chemie der Heinrich-Heine-Universität
Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany
e-mail: thomasjj.mueller@uni-duesseldorf.de
26 T.J.J. Müller
3 Multicomponent Synthesis of Heterocycles by Coupling-Cycloaddition Sequences . . . . . . 38

3.1 Isoxazoles by a Consecutive 3CR of Acid Chlorides,
Alkynes, and Nitrile Oxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.2 Indolizines by a Consecutive 3CR of Acid Chlorides,
Alkynes, and Pyridinium Ylids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4 Multicomponent Synthesis of Heterocycles by Coupling-Addition-Cyclocondensation
Sequences Concluded by Michael Addition in Basic Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4.1 Pyrazoles by a Consecutive 3CR of Acid Chlorides,
Alkynes, and Hydrazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.2 Pyrimidines by a Consecutive 3CR of Acid Chlorides,
Alkynes, and Amidinium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
4.3 Pyrimidines by a Consecutive 4CR of (Hetero)aryl Iodides,
Carbon Monoxide, Alkynes, and Amidinium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4.4 Pyrimidines by a Two-Step Sequence of Consecutive 3CR of (Hetero)Arenes,
Oxalyl Chloride, Alkynes, and Cyclocondensation with Guanidinium Salts . . . . . . . . 48
4.5 Benzo[b][1,4]Diazepines by a Consecutive 3CR of Acid Chlorides,
Alkynes, and Ortho-Phenylene Diamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
4.6 Benzo[b][1,5]Thiazepines by a Consecutive 3CR of Acid Chlorides,
Alkynes, and Ortho-Amino Thiophenols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
5 Multicomponent Synthesis of Heterocycles by Coupling-Addition-Cyclocondensation
Sequences Concluded by Michael Addition and Steps in Acidic Media . . . . . . . . . . . . . . . . . . . 53
5.1 3-Halo Furans by a Consecutive 3CR of Acid Chlorides,
Propargyl Ethers, and Halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
5.2 Oxazoles by a Consecutive 3CR of Acid Chlorides, Propargyl Amine,
and Acid Chlorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
5.3 3-Iodo Pyrroles by a Consecutive 3CR of Acid Chlorides,
Propargyl Amides, and Iodide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
5.4 Tetrahydro-b-carbolines by a Consecutive 4CR of Acid Chlorides, Alkynes,
Tryptamines, and Acroyl Chlorides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
6 Multicomponent Synthesis of Annelated Thiopyranones
by Coupling-Addition-Nucleophilic Aromatic Substitution Sequence . . . . . . . . . . . . . . . . . . . . . 62
7 Multicomponent Synthesis of Heterocycles by Coupling–
Isomerization–Cyclocondensation Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
7.1 Pyrazoles by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl
Alcohols, and Hydrazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
7.2 Pyrimidines by a Consecutive 3CR of (Hetero)aryl Halides, Propargyl
Alcohols, and Amidinium Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
7.3 Benzoheteroazepine by a Consecutive 3CR of (Hetero)aryl Halides,
Propargyl Alcohols, and Ortho-Amino
or Ortho-Thio Substituted Anilines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
7.4 1,4-Diketones by a Consecutive 3CR of (Hetero)aryl
Halides, Propargyl Alcohols, and Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
7.5 Annelated and Substituted Pyridines by a Consecutive 4CR of (Hetero)aryl
Halides, Propargyl Alcohols, Enamines, and Ammonium Chloride . . . . . . . . . . . . . . . . . 69
7.6 Annelated and Substituted Pyridines by a Consecutive 4CR of (Hetero)aryl
Halides, Propargyl Amides, Ketene Acetals or S,N-Aminals,
and Ammonium Chloride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
8 Domino Syntheses of Heterocycles by Coupling-
Isomerization Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
8.1 Domino Synthesis of 2-Substituted Quinolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
8.2 Domino Synthesis of Spiro-Benzofuranones
and Spiro-Benzoindolones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
9 Conclusion and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Palladium-Copper Catalyzed Alkyne Activation as an Entry 27
Abbreviations
Ac Acetyl
AcO Acetyloxy
atm Atmosphere [bar]
Boc Tert-butyloxycarbonyl
Bu Butyl
CNS Central nervous system
COX-2 Cyclooxygenase-2
D Heating
DBU Diazabicyclo[5.4.0]undecene
DFT Density functional theory
DMF N,N-dimethylformamide
DME 1,2-Dimethoxyethane
equiv Equivalent(s)
EWG Electron-withdrawing group
Et Ethyl
GC-MS Gas chromatography-mass spectrometry
Hal Halogen
HIV Human immunodeficiency virus
HMG-CoA 3-Hydroxy-3-methyl-glutaryl-CoA
kobs Observed rate constant
L Ligand
LUMO Lowest unoccupied molecular orbital
MCR Multicomponent reaction
Me Methyl
MW (Heated in a) microwave (oven)
nCR n-Component reaction
NMP N-Methylpyrrolidone
Nu Nucleophile
OLED Organic light emitting diode
p Conjugated p-electron system
Ph Phenyl
Pr Propyl
PTSA p-Toluenesulfonic acid
R Organic substituent
r.t. Room temperature (20 C)
THF Tetrahydrofuran
THP Tetrahydropyranyl
TLC Thin layer chromatography
TBDMS Tert-butyldimethylsilyl
Tos p-Tolylsulfonyl
TMS Trimethylsilyl
UV Ultraviolet
vis Visible
28 T.J.J. Müller
1 Introduction
Heterocycles are ubiquitous in all aspects of modern chemistry, such as medicinal

chemistry, bioorganic and bioinorganic chemistry, and materials sciences. Their
facile preparation has remained among of the most challenging goals for synthetic
chemistry. However, addressing issues like simplicity, safety, brevity, selectivity,
yield, environmental demands, availability of starting materials, and diversity all at
the same time in the sense of an ideal synthesis [1] is an endeavor almost like
squaring the circle (Fig. 1). Consequently, synthetic chemists have sought and
devised fruitful strategies that inevitably tackle the very fundamental principles
of efficiency and efficacy. Besides the criteria of selectivity, i.e., chemo-, regio- and
stereoselectivity, they encompass also, and with increasing importance, economical
and ecological aspects. Concise, elegant and conceptually novel syntheses have
become an inspiring and steadily accelerating driving force both in academia and
industry.
Besides combinatorial and parallel synthetic strategies [2, 3] in the past two
decades the productive concepts of multicomponent processes, domino reactions
and sequential transformations have considerably stimulated the synthetic scientific
community [4–15]. In particular, combination of diversity and creation of function-
ality has merged into the field of diversity oriented syntheses [16–20] that have
found broad application in the discovery and development of pharmaceutical
lead structures, and quite recently and steadily increasing also in the conception
of functional p-electron systems, such as chromophores, fluorophores, and electro-
phores [21, 22].
Generally, domino reactions [23–26] are regarded as sequences of uni- or
bimolecular elementary reactions that proceed without intermediate isolation or
workup as a consequence of the reactive functionality that has been formed in the
previous step (Fig. 2). Besides uni- and bimolecular domino reactions that are
generally referred to as “domino reactions,” the third class is called multimolecular
domino reactions or multicomponent reactions (MCRs).
simple safe
preserving
in one resources
step
Ideal
Synthesis
100 %
yield environmentally
benign
Fig. 1 The ideal synthesis – readily available diverse,

squaring the circle? starting materials but selective
Domino Reactions
unimolecular bimolecular multimolecular
Perspective: High Complexity

Goals: High Diversity, Functionality
Multi-component Reactions
Domino Sequential Consecutive

All components are initially Addition in a defined order, Conditions are changed
present, intermediates are constant conditions, stepwise, intermediates
not isolable intermediates are isolable are isolable
Perspective: High Diversity

Goals: Structural Complexity, Functionality
Fig. 2 Multicomponent and domino reactions – enhancing synthetic efficiency
Whereas uni- and bimolecular domino reactions inevitably cause a significant

increase in the degree of molecular complexity, MCR inherently lead to an increase
in molecular diversity. Therefore, MCR bear some significant advantages over uni-
and bimolecular domino reactions. Besides the facile accessibility and high diver-
sity of starting materials multicomponent syntheses promise high convergence and
enormous exploratory potential. In addition to a purist standpoint where all ingre-
dients of MCR have to be present from the very beginning of the process (MCR in a
domino fashion), nowadays sequential (subsequent addition of reagents in a well-
defined order without changing the conditions) and consecutive (subsequent addi-
tion of reagents with changing the conditions) one-pot reactions are as well counted
to the class of MCR [4, 6, 11].
Transition metal catalyzed cross-coupling reactions [27] have considerably
revolutionized the conceptual construction of molecular frameworks. For devising
consecutive multicomponent, most advantageously the cross-coupling methodol-
ogy displays an excellent compatibility with numerous polar functional groups as a
consequence of the mild reaction conditions. Therefore, polar functionalities, which
are most favorably for performing one-pot sequences, can be easily introduced
and conveyed for subsequent transformations. Mastering unusual combinations of
elementary organic reactions under similar conditions is the major conceptual
defiance in engineering novel types of sequences for the synthesis of heterocycles
in a concise one-pot fashion. Thus, the prospect of transition metal catalysis in
MCR syntheses of heterocycles [28–30] and also sequentially palladium catalyzed
processes [31] promise multiple opportunities for developing novel lead structures of
pharmaceuticals, catalysts and even novel molecule based materials. The following
account summarizes in a comprehensive fashion the concept of catalytic alkyne
30 T.J.J. Müller
activation as an entry to multicomponent and domino syntheses of heterocycles that

has been developed over the past decade in our group.
2 Alkyne Activation by Cross-Coupling
Reactive three-carbon building blocks such as alkynones [32] and 1,3-diaryl pro-
penones (chalcones) (for a review on the chemistry of 1,3-diaryl propenones, see
e.g. [33]) which can react with bifunctional nucleophiles in a sequence of Michael
addition and cyclocondensation open a facile access to five-, six-, and seven-
membered heterocycles (Scheme 1). As a consequence, this general strategy has
found broad application. However, standard syntheses of alkynones [34] and
chalcones [33] are often harsh and require either strongly basic or strongly Lewis
or Brønsted acidic conditions. Therefore, the application in one-pot methodology,
where delicately balanced reaction conditions are a prerequisite, is largely
excluded.
Therefore, mild reaction conditions for the catalytic generation of ynones and
enones, which are compatible with following transformations, are highly desirable.
In particular, transition metal catalysis opens many opportunities for functional
group tolerant product formations. Therefore, a catalytic access to ynones and
enones turns out to be a versatile entry to consecutive multicomponent syntheses
of heterocycles.
Taking into account the excellent compatibility of polar functional groups that
often dispenses with tedious protection–deprotection steps, the Sonogashira cou-
pling [35–40], a straightforward alkyne-to-alkyne transformation, is a highly favor-
able tool for devising novel synthetic strategies to functional p-electron systems.
Conceptually, the installation of a reactive functional group such as an alkyne with
an electron-withdrawing substituent predictably could result in an in situ activation
of alkynes towards Michael-type addition, i.e., an entry to a coupling-addition
sequence (Scheme 2).
O
HNu XH2 Nu X
R1
R2 R1 R2
Alkynone
Catalytic
Accesses? Oxidation
O
HNu XH2 Nu X
R1 R2
Alkenone R1 R2
Scheme 1 Ynones and enones as three-carbon building blocks in heterocycle synthesis

[Pd0, CuI], base

R 1 π Hal + R1 π
Sonogashira R2
R2
Reaction
electron triple bond

withdrawing group activation
(EWG) (Michael acceptor)
Scheme 2 Alkyne activation by Sonogashira coupling of an electron-poor halide as an entry to

coupling–Michael addition sequences
2.1 The Coupling-Addition Sequence
2.1.1 Sonogashira Coupling of Highly Electron-Deficient Heterocycles

to Activated Alkynes and Subsequent Amine Addition
Applying fairly electron-deficient heteroaromatic halides in Sonogashira couplings

with terminal alkynes lead to a transposition of the electron-withdrawal onto the
coupled alkynyl moiety and result in activation towards nucleophile addition. As a
consequence this concept was illustrated as an entry to intensely colored, highly
solvochromic b-amino vinyl nitrothiophenes (Scheme 3) [41]. Simultaneously, Lin
[42] has also reported that 2-alkynyl 5-nitrothiophenes 1 react very smoothly with
secondary amines 2 to furnish b-amino vinyl nitrothiophenes 3. We have closely
investigated these novel types of push-pull chromophores with respect to their NLO
and thermal properties [41]. Hyper Rayleigh scattering measurements at a funda-
mental of 1,500 nm have revealed that b-values are surprisingly large for such short
dipoles (3a: b0333 ¼ 31 1030 esu; 3b: b0333 ¼ 29 1030 esu). With respect to the
relatively low molecular mass, these chromophores display a rather favorable
molecular figures of merit, b0m/Mw, where Mw is the molar mass. Furthermore,
selected push–pull chromophores 3 were investigated by differential scanning
calorimetry revealing relatively low Tg, i.e., glass transitions, a favorable property
for composites in photo refractive materials.
Based upon the peculiar reactivity of nitrothienyl substituted alkynes a one-pot
three-component coupling-aminovinylation sequence to push-pull chromophores
was readily developed [43]. Terminal alkynes 4 and sufficiently electron-deficient
heteroaryl halides 5 were transformed under Sonogashira conditions into the
expected coupling products, which were subsequently reacted in a one-pot fashion
with secondary amines 2 to furnish the push-pull systems 6 in good yields
(Scheme 4). The critical step in this consecutive reaction is the addition of the
amine to the intermediate internal acceptor substituted alkyne. According to semi-
empirical and DFT calculations, the crucial parameters for the success of the
amine addition are the relative LUMO energies and the charge distribution at the
b-alkynyl carbon atom. Therefore, only very electron deficient substrates with high
32 T.J.J. Müller
R′
N H 2
R″ R′
R″
NO2 N
S MeOH, Δ NO2
S
1 or
THF, r.t. 3 (7 examples, 43-99%)
N N
NO2 NO2
S S
3a 3b
λmax (pentane) = 450 nm λmax (pentane) = 443 nm
λmax (CHCl3) = 520 nm λmax (CHCl3) = 513 nm
b0 = 31 × 10–30 esu b0 = 29 × 10–30 esu
b0μ /Mw = 1.34 b0μ /Mw = 1.23
Scheme 3 Michael-type addition of secondary amines to nitrothienyl substituted alkynes and

NLO data of selected b-amino vinyl nitrothiophenes
2% (Ph3P)2PdCl2, 4% CuI R1
NEt3 / THF (1:10), r.t.
R1 + Br heteroaryl NO2 R2R3N heteroaryl NO2
then: R2R3NH (2), MeOH, Δ
4 5 6 (10 examples, 31-76%)
O
Ph Ph Ph
N Et2N O N Ph
NO2 NO2 NO2 N
S S S NO2
S
6a (57%) 6b (67%) 6c (76%) 6d (52%)
NO2 NO2
n Ph Ph
Bu
N N S S
N O N
NO2 NO2
NO2 S
S N
Et2N S NEt2
6e (71%) 6f (42%) 6g (69%) 6h (67%)
Scheme 4 A coupling–aminovinylation sequence to b-amino vinyl hetero arenes 6
polarizability of the p-electron system are suited to participate in this coupling-

addition sequence.
2.1.2 Modified Sonogashira Coupling of Acid Chlorides to Alkynones
A carbonyl group in conjugation with the triple bond exerts a strong polarization
of the alkyne. Thus, Sonogashira coupling of acid chlorides 7 and terminal alkynes
4 furnishes alkynones 8 in a catalytic fashion [44–46]. Scrutinizing the reaction

conditions revealed that virtually only one equivalent of triethylamine is stoichio-
metrically necessary for scavenging hydrochloric acid, and as a consequence, to
achieve complete conversion (Scheme 5) [47, 48]. This not only reduces the amount
of base but also leads to an essentially base-free reaction medium after the cross-
coupling event. Furthermore, it is also possible to reduce reaction times
by dielectric heating (microwave irradiation, MW) instead of conductive heating
(oil bath).
Prior to our studies trimethylsilyl (TMS) acetylene (4a) has turned out to be a
notorious problem in standard acid chloride couplings and there was no report on its
successful transformation. We have optimized the coupling conditions and we
exemplified them for several (hetero)aroyl chlorides 7 as coupling partners
(Scheme 6). It is noteworthy to mention that the yields for the corresponding Stille
couplings with tributylstannyl TMS acetylene as alkyne coupling partner give with
70% (8a) [49], 51% (8b) [50], and 45% (8c) [51] substantially lower yields.
Alkynones are reactive synthetic equivalents of 1,3-dicarbonyl compounds,
and thus TMS alkynones can be considered to be surrogates of b-ketoaldehydes
[52] which are very important and well-established three-carbon building blocks for
cyclocondensations in heterocyclic chemistry [53, 54]. Furthermore, a common
synthetic pathway to other synthetic equivalents of 1,3-dicarbonyl compounds,
such as b-ketoacetals [55, 56], b-ketoenolethers [57, 58], and enaminones
[59–64] is the Michael addition of alcohols or amines to alkynones (ketovinylation)
[65–68]. Since alkynones are even more electrophilic than all other synthetic
equivalents of b-ketoaldehydes a mild catalytic generation of alkynones 8 sets
the stage for consecutive transformations to heterocycles in a one-pot fashion.
Therefore, the generation of alkynones under mild reaction conditions and in
suitable reaction media to allow subsequent transformations represents a major
methodological improvement for modular heterocycle synthesis by cyclocondensation
strategies.
[Pd0, CuI] O
O NEt3, (1.0 equiv), THF, 1 h, r.t.
+ R1
or
R1 Cl R2
[Pd0, CuI] R2
NEt3, (1.0 equiv), THF
7 4 10 min, 90°C, MW 8
Scheme 5 Alkynones 8 by modified Sonogashira cross coupling of acid chlorides 7 and alkynes 4
O
2% Pd(PPh3)2Cl2, 4% CuI 8a (R1 = p -MeOC6H4, 82%)
7 + R1 8b (R1 = p -O2NC6H4, 65%)
SiMe3 NEt3 (1.0 equiv), THF, 1 h, r.t. 8c (R1 = o -BrC6H4, 61%)
SiMe3
8d (R1 = o -AcOC6H4, 73%)
4a 8e (R1 = 2-thienyl, 82%)
Scheme 6 Trimethylsilyl alkynones 8a–e by modified Sonogashira cross coupling

34 T.J.J. Müller
2.1.3 Coupling-Addition Sequence to Enaminones
The concept of alkyne activation by Sonogashira coupling was then successfully

extended to the consecutive one-pot reaction principle of the coupling-addition
sequences leading to an enaminone synthesis [48, 69, 70]. Besides their enormous
synthetic potential as well-established three-carbon building blocks for cyclocon-
densations in heterocyclic chemistry [53, 54] enaminones [59–64] in their own
right are highly pharmacologically active and reveal a pronounced anticonvulsant
[71–74] and nonsteroidal anti-inflammatory activity [75]. In the sense of a consecu-
tive three-component one-pot reaction, after reacting various acid chlorides 7 with
terminal alkynes 4 under modified Sonogashira conditions to furnish the desired
alkynones 8 and subsequent addition of primary and secondary amines 9, heating
for several hours furnishes the enaminones 10 in good to excellent yields
(Scheme 7). Primary amines 9 with R4 ¼ H exclusively give rise to the formation
Z-configured enaminones (see e.g., 10h), whereas secondary amines 9 with R4 6¼ H
furnish E-enaminones in good E/Z-selectivity. This one-pot coupling-addition
enaminone synthesis is of a fairly broad scope and of excellent chemoselectivity.
For example, tryptamine (e.g., 10h) neither needs to be protected at the indole
nitrogen nor any enamine side reaction can be detected.
2.2 The Coupling-Isomerization Sequence
Besides activating the triple bond towards Michael addition the electron-withdrawing
group (EWG) introduced by Sonogashira coupling can also exert an activation of
the remote propargyl position (Scheme 8). This propargyl activation could for
2% Pd(PPh3)2Cl2, 4% CuI O R2
7 + 4 R3
NEt3 (1.0-1.25 equiv), THF, 1 h, r.t. R1 N
Then: R3R4NH 9, methanol, Δ R4
10 (11 examples, 74-99%)
O Ph O Ph Cl O Ph O Ph
Et Et Et
Ph N Ph N N S N
Et O Et Et
10a (97%, E:Z = 30:1) 10b (99%, E:Z = 4:1) 10c (96%, E:Z = 100:0) 10d (95%, E:Z = 14:1)
H
n
O Ph O Bu O N
H
t Et Et Et O N
Bu N Ph N Ph N
Et Et Et S Ph
10e (76%, E:Z = 100:0) 10f (97%, E:Z = 100:0) 10g (74%, E:Z = 100:0) 10h (78%, E:Z = 0:100)
Scheme 7 Coupling-addition three-component one-pot synthesis of enaminones 10

[Pd0, CuI], base

R1 π Hal + R1 π
Sonogashira R2
R2
Reaction
electron propargyl
withdrawing group activation
(EWG) (towards isomerization)
Scheme 8 Propargyl activation by Sonogashira coupling of an electron-poor halide as an entry to

coupling–isomerization (CI) sequences
instance trigger an alkyne-allene isomerization, over the complete sequence a

coupling-isomerization (CI) reaction would be the consequence.
As mentioned before enones and, in particular, chalcones (1,3-diaryl propenones)
are predominantly synthesized under aldol conditions, which are relatively harsh
and not always suitable for establishing multicomponent synthesis. The major short
comings in the aldol condensation approach are strongly basic or acidic additives
and reagents and the sometimes vigorous conditions in the condensation step.
Therefore, mild reaction conditions as in transition metal catalyzed cross-coupling
reactions are particularly favorable and promise a high level of functional group
tolerance. Generating the enone functionality in a domino fashion en route [26, 28, 76]
could pave the route to manifold opportunities for developing novel lead structures
of pharmaceuticals, catalysts and even novel molecule based materials in a one-pot
scenario.
A couple of years ago we have disclosed a new mode of alkyne activation
towards isomerization as a detouring outcome of the Sonogashira coupling. As a
result of coupling electron deficient (hetero)aryl halides (or a,b-unsaturated b-halo
carbonyl compounds) 11 and aryl propargyl alcohols 12 a new access to 1,3-di
(hetero)aryl propenones 13, i.e., chalcones, was established (Scheme 9) [77, 78].
The scope for electron deficient (hetero)aromatic halides 11 is fairly broad and even
organometallic complexes like 13c can be synthesized by this sequence.
Prior to our studies this unusual reaction has only been observed and discussed
by Minn [79] and Kundu [80, 81] for the coupling of 2-halogen substituted pyrimidines
with 1-phenyl propargyl alcohol. Therefore, Kundu speculated on the mechanism
by assuming coordination of an intermediate during a hydropalladation–
dehydropalladation catalytic cycle to the heterocyclic nitrogen atom [81]. How-
ever, due to a lack of heteroatom coordination in many cases this explanation fails
in most instances. Based upon detailed mechanistic studies, such as performing the
coupling-isomerization reaction (CIR) in deuterated protic solvents or with a
selectively deuterated propargyl alcohol and by 19F NMR kinetic measurements
on the isomerization step of a para-fluoro phenyl substituted propargyl alcohol, the
CIR can be rationalized as a sequence of a rapid Pd-Cu catalyzed alkynylation
followed by a slow (kobs (75 C) ¼ 1.66 · 104 mol L1s1 for a pseudo first order
rate law) amine base catalyzed propargyl alcohol-enone isomerization [78].
36 T.J.J. Müller
Analysis of the activation parameters from temperature dependent kinetics has

revealed a significant decrease of the activation entropy indicating a high degree
of organization in the rate determining transition state. Therefore, the general
mechanistic picture of the CIR rationalizes as follows (Scheme 10). After the
Sonogashira coupling of the halide 14 with propargyl alcohol 15 the presumed
and actual intermediate is the internal propargyl alcohol 17. Now the isomerization
OH 5% PdCl2(PPh3)2, 1% CuI O
EWG–π–Hal +
NEt3, THF, Δ, 6−24 h EWG π (hetero)aryl
(hetero)aryl
11 12
13 (28 examples, 41-98%)
EWG: electron withdrawing group
O
O O
O Ph S
OHC S
O2N Ph Ph
Ph Cr N
CO
OC CO
13a (80%) 13b (85%) 13c (79%) 13d (75%)
O
O O
O
NC F
NC
MeO2C NC
S
Br
13e (90%) 13f (83%) 13g (93%) 13h (66%)
Scheme 9 Chalcones 13 by coupling–isomerization reaction (CIR)
O
OH [Pd0, CuI], NEt3
π R1 π R2
R1 Hal + H Coupling
R2 Isomerization
Sequence
14 15 16
Coupling Tautomerization
Alkyne-Allene Isomerization
OH OH OH
NEt3 H
R1 π H R1 π •
R2 π
R2 R2
HN+Et3 R1
17 18 19
Scheme 10 The mechanistic scenario of the CIR

commences by deprotonation at the propargylic position giving rise to a resonance

stabilized propargyl-allenyl anion as a contact ion pair 18 in a solvent cage.
Protonation either returns to the propargyl alcohol 17 or proceeds to the allenol
19. The later enol is elusive and will immediately tautomerize towards the thermo-
dynamic sink on the energy hypersurface delivering the ultimate enone product
16 of the sequence.
Encouraged by the mechanistic insight it became apparent that the CIR could be
generalized to electro neutral and even electron rich halide substrates and also to
aliphatic propargyl alcohols by overcoming the activation barrier either by increas-
ing the temperature, by increasing the strength of the catalytic base in the isomeri-
zation step, or by both approaches.
Indeed, the practical solution for a general CIR turned out to be the microwave-
assisted version of the CIR (MACIR) (Scheme 11) [82].
In comparison to conductive heating in an oil bath under comparable conditions,
dielectric heating furnished higher yields in the model reaction at shorter reaction
times. Whereas electron deficient (hetero)aryl halides are rapidly coupled and
isomerized with triethylamine as a base, for electro neutral and electron rich aryl
halides DBU has to be applied to achieve comparable reaction times and yields.
Most remarkably the alkyl substituted propargyl alcohol 15 with R2 ¼ nPr can be
successfully transformed giving rise to the enone 16f in moderate isolated yield.
In addition the reaction scope of the CIR was extended to sequential catalysis
[31]. A designed substrate bearing an aryl bromide functionality in an nonactivated
stage, such as a p-bromo phenyl substituted propargyl alcohol, was selectively
coupled with an electron deficient halide furnishing the coupled p-bromo phenyl
propargyl alcohol. Upon slow base catalyzed isomerization the chalcone is gener-
ated, which now display an activated p-bromo substituent ready for rapid oxidative
addition of a Pd(0) species. Indeed, the CIR literally switches on the activated
halide functionality for a subsequent coupling, e.g., Sonogashira coupling, Suzuki
coupling, Heck reaction or CIR, in the same reaction vessel without further addition
of catalysts [83]. Likewise, also the aryl halide functionality can be designed to
O
OH 2% PdCl2(PPh3)2, 1% CuI, 20% PPh3
1 Hal +
R H
THF, NEt3 (5 equiv) or DBU (2 equiv) R1 R2
R2 MW (120-150°C) 1 2
15-30 min 16a (R = p-NCC6H4, R = Ph, 96%)
1 2
16b (R = 2-pyrimidyl, R = Ph, 84%)
14 15 1 2
16c (R = 2-pyridyl, R = Ph, 78%)
16d (R1 = p-H2NSO2C6H4, R2 = Ph, 62%)
16e (R1 = p-NCC6H4, R2 = 3-thienyl, 70%)
16f (R1 = p-NCC6H4, R2 = nPr, 62%)
1 2
16g (R = Ph, R = Ph, 92%)
16h (R1 = p-MeC6H4, R2 = Ph, 92%)
1 2
16i (R = p-MeOC6H4, R = Ph, 85%)
16i (R1 = m-H2NC6H4, R2 = Ph, 73%)
Scheme 11 Microwave-assisted CIR (MACIR) of (hetero)aryl halides 14 and propargyl alcohols

15 to give (hetero)aryl enones 16
38 T.J.J. Müller
HNTos N Tos
2% Pd(PPh3)4, 1% CuI
11 + 1
(hetero)aryl NEt3, THF, Δ R (hetero)aryl
20 21 (7 examples, 40-100%)
N Tos N Tos N Tos N Tos
NC O2N S F3C
N
OPh OMe OMe

21a (94%) 21b (49%) 21c (100%) 21d (100%)
Scheme 12 Enimines 31 by coupling-isomerization reaction (CIR)
express an electron withdrawing functionality, which simultaneously is a dormant

organometallic functionality. Indeed, bromo aryl pinacolyl boronates trigger the
CIR with a propargyl alcohol on one hand as electron withdrawing groups. On the
other hand by addition of potassium carbonate and another aryl halide the boronates
are activated after CIR towards subsequent Suzuki coupling in the same reaction
vessel without further addition of catalysts [84].
Finally, in analogy to the chalcone formation by CIR, the use of N-tosyl
propargyl amines 20 leads to the formation of N-tosyl enimines 21 in moderate to
excellent yields (Scheme 12) [85].
The mild reaction conditions (relatively weak amine bases, short reaction times)
of the CIR of (hetero)aryl halides and 1-(hetero)aryl propargyl alcohols opens
a modular entry to chalcones, which are as Michael acceptors suitable starting
points for consecutive multicomponent syntheses of heterocycles in a one-pot
fashion [28, 86]. Both catalytic generations of ynones and enones have set stages
for diversity-oriented multicomponent syntheses of heterocycles in a consecutive
one-pot fashion.
3 Multicomponent Synthesis of Heterocycles by

Coupling-Cycloaddition Sequences
Besides their pronounced Michael reactivity (vide supra and infra) alkynones are
perfectly suited as highly polarized and reactive dipolarophiles for (3 þ 2)-cycload-
ditions giving rise to five-membered heterocycles. Taking into account the mild
and catalytic access to ynones, the implementation of coupling-cycloaddition
sequences as a three-component approach to five-ring heterocycles lies at hand
(Scheme 13). According to this concept the three-component syntheses of isoxa-
zoles and indolizines have been realized to date.
O
O
Catalytic Access (3 +2)-Cycloaddition R1
R1 Z
R2 R2 Y
X
Scheme 13 Catalytic generation of alkynones and (3 þ 2)-cycloaddition
3.1 Isoxazoles by a Consecutive 3CR of Acid Chlorides,

Alkynes, and Nitrile Oxides
The pronounced biological activity has rendered many substituted isoxazoles an

important motif in medicinal chemistry. For instance, isoxazoles are potent and
selective agonists of human cloned dopamine D4 receptors [87], they exhibit
GABAA antagonist [88] analgesic, antiinflammatory, ulcerogenic [89] COX-2
inhibitory [90, 91] antinociceptive [92], and anticancer [93] activity.
Besides carbonyl and alkynone condensation [94, 95] of hydroxylamine, the
(2+3)-cycloaddition of aromatic nitrile oxides, a class of propargyl type 1,3-dipoles,
is a very general access to isoxazoles [96, 97]. Since aromatic nitrile oxides tend to
be very unstable, it is favorable to generate them in situ by dehydrochlorination of the
corresponding hydroximinoyl chlorides with a suitable base. If triethylamine is the
base, this step can be expected to be fully compatible with a preceding alkynone
formation.
Therefore, after reacting acid chlorides 7 with terminal alkynes 4 for 1 h at room
temperature under modified Sonogashira conditions, subsequently, hydroximinoyl
chlorides 22 and triethylamine are added. After dielectric heating for 30 min, the
isoxazoles 23 are obtained in moderate to excellent yields and with excellent
regioselectivity, often as crystalline solids (Scheme 14) [98]. This coupling-cyclo-
addition sequence commences with the coupling of acid chloride 7 and alkyne
4 furnishing the alkynone 8, which now can act as a dipolarophile (Scheme 15). The
suitable nitrile oxide dipole 24 is generated from 22 by dehydrochlorination with
an additional equivalent of triethylamine. As a consequence of the inherent high
reactivity of nitrile oxides, the concluding 1,3-dipolar cycloaddition to give the
desired isoxazoles 23 is preferentially performed by dielectric heating. Performing
the concluding cycloaddition step under conductive heating has proven to be time-
consuming and often not efficient. The major drawback of extended reaction times
is a side reaction of the in situ generated nitrile oxides giving rise to the formation of
furoxan oxides.
Besides the mild conditions and excellent chemo- and regioselectivity the scope
of this one-pot coupling–cycloaddition isoxazole synthesis is fairly broad. Due to
acid chlorides as halide coupling partners, amines and hydroxy groups inevitably
need to be protected prior to the reaction. Therefore, the use of acid chlorides
7 is principally limited to (hetero)aromatic compounds and derivatives without
a-hydrogen atoms. As an exception, the cyclopropyl group is tolerated as a
40 T.J.J. Müller
R1 O
2% PdCl2(PPh3)2, 4% CuI
2
O NEt3(1.05 equiv), THF, 1 h, r.t. R R3
+ 2
R1 Cl R Then: Cl OH O N
N 22 (1.0 equiv) 23 (24 examples, 12-78 %)
7 4
R3
NEt3 (1.0 equiv), 90°C, 30 min, MW
O2N
O S S O S O
NO2 OMe OMe
n
Bu N Cl
Me
O N O N O N
23a (67%) 23b (55%) 23c (78%)
t
S O Bu O O
OMe OMe OCH3
Me3Si Me3Si Me3Si
O N O N O N
23d (77%) 23e (56%) 23f (54%)
MeO
S O O
n n
Bu Pr
S
O N O N
23g (68%) 23h (66%)
Scheme 14 Coupling-cycloaddition three-component synthesis of isoxazoles 23
Scheme 15 Mechanistic 22
rationalization of the NEt3
coupling–cycloaddition
sequence to isoxazoles 23
R3 N+ O–
[Pd0, CuI], NEt3 24
7 + 4 [8] 23
Coupling 1,3-Dipolar
Cycloaddition
substituent in both steps of the sequence (see compound 23f). Aliphatic as well as
electron rich and electron poor aromatic alkynes can be employed. Even heterocy-
clic alkynes can be efficiently used as starting materials. TMS acetylene also easily
undergoes the coupling procedure. With respect to the 1,3-dipole nitrile oxide,
electron rich, polycyclic, electron deficient and heterocyclic substituents are all
tolerated and react readily with the alkynone intermediates 8.
NEt3 (1.05 equiv), THF, 1 h, r.t.
7 + 4 23 (7 examples, 29-79%)
Then: Cl OH
N 22 (1.0 equiv)
R3
NEt3 (1.0 equiv), 4 h, r.t.
Fe Fe Fe
O O O
OMe OMe
Me3Si Me3Si
Fe
O N O N O N
23i (79%) 23j (62%) 23k (47%)
Scheme 16 Coupling-cycloaddition three-component synthesis of ferrocenyl substituted

isoxazoles 23
In addition, testing scope and limitations of this sequence and the conditions,
ferrocenyl substituted isoxazoles 23 were synthesized from ferrocenyl carbonyl
chloride (R1 ¼ ferrocenyl) and/or ethynyl ferrocene (R2 ¼ ferrocenyl), and were
often obtained as red crystals [99]. Unfortunately, standard conditions of the
cycloaddition step failed, which had to be conducted at room temperature
(Scheme 16).
Cyclic voltammetry revealed that all ferrocene derivatives can be reversibly
oxidized. The number of reversible waves in the cyclic voltammograms corre-
sponds to the number of the redox sensitive moieties in the molecule. With respect
to ferrocene the half-wave potentials of the compounds are shifted anodically.
Furoxanes were isolated in minor amounts as the expected byproducts resulting
from dimerization of the nitrile oxides.
3.2 Indolizines by a Consecutive 3CR of Acid Chlorides,

Alkynes, and Pyridinium Ylids
Indolizine is an aromatic 10p-electron system and constitutional isomer of 1-H

indole and, consequently, has received a considerable theoretical and practical
interest [100]. Considering the well-established fluorescence properties of indoli-
zines [101–103] and biindolizines [102], and the steadily increasing importance of
fluorophores in biolabeling and environmental trace analysis, we have been seeking
for a new, efficient synthesis of fluorescent indolizines. Two general ways of
indolizine syntheses have been known so far [100]. The first route is based on
the intramolecular formation of the indolizine by cyclocondensation of suitable
pyridinium precursors. However, the second approach takes advantage of a [3 þ 2]
42 T.J.J. Müller
cycloaddition of pyridinium ylides with various double or triple bond Michael

systems [104–107]. Therefore, the catalytic access to alkynones is well suited for
devising a coupling-cycloaddition access to indolizines in a consecutive multicom-
ponent fashion. Thus, submitting (hetero)aroyl chlorides 7 and terminal alkynes
4 to the reaction conditions of the modified Sonogashira coupling in a mixture of
THF and triethylamine at ambient temperature and after adding 1-(2-oxoethyl)
pyridinium bromides 25 and stirring for 14 h at room temperature the indolizines
26 were obtained in 41–59% yield as pale yellow to yellow green crystalline solids
(Scheme 17) [108].
Mechanistically, this sequence can be rationalized by initial alkynone formation
upon coupling of acid chloride 7 and alkyne 4 furnishing the alkynone 8, which now
can act as a dipolarophile (Scheme 18). The amount of triethylamine is sufficient
to deprotonate the 1-(2-oxoethyl)pyridinium bromide 25 giving rise to the zwitter-
ionic pyridinium ylide 27, an allyl-type dipole suitable for the subsequent
1,3-dipolar cycloaddition to give the dihydroindolizine 28. Under either aerobic
or anaerobic conditions in the final cycloaddition step oxidative aromatization
directly furnishes the desired indolizines 26.
The just discussed sequence is another methodological showcase for the combi-
nation of cross-coupling and cycloaddition in the same reaction vessel, giving rise
to a broad variety of indolizines 26. In particular, 7-(pyridin-4-yl)-substituted
R4
O NEt3 (20 equiv), THF, 2 h, r.t. O
+ N
R2 R4
R1 Cl Then: R1
7 4 O
R2
R3
N+ 25
Br– 26 (11 examples, 41-59%)
O
R3
14 h, r.t.
N
N
O
N
O Ph O
N O N
Ph Ph O
O O N
Ph MeO Ph
EtO
TBDMSO O
Ph
MeO EtO
OMe
26a (55%) 26b (51%) 26c (53%) 26d (59%)
Scheme 17 Coupling-cycloaddition three-component synthesis of indolizines 26

25
NEt3
R4
N+
– O R4
R3
[Pd0, CuI], NEt3 O H
27
7 + 4 [8] N 26
Coupling 1,3-Dipolar R1 Oxidative
Cycloaddition O Aromatization
R2 H
R3
28
Scheme 18 Mechanistic rationalization of the coupling–cycloaddition sequence to indolizines 26
representatives display pronounced fluorescence and even strong day-light fluores-

cence upon protonation. The reversible protonation as well as the protochromicity
of the fluorescence response in weakly acidic media render 7-(pyridin-4-yl)indoli-
zines ideal candidates for fluorescence labels and for studying pH-dependent and
pH-alternating cellular processes.

Coupling-Addition-Cyclocondensation Sequences
Concluded by Michael Addition in Basic Media
Alkynones are potent Michael acceptors in heterocyclic chemistry and many five-,
six-, and seven-membered heterocycles can be synthesized from reactive, bifunc-
tional three-carbon building blocks such as alkynones by classical heterocyclic
chemistry [32]. Taking into account the mild, catalytic access to alkynones the
coupling-addition-cyclocondensation sequence for multicomponent approaches to
five-, six-, and seven-ring heterocycles lies at hand (Scheme 19).
As a consequence, this synthetic concept of the following MCRs is based on a
Sonogashira coupling and the subsequent reaction with binucleophilic substrates.
First a Michael addition furnishes an enone which reacts by intramolecular nucleo-
philic attack and subsequent condensation concludes the sequence with the forma-
tion of the heterocycle (Scheme 20). Compared to 1,3-diketone condensations this
modus operandi implements a huge advantage, since selectively only one of two
possible regioisomers is formed. In most cases, the reaction conditions for the
second addition-cyclocondensation step are neutral to slightly basic, i.e., more or
less identical to those of the preceding Sonogashira coupling.
44 T.J.J. Müller
O 1
Catalytic Access Addition-Cyclocondensation R R2
5–, 6–, and 7–
R1 Membered Rings
2 X Z
R (Y)
Scheme 19 Catalytic generation of alkynones and subsequent addition–cyclocondensation
O H2Nu
+ Nu Nu
R1
HNu
R2 R1 R2
–H2O
H2Nu
O HNu Nu
Nu
HO
R1 R2
R1
R2
Scheme 20 General mechanistic rationale of the reaction of a binucleophile and an alkynone
4.1 Pyrazoles by a Consecutive 3CR of Acid Chlorides,

Alkynes, and Hydrazines
The direct conversion of hydrazines with alkynones 8 to pyrazoles by Michael

addition-cyclocondensation has been known for more than a century [49, 109–111].
However, neither the regioselectivity issue was studied in detail nor the occurrence
of regioisomers was reported [110]. Despite of very few examples [112] the
regioselective formation of N-substituted pyrazoles by the alkynone pathway
has remained unexplored prior to our studies. With respect to the interesting
pharmacological and electronic properties of pyrazoles, in particular as fluoro-
phores, and the increasing quest for tailor-made functional p-electron systems by
diversity-oriented strategies, we have developed a regioselective one-pot synthesis
of substituted pyrazoles.
After coupling of (hetero)aroyl chlorides 7 and terminal alkynes 4, hydrazines
29, and acetic acid are added and reacted in the same reaction vessel. Best results
for the formation of pyrazoles 30 are obtained by dielectric heating in the micro-
wave oven at 150 C for 10 min in the presence of methanol. Pyrazoles 30 are
obtained in good to excellent yields, predominantly as colorless crystalline solids
(Scheme 21) [113]. This concept has also been applied to the nonregioselective
synthesis of 3,5-disubstituted pyrazoles 30 (R3 ¼ H) upon conductive heating in
the cyclocondensation step [114].
O NEt3 (1.05 equiv), THF, 1 h, r.t.
R1 R2
+
R1 Cl R2 Then: H2N–NH 29 (1.10 equiv)
3 N N
R
7 4 R3
CH3OH, CH3COOH, 10 min, 150°C (MW) 30 (25 examples, 13-95 %)
Me Cl MeO
n
Ph Bu Ph
S
N N N N N N N N
H H H Me
30a (94%) 30b (82%) 30c (83%) 30d (93%)
MeO
Cl S
CN Cl CN
S
N
N N
N N N N n
hexyl
Me Me Me
30e (87%) 30f (59%) 30g (87%)
OMe
MeO NC OMe MeO CN
N N N N N N
Me Me Me
30h (77%) 30i (58%) 30j (44%)
MeO OMe
Cl
n
Cl butyl
Ph N N
N N
N N Ph
N N
Br
Me Me
30k (68%) 30l (81%) 30m (70%)
Scheme 21 Coupling–addition–cyclocondensation three-component synthesis of pyrazoles 30
Three types of hydrazines have investigated in these methodological studies,

i.e., hydrazine (R3 ¼ H), methyl hydrazine (R3 ¼ Me), and aryl hydrazines (R3 ¼
aryl). In agreement with theory in every case only one of the two possible regioi-
somers, depending on the nature of the hydrazine substituent R3, was preferentially
formed. Only trace amounts of the other regioisomer could be detected (regios-
electivity >97: <3). Therefore, it is possible to access 1,3,5-trisubstituted pyrazoles
almost in a specific fashion (see compounds 30i and 30j). With diynes bridged
dipyrazoles can be quite efficiently prepared in the sense of a pseudo five-component
reaction (see compound 30k). The rapid, diversity-oriented synthetic approach
to fine-tunable fluorophores (with fluorescence quantum yields up to 0.78) is particu-
larly interesting for the development of tailor-made emitters in organic light emitting
diode (OLED) applications and fluorescence labeling of biomolecules, surfaces or
mesoporous materials.
46 T.J.J. Müller
+ S
Cl Then: MeNHNH2 (29b) (1.10 equiv) Me
CH3OH, CH3COOH, 10 min, 150°C (MW) N N
S Br
Then: p-MeC6H4B(OH)2, K2CO3, (3 equiv) Me
0.20 eq PPh3 (0.2 equiv), H2O
31 (52%)
20 min, 150°C, MW
Scheme 22 Coupling–addition–cyclocondensation–coupling four-component synthesis of

pyrazole 31
As another show case of a sequentially Pd-catalyzed process [31] a one-pot

four-component synthesis of pyrazole 31 encompasses a coupling-addition-cyclo-
condensation-coupling sequence where, without further catalyst addition, the Pd
catalyst of the Sonogashira coupling is exploited in the terminal Suzuki coupling
step (Scheme 22) [113].
4.2 Pyrimidines by a Consecutive 3CR of Acid Chlorides,

Alkynes, and Amidinium Salts
Pyrimidines represent an important class of heterocycles [115–120] and their

structural framework not only is a key constituent of nucleic bases, alkaloids, and
numerous pharmacophores with antibacterial [121], antimicrobial, antifungal
[122], antimycotic [123], antiviral, and antitumor activity [124, 125], but also as
a central unit in grid-forming ligands for supramolecular scaffolds [126–130]. As a
consequence many pyrimidine syntheses are known, the most efficient of them
applying cyclocondensations of 1,3-dicarbonyl compounds or their synthetic
equivalents with amidines as a key step [53, 54, 131]. Among these approaches
the reaction of alkynones and amidinium salts [132–137] represents an intriguing
entry to pyrimidines, and, thus, the catalytic alkynone generation by Sonogashira
coupling should be perfectly suited for accessing pyrimidines by multicomponent
syntheses. Therefore, a consecutive three-component synthesis of 2,4-disubstituted
and 2,4,6-trisubstituted pyrimidines 33 is readily achieved via modified Sonogashira
coupling of (hetero)aroyl chlorides 7 and terminal alkynes 4, and the subsequent
cyclocondensation with amidinium salts 32 (Scheme 23) [47, 69].
4-Substituted 2-amino pyrimidines represent highly potent tyrosine kinase inhi-
bitors [124], and representatives like 33a are readily formed upon applying guani-
dine as a binucleophile in the addition-cyclocondensation step. Interestingly, this
one-pot reaction can also be applied to furnish complex ligand type pyrimidines
such as 33h or 33i. At first sight the yields do not seem to be too breathtaking,
however, if one considers that six CC and CN bonds are formed in this consecutive
process it becomes apparent that the average yield for each bond forming step is
74%. In a multistep synthesis by Lehn the overall yield of a ligand with comparable
complexity as compound 33h was 15% [138].
O NEt3 (1.05 equiv), THF, 1 h, r.t. R1 R2
+ +
2
R1 Cl R Then: H2N NH2 32 (1.10 equiv) N N
Cl–
7 4 R3 R3
Na2CO3 · 10 H2O (2.5-3.0 equiv), 12-14 h, rfl. 33 (17 examples, 17-84%)
nBu
nBu
S S Ph
N N N N
S S OTBDMS N N
N N N N
S
NH2 SMe
OMe OMe
33a (51%) 33b (81%) 33c (84%) 33d (56%) 33e (67%)
CO2Et
nBu nBu
HN nBuTosN nBu N S S
N N N N N N N N
N N N N EtO2C
S S S S
S S
33f (60%) 33g (61%) 33h (17%) 33i (21%)
Scheme 23 Coupling–addition–cyclocondensation three-component synthesis of pyrimidines 33
4.3 Pyrimidines by a Consecutive 4CR of (Hetero)aryl Iodides,

Carbon Monoxide, Alkynes, and Amidinium Salts
An alternative catalytic three-component access to alkynones 8 can be conceived by

carbonylative alkynylation of aryl iodides 34, terminal alkynes 4, and carbon
monoxide [139, 140] or Mo(CO)6 [141, 142] (Scheme 24).
After carbonylative alkynylation of aryl iodides 34 with terminal alkynes 4 and
in the presence of carbon monoxide under ambient pressure the subsequent addition
of an amidinium salt 32 gives rise to the formation of 2,4,6-trisubstituted pyrimi-
dines 33 in the sense of a four-component reaction (Scheme 25) [143].
Additionally, this approach, albeit as a two step carbonylative alkynylation–
cyclocondensation sequence, is applicable to concise syntheses of naturally occurring
and highly biologically active meridianins and variolin analogs 36. Carbonylative
alkynylation of suitable Boc-protected 3-iodo indoles, also with bromo substituents
on the benzo core, or Boc-protected 3-iodo 7-aza indoles first furnish the
corresponding TMS alkynones 35 in good yields. Then, in a separate step an
aqueous guanidine solution concludes the syntheses by addition-cyclocondensation
and concomitant desilylation and Boc-deprotection in good yields (Scheme 26)
[143]. Meridianins and variolin analogs 36 were found to inhibit “metabolic
syndrome” and oncologically relevant protein kinases at a low micromolar and
even nanomolar level.
48 T.J.J. Müller
O
[Pd0, CuI], Base
I + R1
R1 R2 CO(1 atm) or Mo(CO)6
R2
34 4 8
Scheme 24 Alkynones 8 by carbonylative alkynylation
2% PdCl2(PPh3)2, 4% CuI R1 R2
NEt3 (2.0 equiv), CO (1 atm), THF, 48 h, r.t.
34 + 4 N N
Then: H2N NH2
Cl – 32 R3
R3
Na2CO3 · 10 H2O (2.5-3.0 equiv), 12-14 h, rfl. 33j-n
Me
MeO2C n
Bu
Ph Ph
S
N N
N N N N
O2N NH
Me Me
Me
33j (56%) 33k (43%) 33l (29%)
NC MeO
n n
Bu Bu
N N N N
S S
33m (28%) 33n (51%)
Scheme 25 Carbonylation–coupling–addition–cyclocondensation four-component synthesis of

pyrimidines 33
4.4 Pyrimidines by a Two-Step Sequence of Consecutive

3CR of (Hetero)Arenes, Oxalyl Chloride, Alkynes,
and Cyclocondensation with Guanidinium Salts
Based on mechanistic reasoning, the use of carbon monoxide or molybdenum

hexacarbonyl as suitable CO sources necessitates of application of aryl halides. In
addition, the effective concentration of CO in the reaction medium plays a crucial
N
NH2
O SiMe3
guanidine (2.5 equiv) N
Na2CO3 (1.0 equiv)
R′
CH3CN, t BuOH R′
X N 80°C, 40 h N
X
Boc H
35 (X = CH, N) 36 (X = CH, N, 59-78%)
N N N
N NH2 NH2 NH2
NH2
N N N
N
Br
N Br N N
N N
H H H
H
36a (Meridianin G) 36b (Meridianin C) 36c (Meridianin D) 36d (Variolin analog)

(66%) (73%) (78%) (59%)
Scheme 26 Synthesis of meridanins G, C, D, and a variolin analog
role for the outcome of carbonylative alkynylation. An alternative mode, which

additionally avoids the use of aryl halides, could be a decarbonylation of an
a-dicarbonyl compound. Rhodium mediated decarbonylations of aldehydes
(Tsuji–Wilkinson reaction) are well precedented [144–146], however, the process
becomes catalytic only at temperatures over 200 C. Decarbonylations of acid
chlorides are rare [147] and palladium complexes are not commonly used for
decarbonylations. Besides decarbonylative carbostannylations [148], decarbonyla-
tive Heck reactions with reaction times of 16 h at 160 C in NMP as a solvent were
reported [149, 150]. Just recently, Pd/Cu-catalyzed decarboxylative cross-couplings
of a-oxocarboxylates with aromatic bromides [151] and chlorides [152] at high
temperatures and long reaction times have been introduced. Interestingly, although
oxalyl chloride has been applied in the presence of aluminium chloride as a phosgene
surrogate for Friedel–Crafts acylations [153] or as a source of carbon monoxide in
stoichiometric copper mediated synthesis of cyclopentadienones from organolithium
and organozirconium compounds [154], its use in any catalytic application has
remained unexplored prior to our studies. Therefore, we have developed a novel
mild carbonylative coupling method without the use of toxic carbon monoxide. Our
first findings on the consecutive three-component synthesis of 3-indolyl alkynones 37
by decarbonylative Sonogashira coupling start from electron rich heterocycles and
oxalyl chloride as a source of carbon monoxide via intermediary glyoxylyl chlorides
[155]. Conceptually, this methodology complements the carbonylative alkynylation
of heterocyclic halides with diminished electron density [143].
The glyoxylative-decarbonylative coupling rationalizes as follows (Scheme 27).
After the oxidative addition of indole-3-glyoxylyl chloride 38, adduct 39 undergoes
a migratory de-insertion and elimination of carbon monoxide furnishing the acyl-Pd
50 T.J.J. Müller
O O
O Cl
Cl Cl
O R2 O
N N
38
R1 R1
N PdLn
R1 oxidative
37 addition
O
reductive O
elimination PdLn
Cl
O
PdLn –1 N
1 39
R
N R2 decarbonylative
elimination
R1
41
CO
transmetalation O
PdLn–1
Cl
ClCuLm
N 40
1
R
NEt3 + LmCu
2
R
R2
4
HN+Et3Cl–
Scheme 27 Mechanistic rationale of the decarbonylative Sonogashira coupling of indole-3-

glyoxylyl chlorides 38 and terminal alkynes 2
species 40. The driving force of this reaction is the apparent relative instability of
the dicarbonyl species 39 in comparison to the acyl species 40. Then, transmetalla-
tion of the in situ generated copper acetylide to 40 gives rise to the formation of the
acyl-alkynyl-Pd complex 41, which undergoes reductive elimination to give the
3-indolyl alkynone 37 and the catalytically active Pd0 species is regenerated to start
a new catalytic cycle.
Besides indoles 42 this novel reaction can be extended to 7-aza indoles 43
and substituted pyrroles 44 giving rise to the formation of 3-indolyl alkynones
37, 3-(7-aza indolyl) alkynones 45, and 2-pyrrolyl alkynones 46 (Scheme 28).
With this versatile alkynone synthesis in hand, the application to the pyrimidine
synthesis was tested as well. As previously shown, 4-(indol-3-yl)- and 4-(7-aza-indol-
3-yl)-2-amino pyrimidines 36, which are structurally related to the marine natural
products class of meridianins, have displayed a considerable potential as kinase
inhibitors [143]. Therefore, upon reacting indolyl (37, X ¼ CH) and 7-aza-indolyl
(45, X ¼ N) substituted alkynones or the pyrrolyl ynones 46 with an excess of
guanidinium hydrochloride and potassium carbonate in 2-methoxy ethanol at
120 C for 12–24 h the heteroaryl substituted 2-amino pyrimidines 47, 48, and 49
were obtained in good to excellent yields (Scheme 29).
37a (X = CH, R1 = H, R2 = nBu, 43%)

37b (X = CH, R1 = CH2Ph, R2 = nBu, 74%)
37c (X = CH, R1 = CH2Ph, R2 = CH2OMe, 66%)
O R2 37d(X = CH, R1 = CH2Ph, R2 = Ph, 85%)
37e (X = CH, R1 = CH2Ph, R2 = SiMe3, 76%)
(COCl)2 (1.0 equiv) 37f (X = CH, R1 = Me, R2 = SiMe3, 76%)
37g (X = CH, R1 = SiiPr3, R2 = nBu, 45%)
X N
THF, 4 h, 0°C to r.t.
R1 X N 45a (X = N, R1 = CH2Ph, R2 = nBu, 63%)
or
42 (X = CH) DME, 2 h, 0 to 105-110°C R1 45b(X = N, R1 = Me, R2 = Ph, 61%)
43 (X = N)
or
Then:
or
1% PdCl2(PPh3)2, 1% CuI, R2
1 2 n
alkyne 4 (1.0 equiv) 46a (R = Me, R = Bu, 61%)
1 2 n
NEt3 (2.0 equiv) 46b (R = CH2Ph, R = Bu, 43%)
N 1 h to 2 d, r.t. N
O
R1 R1
44
Scheme 28 Three-component glyoxylative-decarbonylative alkynylation synthesis of alkynones

37, 45, and 46
47a (X = CH, R1 = H, R2 = nBu, 81%)

R2 47b (X = CH, R1 = CH2Ph, R2 = nBu, 86%)
N 1 2
NH2 47c (X = CH, R = CH2Ph, R = CH2OMe, 88%)
N 47d (X = CH, R1 = CH2Ph, R2 = Ph, 82%)
47e (X = CH, R1 = CH2Ph, R2 = H, 88%)
47f (X = CH, R1 = Me, R2 = H, 68%)
47g (X = CH, R1 = H, R2 = nBu, 68%)
H2N+ NH2 X N 48a (X = N, R1 = CH2Ph, R2 = nBu, 81%)
Cl– (2.5 equiv) R1 48b (X = N, R1 = Me, R2 = Ph, 86%)
NH2
37, 45 or 46 or
Na2CO3 · 10 H2O (2.5 equiv)
2-methoxyethanol
R2
12-24 h, 120°C
1 2 n
N 49a (R = Me, R = Bu, 92%)
N
R1 N 49b (R1 = CH2Ph, R2 = nBu, 94%)
NH2
Scheme 29 Cyclocondensation of alkynones 37, 45, and 46 to 4-(indol-3-yl)-(47), 4-(7-aza-indol-

3-yl)-(48), and 4-(pyrrol-2-yl)-2-amino pyrimidines 49
Glyoxylative–decarbonylative alkynylations proceed considerably faster than

carbonylative alkynylations of (hetero)aryl iodides with carbon monoxide and a
lower catalyst loading is needed [143]. The mild conditions for decarbonylations
are unprecedented, and the reagents are applied only in equimolar quantities with a
high tolerance for various substituents. In addition, the application of alkynones 37,
45, and 46 in a subsequent transformation into heteroaryl 2-amino pyrimidines also
illustrates the vast potential to diversity-oriented syntheses of heterocycles.
4.5 Benzo[b][1,4]Diazepines by a Consecutive 3CR of Acid

Chlorides, Alkynes, and Ortho-Phenylene Diamines
Benzodiazepines and their dihydro derivatives constitute an important class of

psychopharmaca [156–161]. In particular, derivatives of benzo[b][1,4]diazepines
have aroused considerable interest as CNS active anticonvulsant drugs [162–164],
52 T.J.J. Müller
antianxiety, analgesic, sedative, antidepressive, and hypnotic agents [165–168].

Among the most frequently used methods for the synthesis of benzo[b][1,4]diaze-
pines is the cyclocondensation of ortho-phenylene diamines with 1,3-dicarbonyl
compounds [169] or equivalent 1,3 biselectrophiles such as epoxy ketones,
a,b-unsaturated carbonyl compounds, or b-haloketones [170–172].
Therefore, the one-pot three-component approach to benzo[b][1,4]diazepines 51
by virtue of alkynones as key intermediates commences with the coupling of
(hetero)aroyl chlorides 7 and terminal alkynes 4, and concludes by subsequent
addition-cyclocondensation of ortho-phenylene diamines 50 under dielectric or
conductive heating to furnish the desired seven-membered heterocycles
(Scheme 30) [173]. A related three-component synthesis according to our concept
enabled the synthesis of benzo[b][1,4]diazepines 51 in water under conductive
heating [174].
In addition, all representatives are highly fluorescent in the solid state, but
essentially nonfluorescent in solution at room temperature. Upon cooling the solu-
tions of benzo[b][1,4]diazepines 51 cryo-fluorescence is observed, which can be
attributed to a freezing of the ring interconversion and aggregation. This thermo
responsive behavior of fluorophores as a consequence of restricted conformational
R1
O
N R3
+
R1 Cl R2 H2N R3 R3
N
Then: R2
50 (1.10 equiv)
7 4 H2N R4 51 (15 examples, 40-88%)
CH3COOH, 16 h, 80°C (oil bath)

or 1 h, 120°C (MW)
MeO
S MeO
N Cl N Cl
N
N Cl Cl N
N
N
N
MeO MeO Ph
O O MeO
51a (81%) 51b (64%) 51c (88%) 51d (63%)
O2N Cl
S
N S
N
N Cl N Cl
N
N
n N Cl N Cl
N Bu n n
Bu Bu
51e (54%) 51f (58%) 51g (86%) 51h (59%)
Scheme 30 Coupling–addition–cyclocondensation three-component synthesis of benzo[b][1,4]

diazepines 51
changes opens new avenues for the development of tailor-made emitters in thermo
sensors and the fluorescence labeling of biomolecules, surfaces or mesoporous
materials.
4.6 Benzo[b][1,5]Thiazepines by a Consecutive 3CR of Acid

Chlorides, Alkynes, and Ortho-Amino Thiophenols
The 1,5-benzothiazepine framework has been identified as a pluripotent pharma-

cophore with derivatives encompassing CNS acting agents, anti-HIV and antican-
cer drugs, angiotensin converting enzyme inhibitors, antimicrobial and antifungal
compounds, calmodulin antagonists, bradykinin receptor agonists, as well as Ca2+
blockers [175]. In addition, dihydro 1,5-benzothiazepines have become increas-
ingly interesting since many derivatives exhibit antifungal, antibacterial [176–178],
antifeedant [179], anti-inflammatory, analgesic [180], and anticonvulsant [181]
activity. Likewise, the related 1,5-benzothiazepines display a comparable spectrum
of biological activity [182, 183].
Syntheses of 1,5-benzothiazepines can be achieved through various routes
starting from 2-aminothiophenol and 1,3-difunctional three-carbon building blocks
[184, 185]. Among them, a,b-unsaturated carbonyl compounds such as enones
[186–188] and ynones [189–192] are suited best for Michael addition and
subsequent cyclocondensation.
After coupling of (hetero)aroyl chlorides 7 and terminal alkynes 4, ortho-amino
thiophenols 52 and acetic acid are added and reacted in the same reaction vessel
under dielectric heating for 30 min at 60 C to furnish 2,4-disubstituted benzo[b][1, 5]
thiazepines 53 via a coupling-addition-cyclocondensation sequence (Scheme 31)
[193]. In the concluding heterocyclization step, dielectric heating is clearly superior
over conductive heating. Although the Michael addition and cyclocondensation
are essentially completed after 10 min at 60 C in the microwave cavity for electroni-
cally diverse substitution a reaction time of 30 min at 60 C has proven to be optimal.
In contrast to 2,4-disubstituted benzo[b][1,4]diazepines 51 (vide supra), benzo[b]
[1, 5]thiazepines 53 are essentially nonfluorescent.

Coupling-Addition-Cyclocondensation Sequences Concluded
by Michael Addition and Steps in Acidic Media
The distinctive feature of the catalytic generation of alkynones under modified

Sonogashira conditions is the usage of one stoichiometrically necessary equivalent
of triethylamine per bond forming reaction [47, 48]. Since the base is inevitably
consumed in binding the liberated hydrogen halide the reaction medium is
54 T.J.J. Müller
R1
2% PdCl2(PPh3)2, 4% CuI N X
+
R1 Cl R
2
H2N R3 S
Then: R2
52 (1.10 equiv)
7 4 HS 53 (14 examples, 45-77 %)
CH3COOH, 30 min, 60°C (MW)
NC MeO
Me
N
S
N N N
S
S S S
Me3Si
MeO
53a (68%) 53b (65%) 53c (77%) 53d (45%)

MeO
Cl Cl
S
N N Cl
N N
S S
S S
Fe
N
NC
53e (57%) 53f (57%) 53g (59%) 53h (61%)
Scheme 31 Coupling–addition–cyclocondensation three-component synthesis of 2,4-disubstituted

benzo[b][1,5]thiazepines 53
essentially base-free. As a consequence not only subsequent reactions under neutral

conditions can be readily performed but also the medium can be immediately
converted into an acidic environment without neutralization. Therefore, the cou-
pling can be followed by a sequential transformation under Brønsted or Lewis
acidic conditions facilitating unusual combinations of elementary processes.
5.1 3-Halo Furans by a Consecutive 3CR of Acid Chlorides,

Propargyl Ethers, and Halides
The peculiar circumstance of an essentially base free reaction medium now allows
an entry to Lewis or Brønsted acidic conditions, still in a one-pot fashion. In the
presence of hydrogen halide acids g-hydroxy alkynones can be successfully
cyclized to give 3-chloro-, 3-bromo-, and 3-iodofurans [194]. Therefore, a sequence
of a Sonogashira coupling of (hetero)aroyl chlorides 7 and THP-protected propar-

gyl alcohols 54, followed by an acid-mediated Michael addition of sodium chloride
or sodium iodide in the presence of p-toluene sulfonic acid (PTSA) furnishes by
concomitant deprotection and cyclocondensation 3-halo furans 55 in moderate to
good yields (Scheme 32) [195, 196].
Mechanistically, it is very likely that the acid not only catalyzes the deprotection
of the THP-protected alkynone 56 by transacetalization to liberate the g-hydroxy
alkynone 57 but also mediates the Michael addition of the halide to the alkynone
intermediate 57 (Scheme 33). Subsequently, the E-configured b-halo hydroxy
2 % PdCl2(PPh3)2, 4 % CuI
O Hal
+ OTHP
R1 Cl Then:
R1 O R2
R2 NaCl (2.0 equiv), PTSA · H2O (1.1 equiv)
CH3OH, 20 h, 60 °C
7 54 or 55a (Hal = Cl, R1 = Ph, R2 = H, 63 %)
NaI (5.0 equiv), PTSA · H2O (1.1 equiv) 55b (Hal = Cl, R1 = p-MeOC6H4, R2 = H, 71 %)
CH3OH, 2 h, r.t. 55c (Hal = Cl, R1 = p-O2NC6H4, R 2 = H, 24 %)
55d (Hal = Cl, R1 = o-FC6H4, R2 = H, 47 %)
THP = tetrahydropyran-2-yl
55e (Hal = Cl, R1 = 1-cyclohexenyl, R2 = H, 64 %)
PTSA = p-tolylsulfonic acid
55f (Hal = Cl, R 1 = Ph, R2 = Et, 70 %)
55g (Hal = Cl, R1 = 2-thienyl, R2 = Et, 59 %)
55h (Hal = Cl, R1 = Ph-CH=CH, R2 = Et, 73 %)
55i (Hal = I, R1 = Ph, R2 = H, 63 %)
55j (Hal = I, R1 = p-MeOC6H4, R2 = H, 63 %)
55k (Hal = I, R1 = p-O2NC6H4, R2 = H, 40 %)
55l (Hal = I, R1 = Ph-CH=CH, R2 = H, 61 %)
55m (Hal = I, R1 = Ph, R2 = Et, 72 %)
55n (Hal = I, R1 = 2-thienyl, R2 = Et, 49 %)
55o (Hal = I, R 1 = Ph, R2 = p-MeOC6H4, 39 %)
55p (Hal = I, R1 = i Pr, R2 = p-MeOC6H4, 29 %)
Scheme 32 Coupling–transacetalization–addition–cyclocondensation three-component synthesis

of 3-halo furans 55
[Pd0, CuI], NEt3 R1

7 + 54 OTHP
Coupling
2
R
56
[PTSA],
CH3OH
Transacetalization
–THPOCH3
O Hal
PTSA,
R1 NaHal R 1
R2 – H2O
OH 55
Michael addition O HO Cyclocondensation
R2
57 58
Scheme 33 Mechanistic rationalization of the coupling–deprotection–addition–cyclocondensa-

tion sequence to 3-halo furans 55
56 T.J.J. Müller
enone E-58 undergoes a cyclocondensation to furnish the 3-halo furan 55. The
Z-configured b-halo hydroxy enone Z-58, which does not undergo cyclocondensa-
tion at comparable rate, is only detected in trace amounts according to TLC (as a
highly polar byproduct) and GC-MS (the mass corresponds to a halo hydroxy enone
isomer).
Furthermore, the concept of a sequential nucleophilic addition in acidic medium
can be transposed to the conversion of the ynone intermediates with iodine mono-
chloride [197] and subsequent cyclization [198] into chloro iodo furans in a one-pot
fashion. Therefore, after coupling of (hetero)aroyl chlorides 7 and THP-protected
propargyl alcohols 54, NaCl, iodine monochloride, and PTSA were added to give
after 4 h of stirring at room temperature the substituted 3-chloro-4-iodo furans 59 in
moderate to decent yields (Scheme 34) [196].
5.1.1 Trisubstituted Furans by Coupling-Transacetalization-Addition-

Cyclocondensation-Coupling Sequence
As a consequence of the mild reaction conditions in the sequence to 3-halo furans

55 the palladium catalyst should be still intact to trigger another Pd-catalyzed
coupling in the sense of a sequentially Pd-catalyzed process [31]. As a conse-
quence, a sequential Sonogashira–deprotection–addition–cyclocondensation–
Suzuki reaction, where the same catalyst system is applied in two consecutive
significantly different cross-coupling reactions in the same reaction vessel should
be feasible. Therefore, upon consecutive reactions of (hetero)aroyl chlorides 7 and
THP-protected propargyl alcohols 54, NaI and PTSA, and finally, addition of 1.05
equiv of boronic acids 60 and sodium carbonate, the substituted 3-aryl furans 61 can
be obtained in decent yields (Scheme 35).
59a (R1 = Ph, R2 = H, 52%)

2% PdCl2(PPh3)2, 4% CuI I Cl 1 2
59b (R = p-MeOC6H4, R = H, 42%)
NEt3 (1.05 equiv), THF, 2 h, r.t. 1 2
7 + 54 59c (R = p-O2NC6H4, R = H, 31%)
1 2
Then: R1 R2 59d (R = 2-thienyl, R = H, 31%)
O 1 2
ICl (1.5 equiv), NaCl (2.5-5 equiv) 59e (R = p-MeOC6H4, R = Et, 64%)
PTSA · H2O (1.1 equiv) 1 2
59f (R = Ph-CH = CH, R = Et, 57%)
MeOH, r.t. 4 h 1 2
59g (R = p-MeOC6H4, R = p-MeOC6H4, 51%)
Scheme 34 Coupling–transacetalization–addition–cyclocondensation three-component synthesis

of 3-chloro-4-iodo furans 59
5% PdCl2(PPh3)2, 4% CuI R3 61a (R1 = p-MeOC6H4, R2 = H, R3 = Ph, 50%)

1 2 3
NEt3 (1.05 equiv), THF, 2 h, r.t. 61b (R = 2-thienyl, R = p-MeOC6H4, R = Ph, 52%)
7 + 54
Then:
1
R R2 61c (R1 = Ph-CH=CH, R2 = Et, R3 = 2-thienyl, 42%)
O 1 i 2 3
NaI (5.0 equiv), PTSA · H2O (1.1 equiv) 61d (R = Pr, R = H, R = 1-naphthyl, 52%)
CH3OH, 2 h, r.t.
Then:
3
R B(OH)2 60 (1.05 equiv )
Na2CO3 (8.0 equiv), 90°C, 16-46 h
Scheme 35 Coupling–transacetalization–addition–cyclocondensation–Suzuki coupling four-

component synthesis of 3-aryl furans 61
MeO
5 mol% Pd(PPh3)2Cl2, Cl
p-CH3OC6H4B(OH)2 (60d) (1.05 equiv)
59g
Na2CO3 (8 equiv), H2O,
THF/MeOH, 24 h, 90°C O
MeO OMe
62 (59%)
Scheme 36 Suzuki coupling of the 3-chloro-4-iodo furan 59g
3-Chloro-4-iodo furans 59 can be valuable building blocks for the synthesis of

highly substituted furans as illustrated by the Suzuki coupling of chloro iodo furan
59g with boronic acid 60d (R3 ¼ p-MeOC6H4) furnishing trisubstituted chloro
furan 62 in 59% yield (Scheme 36). Expectedly, the coupling selectively occurs
at the carbon–iodine bond.
5.2 Oxazoles by a Consecutive 3CR of Acid Chlorides,

Propargyl Amine, and Acid Chlorides
Mechanistically, altering the intermediate propargyl alcohols 57 to the corres-

ponding propargyl amines should facilitate suitable access to pyrroles in the same
manner. However, with most of the generated amides this is not the case. Yet,
propargyl amine (63) is readily amidated with acid chlorides 7 under mild reaction
conditions to furnish propargyl amides. Without isolation these propargyl amides
are reacted with acid chlorides 7’ under modified Sonogashira conditions to give
rise to functionalized oxazoles 64 in good yields, but not to pyrroles (Scheme 37)
[199, 200]. Indeed, Sonogashira coupling in this case is not the initial step but it is
placed within the sequence.
The interesting aspect of this sequence is the regiospecific introduction of
substituents on the oxazole core by determining the order of amidation and cou-
pling. The mechanism of this consecutive amidation–coupling–cycloisomerization
sequence can be rationalized as follows (Scheme 38). The first acid chloride 7 and
propargyl amine (63) are coupled by amidation to give the terminal alkyne 65,
which is a propargyl amide. Upon addition of the second acid chloride 7’, palladium
and copper catalysts and triethylamine, the Sonogashira coupling furnishes the
alkynone 66. Although the terminal cycloisomerization with concomitant aromati-
zation to give the oxazoles already proceeds under the coupling conditions, optimal
rates were achieved by adding PTSA and tert-butanol and gentle heating after the
Sonogashira step.
As already discussed for the pyrimidine syntheses, this process can also be
conducted in the sense of a four-component amidation–carbonylative alkynylation–
cycloisomerization sequence [199].
58 T.J.J. Müller
O 1.0 equiv. NEt3, O

N
THF, 1 h, 0°C to r.t.
1
R Cl
+ NH2 R O
1
R2
Then:
2% PdCl2(PPh3)2, 4% CuI 64 (18 examples, 42-75%)
7 63
R2COCl 7¢ (1.0 equiv), NEt3 (1.0 equiv)
THF, 2 h, r.t.
Then:
PTSA · H2O (1.0 equiv)
t
BuOH, 1 h, 60°C
N O O N O
N
S
O Ph Ph Ph
O O
Cl S
64a (75%) 64b (70%) 64c (53%)
N O N O N O
F3C O O
O
Me Me
OMe Br Cl
64d (46%) 64e (50%) 64f (74%)
N O N O N O
Ph
O O O
O2N S
Me Me
64g (56%) 64h (57%) 64i (66%)
Scheme 37 Amidation–coupling–cycloisomerization three-component synthesis of oxazoles 64
7¢ O [PTSA]
NEt3 H [Pd0, CuI], NEt3 t
R2 BuOH
7 + 63 N R1 H 64
Amidation Coupling N R1
Cycloisomerization
O
O
65 66
Scheme 38 Mechanistic rationalization of the amidation-coupling-cycloisomerization sequence

to oxazoles 64
5.3 3-Iodo Pyrroles by a Consecutive 3CR of Acid Chlorides,

Propargyl Amides, and Iodide
Nevertheless, halo pyrroles are valuable synthetic building blocks for various
transformations, and therefore a multicomponent access would be highly desirable.
For the three component synthesis of the 4-iodo pyrroles with a nitrogen protecting
group, propargyl amides still appear to be the most suitable starting materials. As
shown, the cycloisomerization to oxazoles 64 under acidic conditions jeopardizes
this endeavor. So the choice of the right nitrogen protecting group plays a crucial
role. The Boc group is a versatile carbamate protecting group for the pyrrole
nitrogen atom, useful for many transformations on the pyrrole core and easily
removable. Therefore, upon reacting (hetero)aroyl chlorides 7 and N-Boc-protected
propargyl amine (67) under modified Sonogashira conditions, the intermediate
68a (R1 = p-MeC6H4, 73%)

68b (R1 = m-MeC6H4, 74%)
I 68c (R1 = o-MeC6H4, 72%)
H
O 2% PdCl2(PPh3)2, 4% CuI 68d (R1 = p-MeOC6H4, 73%)
N
+ Boc
R1 68e (R1 = Ph, 72%)
R1 Cl N 1
68f (R = p-ClC6H4, 62%)
Then:
NaI (5.0 equiv), PTSA · H2O (2.0 equiv) Boc 68g (R1 = p-FC6H4, 75%)
t
7 67 BuOH, 1 h, r.t. 68h (R1 = 2-thienyl, 63%)
68i (R1 = β-styryl, 70%)
68j (R1 = cyclopropyl, 69%)
68k (R1 = 1-adamantyl, 61%)
Scheme 39 Coupling–addition–cyclocondensation three-component synthesis of 4-iodo

pyrroles 68
alkynone 8 is generated [201]. Without isolation, the concluding addition-cyclocon-

densation with sodium iodide and PTSA furnishes the N-Boc-4-iodo-2-substituted
pyrroles 68 in good yields (Scheme 39).
The sequence starts with easily accessible starting materials and gives good yields
of 4-iodo pyrroles 68. The reaction is quite general with respect to the underlying
acid chlorides 7. Aromatic substituents bearing electron neutral, electron withdraw-
ing, and electron donating substituents even in the ortho-position are tolerated.
Furthermore, heteroaryl, alkenyl, cyclopropyl and sterically demanding adamantyl
substituents can be effectively carried through the sequence. Boc as an electron
withdrawing group allows handling 4-iodo pyrroles 68, which are notoriously
unstable towards oxidation with electron donating groups at the pyrrole nitrogen.
5.3.1 3-Alkynylated Pyrroles by Coupling-Addition-Cyclocondensation-

Coupling Sequence
The synthesized N-Boc-protected 4-iodo pyrroles 68 are highly useful synthetic

building blocks, and the first scouting experiments were performed in the sense of a
sequential Pd/Cu-catalyzed process [31], assuming that the catalyst system is still
active after the coupling-addition-cyclocondensation sequence. Therefore, just upon
addition of another terminal alkyne 4 to the reaction mixture, N-Boc-2-aryl-4-alkynyl
pyrroles 69 can be obtained in good yields (Scheme 40) [201]. The conditions are
sufficiently mild to leave the Boc group uncleaved.
5.4 Tetrahydro-b-carbolines by a Consecutive 4CR of Acid

Chlorides, Alkynes, Tryptamines, and Acroyl Chlorides
The fundamental principles of MCRs demand that products of consecutive trans-

formations are expected to contain substantial fragments of all starting materials,
thus providing a high degree of atom-efficiency. As a consequence for heterocyclic
synthesis, b-enaminones should be considered to be more than just synthetic
equivalents of 1,3-dicarbonyl compounds. This aspect can be easily envisioned
60 T.J.J. Müller
R2
H 2% PdCl2(PPh3)2, 4% CuI
O
N NEt3 (1.05 equiv), THF, 2 h, r.t.
+ Boc
R1
Cl Then: R1 N
NaI (5.0 equiv), PTSA · H2O (2.0 equiv) Boc
t
BuOH, 1 h, r.t.
1 2 n
7 67 Then: 69a (R = p-tolyl, R = Bu, 58%)
2
R CCH (4)(2 equiv) 69b (R = p-MeOC6H4, R2 = TIPS, 53%)
1
Cs2CO3 (4 equiv), 70°C, 1 h 69c (R = p-MeOC6H4, R2 = Ph, 67%)

1
Scheme 40 Coupling–addition–cyclocondensation–coupling four-component synthesis of 4-alky-

nyl N-Boc pyrroles 69
O 2% PdCl2(PPh3)2, 4% CuI R1
n
+ Bu n
R1 Cl Bu
N O
Then:
R2NH2 70, Δ R2
7 4c Then: O 72a (R1 = 2-thienyl, R2 = CH2Ph, 31%)
(71a), Δ 72b (R1 = p-MeOC6H4, R2 = CH2Ph, 63%)
Cl 72c (R1 = 2-thienyl , R2 = 3,4-(MeO)2C6H3CH2CH2, 69%)
Scheme 41 Coupling–amination–aza–annulation four-component synthesis of 5-acyl dihydro-

pyrid-2-ones 72
taking advantage of the unique electronically amphoteric reactivity of b-enami-

nones. Therefore, trying to conserve all atoms in the final product the enamino
nitrogen atom should reside in the target molecule. The aza-annulation reaction
[202, 203] of enamino carbonyl compounds and a,b-unsaturated acid chlorides is
known to furnish 5-acyl dihydropyrid-2-ones 72. Therefore, after coupling of
(hetero)aroyl chlorides 7 and 1-hexyne 4c, primary amines 70 are added to furnish
enaminones 10. Without isolation acroyl chloride (71a) is added and reacted in the
same reaction vessel to give after aza-annulation reaction the 5-acyl dihydropyrid-
2-ones 72 in moderate to good yields (Scheme 41) [70, 204].
In particular, the consecutive one-pot four-component reaction of (hetero)aroyl
chlorides 7, alkynes 4, tryptamine derivatives 73 as primary amines and a,b-unsatu-
rated acid chlorides 71 to form tetrahydro-b-carbolines 74 most clearly demonstrates
the potential of this concept and methodology for the rapid construction of highly-
substituted, complex heterocycles. Five new s-bonds and four new stereocenters can
be installed in a sequence of consecutive one-pot transformations (Scheme 42).
Mechanistically, the sequence commences by coupling of the (hetero)aroyl
chloride 7 and the alkyne 4 to give the alkynone 8 (Scheme 43). Upon addition of
the tryptamine derivative 73 the enaminone 75 is obtained. Finally, the addition
of the a,b-unsaturated acid chloride 71 triggers the aza-annulation reaction to
furnish the acyliminium ion 76 which terminates the sequence by a Pictet-Spengler
cyclization.
Interesting is the excellent diastereoselectivity of the sequence where the R2,
acyl-R1, and R5 substituents are exclusively placed in a syn-syn arrangement,
whereas with a substituent R4 other than hydrogen, epimers are formed with
R3
O 2% PdCl2(PPh3)2, 4% CuI O
NEt3 (1.05 equiv), THF, 2 h, r.t. N
1 +
R Cl R2 Then: R3 N 2 R4
H R
NH2 O R5
7 4 R1
N 1 2 n 3 4 5
H 74a (R = 2-thienyl, R = Bu , R = R = R = H, 52%)
73, 24 h, 70°C 74b (R1= p-O2NC6H4, R2 = nBu , R3 = R4 = R5 = H, 43%)
Then: R4 74c (R1= p-MeOC6H4, R2 = nBu , R3 = R4 = R5 = H, 59%)
1 2 3 4 5
R5 Cl 74d (R = 2-thienyl, R = Ph, R = R = R = H, 41%)
74e (R1 = 2-thienyl, R2 = nBu, R3 = R4 = H, R5 = CH3, 50%)
O 74f (R1 = 2-thienyl, R2 = nBu, R3 = R5 = H, R4 = CH3, 54%,
71, 3 h, 70°C syn-syn / syn-anti = 4.5:1)
1 2 3 4 5
74g (R = 2-thienyl, R = R = R = R = H, 32%)
74h (R1 = 2-thienyl, R2 = nBu , R3 = CO2Me, R4 = R5 = H, 45%)
1 2 3 4 5
74i (R = 2-thienyl, R = CH2OTBS, R = R = R = H, 30%)
74j (R1 = N-(phenylsulfonyl)-3-indolyl, R2 = nBu,
R3 = R4 = R5 = H, 36%)
1 i 2 n 3 4 5
74k (R = Pr, R = Bu , R = R = R = H, 36%)
Scheme 42 Coupling–amination–aza–annulation–Pictet–Spengler four-component synthesis of

tetrahydro-b-carbolines 74
R3
[Pd0, CuI], NEt3 73

NH O
7 + 4 [8]
Coupling Addition 2
N R R1
H
75
Aza-Annulation 71
R3
Cl– O
N R4 –HCl
74
2 Pictet-Spengler
N R 5 cyclization
R
H
O R 1
76
Scheme 43 Mechanistic rationalization of the coupling–amination–aza–annulation–Pictet–

Spengler sequence to tetrahydro-b-carbolines 74
moderate selectivity (compound 74f, d.r. ¼ 4.5: 1). Most surprisingly, with (S)-(-)-
tryptophane methyl ester (73b, R3 ¼ CO2Me) as a tryptamine derivative the only
cyclization product isolated in 45% yield is tetrahydro-b-carboline 74h that is formed
as a single diastereomer.
In order to rationalize the exclusive diastereoselectivity of the sequence, two
mechanistic pathways can be proposed for the stereogenic aza-annulation step
62 T.J.J. Müller
H R′
H R′ O
O N+ 2
N+ 1 R
R2 R
R1 –
O
[3,3] H
– H Cl
O Cl Aza-Cope R4
H
Path A R4 H R3
R5 Cl– O
R5
77 78 +N
R4
75 71
R4 R4 R2
O N R5
O H
5 5 O 1
Path B R R R
Cl H H Cl H H
O 76
R′ N O Aza-Ene R' N
1 1
2 R
R2 R R
H H
79 80
74
Scheme 44 Mechanistic rationalization of the coupling–amination–aza–annulation–Pictet–

Spengler sequence to tetrahydro-b-carbolines 74
(Scheme 44). First, the (Z)-configured b-enaminone 75, arising from the addition of
tryptamine 73 to ynones 8, reacts with an a,b-unsaturated acid chloride 71 either via
a cationic aza-Cope-type rearrangement (path A) or via an aza-ene reaction (path B)
[205]. In the pathway A, the chair-like transition state 77 is preferred, while in the
latter pathway B the transition state 79 adopts an envelope conformation with an
endo-electron withdrawing group lying over the fold of the envelope [206]. Both
mechanistic scenarios rationalize the mutual syn-orientation of the R5 and the
carbonyl substituents. Finally, for the resulting acyliminium species 76 an intramo-
lecular nucleophilic attack by the indole can be expected to occur predominantly
anti with respect to the more bulky carbonyl group, leading mainly to the syn
diastereomer of 74 (with respect to R2 and carbonyl substituents). Two diastereo-
mers observed in the reaction with methacryloyl chloride (R7 ¼ CH3) were formed
most probably via epimerization.
The overall yields for the stepwise reaction with intermediate isolation of
the enaminone 75 after the coupling-addition sequence and its subsequent
aza-annulation-Pictet-Spengler transformation lie in the same range as for the
coupling-amination-aza-annulation-Pictet-Spengler sequence. However, avoiding
the isolation and purification of the intermediate b-enaminone favors the applica-
tion of the one-pot approach.
6 Multicomponent Synthesis of Annelated Thiopyranones

by Coupling-Addition-Nucleophilic Aromatic
Substitution Sequence
Thiopyranone is the thio homologue of pyranone, a core constituent of many

natural products. In their own right, thiochromenones, benzo annelated thiopyra-
nones that are related to the class of flavones, are as well potent drug candidates and
serve as key intermediates for the synthesis of biological active compounds. As a

consequence many thiochromenones are known to exhibit antimicrobial and anti-
fungal [207], antibacterial [208], antibiotic [209], and anticarcinogenic [210] activ-
ity. Some derivatives are used as antimalaria agents [211], oxidized representatives
reversibly inhibit the human cytomegalovirus protease [212].
In general, 4H-thiochromen-4-ones are synthesized either by condensation of
b-keto esters and thiophenols with polyphosphoric acid [213–215] or by cyclization
of b-substituted cinnamates derived from thiophenols and appropriate propiolates
[211, 216, 217].
Conceptually, the alkynone entry to annelated 4H-thiochromen-4-ones can be
conceived by a cyclization based upon a Michael addition and a nucleophilic
aromatic substitution [218, 219]. Therefore, upon chemoselective coupling of
ortho-halogenated (hetero)aromatic acid chlorides 81 and electron rich terminal
alkynes 4, and subsequent reaction with sodium sulfide nonahydrate upon dielectric
heating furnishes 4H-thiochromen-4-ones 82, 4H-thiopyrano[2,3-b]pyridin-4-ones
83, 2-chloro-4H-thieno[2,3-b]thiopyran-4-ones 84, or 7H-benzo-[b]thieno[3,2-b]
thiopyran-7-ones 85 in the sense of a consecutive coupling-addition-substitution
one-pot sequence (Scheme 45) [220, 221]. In comparison, the existing protocols
for the synthesis of 4H-thiochromen-4-ones 82 generally require several steps,
sometimes harsh reaction conditions, longer reaction times, and give significantly
lower overall yields. This sequence represents a straightforward and rapid access to
annelated 4H-thiochromen-4-ones in a one-pot fashion and with a broad scope in
the starting materials in acceptable yields.
X Hal
NEt3 (1.05 equiv), THF, 2 h, r.t. X S R2
+
Cl 2
R Then: Na2S · 9 H2O (1.5 eqiuv)
EtOH, 90 min, 90°C, MW
O O
81 (Hal = F, Cl) 4 82-85 (28 examples, 15-79%)
R1 S R2 N S R2 S S R2
Cl
O O O
82a (R1 = R2 = H, 39%) 83a (R2 = H, 62%)
2
84a (R2 = Ph, 40%)
1 2
84b (R2 = p -tBuC6H4, 63%)
82b (R = H, R = Ph, 73%) 83b (R = C6H5, 55%)
82c (R1 = H, R2 = p -tBuC6H4, 76%) 83c (R2 = p -MeC6H4, 23%)
84c (R2 = 3,4-(MeO)2C6H3, 51%)
82d (R1 = H, R2 = p -MeOC6H4, 77%) 83d (R2 = p -tBuC6H4, 15%)
84d (R2 = nBu, 36%)
82e (R1 = H, R2 = 3, 4-(MeO)2C6H3, 73%) 83e (R2 = p -ClC6H4, 31%)
2
82f (R1 = H, R2 = p -ClC6H4, 52%) 83f (R = ferrocenyl, 19%) S R2
82g (R1 = H, R2 = nBu, 59%) 83g (R2 = nBu, 17%)
1 2 2
82h (R = H, R = ferrocenyl, 63%) 83h (R = cyclopropyl, 53%) S
82i (R1 = H, R2 = 6-methoxynaphthalen-2-yl, 51%)
1 2 O
82j (R = Cl, R = p -MeC6H4 48%) 2
85a (R = Ph, 46%)
82k (R1 = Cl, R2 = p -FC6H4, 47%) 85b (R = p -tBuC6H4, 41%)
2
1 2
82l (R = Cl, R = 3, 4-(MeO)2C6H3, 59%) 2
85c (R = p -FC6H4, 27%)
85d (R2 = cyclopropyl, 32%)
Scheme 45 Coupling–addition–nucleophilic aromatic substitution three-component synthesis of

4H-thiochromen-4-ones 82, 4H-thiopyrano[2,3-b]pyridin-4-ones 83, 2-chloro-4H-thieno[2,3-b]
thiopyran-4-ones 84, or 7H-benzo-[b]thieno[3,2-b]thiopyran-7-ones 85
64 T.J.J. Müller
X Hal Hal S–
R2 Na2S X
[Pd0, CuI], NEt3 –Hal –
R2 82-85
81 + 4 Nucleophilic
Coupling Addition
Aromatic
O Substitution
O
86 87
Scheme 46 Mechanistic rationalization of the coupling–addition–nucleophilic aromatic substitu-

tion sequence to annelated 4H-thiochromen-4-ones 82–85
Mechanistically, the one-pot transformation can be rationalized by a sequence of

chemoselective coupling of ortho-halogenated (hetero)aromatic acid chlorides 81
and electron rich terminal alkynes 4, followed by nucleophilic addition of the
sulfide ion to the a,b-unsaturated system 86 to furnish the anionic Michael adduct
87, and finally an intramolecular nucleophilic aromatic substitution in the sense of
an addition–elimination process concludes the sequence (Scheme 46).
Furthermore, as a consequence of pronounced zwitterionic character of the
computed electronic ground state, intense bathochromic halochromicity of the
longest wavelength absorption bands with concomitant weak orange fluorescence
can be observed upon protonation [221].
7 Multicomponent Synthesis of Heterocycles by Coupling–

Isomerization–Cyclocondensation Sequences
The CI sequence introduced in Chap. 2.2 represents a mild and catalytic access
to chalcones. 1,3-Diarylprop-2-en-1-ones are bifunctional electrophilic Michael-
systems and per se important three-carbon building blocks in synthetic heterocyclic
chemistry [33]. Among many classes of five-, six-, and seven-membered hetero-
cycles the underlying principle is always the Michael-addition-cyclocondensation
sequence of chalcones and bifunctional nucleophiles [176–181, 222–229]. Further-
more, chalcones can also participate in cycloadditions , as dienophiles and dipolar-
ophiles and furnish in the case of 1,3-dipolar cycloadditions with diazo alkanes
pyrazolines [230, 231], with azides triazolines [232], with nitrones isoxazolidines
[233] with azomethinylides pyrrolidines [234], or with nitriloxides isoxazolines
[235]. Therefore, the mild, catalytic access to chalcones by the CIR excellently sets
the stage for the development of consecutive MCRs based upon cyclocondensation
strategies.
7.1 Pyrazoles by a Consecutive 3CR of (Hetero)aryl Halides,

Propargyl Alcohols, and Hydrazines
Thus, upon CIR of electron-deficient (hetero)aryl halides 11 and phenyl propargyl

alcohol 12a, and subsequent addition of a hydrazine (29b) (R3 ¼ Me) 3,5-disubstituted
CH3
OH NEt3, THF, Δ, 10 h N N
EWG π Hal + EWG π
Then:
Ph Ph
N-methyl hydrazine (29b)(4 eqiuv)
11 12a Δ, 5 h 88 (4 examples, 63-90%)
CH3
CH3 N N CH3 CH3
N N N N S N N
Ph
O2N N
Ph Cr Ph N Ph
CO
OC CO
88a (90%) 88b (63%) 88c (77%) 88d (69%)
Scheme 47 CI–cyclocondensation three-component synthesis of pyrazolines 88
2% PdCl2(PPh3)2, 1% CuI EWG π (hetero)aryl

OH NEt3, THF, Δ, 10 h
EWG π Hal + N N
+
(hetero)aryl Then: H2N NH2 32 (1.0 equiv)
R
Cl–
11 12 R 89 (8 examples, 41-70 %)
89a (EWG– π = p-O2NC6H4, (hetero)aryl = Ph, R = 2-thienyl, 57%)

89b (EWG– π = p-O2NC6H4, (hetero)aryl = Ph, R = p-BrC6H4, 56%)
89c (EWG– π = p-O2NC6H4, (hetero)aryl = Ph, R = p-O2NC6H4, 46%)
89d (EWG– π = p-O2NC6H4, (hetero)aryl = Ph, R = 4-pyridyl, 51%)
89e (EWG– π = p-O2NC6H4, (hetero)aryl = p-MeOC6H4, R = m-BrC6H4, 50%)
89f (EWG– π = p-O2NC6H4, (hetero)aryl = p -BrC6H4, R = 2-thienyl, 56%)
89g (EWG– π = p-O2NC6H4, (hetero)aryl = 3-thienyl, R = 2-thienyl, 70%)
89h (EWG– π = 4-pyridyl, (hetero)aryl = Ph, R = m-BrC6H4, 41%)
Scheme 48 CI–cyclocondensation three-component synthesis of 2,4,6-trisubstituted pyrimidines 89
2-pyrazolines 88 can be obtained in a consecutive three-component reaction in

good to excellent yields (Scheme 47) [77]. Considering the pharmacological activ-
ity of 3,5-diaryl-2-pyrazolines [236–240] this facile approach to 3,5-disubstituted
2-pyrazolines offers also the possibility to combinatorial lead finding.
7.2 Pyrimidines by a Consecutive 3CR of (Hetero)aryl Halides,

Propargyl Alcohols, and Amidinium Salts
Likewise, upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl

propargyl alcohols 12, and subsequent addition of amidinium salts 32, 2,4,6-trisub-
stituted pyrimidines 89 can be obtained in a consecutive three-component reaction
in good yields (Scheme 48) [241]. Interestingly, in all cases the aromatic products
89 are found and not the expected dihydropyrimidines, regardless whether the
reaction has been performed under an anaerobic or an aerobic atmosphere. There-
fore, it can be assumed that the presence of the transition metal catalysts is
beneficial for a terminal aromatizing dehydrogenation.
66 T.J.J. Müller
7.3 Benzoheteroazepine by a Consecutive 3CR of (Hetero)aryl

Halides, Propargyl Alcohols, and Ortho-Amino
or Ortho-Thio Substituted Anilines
Following the same rationale, the CI sequence can also be applied to the synthesis
of seven-membered heteroazepines. Thus, upon CIR of electron-deficient (hetero)
aryl halides 11 and (hetero)aryl propargyl alcohols 12, and subsequent addition of
ortho-phenylene diamines 50 or ortho-amino thiophenols 52, 2,4-di(hetero)aryl
substituted 2,3-dihydro benzo[b][1,4]diazepines 90 or di(hetero)aryl substituted
2,3-dihydro benzo[b][1,4]thiazepines 91 can be obtained in a consecutive three-
component reaction in moderate to good yields (Scheme 49) [242, 243].
7.4 1,4-Diketones by a Consecutive 3CR of (Hetero)aryl

Halides, Propargyl Alcohols, and Aldehydes
Besides the Michael addition of heteroatomic nucleophiles initiating cycloconden-

sations, acceptor substituted unsaturated systems can also be reacted with carbon
nucleophiles stemming from aldehydes in the sense of an umpolung, generally
referred to as the Stetter reaction [244–246]. This process is organocatalytic and
furnishes in turn 1,4-dicarbonyl compounds, intermediates that are well suited for
Paal–Knorr cyclocondensations giving rise to furans or pyrroles. Among numerous
heterocycles furans and pyrroles have always been the most prominent ones since
they constitute important classes of natural products [247–249], of synthetic
2% PdCl2(PPh3)2, 1% CuI EWG

NEt3, THF, Δ, 10 h π (hetero)aryl
OH
EWG π Hal + X N
(hetero)aryl Then: HX NH2 32 (1.0 equiv)
11 12
R R
acetic acid (for X = S), Δ, 8-36 h 90 (X = NH) and 91 (X = S)
(13 examples, 38-85%)
EWG EWG
π (hetero)aryl π Ph
HN N S N
90a (EWG – π = p -O2NC6H4, (hetero)aryl = Ph, 52%) R

90b (EWG – π = p-O2NC6H4, (hetero)aryl = p-MeOC6H4, 44%) 91a (EWG – π = p-O2NC6H4, R = H, 67%)
90c (EWG – π = p-NCC6H4, (hetero)aryl = Ph, 79%) 91b (EWG – π = p-O2NC6H4, R = CF3, 50%)
90d (EWG – π = o-NCC6H4, (hetero)aryl = Ph, 39%) 91c (EWG – π = p-NCC6H4, R = H, 71%)
90e (EWG – π = 4-thiazolyl, (hetero)aryl = Ph, 58%) 91d (EWG – π = p-NCC6H4, R = CF3, 75%)
91e (EWG – π = o-NCC6H4, R = H, 85%)
91f (EWG – π = 4-pyridyl, R = H, 38%)
Scheme 49 CI–cyclocondensation three-component synthesis of 2,3-dihydro benzo[b][1, 4]

heteroazepines 90 and 91
pharmaceuticals [247] and also of electrically conducting materials such as poly-

pyrroles [250]. In particular, 2,3,5-trisubstituted furans and 1,2,3,5-tetrasubstituted
pyrroles are highly biologically active and have proven to display antibacterial
[251] antiviral (also anti-HIV-1) [252, 253] anti-inflammatory [254, 255], and anti-
oxidant [256] activity as well as to inhibit cytokine mediated diseases [257, 258].
Interestingly, the mild reaction conditions of the CIR are fully compatible with
the Stetter reaction. As a result a sequence of transition metal, base and organoca-
talysis can be easily conceived. Upon CIR of electron-deficient (hetero)aryl halides
11 and (hetero)aryl propargyl alcohols 12, and after subsequent addition of aliphatic
or aromatic aldehydes 92 and catalytic amounts of thiazolium salt 93 1,4-diketones
94 are obtained in moderate to excellent yields in a one-pot procedure (Scheme 50)
[259, 260]. For aromatic aldehydes the catalyst precursor of choice is 3,4-dimethyl-
5-(2-hydroxyethyl) thiazolium iodide (93a) (R’ ¼ Me), and for aliphatic aldehydes
3-benzyl-4-methyl-5-(2-hydroxyethyl)-thiazolium chloride (93b) (R’ ¼ CH2Ph) is
applied.
2% PdCl2(PPh3)2, 1% CuI EWG

OH NEt3, THF, Δ, 10 h π (hetero)aryl
EWG–π–Hal + 1
Then: R -CHO 92 (1.0 equiv) O
(hetero)aryl
R1 O
11 12 HO S 94 (12 examples, 34-88%)
20% 93
N+ –
I
R′
R′ = Me (93a), CH2Ph (93b)

NEt3, Δ, 8-24 h
NC
NC N
O
O O
O O
O O O
O
O MeO
CN
94a (81%) 94b (70%) 94c (69%)
NC NC
NC
O HO O
n
O O
pentyl O O
94d (76%) 94e (66%) 94f (59%)
Scheme 50 CI–Stetter addition three-component synthesis of 1,4-diketones 94

68 T.J.J. Müller
This straightforward three-component approach to 1,4-diketones can readily

expanded to a CIR–Stetter–Paal–Knorr synthesis of furans 24 and pyrroles 25
in the sense of a consecutive three-component or four-component reaction in a
one-pot fashion.
7.4.1 Furans by a Consecutive 3CR of (Hetero)aryl Halides,

Propargyl Alcohols, and Aldehydes
Thus, upon CIR of electron-deficient (hetero)aryl halides 11 and phenyl propargyl

alcohol 12a, after subsequent Stetter reaction with aldehydes 92 in presence of
catalytic amounts of thiazolium salt 93, and after addition of glacial acetic acid and
concentrated HCl, the 2,3,5-trisubstituted furans 95 are obtained in moderate to
good yields in a one-pot procedure (Scheme 51) [260].
7.4.2 Pyrroles by a Consecutive 4CR of (Hetero)aryl Halides,

Propargyl Alcohols, Aldehydes, and Amines
Likewise, pyrroles are accessible if in the last cyclocondensation step a primary

amine is applied. Therefore, upon CIR of electron-deficient (hetero)aryl halides 11
and (hetero)aryl propargyl alcohols 12, after subsequent Stetter reaction with
aldehydes 92 in presence of catalytic amounts of thiazolium salt 93, and after
addition of primary amines 96 or ammonium chloride and glacial acetic acid, the
1,2,3,5-tetrasubstituted or 2,3,5-trisubstituted pyrroles 97 are obtained in good
yields in a one-pot procedure (Scheme 52) [259, 260].
Most conspicuously, all furans 95 and pyrroles 97 display an intense blue
luminescence upon irradiation with UV light (Scheme 53). The fluorescence
behavior of both heterocycle classes are fairly similar as illustrated by furan 95a
and pyrrole 97a, having the same substitution pattern and a difference of Stokes
shifts of only 200 cm1. The phenomenon of large Stokes shifts arises from
significant structural changes upon excitation from singlet ground state S0 and
subsequent relaxation to the lowest vibrational level of the first excited singlet
EWG
OH NEt3, THF, Δ, 10 h π
EWG–π–Hal +
Then: R1-CHO 92 (1.0 equiv)
Ph
R1 O
11 12a HO S
93
20% 95a (EWG–π = p-NCC6H4, R1 = Ph,79%)
N+ – 95b (EWG–π = p-NCC6H4, R1 = 2-furyl, 74%)
I
R′ 95c (EWG–π = 4-pyridyl, R1 = p-FC6H4, 46%)
95d (EWG–π = 4-thiazolyl, R1 = Ph, 42%)
R′ = Me (93a), CH2Ph (93b) 95e (EWG–π = p-NCC6H4, R1 = npentyl, 64%)
NEt3, Δ, 8-24h
Then: conc. HCl, HOAc, Δ, 6-12h
Scheme 51 CI–Stetter addition–Paal–Knorr three-component synthesis of 2,3,5-trisubstituted

furans 95
EWG
OH NEt3, THF, Δ, 10 h π
EWG–π–Hal +
1
Then: R -CHO 92 (1.0 equiv)
Ph
R1 N
HO S R2
11 12a 20% 93
N+ –
I
R′ 97a (EWG–π = p-NCC6H4, R1 = Ph,
R′ = Me (93a), CH2Ph (93b) R2 = H, 70%)
NEt3, Δ, 8-24 h 97b (EWG–π = p-NCC6H4, R1 = p-MeOC6H4,
Then: R2-NH2(96) or NH4Cl R2 = H, 60%)
HOAc, Δ, 22-120h 97c (EWG–π = 4-pyridyl, R1 = p-FC6H4,
R2 = H, 54%)
97d (EWG–π = p-NCC6H4, R1 = npentyl,
R2 = H, 59%)
97e (EWG–π = p-NCC6H4, R1 = (CH2)5OH,
R2 = H, 53%)
97f (EWG–π = p-NCC6H4, R1 = Ph,
R2 = CH2Ph, 60%)
97g (EWG–π = p-NCC6H4, R1 = 2-furyl,
R2 = CH2Ph, 55%)
97h (EWG–π = p-NCC6H4, R1 = Ph,
R2 = CH2CO2Et, 54%)
97i (EWG–π = p-NCC6H4,
R1 = 2,6-dimethylhept-5-enyl,
R2 = CH2CONH2, 56%)
97j (EWG–π = p-NCC6H4, R1 = Ph,
R2 = CH2CH2OAc, 57%)
97k (EWG–π = p-NCC6H4, R1 = npentyl,
R2 = i Pr, 59%)
Scheme 52 CI–Stetter addition–Paal–Knorr four-component synthesis of 1,2,3,5-tetrasubstituted

and 2,3,5-trisubstituted pyrroles 97
state S1 [261]. In particular, since all furans 95 and pyrroles 97 are acceptor
substituted, a considerable charge transfer character of the excited state can be
expected. However, the interpretation is complicated since these systems are highly
substituted. Therefore, additional subchromophores as in the pair 97a/97b have
to be taken into account where the electron-rich anisyl group (97b) causes a
bathochromic shift only of the emission maximum. The same situation is found
in the pair 97f/97g where the furyl substituent (97g) acts as a donor and enhances
the push–pull character and its influence in the stabilization of the S1 state.
Fluorescent compounds are of significant interest in molecular photonics and
biophysical analytics.
7.5 Annelated and Substituted Pyridines by a Consecutive

4CR of (Hetero)aryl Halides, Propargyl Alcohols,
Enamines, and Ammonium Chloride
Among six-membered aromatic heterocycles the pyridyl core [262] adopts a central
role. In nature, pyridine is the constituting structural unit in the coenzyme vitamin
70 T.J.J. Müller
NC NC
NC
N
S
Ph O Ph Ph N Ph N Ph
Ph Ph
O
H MeO H
95a 95d 97a 97b

λmax, abs 313 nm λmax, abs 312 nm λmax, abs 317 nm λmax, abs 319 nm
λmax, em 432 nm λmax, em 407 nm λmax, em 436 nm λmax, em 451 nm
Δn 8800 cm–1 Δn 7500 cm–1 Δn 8600 cm–1 Δn 9100 cm–1
NC NC NC NC
Ph N Ph N Ph N Ph N Ph
CH2Ph O CH2Ph CH2CONH2
97f 97g 97i 97k

λmax, abs 318 nm λmax, abs 320 nm λmax, abs 312 nm λmax, abs 327 nm
λmax, em 428 nm λmax, em 446 nm λmax, em 401 nm λmax, em 425 nm
Δn 8000 cm–1 Δn 8900 cm–1 Δn 7200 cm–1 Δn 7100 cm–1
Scheme 53 Selected UV absorptions (lmax,abs), luminescence (lmax,em), and Stokes shifts D~

v of
furans 95 and pyrroles 97 (recorded in CHCl3, excitation at lmax,ex = lmax,abs + 20 nm)
B6 family (pyridoxal, pyridoxol, pyridoxamine) and an important subunit in numer-

ous alkaloids [263, 264]. Also as versatile building blocks in the syntheses of
natural products and as ligands in supramolecular coordination chemistry, pyridine
derivatives find broad applications. In pharmaceutical chemistry, highly substituted
[265–267] and annelated [268, 269] pyridines, like 6,7-dihydro-5H-[1]pyrindines
and 5,6,7,8-tetrahydroquinolines, recently have gained a considerable interest as
antiarteriosclerotics since they efficiently inhibit HMG-CoA reductase and choles-
terol transport proteins. Besides, the classes of pyrindine, tetrahydroquinoline and
naphthyridine derivatives additionally display antimycobacterial [270], fungicidal
and bactericidal [271], antiulcer [272, 273], antivertigo [274], antiviral [275–277],
and anti-inflammatory activities [278]. There are numerous synthetic approaches to
highly substituted pyridines, however, novel multicomponent strategies, compara-
ble to the powerful, classical Hantzsch dihydropyridine synthesis [53, 54] remain
particularly challenging.
Besides Michael additions the mild reaction conditions of CIR are also compat-
ible with cycloadditions. Since chalcones can also be considered as heterodienes,
Diels-Alder reactions with inverse electron demand are suitable elementary steps
that are applicable for heterocycle synthesis. Therefore, after CIR of electron-
deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, (hetero)
cyclic and acyclic morpholino enamines 98 are added and, finally, after adding
ammonium chloride in the presence of acetic acid, dihydropyrindines 99, tetrahy-

droquinolines 100, naphthyridines 101, or substituted pyridines 102 are formed in
moderate to good yields (Scheme 54) [279, 280]. Mechanistically, after the CI of
electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12
furnishing the chalcone 13, indeed a (4+2)-cycloaddition with inverse electron
demand of the chalcone 13 as heterodiene and the enamine 98 as dienophile
gives rise to the formation of the cycloadduct 103 (Scheme 55). In one case, this
EWG
π
OH NEt3, THF, Δ, 10h
EWG–π–Hal +
O
(hetero)aryl N (hetero)aryl
Then:
99-102 (18 examples, 31-70%)
N 98
11 12
(1.25-1.5 equiv)
Δ, 16h
Then: NH4Cl, HOAc, Δ, 24-48h
EWG
99a (EWG–π = p-NCC6H4, (hetero)aryl = Ph, 48%)
π 99b (EWG–π = p-EtO2CC6H4, (hetero)aryl = Ph, 42%)
99c (EWG–π = 2-pyridyl, (hetero)aryl = Ph, 62%)
99d (EWG–π = 2-pyrimidyl, (hetero)aryl = Ph, 59%)
99e (EWG–π = p-F3CC6H4, (hetero)aryl = Ph, 54%)
N (hetero)aryl 99f (EWG–π = p-NCC6H4, (hetero)aryl = p-MeOC6H4, 31%)
EWG
π 100a (EWG–π = p-NCC6H4, (hetero)aryl = Ph, 70%)
100b (EWG–π = 2-pyridyl, (hetero)aryl = Ph, 64%)
100b (EWG–π = 2-pyrimidyl, (hetero)aryl = Ph, 50%)
100d (EWG–π = p-NCC6H4, (hetero)aryl = p-MeOC6H4, 48%)
N (hetero)aryl
EWG
π 101a (EWG–π = p-NCC6H4, 61%)
101b (EWG–π = 2-pyridyl, 41%)
EtO2C
N 101c (EWG–π = 2-pyrimidyl, 57%)
101d (EWG–π = p-F3CC6H4, 58%)
N Ph
EWG
π 102a (EWG–π = p-NCC6H4, R = p-MeOC6H4, 54%)
102b (EWG–π = p-NCC6H4, R = 2-thienyl, 46%)
102c (EWG–π = 2-pyrimidyl, R = Ph, 68%)
102d (EWG–π = 2-pyrimidyl, R = p-MeOC6H4, 39%)
R N Ph
Scheme 54 CI–cycloaddition–cyclocondensation four-component synthesis of dihydropyrindines

99, tetrahydroquinolines 100, naphthyridines 101, and substituted pyridines 102
72 T.J.J. Müller
EWG
π
H
0 I
[Pd , Cu ], NEt3 98 NH4Cl
11 + 12 [13] 99-102
Coupling- (4 +2)– Elimination-
O (hetero)aryl
Isomerization Cycloaddition N Cyclocondensation
Dehydrogenative
O Aromatization
103
Scheme 55 Mechanistic rationalization of the CI–cycloaddition–cyclocondensation sequence to

annelated and substituted pyridines 99–102
cycloadduct was isolated and its structure was unambiguously elucidated by an

X-ray structure analysis [280]. If the reaction mixture is hydrolyzed after the
cycloaddition step then the expected 1,5-dicarbonyl compounds can be isolated
and unambiguously characterized.
Then, the sequence concludes by cyclocondensation of ammonium chloride
and adduct 103 with concomitant aromatization giving rise to the annelated and
substituted pyridines 99–102. Only with 3-amino crotonate as an enamine compo-
nent and strongly electron deficient substituted aryl halides the expected dihydro-
pyridines, i.e., the unsymmetrical Hantzsch products, were isolated as byproducts.
Presumably, the presence of the transition metal catalysts supports the aromatiza-
tion by dehydrogenation. Interestingly, with primary and secondary b-amino cro-
tonamides or butenones as enamine components and dielectric heating the outcome
of the cycloaddition-cyclocondensation step is different and furnishes 1-acetyl-2-
amino-cyclohexa-1,3-dienes 104 or 6-N,N-dimethyl carbamoyl-cyclohexenones
105 in moderate to good yields as a consequence of a concluding intramolecular
aldol condensation (Schemes 56 and 57) [281].
7.6 Annelated and Substituted Pyridines by a Consecutive 4CR

of (Hetero)aryl Halides, Propargyl Amides, Ketene Acetals
or S,N-Aminals, and Ammonium Chloride
The CI sequence, as already disclosed in Chap. 2.2, can be successfully transposed to

electron-deficient (hetero)aryl halides 11 and N-tosyl propargyl amines 20 giving rise
to the formation of N-tosyl enimines 21. As previously shown for chalcones, N-tosyl
enimines are also heterodienes suitable for Diels–Alder reactions with inverse elec-
tron demand [282–284] for the generation of pyridines. However, in this case the
pyridyl nitrogen is already present in the enimine substrate and the tosyl group is a
suitable leaving group in elimination processes. In addition, the dienophiles have to
be electron-rich alkenes such as ketene acetals or N,S-ketene acetals.
Thus, upon CIR of electron-deficient (hetero)aryl halides 11 and N-tosyl p-anisyl
propargyl amine 20a, and subsequent addition of diethyl ketene acetal (106)
EWG
2% PdCl2(PPh3)2, 1% CuI O π
OH THF, NEt3, MW (150°C), 15 min
EWG–π–Hal +
R
(hetero)aryl Then: O HN
HN (hetero)aryl
R
11 12
HOAc (3 equiv) 104 (10 examples, 30-74%)
MW (150°C), 10 min
CN CN CN
N N CN
O
O O O
O
HN Ph
HN Ph HN Ph
HN
S
HN Ph
n
Bu
HN
HN HN OMe
104a (68%) 104b (74%) 104c (64%) 104d (54%) 104e (30%)
Scheme 56 CI–cycloaddition–cyclocondensation three-component synthesis of 1-acetyl-2-

amino-cyclohexa-1,3-dienes 104
EWG
2% PdCl2(PPh3)2, 1% CuI O π
OH THF, NEt3, MW (150°C), 15 min
EWG–π–Hal +
R Me2N
Ph Then: HN
O
O Ph
Me2N 105a (EWG–π = p -NCC6H4, 66%)
11 12a
HOAc (3 equiv) 105b (EWG–π = p -F3CC6H4, 70%)
MW (150°C), 10 min 105c (EWG–π = 2-pyridyl, 68%)
105d (EWG–π = 2-pyrimidyl, 48%)
Scheme 57 CI–cycloaddition–cyclocondensation three-component synthesis of 6-N,N-dimethyl

carbamoyl-cyclohexenones 105
2-ethoxy substituted pyridines 107 can be obtained in a consecutive three-component

reaction in moderate to good yields (Scheme 58) [85]. After the CIR N-tosyl
enimines 21 are generated, which now can serve as electron-deficient dienes in
Diels–Alder reactions with inverse electron demand. With diethyl ketene acetal
(106) as electron-rich dienophile the (4+2)-cycloaddition proceeds to furnish the
tetrahydro pyridine core that bears two potential leaving groups. The sequence is
concluded by elimination of ethanol and p-tolyl sulfinate and thereby yielding the
aromatic pyridine.
74 T.J.J. Müller
EWG
π
HN Ts 2% PdCl2(PPh3)2, 1% CuI
EWG π Hal + THF or CH3CN / NEt3, Δ, 24 h
Then: OEt
EtO N
106 (4 equiv)
OEt OMe
OMe THF, Δ, 24 h
11 20a 107a (EWG–π = p -NCC6H4, 57%)
107b (EWG–π = p -EtO2CC6H4, 25%)
107c (EWG–π = p -F3CC6H4, 30%)
107d (EWG–π = 2-pyridyl, 65%)
107e (EWG–π = 2-pyrimidyl, 46%)
Scheme 58 CI–cycloaddition–elimination three-component synthesis of 2-ethoxy substituted

pyridines 107
EWG
2% PdCl2(PPh3)2, 1% CuI π
HN Ts
THF or CH3CN / NEt3, Δ, 24 h
EWG π Hal +
n
(hetero)aryl
Then: N
n
108 (5 equiv) N (hetero)aryl
n = 1, 2, 3 Me
MeS N
11 20 109-111 (10 examples, 31-66%)
Me
THF, Δ, 12 h
EWG EWG EWG
π π π
N N N N (hetero)aryl N (hetero)aryl
N
Me Me Me
OMe
109a (EWG-π = p -NCC6H4, 64%) 110a (EWG-π = p -NCC6H4, 111a (EWG-π = p -NCC6H4,
109b (EWG-π = 2-pyridyl, 49%) (hetero)aryl = p -MeOC6H4, 31%) (hetero)aryl = p -MeOC6H4, 52%)
109c (EWG-π = 2-pyrimidyl, 66%) 110b (EWG-π = p -NCC6H4, 111b (EWG-π = p -NCC6H4,
(hetero)aryl = p -PhOC6H4, 43%) (hetero)aryl = p -PhOC6H4, 43%)
110c (EWG-π = 2-pyridyl, 111c (EWG-π = 2-pyridyl,
(hetero)aryl = p -MeOC6H4, 48%) (hetero)aryl = p -MeOC6H4, 52%)
111d (EWG-π = 2-pyrimidyl,
(hetero)aryl = p -MeOC6H4, 56%)
Scheme 59 CI–cycloaddition–elimination three-component synthesis of pyrrolo(2,3-b)pyridines

109, 1,8-naphthyridines 110, and pyrido(2,3-b)azepines 111
Likewise, this in situ generation of enimines can also be applied in a consecutive

CIR-cycloaddition-aromatization sequence with highly reactive cyclic N,S-ketene
acetals to furnish annelated pyridines. Thus, upon reaction of electron poor (hetero)
aryl halides 11, terminal propargyl N-tosyl amines 20, and cyclic N,S-ketene
acetals 108, annelated 2-amino pyridines such as pyrrolo(2,3-b)pyridines 109,
1,8-naphthyridines 110, and pyrido(2,3-b)azepines 111 can be synthesized in moder-
ate to good yields (Scheme 59) [285]. The sequence to annelated 2-aminopyridines
109–111 can be rationalized as previously discussed for the one-pot synthesis of
2-ethoxypyridines (Scheme 60). After the CI of 11 and 20 the enimine 21 undergoes a
(4+2)-cycloaddition with cyclic N,S-ketene acetal 108 to give the bicyclic
EWG
π
– MeSH
[Pd0, CuI], NEt3 108 H
– Ts – HN+Et3
11 + 20 [21] 109-111
Coupling- (4 + 2)– n
Aromatization
Isomerization Cycloaddition N N (hetero)aryl By
Me SMe Twofold
Ts Elimination
112
Scheme 60 Mechanistic rationalization of the CI–cycloaddition–elimination sequence to anne-

lated 2-aminopyridines 109–111
cycloadduct 112. In the presence of triethylamine as a base a twofold elimination of

methyl mercaptane and p-tolyl sulfinate yields the aromatic pyridine core in the
bicyclic product 109–111.
Interestingly, all annelated 2-aminopyridines 109–111 are highly fluorescent and
the luminescence color of the pyrido(2,3-b)azepines 111 is highly protochromic in a
small pH range and can be shifted from blue (alkaline) to green (acidic) [285].
8 Domino Syntheses of Heterocycles by Coupling-

Isomerization Sequences
The mechanistic rationale of the CI sequence provides reactive intermediates such

as enones and elusive allenols (vide supra) that can be exploited even in a domino
sense, if a suitable trapping functionality is present. For the synthesis of hetero-
cycles two bimolecular sequences have been elaborated. One is terminated by an
intramolecular cyclocondensation with an amino group, which is unprotected and
carried through the sequence to trap the evolving enone functionality. The other
exploits the generation of a vinyl allene intermediate, which is captured by an
intramolecularly tether dienophile in the sense of a (4þ2)-cycloaddition.
8.1 Domino Synthesis of 2-Substituted Quinolines
Quinolines represent an important class of heterocycles, and the quinoline skeleton

is present in various natural products, especially in alkaloids. Among them quinine
is an active ingredient for the treatment of malaria [286]. Despite its relatively low
efficacy and tolerability, quinine still plays an important role in the treatment of
multiresistant malaria, one of the world’s most devastating infectious diseases
[287]. Therefore, the design of many drugs and affordable chemotherapies are
based upon synthetic quinoline derivatives, such as chloroquine, mefloquine or
quinacrine [288–292]. In addition, chimanine alkaloids, are also effective against
parasitic diseases such as leishmaniasis and trypanosomiasis [293–295]. Besides,
76 T.J.J. Müller
R1
THF, DBU (2 equiv) R1
I OH microwave (120-150°C), 30 min
+
NH2 R2 N R2
113 15 114 (9 examples, 40-92%)
Me
N
N Ph N N N Ph N Ph Ph N N Ph
114a (81%) 114b (40%) 114c (79%) 114d (78%) 114e (64%)
Scheme 61 CI domino synthesis of 2-substituted quinolines 114
leishmania-HIV coinfection has been regarded as an emerging infectious disease.

Several two-substituted quinolines [296] have been shown to possess in vitro
activity against causal agents of cutaneous leishmaniasis, visceral leishmaniasis,
African trypanosomiasis and Chaga’s disease as well as against HIV-1 replication.
Thus, substituted quinolines are generally attractive as antimalarials, antibacterials,
protein kinase inhibitors, NADH models, and as agrochemicals.
Applying dielectric heating and stronger bases such as DBU facilitates the CI
of electroneutral and even electron-rich aryl halides as substrates as discussed in
Chap. 2.2. Ortho-iodo anilines and their pyridyl analogs contain an amino group,
which can be carried through the sequence without protection. Then, this amino
functionality is able to cyclocondense intramolecularly with the adjacent enone
carbonyl group to complete the annelating heterocyclization. Therefore, reacting
ortho-iodo aniline derivatives 113 and propargyl alcohols 15 under microwave-
assisted CI conditions with DBU as a base furnishes the two-substituted quinolines
114 in good to excellent yields (Scheme 61) [297].
This domino methodology not only allows to access naturally occurring quino-
lines such as 114a and 114b (chimanine B), but also a rapid access to the antima-
larial active 1,8-naphthyridine 114c, which inhibits the growth plasmodium
falciparum at a lower micromolar level [297].
8.2 Domino Synthesis of Spiro-Benzofuranones

and Spiro-Benzoindolones
Based upon the studies on the mechanism of the CI sequence we rationalized that
the elusive allenol intermediate 19 (Chap. 2.2) could participate in intramolecular
trapping reactions as an allenyl ether. Furthermore, vinyl allenes are perfectly
suited as dienes in Diels–Alder reactions. Considering both reactive functionalities,
allenyl ethers and vinyl allenes, which are perfectly suited for domino processes,
we designed an insertion sequence based upon cyclizing carbopalladation [76],
where the vinyl allene results from an isomerization of an alkynylation of a vinyl
(hetero)aryl
R2 O
Ph 5% PdCl2(PPh3)2
1
R 2.5% CuI R2
I toluene, NEt3, 72 h
+ O R1
Ph
O O O
(hetero)aryl O
115 116 117a (R1 = R2 = H, (hetero)aryl = p -NCC6H4, 51%)
117b (R1 = R2 = H, (hetero)aryl = o -FC6H4 (50%)
117c (R1 = R2 = H, (hetero)aryl = p -MeOC6H4 (66%)
117d (R1 = R2 = H, (hetero)aryl = p -EtOC6H4 (46%)
117e (R1 = R2 = H, (hetero)aryl = p -Me2NC6H4 (32%)
1 2
117f (R = CH3, R = H, (hetero)aryl = p -EtOC6H4 (29%)
117g (R1 = CH3, R2 = H, (hetero)aryl = 2-thienyl (49%)
117h (R1 = R2 = CH3, (hetero)aryl = p -MeOC6H4 (33%)
Scheme 62 Insertion–CI–Diels–Alder domino reaction to spiro-benzofuranones 117
palladium species. Therefore, reacting alkynoyl ortho-iodo phenolester 115 and

propargylallyl ethers 116 under CI conditions with triethylamine as a base furnishes
(tetrahydroisobenzofuran) spiro-benzofuranones 117 in moderate yields
(Scheme 62) [298, 299].
Likewise, upon reacting alkynoyl ortho-iodo anilides 118 and propargylallyl
ethers 116 under CI conditions in a boiling mixture of butyronitrile and triethyla-
mine (tetrahydroisobenzofuran) spiro-indolones 119 can be isolated in moderate to
excellent yields (Scheme 63).
Based upon the product analysis the hetero domino sequence can be interpreted
as a combination of a transition metal catalyzed insertion cascade that concludes in
a pericyclic final step. Intramolecular Heck reactions [300] have been developed to
a broad methodology and have culminated in impressive domino sequences like
Negishi’s zippers [76], however, the termination of insertion cascades by Sonoga-
shira alkynylation has received only little attention [301, 302]. As a consequence,
the hetero domino sequence can be described as an insertion-alkynylation followed
by a base catalyzed isomerization of an electron-poor vinylpropargyl allyl ether to
give an electron poor vinyl allene that reacts in an intramolecular (4+2)-cycloaddi-
tion through an anti-exo transition state to conclude the sequence by formation of
the spirocycles 117 or 119. Methodologically, upon formation of four new carbon–
carbon bonds with concomitant generation of a complex tetracyclic framework in
high efficiency, this insertion–CI–Diels–Alder domino reaction furnishes spirocyc-
lic benzofuranones 117 and dihydroindolones 119 in moderate to excellent yields.
Mechanistically, this new insertion–CI–Diels–Alder hetero domino sequence
can be rationalized as follows (Scheme 64): After the oxidative addition of the
aryl halide 115 or 118 to the in situ generated Pd(0) species the arylpalladium halide
120 intramolecularly coordinates and inserts into the tethered triple bond via a syn-
carbopalladation to furnish cyclized vinylpalladium species 121 with a b-acceptor
substitution in a stereospecific fashion. Transmetallation of the in situ generated
copper acetylide 122 gives rise to the diorganylpalladium complex 123 that readily
undergoes a reductive elimination and liberates the electron poor vinylpropargylallyl
ether 124. The triethylamine catalyzed propargyl-allene isomerization furnishes the
78 T.J.J. Müller
O (hetero)aryl
R2
R4 5% PdCl2(PPh3)2
R1 2.5 % CuI
I butyronitrile, NEt3, 72 h R2
+ O R1
R4
N O O
(hetero)aryl
R3 N
R3
118 116 119
119a (R1 = R2 = H, (hetero)aryl = p -MeOC6H4, R3 = Ts, R4 = Ph, 81%)

119b (R1 = CH3, R2 = H (hetero)aryl = 2-thienyl, R3 = Ts, R4 = Ph, 72%)
119c (R1 = R2 = CH3, (hetero)aryl = p -OHCC6H4, R3 = Ts, R4 = Ph, 71%)
119d (R1 = R2 = CH3, (hetero)aryl = p -ClC6H4, R3 = Ts, R4 = Ph, 86%)
119e (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ts, R4 = Ph, 86%)
119f (R1 = R2 = CH3, (hetero)aryl = 2-thienyl, R3 = Ts, R4 = Ph, 72%)
119g (R1 = R2 = CH3, (hetero)aryl = p -MeOC6H4, R3 = Ts, R4 = Ph, 79%)
119h (R1 = R2 = CH3 (hetero)aryl = p -ClC6H4, R3 = Ts, R4 = nBu, 81%)
119i (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ts, R4 = nBu, 79%)
119j (R1 = R2 = CH3, (hetero)aryl = p -MeOC6H4, R3 = Ts, R4 = nBu, 77%)
119k (R1 = R2 = CH3, (hetero)aryl = p -ClC6H4, R3 = Ts, R4 = iPr3Si, 79%)
119l (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ts, R4 = iPr3Si, 85%)
119m (R1 = R2 = CH3, (hetero)aryl = p -MeOC6H4, R3 = Ts, R4 = iPr3Si, 77%)
119n (R1 = R2 = CH3, (hetero)aryl = p -ClC6H4, R3 = Ms, R4 = p -MeOC6H4, 53%)
119o (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ms, R4 = p -MeOC6H4, 63%)
119p (R1 = R2 = CH3, (hetero)aryl = p -MeOC6H4, R3 = Ms, R4 = p -MeOC6H4, 63%)
119q (R1 = R2 = CH3, (hetero)aryl = p -OHCC6H4, R3 = Ts, R4 = p -MeOC6H4, 66%)
119r (R1 = R2 = CH3, (hetero)aryl = p -ClC6H4, R3 = Ts, R4 = p -MeOC6H4, 87%)
119s (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ts, R4 = p -MeOC6H4, 88%)
119t (R1 = R2 = CH3, (hetero)aryl = p -ClC6H4, R3 = Ts, R4 = 10-methylphenothiazin-3-yl, 58%)
119u (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = p -(AcOCH2CH2OC6H4SO2, R4 = Ph, 73%)
119v (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Ac, R4 = Ph, 46%)
119w (R1 = R2 = CH3, (hetero)aryl = Ph, R3 = Me, R4 = Ph, 38%)
Scheme 63 Insertion–CI–Diels–Alder domino reaction to spiro-indolones 119
electron poor enallene 125 that reacts in an intramolecular (4+2)-cycloaddition

to conclude the sequence with the formation of the spirocycle 117 or 119 via an
anti-exo transition state in the Diels–Alder step.
Most interestingly, upon irradiation with UV light all members of this class of
pale yellow to yellow absorbing spirocycles display a pronounced and intense blue
over green to yellow orange fluorescence with large Stokes shifts in solution
(4,300–9,600 cm–1) and in the solid state. UV/vis and emission spectroscopic
studies reveal that both absorption and emission properties are strongly affected
by minute substituent variations or conformational biases.
All chromophores absorb between near UV and the edge to visible where the
longest wavelength absorption maxima are between 327 and 398 nm. In the
fluorescence spectra, the shortest wavelength emission maxima range from 433 to
545 nm and are always accompanied by either a blue or red shifted shoulder. The
large Stokes shift is most probably caused by a distortion of the molecular
115
or
118 Reductive
(hetero)aryl
Elimination
PdLn O
Oxidative
Addition R4
toluene or butyronitrile R1
NEt3, Δ, 3 d R2
O Isomerization
X
I L R
4
R2 R1
Pd 124
Ln [NEt3]
Pd 4
R
X O O O
120 • R4
(hetero)aryl O
X (hetero)aryl R2
Ln
123 R1 O
Pd R4
I X
125
Alkyne Insertion O
Transmetallation
(Carbopalladation) X
R2 (4 + 2 ) Cycloaddition
121
R1
O
117
CuLn
or
(hetero)aryl 119
122
Scheme 64 Mechanistic rationale of the insertion–CI–Diels–Alder domino sequence to spiro-

benzofurans 117 and spiro-dihydroindolones 119
framework in the excited state as reported for coumarin derivatives [303]. The latter
notion arises because the model trans-cis 1,4-diphenyl butadiene does not fluoresce
at all upon photo excitation, but rather undergoes a conformational twisting and an
efficient internal conversion back to the ground state [304]. This deviating peculiar
behavior of the spirocyclic 1-(hetero)aryl-4-(hetero)aryl butadienes 117 and 119
can be unequivocally attributed to structurally fixed conformations in the excited
state. The ongoing quest for high performance fluorophores in OLED with peculiar
properties is a stimulating challenge [305], which can be addressed with spirocyclic
lumophores.
9 Conclusion and Outlook
The catalytic generation of alkynones and chalcones by palladium catalyzed reactions

is an entry to sequential, consecutive, and domino transformations and opens new
routes to heterocycles by consecutive coupling-cyclocondensation or CI-cyclocon-
densation sequences. The advantages are not only the compatibility of similar
reaction conditions but also the tunable reaction design that allows the combination
of several organic and organometallic elementary reactions to new diversity oriented
syntheses. Future developments will address also sequentially catalyzed processes
80 T.J.J. Müller
and the extension to hetero domino reactions for the rapid construction of complex
molecular frameworks.
Transition metal catalysis has considerably fertilized the development of diver-
sity-oriented synthesis of heterocycles, namely by disclosing new transition metal
catalyzed MCRs. Besides purely insertion based domino processes, sequential and
consecutive one-pot reactions have significantly expanded the playground for reac-
tion design. Conceptually, many applications such as in natural product synthesis, in
medicinal chemistry, for the design of functional fluorescent and redox active
molecular materials, or in ligand syntheses for catalysis and coordination chemistry
can be tackled by this methodological approach. Still many other transition metal
complexes, that are known to catalyze uni- and bimolecular transformations, are
waiting to be discovered for inventing new sequences. Undoubtedly, the future holds
surprising sequences in store.
Acknowledgments The work summarized in this account was continuously supported by the
Deutsche Forschungsgemeinschaft, the MORPHOCHEM AG, Merck Serono GmbH, the Fonds
der Chemischen Industrie, and the Dr.-Otto-Röhm Gedächtnisstiftung. The dedication, the intel-
lectual input and the skill of the group members and students who actually carried out the research
in the laboratories is gratefully acknowledged.
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DOI: 10.1007/7081_2010_44
Multicomponent Reaction Design Strategies:

Towards Scaffold and Stereochemical Diversity
Rachel Scheffelaar, Eelco Ruijter, and Romano V.A. Orru
Abstract In the past decade, it has been extensively demonstrated that multicom-
ponent chemistry is an ideal tool to create molecular complexity. Furthermore,
combination of these complexity-generating reactions with follow-up cyclization
reactions led to scaffold diversity, which is one of the most important features of
diversity oriented synthesis. Scaffold diversity has also been created by the devel-
opment of novel multicomponent strategies. Four different approaches will be
discussed [single reactant replacement, modular reaction sequences, condition
based divergence, and union of multicomponent reactions (MCRs)], which all led
to the development of new MCRs and higher order MCRs, thereby addressing both
molecular diversity and complexity.
Keywords Complexity Diversity oriented synthesis Multicomponent reactions

Scaffold diversity Synthesis
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
1.1 Complexity and Diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
1.2 Multicomponent Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
2 Molecular Diversity Involving MCRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
3 Novel Multicomponent Strategies Towards Scaffold Diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
3.1 Single Reactant Replacement (SRR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
3.2 Modular Reaction Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
3.3 Condition-Based Divergence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
3.4 Union of MCRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
4 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
R. Scheffelaar, E. Ruijter, and R.V.A. Orru (*)

Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De
Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands
e-mail: orru@few.vu.nl
96 R. Scheffelaar et al.
Abbreviations
Ac Acetyl
Ar Aryl
BINAP 2,20 -bis(diphenylphosphino)-1,10 -binaphthyl
Bn Benzyl
Bu Butyl
tBu Tert-butyl
CBD Condition-based divergence
Cp Cyclopentadienyl
CR Component reaction
3D Three dimensional
DA Diels-Alder
DCM Dichloromethane
de Diastereomer excess
DIPEA N,N-diisopropylethylamine
DMAD Dimethyl acetylenedicarboxylate
DMF Dimethylformamide
DMSO Dimethyl sulfoxide
DOS Diversity oriented synthesis
dppf 1,10 -bis(diphenylphosphino)ferrocene
dr Diastereomer ratio
ee Enantiomer excess
Et Ethyl
EWG Electron withdrawing group
FG Functional group
HWE Horner-Wadsworth-Emmons
IMCR Isocyanide based multicomponent reaction
mCPBA m-chloroperoxybenzoic acid
Me Methyl
MeCN Acetonitrile
min. Minute(s)
MRS Modular reaction sequences
MS Molecular sieves
MTBE Methyl tert-butyl ether
MW Microwave
n.d. Not determined
Nu Nucleophile
P-3CR Passerini 3-component reaction
Ph Phenyl
PMP p-methoxyphenyl
rt Room temperature
SRR Single reactant replacement
Multicomponent Reaction Design Strategies 97
Tf Trifluoromethanesulfonyl (triflyl)
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TMS Trimethylsilyl
Ts Tosyl, 4-toluenesulfonyl
U-4CR Ugi 4-component reaction
1 Introduction
1.1 Complexity and Diversity
The importance of small molecules1 in contemporary chemical biology and medic-

inal research is undisputed. Studying the interaction of small molecules with
biological systems is crucial for understanding all fundamental processes of life,
both in health and disease [2]. Synthetic organic chemists enable access to struc-
turally complex and functionally diverse sets of small molecules and thus supply
the feedstock for advanced chemical biology and medicinal research studies.
Current drug discovery involves the screening of small molecules for their
ability to bind to a preselected protein target (found by biological methods) [3].
This is rather time-consuming and leads to the development of drugs for only a
small selection of protein targets.
The ultimate goal, however, is to identify molecular modulators for all cellular
processes, which emerge from growing insights in genome biology, including
nonclassical biological targets that are currently considered “undruggable”.2 This
can be done by screening small molecules for their ability to modulate a biological
pathway in cells or organisms, without considering a specific protein target. This
will result in the simultaneous identification of the therapeutic protein target and its
chemical modulator [3].
Since the protein target and the chemical modulator are unknown, for this
drug development strategy methodologies are required that lead to structurally
complex and diverse small molecules covering a broad region of the so-called
“chemical space”3 [2, 6]. This is one of the main focuses of diversity-oriented
1
Small molecules are typically compounds with a molecular weight less than 500 Da: [1].
2
Molecules/interactions that are considered to be “undruggable”, comprise transcription factors,
regulatory RNAs, interactions between proteins (especially intracellular) and between proteins and
DNA. There are only about 500 “druggable” targets: [4].
3
The chemical space is a multidimensional area with each dimension defined by a descriptor which
can be molecular weight, polarity, solubility, membrane permeability, binding constant. H-bond-
ing properties etc. and encompasses all small carbon-based molecules that could in principle be
created: [5].
Fig. 1 Representation of (a) target oriented synthesis (TOS), (b) combinatorial chemistry and
(c) diversity oriented synthesis (DOS) in chemical space [2]
synthesis (DOS, Fig. 1c) [2, 7–9]. The aim of DOS, i.e., to access as many points in
the chemical space, differs very much from target oriented synthesis (TOS, Fig. 1a)
and combinatorial chemistry (Fig. 1b), which access just a single point or dense
region in chemical space. TOS is especially used in drug discovery involving
preselected protein targets and makes use of retro-synthetic analysis [3]. TOS
primarily relies on nature to discover small bioactive compounds. After isolation
and characterization of a natural product, it can become a target for chemical
synthesis. Closely related to this approach is combinatorial chemistry, which
often uses these natural products or other known drugs, as a starting point to obtain
a collection of molecules derived from the parent skeleton (focused libraries), for
example, by changing substituents around a common skeleton.
In contrast to retrosynthetic analysis used for TOS and combinatorial chemistry,
DOS requires “forward synthetic planning” that enables the conversion of simple
starting materials into complex and diverse products.
Molecular complexity (generally found in natural products) seems to be
extremely important to obtain an optimal perturbation function and specificity of
action of the chemical modulators on their protein targets [2, 9]. The goal of
achieving molecular diversity can be divided in three different diversity elements:
(a) appendage diversity (combinatorial chemistry), (b) stereochemical diversity,
and most importantly (c) scaffold diversity (Fig. 2) [2].
Appendage diversity (Fig. 2a) is the central feature of combinatorial chemistry
and involves the introduction of different appendages to a common molecular
skeleton. Although diversity is generated, these compounds all have a common
molecular skeleton, thereby displaying related chemical information in the 3D
space (same molecular shape) resulting in a limited amount of potential binding
partners. For DOS, it is especially important to create compounds that display
diverse 3D information. This can be realized by developing synthetic pathways
that incorporate the two other diversity elements, stereochemical and scaffold
diversity. Stereochemical diversity (Fig. 2b) involves the generation of as many
stereoisomers of the same molecule, however, not as mixtures, but selectively.
a Appendage diversity b Stereochemical diversity c Scaffold diversity
B B
B B
Fig. 2 The three different elements of molecular diversity
Fig. 3 Schematic illustration of a multicomponent reaction toward a complex product
For this, stereospecific reactions are required that allow selective access to different
stereoisomers by, for example, changing the stereochemistry of the catalyst or the
chiral substrates.
Finally, scaffold diversity (Fig. 2c), probably the most important element of
diversity, is the generation of a collection of products with different molecular
skeletons (scaffolds). This can, for example, be realized by changing the reagents
added to a common substrate (reagent-based approach) or by transforming a
collection of substrates having suitable preencoded skeletal information with simi-
lar reaction conditions (substrate-based approach) [2, 10].
For DOS to succeed, highly efficient (max. 3–5 reaction steps), versatile, and
robust synthetic methodologies are needed. This requires new concepts and novel
design approaches that focus on complexity- and diversity generation and do not
require protective group manipulations: a clear challenge for the synthetic organic
chemist.
A powerful strategy to address these challenges involves the use of multicom-
ponent reactions (MCRs), which are reactions of at least three different simple
reagents reacting in a well-defined manner to form a single product (Fig. 3)
[11–17]. This highly convergent methodology allows molecular complexity to be
created by the facile formation of several new covalent bonds in a one-pot transfor-
mation. At the same time MCRs proceed with remarkably high atom economy [18]
and low E factors4 minimizing the number of functional group (FG) manipulations
towards a given complex molecular target, thus avoiding the use of protective
groups. As such, syntheses involving MCRs save time and energy (step efficiency)
and quite closely approach the concept of the ideal synthesis, making them very
useful to apply in DOS [13].
1.2 Multicomponent Reactions
The first important MCR was developed by Strecker in 1850 (Scheme 1) [20].
In this reaction ammonia, an aldehyde and hydrogen cyanide combine to form
a-cyano amines 1, which upon hydrolysis form a-amino acids 2. Also, heterocyclic
compounds were obtained using MCRs. An example of this is the Hantzsch
reaction, discovered in 1882 [21]. This reaction is a condensation of an aldehyde
with two equivalents of a b-ketoester in the presence of ammonia resulting in the
formation of dihydropyridines 3. A comparable reaction is the Biginelli reaction,
founded in 1893 ([22] and see for review: [23]). This reaction is a 3-component
reaction (3CR) between an aldehyde, a b-ketoester and urea to afford dihydropyr-
imidines 4.
Strecker O R1 R1
H+
reaction 1 NH3 + HCN H2N CN H2N
(1850) R H+ – H2O H2O COOH
1 2
O R1 O
O O O R3 R3
Hantzsch + 2 R 3 O O
reaction R
1
H+ NH3 R2 O –3 H2O
(1882) R2 N R2
H
3
Biginelli O O O O O R1
reaction 1 + + 2 R3 –2 H O R3
H H2N NH2 R O O NH
(1893) R
2
2
R N O
H
4
Mannich O R1 O
O
2 4 R2
reaction
1 + R – NH + R R6 N R6
(1912) R H –H2O
R3 5 R3 R 4 R
5
R
5
Scheme 1 Overview of one of the first reported MCRs
4
The E factor is defined as the mass ratio of waste (everything but the desired product) to desired
product. For a recent overview, see: [19].
Another well-known 3CR is the Mannich reaction, developed in 1912, in which

formaldehyde or a nonenolizable aldehyde and an amine form an intermediate
Schiff base which subsequently reacts with an a-acidic compound, to afford
b-amino carbonyl 5 [24].
A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9
which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an
isocyanide 7 (Scheme 2) ([25] and see for review: [26]). Since the first synthesis of
isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component
reaction (P-3CR) was the first MCR involving these reactive species. It has become
one of the renowned examples of an important subclass of MCRs, the isocyanide-
based MCRs (IMCRs). Especially important for the Passerini reaction, but also
for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by
reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic
O O O
+ R3–N C + R3 O R4
R1 R2 R4 OH N
H R1 R2 O
6 7 8
9
Passerini reaction
(1921)
R4
H
O O C
+ O O
R1 N
O R 4 R3 H
R2 N
R3 O
10 7 R1 R2
11
O O O R5
+ R5– NH2 + R3–N C + R3
N R4
R4 –H2O N
R1 R2 OH
H R1 R2 O
6 12 7 8
13
Ugi reaction
–H2O
(1959)
O
4
R O R5
H R5 R5 16
C NH NH
N
+ N R1 R1 O R4
C C
R1 R2 R 3 R2 N R2
R3 N O
14 7 15 R3
17
Scheme 2 The Passerini and Ugi MCRs and their proposed mechanisms
Fig. 4 Frontier orbitals of the

isocyanide, explaining the R N C R N C
reactivity of this important
functional group in filled non-bonding empty π∗-orbital
multicomponent chemistry σ-orbital
character of the isocyanide carbon can be explained by the filled nonbonding

s-orbital. The electrophilic character is explained by the empty p*-orbital posses-
sing a high orbital coefficient on carbon (Fig. 4) [13]. Even though the isocyanide
carbon is nucleophilic, good electrophiles such as protonated carbonyl or iminium
ions are typically required for a reaction to occur [28].
The Passerini reaction is typically carried out at high concentrations of starting
materials in aprotic solvents (generally DCM), at or below room temperature.
The reaction shows a high substrate scope and variation of all three components
is extensively possible.
Since the Passerini reaction is accelerated in aprotic solvents, it is assumed that
the reaction follows a nonionic pathway. The most plausible mechanism of the
reaction is depicted in Scheme 2 ([25] and see for review: [26]; [13]).
Initially, a loosely bound hydrogen bonded adduct 10 is formed, from the
carboxylic acid 8 and the carbonyl compound 6. The next step is the formation of
the a-adduct 11 by reaction of the isocyanide with the nucleophilic carboxylate and
the electrophilic protonated carbonyl compound. a-Adduct 11 then rearranges to
give a-acyloxy amide 9.
About 40 years later, in 1959, Ugi developed a four-component variant of this
reaction that involves an aldehyde or ketone 6, carboxylic acid 8, an amine 12
and an isocyanide 7 yielding a-acylamino amide 13 (Ugi 4-component reaction
[U-4CR], Scheme 2) [29]. Like the Passerini reaction, the Ugi reaction shows a high
substrate scope. The reaction is favored in polar protic solvents and is usually
performed in methanol, though several other solvents have been reported [13, 30].
Although different mechanisms have been reported [17], the Ugi reaction will
presumably proceed via nitrilium ion intermediate 15, formed by a reaction of the
isocyanide 7 with the in situ generated iminium ion 14. Subsequent trapping of 15
with the carboxylate 16 generates the instable a-adduct 17, which undergoes an
intramolecular acylation called the Mumm rearrangement to afford a-acylamino
amide 13 [28, 31].
2 Molecular Diversity Involving MCRs
As already became clear from the previous examples, MCRs are ideal to obtain
complex products in an easy way. However, DOS also requires molecular diversity
(appendage, stereochemical and scaffold diversity), which can also be accomplished
using MCRs.
MCRs are ideal to achieve appendage diversity, because all individual compo-
nents can be varied to create a large library of products that have the same skeleton
but differ in the substituents around it. If, for example, a 4-component reaction
(4CR) is considered and 40 inputs of all four components are combined, this will
result in 404 ¼ 2,560,000 reaction products [32].
To create stereochemical diversity within MCRs there is need for stereoselective
(or -specific) reactions. Since many MCRs involve flat intermediates, like imines
and a,b-unsaturated ketones, they result in the formation of racemic products.
Moreover, often mixtures of diastereomers are obtained if more than one stereo-
genic centre is formed. However, there are several examples known of asymmetric
induction, by the use of chiral building blocks (diastereoselective reactions). For
example, it has been successfully applied to the Strecker, Mannich, Biginelli,
Petasis, Passerini, Ugi, and many other MCRs, which has been excellently reviewed
by Yus and coworkers [33]. Enantioselective MCRs, which generally proved to be
much harder, have been performed with organometallic chiral catalysts and orga-
nocatalysts [33, 34].
An interesting example that shows the possibility of stereochemical diversity, is
the Mannich reaction involving organocatalysis (Scheme 3) [35–37]. By changing
the nature of the organocatalyst (L-proline (20) vs. (3R,5R)-5-methyl-3-pyrrolidi-
necarboxylic acid (25)) the (2S,3S)-syn and (2S,3R)-anti diastereomers 21 and
26 could be formed selectively in high diastereo- and enantioselectivities. The
difference in stereochemical outcome of the two reactions can be explained by
the different steric influence of the pyrrolidine ring. For L-proline (Pathway A),
enamine conformation 24 is favored over 23 due to steric hindrance of the carbox-
ylic acid and the double bond in conformation 23. The facial selection (the re face
of the enamine reacts with the si face of the imine) is controlled by the carboxylic
acid, which activates the imine (transition state I). For organocatalyst 25 the steric
bulk is on the five-position of the pyrrolidine ring instead of the two-position.
This results in a favored enamine conformation 29, with the carboxylic acid and the
PMP PMP
O HN O HN
S R
H R CO2Et
H R CO2Et
COOH
R R
27 COOH 22
Me N N PMP
PMP H O HN
O HN H O PMP
R 25 1-5 mol% N 20 5 mol% S
H S CO Et H + H S CO2Et
2 DMSO CO2Et dioxane, rt
R R R
26 anti 18 19 21 syn
Pathway B Pathway A
O COOH COOH
O O
Me N COOH N COOH PMP N
Me PMP H Me N N N H O
N H H H
N H H H H H
H H H H CO2Et
H R R R
H CO2Et R R
R
II 29 28 23 24 I
Scheme 3 Introduction of stereochemical diversity in the Mannich reaction applying organocatalysis

enamine double bond to the same side. The carboxylic acid will direct the approach
of the enamine to the imine (transition state II) similarly as described for L-proline,
resulting in the formation of anti-diastereomer 26.
Evidently, by taking the enantiomers of the organocatalyst the two enantiomeric
products 22 and 27 (depicted in grey) are accessible, making it possible to access all
four possible stereoisomers for this MCR [36].5
Regarding scaffold diversity it is evident that any single MCR does not lead to
multiple scaffolds, since ideally, three or more components combine to form a
single product (one of the criteria for MCRs). As a result several research groups
have introduced scaffold diversity by combining MCRs with cyclization reactions,
as illustrated in Fig. 5 [40, 41].
This concept of introducing scaffold diversity by intramolecular cyclizations is
nowadays commonly referred to as the build/couple/pair strategy, introduced by
Schreiber in 2008 [42].
The build phase involves the (asymmetric) synthesis of (chiral) building blocks
containing orthogonal sets of functionalities that can be used for the coupling and
subsequent pairing reactions. In this stage, smart selection of building blocks will
lead to a large number of different scaffolds in the pairing (cyclization) stage. The
couple phase involves intermolecular coupling reactions that combine the different
building blocks, resulting in densely functionalized substrates ready for use in the
pairing phase. Considering MCRs as coupling reactions, there is a need for versatile
MCRs that are able to use a lot of different substrates (high FG tolerance/broad
Fg1 Fg2
MCR cyclize
+ couple pair
build
Fg3 Fg4
Fig. 5 The generation of scaffold diversity, by combining MCRs with cyclization reactions6
5
Although the authors used a pre-formed imine, there are several examples known of proline
catalyzed one-pot three component Mannich reactions. However, if aromatic aldehydes are used in
this one-pot procedure, the obtained Mannich products had to be reduced (by NaBH4) to the
corresponding alcohols to avoid epimerization: [38, 39].
6
This figure is a slightly modified figure as published in [40].
substrate scope). Furthermore, it would be ideal that the MCR can provide every
possible stereoisomer, to obtain stereochemical diversity. The pair phase involves
intramolecular coupling reactions (FG pairing reactions [43]) that join the FGs that
were strategically planned in the build phase. Carefully adapting the reaction
conditions in this pairing phase leads to pairing of different FGs, resulting in the
formation of a variety of different scaffolds.
Since the build/couple/pair strategy requires versatile MCRs it is not surprising
that the Ugi reaction is often used for this purpose as coupling reaction. A wide
variety of Ugi (couple) postcyclization reactions (pair) is reported [40, 44]. A small
selection of these sequencing reactions is depicted in Scheme 4 [45–50]. As is clear
from the scheme, by variation of the Ugi building blocks and applying the proper
cyclization reaction, different scaffolds are accessible in only two to three steps. For
example, if 4-bromo-1H-indole-3-carbaldehyde, allylamine, 3-butenoic acid and
isopropyl isocyanide are used as Ugi inputs, the two retained alkene functionalities
in Ugi product 33 allow ring-closing metathesis to afford 34. This product possesses
an aryl bromide and an alkene functionality that can undergo a second cyclization
by a subsequent intramolecular Heck reaction occurring with excellent diastereos-
electivity to afford 35 in 59% overall yield (product is racemic) [45].
MeO
N O Cl
O MeO
CO2Et
O N
NH H 30
H 53% H O
O N O N
N
41 Ugi / Pictet-Spengler 32 NH
O
70% 87%
dr = 3:2 H
dr = 92:8 O
TFA
stereochemistry C9 n.d. Ugi / [2+2] Ene-Enone Photocycloadditions
Ugi / Diels-Alder Spontaneous MeO
Cl
HN O hv
O MeO O
CO2Et MeOH
H N
N H O
N O O N
O N
O
31
41% O N
Pd(OAc)2, dppf H
O OMe O
H n -Bu4NBr, K2CO3 O OMe O
N 1 2 3 NH2 O Grubbs II
N DMF, 80°C H R R R NH
N NH DCM N
O N N Br
N + O Br
N O O
I O
40 39 4 NC 5
OH
R R 33 34
92% 88% N
Cl 73% N 94% H
Cl H
Ugi / Arylation Pd(PPh3)2Cl2
Et3N, DMF
110°C, MW
H
N
N O
I O
O O N
36 H
85% N
XPhos H
Pd(dba)2 BINAP 35 N
Cs2CO3 86% H
dioxane / MeCN (85 / 15) O dr = >98:2
N O
MW, 150°C N Ugi / RCM / Heck
N O
O 37 NH 38
80%
91%
dr = 1:1
Ugi / N-arylation
Ugi / a -CH arylation
Scheme 4 The introduction of scaffold diversity by the Ugi-4CR (couple) and follow-up cycliza-
tion reactions (pair)
In some of the examples, i.e., Ugi/Diels-Alder and Ugi/Pictet-Spengler, the

reactions were performed in a single pot (although step-wise), but in the majority
of the examples the Ugi intermediate was first isolated.
A second, very elegant, example of build/couple/pair strategy in DOS is per-
formed by Schreiber and co-workers (Scheme 5) [51]. This example uses the
Petasis reaction of (S)-lactol 42, L-phenylalanine methyl ester (43), and (E)-2-
cyclopropylvinylboronic acid (44) as coupling reaction, which is followed by a
Ph OH Ph
Ph Br Ph
O O Couple
Build H2N CO2Me Petasis 3-CR HN Couple
CO2Me N CO2Me
+
42 43 EtOH DMF
Ph Ph
NaHCO3
OH OH
45 (85%) 46 (86%)
(HO) 2B 44
Pair Pair Pair Pair Pair Pair Pair

Pd-cat Ru-cat I Ru-cat II Au-cat [Co2(CO)8] NaH mCPBA
MeOH
Ph Ph Ph Ph
CO2Me
MeO2C N MeO2C N MeO2C N
N
Ph O
H Ph Ph
HH H O
OH OH OH H Ph
OH
A (81%) C (85%) E (85%) G (87%)
Pair
N Ph Ph Ph Ru-cat I
O O
N N CO2Me O
MeO2C N MeO N N
Ph
O O
Diels-Alder Ph CO2Me
H H H
OH Ph Ph N
B (89%) D (80%) F (88%) O
Ph
Pair Ph
MeO2C N Pair Pair Pair H (90%)
Ru-cat I Ru-cat II Pd-cat [Co2(CO)8] OH
Ph
H N N
OH
Ph Ph N
O O O Diels-Alder
N O
I (72%) O O N N
N N
Ph
O O
CO2Me
H H
O N O Ph
Diels-Alder Ph N
J (87%) K (70%) O
N N
Ph Ph N
Ph Ph N O
O O OH N
N O N O
N
O O L (80%)
O
H N N HH
HH O
Ph Ph
O Ph
N O
M (65%) N (91%) O (85%)
Pd-cat = [Pd(PPh3)2(OAc)2] : cycloisomerization
Ru-cat I = Hoveyda-Grubbs II : Enyne metathesis
Ru-cat II = [CpRu(CH3CN)3PF6] : cycloisomerization ([5 + 2]-reaction)
Au-cat = NaAuCl4 : cycloketalization
[Co2(CO)8] : Pauson-Khand reaction
NaH : lactonization
m CPBA : Meisenheimer rearrangement
Scheme 5 The use of the Petasis 3CR as coupling reaction and several pairing reactions to afford
15 distinct scaffolds
propargylation to obtain the densely functionalized substrate 46 in >99% de.

Although the Petasis reaction was not sufficient to introduce all required function-
alities, making an additional coupling step necessary, it can easily introduce
stereochemical diversity. This is because the anti-diastereomer is exclusively
formed, directed by the a-hydroxy functionality of the intermediate imine. By
combining both enantiomers of the lactol and the amino acid, four stereoisomers
are accessible. As is common for the build/couple/pair strategy, the scaffold
diversity is created in the pairing phase.
Remarkably, Schreiber was able to use every single functionality of 46. Seven
different highly selective pairing reactions were performed, to obtain seven differ-
ent scaffolds (A–G), which is quite remarkable since they are all obtained from one
single substrate. To come back to a term earlier introduced, this is an example of a
reagent-based approach since a single substrate is converted by different reaction
conditions, producing a diversity of scaffolds [42].
Products F and G were in turn substrates for subsequent pairing reactions to
obtain multicyclic compounds J, N, K, O, and H. Finally, products B, J, and H,
which all comprise a diene functionality could be further converted by a subsequent
Diels-Alder (DA) reaction with 4-methyl-1,2,4-triazolin-3,5-dione to obtain the
highly complex products I, M, and L. This example shows that by applying the
build/couple/pair strategy a collection of 15 highly diverse (and complex) scaffolds
can be obtained in only three to five steps.7
3 Novel Multicomponent Strategies Towards Scaffold Diversity
From the previous examples it is clear that scaffold diversity can be achieved using
MCRs and post condensation cyclizations. However, during the last decade much
work has also been devoted to obtain scaffold diversity by using MCR strategies
exclusively. Besides scaffold diversity, this has also lead to the development of a
number of novel MCRs. These new multicomponent design strategies, to achieve
scaffold diversity, can be divided into four main approaches:
l Single reactant replacement (SRR)
l Modular reaction sequences (MRS)
l Condition-based divergence (CBD)
l Union of MCRs (MCR2)
As will be clear from the following examples, many of these are illustrations of
rationally designed MCRs that could generally only succeed because of chemists’
insight into mechanisms and FG reactivities, although some MCRs are still found
serendipitously.
7
For more examples of the Build/Couple/Pair principle applied in DOS: [52–54].
3.1 Single Reactant Replacement (SRR)
The SRR strategy (Fig. 6), a phrase first introduced by Ganem, involves the
development of new MCRs by systematic assessment of the mechanistic or func-
tional role of each component in a known MCR [55]. In this method one reactant
(C) is substituted for reactant (D) that displays a similar chemical reactivity mode
required for condensation with A and B. By incorporation of an additional reactiv-
ity or functionality into D, the resulting MCR might be directed to a different
outcome, leading to scaffold diversity [55].
Probably one of the first examples of SRR is performed by Ugi and co-workers,
who replaced the carbonyl component 6 of the Passerini reaction by a different
electrophile, i.e., imine 47, which resulted in the well-known Ugi reaction affording
13 (Scheme 6) [29].
Ugi furthermore replaced the carboxylic acid (8) input of the Ugi reaction by
different acidic components 48 to afford various different scaffolds (Scheme 6)
[56]. It is required that the selected components are acidic enough (to activate the
imine) but their conjugated bases should moreover be able to attack the intermedi-
ate nitrilium ion as a nucleophile. Consequently, Ugi was able to use HNCO and
HNCS to afford hydantoin- (49a) and thiohydantoinimides (49b), respectively.
These are formed from the corresponding a-adducts, by an intramolecular acyla-
tion. Also, hydrazoic acid was used, resulting in the formation of tetrazole 50 by
spontaneous cyclization of the a-adduct. By applying water or hydrogen selenide
the corresponding a-adducts are transformed by tautomerization, to obtain the final
products 51a and b, respectively.
Ganem and coworkers changed the carboxylic acid in the Passerini reaction
for a Lewis acid (TMSOTf, 53) to activate the carbonyl compound 6. Reaction
of several carbonyls, morpholinoethylisonitrile 52 and Zn(OTf)2/TMSCl (which
forms TMSOTf in situ) resulted in the formation of a-hydroxyamide 56 (Scheme 7).
Ganem realized that a neighboring stabilizing group like in this example the
morpholine ring, was required to stabilize the nitrilium ion 54 (formed by attack
of the isonitrile to the activated carbonyl), since simple isonitriles did not result in
A + B + C A C B
SRR
A B
A + B + D
D
Fig. 6 Schematic representation of the single reactant replacement (SRR) strategy to scaffold
diversity
Y H
R3 N 5
N R
H R1 R2
N N
Y = O (51a), Se (51b) H
N N
N R5
2
R3 R1 R
HX = H2O, 50
H2Se
HX = HN3
R1 R2
R5 R5 R3
O 5 N 3 N
+ R – NH2 + R –N C + HX N U-variant 4CR
2 HX = HSCN,
R1 R R1 R
2
Y N
HOCN H
6 12 47 7 48
Y = O (49a), S (49b)
SRR2
O R5
O R5 O
+ R5– NH2
N 3 R3 N R4
+ R –N C + N U-4CR
R 1 R2 1 2 R4 OH H R1 R2 O
R R
6 12 47 7 8 13
SRR1
O O O
+ R3 N C + R3 O R4
1 2 4 N P-3CR
R R R OH
H 2
6 7 8 R1 R O
9
Scheme 6 One of the first examples of SRR performed by Ugi and co-workers
any reaction [57]. These mechanistic insights lead Ganem to study other donating
groups at the isocyanide component, applying, for example, isocyano esters or
amides (57). Indeed, the esters and amides were able to function as stabilizing
group, leading to the formation of ethoxy- and morpholinooxazoles 60 [57].
Further SRR could be achieved by replacing carbonyl 6 to imine 61, which
resulted in the formation of bis-amino oxazoles 65 (catalyzed by a Brønsted acid).8
Finally, our research group serendipitously discovered the formation of N-(cyano-
methyl)amides 70 when primary a-isocyanoamide 67 was used as an input
(Scheme 7, SRR4, Brønsted acid was applied only with primary amines) [60].
The mechanism of this reaction will be discussed further in Sect. 3.3.
Another nice example of SRR is depicted in Scheme 8. The original reaction was
developed by Diels and Harms in 1936 [61]. Reaction of isoquinoline 71 with
dimethyl acetylenedicarboxylate (DMAD, 72) initially forms zwitterionic interme-
diate 73, which is reacted with a second equivalent of DMAD to form benzoqui-
nolizine 74. This is, however, not a true 3CR reaction, since two components are
identical. In 1967, Huisgen reported three variations of this reaction in which
8
It has to be noted that this reaction was first developed by Zhu and coworkers in 2001, even before
the previous mentioned carbonyl variant of Ganem and co-workers: [58]. Later on, Ganem
published a similar reaction with unsubstituted isocyanoamides: [59].
O O O
3 4
+ R3 N C + R O R
R
1 2 4 OH N P-3CR
R R H R1 R2
7 O
6 8
9
1
SRR
TMS
C O 1 TMS
N R O O O O
Zn(OTf )2 / TMSCl 1
O O 2 R H2O N OH
+ lewis acid R 2 N
2 + N N R H 1 2
R
1
R 53 N N R R
O N 56
6
52 2 54 55
SRR
TMS
O 1 TMS TMS
R O
O O 1
R
1
O Zn(OTf)2 / TMSCl
2 R
C R 2
N 2
1
R
2 +
X
+ lewis acid O N O R O R
R
53 X N X N
6 X = OEt,
57 morpholino
X
58 59 60
3
SRR
4
R 4 4
3 R R
R N
1 3 3
R R N R N
2 1 1
R R R
3 4
R R O O R
2
O R
2
N C O N
+ N + bronsted acid
X N X N
1 2 X
R R 5 X 5
61 R R
63 64
X = NMe2, 65
62 morpholino
O 4
R
1
+ HN R3
2
R R 4
SRR
6 66
2 4 2
R R 1
1 R R 4
R N R 1 2
3 4 3 O N N H R R 4
R R O C R 3 N R
N C + bronsted acid N R N
+ N O N N
H2N H 5
O 3
1 2 5 R R
R R 5 5 R
R H NH R H
61 67 69
68
Scheme 7 Four successive SRRs, resulting in four new scaffolds
intermediate 73, a 1,4-dipole, is trapped with several different dipolarophiles, such

as dimethyl azocarboxylate 75, diethyl mesoxalate 77 and phenylisocyanate 79 to
form tricyclic scaffolds 76, 78 and 80, respectively [62]. Other examples of
replacement of the second equivalent of DMAD have been published by Nair
et al. who applied 2,5-dimethyl-1,4-benzoquinone 81 to obtain spiro[1, 3]oxazino
[2,3-a]isoquinoline derivative 82, N-tosylimines 83 to afford 2H-pyrimido-[2,1-a]
isoquinolines 84 and arylidinemalononitriles 85 to yield tetrahydrobenzoquinoli-
zine derivatives 86 [63–65]. Recently, Yavari et al. reported a 3CR to pyrrolo[2,1-a]
isoquinolines 88, by reacting 71, 72, and aroylnitromethanes 87 in good yields [66].
The reactions reported here, obtained by SRR, are all one-pot 3CRs. For additional
MCRs involving intermediate 73, see [67–74].
From the reported examples in this paragraph9 it is clear that SRR is a fast way of
developing new MCRs and extremely useful for application in DOS, since it can
quickly afford many different scaffolds.
9
In addition to the examples reported here there are several other publications that apply SRR to
achieve new scaffolds, thereby discovering new MCRs: [55, 75, 76].
N CO2Me
N
MeO2C N CO2Me
N CO2Me N CO2Me
CO2Me
MeOOC CO2Me 76 O CO2Me

COOMe EtO2C CO2Et
74 O
MeO2C 78
N
EtO2C CO2Et
N
MeO2C 77
DMAD, 72 CO2Me
75 N
PhNCO
79 N
Ph CO2Me
CO2Me O
80
N CO2Me
+ O O
N
CO2Me CO2Me
71 DMAD, 72 73 81
N CO2Me
H
O 2N O
COAr CN CO2Me
Ts
87 Ar N
CN
85 Ar 82
83 O
N N CO2Me
CO2Me N CO2Me
N
Ts CO2Me
ArOC NC
88 CO2Me CO2Me
NC Ar
Ar 84
86
Scheme 8 Replacement of DMAD in the original reaction to 74, by different third components
yielding several new isoquinoline based MCRs
3.2 Modular Reaction Sequences
The second MCR development strategy leading to scaffold diversity involves MRS
(Fig. 7), which is closely related to SRR but involves a versatile reactive interme-
diate that is generated from substrates A, B, and C by an initial MCR. This
intermediate is then reacted in situ with a range of final differentiating components
(D, E and F) to yield a diverse set of scaffolds.
One striking example is the use of 1-azadiene 92 as intermediate to scaffold
diversity which is generated in situ from a phosphonate 89, a nitrile 90 and an
aldehyde 91 via a 3CR involving a Horner–Wadsworth–Emmons (HWE) reaction
(Scheme 9) [77, 78].
In 1995, Kiselyov reported the first MCR involving this 1-azadiene which he
reacted with sodium or potassium salts of aryl-substituted acetonitriles 93 to afford
2-amino pyridines 94 in 61–72% yields (three examples, R1 ¼ H, R2 ¼ R3 ¼ Ar)
[79]. Furthermore, he reacted the 1-azadiene with sodium enolates of methyl aryl
ketones 95 to afford 2,4,6-substituted pyridines 96 in 63–67% yield (three examples,
R1 ¼ H, R2 ¼ R3 ¼ Ar) [79].
B
A D
C
D
B B
A B E
+ A A E
C
C F C
versatile reactive
intermediate B F
A F
C
Fig. 7 Schematic representation of the modular reaction sequence (MRS) strategy to scaffold
diversity
Ten years later, Kiselyov published an extension of this work, by reacting the
1-azadiene 92 with amidines (97, R4 ¼ alkyl, aryl) and guanidines (97, R4 ¼
NHR) to afford the polysubstituted pyrimidines 98 in 22–73% yield. This MCR
proved to have a rather high substrate scope since all components could be varied to
some extent (19 examples, R1 ¼ H, alkyl, Ph, R2 ¼ R3 ¼ Ar)10 [80]. Furthermore,
the one-pot reaction of 92 with 5-amino pyrazoles (99, X ¼ N, Y ¼ C) and 2-
amino imidazoles (99, X ¼ C, Y ¼ N) resulted in the formation of bicyclic com-
pounds 100 and 101 (12 examples, 52–77%, R1 ¼ H, R2 ¼ R3 ¼ Ar) [81]. In
another one-pot procedure, Kiselyov reacted 92 with the dianion of methyl imida-
zolyl acetates 102 to yield imidazo[1,2-a]pyridines 103 (12 examples, 54–75%,
R1 ¼ H, R2 ¼ R3 ¼ Ar) [82].
Our group has also contributed to these 1-azadiene derived MCRs by reacting 92
with isocyanates 104 to selectively afford functionalized 3,4-dihydropyrimidine-
2-ones 105 (29 examples, 15–90% yield) [83, 84] and triazinane diones 106
(17 examples, 25–91% yield) [85, 86] depending on the nature of the isocyanate
(Scheme 9). The use of isocyanates with strongly electron-withdrawing groups
(Ts, p-NO2Ph, CO2Me, C(O)Ph) resulted in the exclusive formation of the dihy-
dropyrimidones 105, while isocyanates with less electron-withdrawing (Ph, PMP)
or donating substituents (Et, benzyl) resulted in the formation of triazinane diones
106. Dihydropyrimidones are most likely formed by nucleophilic attack of the
1-azadiene nitrogen to the isocyanate (with electron-withdrawing substituent),
10
The use of phosphonates with large R1 substituents resulted in a significant decrease in yield, 22–
39% for R1 ¼ Ph and i-pentyl.
O
1
EtO P R
EtO
89
+
R3
R3 R3 R2CN R3CHO
4 R1 R4
R1 R MW R1
N S 90 91
R4 R2 N R5
R2 N S R2 N N
H H 4 5
94 R = Ar, R = NH2
109 108 R4 = alkyl, aryl n BuLi R4
4 5
96 R = H, R = Ar
R4NCS
CN
107
93 O
4
R 5
R
95
3
R NH2 R3
O
R1
R4 4
R R NCO
4 R 4
NH HCl R1
N N N
R2 104 97
R2 NH R2
R3 N O N R4
H DIPEA
R1 92 98
106 R4 = alkyl, aryl R
4 R4 = alkyl, aryl,
Y NH-alkyl, NH-aryl
NH2
4 X N
R NCO
N N H 99
104
R3
3
R EWG R1
4 102 N
R1 R
N R
3
R2 N Y
R2
N O R1 EWG X R4
H
4
105 R = Ts, p -NO2Ph, 100 X = N, Y = C
R2 N N 101 X = C, Y = N
CO2Me, C(O)Ph
103
Scheme 9 Modular reaction sequence involving the 1-azadiene 3CR as initial MCR, to which
several fourth components were added
followed by cyclization. On the other hand, when isocyanates with less electron-
withdrawing or donating substituents are used, the initial condensation product (of
the 1-azadiene to the isocyanate) can act as a nucleophile and react with a second
equivalent of isocyanate, which can then ring-close to afford the thermodynami-
cally favored six-membered triazinane diones. Both reactions showed to have a
broad substrate scope (appendage diversity) and the R2 and R3 substituents could
be varied extensively. However, variation of the R1 substituent was limited (only
H and Me).
A modification of the dihydropyrimidone MCR was performed by applying
isothiocyanates 107 as the fourth component, which resulted in the formation of
2-aminothiazines 108 which upon microwave heating could rearrange (Dimroth
rearrangement) to dihydropyrimidine-2-thiones 109 [87].
A second example that uses MRS was reported by Zhu and coworkers. They
combined the bis-amino oxazole (113) MCR with primary amines, discussed earlier
in the SRR paragraph, with a subsequent N-acylation using a,b-unsaturated acyl

chloride 114 (fourth component) affording polysubstituted pyrrolopyridinones 119
(Scheme 10) [58, 88]. After acylation and upon heating, the formation of 119 can be
explained by an intramolecular DA reaction affording the bridged tricyclic inter-
mediate 116. Subsequent base-catalyzed retro-Michael cycloreversion, with loss of
morpholine (117) and final tautomerization gives 119.
A variation of this reaction (Scheme 10), which involves the same intermediate
oxazole MCR product 113, uses activated alkynoic acid derivatives 120 as the
acylating agent (fourth component) [89]. The resulting intermediate again under-
goes an intramolecular DA reaction, followed by a retro-Diels Alder, resulting in
the loss of nitrile 123 and giving dihydrofuropyrrolone 124. This product itself is a
diene that can react with dienophile 125 (fifth component) in a second DA reaction,
to give hexasubstituted benzenes 127 after loss of water. Since these steps all occurs
in one pot, this reaction has evolved from a three- to a 5-component reaction by
applying a very elegant modular reaction sequence. All together, three different
highly functionalized scaffolds have been developed, originating from a single 3CR
towards bis-amino oxazoles (Scheme 10).
In summary, MRS have proven to be extremely useful for the fast generation of
scaffold diversity. It can be argued that these example belong to the SRR strategy.
However, since the intermediate is formed by a MCR, we have divided this as a
2
O R R1
2 R1 R1 2
R N retro- 2 R
N R4 O R N N
aza-DA O Micheal N
N R3
O N
R1 N O R3 O
H NEt3 O
N R3 R4 119
N R4 HO
115 R3 HN O O R4
116 118
O 117
Et3N Cl R4
toluene,
110°C, 12h O 114
O 2
R O O
NH2 2
R1 R
2 NH R
2
R4 –H2O R R4
NH4Cl N N
110 + 111
R1 O
O N O N O
toluene, 60°C
N O
R1 O R1
N
NC
N R5 R6 R 5 R6 127
113 R3 126
O R3
O
112
Et3N
toluene, X
R5 R6 toluene,
110°C, 12h R4 125 110°C,
X = Cl, OC6F5 12h
DA
120
O O O
2
2 2 R4 R R4
R R retro-DA N
N aza-DA N
R4 N O
R1 O R1 O –R3CN R1 O
N N
N 123
N R1 124 O
121 122
R3
Scheme 10 Modular reaction sequences reported by Zhu and co-workers, involving an initial
bis-amino oxazole MCR
separate strategy. The generation of the intermediate via a MCR gives the possibility
for easy appendage diversity, since generally all the components can be varied.
3.3 Condition-Based Divergence
CBD in MCRs (Fig. 8) generates multiple molecular scaffolds from the same
starting materials by merely applying different conditions. It is evident that for
reactions involving simultaneous molecular interactions of three or more compo-
nents, different potential reaction pathways leading to different products are acces-
sible. A good MCR follows one pathway selectively. However, it is certainly of
great interest to modulate the selectively to a different pathway by changing the
reaction conditions, which is the major goal of CBD [90].
For example, depending on the catalyst, solvent or temperature that is used, a set
of inputs A, B and C may react via different pathways to produce distinct scaffolds.
As can be understood this is not a simple task, which is expressed by the limited
amount of reported examples.
In 2008 Liu et al. demonstrated this concept by the organocatalytic asymmetric
one-pot 3CR of aldehydes 128 (generally aromatic), diethyl a-aminomalonate 129
and nitroalkenes 130 (Scheme 11) [91]. By altering the organocatalyst they could
selectively obtain either Michael addition product 132 or [3 þ 2] dipolar cycload-
dition product 134. In the absence of a catalyst, reaction control generally proved to
be poor. Initially, for both reaction pathways, a-imino esters are formed in situ by
reaction of the aldehyde with the a-aminomalonate. The use of organocatalyst 131,
which activates both the a-imino ester (producing an azomethine ylide) and the
nitroalkene (via a doubly hydrogen-bonded interaction), resulted in the selective
formation of Michael adduct 132 with high enantioselectivity (16 examples,
B
A C
.1
nd
B
co
A B cond.2
+ A C
co
C
nd.
3
Fig. 8 Schematic
representation of the A B
Condition Based Divergence
(CBD) strategy to scaffold C
diversity
CF3
N N CF3
H H O2N R
N
131 10 mol%
CO2Et
toluene, 4Å MS, 0°C Ar N CO2Et
132
O EtO2C
CF3
NH2
Ar H EtO2C S
+ 129
128
NO2 CF3
N N
H H
Ar N Ar
R 130 Ar = 3,5-F2Ph R
O2N
133 20 mol%
CO2Et
Ar N
MTBE, 4Å MS, –20°C H CO2Et
134
Scheme 11 Reaction control in the 3CR of aldehydes diethyl a-aminomalonate and nitroalkenes
48–95%, 94–98% ee). This product is stable and does not react further to form the
cycloaddition product 134.
When, on the other hand, organocatalyst 133 (possessing a bulky 2,5-diaryl-pyrrole
moiety) is applied, product 134 was selectively formed by a highly diastereo- and
enantioselective 1,3-dipolar cycloaddition (11 examples, 56–90%, 60–91% ee). This
reaction most likely involves activation of the nitroalkene by the thiourea, via the
earlier mentioned doubly hydrogen-bonded interaction, followed by a concerted
attack of the in situ formed azomethine ylide (this ylide is not activated by nor
coordinated to the organocatalyst, because of the bulky, nonbasic pyrrole group, but
is most likely formed via a 1,2-prototropic rearrangement [92]).
Although Liu et al. established the formation of two different reaction products
starting from the same three components, the degree of structural diversity is rather
limited, since Michael product 132 is formally an intermediate to 134 (although this
product is presumably not formed step-wise but concerted). Nevertheless, both
products are formed under high stereocontrol, and the enantiomeric products are
theoretically accessible by taking the enantiomeric organocatalysts giving rise to
stereochemical diversity.
In 2008, Chebanov et al. reported an excellent example of condition base
divergence by the MCR of 5-amino pyrazoles 135, cyclic 1,3 diketones 136 and
aromatic aldehydes 137 (Scheme 12) [90].11 5-Amino pyrazoles 135 have at least
11
Several other research groups have been involved in MCRs with aminoazoles, 1,3-diketones and
aldehydes. For a recent overview see: [93].
Ar O Ar O
Ph
N N
N Ph
R R
N N N
H R H R
H
139 144
Hantzsch-type EtOH, Et3N Biginelli-type
150 °C
(MW or conventional) EtOH, sonication
15 min. rt, 30 min.
–H2O O –H2O
R
Ar O Ph O
Ph 136 R Ar O
NH2
N N O N N
N H + Ph
R R
N N 135 Ar H
H R N
H OH 137 H OH R
138 143
EtOH, t BuOK
150 °C
Nu-
(MW or conventional)
15 min.
Ph Ar O Nu
OH R
Ar
N R
R N
N N
H H OH R
N NH O
140
142
–Nu–
Ph Ar O Nu
N
R
N N
H H OH R
141
Scheme 12 Tuning the 3CR to three different scaffolds by adapting the reaction conditions
three nonequivalent nucleophilic centers (N1, C4, NH2), but the authors were able
to drive the reaction to three distinct scaffolds 139, 142, and 144 by changing the
reaction conditions.
Under reflux conditions in ethanol, a mixture of 139 and 144 was always
obtained. However, performing the reaction at 150 C in a sealed vessel (MW or
conventional heating) in the presence of NEt3 led to the exclusive formation of
Hantzsch product 139 (eight examples, 70–91% yield). This indicates that the
Hantzsch product is most likely the thermodynamic product in this transformation.
Although a thorough mechanistic study was not performed, the reaction likely
proceeds via intermediate 138, which upon loss of water provides Hantzsch
product 139.
In their search for the optimal base for the selective formation of 139, the authors
unexpectedly found a different reaction product, namely 142 (nine examples,
38–75% yield). This product is formed when a nucleophilic base such as sodium
ethoxide or potassium tert-butoxide was used instead of NEt3 (under otherwise
identical reaction conditions as for the formation of 139). The formation of 142 is
explained by nucleophilic attack of ethoxide or tert-butoxide to intermediate 138
followed by a ring-opening/recyclization.
Conversely, neutral and ambient conditions lead to the formation of the kineti-
cally controlled Biginelli product 144 (eight examples, 51–70%). The authors
found that sonication was required to obtain the final product, since simple stirring
of the three components at rt did not result in any desired reaction. They explained
this observation by the improved mass transfer through cavitation phenomena.12
This reaction presumably involves intermediate 143.
Recently, our group also contributed to CBD as a tool for DOS. By judicious
selection of the reaction conditions, the 3CR between a-acidic isocyanides 145
(isocyano amides13 and isocyano esters14), carbonyl components 6 and primary
amines 146 could be directed towards either 2H-2-imidazolines 150 or trisubsti-
tuted oxazoles 152 (Scheme 13) [98].
By applying 2 mol% AgOAc as the catalyst 2-imidazolines 150 were obtained
selectively, while the use of a Brønsted acid (for R4 ¼ NR2) or a polar aprotic
solvent (for R4 ¼ OR) selectively provided the corresponding oxazoles 152. The
formation of 2-imidazolines 150 can be mechanistically explained by coordination
of the isonitrile carbon to Ag+, which enhances the a-acidity of the isocyanide
(Pathway A), and blocks the nucleophilicity of the isonitrile (preventing pathway
B). Upon loss of a proton the isocyano anion 147 can perform a Mannich type
addition to the iminium ion 148, which subsequently cyclizes to form the
2-imidazoline 150 after a final proton shift. When, on the other hand, a Brønsted
acid is applied (Pathway B), the slight decrease in pH will lower the concentration
of the isocyanide a-anion, thereby making the imidazoline pathway less favorable
(Pathway A). Since the imine is activated by the Brønsted acid, the isonitrile carbon
of 145 can attack the iminium ion 148 as a nucleophile, leading to nitrilium
intermediate 151. After proton abstraction and ring closure oxazole 152 is formed.
For isocyano esters, however, the use of methanol and Brønsted acid was not
12
Propagation of ultra sound waves into the liquid medium results in a series of high-pressure
(compression) and low-pressure (rarefaction) cycles, with rates depending on the frequency.
During the low-pressure cycle, high-intensity ultrasonic waves generate small vacuum bubbles
in the liquid, which can reach a volume at which they are not stable anymore resulting in a violent
collapse. This phenomenon is termed cavitation: [94, 95].
13
It has to be noted that the formation of oxazoles using isocyano amides has been well studied by
Zhu and co-workers (see [58, 59]). With the work of Elders et al. the oxazole MCR has been
expanded with a wide range of isocyano esters. The MCR with isocyano amides can now also be
directed to the 2-imidazolines.
14
The directing properties of the MCR involving isocyano esters could exclusively be performed
using a-aryl isocyano esters, since the use of a-alkyl isocyano esters always resulted in the
formation of 2-imidazolines, in various solvents, even without AgOAc, see [96] and [97].
R2 R3
O Ag
R1 N H C
H N
R5 R4
N C N R2 +
R4 Ag R 3 R5
O
149 148 147
+ Ag
–Ag Pathway A – H2O
O
C
R2 R3 N O
MgSO4 R4 R4 1 2
N MgSO4 O R R
R1 AgOAc 145 R5 + R1 R2
R5 6 N HN R3
N MeOH, rt R 3
MeOH, Et3N•HCl (R4 = NR6R7), 60°C R5
R4 4 6 7 NH2 or DMF (R4 = OMe), rt 152
O R = OMe, NR R Oxazole
150 146
2-Imidazoline
+H
Pathway B –H
–H2O
R1 R2
O
C H O R3
N C N
R4 R2 N N H
+ R3 R4
5
R5 H R
R1
151
145 148
Scheme 13 Directing the MCR of a-acidic isocyanides, carbonyl components and primary amines
towards 2H-2-imidazolines 150 and trisubstituted oxazoles 152 and their proposed mechanisms
sufficient to exclusively form the oxazole, since polar protic solvents turned out to
promote the formation of 2-imidazolines [96]. The use of aprotic solvents seemed
to be the best choice for directing the 3CR with isocyano esters to the trisubstituted
oxazoles (best results were obtained with DMF).
An elaboration of this work involves the 3CR between primary a-isocyanoa-
mides 67, carbonyl components 6 and primary amines 146, which could be directed
towards either 2H-2-imidazolines 153 or N-(cyanomethyl)amides 156 by
Ag+-catalysis vs. Brønsted acid mediated reaction, respectively (Scheme 14) [60].
The selective formation of N-(cyanomethyl)amides 156 (also earlier mentioned in
the SRR approach, Scheme 7) can be rationalized by the same criteria as the
formation of trisubstituted oxazoles 152 (Scheme 13), since the use of a Brønsted
acid, prevents the formation of 2-imidazolines 153 by the decreased pH. By
applying a Brønsted acid, the reaction initially proceeds via the same mechanism
as for the oxazole MCR. However, when intermediate 155 is formed, it does not
tautomerize to form the 5-aminooxazole 157. Instead, proton abstraction at the
exocyclic imine nitrogen and subsequent ring opening gave the corresponding
N-(cyanomethyl)amides 156.
Again Ag+ catalysis promotes the formation of 2-imidazolines 153, for the same
reasons as discussed before.
In conclusion, the CBD approach makes it possible to obtain scaffold diversity
starting from the same reaction inputs by adapting the temperature, reaction
promoter or solvent.
3 O O
R2 R MgSO4 C MgSO4
H R1 R2
N N Et3N•HCl N
R1 AgOAc H2N R1 R2 N R3
4 4 N
R N 67 R + 6 4
1
MeOH, rt
2
MeOH, 60°C R O H
H2N R = R = Me R3
O 156
R 3 = Bn
153 146 NH2 N-(cyanomethyl)amide
2-Imidazoline
4 21-97%, 13 examples
39% R = H
48% R4 = Ph +H –H
–H2O
2 1
R R1 R2 3 N 1 H2N O R
R1 O R H O R R2
O CN R2
C + HN H N 3
N 3 N H 4 N HN R3 R4 N HN R
H2N R R
148
H R4 157
R4 H 5-aminooxazole
154
67 155
Scheme 14 Directing the MCR towards 2H-2-imidazolines 153 and N-(cyanomethyl)amides

156 and the suggested mechanism for the formation of N-(cyanomethyl)amides 156
3.4 Union of MCRs
The Union of MCRs (MCR2, Fig. 9) is a fourth strategy for the rational design of
novel MCRs that combines two (or more) different types of MCRs in a one-pot
process.
The presence of orthogonal reactive groups in the product of the primary MCR
(which is either formed during the primary MCR or present in one of the inputs)
allows the union with the secondary MCR [17, 99]. By varying the secondary MCR
(e.g., by addition of inputs E/F or G/H), diverse (and complex) scaffolds will be
available, making this strategy excellent for application in DOS.
The combination of MCRs in one pot is not new. It was first introduced by
Dömling and Ugi who developed a 7-component reaction (7CR), that was basically
a one-pot combination of a modified Asinger 4CR and U-4CR (Scheme 15) [100,
101]. In this 7CR, an a- or b-bromo/chloro aldehyde 158, NaSH/NaOH, NH3,
another aldehyde 161, an isocyanide 166, CO2, and a primary alcohol (solvent)
are combined to afford 167 efficiently. However, NaSH/NaOH, NH3 and CO2 are
invariable components in this reaction which limits the substitutional diversity
(appendage diversity) and thereby the scope of the MCR.
Another example, also reported by Ugi and co-workers, is the combination of an
Ugi five center 4-component reaction (U-5C-4CR) with a Passerini-3CR
(Scheme 16) [102]. This one-pot procedure uses an a-amino acid (L-aspartic acid,
168) as a 2-center-1-component input, which explains the origin of the U-5C-4CR.
The reaction mechanism most likely involves an initial condensation of the
amino functionality of the a-amino acid 168 with the aldehyde 169 to form iminium
ion 171. After a-addition, intermediate 172 is formed which is attacked by the
solvent methanol, to form derivative 174 after rearrangement. This compound still
has a free carboxylic acid, which can undergo a P-3CR in the same pot to afford
175. The drawback of this procedure is that two equivalents of the aldehyde and
isonitrile inputs are used, which also limits the substituent variability.
A B D E
E F
C
A B D MCR2
MCR1 A B D
+
C G H
C G
H
A B D
Fig. 9 Schematic representation of the union of MCRs (MCR2) to scaffold diversity
CO2 R3OH
163 164
R4
O HN O
R3 + R4NC O
NaXH 1 1
O 159
R HO O R R3
n O N 165 166 N O
Y = O, S Asinger 4CR
Y H
R2 H n X R2 Ugi reaction n X R2
R1 +
161 162 167
158 NH3
Y = Cl, Br 160
n = 0, 1
Scheme 15 Asinger 4CR-Ugi 4CR, a one-pot 7-component reaction
In 2009, our group demonstrated that the MCR2 strategy can also be used to
obtain complexity as well as scaffold diversity (Scheme 17) [103]. The strategy is
based on the abovementioned 3CR to 2H-2-imidazolines (reacting an isocyano
ester, aldehyde or ketone and an amine) that shows extraordinary FG and solvent
compatibility [96]. By incorporation of a second orthogonally reactive group in one
of the starting materials, this MCR can be coupled to a second MCR.
This concept has been demonstrated by the use of diisocyanide 176 in the
2-imidazoline MCR. These two isocyanide functionalities show intrinsic different
reactivities, resulting in the chemoselective formation of 2-imidazoline 177.15 The
retention of the isocyanide moiety in 177 provides an handle for subsequent
isocyanide based MCRs.
The goal of obtaining different final scaffolds has been demonstrated by varying
the secondary isocyanide based MCR. Since the 2-imidazoline MCR can be
performed in a wide range of solvents, the solvent of the one-pot procedure will
15
The a-isocyanide is a-acidic and will react in the 3CR to yield 2H-2-imidazolines, while the
other isocyanide is an aliphatic isocyanide and remains unaffected.
O NH
O
OH CH3OH
O O
173 H
O
OH
+ 2 H + 2 NC N
N
O
H2N H
O O
168 O 169 170 175
O
–H2O
+ NC
U-5C-4CR P-3CR H
169 170
OH O
171
HO OH
O
O O H O
HN HN H
O N O
O O N
173 H
N O O
N 172 174
170
Scheme 16 Mechanism of the Ugi-5C-4CR [ Passerini-3CR
be selected based on the optimal solvent for the secondary MCR. For example, the
2-imidazoline MCR has been combined with the Passerini MCR to give 180 and
181. This one-pot MCR2 reaction has been performed in CH2Cl2, since this is the
best solvent for the Passerini reaction. The initial MCR could also be combined
with the U-4CR (in MeOH) to give 184, an Ugi variant [104] (in MeOH) using the
tethered keto acid, levulinic acid (188), to give 189 and with a recently reported
3CR towards highly substituted 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives
186 [105] (in EtOH), to yield 187.
The possibility of obtaining scaffold diversity by the MCR2 strategy has been
further demonstrated using the N-(cyanomethyl)amide 3CR [60] (discussed earlier)
as the primary MCR [103]. By applying the primary a-isocyano amide derivative of
176, this MCR could be connected to the Passerini, the Ugi and the Ugi Smiles
[106, 107] MCRs resulting in various new scaffolds.
Interestingly, it was even possible to combine the 2-imidazoline and the
N-(cyanomethyl)amide 3CRs with the U-4CR to afford a novel 8-component
reaction, which is a landmark in this field [103].
In conclusion, the MCR2 strategy has proven to be a useful tool to achieve
complex scaffolds in a simple one-pot procedure. Furthermore our group has
demonstrated that by choosing MCRs that show unique solvent and FG tolerance
as the primary MCR, these can be easily coupled to various secondary MCRs to
produce several new scaffolds.
N
O
H
N N
O O O
+ O MeO O
5 6 7
R R HO R
178 179 180, 69%, dr = 1:1
DCM, rt
N
P-3CR O
H
N N
O
O MeO O
181, 41%, dr = 1:1
O O Ph
+ HO +
H NH2 N
O
169 182 183 H
N N
N
MeOH, rt O MeO O
U-4CR
184, 69%, dr = 48:52

O 3
2
O CN R R
1 2 1
R R MgSO4 R N
4 NC 6
R O
+ 3 4 N
R solvent, rt R O
176
NH2 O
177
NC 146
O NC NH2
R = Me, Et N
H
Ph + NC NC N N
NH2 N
185 186
EtO O
NC N
TsOH (2 equiv.) H
EtOH, rt
187, 53%, dr = 1:1
O Ph
HO + NH 2
O N
188 O 183 N H
N N
MeOH, rt
Ugi variant O MeO O
189, 78%, dr = 47:53
Scheme 17 MCR2 using diisocyanide 176 in the initial 2-imidazoline MCR
4 Concluding Remarks
Diversity-oriented synthesis of small molecules is a great challenge for synthetic

organic chemists. DOS requires the development of new methodologies that gener-
ate scaffold diversity in addition to appendage and stereochemical diversity.
MCRs have been demonstrated to be extremely useful for DOS, since these
complexity-generating reactions can easily be combined with several follow-up
cyclization reactions resulting in the rapid synthesis of diverse (heterocyclic)
scaffolds. Furthermore, novel MCR design strategies have emerged as important
tools to generate scaffold diversity. Four different approaches (SRR, MRS, CBD
and MCR2) have been applied, which all led to the development of new MCRs and
higher order MCRs, thereby addressing both molecular diversity and complexity.
Most examples described in paragraph 3, however, did not address the concept
of stereoselectivity, since nearly all products products obtained were isolated as
racemic mixtures and/or mixtures of diastereomers. The development of stereo-
selective MCRs (to be able to introduce stereochemical diversity) remains a major
challenge for the future.
Acknowledgment This work was performed with financial support of the Dutch Science Foun-
dation (NWO, VICI grant).
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DOI: 10.1007/7081_2010_42
Recent Developments in Reissert-Type

Multicomponent Reactions
Nicola Kielland and Rodolfo Lavilla
Abstract The chapter reviews the classic Reissert reaction, the keystone of a broad
family of multicomponent reactions involving azines, electrophilic reagents and
nucleophiles to yield N,a-disubstituted dihydroazine adducts. The first sections deal
with the standard nucleophilic attack upon activated azines, including asymmetric
transformations. Section 5 focuses on the generation of dipolar intermediates by
azine activation, and on their subsequent transformation; chiefly in cycloadditions.
Lastly, Sect. 6 is primarily devoted to a special branch of this chemistry involving
isocyanides. It also covers the reactivity of dihydroazines and reviews the mechanistic
proposals for related reactions.
Keywords Azines Isocyanides Multicomponent reactions Reissert reaction
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
2 Range of Activating Agents in Reissert-Type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
3 Range of Nucleophiles in Reissert-Type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
4 Asymmetric Reissert-Type Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
5 Dipole Formation and Domino Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
6 MCRs Involving Azines and Isocyanides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
N. Kielland and R. Lavilla ð*Þ

Barcelona Science Park, University of Barcelona, Baldiri Reixac 10-12, 08028 Barcelona, Spain
e-mail: rlavilla@pcb.ub.es
128 N. Kielland and R. Lavilla
Abbreviations
3CR Three component reaction

4CR Four component reaction
Al2O3 Alumina
Boc tert-Butoxycarbonyl
Boc2O Di-tert-butyl dicarbonate
Cbz Carbobenzyloxy
CO2 Carbon dioxide
DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
DHP Dihydropyridine
E Electrophile
FMOC 9H-fluoren-9-ylmethoxycarbonyl
HF Hydrogen fluoride
IBX 2-Iodoxybenzoic acid
ICl Iodine monochloride
KOH Potassium hydroxide
LDA Lithium diisopropylamide
MC Multicomponent
m-CPBA m-Chloroperoxybenzoic acid
NMDA N-methyl D-aspartate
Nu Nucleophile
O3 Ozone
PINAP N-(alkyl(phenyl)methyl)-4-(2-(diphenylphosphino)naphthalen-1-yl)
phthalazin-1-amine
POCl3 Phosphorus (V) oxychloride
TCAA Trichloroacetic anhydride
Tf2O Triflic anhydride
TFAA Trifluoroacetic anhydride
THF Tetrahydrofuran
TMS-CN Trimethylsilyl cyanide
TMS-N3 Trimethylsilyl azide
TOSMIC p-Toluenesulfonylmethyl isocyanide
1 Introduction
Multicomponent reactions (MCRs) have recently become a fruitful route to synthe-

sizing diverse scaffolds in single-step operations [1, 2]. Perhaps the most attractive
strategy in this field, and one which is widely employed, is the use of reactants
bearing functional groups featuring complementary (ambivalent) reactivity: those
Recent Developments in Reissert-Type Multicomponent Reactions 129
which can interact with two or more distinct species. Isocyanides are the paradig-
matic example of Type I MCR reagents (see Type I in Scheme 1). Their carbene-like
electronic structure enables formal addition of nucleophilic and electrophilic part-
ners, thereby leading to MCRs. Other functional groups display this behavior, and
combinations of these constitute the core of a family of MCRs marked by high
bond-forming efficiency and structural diversity [3]. Electron-deficient alkenes and
alkynes have often been employed with this purpose in MCRs. Arynes, in which the
nucleophile and the electrophile react at two contiguous positions, are another
relevant group (Type II in Scheme 1). Imines, which have a nucleophilic nitrogen
linked to an electrophilic carbon atom, are among the most used components in
many classic MCRs and also participate in processes of this type. As such, azines
could be regarded as heterocyclic surrogates of imines and thus, are a useful source
of reactive inputs for this chemistry (Type III in Scheme 1, Reissert reactions in a
broad sense). This is especially relevant, since nitrogen heterocycles are ubiquitous
common motifs in natural products, drugs, and bioactive compounds; involving these
species in MCRs has, therefore, important consequences in organic synthesis [4].
The interaction of the azine nitrogen with electrophiles is normally fast and
could display a reversible nature, while the addition of a nucleophile at the position
a of the activated heterocyclic system B implies the loss of aromaticity and is often
the rate determining step of the reaction. The resulting substituted dihydroazines
C display a rich reactivity, and may be subsequently transformed into a variety
of heterocyclic systems D with diverse oxidation degrees [5, 6]. Alternatively,
reaction of azines with several activating agents can generate azinium ylides E,
species which can undergo [3þ2] cycloadditions with dipolarophiles (Scheme 2).
In some cases the result of these combinations produces reactive intermediates,
triggering complex cascade reactions [7]. This chemistry has enabled practical
syntheses of alkaloids and heterocyclic structures as well as pilot scale production
of major drugs and synthetic intermediates.
Type Ι Type ΙΙ
Nu Nu R
+ – R Nu Nu
R N Carbene Nu
E E E
R R E E
Type ΙΙΙ
E
R
N N N
R E
Nu E
Nu Nu
Scheme 1 Examples of common complementary reactants used in MCRs

In 1905, Arnold Reissert described the addition of cyanide to the a-position of a

quinoline (1, Scheme 3) activated by an acylating agent [8–14]. The resulting
substituted dihydroquinoline 2, generally called a Reissert compound, can be
hydrolyzed with aqueous HCl to afford the quinoline-2-carboxylic acid 3 and an
equivalent of the aldehyde, after spontaneous dismutation of the intermediate
dihydroazine derivative. Reissert originally performed the reaction in aqueous
media; however, under these conditions, the acid chlorides hydrolyze quickly. To
overcome this limitation, in 1940, Woodward explored the reaction in sulfur
dioxide, using several aromatic acyl chlorides [15, 16]. Later, Fischer extended
the acyl chloride range to include aliphatic derivatives using benzene as solvent,
demonstrating that hydrolysis of these adducts was a useful way to convert the acid
chlorides used as activating agents into aldehydes [17–19]. Interestingly, reactions
of Reissert compounds with aldehydes or ketones bring new synthetic possibilities
(see Scheme 3). For instance, the nucleophilic a-amidonitrile moiety of the
E R
–
+
N N +
E+ E+ N
Nu
base
B A E
Cationic Dipolar
intermediates intermadiates
R
E X
R
N Nu R′ Y
N N
R′′
Dihydroazine Dihydroazine
C reactivity D R′′′ reactivity C¢
Scheme 2 Azine activation modes
N CO2H
O H+ + R–CHO
+ O R
2 red
R Cl 3
N N CN R1 O
R1– CHO N
O R
+ KCN
1 4
Reissert O
Compound H
H2 / Cat. N
N R
H
5
Scheme 3 Reissert reactions and post-condensation transformations

dihydroquinoline 2 can attack the carbonyl of aldehydes or ketones to afford the

substituted quinoline ester 4 (after an acyl shift and subsequent cyanide elimina-
tion) [20–23]. Alternatively, the catalytic hydrogenation of the Reissert adduct
afforded the tetrahydroquinoline 5 with concomitant migration of the acyl group
to the primary amine moiety [24]. Indeed, the chemistry and synthetic uses of the
Reissert adducts have been covered in several reviews [25, 26].
Apart from quinolines, isoquinolines (Scheme 4a, b) are also excellent sub-
strates, even when substituted at position 1 [27–29]. The group of Popp extensively
explored the azine range of the Reissert reaction: 1-azapyrene, 2-azafluoranthene,
diazaaromatic systems, benzimidazoles, quinazolines, and even the analogous
oxygen system of 2-benzopyrylium salts, all of which made suitable substrates
for this process [30–35]. More recently, Reissert compounds of imidazolium and
imidazolinium salts have been employed to synthesize new carbene complexes
[36]. Although pyridines do not afford the expected adduct under classic Reissert
conditions, N-alkylpyridinium salts do work [37]. Similarly, carbonyl derivatives
such as acetophenone 11 have been used as nucleophiles in a regioselective addition
through the N-acylpyridinium salt intermediate, demonstrating that non-cyanide
nucleophiles could be employed in Reissert-type reactions (Scheme 4c) [38].
a
CN O
O
N + + KCN N R
R Cl 7
6
b
R
R CN O
O
N KCN N R
+ +
R Cl
6a 8
c
O
+ O
10
N Cl O
+ N
O 4 months
12
9 25%
11
d
O
+ O O
N O 13
Cl N CN 15
+ AlCl3
R 9 Si N Yields: 3-50%
14 R
Scheme 4 Isoquinolines and pyridines in Reissert reactions and related processes

R2 NO2 PhNCO
R
R in situ Et3N (Cat.)
R R
+ –
1.R2 C N O
N LDA 19
+ N N 20
6b N
TMS-CN 14 R1 CN O 2. KOH O N
16 CN O I
17 18
Cl R1 R1
+ R2
Overall yields 25-27%
O
Scheme 5 Solid-phase Reissert reaction
In 1987, Popp et al. described the first Reissert reaction with pyridine as substrate
using TMS-CN (14), in the presence of a catalytic amount of aluminum chloride
[39]. Further modifications included the use of diethylaluminiumcyanide and
tri-n-butyltin cyanide as alternative cyanide sources (Scheme 4d) [29, 40, 41].
In 1996 the Kurth group described the first sold-phase Reissert reaction
(Scheme 5) [42, 43]. Activation of a carboxylic acid functionalized resin to the
corresponding acyl chloride, followed by treatment with isoquinoline and TMS-CN
(14) afforded the resin-linked Reissert adduct 16. This intermediate was subse-
quently alkylated at the a-position by treatment with LDA and alkyl iodides 17.
Some of these adducts were further manipulated, and finally the substituted
isoquinolines 20 were conveniently released using a traceless cleavage with
KOH/THF.
This account reviews recent advances in Reissert-type transformations, focusing
on the use of different reactants, asymmetric versions of the process, and also on
dipole-related reactivity and on the participation of activated azines in isocyanide-
MCRs.
2 Range of Activating Agents in Reissert-Type Reactions
Besides the classic Reissert process, a wide range of modifications have been
described. Structural variations on each component have been extensively screened,
and several approaches have been designed based on the interaction of azines,
activating agents, and nucleophiles to yield substituted dihydroazines or related
compounds. This chapter does not provide an exhaustive list of these many trans-
formations; rather, it offers a general overview of the field (Scheme 6).
Different types of activating agents have been employed in Reissert-related
reactions (Scheme 6). In many cases, it is mandatory to generate, or even isolate,
the corresponding azinium salt intermediate, and sequentially proceed with the
nucleophilic addition. Moreover, since the former step often takes place selectively
and at a fast rate, the transformation can be performed in a multicomponent manner
without any functional group interference.
R1 = Alk, Ar, silyl etc. 22

N Nu
N CO2Me 24
R O
39
N Nu
CO2Me
O R
CO2Me 21 O O
R1
37 H 38 R Cl
O
23
N H CO2Me R R
O Cl
R1 N N
H R
CO2Me KCN
CO2Me 26 NC O
CO2Me O
or
N N R
N Cl
9 1
Nu R 25
R3SiOTf
or + Nu
35 N KCN
6
N Cl
36 Tf2O (RO)2P
Si 27 N
OMe 33 KCN X P(OR)2
R R
R 29 O 28 NC X
31
i RSO2Cl R F
Me2N ii base
32 30
34
N Nu
N
N CN R O
Tf
Scheme 6 Range of activating agents used in Reissert processes
Acid chlorides 21 and chloroformates 23 are the most commonly used activating
agents and the preferred reagents for evaluating the reactivity of other components
in new Reissert-type processes. For example, in studies on the total synthesis of the
indolopyridine alkaloids 42, acetyl chloride was used in the key step to prepare the
common synthetic intermediate 41. In this case, an enamide moiety intramole-
cularly attacks the in situ generated N-acylazinium salt, and the Reissert adduct
is spontaneously oxidized and hydrolyzed to regain aromaticity in the last step
(Scheme 7) [44, 45].
N,N-dialkyl- or diaryl-carbamoyl chlorides 25 are far less frequently used in this
chemistry, although they were successfully employed by Popp in a Reissert-related
process [28]. This group also investigated the use of chlorophosphates and chlor-
othiophosphates 27 as activating agents. The resulting Reissert analogs can be
converted by base treatment into anions that can be alkylated or undergo elimination
to isoquinaldonitrile [46]. Interestingly, acid fluorides have also been used [47].
Reissert compounds arising from sulfonyl chlorides are often unstable; however, the
corresponding 2-substituted azines 32 can be obtained by treating the crude product
of these reactions with a mild base [48]. Triflic anhydride (33) has been successfully
used for promoting the incorporation of less reactive nucleophiles. The Corey group
O
O N
O
N N
N AcCl N N
H N N Ac H
N DCM H 41
40 Br
Br Br 84%
O Pd
N chemistry
Indolopyridine
N N 42
Alkaloids H
R
Scheme 7 Synthesis of indolopyridine alkaloids based on a Reissert-type process
N
O O CO2Me
Cl 9 H2N O
N O NH
+ MW
Cl N
N
43 O O O
44 N
+ CO2Me O
Scheme 8 Reissert-type cascade promoted by an activated double bond
used this activating agent in a direct arylation of pyridines that did not require
an organometallic species [49]. The bulky trialkylsilyloxytriflates 35 have been
used to activate pyridines in the presence of Grignard reagents: they protect the
a-position of the azine, thereby leading to g-regioselective nucleophilic attack.
Additional examples of these activating agents are discussed in the following
sections of this chapter. Substituted alkynes such as 38 (normally with electron-
withdrawing groups) constitute a common class of activating agents. They interact
with azines to form dipoles that can react in cycloadditions (see Sect. 5). However,
in some cases, the anion moiety can trap a proton, generating an azinium species,
which then enables subsequent nucleophilic addition. For instance, adducts 37 and
39 (Scheme 6) have been obtained by using a terminal alkyne as the nucleophile, in
reactions catalyzed by copper or gold chlorides [50, 51]. Appropriately substituted
p-acceptors such as 43 can also activate azines, through addition–elimination
processes, consequently promoting cascade reactions based on Reissert chemistry
(Scheme 8)[52].
3 Range of Nucleophiles in Reissert-Type Reactions
The range of nucleophiles used in these processes is very wide (Scheme 9).
Although alcohols and amines cannot be directly used – as they would quickly
trap the electrophilic partner, and therefore, bypass the intervention of the azine –
the literature does contain a few examples of sequential use of these compounds.
N
N CO2t-Bu CO2R
Tf 60
45 Ot-Bu N
CO2 CO2R N CO2R

59 Ph
MeS MeS
(Boc)2O O 47
Tf2O RO2C
33 O Ph 46
NH
O 57
Bu O X
O 9
O Bu N
or N N
58 N N RCOX
33 Tf2O
N 1 9 R O
ROCOCl or 48
Tf
or 33 Tf2O O
N 49
55 MeNO2 (RO)2P
6
H
R4 53 50
EtOOC ROCOCl
RO2C or N P(OR)2
N EtOOC CO2R NH
CO2R R1 O
ROCOCl
R4 51 R1 = Tf, CO2R
O2N
56
CO2R
R4 = H, CO2R R2 = CO2R,
N CO2R
CO2R
54 N
RO2C
EtOOC COOEt 52 R2 NH
Scheme 9 Range of nucleophiles used in Reissert-type reactions
This entails preformation of the activated azinium ion and subsequent reaction of
the nucleophile to generate the desired adduct [53–56]. In this regard, an interesting
possibility is the use of symmetric carbonates. For example, the dihydroisoquino-
line 45 (Scheme 9) was synthesized using this strategy. The nucleophilic alkoxide is
released during the interaction between the azine and Boc2O with loss of CO2.
Adduct 45 is an efficient tert-butoxycarbonylation reagent for phenols, aromatic
and aliphatic amines in the absence of bases under mild conditions [57, 58].
Even poor nucleophiles such as the amides 46 can react with azines in the
presence of alkynes as activating agents [59, 60]. Various nucleophiles (including
alkoxides, thiols, amines and nitrogen heterocycles) were recently employed in a
related process with N-oxide azaindoles (Reissert–Henze reaction, Scheme 10). In
the process, the oxygen is alkylated with dimethyl sulfate and, after the nucleophilic
attack, methanol is released to aromatize the initial adduct [61, 62]. Following similar
mechanistic trends, N-heteroatom-activated azines afford the corresponding substi-
tuted adducts. Likewise, N-tosylated isoquinoline [63, 64] and N-fluoropyridinium
salts [65] are also reactive substrates in Reissert–Henze type processes.
Cl
(MeO)2SO2 Nu: cyanide
+ Nu N N alkoxydes
N N Nu, Base H thiolates
H
O O O– (MeO)2SO2
azoles
H –MeOH ammonia
primary amines
Nu
+ Nu secondary amines
N N N N amino acids
H H H Yields: 50-90%
O O aminoalcohols
Scheme 10 Nucleophiles used in the Reissert–Henze reaction
a
CN CN
Ar CN Ar CN
CN
+
ClCH2CN + Ar-CHO + +
61 CN N Ar NH2 Ar N
9 N
62 CN 63 64
b Ar
61
66
ClCH2CN
+
N+ N+ N CN
N Cl– CN NC
9 Pyr Pyr+H Ar CN
–
NC NC NC Pyr
CN Ar CN
65 –
NC CN Pyr+H
Ar-CHO +
CN 62
CN CN
CN Ar Ar
Ar CN
Ar CN Ar CN –
– CN – CN
Ar N – NC NC
Ar CN CN
NC CN N
NC CN
Pyr
CN
CN CN
CN Ar CN
Ar CN Ar CN
Ar CN Reissert-type
process –HCN Ar N
Ar N– Ar N
Ar NH2 NC N+ NC N 64
N –2H
CN 63
67
Scheme 11 Cascade process terminating with a with Reissert-type reaction
In a chemodifferentiating ABB’ process [66], King and coworkers characterized

the adduct 48, arising from the nucleophilic attack by pyridine upon an N-acyl-
pyridinium intermediate (Scheme 9) [67]. The Yan group described an impressive
cascade reaction involving chloroacetonitrile (61), malononitrile (62), aromatic
aldehydes and pyridine (9, Scheme 11a). Alkylation and Knoevenagel-type reac-
tions are suitably engaged with conjugate additions, cyclopropane ring formation
and subsequent ring-opening to finish with an intramolecular Reissert-type reac-
tion, leading to the complex heterocyclic system 64 (Scheme 11b). The different
roles played by pyridine in this sequence are noteworthy [68].
a
R 1 O3
R1COCl 2 Base R CHO
R N PO(OMe)2 N
N P(OMe)3 69 COR1
1 68 COR1
b
O POCl3
+ + Me N
N Me N 70
N NH
1 51 H H N
Me
c
O
O 6
71 + N N
+ Ph
+ RHNOC Ph O
H2N R 73
PhOC COPh 72 MeOC OH
–
N+ H
COPh N
O O COPh
COPh
R H COPh
N Me N
H R Me
74 75
O O
Scheme 12 Phospho- and carbo-Reissert-type processes
Dialkyl phosphites such as 49 (Scheme 9) have been reacted as nucleophiles

with activated pyridines [69, 70]. The first examples of this chemistry involved
either N-alkyl-pyridinium salts in the presence of DDQ, or pyridine and terminal
alkynes as activating agents in a one-step protocol. The reaction proceeds under
mild conditions that include Al2O3 catalysis. Quinolines 1 and chloroformates
afford the expected adducts 68. The latter structures can be easily oxidized with
O3 to provide the substituted indoles 69 (Scheme 12a). Isoquinolinephosphonates
obtained this way have been used in Wittig–Horner chemistry. The whole sequence
offers ready access to alkyl substituted isoquinolines [71]. Analogously, silyl sub-
stituents have been introduced into N-acylated pyridines by using silylcuprates [72].
Several classes of carbon nucleophiles have been successfully used in these
systems, reflecting the utility of Reissert chemistry for derivatizing azines via
carbon–carbon bond formation. Apart from cyanide anion, other classes of carbon
nucleophiles have been explored. For instance, addition of indole (51) to N-acyla-
zinium salts proceeds selectively at the a-position (Scheme 9). Pyrrole, quinolines
and isoquinolines all behave similarly [73–76]. A related reaction, yielding adduct
70 (Scheme 12b) has also been described. In this case, azine activation is promo-
ted by Vilsmeier reagents (generated by reaction of amides with POCl3) [77].
b-Dicarbonyls are reactive inputs in this chemistry, and dialkyl malonates 53
have been added to quinolines and isoquinolines in the presence of chloroformates

[78]. In a related 4CR (Scheme 12c), the dicarbonyl 74 is first generated in situ by
interaction of diketene 71 and a primary amine, then reacts with an isoquinoline
dipole (presumably via proton transfer and nucleophilic addition) to give interme-
diate 75, which by intramolecular addition of the acidic methine, provides the final
adduct 73 [79, 80]. Nitroalkanes 55, (Scheme 9) are also reactive as carbon
nucleophiles in Reissert-type processes [81, 82]. Use of stronger activating agents
such as triflic anhydride (33) enables functionalization of pyridines with electron-
rich aromatic rings, as well as azulene derivatives (59), pyrroles, allylstannanes,
and even substituted ketones 57 [49, 83, 84].
Allyl groups can be easily attached to azines through the standard activation-
nucleophilic attack approach. Quinoline (or isoquinoline) smoothly reacts with
chloroformate and allylsilanes (76) in the presence of iodine or triflate catalysts
(Scheme 13). Using two equivalents of silane reagent in the isoquinoline reaction,
gives adduct 79 [85–87].
Triallylborane 80 reacts both as activating agent and nucleophile. Interestingly,
due to the lability of the N–B bond, the process leads to N–H derivatives, ready for
further derivatization. A noteworthy transformation is the double allylation of
pyridines by triallylboron 80 leading to the tetrahydropyridine derivative 81.
77 78 Me3Si
N N 79
94 CO2R N
CO2R
SiMe3 or N
Et CO2R
Me
76
O SiMe3
76
Me3Si ROCOCl
ROCOCl
O
81
N 80
E Et Me
92 R R 93 3B N
R H
O
or
R O OTBS N
O 1 N 9
91
1. RLi
R l 2. (All)3B 80
COC or
1. RO 89 N 82
N OMe
6
2. SiMe3 83
OMe O N R
ROCOCl ROCOCl H
MeO2C ROCOCl
O R187 SnBu3
3. DDQ (i-PrO)3Ti
90 R2 OSiMe3
O EtO O 84
R2 85
Me3SiO
R1 OH N
CO2R
CO2R
88 N OEt
N O 86
CO2R
Scheme 13 Activated alkenes and related species as nucleophiles in Reissert chemistry

a
3B
3B
80 N 80
N
B N H2O, OH –, Δ H
N H
9 81 96
95
b
3B
RLi 80
N R N R
N one pot N R
Li All3B H
9 97
Scheme 14 Allylboration of pyridine
After coordination with the azine nitrogen, the activated complex 95 (Scheme 14a)
undergoes a stereoselective diallylation to afford the trans-2,6-diallyl-tetrahydro-
pyridine (81). Furthermore, 81 can be transformed into its cis-isomer (96) by
heating. Isomerization can also occur at a dihydropyridine (DHP) intermediate
following incorporation of an alkyl group via organometallic attack upon a pyridine
in a one-pot transformation (Scheme 14b) [88–90].
An alternative method for allylating pyridines entails use of the corresponding
organometallic reagents. For example, allyltin derivatives (83, Scheme 13) offer
good yields and regioselectivity [91]. Moreover, interaction of chiral ligands of
bisoxazoline type with allylzinc derivatives and N-acylpyridinium salts enables
selective transformations, although with poor enantiomeric excesses [92]. A variety
of enol derivatives have been used as functionalized nucleophiles in these pro-
cesses, including titanium- and silicon-enolates 85 [93]. Addition of the ketene silyl
acetal 89 to quaternized methyl nicotinate, followed by oxidation with DDQ, yields
the g-substituted pyridine 90, an advanced intermediate in the total synthesis
of ()-sesbanine (Scheme 13) [94, 95]. Reaction of isoquinolines, silyloxyfurans
91 and activating agents have yielded diverse isoquinolinobutyrolactones with
excellent diastereoselectivity, even for a-substituted azine substrates (Scheme 13).
Furthermore, use of a chiral auxiliary has enabled formation of single stereoisomers
in excellent yields [96]. The Rudler and Langer groups have developed this
approach by using 1,1-bis(trimethylsilyloxy)ketene acetals 87 [97]. This versatile
reactant can promote further bond-forming events, as the resulting carboxylic
acid moiety may react as a nucleophile, trapping the iminium ion generated from
the dihydroazine upon interaction with an external electrophile. The sequential
addition–lactonization process can be induced by halogens or epoxidizing agents
(Scheme 15a). Several azines (e.g., pyrazines and isoquinoline) react under these
conditions to afford d- or g-lactones, thereby reflecting the generality of the
methodology (Scheme 15b, c) [98–106].
Charette recently described an innovative activation protocol in which lactams, in
the presence of triflic anhydride (33), react with pyridines to afford the pyridinium
imidate 107 in good yield. Subsequent addition of metal enolates to this species leads
to 2-substituted tricyclic dihydropyridines, advanced intermediates for the total
synthesis of the natural alkaloid ()-tetraponerine T4 (109, Scheme 16) [107].
a
R2
R1 O
I
O
R1 OSiMe3
O I2 N
R2 R2 99
87 OSiMe3 COOMe
R1 OH R=H
+
ClCOOMe
+ Me Me Me Me
R m-CPBA Me Me
88 N O
O O
COOMe HO HO
N R H+
O O O O
R = Ph
98 R1 = R2 = Me N Ph N+ Ph N Ph
100 COOMe
COOMe COOMe
b
R1 OSiMe3
+ MeOOC
N 2 R1
R R2
87 OSiMe3 N
N + O
ClCOOMe O
N
101 102
c COOMe
OSiMe3 I
H
+
n-Bu OSiMe3 R O
103 N I2 105
N
COOMe
N + H O R = CO2Me
H
6 ClCOOMe 104 n-Bu COOH n-Bu
Scheme 15 Sequential Reissert–lactonization processes
O
OMet
NH
TfO– 1. hydrogenation H
+
+ 108 N 2. reduction N
106 N – H
TfO +
H
N + N
9 Tf2O N
33 N 107 OH 109
tetraponerine T4
one pot
Scheme 16 Charette’s activation protocol
Besides lithium, zinc and tin derivatives (see Scheme 13), other types of organo-
metallic reagents have been used as nucleophiles in related processes (Scheme 17).
Yoon described a 3CR, resembling a Petasis process, in which isoquinolines or
quinolines are reacted with activating agents and boronic acids to yield the expected
a-arylated dihydroazines 111 [108].
Azines have been benzylated via the corresponding organostannanes [91, 109,
110], and alkylated or arylated via the organocuprate precursors [111–113]. Vinyla-
tion of isoquinolines or quinolines with alkenylzirconocene chlorides 116 proceeds
in excellent yields. Interestingly, an analogous reaction of a reduced derivative,
catalyzed by a copper (I) salt in the presence of a chiral amine ligand, furnishes
the corresponding adduct 117 in an enantioselective manner. (Scheme 17) [114].
O
Si(i -Pr)3 N
+ Si(i -Pr)3 111
N CO2R
N
[A] =
B(OH)2 N
TfO– CO2Et
Ph (i -Pr)3SiOTf 128 O 113
Bn Ph
130 110 Ph
BnMgBr 129 ROCOCl
SnMe3
A (CH2)nR
R ROCOCl Ph 112
125 t-BuMe2SiOTf EtO2C
115
126 RMgBr / O2 R
127
R N
N 1. R(CH2)nCu(CN) ZnI 114
or 2. S8
123 N N
1 9
MgCl 116
SnMe3 Ph
or ZrCp2
N Cl
124
6 ROCOCl
N
N CO2R
RLi [B] preformed 117
E 119 Et2Zn
CuCN·2LiBr PhCOCl
ROCOCl Ph
CO2R
[B] =
N+
N N Et N Bu
CO2R CO2R i-Bu Al–
Bu
122 R R 121 Ph O 118 i-Bu
ratio 30:70
120
N
CO2R
Scheme 17 Organometallic addition to activated azines
In a related process, pyridines, vinyl alanes, and acid chlorides are reacted to afford
the MC adduct 118 [115]. Also, reaction of pyridines, chloroformates,
and organozinc reagents proceeds with high yields and regioselectivity in position
g [116]. Organolithium compounds are also useful nucleophiles, reacting with
activated azine derivatives under standard conditions. In this respect, Clayden has
developed remarkably elegant cyclizations of N-benzylpyridine- and quinoline-
carboxamides, promoting the in situ formation of the carbanion (by deprotonation
with a base) with subsequent azine activation with chloroformates (Scheme 18a)
[117]. This route provides ready access to the spiro b-lactam system 133.
Sequential reaction of azines with alkyl lithium compounds and chloroformates
usually affords the expected Reissert-type products 136, together with minor
amounts of doubly acylated compounds 135 (Scheme 18b). Isoquinoline is likely
to react directly with the alkyl-lithium compound to generate the alkylated lithio-
enamine intermediate E, and this species may account for the formation of
dihydroisoquinolines 135 and 136, through interaction with the electrophilic part-
ner. Mamane recently expanded this concept by replacing the acylating agent with
different electrophiles. These combinations lead exclusively to isomers 134
(Scheme 18) [118–120].
a
O O O O
t Bu tBu – tBu
N N ClCO2Me Cl N t Bu
MeO2C N N
N LDA N N
Ph Li Ph MeO2C + Li Ph
Ph
131 132 133
b E
RLi EX
NLi N
N
6 R E 134 R
C-Acylation N-Acylation
CO2Me CO2Me
N +
ClCO2Me N N
CO2Me CO2Me
R 135 R ratio 30:70 R 136
Scheme 18 Reaction of organolithium compounds with azines and electrophiles
Grignard reagents also have been explored as nucleophiles in these types of

processes. The regioselectivity of the addition of these reagents to acylated pyr-
idines strongly depends on the substrates [121]. However, the nucleophilic attack
can be directed to the g-position by using a stoichiometric organocuprate derivative
or catalytically, with small amounts of copper iodide. Alternatively, the attack
can be guided to the a-position by blocking the g-site with a bulky substituent,
regioselectively providing adduct 124 (Scheme 17) [122, 123]. To improve the
poor regioselectivity often observed in nucleophilic additions of organometallics
to pyridinium salts, the Akira group employed tert-butyldimethylsilyl triflate 125
as activating agent (Scheme 17). This bulky reagent efficiently protects the
a-positions of the pyridine ring, and consequently, the Grignard reagent selectively
attacks the g-position. Furthermore, the silyl group can be easily removed, and
oxidation of the dihydropyridine adduct smoothly regenerates the aromatic azine
nucleus. Directed substitution has also been investigated in quinolines. Although
this reaction is considerably more challenging, Mani achieved a 60:40 ratio of
g-substituted to a-substituted product [124]. More recently, Wanner had success
with g-substituted pyridines, obtaining even in these cases the corresponding
adducts with excellent g-regioselectivity [125].
4 Asymmetric Reissert-Type Processes
The need of enantiopure compounds has fuelled the development of asymmetric

transformations in this field. This is especially challenging due to the mechanistic
complexity of MCRs and to the lability of the dihydroazine moieties of the final
adducts. Nevertheless, significant progress has been reported in the area. Shibasaki
a
Z
Ar Ar Si
O P CN
137 Al Cl O
O N
+ RCOCl O O
+
Z
N CN Al R
+ 2 O Cl
N R O
Z = PO(Ar)2 P(O)Ar2
1 Si N
14 Yield: 74-91%
ee: 85-89%
b Me
Chiral HN Ph
ligand
1
R
1 + RCO2Cl 5% CuCI R N
5.5% chiral L 139
N
+
i Pr2NEt N
N R
3
H 2 3 MeO PPh2
CO2R R
138 Yield: 72-92%

ee: 70-84%
c
Catalyst 10% mol
1.TrocCl t Bu S
i-Bu2N
N NTroc 141 N N
OTBS H H
2. 140 O N
Yield: 55% Me Ph
6
OMe ee: 85% 142
CO2Me
3. NaOMe (quench)
Scheme 19 Catalytic enantioselective Reissert-type processes
recently described the first catalytic enantioselective Reissert reactions of quino-

lines (and isoquinolines) using the bifunctional aluminum catalyst 137 (Scheme 19a).
The Lewis acidic and basic sites of the catalyst are critical for its coordination to the
N-acylazinium salt and for directing the nucleophile with facial selectivity. In this
manner, excellent yields and enantioselectivities of the desired Reissert adducts were
obtained [126–129]. This process allowed the preparation of a potent NMDA recep-
tor antagonist [130]. A few years later, an analogous catalyst was used to promote the
first enantioselective Reissert reaction of pyridine derivatives [131]. Arndtsen
recently described the copper catalyzed reaction of pyridines or quinolines with
terminal alkynes and acylating agents to yield the dihydroazine adducts 138. Several
chiral ligands were analyzed, and the best results were obtained with the PINAP
derivative 139, reaching enantiomeric excesses greater than 80% with excellent
chemical yields (Scheme 19b) [132]. In this context, Feringa et al. recently described
the catalytic enantioselective addition of dialkylzinc reagents to 4-methoxypyridine
[133]. Moreover, thiourea organocatalyst 142 has enabled enantioselective addition
of silyl enol esters to activated N-acylisoquinolinum salts, conveniently providing the
corresponding adduct 141 (Scheme 19c) [134].
In a different approach, chiral auxiliaries have been widely used in Reissert-type
chemistry to provide practical access to enantiopure addition adducts. For example,
the stereoselective addition of cyanide to isoquinoline or quinoline with a modified
TfO– TfO–
Re Re Re H
ON PPh3 ON PPh3 ON R N
N+ R N N PPh3
RMgCl R′OTf R + NaBH4
– R′
R′ + CN
143 144 145 146

Yield: 77-96% Yield: 72-83 % Yield: 91%
de: 70-88% de: 88 % Re de: 88%
ON PPh3
recyclable CN
b
Chiral Auxiliary
H H Et
Chiral X ClCO2Me X Et
H
O Auxiliary Et2CuLi HCl 5% O N Ph
X X
147 N 148 149 150 N

N N N Ph
CO2Me H
Yield: 80-90% CO Me
2
de: 80-90%
c
O O O
SnBu3
Br
R N R
83 O 153
N N N
152 Bn In
CO2Me CO2Me
ClCO2Me
151 Yield: 90% 154 Yield: 82%
de: 84% de: 84%
Scheme 20 Chiral auxiliaries linked to the azine moiety
Evan’s-type chiral oxazolidinone as the activating agent has been described [135].
Gladysz reported coordination of the azine nitrogen to a chiral metal complex as an
efficient tool for activating the azine and promoting the diastereoselective addition
of a Grignard reagent (Scheme 20a) [136, 137]. Pyridine carboxyaldehyde (147)
has been used as the azine input in asymmetric processes; its condensation with
chiral diols or diamines affords the chirally modified pyridine derivatives 148,
which can be activated for stereoselective addition. The synthetic sequence ends
with hydrolytic removal of the auxiliary (Scheme 20b) [111]. Yamada reported a
regio- and diastereo-selective process to prepare enantiopure a- and g-substituted
addition adducts based on the use of a chiral oxazolidine linked to the nicotinic
moiety involving either the allyl tin derivative 83 (which leads to attack at the more
reactive a-sites) or an allyl indium reagent (which affords the g-substituted isomers
154), both of which offer good diastereomeric excess (Scheme 20c) [138, 139].
In a different context, chiral reagents have been implemented in this chemistry.
For instance, Liebscher and Itho developed the use of chiral acylating agents such
as amino acid-fluorides 158 and -chlorides 156, respectively, (Scheme 21). The
outcome of the reaction of isoquinoline (6), TMS-CN (14) and N-protected a-amino
acid fluorides is dictated by the nature of the protecting group: whereas Cbz- and
NO2
NO2 Cbz
HN
N
Alk
156 R CN O
Me O2S
NH O NH
N SO2 160
N O
Me F Alk Yield: 44-89%
O O H F– R
Cl 158 HN de: 70-95%
155 N N 1
+ R
6 Si N
OSiMe3 159 O
MeO 14
OMe MeO AlCl3
157 N
OMe O
H
N
ArO2S Alk
Yield: 47%
161
de: 95%
Scheme 21 Acid fluorides and chlorides in asymmetric Reissert-type processes
FMOC-protected amino acid fluorides afford the expected Reissert adducts 160
with a good stereoselectivities, the a-sulfonylamino acid fluorides undergo cycliza-
tion to adduct 161 [47, 140, 141]. Itho’s protocol is amenable to using silyl enol
ethers 157 as nucleophiles [142]. Gibson has used bulky asymmetric acid chlorides
as substrates in a Reissert reaction with TMS-CN; the corresponding Reissert
compound was then treated with aldehydes and sodium hydride to obtain the
enantiopure adducts 4 (Scheme 3) [143].
An area that deserves special attention is the Comins methodology, which
exploits the reactivity of p-methoxypyridine (162) in Reissert-type reactions
(Scheme 22). This powerful and versatile synthetic approach represents an impor-
tant tool for the preparation of natural products [144, 145]. The activation-nucleo-
philic addition protocol generates N-substituted-tetrahydropyridones, arising from
the hydrolysis of the enol ether moiety of the initial adduct. This strategy was
employed to prepare ()-lasubine II (163) in three steps, using a Grignard reagent
as nucleophile in the Reissert-type reaction (Scheme 22a) [146]. Chiral chloro-
formates provide the corresponding enantiopure adducts, which are versatile build-
ing blocks for the synthesis of alkaloids belonging to different groups. In this way,
p-methoxypyridines can be further functionalized; the use of activating agents such
as (+)-trans-2-(R-cumyl)cyclohexyl chloroformate can direct the attack of organo-
metallic species to afford the expected adducts with good diastereomeric excesses.
(+)-Hyperaspine (165) was obtained in six steps using this strategy (Scheme 22b)
[147]. Charette recently published an asymmetric version of a protocol using a
chiral amide-derived activating group (Scheme 22c). First, 4-methoxypyridine
(162) was reacted with triflic anhydride (33) and the chiral amide 166 to generate
in situ the salt 167. Subsequent addition of a Grignard reagent yielded the
tetrahydropyridone 168, which is an advanced intermediate in the total synthesis
of (-)-barrenazines A and B (169) [148, 149].
Incidentally, although in a different context, this Reissert-type chemistry has
also been done on solid phase. In this regard, Munoz loaded a 4-hydroxypyridine
a
OH
O
OMe
PhCH2OCOCl 3 steps
(+/–)-lasubine II
OMe N 28% overall yield
3, 4-(MeO)2PhMgBr N
N
75% CO2Bz OMe
162 OMe 163 OMe
b
OMe OZnCl
O Me H
SiR3 5 steps H O N
SiR3
O O
+ –
Cl O
N H+ Me N Yield: 72%
N
164 CO R* (+)-hyperaspine
2 CO2R* de: 93% 165 21% overall yield
R* = (+)-trans-2-(R-cumyl)cyclohexyl Bu
c
OMe OMe O
Yield: 65-85%
– de: 83-95%
+ 33 Tf2O OTf N R
N N + 1. RMgX HN
N R
162 O NH
DCM
2. H3O+ R N
–78°C to rt Ph N Ph N
Ph NH OMe OMe
OMe 169 (-)-barrenazine A and B
166 167 168
d
O
ClCOR + O 1. RMgX
O N O N
R 2. H2O
N R
170 171
Cl–
R O
e
O + 1. RMgX
N OMe HN O
O 2. H3O+
R 172
Scheme 22 Use of 4-methoxypyridines in activation–addition protocols
onto a Wang resin, and then reacted the resulting solid-supported pyridine 170 with
acid chlorides and Grignard reagents to obtain the N-acyl-2-substituted-tetrahydro-
4-pyridones 171, which were isolated after cleavage under mild acidic conditions
(Scheme 22d). A synthetic variant in which the 4-methoxypyridine is activated
by the resin, produces the final adduct 172, released as the corresponding N–H
pyridone derivative (Scheme 22e) [150–154].
Coordinating groups have been introduced in the chiral activating agent, to
direct the attack of the organometallic reagents. Charette has shown that the ether
moiety in adduct 175 can coordinate with the Mg atom of a Grignard compound,
and thereby guide the nucleophilic attack to one face of the azine (Scheme 23a)
[155, 156]. Finally, the chirality can be directly transmitted from the nucleophile.
Yamaguchi successfully employed this approach, using the chiral allylsilane 176
to prepare enantioenriched dihydroisoquinoline 178 (Scheme 23b) [157].
a
Aux
1. Tf2O, 2-ClPyr
H 2. R1MgX N R1
N
MeO N
O 173 174 NAux
Tf2O, 2-ClPyr
TfO–
TfO– +
N+ N
R1
N N Mg X
MeO
O Me
175
b
ClCO2Ph
+
AgOTf H , Pd / C
* N CO Ph 2 * N CO Ph
2 2
N
6 + 177 Ph 178 Ph
SiMe3
yield 83%
Ph H 176 ee 59%
Scheme 23 Use of coordinating chiral auxiliaries and chiral nucleophiles
In summary, a wide variety of methods are available to prepare enantiopure

Reissert-type adducts. Depending on the synthetic requirements, the use of chiral
auxiliaries, enantioselective catalysis or chiral reagents may be the most suitable
option.
5 Dipole Formation and Domino Reactions
Dipoles enable a rich variety of transformations, with a considerable impact in

organic synthesis; among them dipolar cycloadditions are especially productive. In
some cases, complex domino reactions, processes in which the product of one
elemental step is the reactant of the next one, are the result of apparently simple
combinations.
When the reaction of an azine with activating agents involves the conjugate
addition of a Michael acceptor or related species, a dipole is generated. Huisgen’s
systematic studies on dipolar cycloadditions include several reactions of this kind
[158, 159]. The dipolar intermediates can react with other complementary partners,
typically in concerted processes, or can trigger complex domino reactions. The
most widely used activating agents for this chemistry are substituted alkynes
(Scheme 24).
Nu E
N R N R
+ R R +
N Nu
Nu –
R R
E
E
Scheme 24 Dipole formation from reactions of azines and substituted alkynes
N O
MeO2C
N CO2Me MeO2C S
CF3 N O
180
MeO2C CO2Me MeOOC O
O MeOOC S
196 CO2Me
MeO2C
38 182
179 S
CO2Me O
N CO2Me O
CF3 N O
181
S O
N MeOOC NH
MeO2C N CO2Me
O MeOOC
195 CO Me
2 or 184
N O
MeO2C N 1 N 9 N
H 183
N or
193 CO2Me N
6 O O 185
+
CO2Me RO2C CO2R
N N NC
CN N COOMe
N
MeO2C CO2Me NC
Ph 187 O
194 CO2Me 191 CN COOMe
N
189 N
C Ts 186
O
CN O
N CN N COOMe
CN
MeO2C CN Ph N
N N Ts COOMe
192 CO2Me
MeO2C O
190 CO2Me 188
Scheme 25 MCRs involving dipolar intermediates
Scheme 25 shows representative examples of various chemotypes that can be

generated with this simple and efficient strategy. Practically, all common azines and
Michael acceptors react in these processes, and the range of the third component
is also extremely wide. Aldehydes (such as 179), ketones and a-dicarbonyls (such
as 181) afford the expected products in good yields; moreover, the cyclic carbonyl
derivatives 183 and 185 lead to spiro-polyheterocycles 184 and 186, respectively
[160]. Interestingly, activated imines (such as 187) are also reactive, which naturally
leads to 4CRs involving azines, alkynes, aldehydes, and amines. Isocyanates 189
yield the cyclic amides 190. Tetracyanoethylene 191 is another good substrate,
affording the highly substituted quinolizine 192 in a single step [161–170]. The
reaction with azodicarboxylates 193 has been described by Huisgen in his compre-
hensive review [158, 159]. In the absence of a third component, two equivalents of
alkyne can react to form adduct 196 in a chemodifferentiating ABB’ process [66].
This historically relevant reaction was reported in a review by Krohnke in 1953
[171]. The Mironov group recently described an innovative approach for a combina-
torial search for new MCRs based on this rationale, which enabled then to discover
novel mechanistically related processes [172]. In this context, the Ma group described
interesting related reactions involving other kinds of N-heterocycles [173, 174].
Modified versions of these reactions also have been described. Particularly
attractive are the processes in which some of the components are linked. For
instance, 4-hydroxybut-2-ynenitrile (197, Scheme 26a) contains both the activating
alkyne moiety and the nucleophilic alcohol: thus, once the dipole is generated, a
proton shift gives raise to the alkoxide anion ready to trap the azinium ion in an
intramolecular manner to yield adduct 198 [175–178]. Similarly, an enolate
(derived from the reaction of Michael acceptor 199 and pyridine) can trap the
intermediate azinium moiety, to afford the quinolizidine ring system 200. Interest-
ingly, subtle changes in the substitution pattern of the reactive inputs can
completely modify the reaction pathway. For instance, a tosyl group at the nitrogen
a
R2
R1 CN
+ +
OH +
197 N N – N O
R1 NC O
NC
NC R2
1 –
2
R1 R2 R1
N HO R 198
b
H
N O CO2t-Bu
9 Boc
N
CO2t-Bu O
H +
N or N Ts
R N
199 O 200 201
CO2t-Bu
a b
R R: Ts
NH R: Boc
R NH
a
+
N+ N
b
C
–O CO2t-Bu –O CO2t-Bu
Scheme 26 Dipolar processes with bifunctional substrates

a
1 CO2Et
N N+ N+ N
N+ COR
+ – CO2Me CO2Me
MeO2C CO2Me H MeO2C MeO2C MeO2C
MeO2C CO2Me
38 R H OEt R OEt
+ R CO2Me 203
R OEt
OEt O O O O 55%
–
O O 202 O
–
O
b
O
N
O CO2R
N + RO2C CO2R +
6 CO2R 205
204 O O
80%
Scheme 27 b-Dicarbonyls in dipolar processes
Br–
CO2Et N COR –H2 N
+ Br + COR
206 O
COR EtO2C
COR
O
N N +
COR EtO2C O 207
6
+
–
ROC COR COR
+ Ph N CO2Me N
O2N CO2Me
–HNO2
208 O Ph
NO2 CO2Me –H2 Ph
CO2Me
O 209 O
Scheme 28 Access to pyrroloisoquinolines via dipolar MCRs of azines
of the aminoalkyne 199 leads to the azepinone 201 (i.e., pyridine acts as leaving
group in the dipole), whereas a Boc substituent in this reagent, leads to the normal
dipolar process, affording the quinolizine 200 (Scheme 26b) [179].
Likewise, b-dicarbonyls 202 [180] react with quinolines and the acetylene
dicarboxylates 38 to produce the pyrroloquinolines derivatives 203 in a single
step (Scheme 27a), whereas the cyclic derivatives 204 lead to the corresponding
spiro-compound 205 (Scheme 27b) [181, 182].
Distinct functional groups with acidic hydrogens can also promote these trans-
formations. For instance, benzoylnitromethane (208) or ethyl bromopyruvate (206)
react with isoquinoline (6) and acetylenedicarboxylates via the same dipolar mech-
anism to generate a pyrrolo[2,1-a]isoquinoline scaffold. However, in these cases,
after closure of the 5-membered ring, a double-bond formation via dehydrogenation
or nitrous acid elimination yields the fully aromatic ring systems 207 and 209
(Scheme 28) [82, 183].
O
N
R2 O
R Cl
N O
Ph-C NOH
R
1 213 N O 218 N
R
1
R TMS 1
R 215 O N O
O Ph
N O O
OTf O
212 R
216
O N O
214
R
O R R N Cl Ph
R X O O
2 N
R Ph-C NOH
O O
211 –HX 214 N 218
+ N +N O
N 210 R
2 N
– O – O
X
O R2
R2 R2 N O
O
H R 217 N 219
O
N O CO2Me R
3 4 Cl
R R
Ph-C NOH Ph
R3 N 218
MeO2C N N
O
R4 MeO2C N O
222 R2 220 O
221
O
R2
2
R
Scheme 29 Azine-based dipolar [3þ2] cycloadditions
Alkylation of the azine input with a-haloketones 211 or related compounds

yields a different type of dipole (Scheme 29). Thus, the initially generated azinium
salt, having highly acidic methylene hydrogens, can provide species suitable for
undergoing [3þ2] cycloadditions with a variety dipolarophiles. Interestingly, the
resulting adducts (215, 217, and 220), featuring a dihydroazine moiety, may be
engaged in a second cycloaddition with a nitrile oxide (218), leading to the final
polycyclic products (216, 219, and 221, respectively) with high diastereoselectivity.
The Huang group successfully introduced arynes (generated from the corresponding
o-silylaryltriflates 212) as dipolarophiles in this chemistry. Using this method, they
obtained benzoindolizine 213, which displays a scaffold frequently found in highly
fluorescent materials, and is also a structural analog of the antitumor agent batracy-
clin [184]. These [3þ2] cycloadditions occur also with other common dipolaro-
philes such as maleimides and substituted alkenes. Solid-supported versions of these
processes have also been described [185–187].
The structural variety obtained through the methodologies listed in this section
is quite remarkable. The high bond-forming efficiency displayed in these transfor-
mations is also noteworthy. Most likely, the above mentioned features would be
crucial to extend the use of this family of reactions in diversity oriented synthesis.
6 MCRs Involving Azines and Isocyanides
Use of isocyanides in Reissert-type MCRs greatly amplifies the complexity that can
be generated in a single step. Indeed, the well-known carbene-like reactivity of
isocyanides, combined with the rich chemistry of azines enables a wealth of
transformations and cascade processes (Scheme 30). The synthetic outcome of these
reactions is often controlled by the electronic effects of the substituents on the
respective inputs. In Reissert-type chemistry, isocyanides typically react as nucleo-
philes, affording products of the general structure G. The carbon atom of the
isocyanide normally ends up directly connected to the a-carbon of the azine.
Alternatively, the isocyanide may attack the carbonyl of the acylazinium salt. In
this case, an “imine-type” intermediate would be generated, and its nucleophilic
nitrogen could promote a cyclization yielding adducts H. The same kind of
structure can arise if the isocyanide reacts first with the activating agent and
then with the azine nitrogen. Also, the intermediate formed by interaction of an
isocyanide with an electrophilic partner can lead to undesired (in this context)
polymerization processes (Scheme 30).
The mechanism leading to adduct G presents clear analogies with that of the
well established Ugi MCR, in which the isocyanide attacks the electrophilic carbon
of an iminium ion; for this reason, this process could be called the Ugi–Reissert
reaction (Scheme 31). However, in this transformation, the adduct arises after a
final hydration of the nitrilium ion, instead of undergoing the Mumm rearrangement
as in the traditional Ugi reaction [188]. The novelty here lies in the use of
N-acylazinium salts as a new source of reactive iminium ions for Ugi-type processes.
The Ugi–Reissert reaction is quite general [188]; it accepts a wide array of
isocyanides, azines (excluding pyridine and derivatives lacking unsubstituted
a-positions) and activating agents (chloroformates, acid chlorides, anhydrides,
+
R N C E
N+ N
E A F
B +
+
–
– R N C– + E+
C –
C
C N+
+N
R +N R
R N
N A Isocyanide
E polymerization
N processes
E N
R
HN O G H
R
Scheme 30 Azine-isocyanide MCRs

Reissert type N N+ N
E E
reaction + Nu + E Nu Nu
R3NC R1 R1
RCHO + R1NH2 + O
Ugi reaction N 3
H R N
+ R3NC + R2COOH R2COOH N R2
R quenching + H
R
rearrangement
Cl –
Ugi-Reissert +
reaction N N R N R
H2O
+ R3NC + RCOCI R3NC O quenching R3 O
N O
H
Scheme 31 Analogies between Reissert and Ugi MCRs
R
t-Bu
1
i) R -COCl R 2
N NH
R2 + R N
R3–N=C N O
N CO-R1 t-BuHN O Me-O O
ii) H2O quenching 3 225 R2 226
R
N O 224 Me
H
N O
Yields: 60-90% O 227
R3 O
Scheme 32 The Ugi–Reissert reaction and representative adducts
and tosyl chlorides), affording the corresponding adducts in good to moderate

yields (Scheme 32). In these reactions, the intermediate nitrilium ion is assumed
to be stabilized via coordination with the nucleophilic species (either the carbonyl
group or the chloride counter ion) and to be hydrolyzed via quenching during
aqueous work up.
A solid-phase Ugi–Reissert reaction on chloroformate resin, has been reported.
The product, the a-carbamoylated isoquinoline 230, is released by oxidative cleav-
age (Scheme 33a). Interestingly, the enamide moiety in the adduct can be exploited
to perform this process in tandem with a Povarov MCR [189, 190]. In this way, by
interaction of dihydroisoquinoline 231 with aldehydes, anilines and a suitable
Lewis acid catalyst, the polyheterocyclic system 232 was prepared (Scheme 33b).
The Zhu group devised an innovative approach for the synthesis of this class of
compounds. They employed the heterocyclic amine 233, which was oxidized in situ
to the dihydroisoquinoline 234 with IBX, to undergo the classic Ugi reaction.
Remarkably, all the components are chemically compatible, allowing the sequence
to proceed as a true MCR (Scheme 33c) [191].
a
O i) N O
Cl N N
6 DDQ
O O
t-Bu
tert-Bu-NC O 1, 4-Dioxane O N
CH2Cl2 NH 70% H
228 229 230
ii) H2O t-Bu
b
H
N CO2Et
Me NH2
H
i) Me-OCOCl
Me Me
tert-Bu-NC OHCCO2Et H
O N O N
N CH2Cl2 Sc(OTf)3 Me
6 ii) H2O O CH3CN O
O NHtBu O NH-tBu
231 232
c
60%
+ R–NC IBX R1 N
HN N
+ R1–COOH O R 235
233 234 O N
H Yields:
50-97%
Scheme 33 Ugi–Reissert MCRs: a solid-phase version, post-synthetic transformations, and

analogous processes
Zhu and coworkers implemented a family of Ugi-type MCRs, based on intramo-

lecular trapping of the intermediate nitrilium ion by a carboxamido group,
to prepare diversely substituted oxazoles as versatile synthetic intermediates
[192–194]. They later reported an interesting example of the Ugi–Reissert process
using this feature (237, Scheme 34a) [195]. This strategy enabled the direct addition
of isocyanides to the N-alkyl nicotinamide salts 239. However, the different
substitution pattern of the carboxamido group, led to a different outcome: isomeri-
zation of the putative bis-iminofurane intermediate to the cyano-carbamoyl deriva-
tive 240. Remarkably, the process is also efficient in a Reissert-type reaction
(Scheme 34b, c) [196].
In a similar context Arndtsen developed a new pyrrole synthesis from alkynes,
acid chlorides either imines or isoquinolines, based on the reactivity of isocyanides
(Scheme 35a) [197]. Although all atoms from the isocyanide are excluded from the
final structure, its role in the reaction mechanism is crucial. The process takes place
through the activation of the imine (isoquinoline) by the acid chloride to generate
the reactive N-acyliminium salt, which is then attacked by the isocyanide to furnish
a nitrilium ion. This cationic intermediate coordinates with the neighboring
carbonyl group to form a münchnone derivative, which undergoes a [3þ2] cyclo-
addition followed by subsequent cycloelimination of the isocyanate unit, to afford
the pentasubstituted pyrrole adducts 243 and 244 (Scheme 35a, b).
a
CO2Me
N N N
N OMe CO2Me CO2Me
6
+ NC CO2Me
ClCO2Me O 38 CO2Me N MeO2C
N O O O
O
Bn Bn CO2Me
3+2 MeO2C N
N Bn N cycloaddition N
237 238
236 O
76% O 35%
O O
b c
– Bn COOR2
Bn Bn
– + B Br N N
N N N
Br 2
C6H11NC ClCOOR
HN H2N
H 2N NC NC
R1NC
O O
O HN O HN O
239 NC6H5
C6H11 240 241
R1
242
B-H
Scheme 34 Internal trapping of the nitrilium intermediate by carboxamido groups
a 1
1 R
R
N O R NC 5 N 2
4 3 R R
+ + R R
5 2 i
R H Cl R NEt Pr2
4 3 243
R R
b O
C6H11–NC OMe
Cl N
N +
MeO2C CO2Me
6 OMe 38 244
MeO2C CO2Me
MeO2C CO2Me
38 C6H11–N C O
–
Cl OMe
N OMe OMe
+ + – N
N C6H11–NC +
H
O O
i
O N NEt Pr2 N
C6H11
C6H11
Scheme 35 Arndtsen pyrrole synthesis
In many of the precedent reactions, pyridines are inert, and activation of this
fundamental heterocycle remains problematic. To overcome this problem, more
powerful activating agents have been tested. For instance, Corey explored the use of
triflic anhydride (35) as an efficient method to link a variety of nucleophiles to the
pyridine g-position (see 34, Scheme 6) [49]. This reaction in the presence of
isocyanides affords a mixture of the a-and g-carbamoylated dihydropyridines 245
and 246 together with the corresponding oxidized products 2450 and 2460 , respec-
tively, in low overall yield (Scheme 36a). A major problem here is the massive
degradation of the isocyanide under these rather drastic conditions. Trifluoroacetic
a
Tf
N N
H H
N N
C6H11 C6H11
N C6H11 NC 245 O 245¢ O
Tf
N N
Tf2O H H
9 33 N N
C6H11 C6H11
O 246 O 246¢
Low overall yield
b
O H
N O
F C6H11 CF3
N C6H11 NC –
+
N
O N O
O O
N
9 C6H11
F3C O CF3
247 Not detected
54%
c
C6H11 O
N F
N C6H11 NC
–
O O N+ O
6 F3C O CF3 248

85%
Scheme 36 Tf2O- and TFAA-promoted isocyanide-azine MCRs
anhydride (TFAA) was then evaluated as a milder surrogate. Surprisingly, the

reaction did not yield the expected Ugi–Reissert product, but instead gave the
mesoionic acid fluoride 247 (Scheme 36b). Isoquinoline behaves similarly afford-
ing the analogous product 248, although in higher yields (Scheme 36c) [198].
The unusual connectivity pattern of the dipoles 247 and 248, whereby the
isocyanide nitrogen is linked to the a-carbon of the azine, suggests a markedly
distinct reaction mechanism (Scheme 37) to that of the Ugi–Reissert reaction. A
reasonable mechanistic proposal may involve the formation of the N-acylazinium
salt I, which would then be attacked at its a-position by the isocyanide, then leading
to the Arndtsen-type dipoles 249 (which have been isolated in some cases).
Alternatively, the isocyanide can attack the activated carbonyl group in I, triggering
a cascade leading to the generation and subsequent transformation of intermediate
L. This species can undergo cyclization, followed by ring closure to epoxide
M, rearrangement, formal elimination of HF, and aromatization, to yield dipole
248. Yet another possibility is that the isocyanide attacks the anhydride to form
the intermediate K, a direct precursor of the dipolar species L. This mode of
activation for isocyanides has been investigated by El Kaim, who promoted a series
of useful transformations based on this reactivity, leading to products such as
trifluoropyruvamides 250 (R ¼ F) [199–201].
N O
+ – R2
R2–N C – R1
6 O N+
O + O F F O
or O
R1 C R1
O C R1 C R1
N+ N C
F F + F F F F F2
+ –
I
2
R –N C J
R2 R2
R1 N
N OOCF2R1
O F O
R 1
O R1 R1
F + C F + C– C
F C O N F N F2
F O
K –
N L
N
6
R2 – 249
-F -F, -H, -Ph,
R1=
-CF3, -CF2CF3
H2O
R2 O O R2 O
R1 R2
N N 1
N R1
F F O H H R C–
2
C F + C +
R N O N N
R1 N – O O
HO OH H -F
250 M N 248
Scheme 37 Mechanistic proposals for the MCR of azines, isocyanides, and TFAA
N
O O O
Cl Cl 6 N
O – N
+
Cl Cl Cl Cl C6H11–NC N CCl3 251
O 30%
–CO2
CCl3–CO2–
O N
c-Hex O
N Cl
– N N
+ 6 –
+ +
N
O N
O
O P
Scheme 38 Cascade reaction of azines and isocyanides promoted by TCAA
The scope of the reaction is quite general, allowing reasonable variation for
each component. Apart from TFAA, substituted difluoroanhydrides also react,
yielding the expected derivatives with diverse groups attached to the exocyclic
carbonyl moiety. Chlorinated anhydrides are less reactive: and only trichloroacetic
anhydride (TCAA) leads to dipole 251 in moderate yield (Scheme 38). A new
a
NHR2 NHR2
Cl –
NR1 2 NR2
R –NC N+ NR1
N
+
+
N R1 +
MeS Cl N N+ NR1
252 SMe Cl – Cl –
9 SMe
SMe
253 254
b Yield: 60-100% Yield: 50-90%
Ph CN
+
255 CN N
N Ph Ph
+
+
N –
Ar–NC CN CN
6 N CN Ar–N
Ar CN
c 256
Yield: 40-90%
+
N ArNCS R2 –NC
O Br – PS-NEt2 N +
257 S–
R1 NHR2
NHAr N
258 2
R
+ N
Yield: 60-90% N–R2 NHAr
N N R1
Br R1 = 4–Br–C6H4–CO–
S– S 259
R1 R1
Yield: 20-50%
NHAr NHAr
d
Ar Ar
Ar-NC F–
F2 H2O NH N
+ N N N
N N+ N N–Ar 260 O N N
9 F– 66%
F F
261
TMS-N3 84%
Scheme 39 Isocyanide-azine MCRs promoted by various activating agents
domino reaction derives, in this case, from the higher reactivity of the putative acid
chloride adduct O, which can interact with another isoquinoline unit to generate a
new N-acylisoquinolinium cation P, which in turn may undergo an a-trichloromethy-
lation [198, 202].
Other electrophilic reagents have been used to activate azines in isocyanide-
promoted reactions. For example, reaction of the methyl chlorothioimidates 252
with pyridines and isocyanides provides convenient access to the fused imidazo-
lium salts 253 (Scheme 39a). The isocyanide attacks the a-carbon of the activated
pyridinium salt, and the resulting intermediate is then trapped by the nitrogen of the
activating agent to yield the product. The competing reaction of double isocyanide
insertion to give 254 has also been described [203]. Substituted alkenes also react
efficiently in analogous processes. For example, pyrroloisoquinoline derivative 256
was obtained in a straightforward manner by interaction of isoquinoline, Michael
acceptor 255 and aromatic isocyanides (Scheme 39b) [172, 204, 205]. Similarly,
Ley reported that reaction of an isocyanide with the isoquinolinium dipole 258
(generated from the interaction of the salt 257 with isothiocyanate) initiates a
sequence yielding amino-substituted pyrroloisoquinolines (259), pyrroloquinolines
and indolizines (Scheme 39c) [206]. Fluorine has also been used as activating agent
in a bicomponent processes in which pyridine and isocyanides react to form the
picolinamides 260 or the tetrazoles 261, whereby the intermediate nitrilium ion is
hydrolyzed or trapped with TMS-N3, respectively (Scheme 39d) [207, 208].
Alternative activating pathways are based on the coordination of the isocyanide
to the electrophilic reagent to furnish a nitrilium intermediate, which is the actual
reactive species attacked by the azine (see intermediate K in Scheme 37) [201]. In
this regard, Berthet described the reaction of azines and isocyanides with triflic acid
to obtain the imidazopyridinium salts 262, presumably through a cascade involving
double isocyanide incorporation. Interestingly, one equivalent of the isocyanide
generates the initial electrophilic intermediate, which goes on to be attacked by the
azine, and subsequently, the second equivalent of the isocyanide acts as the next
nucleophile; the sequence terminates upon nucleophilic ring closure promoted by
the amidine nitrogen (Scheme 40a) [209]. Related processes, in which the isocya-
nide is activated by acidic species, have been described by Shaabani [210–212].
Similar connectivity patterns arise from the interaction of azines with TOSMIC or
isocyanoacetate [213, 214]. This reactivity (isocyanide activation) was further
exploited by Mironov et al., who reacted isocyanides with isothiocyanates and
azines (isoquinolines or phtalazines) to prepare compounds 264 (Scheme 40b).
Mechanistically related processes include the reaction of isocyanides with alde-
hydes for in situ generation of the activated species, which is then attacked by the
azine (Scheme 41a). This strategy has been harnessed in a convenient synthesis of
a
+ R–NC R TfO – TfO –
TfO – +
+ TfOH TfO – N+ N
+
N R NHR
+ N N–R N
N N N
H N H N H H
9 R R
R 262
Yield: 50-70%
b
R N R HN R
+ N X S –S
+ R–NC N
N N X + N X
+ N N
X R1–NCS R1
S R1
– N
263
X = CH or N R1 264
Yield: 40-90%
Scheme 40 MCRs involving isocyanide activation mechanisms

a
+ R–NC
R
+ + N
N N R N N
H O R NH
N
– N
NF H O N N
F H O O
Q F
F
265 266 267
b R
R–NC N + H
R′
+ R
N R N
N NH2 C C
R′– CHO CHR′ CHR′
N N
H+ or LA N N N N
+ H H
268 (LA) R 269
Scheme 41 Additional isocyanide-activation processes
the fused dihydrooxazoles 267: the dipolar intermediate Q activates the azine,
whereas the alkoxide attacks as the nucleophile; the final product is obtained after
a proton shift [215]. The Bienaymé-Blackburn-Groebcke MCR – in which an
a-amino-azine, an aldehyde and an isocyanide react to yield the fused imidazo-
azine systems 269 (Scheme 41b) – could be considered in this section, as the
heterocyclic nitrogen of the azine intramolecularly attacks the activated nitrilium
species R, which is formed by addition of the isocyanide to the in situ generated
imine. In fact, this MCR constitutes the most reliable access to these products.
The process has been widely modified in each component, and has enabled the
preparation of a wide range of bioactive compounds [216–222].
Alternative reaction pathways exploring different synthetic possibilities have
been studied. For instance, electron-rich dihydroazines also react with isocyanides
in the presence of an electrophile, generating reactive iminium species that can then
be trapped by the isocyanide. In this case, coordination of the electrophile with
the isocyanide must be kinetically bypassed or reversible, to enable productive
processes. Examples of this chemistry include the hydro-, halo- and seleno-carba-
moylation of the DHPs 270, as well as analogous reactions of cyclic enol ethers
(Scheme 42a) [223, 224]. p-Toluenesulfonic acid (as proton source), bromine
and phenylselenyl chloride have reacted as electrophilic inputs, with DHPs and
isocyanides to prepare the corresponding a-carbamoyl-b-substituted tetrahydro-
pyridines 272–274 (Scheme 42b). Wanner has recently, implemented a related
and useful process that exploits N-silyl DHPs (275) to promote interesting MCRs.
These substrates are reacted with a carboxylic acid and an isocyanide in an
Ugi–Reissert-type reaction, that forms the polysubstituted tetrahydropyridines
276 with good diasteroselectivity (Scheme 42c) [225]. The mechanism involves
initial protiodesilylation to form the dihydropyridinum salt S, which is then
attacked by the isocyanide, en route to the final adducts.
Suprisingly, the use of iodine in an attempted iodocarbamoylation of a DHP led
instead to the benzimidazolium salt 279; in contrast, iodine monochloride (ICl)
a
Me E+ Me Me O
+
N
R-NC N+ N R
N
H
EWG EWG E EWG E
270 +
R–N C–E 271
b
Me
N
+ C6H11 – NC
EWG
270
RSO3H Br2 Ph-SeCl
Me O Me O Me O
N C6H11 N C6H11 N C H
N N N 6 11
H H H
EWG EWG Br EWG Se–Ph
272 273 274
c
iPr iPriPr R1 O O
Si R1COOH O –
H
N + N R2 O R1
R2NC N via : N+
H
275 276 S
Ph i Pr Ph i Pr Yield: 30-80% Ph i Pr
Scheme 42 Hydro-, halo- and seleno-carbamoylation of dihydropyridines
afforded the expected iodo-carbamoylated tetrahydropyridine 277 (Scheme 43)

[226]. The scope of this unprecedented transformation was studied through system-
atic variation of the substituents and was found to be quite general: aliphatic,
aromatic, and benzylic isocyanides have been reacted with a variety of DHPs
bearing several electron-withdrawing groups (Scheme 43). The use of labeled
precursors (2H-DHPs and 13C-isocyanides) provided meaningful data for establishing
a mechanistic rationale.
Although isolated in small amounts, the pyridinium salts 282 (arising from the
iodine-mediated oxidation of DHPs 281) do not afford benzimidazolium salts 279
in the presence of isocyanides. A likely pathway may start with the iodo-dihy-
dropyridinium intermediate 280, which can be formed by interaction of iodine with
the reactive double bond of the DHPs (Scheme 44). The isocyanide may subse-
quently attack these species to generate the nitrilium ion T, which interacts with
a second equivalent of isocyanide to form cation U. This intermediate undergoes
an intramolecular trapping by the enamine unit to close the bicyclic system V
I–
R O R +
C6H11 R
N C6H11 N N N
N ICl I2
H + C6H11 – NC R = Alk,
HN Ar, Bn
MeOOC I MeOOC C6H11
277 278 279
MeOOC
Scheme 43 Reactions of isocyanides, DHPs and different iodonium sources
1
R1 I– R R1 I– R
1
R–N +
N N I2 N I2 N
R–NC + +
I R2 I R2 R2 R2
280 282 R–NC
T 281
R–NC Detected
R
H2O –IH N
H
R N N + R1
1 R
N R
I–
R1 N
2
RHNOC N + R
N I 279
R R2
U 1 + R1
I R2 R N+ N
R
277 I– R–N Formed bonds
N
From ICl reactions
R–N
R2 2
R–N V X R
Scheme 44 Mechanistic proposal for the formation of benzimidazolium salts 279
(Scheme 44). Iodoiminium X may then be formed by iodide-mediated fragmenta-

tion, possibly evolving through ring closure and subsequent aromatization to yield
the final product 279. In the presence of ICl, the halocarbamoylated tetrahydropyr-
idine 277 is formed by the standard hydrolysis of nitrilium ion T. Therefore, the
nature of the free anion in the mixture appears to be critical for stabilizing the
nitrilium species and consequently promoting the formation of either 279 or 277.
Furthermore benzimidazolium salts 279 were tested in screening assays, looking for
new inhibitors for human Prolyl Oligopeptidase, (an enzyme expressed in the
central nervous system and involved in mental disorders), and some derivatives
displayed potent and selective inhibitory activities [227].
As a final remark for this section, it is evident that the complexity of some
processes together with the strikingly different synthetic outcomes, originated by
slight changes in the reactants, reflects our low capacity of prediction for these
MCRs. Therefore, more experimental work is needed to generate enough data that
may enable a future rationalization for these fascinating cascades.
7 Conclusions
Reissert’s initial discovery sparked research that continues to provide ever-growing

combinations of azines, activating agents, and nucleophiles for countless synthetic
applications. The structure of azines enables reactions with at least two other
components, thus making them a privileged class of reactants for the development
of new MCRs. The combination of azines with other types of bidentate compounds,
such as alkenes and isocyanides, can trigger complex cascade reactions, elegantly
leading to the corresponding MC-adducts in a single step. These products often
feature intricate connectivities and structural motifs, that are nearly impossible to
construct through classical stepwise approaches. The Reissert reaction and mecha-
nistic variations thereof provide ready access to several types of N-heterocyclic
systems, including the most common scaffolds found in natural products and
bioactive compounds. Furthermore, the modularity of this chemistry makes it very
attractive for generating the structural diversity sought in drug discovery. Future work
in this area should expand the already great impact of these methodologies on organic
synthesis.
Acknowledgments We warmly thank all the members of our research group involved in this
project for their enthusiasm and dedication. Financial support from the DGICYT (Spain, projects
CTQ 2003-00089, 2006-03794 and 2009-07758) is acknowledged. N. K. thanks the Spanish
Ministry of Science and Education for a grant. We are especially thankful to Laboratorios Almirall
and Grupo Ferrer (Barcelona) for their support.
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DOI: 10.1007/7081_2010_45
Microwave Irradiation and Multicomponent

Reactions
Jitender B. Bariwal, Jalpa C. Trivedi, and Erik V. Van der Eycken
Abstract A common theme throughout drug discovery and process development is

speed. With the emergence of combinatorial chemistry and high-speed parallel
synthesis, multicomponent reactions (MCRs) have seen a resurgence of interest.
MCRs are therefore becoming increasingly popular since they provide the possibil-
ity to introduce a large degree of chemical diversity in only one step! Microwave
irradiation under controlled conditions has been shown to be an invaluable technol-
ogy since it often allows to dramatically reduce reaction times from days or hours to
minutes or even seconds. Compound libraries can be rapidly synthesized in either a
parallel or sequential way using this new, enabling technology. The current chapter
highlights the application of microwave irradiation for MCRs during the last 4
years. More than 110 recent literature reports have been covered.
Keywords Microwave-assisted organic synthesis (MAOS) Multicomponent

reaction (MCR)
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
2 Recent Literature Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
2.1 Pyridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
2.2 Pyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
2.3 Quinolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
2.4 Imidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
2.5 Thiazolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
2.6 Pyrazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
2.7 Acridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
J.B. Bariwal, J.C. Trivedi, and E.V. Van der Eycken (*)
Department of Chemistry, Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Katholieke Universiteit Leuven, Celestijnenlaan 200F, 3001, Leuven, Belgium
e-mail: erik.vandereycken@chem.kuleuven.be
170 J.B. Bariwal et al.
2.8 Oxazepines, Thiazapines and Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

2.9 Chromens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
2.10 Pyrans and Furans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
2.11 Propargylamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
2.12 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
3 Conclusions and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
1 Introduction
One of the major tasks facing the pharmaceutical industry is improving the effi-
ciency of its explorative research. The development of chemical compounds with
desired biological properties is time-consuming and expensive. Therefore there
is an ever-growing interest in the development of high-throughput techniques that
allow for the fast synthesis and screening of chemical substances to identify
compounds with the required characteristics. The application of combinatorial
compound libraries plays nowadays an important role for reaching this goal and
multicomponent reactions (MCRs) are viewed as ideal tools to assemble large
compound libraries for medicinal purposes [1–4]. By minimizing the number of
synthetic operations while maximizing the buildup of structural and functional
complexity, these reactions are particularly appealing in this context. Since the
development of what we commonly know as the ur-MCRs as the Strecker amino
acid synthesis [5, 6], the Hantsch dihydropyridine synthesis [7, 8], the Biginelli
dihydropyrimidine synthesis [9, 10], the Mannich reaction [11, 12] and the iso-
cyanide-based Passerini reactions [13–15] and Ugi four-component reactions
[16–18], a rich arsenal of novel MCRs has been developed in recent years. The
fact that most MCRs are highly suited for automation makes them extremely
valuable for high-throughput synthesis.
According to Ugi, MCRs are one-pot procedures in which at least three easily
accessible starting materials react to give a single reaction product, in which all of
the atoms of the starting materials are incorporated [15]. However, considering the
wealth of existing literature nowadays concerning MCRs, we have to introduce the
concept of tandem reactions. Generalizing the definition given by Denmark, tandem
reactions are best described as one-pot sequences of two or more reactions [19].
In this regard, MCRs can be regarded as a subclass of either tandem sequential
or higher order tandem domino reactions. Tandem sequential reactions require the
addition of a supplementary reactant after completion of the first reaction step
enabling the propagation of the sequence [20]. Tandem domino reactions [21] are
processes in which every reaction step brings about the structural change required
for the following reaction step. The reaction proceeds without modification of the
conditions or addition of supplementary reagents. Ideally, at least the last reaction
step of a MCR should be irreversible in order to avoid the formation of a mixture
of products.
Microwave Irradiation and Multicomponent Reactions 171
The main concern for the development of high-throughput procedures is the rate
of the applied reactions. In this regard, the application of microwave irradiation has
been proven to be very useful. Since its dawn in 1986 with the first seminal publica-
tions of the groups of Gedye [22] and Giguere [23] the application of microwave
irradiation in organic synthesis has gained increasing popularity in the organic
synthetic lab. Started as a curiosity, this way of transferring energy to a reaction
mixture is steadily becoming the Bunsen burner of the present day [24]. Controlled
microwave irradiation under sealed vessel conditions has been shown to dramatically
reduce reaction times, increase product yields and to enhance product purity by
reducing unwanted side reactions compared to conventional synthetic methods
[25–28]. Microwave chemistry generally relies on the ability of the reaction mixture
to efficiently absorb microwave energy, taking advantage of “microwave dielectric
heating” phenomena such as dipolar polarization or ionic conduction mechanisms
[25]. The very efficient internal heat transfer results in minimized wall effects which
may lead to for example diminished catalyst deactivation [25]. Besides the generally
accepted thermal effects, one believes that there are some specific (but also thermal)
microwave effects, as e.g., the formation of “hot spots.” There is still some contro-
versy about the existence of nonthermal (athermal) microwave effects. At the present
time, new techniques as “cooling while heating” are being investigated and the
problem of upscaling for industrial purposes has been tackled with the introduction
of continuous and stop-flow microwave systems, although certainly still a long way
has to be gone. Therefore, it is no surprise that the application of microwave irradia-
tion has found its way to multicomponent chemistry as several of these MCRs suffer
from long reaction times [4, 29].
The present chapter is organized according to the class of scaffold that is
accessed via a MCR covering the literature from 2006 until present. A clear
distinction is made between the application of dedicated microwave instruments
and domestic microwave ovens. Although application of the last does not allow full
control of the parameters, we reasoned that it was nevertheless worthwhile to
include few of these examples. For more precise information about the conditions
the reader is referred to the appropriate literature. Taking into account the current
explosive developments in the field of MCRs, the present overview cannot be
regarded as being exhaustive but is rather meant to provide a useful introduction.
2 Recent Literature Reports
2.1 Pyridines
2.1.1 Dihydropyridines
1,4-Dihydropyridines, are very attractive targets because of their wide range of

pharmacological activities; they have been reported for their vasodilating, anti-
hypertensive, bronchodilating, anti-atherosclerotic, antioxidant, hepatoprotective,
antitumor, antimutagenic, antidiabetic, geroprotective, and photosensitizing

effects [30–34]. They are also important reducing agents for nicotinamide adenine
dinucleotide coenzyme [NAD(P)H] models [35, 36]. Many drugs possess the
1,4-dihydropyridine nucleus, such as nifedipine, [37, 38] which has been used in
clinical medicine since 1975, benidipine and lacidipine which are novel second
generation calcium channel antagonists [39] and BAY K 8644 which is a calcium
channel agonist [40].
Although numerous procedures have been developed for the synthesis of
1,4-dihydropyridines, the application of MCRs has been proven to be an excellent
strategy to prepare libraries of these compounds.
Li and co-workers [41] reported a facile one-pot two-step, MCR of a b-aroyl
thioamide, an aldehyde, an acetonitrile and an alkyl halide using microwave
irradiation to access highly functionalized hexa-substituted 1,4-dihydropyridines
1 in high yield in mere 18–25 min. The protocol was applied to aryl aldehydes
bearing electron-withdrawing as well as electron-donating groups and also to
aliphatic aldehydes. The nature of the substituents of the aryl aldehydes has no
significant impact on the conversion (Scheme 1).
A new series of some spiro-1,4-dihydropyridines 2 has been synthesized by
Hatamjafari [42] in good yields using a four-component, solvent-free process by the
condensation of isatin, a primary amine, ethyl cyanoacetate and cyclohexanone
absorbed on different solid supports under microwave irradiation applying a
domestic oven. The report reveals that the application of montmorillonite K10 led
to higher yields as compared to other solid supports (Scheme 2).
R2 O
O S
NC R3 1. Et3N R3
2. KI, KOH, R4X R1
NHPh +
R1 H2N 4
O MW, 78°C, N SR
18-25 min
R2 H
1
33 examples, 41-84%
Scheme 1
R2
N
R2 NC COOEt
O R1
O
N COOEt
Montmorillonite K10
O + + +
R1 R3–NH2 MW, 4 min
N NH2
O
R3
2
7 examples, 78-97%
Scheme 2
2.1.2 Pyridines
The pyridine nucleus is a key constituent of many synthetic and naturally occurring
bioactive compounds [43–46]. Streptonigrin, streptonigrone, and lavendamycin are
described as anticancer drugs and cerivastatin is reported as a HMG-CoA enzyme
inhibitor [47]. Substituted pyridines are used as leukotriene B-4 antagonists [48].
Pyridines have been invoked as functional modules within the domain of supramo-
lecular chemistry, coordination chemistry, and material science [49–51]. They are
employed as chelating ligands in coordination chemistry, as building blocks in
supramolecular chemistry, as metal-containing polymers and in molecular elec-
tronics, optoelectronic devices, light-emitting diodes, solar cells and photoactivated
species [52, 53]. Therefore, it is no surprise that much attention has been paid to the
development of efficient procedures for the synthesis of functionalized pyridines.
Yen and co-workers [54] have reported an efficient one-pot procedure for the
synthesis of 4,6-diaryl-2-pyridinones 3 based on a cyclocondensation reaction of
N-ethoxycarbonyl-methylpyridinium chloride or N-carbamoylmethyl pyridinium
chloride with an aromatic aldehyde and a substituted acetophenone. The MCR
was performed under microwave irradiation (domestic oven) with NH4OAc/AcOH
as the reaction medium. The nature of the substituents on the aromatic aldehyde
and ketone seem to have little influence on the obtained yields. The highlights of
this approach include a convenient and simple experimental procedure with easy
product isolation (Scheme 3).
Recently, Tu and co workers [55] reported a green and facile synthesis of
2,6-diaryl-4-styrylpyridines 4 via a microwave-assisted MCR of an 3-arylacrylal-
dehyde oxime, a 1-arylethanone and ammonium acetate under solvent-free condi-
tions. Electron-donating groups on the 3-arylacrylaldehyde oxime seem to prolong
the reaction time. This protocol offers a broad scope of applicability (Scheme 4).
Tu and co-workers [56] have developed a facile and selective synthesis of
N-substituted 2-aminopyridines 5 via a microwave-assisted MCR which is con-
trolled by the basicity of the amine and the nature of the solvent. When reacted in a
solvent mixture of DMF/HOAc (1:1), the desired aminopyridine 5 was formed next
to 2,6-dicyanoanilines in nearly equal amounts. However, when the volume ratio
was increased to 1:4, compound 5 was obtained as the main product. The elaborated
Ar1
Ar1CHO
NH4OAc/AcOH
+ Cl –
N MW, 2-4 min Ar2 N OH
Ar2COCH3
E
3
O
7 examples, 65-82%
E = NH2, OEt
Scheme 3
Ar1
H
H
O solvent free
+ + NH4OAc
Ar1–CH=CH–CH=N–OH
Ar2 MW, 110°C,
6-18 min
Ar2 N Ar2
4
12 examples, 76-87%
Scheme 4
Ar1
Ar1
NC CN DMF/AcOH (1:4) NC
+ R1
R1–NH2 MW, 100°C, N N Ar2
O Ar2 3-9 min H
5
29 examples, 76-90%
Scheme 5
Ar O
NC CN NC
Glycol/AcOH O
ArCHO +
NH2 O MW, 120°C, H2N N
6-10 min
O 6
11 examples, 82-89%
Scheme 6
method is superior to the existing ones in view of the simplicity of the purification
(recrystallization) and the good yields that are obtained (Scheme 5).
The same group also published a facile one-step synthesis of methyl 4-substituted-
6-amino-5-cyano-2-methylpyridine-3-carboxylates 6 via a three-component reac-
tion of an aromatic aldehyde, malononitrile and methyl 3-aminobut-2-enoate under
microwave irradiation. A mixture of glycol/HOAc (2:1) was used at a ceiling tem-
perature of 120 C delivering the compounds very rapidly in excellent yields.
Aromatic aldehydes, bearing electron-donating or electron-withdrawing functional
groups and heterocyclic aldehydes have been proven to show excellent reactivity
under these conditions [57] (Scheme 6).
Sridhar and co-workers [58] investigated the synthesis of 2-amino-3,5-dicarbo-
nitrile-6-thio-pyridines 7 via a MCR of a suitable aldehyde with malononitrile and
thiophenol, using a variety of Lewis acid catalysts such as ZnCl2, AlCl3, FeCl3, I2,
Cu(OTf)3, InCl3 and BF3·Et2O under microwave irradiation at a ceiling temperature
of 100 C in ethanol. ZnCl2 was found to be highly efficient yielding the derived
compounds in 46–77% yield in mere 2–3 min. Applying the optimized protocol, a
variety of substituted pyridines was synthesized using aliphatic and (hetero)aro-

matic aldehydes (Scheme 7).
A series of 4-aryl-3,5-dicyano-2,6-di(30 -indolyl)pyridines 8 was synthesized by
Ji and co-workers [59] via a one-pot MCR of an aromatic aldehyde, a 3-cyanoacetyl
indole and ammonium acetate under microwave irradiation. The optimum ceiling
temperature was found to be 140 C with AcOH/glycol (1:2) mixture as the solvent
of choice. This protocol can be applied to aromatic aldehydes bearing electron-
withdrawing as well as electron-donating groups and also to heterocyclic aldehydes.
This MCR allows the incorporation of both the indole and the 3,5-dicyanopyridine
moiety into a single molecule (Scheme 8).
A series of 4-aryl-6-(1H-indol-3-yl)-2,2-bipyridine-5-carbonitriles 9 was syn-
thesized by Perumal and co-workers [60] via a one-pot MCR of an aromatic
aldehyde, a 3-(cyanoacetyl)indole, 2-acetyl pyridine and ammonium acetate by
microwave irradiation under solvent-free conditions. The compounds were obtained
in high yields and in a very short period of time as compared to conventional heating.
Remarkably, when 2,4-dichlorobenzaldehyde was used in this reaction, only the
Hantzsch 1,4-dihydropyridine was isolated which had to be separately dehydroge-
nated to get the targeted pyridine (Scheme 9).
R1
O 2NC CN NC CN
+ ZnCl2, Ethanol
1
R H
Ph–SH MW, 100°C, S N NH2
2-3 min Ph 7
9 examples, 46-77%
Scheme 7
Ar
CN NC CN
O
NH4OAc, R1 R1
AcOH/glycol
+ ArCHO N
2R1 MW, 140°C,
HN NH
N 12-16 min 8
H
16 examples, 71-86%
Scheme 8
CN Ar
O
NC
NH4OAc
+ + ArCHO N
N N MW, 120°C, N
H HN
13-18 min 9
O
10 examples, 77-90%
Scheme 9
Patel and co-workers [61] have reported the microwave-assisted synthesis of

a series of 3-(2,6-diphenyl-4-pyridyl)hydroquinolin-2-ones 10 by a one-pot cyclo-
condensation reaction under Krohnke’s reaction conditions using 2-chloro-3-for-
myl quinoline, an acetophenone and N-phenacylpyridinum chloride in a mixture of
ammonium acetate and acetic acid. Different kinds of substituents on the quinoline
and acetophenone are well tolerated and most compounds 10 are obtained in
high yield. This method allows the easy introduction of various substituents in
the 2-, 4- and 6-positions of the pyridine 10 (Scheme 10).
Zhou and co-workers [62] have reported a series of 2-amino-6-(2-oxo-2H-
chromen-3-yl)-4-pyridine-3-carbonitriles 11 by a one-pot, MCR of 3-acetyl-
coumarin, an aromatic aldehyde, malononitrile, and ammonium acetate in acetic
acid using a domestic microwave oven. Aromatic aldehydes bearing electron-
withdrawing groups gave rather low yields of 11 (Scheme 11).
The microwave-assisted synthesis of indeno[1,2-b]pyridines 12 and 13 have
been reported by Tu and co-workers [63]. The 5H-indeno[1,2-b]pyridin-5-one
framework is present in the alkaloids from Annonaceae species that represent a
small but biologically intriguing group of compounds [64, 65]. Applying a micro-
wave-assisted MCR with a suitable aldehyde, an acetophenone, a 1,3-indanedione
or a 1-indenone and ammonium acetate in DMF, a small library of compounds 12
R1
O NH
N
+ O
Cl– NH4OAc, AcOH
+
COCH3 MW, 118°C,
R1 CHO 3-5 min N
R2
N Cl 10
R2 24 examples, 82-92%
Scheme 10
Ar
CN
O
ArCHO NH4OAc/AcOH
N NH2
+ CN
MW, 10-13 min O O
O O
CN 11
9 examples, 61-86%
Scheme 11
Ar1 O
O Ar1CHO
NH4OAc /DMF
+
MW, 120°C Ar2 N
Ar2COCH3 6-15 min
O 12
26 examples, 57-89%
Scheme 12
O Ar1
Ar1CHO
NH4OAc/DMF
+
MW, 120°C
Ar2COCH3 Ar2 N
8-15 min
13
9 examples, 57-83%
Scheme 13
O Ar O
CN
NC
Ar + DMF
NC + R1SH or R1NH2
MW, 120°C, R1
X N
O 4-12 min
X = S, NH
14
31 examples, 78-91%
Scheme 14
and 13 was synthesized in good yields. Aromatic aldehydes bearing electron-rich

group require longer reaction time (Schemes 12 and 13).
The same group has also developed a novel microwave-assisted three-component
reaction between an arylidenemalononitrile, a 1,3-indanedione and a mercaptoacetic
acid or a 4-methyl-benzenethiol or a substituted amine to afford a series of new
polysubstituted indeno[1,2-b]pyridines 14 bearing a mercapto group or an amino
group in the 2-position (Scheme 14). Arylamines containing either electron-donating
groups or electron-withdrawing groups gave excellent results [66].
DiMauro and co-workers [67] have developed a rapid and efficient synthesis
of 3-amino-imidazopyridines 16 using a microwave-assisted one-pot cyclization.
The intermediate 15 was further reacted with various aryl bromides in the presence
of a catalytic amount of Pd(dppf)Cl2 to yield the target compounds 16. The reac-
tion scope is quite broad with respect to the aldehyde and aryl bromide compo-
nents which might be electron-rich, electron-poor, aromatic, aliphatic, or sterically
encumbered (Scheme 15).
NH2 R1CHO, CNR2 N R3Br, aq K2CO3

N
MgCl2 (4 Mol%), R1 Pd(dppf)Cl2
N N R1
MeOH O (10 Mol%) N
B R3
MW, 160°C, O NH MW, 90°C, NH
R2 30 min R2
B 10 min
O O
15 16
15 examples, 0-68%
Scheme 15
N
NH2 R1
ZnCl2 (5 mol %) N
N + R1CHO + CNR2
MW, 60 min NH
R2
17
8 examples, 14-78%
Scheme 16
The synthesis of the same nucleus (imidazo[1,2-a]pyridines) 17 has been

described by Rousseau and co-workers [68] applying zinc chloride. In a domestic
microwave oven, in one-pot fashion, a number of imidazo[1,2-a]pyridines has
been synthesized in reasonable yields and with short reaction times. The reaction
with nicotinaldehyde did not proceed to completion, as zinc chloride form a stable
complex with the imine. However, when Montmorillonite clay K10 was used as
catalyst, the desired product was obtained in good yield (Scheme 16).
Similarly, a novel one-pot microwave-assisted reaction has been described
by Hulme and co-workers that enables the selective formation of 3-iminoaryl-
imidazo[1,2-a]pyridines 19 and imidazo[1,2-a]pyridyn-3-ylamino-2-acetonitriles
20, in good yields. Reactions were performed in methanol by mixing a suitable
a-aminopyridine, an aldehyde and trimethylsilylcyanide (TMSCN) with polymer-
bound scandium triflate, to afford either product 19 or 20 (Scheme 16). Initially, the
3-iminoaryl-imidazo[1,2-a]pyridine 19, was observed as a minor side product (0–
10%) during the pseudo-Ugi reaction affording the 3-aminoimidazo[1,2-a]pyridine
18. However, by increasing the aldehyde input to 2.2 equiv the reaction could
be directed to the formation of 19 in moderate yields. Interestingly, low yields of
20 were detected with aromatic aldehydes, whereas nonaromatic aldehydes were
easily undergoing the second Strecker reaction in high yields [69] (Scheme 17).
Yadav and co-workers [70] described two very efficient and unprecedented
one-pot high-yielding synthetic approaches to imidazo[1,2-a]pyridine scaffolds
21 starting from carbohydrates. The first approach involves a microwave-assisted
acid-catalyzed domino reaction of unprotected D-glucose or D-xylose with am-
monium acetate and a benzoin to afford a polyhydroxy iminosugar-bearing
tetrahydroimidazo[1,2-a]pyridine 21a or 21b. In the second approach, poly-
hydroxy iminosugar-bearing tetrahydrobenzimidazo[1,2-a]pyridines 21c and 21d
R2 R2
PS-Sc(OTf)3 NH2 HN
R2CHO (5 mol %) N
CN
1 N + MeOH N N N
R R 1
R 2
R1
R2 R1 R2
NH2 Si CN MW, 140°C, N N N
5-20 min 18 19 20
6 examples, 31-51% 6 examples, 62-77%
Scheme 17
OH
OH HO OH
HO OH
N N
N N OH
OH
Ar2 CHO
Ar1 n=4 n=4
21a oxalic acid (CHOH)n oxalic acid 21c
CH2OH OH
OH MW, 80°C, MW, 80°C,
D-glucose, n=4 8-14 min HO OH
HO OH n=3 9-13 min D-xylose, n=3 n=3
Ar 2 O NH2
N N N
N
1
Ar OH NH2
Ar2 Ar1 +
21b NH2OAc
21d
8 examples, 80-96%
8 examples, 79-81%
Scheme 18
were synthesized by reacting D-glucose or D-xylose and 1,2-diamines in the pres-

ence of 10 mol% of oxalic acid under solvent-free microwave irradiation condi-
tions. The protocol is generally high yielding and offers an easy access to
chemically and pharmaceutically relevant products (Scheme 18).
Li and co-workers [71] have presented a green and efficient reaction using
KF/neutral Al2O3 cooperating with PEG 6000 an environmentally friendly, highly
active catalyst. Under microwave irradiation the reaction leads to the unusual
thiochromeno[2,3-b]pyridines 22 via a sequence of Knoevenagel condensation,
Michael addition, cyclization, and intramolecular nucleophilic substitution. In this
one-pot, three-component reaction, seven different active sites are involved and two
C–C bonds, one C–S bond, one C–N bond, and two new rings are constructed. The
nature of the solvent is significantly affecting the yield of the reaction. In general
the application of protic or polar solvents such as ethanol, results in high yields
while, non polar solvents like dichloromethane afford low yields due to the forma-
tion of many byproducts. Interestingly, the reaction is also working better with
aromatic aldehydes (Scheme 19).
Chebanov and co-workers [72] studied the microwave-assisted three-component
reaction of a 3-substituted 5-aminopyrazole with pyruvic acid and an aromatic
aldehyde yielding a pyrazolo[3,4-b]pyridine-4-carboxylic acid 23 as the major
KF/neutral Al2O3 O R2
NC CN R2CHO cat. PEG 6000 CN
+ EtOH R1
O S
MW, 80°C, S N NH2
NHPh 20-35 min Ph
R1
Cl 22
29 examples, 62-88%
Scheme 19
O OH
R1
R1 O
Ethanol, HCl
+
N OH + ArCHO N
N NH2 MW, 150°C N N Ar
O
R2 10 min R2
23
8 examples, 35-45%
Scheme 20
O R2
CN
CN
R1 Glycol R1
N
+ R2CHO + N NH2 MW, 150°C,
N N N
N Ph
H Ph 6-15min
NH
24
20 examples, 67-88%
Scheme 21
product. They found that this condensation could be carried out very efficiently
either in acetic acid or in ethanol in the presence of HCl as catalyst. Yields for both
protocols were similar and also comparable to the yields obtained under conven-
tional reflux conditions, although the microwave-assisted reactions were much
faster (Scheme 20).
Ji and co-workers [73] have elaborated a simple and efficient approach for the
synthesis of highly functionalized pyridines 24 via a one-pot, three-component
reaction under microwave irradiation. This method enables the incorporation of a
pyrazolo[3,4-b]pyridine and an indole moiety into the same molecule. The synthe-
sis was achieved by reaction of a suitable aldehyde and 3-cyanoacetyl indole with
5-aminopyrazol. Particularly valuable features of this method include high yields,
broad substrate scope, and short reaction times. It has been observed that when
there are electron-withdrawing groups on the aryl aldehyde this results in a faster
and higher yielding reaction (Scheme 21).
Tu and co-workers [74] have synthesized a series of new polycyclic-fused
isoxazolo[5,4-b]pyridines 25–29 by a one-pot tandem reaction under microwave
O Ar
O
Water
ArCHO + H2N N + O O N
O MW, 120°C, O
O N
3-7 min
25
8 examples, 84-91%
O Ar
O
Water N
ArCHO + H2N N +
O N O
MW, 120°C,
O 5-8 min 26
10 examples, 88-94%
O O Ar O Ar
Water
ArCHO + H2N N + N or N
O O O
MW, 120°C, N N
O H
27-28 29
27 = 12 examples, 8 examples,
6-9 min, 87-95% 3-6 min, 83-89%
28 = 6 examples,
4-6 min, 84-95%
O O O O
O
=
O
O O O O
for 27 for 28 for 29
Scheme 22
irradiation in water. Interestingly, the reaction proceeds without any catalyst but
the aliphatic aldehydes did not work under this protocol. It is noteworthy that with
cyclohexane-1,3-dione, 1,4-dihydropyridines 28 are obtained. This method repre-
sents a green protocol and is highly suitable for library synthesis in drug discovery
programs (Scheme 22).
A one-pot, multicomponent, microwave procedure was efficiently applied for
the synthesis of a series of diaza- and dibenzofluorenediones. The synthetic
sequence starts by reacting 6,7-dichloroquinoline-5,8-dione or its metal complex
with pyridine or 4-methyl pyridine and ethyl acetoacetate to get two regioisomers,
N,N-syn 30 or 32 and N,N-anti 31 or 33. It has been found that DMSO is the solvent
of choice resulting in high regioselectivity and good yields. However, when a
catalytic amount of MgCl2 was used, a different regioselectivity was observed
yielding 30/31 in the ratio of 8:92 [75] (Scheme 23).
Similarly, pentacyclic ring systems were accessible when isoquinoline was used
instead of pyridine, resulting in the formation of diaza-dibenzofluorenediones 34
O
O O
O
Cl
N N R1
N Cl R1
O
O O O
or + + DMSO 30 R1 = H, 32 R1 = CH3
O O +
N MW,110-140°C O
Cl 4-6 min R1
N
N Cl
R1 = H, CH3 N
Mn+ O
O O
O
31 R1 = H, 33 R1 = CH3
30 /31 (80:20), Yield 94%
32 / 33 (80:20), Yield 85%
Scheme 23
O
O O
O N N
Cl O O O
DMSO 34
+
N+ O
N Cl MW,110-140°C +
O
O 4-6 min
N
N
O O
O
35
34/35 (72:28), Yield 87%
Scheme 24
and 35. A high selectivity of 72:28 was observed when DMSO was used as the
solvent. Applying a catalytic amount of MgCl2, the ratio of 34/35 shifted to 15:85
[75] (Scheme 24).
Shu-Jiang and co-workers [76] have developed a green approach for the synthe-
sis of biologically important indeno[2,1-e]pyrazolo[5,4-b]pyridines 36 via a MCR
of a suitable aldehyde, 3-methyl-1-phenyl-1H-pyrazol-5-amine and 1,3-indane-
dione in water under microwave irradiation without the aid of any catalyst. This
protocol has the prominent advantages of being environmentally benign and having
O Ar O
N Water
ArCHO + + N
N MW, 100°C, N N
Ph NH2 O 5-9 min Ph
36
10 examples, 92-97%
Scheme 25
Ar Ar
OH O
NH4OAc O
Catalyst + 4H2O
+
MW, 150°C, N
ArCHO
50 min
OH
37
Cl– 14 examples, 40-71%
Catalyst = OSO3H
H3C N N
+
Scheme 26
a broad scope delivering the compounds in a short reaction time, with excellent
yields (Scheme 25).
Wu and co-workers [77] have developed a novel, simple and efficient method for
the synthesis of 2,4,5-triaryl-5H-chromeno[4,3-b]pyridines 37 under microwave
radiation via a three-component cascade reaction of 2-hydroxyacetophenone, an
aromatic aldehyde and ammonium acetate catalyzed by 2-10 -methylimidazolium-
3-yl-1-ethyl sulfate. When an insufficient amount of (or no) catalyst was used,
solely the corresponding chalcone was formed. Nine new bonds and two new rings
are generated in a one-pot process with water as the only byproduct (Scheme 26).
2.2 Pyrimidines
2.2.1 Dihydropyrimidines
Dihydropyrimidines (DHPMs) and their derivatives have received significant

attention owing to their wide range of pharmacological properties such as anti-
viral [78], antimitotic [79], anticarcinogenic [80], antihypertensive [81], calcium
channel modulator [82], a1-antagonist [83] and neuropeptide Y (NPY) antagonist
activity [84]. Additionally, the marine alkaloids batzelladine A and B containing
the DHPMs core, have been used to inhibit the binding of HIV gp-120 to CD4
cells [85]. Therefore, efforts for the development of simple, convenient, rapid and
environmentally benign procedures for the synthesis of DHPMs based on the idea
of green chemistry were elaborated in recent years.
Sulfated zirconia (ZrO2/SO42) solid superacid has been proven by
Gopalakrishnan and co-workers [86] to be an efficient reusable heterogeneous cata-
lyst for the three-component one-pot cyclocondensation reaction of a b-dicarbonyl
compound and (thio)urea with an aromatic aldehyde under solvent-free conditions
furnishing the corresponding 3,4-dihydropyrimidin-2(1H)-ones and -thiones 38 in
good to excellent yields. A substantial improvement of the yields was established
when the reactions were run under microwave irradiation instead of conventional
heating. The yields were practically unaffected upon recycling the ZrO2/SO42
solid superacid up to five times (Scheme 27).
The Biginelli reaction has been investigated by Chang, Ahn and co-workers [87]
under solvent-free conditions, catalyzed by porous material or Lewis acid supported
porous material, such as MCM-41, SBA-15, VSB-5, Nanopore Silica, FeCl3/MCM-
41, FeCl3/Nanopore Silica, CeCl3/Nanopore Silica and InCl3/Nanopore Silica.
Aromatic aldehydes carrying either electron-donating or electron-withdrawing
substituents afforded good yields of the products 39 using MCM-41 as the catalyst.
When FeCl3/Nanopore Silica was employed as heterogeneous catalyst, the yield of
the Biginelli products 39 was found to increase dramatically. This reaction repre-
sents a very cost efficient procedure (Scheme 28).
A new microwave-assisted protocol for the generation of diversely substituted
3,4-dihydropyrimidine-5-carboxylic acid esters 40 has been developed by Kappe
and co-workers [88, 89] using trimethylsilyl chloride (TMSCl) as a mediator for
the Biginelli MCR. This involved the reaction of S-ethyl acetothioacetate or
ethyl acetoacetate, an aromatic aldehyde and (monosubstituted) urea or thiourea
as building blocks. Also sterically hindered aromatic and heterocyclic aldehydes
O Ar
ArCHO
R1
O O + NH2 ZrO2 /SO42– O NH
R1 H2N MW, 53-69°C H3C N X
O X
30-60 s H
38
X = O, S
20 examples, 87-98%
Scheme 27
O Ar
ArCHO
O
+ FeCl3 / Nanopore Silica EtO NH
EtO NH2
MW, 180°C, N O
H
O H2N O 12 min
39
7 examples, 36-73%
Scheme 28
performed well in this reaction. Compared to the use of other Lewis acids, the
desired DHPMs were obtained in short reaction times and high yields (Scheme 29).
The microwave-assisted Biginelli reaction was also optimized by the same
authors under continuous flow conditions [90]. An equimolar reaction mixture of
benzaldehyde, ethyl acetoacetate and urea was injected at a flow rate of 2 mL/min at
a ceiling temperature of 120 C providing 52% of the desired DHPM 41 in 13 min of
total processing time (5 min residence time in the cell). This flow rate allows the
preparation of compound 41 on a 25 g/h scale (Scheme 30).
Nanosized sulfated tin oxide (STO) particles dispersed in the micropores
of Al-pillared clay (STO/Al-P), were used by Mishra and co-workers [91] as
an environmentally benign, recyclable and efficient catalyst for the solvent-free
synthesis of 3,4-dihydropyrimidin-2(1H)-ones 42 using a domestic microwave
oven. The protocol offers advantages in terms of simple experimentation, reusable
catalyst, excellent yields, short reaction times, and preclusion of toxic solvents
(Scheme 31).
ArCHO O Ar
O
TMSCl, MeCN
+ NH2 EtX NH
EtX
MW,120°C,
HN O/S 10 min N O/S
O
R1 R1
X = O, S R1 = H, CH3,C2H5 40
13 examples, 53-94%
Scheme 29
O Ar
ArCHO
O EtOH/AcOH/HCl EtO NH
+
EtO NH2 Batch: MW,120°C, N O
5 min residence time H
O H2N O (2 mL /min flow rate) 41
52%
Scheme 30
O Ar
ArCHO
STO/Al-P, solvent free
R1 NH
O
O O + MW, 60-120 s
R2 N O
H2N NH2 H
R1 R2
42
13 examples, 83-94%
Scheme 31
A novel and efficient ionic liquid synthesis of DHPMs has been developed by
Bazureau and co-workers [92] in which ionic liquid-phase bound acetoacetate was
reacted with (thio)urea and a suitable aldehyde in the presence of HCl affording
ionic liquid-phase supported 3,4-dihydropyrimidine-2-(thi)ones 43. The desired
3,4-dihydropyrimidine-2-(thi)one was easily cleaved from the ionic liquid-phase
by transesterification under mild conditions in good yield and with high purity.
Advantageously, the ionic liquid-phase linked DHPM could be crystallized from
the excess of (thio)urea (Scheme 32).
A simple, efficient and modified Biginelli procedure was developed by Shah
and co-workers [93] for the synthesis of tetrahydropyrimidines 44 by a solvent and
catalyst-free condensation of a 1,3-dicarbonyl compound, an aryl aldehyde and
(thio)urea applying microwave irradiation. The desired compounds 44 were
obtained in short reaction times and in better yields compared to conventional
heating (Scheme 33).
An efficient and high-yielding protocol was established by Wang and co-workers
[94] for the synthesis of 5-unsubstituted-3,4-dihydropyrimidin-(1H)-ones 45 involv-
ing a three-component, one-pot solvent-free condensation of an aromatic aldehyde,
acetophenone and urea using ZnI2 as the catalyst applying a domestic microwave
oven. Aliphatic aldehydes did not deliver the expected products 45 using this protocol
(Scheme 34).
Sheibani and co-workers [95] reported the synthesis of 4-amino-5-pyrimidine-
carbonitriles 46 via a three-component reaction of malononitrile, an aldehyde and a
N-unsubstituted amidine in water, in the presence of sodium acetate applying a
domestic microwave oven. This method provides a new route to produce pyrimi-
dine derivatives in good to excellent yields (Scheme 35).
+ O
N O
N – N
O O .PF6 N
HCl (cat.) HN O +
+ X O
MW, 10 min X N .PF6–
O H
O H N NH2 O
2
O 43
X = O, S
2 examples, 96-98%
Scheme 32
O Ar
O ArCHO H H
+ NH2 Solvent free NH
HO
O F3C O H2N X MW, 110-120°C, O F3C N X
H
1.5-6.5 min
44
X = O, S
15 examples, 78-85%
Scheme 33
O O
H2N NH2 HN NH
Znl2, solvent-free
+
ArCHO MW, 8 min Ph Ar
PhCOCH3
45
16 examples, 71-96%
Scheme 34
NH Ar
H2O CN
R1 NH2 · HCl N
+ ArCHO CH3CO2Na
R1 N NH2
MW, 25-120 s
NC CN 46
11 examples, 67-96%
Scheme 35
2.2.2 Fused Pyrimidines
Moving to fused pyrimidines, Tu and co-workers [96] elaborated a microwave-

assisted three-component reaction for the synthesis of 2-amino pyrido[2,3-d]pyr-
imidines 47–50. 2,6-Diaminopyrimidin-4-one was reacted without any catalyst
with an aldehyde and malononitrile, ethyl cyanoacetate, 2-cyanoacetamide or
Meldrum’s acid. Importantly, aromatic and aliphatic aldehydes perform equally
well in the reaction to give the desired products in good yields (Scheme 36).
A new procedure has been developed by Prajapati and co-workers [97] for the
synthesis of pyrimido[4,5-d]pyrimidines 51. The condensation was carried out in
the solid state under microwave irradiations by reacting electron-rich 6-[(dimethy-
lamino)methylene]amino uracil that undergoes a [4+2] cycloaddition reaction with
in situ generated glyoxylate imine to provide novel pyrimido[4,5-d]pyrimidines 51
in excellent yields (Scheme 37).
A series of 1,2,4-triazolo[4,3-a]pyrimidines 52 was synthesized in excellent
yield by Dandia and co-workers [98] via a microwave-assisted reaction of the
1H-1,2,4-triazol-5-amine, a suitable carbonyl compound and malononitrile in aque-
ous medium. A variety of aromatic aldehydes and cyclic and aliphatic ketones was
successfully used to give the desired compounds 52 in good to excellent yields. The
reactions were carried out in a domestic microwave oven (Scheme 38).
Boruah and co-workers [99] developed an efficient procedure for the synthesis
of ring-A fused [3,2-b]pyrimidines 53 in a steroidal moiety. The novel steroidal
pyrimidines were prepared via a solid phase three-component reaction of a 2-hydro-
xymethylene-3-keto steroid, an arylaldehyde and ammonium acetate under micro-
wave irradiation. This protocol has been applied successfully to the cyclization of
bicyclic, monocyclic and acyclic 2-hydroxymethylene ketones with diversely sub-
stituted aromatic aldehydes (Scheme 39).
O R1
CN
HN
H2N N N O
H
49
8 examples, 73-94%
MW, 120°C
NC CONH2 6-8 min
O
O O
O R1 O R1
CN HN O O
NC CN HN
HN
H2N N NH2
H2N MW, 120°C MW, 120°C H2N N N O
N N NH2 + 7-10 min H
6-8 min 50
47 R1CHO
8 examples, 74-99% 8 examples, 78-93%
MW, 120°C
NC COOEt 6-8 min
O R1
CN
HN
H2N N N O
H
48
8 examples, 73-94%
Scheme 36
O O COOEt
Ar
N N N
Neat conditions
O N N NMe2 O N N
MW, 110°C,
3.5-4.5 min
COOEt + ArNH2 51
CHO 6 examples, 80-95 %
Scheme 37
N N
N NH O aq. medium NH
+ NC N
CN +
N NH2 MW, 7-13 min NH2
CN
Substituted aromatic
aldehyde or cyclic 52
ketone
10 examples, 78-94%
Scheme 38
A efficient three-component solution-phase condensation of a 3-amino-5-

alkylthio-1,2,4-triazoles with an aromatic aldehyde and an acetoacetamide was
developed by Chebanov and co-workers [100] for the rapid synthesis of 7-aryl-
2-alkylthio-4,7-dihydro-1,2,4- triazolo[1,5-a]pyrimidine-6-carboxamides 54. All
reactions were completed within 5 min of microwave irradiation at 120 C and
provided the desired dihydroazolopyrimidines 54 in high yields and with excellent
purities. The cyclocondensation reactions were performed in ethanol and a signi-
ficant decrease of the product yield was observed when switching the solvent to
acetic acid or DMF or when an acidic catalysts was added (Scheme 40).
Tu and co-workers [101] reported the synthesis of a series of novel pyrimido
[5,4-b][4, 7]phenanthroline-9,11(7H,8H,10H,12H)-diones 55 via a microwave-
assisted three-component reaction of barbituric acid, an aldehyde and quinolin-
6-amine in DMF without any catalyst. The results suggest that aldehydes bearing
electron-withdrawing groups have higher reactivity providing higher yields in
shorter reaction times (Scheme 41).
R1 R1
HO MW, 120°C
A N
A
O 6-9 min
H Ar N
H
+
ArCHO NH4OAc 53
7 examples, 79-88%
Scheme 39
Ar O
ArCHO R2 R2
O EtOH N N
NH N
+ S H
N NH O MW, 120°C, 5 min R1 N N
S NH2 H
N
R1 54
15 examples, 75-95%
Scheme 40
O O Ar
H2N DMF N
HN HN
+ + ArCHO
N MW, 110°C,
O O N O N N
H 6-15 min H H
55
9 examples, 72-92%
Scheme 41
An interesting approach for the synthesis of some fused pyrimidines has been
reported by Shaaban [102] via reaction of 4,4,4-trifluoro-1-(thien-2-yl)butane-
1,3-dione in the presence of triethylorthoformate with 5-aminopyrazole or 1,2,4-
aminotriazole or 2-aminobenzimidazole under microwave irradiation. The resulting
trifluoromethyl derivatives of pyrazolo[1,5-a]pyrimidine 56, 1,2,4-triazolo[1,5-a]
pyrimidine 57 and pyrimido[1,2-a]benzimidazoles 58 were obtained in excellent
yields and purity (Scheme 42).
Tu and co-workers [103] have elaborated an efficient microwave-assisted
synthesis of 4,5-bis-phenyl substituted benzo[4,5]imidazo[1,2-a]pyrimidines 59
through a MCR of an aromatic aldehyde with 1,2-diphenylethanone and 2-amino-
benzimidazole. PEG-300 was used as an inexpensive, nontoxic, and recyclable
reaction medium which can be reused up to three times without reduction of
the product yield although a weight loss of 10% PEG was observed per cycle
(Scheme 43).
O CF3 R2 NH2
N N
NH2 O CF3
N R1 NH N
S N H N
N R2 CF3
MW, 100°C S MW, 100°C S
N 5 min O O 5 min N N
R1 N
56 +
57
5 examples, 75-89%
CH(OEt)3 91%
N
MW, 100°C NH2
5 min N
H
O CF3
N
S
N N
58
83%
Scheme 42
Ar
H
Ph N PEG-300, K2CO3 Ph
O + H2N N
ArCHO +
N MW, 120°C, 10-18 min N N Ph
Ph H
59
11 examples, 75-87%
Scheme 43
O Ar O
N N H2O
+ N
ArCHO + N
O N
NH MW, 110°C N
Ph NH2 N N O
O 5-10 min H
Ph
60
12 examples, 80-88%
Scheme 44
O
O Ar N
R1 R1 H2N S
N N N AcOH/Glycol (1:1) R1
ArCHO + + N
O O S MW, 130°C, 5 min O N N
H
R1
61
10 examples, 90-93%
Scheme 45
A green approach for the synthesis of polyfunctionalized pyrazolo[40 ,30 :5,6]pyrido

[2,3-d]-pyrimidines 60 was elaborated by Tu and co workers [104] via a MCR of an
aromatic aldehyde, a 3-methyl-1-phenyl-1H-pyrazol-5-amine and 1-methylbarbituric
acid in water under microwave irradiation without catalyst. The yield of this reaction
was affected by the volume of water. This protocol could be applied to aromatic
aldehydes with either electron-withdrawing or electron-donating groups and also to
heterocyclic aldehydes giving excellent yields (Scheme 44).
The same group [105] has synthesized a series of new pyrido[2,3-d]pyrimidines
61 via a MCR of an aromatic aldehyde, a barbituric acid, and 5-amino-2-methyl-
benzo[d]thiazol applying a solvent mixture of acetic acid and ethylene glycol (1:1)
under microwave irradiation (Scheme 45).
Tu and co-workers [106] also reported a novel and highly stereoselective four-
component protocol reacting 2,6-diaminopyrimidine-4-one with an aryl aldehyde
and a barbituric acid, resulting in the generation of new 6-spirosubstituted pyrido
[2,3-d]pyrimidines 62 as a mixture of two diastereoisomers in which the 5,7-cis
isomer prevails. Water was used as the solvent and the reaction was run under
microwave irradiation. The reaction did not proceed with aliphatic or heteroaryl
aldehydes (Scheme 46).
2.3 Quinolines
2.3.1 Quinolines
The quinoline moiety is an important core structure of several natural and syn-
thetic heterocyclic compounds that show remarkable medicinal activities [107].
In particular, quinolines have played a unique role in the design and synthesis of
O O O
R1 R2 R1 R2
HN N N N N
O R1 O O O O
H2N N NH2 N H2O
Ar Ar + Ar Ar
O
+ N MW, 100°C, O NH O NH
O R2 6-9 min
2ArCHO HN N HN N
NH2 NH2
62 up to 99:1
19 examples, 79-90%
Scheme 46
O Ar
O O
O
R1 EtOH
ArCHO + + + R3–NH2
R2 R1
O MW, 100°C N O
R2
O O 4-9 min R3
63
R1 = H, CH3
R2 = CH3, Cyclopropyl,
p -tolyl
18 examples, 82-96%
Scheme 47
novel biologically active compounds serving as anti-inflammatory, antiasthmatic,

antituberculosis, antibacterial, antihypertensive, antitumor, and antimalarial agents
[108, 109].
A series of N-substituted 4-aryl-4,6,7,8-tetrahydroquinoline-2,5(1H,3H)-diones
63 has been synthesized by Tu and co-workers [110] through a rapid one-pot four-
component reaction of an aldehyde, Meldrum’s acid, a 1,3-cyclohexanedione and
an amine in ethanol under microwave irradiation. This method allows the intro-
duction of substituents at the nitrogen of octahydroquinolones 63. The reaction has
a wide scope as different aromatic aldehydes and a variety of amines (including
aliphatic and aromatic) are well tolerated in this four-component condensation
(Scheme 47).
A new series of polyhydroquinolines 64 has been prepared by Shingare and
co-workers [111] using nanosized Ni as a heterogeneous catalyst in a one-pot syn-
thesis via Hantzsch condensation by reacting an aldehyde, dimedone, ethyl aceto-
acetate and ammonium acetate in a domestic microwave oven. Ni (80 0.5 nm),
having a higher surface to volume ratio, has given the best results in terms of short
reaction times and excellent product yields. This method has demonstrated that
Ni, in the form of nanoparticles, is a potential alternative catalyst for the Hantzsch
condensation. It was demonstrated that the catalyst can easily be recovered and
reused up to four times without noticeable loss of activity (Scheme 48).
Tu and co-workers [112] have elaborated a simple and efficient microwave-
assisted one-pot three-component synthesis of polysubstituted quinoline-3-carbo-
nitriles 65 in excellent yields. An aldehyde, malononitrile and an enaminone were
reacted in acidic medium using microwave irradiation. When the reaction was
performed at high temperature, compound 65 was observed as the main product
(Scheme 49).
An efficient one-pot procedure for the synthesis of 4-aryl-8-arylidene-5,6,7,8-
tetrahydro-2-quinolinones 66 has been developed by Yen and co-workers [54]
based on a cyclocondensation reaction of N-ethoxycarbonylmethylpyridinium chlo-
ride with an aromatic aldehyde and cyclohexanone. The microwave-assisted
(domestic microwave oven) MCR resulted in the formation of compound 66 in
high yields (Scheme 50).
O Ar
O
O O COOC2H5
NH4OAc / Ni-Nanoparticles
ArCHO + +
OC2H5 MW, 1-1.5 min N
O H
64
15 examples, 85-96%
Scheme 48
Ar1 O
NC CN O NC
AcOH
Ar1CHO + R1
R1 MW, 120°C, H2N N
Ar2HN R2
R2 5-8 min Ar2
65
6 examples, 86-92%
Scheme 49
O
Ar
NH4OAc/AcOH
+ 2ArCHO
+
N Cl – MW, 2-4 min O N
H
O Ar
66
O 5 examples, 53-83%
Scheme 50
Sheng and co-workers [113] described an efficient Hantzsch reaction for the
synthesis of polyhydroquinolines 67 applying a solvent-free microwave-assisted
one-pot four-component reaction of PEG-bound acetoacetate, 1,3-cyclohexane-
dione, an aromatic aldehyde and ammonium acetate in the presence of a catalytic
amount of PPA. The target compounds 67 were obtained in excellent yields and
purities, after cleavage from the PEG support using NaOEt in EtOH. The reactions
were carried out in domestic microwave oven (Scheme 51).
Tu and co workers [114] reported a series of new pyrazolo[4,3-f]quinolin-7-ones
68 synthesized by a MCR of an aromatic aldehyde with Meldrum’s acid and
1H-indazol-5-amine in ethylene glycol without any catalyst under microwave
irradiation. Among various polar solvents tested, ethylene glycol gave the highest
yields. Various (hetero)aromatic aldehydes could be used (Scheme 52).
Tu and co-workers [112, 115] elaborated a green protocol for the synthesis
of polysubstituted indeno[1,2-b]-quinolines 69 via condensation of an aldehyde,
1,3-indanedione and an enaminone using p-toluene sulfonic acid as the catalyst in
water under microwave irradiation. A series of 23 indeno[1,2-b]quinolines 69 was
generated in excellent yields. The same authors have also described the microwave-
assisted synthesis of these compounds in acetic acid as solvent (Scheme 53).
Ferrocene derivatives coupled with heterocyclic systems have attracted spe-
cial attention in recent years because of their interesting organic and inorganic
properties. Recently, an efficient and rapid route for the synthesis of 4-aryl-2-
ferrocenyl-quinolines 70 has been described by Tu and co-workers [116] through
a microwave-assisted MCR of acetylferrocene with an aromatic aldehyde and
dimedone in the presence of ammonium acetate in DMF. This novel procedure
provides the target hetero-metallic compounds in excellent yields without the
need of any purification (Scheme 54).
O Ar O
ArCHO
NH4OAc, PPA OEt
O O + O O
MW, 3-4 min N
O H
67
9 examples, 95-97%
Scheme 51
N Ar
O
NH2 Ethylene glycol HN
O
ArCHO + + N
O N MW, 130°C N O
O H 9-12 min H
68
9 examples, 80-88%
Scheme 52
Ar1CHO O Ar1 O
O O
+ H2O, p-TsOH
R2
Ar2HN R2 MW, 150°C, N
R2
O R2 2-7 min Ar2
69
23 examples, 86-94%
Scheme 53
Ar O
O
ArCHO
O
N
DMF H
Fe +
MW, 100°C, Fe
O 9-15 min
NH4OAc 70
9 examples,75-93%
Scheme 54
O O Ar O
O
AcOH
ArCHO + + O
R1 MW, 100°C, R1
O O NHR2 N
R1 5-9 min R1
R2
71
28 examples, 90-98%
Scheme 55
Moving to some complex quinoline derivatives, Tu and coworkers [117] have

developed a sequential three-component reaction of an aldehyde, tetronic acid and
an enaminone using a small amount of glacial acetic acid under microwave irradia-
tion to obtain N-substituted furo[3,4-b]quinolines 71 in excellent yields and puri-
ties. In this way a series of aza-analogs of the antitumor compound podophyllotoxin
was synthesized (Scheme 55).
A number of unusually fused heterocyclic compounds have been reported by Tu
and co-workers [118]. The three-component domino reaction of an aldehyde, an
enaminone 72 and malononitrile resulted in the formation of polysubstituted imi-
dazo[1,2-a]quinazolines 73 and pyrimido[1,2-a]quinolines 74. (Scheme 56) When
enaminone 75 was reacted using the same reaction conditions, this resulted in the
formation of quinolino[1,2-a]quinazolines 76 in good yields. In this one-pot reac-
tion, up to five new bonds were formed accompanied by the generation of the
lactam group. Interestingly, the volume of ethylene glycol used seems to influence
the yield of the product (Scheme 57).
O Ar
CN
ArCHO O
CN Ethylene glycol
+ R1
N NH
CN R1 MW, 120°C, R1
R2HN 4-8 min
R1 R3 n O
R2 = CH2COOH or 3
R = H or CH3
CH3CHCOOH or
CH2CH2COOH 73, n = 0
74, n = 1
72
33 examples, 81-89%
Scheme 56
O O R1
R1CHO CN
CN Ethylene glycol
+
HN MW, 120°C, N NH
CN
HOOC 5-8 min
O
R2 R2
75 76
9 examples, 80-88%
Scheme 57
R1 OH
1 TFA (0.13 equiv.)
R OH
CH3CN NH
+ ArCHO + O
NH2 n
MW, 60°C,
15 min O Ar
n
77
10 examples, 39-59%
Scheme 58
The synthesis of functionalized 8-hydroxy-1,2,3,4-tetrahydroquinolines 77 has

been reported by Dai and co-workers [119] in moderate to good yields via an aza-
Diels–Alder reaction of an 2-aminophenol, a substituted benzaldehyde and a cyclic
alkene catalyzed by TFA under controlled microwave irradiation in acetonitrile. In
general, when electron deficient aromatic aldehydes were used, the adducts could
be isolated in 39–59% yields with a predominance of the trans isomer (Scheme 58).
Ji and co-workers [73] have reported a new series of polysubstituted (30 -indolyl)
benzo[h]quinoline 78, synthesized via a one-pot MCR of an aldehyde, 3-cyano-
acetyl indole, and naphthylamine under microwave irradiations in good yields
(Scheme 59).
Ar
CN
O NC
NH2
Glycol
+ N
N MW, 150°C, HN
H 12-15 min 78
ArCHO 5 examples, 67-72%
Scheme 59
O Ar O
DMSO,
ArCHO + + HN Flow reactor
HN
O N NH2 MW, 29 min N N
H
79
7 examples, 55-94%
Scheme 60
Organ and co-workers [120] described a unique approach to MCRs using a

microwave-assisted, continuous flow process for the synthesis of new series of
tetrahydro-pyrazolo[3,4-b]quinolin-5(6H)-ones 79. An aldehyde, dimedone, and
5-amino-3-methyl-1H-pyrazole were reacted, yielding the desired compound 79
in moderate to excellent yields. It was proved that the electronic properties of the
substituted benzaldehydes have an important impact on the conversions as with
electron-donating groups rather low yields were obtained (Scheme 60).
A microwave-assisted three-component coupling reaction of 5-amino-3-phenyl-
pyrazole, a cyclic 1,3-dicarbonyl compound and an aromatic aldehyde has been
described by Chebanov and co-workers [121]. Depending on the applied reaction
conditions a series of 4-aryl-3-phenyl-1,4,6,7,8,9-hexahydro-1H pyrazolo[3,4-b]
quinolin-5-ones 80, 9-p-tolyl-6,6-dimethyl-2-phenyl 5,6,7,9-tetrahydro-pyrazolo
[5,1-b]quinazolin-8-ones 81, or 4-aryl-5a-hydroxy-4,5,5a,6,7,8-hexahydropyra-
zolo[4,3-c]quinolizin-9-ones 82 can be formed (Scheme 61).
Tu and co-workers [122] have reported the synthesis of a series of new bifunc-
tional compounds 83 containing a bisfuro[3,4-b]quinoline and a bisacridinedione
skeleton through a rapid one-pot three-component reaction of a dialdehyde with an
N-aryl enaminone and a cyclic-1,3-dicarbonyl compound (tetronic acid or cyclo-
hexane-1,3-dione) in a solvent mixture of AcOH/DMF (2:1) using microwave
irradiation. The described compounds 83 were obtained in good to excellent yields.
N-Aryl enaminones bearing electron-withdrawing groups on the aryl substituent
require longer reaction times (Scheme 62).
Ji and co-workers [123] have reported a simple and efficient synthesis of spiro
[indoline-3,40 -quinolines] 84 by a one-pot reaction of an isatin, malononitrile, and
O
Me3SiCl, MeCN N N
Ph
MW, 170°C, R1
N
30 min H R1
81
1 example, > 98%
Ph Ar O
ArCHO O
Ph
EtOH, Et3N N
+ R1
N N
N NH2 R1 MW, 150°C, H R1
N H
O 15 min
H R1
80
8 examples, 70-91%
H OH R1
Ar R1
EtOH, KOtBu N
Ph
MW, 150°C, N NH O
15 min
82
9 examples, 38-75%
Scheme 61
O
H O O
O O
AcOH/DMF (2:1) Ar N
+ +
MW, 120°C, OO N
NH Ar
O O 7-16 min
H Ar
O O O 83
= O or 11 examples, 82-92%
O O
O
Scheme 62
an enaminone under microwave irradiation. The merits of the procedure include a

broad substrate scope, short reaction times and high yields (Scheme 63).
Fulop and co-workers [124] have reported the synthesis of some new (ami-
noalkyl) naphthols and (aminoalkyl) quinolinols 85 in good yields through a one-
pot, microwave-assisted three-component modified Mannich reaction of naphthol
or quinolinol with two equivalents of an aldehyde using ammonium carbamate or
ammonium hydrogen carbonate as solid ammonia sources. It was observed that
aliphatic aldehydes did not lead to the formation of the desired (aminoalkyl)
quinolinols 85 (Scheme 64).
2.3.2 Isoquinolines
An efficient, solid-supported reaction catalyzed by TiO2–silica gel has been inves-

tigated for the synthesis of a series of novel dispiroheterocyclic systems 86–89 by
Raghunathan and coworkers [125]. An azomethine ylide generated from tetrahy-
droisoquinoline-3-carboxylic acid and acenaphthenequinone or isatin were reacted
with various 2-arylidene-1,3-indanediones or (E)-2-oxoindolino-3-ylidene aceto-
phenones in a one-pot three-component tandem reaction to give the products in high
yields applying a domestic microwave oven. From the various solid supports that
were evaluated, the combination of TiO2 with silica gel (1:1) was found to be the
best, resulting in the rapid formation of the compounds in high yields. The reaction
afforded a series of novel dispiroheterocycles 86–89 containing the acenaphthenone
3
R3 R
O O R4
N
CN EtOH O
R2 O + + NH2
R4 R3 MW, 80°C, R2
N CN N
R3 N CN
R1 H 7-10 min O
R1
84
15 examples, 66-85%
Scheme 63
R1
OH OH NH2.HCl
O NH
R2 X Solid NH3 Source R2 X
R2 X 10% aq. HCl
R1
R1
MW, 70-130°C,
+ 30-45 min
85
2R1CHO 8 examples, 68-87%
Scheme 64
R1
O
R1
HO
H H
O
TiO2-Silica gel N O
MW, 2-7 min O
O O R1 86
COOH 5 examples, 82-95%
NH +
H R1
O O
O H
N NH
H H O
N
TiO2-Silica gel O
MW, 2-7 min
87
4 examples, 84-92%
Scheme 65
and oxindole ring systems by a regio- and stereocontrolled cycloaddition of the

azomethine ylide to the exocyclic double bond of 2-arylidene-1,3-indanedione in
all cases (Schemes 65 and 66).
In a recent article by Beifuss and co-workers [126], the synthesis of pyrido
[20 ,10 :2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones 90 has been described in good
yields by means of a microwave-assisted three-component reaction of a 2-amino-
pyridine, an isocyanide and a 2-carboxybenzaldehyde under acidic conditions. The
reactions are easy to perform, robust, and highly efficient. This process allows the
formation of two heterocyclic rings and four new bonds in a single synthetic
operation (Scheme 67)!
2.3.3 Quinazolines
Kaur and co-workers [127] investigated the acid catalyzed condensation of

tetralone, thiourea and a substituted benzaldehyde in acetonitrile under micro-
wave irradiation to obtain 4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-
thiones 91. A domestic microwave oven was used and the targeted compounds were
obtained in moderate yields (Scheme 68).
A microwave-assisted one-pot three-component reaction of a (un)substituted
anthranilic acid, ribosylamine and an (un)substituted benzoic acid has been
R1
O
R1
H HO
H
O
TiO2-Silica gel N O
MW, 2-7 min O
N
H
R1 88
O
COOH 10 examples, 80-95%
NH + O
N H
H
O R1
O
O
N H
H NH
H O
TiO2-Silica gel N
MW, 2-7 min O
N
H
89
5 examples, 82-88%
Scheme 66
R3 R4
R3 R4 N
NH2 MsOH, Toluene
R1 + N
N R1
OHC MW, 160°C N
R2NC 7 min O
COOH R2
90
16 examples, 38-68%
Scheme 67
S
S
H2N NH2
HCl (conc.), CH3CN HN NH
O +
Ar
ArCHO MW, 3.3-6.3 min
91
7 examples, 35-53%
Scheme 68
investigated by Siddiqui and co-workers [128] using a domestic microwave oven to

rapidly access a new series of 2-aryl-3-(b-D-ribofuranosyl)-3H-quinazolin-4-ones
92 as novel N-nucleosides. Montmorillonite K10 clay was used as solid support.
Interestingly this method can be used for glycosylation without protecting the sugar
moiety (Scheme 69).
Li, Tu and co-workers [129] have elaborated a novel four-component domino
reaction of an aromatic aldehyde, a cyclic ketone and a cyanoamide to give highly
functionalized quinazolines 93 under microwave irradiation using K2CO3 as the
base and ethylene glycol as the solvent. The reaction proceeded in mere 10–24 min
with water as the sole byproduct. Four stereogenic centers are generated and the
reaction is highly diastereoselective. The reaction did not seem to work with acyclic
ketones (Scheme 70).
2.3.4 Quinolizines
Chebanov and co-workers [130] described an efficient synthetic route for the
synthesis of some novel derivatives of 5a-hydroxy-4,5,5a,6,7,8-hexahydropyra-
zolo[4,3-c]quinolizin-9-ones 94 which is based on a multicomponent condensation
of a 5-aminopyrazole with a cyclic 1,3-diketone and an aromatic aldehyde
under microwave irradiation. The reaction runs via an unusual base-mediated
ring-opening/recyclization of the cyclic 1,3-diketone moiety (Scheme 71).
R1
R1
Montmorillonite Ar N R2
O NH2 H2N R2 O K10 clay
HO N
+ + O R3
HO OH HO HO Ar
R3 MW, 6-10 min
OH O R4
HO
HO
O R4
92
10 examples, 81-88%
Scheme 69
Ar
H
CN
O CN K2CO3
Ethylene glycol
ArCHO + + 2 HN NH2
O MW,120°C, H
H2N 12-24 min O N O
H
93
26 examples, 74-90%
Scheme 70
R1 Ar H
ArCHO
R1 O
KOH, EtOH N OH
+ N
N N
R2 MW, 100-150°C, H
N O R2
H NH2 R2 25 min O
R2
R2 = CH3, H
94
11 examples, 32-75%
Scheme 71
NC CN NC CN
O
H2N R1 DMSO (cat.) N R1
OH +
OH MW, 125-130°C
H2N R2 N R2
3 min
O
95
3 examples, 77-85%
Scheme 72
NC CN NC CN
O
O + R1 N
R1 K2CO3, DMSO (cat.)
O
O MW, 125-130°C, N
N O N 3 min
H H O
96
3 examples, 68-78%
Scheme 73
2.3.5 Quinoxalines
A microwave-assisted one-pot three-component procedure for the condensation of

ninhydrin with a phenylenediamine and malononitrile under solvent-free conditions
using a catalytic amount of DMSO has been reported by Mohammadizadeh and
co-workers [131] to obtain the corresponding 2-(indenoquinoxalin-11-ylidene)mal-
ononitriles 95. (Scheme 72) Further, this one-pot procedure has been extended for
the preparation in good yields of dicyanomethylene derivatives 96 of tryptanthrin
when potassium carbonate was used as a base (Scheme 73).
2.4 Imidazoles
Imidazoles have received significant attention due to their biological and pharma-
ceutical importance [132]. Several substituted imdazoles are known as potent P38
kinase inhibitors [133], as angiotensin II receptor antagonist [134] and as platelet

aggregation inhibitors in several animal species. Some of them show cytotoxicity
against specific human cancer cell lines.
Nagarapu and co-workers [135] have reported a new synthetic approach for
1,2,4,5-tetrasubstituted imidazoles 97 through a four-component condensation of
benzil, an aldehyde, an amine, and ammonium acetate using potassium dodeca
tungstocobaltate trihydrate (K5CoW12O40·3H2O) as catalyst. The reaction proceeds
under solvent-free conditions in a domestic microwave oven. This method can be
applied to large-scale processes with high efficiency and the catalyst can be reused
for several runs without significant loss of catalytic activity. Under the same
reaction conditions, benzoin (replacing benzil) gave low yields (15–30%) even
after long irradiation times (Scheme 74).
The synthesis of a series of pyrimido[1,2-a]benzimidazoles 98 has been reported
by Dandia and co-workers [136] through a MCR of 2-aminobenzimidazole, mal-
ononitrile or ethylcyanoacetate and a carbonyl compound in water. Cyclic as well
as acyclic carbonyl compounds could be used. The reaction highly benefits from
microwave (domestic oven) irradiation in terms of rate and the compounds 98 were
obtained in good yields (Scheme 75).
Liu and co-workers have elaborated [137] a highly efficient method for the
synthesis of spiroimidazolinones 99 via a microwave-assisted three-component
one-pot domino reaction of a protected amine, an amino acid ester and a carboxylic
acid in the presence of triphenylphosphite in pyridine, providing the desired
O O R1–NH2 K5CoW12O40.3H2O
NH4OAc N
+
MW, 2 min N Ar
ArCHO
R1
97
20 examples, 85-97%
Scheme 74
N N
NH2 NH
N H2O N R1
H CN R2
R1
+ MW, 3.5-11 min H2N
O X
R2 X
98
R1 = H, CH3 X= CN, COOEt
R2 = Ar 8 examples, 78-88%
R1= R2 = –(CH2)4–
Scheme 75
compound 99 in excellent yields. The efficiency and utility of the method have
been demonstrated with the synthesis of the antihypertensive drug Irbesartan
(Scheme 76).
Mohammadizadeh and co-workers [138] applied for the synthesis of tetrasub-
stituted imidazoles 100, a four-component condensation of benzil, an aldehyde, an
amine and ammonium acetate under solvent-free conditions using a domestic
microwave oven. The condensation is catalyzed by TFA and the desired com-
pounds 100 are obtained in mere 4 min in good to excellent yields. Both aliphatic
and aromatic amines could be successfully used (Scheme 77).
A highly flexible and efficient microwave-assisted Ugi-type reaction was
described by Guchhait and co-workers [139] for the generation of a library of
N-fused aminoimidazoles 101 in excellent yields. A heterocyclic amidine or 2-
aminopyridine was reacted with an aldehyde and an isocyanide using zirconium
(IV)chloride as the catalyst and PEG-400 as the solvent. The reaction is very
tolerant to the nature of the substituents of the aldehyde (Scheme 78).
O HO R2 O
P(OPh)3, pyridine n 3
n OR1 + N R
NH2 MW, 250°C, N
BocHN–R3 10 min R2
99
17 examples, 36-78%
Scheme 76
Ph
N
Ph O ArCHO
TFA (20 mol%) Ph N Ar
+ NH4OAc
Ph O R1–NH2 MW, 4 min R1
100
14 examples, 79-94%
Scheme 77
ZrCl4 (10 mol%)

NH2 R2– NC N
Het Ar PEG-400 Het Ar R1
+
N MW, 140°C, 7 min N
R1– CHO
HN R2
101
28 examples, 72-97%
Scheme 78
2.5 Thiazolines
4-Thiazolidinones are an important group of heterocycles found in numerous

natural products and pharmaceuticals known for their antitumor, COX-2 inhibition,
anti-HIV and antibacterial activities [140].
Saidi and co-workers [141] have reported a three-component reaction of differ-
ent thiosemicarbazides with dimethyl or diethyl acetylenedicarboxylate and an
aldehyde under solvent-free conditions applying a domestic microwave oven.
Thiazolines 102 were obtained in good to excellent yields. Interestingly, the
presence of electron-donating groups on the aromatic aldehyde resulted in faster
reactions and higher product yields (Scheme 79).
Mahler and co-workers [140] reported a tandem procedure for the synthesis of
2-hydrazolyl-4-thiazolidinones 103 from a three-component reaction of an alde-
hyde, a thiosemicarbazide and maleic anhydride, efficiently assisted by microwave
irradiation in a solvent mixture of toluene/DMF (1:1). Short reaction times and
high product yields were obtained as compared to conventional heating. This pro-
cess could be generally applied for aromatic as well as for aliphatic aldehydes,
although for aliphatic aldehydes a slightly lower temperature of 100 C should be
used (Scheme 80).
2.6 Pyrazoles
The class of pyrazoles bears a broad spectrum of biological activity, e.g.,

antihyperglycemic, analgesic, anti-inflammatory, antipyretic, antibacterial and
Et / MeOOC COOMe / Et N S
R1 N
solvent free O
+ R1CHO N
H MW, 3 min H O Me /Et
N NH2 O
H2N 102
S
9 examples, 83-92%
Scheme 79
O OH
O R2
S p -TsOH (cat.)
Toluene/DMF (1:1) N S
NH2 + O + R2CHO
R1HN N N
H MW, 100-120°C,
N O
O 5-12 min
R1
103
10 examples, 33-82%
Scheme 80
sedative-hypnotic activity [142, 143]. In addition, several 3,5-diaryl-substituted pyr-

azoles reversibly inhibit monoamine oxidase-A and monoamine oxidase-B [144].
Recently, Müller and co-workers [145] have reported a series of 3,5-disubstituted
and 1,3,5-trisubstituted pyrazoles 104 and 105 by reacting an acyl chloride, a terminal
alkyne and a hydrazine via a consecutive one-pot three-component Sonogashira
coupling/Michael addition/cyclocondensation sequence under microwave irradiation.
The desired products were obtained in good to excellent yields. These obtained
pyrazoles are highly fluorescent, both in solution and in the solid state (Scheme 81).
Botta and co-workers [146] described an efficient microwave-assisted organo-
catalytic domino Knoevenagel/hetero-Diels–Alder reaction (DKHDA) protocol for
the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles 106 using diaryl-prolinol as cata-
lyst and t-BuOH as the solvent. A diastereomeric mixture of compounds 106a and
106b was isolated with a diastereomeric ratio of (4:1). The procedure can be used to
synthesize quickly, novel rigid analogs of potential antitubercular agents (Scheme 82).
2.7 Acridines
Acridine derivatives have been known since the nineteenth century when they were
first used as pigments and dyes [147]. Their antiseptic activity has been discovered
O PdCl2(PPh3)2 (2% ), CuI (4%)

Et3N (1.05), THF, 1h, r.t. R1 R2
R1 Cl + R2
N N
then R3NHNH2
CH3OH, AcOH R3
MW, 150°C, 10 min 104, R3
=H
105, R3 = CH3, Ph
21 examples, 53-95%
Scheme 81
Cl
N Cl
N O diaryl-prolinol (cat.),
t-BuOH
+ + OEt OEt
MW, 110°C, N O
N
30 min
CHO
Cl
Cl
106a (cis) 56%
106b (trans) 12%
Scheme 82
in the early 1900s and some derivatives were extensively used during the First
World War for their antibacterial and antimalarial activities. In the 1920s, their
potential in the fight against cancer was noticed. The synthetic research on acridines
experienced a renaissance during the mid 1960s when wide ranges of this class of
compounds were tested for antimalarial activity [148]. Among them benzo analogs
have received considerable attention [149, 150].
Acridines are also known therapeutic agent as inhibitors of monoamine oxi-
dases, NADH-dehydrogenases etc. [151, 152]. Numerous studies regarding these
applications have been described [153, 154]. Therefore, the synthesis of new
tetracyclic acridine compounds has increased rapidly in the last few years.
Yen and co-workers [155] have described a one-pot MCR for the synthesis of
4,5-dibenzylidene octahydroacridines 107 in high yields. A tandem reaction
was performed with three equivalents of an aromatic aldehyde and two equivalents
of 4-alkylcyclohexanone in NH4OAc/AcOH applying a domestic microwave oven.
Except for one example, most of the reported compounds were obtained in moder-
ate to good yields (Scheme 83).
Some new substituted tetrahydroacridin-8-ones 108 have been synthesized by
Selvi and co-workers [156]. They applied a MCR to dimedone or cyclohexan-1,3-
dione, a-naphthylamine and a substituted benzaldehyde, without the aid of any
catalyst using a domestic microwave oven. Compounds 108 exhibit interesting
antimicrobial activities (Scheme 84).
Following the same strategy, Tu and co-workers [112] have reported a rapid
and direct method for the synthesis of highly functionalized acridine-1,8(2H,5H)-
diones 109 in excellent yields. They employed a multicomponent protocol to a
5-substituted-cyclohexane-1,3-dione, an aldehyde and an enaminone to get the
Ar
O R1 R1
NH4OAc/AcOH
2 + 3 ArCHO N
MW, 3-4.5 min
R1 Ar Ar
107
11 examples, 42-79%
Scheme 83
O NH2 O Ar
Neat conditions
+ + ArCHO
R1 MW, 2-5 min R1
1 O N
R R1 H
R1 = R1 = H
R1 = R1 = CH3 108
14 examples, 92-98%
Scheme 84
targeted compound 109. A wide range of aldehydes can be used. A comparison

between the application of microwave irradiation and conventional heating was
performed and it was concluded that, except for the reaction times, the results were
comparable (Scheme 85).
2.8 Oxazepines, Thiazapines and Benzodiazepines
Several functionalized benzothiazepinones and their fused analogs possess inter-

esting biological properties and many of them have been tested and applied as drugs
[157]. Some pyrimido-oxazepines are potent inhibitors of the epidermal growth
factor receptor (EGFR) [158] which is the biological target of cancer therapeutics as
Iressa and Tarceva [159].
A synthetic approach towards pyrimido[4,5-b][1,4]benzoxazepin-4-amines 111
has been developed by Gustafson and co-workers [160] through the use of micro-
wave irradiation by reaction of 2,4-dichloro-3-amino pyrimidine, a substituted
salicylic acid and an amine using cesium carbonate as the base. The obtained
imines 110 were reduced with NaBH4 leading to the desired compounds 111 in
moderate to good yields. Primary and secondary aliphatic amines could be used,
although aryl amines gave low yields (Scheme 86).
An efficient multicomponent tandem reaction has been described by Tu and
co-workers [161] to access benzothiazepinones 112 in excellent yields in aqueous
media. The reaction is easy to perform using inexpensive starting materials such as
O O Ar2 O
O
AcOH
+ R2 + Ar2CHO
R1 MW, 120°C R1
Ar1HN R2 N R1
R1 O 2-4 min
Ar1
109
6 examples, 89-95%
Scheme 85
HO R1 R2 R1 R2
Cl R3 N N H
NH2 HO N N
N Cs2CO3, i-PrOH N NaBH4 N
+
N Cl MW, 150°C r.t.
H N O N O
N 10 min R3 R3
1 2
R R 110 111
12 examples, 30-98%
Scheme 86
an aromatic aldehyde, an amine and mercaptoacetic acid and the desired products
112 are generated in high yields in a short time. Surprisingly, aldehydes bearing
electron-withdrawing groups gave only thiazolidinones in excellent yields. This
environmentally friendly protocol is highly attractive to access compounds which
are potentially biologically active (Scheme 87).
Dai and co-workers [162] have described an Ugi-type four-component reac-
tion applying a 2-aminophenol, a 2-alknylbenzaldehyde, benzyl isocyanide and
2-chloro-5-nitrobenzoic acid in methanol under microwave irradiation. The result-
ing Ugi product 113 was subsequently treated with aqueous K2CO3 to promote an
intramolecular nucleophilic aromatic substitution, leading to the formation of
highly functionalized dibenz[b, f][1,4]oxazepin-11(10H)-ones 114. This protocol
tolerates a diverse substitution pattern of the 2-aminophenol and affords highly
functionalized products 114 in good yields (Scheme 88).
3H-1,4-Benzodiazepines and 3H-1,5-benzodiazepines are important classes
of compounds because of their interesting pharmacological properties. They show
anticonvulsant, antianxiety, analgesic, sedative, antidepressive, hypnotic, anti-
inflammatory activity and also potent inhibitor of HIV-1 reverse transcriptase.
Besides their biological relevance, benzodiazepines have also found application
as dyes for acrylic fibers [163].
Ar
NH2
SH water S
+ + ArCHO R1
R1 MW, 110°C,
HO O N
7-11 min H O
112
30 examples, 89-96%
Scheme 87
R1
2
R OH O2N
R3 R1 NO2
2 2
O
R3
NH2 R R
+ Cl aq. K2CO3
CN–Bn
Cl MeOH R1 (1.2 eq.) R3 N
N O O
OH H
MW, 80°C, MW, 100°C, N
HOOC NO2 O 10 min Bn
20 min
+ NH O
Bn
CHO 4
R 4
R
113 114
4 7 examples, 57-81%
R
Scheme 88
PdCl2(PPh3)2, CuI, R1
N R3
O Et3N, THF,1h, r.t.
+ R2
R1 Cl Then: AcOH R4
N
MW, 120°C, 60min R2
115
R3 NH2
12 examples, 40-88%
R4 NH2
Scheme 89
A novel one-pot approach for the synthesis of 2,4-disubstituted 3H-benzo[b]

[1, 5]diazepines 115 has been disclosed by Muller and co-workers [163]. The com-
pounds were obtained in good yields by the reaction of an acyl chloride, a terminal
alkyne and a benzene-1,2-diamine via a consecutive one-pot, three-component
Sonogashira coupling/Michael addition/cyclocondensation sequence, under micro-
wave irradiation (Scheme 89).
Andreana and co-workers [164] have developed a novel one-pot, two-step
reaction protocol for the synthesis of regiochemically differentiated 1,2,4,5-
tetrahydro-1,4-benzodiazepin-3-ones 116 and 117. Using protic solvents and con-
trolled microwave irradiation, the Ugi product was synthesized by reacting an
aldehyde, an aromatic amine, an isocyanide and a carboxylic acid. The obtained
Ugi product was then reduced with Fe(0)/NH4Cl to give the target compound in
good yields and high diastereoselectivity. Two pathways were accessible; both
routes utilized bifunctional, o-nitro-substituted arenes leading to either C2, N4,
C5 substitution in compound 116 or C2, N4 substitution in compound 117. Inter-
estingly, when acrylic acid was used as a coupling component, an eight membered
ring was not observed and only the acyclic Ugi product was isolated. These
biologically relevant small molecules can be prepared efficiently and are highly
amenable for further derivatization (Scheme 90).
2.9 Chromens
Chromens and their derivatives are an important class of compounds possessing anti-
estrogenic, [165] potassium channel agonist, hypotensive [166], vasodilator, anti-
hypertensive, b-adrenolytic [167] and antimicrobial activity [168]. Moreover, some
derivatives show high antagonistic affinity for the retinoic acid receptor [169].
Mg/Al hydrotalcite as a heterogeneous base catalyst has been used by Samant
and co-workers [170] in combination with microwave irradiation for the synthesis
of 2-aminochromenes 118 via a multicomponent condensation of an aromatic
aldehyde, malononitrile and 1-naphthol. The hydrotalcite is a heterogeneous basic
catalyst and could easily be separated from the reaction mixture by simple filtration.
The recovered catalyst was used for successive runs to investigate its reusability,
H R4
R2NH2 N
2
Fe(0) and NH4Cl R1 O
NO2 4
EtOH / H2O, (3:1) 5 N
R1 R2
MW, 150°C,
CHO O
30-45 min NH
R3
O (±)-116
R4 OH 5 examples, 70-78%
+
R3–NC
H R4
N
Fe(0) and NH4Cl 2
NO2 R2 O
EtOH / H2O, (3:1) 4
R2 N O
NH2
+ MW, 150°C,
30-45 min R1 HN–R3
R1CHO
(±)-117
2 examples, 85-90%
Scheme 90
OH Mg/Al hydrotalcite O NH2

CN Solvent free
+ + ArCHO
MW, 140°C, CN
CN
5-24 min Ar
118
12 examples, 71-90%
Scheme 91
however, an important reduction of the product yields was observed. The reaction
was rapid, clean and gave the desired products 118 in high yields (Scheme 91).
A short and simple synthesis of chromeno[3,4-b][4,7]phenanthrolines 119 has
been investigated by Tu and co-workers [167] using a three-component reaction of
an aromatic aldehyde, 6-aminoquinoline and 4-hydroxycoumarine in water, under
microwave irradiation without any catalyst. This method has the advantage of short
reaction time, high yields, low cost and being environment-friendly (Scheme 92).
2.10 Pyrans and Furans
2,3-Dihydropyrans represent an attractive and challenging class of compounds as

many of them are key intermediates for the synthesis of several natural products
[171]. In particular, their olefin function has great synthetic value for the further
functionalization to obtain polysubstituted tetrahydropyrans [172] that constitute
O Ar
OH N
N H2O O
+ + ArCHO
N
H2N MW, 140°C, H
O O
5-6 min
119
5 examples, 93-95%
Scheme 92
Grubbs’ cat. 2nd gen. COOEt COOEt COOEt

R1 + OEt toluene ZnCl2
O + O O
O DCM
MW, 80°C, 20 min R1 OEt R1 OEt R1 OEt
EtOOC
120 trans 120 cis 120 trans
8 examples, 40-75%
Scheme 93
the structural core of most carbohydrates as well as of many biologically important

natural products and pharmaceutical agents [173].
Botta and co-workers [174, 175] have described the synthesis of 2,3-dihydro-
pyrans that were obtained as a mixture of cis/trans diastereoisomers 120 through
a microwave-assisted multicomponent enyne cross metathesis/hetero-Diels–Alder
reaction of an acetylene, ethylvinyl ether and ethyl glyoxalate using Grubbs’ catalyst
under microwave irradiation at 80 C. (Scheme 93) The obtained diastereoisomeric
mixture could be equilibrated applying ZnCl2 leading to the unique formation of the
all 120 trans isomer. This MCR was applied for the synthesis of C-linked furanose-
dihydropyranes 122 as a mixture of four diastereoisomers, upon reaction of the
acetylene precursor 121 with ethylvinyl ether and ethylglyoxalate under the same
reaction conditions. Equilibration of this mixture upon treatment with ZnCl2 led to a
1:1 mixture of two diastereoisomers 122a and 122b (Scheme 94).
Organ and co-workers [120] elaborated a synthesis of aminofurans 123 applying
a microwave-assisted continuous flow organic synthesis (MACOS) by reacting
dimethyl acetylenedicarboxylate, cyclohexyl isocyanide and a substituted benzal-
dehyde. The obtained conversions were equal or even higher compared to conven-
tional batch conditions and reactions required only seconds to reach full
completion. Benzaldehydes bearing electron-withdrawing groups gave the highest
conversions (Scheme 95).
2.11 Propargylamines
Propargylamines are versatile synthetic intermediates in organic synthesis and are

also key structural elements in natural products and therapeutic drug molecules [176].
COOEt
Grubbs’ cat.
2nd gen. O
O O COOEt toluene O
BzO + BzO OEt
BzO OBz OEt MW, 80°C, BzO OBz
121 20 min
122, 64%
ZnCl2
DCM
COOEt COOEt
O + O
O O
BzO OEt BzO OEt
BzO OBz BzO OBz
122a 122b
Scheme 94
H
MeOOC COOMe Ar O N
flow process
+
NC ArCHO
MW MeOOC COOMe
123
7 examples, 30-83%
Scheme 95
CuBr (20 mol %)

Toluene R3
R1-NH2 + R2 + R3– CHO R2
MW, 100°C, HN–R1
25 min 124
26 examples, 41-94%
Scheme 96
Recently, Van der Eycken and co-workers [177] have elaborated an effective
protocol for the synthesis of secondary alkylpropargylamines 124 via a microwave-
assisted A3-coupling reaction. The resulting propargylamines were obtained by a
MCR of a primary aliphatic amine, a terminal alkyne and an aldehyde (aliphatic or
aromatic) using CuBr as the catalyst in high yields. Primary aliphatic amines which
were considered as difficult substrates for A3-coupling reactions, react very effi-
ciently under these reaction conditions. Heterocyclic and aliphatic acetylenes were
also explored and gave moderate yields (Scheme 96).
An effective MCR has been developed by Organ and Li and co-workers [178]
for the synthesis of tertiary propargylamines 125 by reacting an aldehyde, an amine
and a terminal alkyne using MACOS. The process is catalyzed by a thin film of
either copper or gold that achieves temperatures exceeding the 900 C when irra-
diated with microwaves. The process works equally well for premixed solutions of
the three starting materials, or as for three separate streams of reagent solutions that
were introduced. The process can be used for a wide variety of aldehydes and
acetylenes (Scheme 97).
Van der Eycken and co-workers [179] have reported a microwave-assisted
A3-MCR of an aniline, an alkyne and biaryl aldehyde to generate a small library
of propargylamines 126 using CuBr as the catalyst. The resulting compounds
126 were isolated in good to excellent yields except when n-butylamine was
used as amine counterpart and were further converted into Steganacin aza-analogs
(Scheme 98).
2.12 Miscellaneous
Shaterian and co-workers [180] have described an efficient and expeditious route
towards the synthesis of 1-amidoalkyl-2-naphthols 127 via a three-component reac-
tion of an aryl aldehyde, 2-naphthol and acetamide in the presence of Fe(HSO4)3
using a domestic microwave oven. The reaction of 2-naphthol with an aromatic
aldehyde in the presence of an acid catalyst gives an o-quinone methide that
is subsequently reacted with acetamide to give the desired product 127. This
solvent-free microwave-assisted green procedure offers the advantages of short
Metal film
H flow process
N Ar R1 R2
R1 R2 + Toluene N
MW R3
R3CHO Temp of film = 950°C
Ar
125
18 examples, 55-84%
Scheme 97
R2 R2
R4
R3NH2 Neat conditions
CHO + CuBr
MW, 90-120°C HN 3
TBSO R4 TBSO R
R1 15 min R1
126
12 examples, 42-89%
Scheme 98
reaction time, simple work-up, excellent yields, and reusability of the catalyst
(Scheme 99).
A new microwave-assisted three-component Knoevenagel-nucleophilic aromatic
substitution reaction of 4-halobenzaldehyde, cyanoacetic acid ester or cyanoaceta-
mide and a cyclic secondary amine was reported by Yu, Shen, Wang and co-workers
[181] to give the compounds of type 128. Via this one-pot domino process a carbon–
carbon double bond and a carbon–nitrogen bond were formed. Taking advantage of
microwave irradiation, the reaction times could be reduced significantly resulting in
high yields even with less reactive benzaldehydes (Scheme 100).
The proline-catalyzed asymmetric Mannich reaction between cyclohexanone,
formaldehyde and an aniline has been described by Bolm and co-workers [182].
With only 0.5 mol% of homochiral catalyst, the Mannich products have been
obtained with excellent ee’s up to 98% after a short irradiation time using a constant
low power of 10–15 W in conjunction with simultaneous cooling with compressed
air. These reaction conditions allow achieving a high reaction rate and an excellent
enantioselectivity. In situ reduction of the resulting ketones 129 afford the N-aryl
amino alcohols 130 in high yield (syn/anti in ratio 1:5) (Scheme 101).
Dai and co-workers [183] have reported a one-pot U-4CR followed by an
intramolecular O-alkylation sequence starting from a 2-aminophenol in com-
bination with an a-bromoalkanoic acid, an aromatic aldehyde and an isocyanide
under controlled microwave irradiation. The U-4CR was carried out in MeOH and
the resulting acyclic intermediate 131 was turned into the 3,4-dihydro-3-oxo-2H-
1,4-benzoxazines 132, without isolation, upon treatment with an aqueous solution
of K2CO3 to promote the intramolecular O-alkylation in high yields (Scheme 102).
OH
Fe(HSO4)3
+ ArCHO + CH3CONH2 Ar NH
OH MW, 5-14 min
O
127
18 examples, 84-97%
Scheme 99
Y n=0–1
X Y CN N
EtOH CN
+ +
CHO N n=0 –1 Z MW, 80°C, Z
H 5-30 min 128
X = F, Cl, Br
Z = COOEt, COOMe, CONH2
Y = CH2 and O, NR1
14 examples, 72-90%
Scheme 100
OH
O O (s)-proline (cat.) O
NaBH4 Ar
DMSO Ar N
H H N H
+ MW, 41-63°C, H
ArNH2 1-4 h 130
129
94-98% ee syn/anti 1:5
3 examples, 70-96%
Scheme 101
Br R2
O R2
OH R2
HO O R1
OH U-4CR R1 Br
MeOH aq. K2CO3 N O
R1 + CN–R3 N O
O
NH2 MW, 80-100°C, O MW, 120-150°C, Ar
Ar
ArCHO 20 min 15 min HN 3
HN R
R3 132
131
14 examples, 52-90%
Scheme 102
COOH O
R3 O NH O R1
R1– CHO H
NH MeOH N
+ N
O O R2– NH2 MW, 80°C, R3
5 min R2 O
NC 133
7 examples, 50-93%
Scheme 103
Similarly, Hulme and co-workers [184] have described an U-4CR under micro-
wave-assisted conditions of an N-Boc-anthranilic acid, n-butylisonitrile, an alde-
hyde, and an amine resulting in the formation of the Ugi products 133 that were
further used in the UDC-protocol (Ugi reaction–Deprotection–Cyclization) for lead
finding (Scheme 103).
Beller and co-workers [185] have developed a solvent-free MCR of crotonalde-
hyde, acetamide and N-methylmaleimide. The described methodology is one of the
most simple and direct approaches for the synthesis of 4-N-acetylamino-2-methyl-
cis-3a,4,7,7a-tetrahydroisoindole-1,3-dione 134. The application of microwave
irradiation resulted in significantly reduced reaction times and increased yields.
Aliphatic and aromatic amides, as well as sulfonamides gave excellent results with
excellent stereoselectivity. However, the application of maleic anhydride, diethyl
O NH O
O O Solvent-free
+ + N N
NH2 H MW, 150°C,
O 20 min O
134
90%
Scheme 104
O O O
O 1. Et3N, DMF, H R1
R1 25°C, 30 min
O(CH2)3C8F17 N O(CH2)3C8F17
N
NH2 + NH
2. MW, 150°C, 30 min
O H
ArCHO O 3. F-SPE
Ar
135
4 examples, 48-94%
Scheme 105
but-2-ynedioate and acrylonitrile as dienophiles resulted in low yields. Advanta-

geously, there is no need for employing additional solvents and the reaction times
are drastically reduced compared to similar thermal reactions (Scheme 104).
Zhang and co-workers [186] reported a microwave-assisted one-pot, three-
component [3þ2] cycloaddition reaction of a fluorous amino ester, an aldehyde
and a maleimide to afford bicyclic prolines 135 in yields up to 94%. Fluorous solid
phase extraction (F-SPE) has been used effectively to separate the product from the
reaction mixture (Scheme 105).
Muthusubramanian and co-workers [187] disclosed a new approach towards the
synthesis of asymmetrical diarylamines 136 by a novel MCR between an aryl
aldehyde, an N-arylhydroxylamine and maleic anhydride using a domestic micro-
wave oven. Interestingly, the role of the methoxy group in the migration of the aryl
group from carbon to nitrogen is very important as it leads to the enone intermediate
136b via another intermediate 136a. The nucleophilic attack of water on interme-
diate 136b, gave the diarylamine 136 via another intermediate 136c. The diaryla-
mines were obtained in high yields within 2–3 min (Scheme 106).
Andreana and co-workers [188] developed a one-pot method for generating
molecular diversity via a multicomponent coupling reaction under microwave
irradiation. The initially formed Ugi four-component coupling products gave rise
to three structurally distinct scaffolds depending on the solvent effects and sterics:
the 2,5-diketopiperazines 137, the 2-azaspiro[4.5]deca-6,9-diene-3,8-diones 138,
and the thiophene-derived Diels–Alder tricyclic lactams 139 (Scheme 107).
Tu and co-workers [189] described a series of new 3-pyrimidin-5-ylpropanamides
140, spiro[5.5] undecane-1,5,9-triones 141 and pyrimidin-5-ylpropanoic acids 142
CHO NHOH O OCH3

H
OCH3 toluene N
X + Y + O Y X
MW, 2-3 min
136
O
16 examples, 60-76%
O
HO O O
HO
O H 2O HO
–
O O
O O
H+ N N
N Y Y
Y O OH
OCH3
H3CO H3CO
X X
X
136a 136b 136c
Scheme 106
O
R3 = 11 examples,
R4 R1
OMe N 81-98%
MeOH N dr < 20:1
R2 R3 137
via Aza-Michael
O
6 examples,
O
R3 = OH R2 60-82%
R2 OH dr < 3:1
MeOH O N
MW, 200°C, 138
R1CHO + R3NH2 via Michael O
20 min HN R1
R4NC R4
O R3
R4
R3 = N N 2 examples,
OMe H S O 23-25%
dr < 10:1
DCM H
139
via Diels-Alder H
R2
Scheme 107
which were selectively synthesized via a microwave-assisted, chemoselective

reaction of arylidene-Meldrum’s acid, 6-hydroxypyrimidin-4(3H)-one and an
amine. The outcome of the reaction depends on the nature of the applied solvent.
Arylidene–Meldrum’s acids bearing electron-withdrawing groups on the aromatic

substituent reacted rapidly under these conditions (Scheme 108).
Hulme and co-workers [190] have reported a novel two-step solution-phase
protocol for the synthesis of an array of triazadibenzoazulenones 144 via a
U-4CR of a mono-Boc-protected-phenylene diamine, a Boc-protected anthranilic
acid, an isonitrile, and an aldehyde. Further, the acid treatment of the Ugi products
143 leads to a tandem ring closing reaction. This two-step protocol is strongly
facilitated by microwave irradiation. Careful selection of the isonitrile enables the
correct order of ring forming events (Scheme 109).
An efficient and environmental friendly multicomponent synthesis of substituted
1,8-naphthyridines 145 has been described by Naik and co-workers applying a
O Ar O
AcOH R1
HN N
H
MW, 100°C N OH
12-22 min 140
34 examples, 69-91%
R1NH2
Ar
O O
O + Ar
O O H2O O
HN
O O MW, 100°C O O
N OH 16-22 min Ar
141
7 examples, 31-42%
O Ar O
HCOOH
HN OH
MW, 100°C
N OH
16-22 min
142
6 examples, 74-89%
Scheme 108
NH2
R2 N R3
R3
2
NHBoc BocHN R1 R
H TFA N
MeOH
1 4
R –CHO + R – NC N NH
O N R4 MW, 130°C, 1
MW,100°C, R
COOH 5 min BocHN O 20 min
O
R3 R2
NHBoc 144
143 12 examples, < 5-72%
Scheme 109
Ar
R1 ArCHO R1 CN
Bi(NO3)3 .5H2O
+
N NH2 MW, 4-5 min N N NH2
NC CN
145
8 examples, 92-96%
Scheme 110
R1 X
R1 O X KF-Alumina
+ + S R2 NH2
MW, 100°C, S
R2 CN
3.5-8 min 146
X = CN, COOEt 16 examples, 55-92%
Scheme 111
domestic microwave oven [191]. A 2-aminopyridine, an aryl aldehyde and mal-

ononitrile were reacted in the presence of Bi(III)nitrate as the catalyst under
solvent-free conditions yielding the desired compounds 145 in 92–96% yields.
The catalyst could be reused several times (Scheme 110).
Sridhar and co-workers [192] have described a microwave-promoted synthesis
of 2-aminothiophenes 146 by reaction of a ketone with a nitrile and elemental sulfur
using KF-alumina as a base via multicomponent condensation reaction. This
method offers an efficient and convenient modification to the Gewald reaction
replacing organic base with KF-alumina (Scheme 111).
3 Conclusions and Outlook
In this contribution, we have tried to present an overview of the application of

microwave irradiation for MCRs in the last 4 years. As these reactions are highly
suited for automation, making them extremely valuable for high-throughput syn-
thesis, the application of microwave irradiation has been intensively investigated to
speed up these reactions, reducing the reaction times from hours or days, to mere
minutes or even seconds and delivering the compounds mostly in higher yields, as
compared to conventional heating. In several cases, MCRs are performed under
solvent-free conditions, e.g., with the components absorbed on a solid support.
Although these conditions allow the safe performance of the reactions in a domestic
oven, it should be emphasized that these methods usually suffer from technical
difficulties related to nonuniform heating and mixing and precise determination of
the reaction temperature. However, with the current dedicated microwave instru-
ments available, one might expect that multicomponent chemistry will shift away
from these techniques. Of interest is also the recent combination of flow chemistry
with microwave irradiation (microwave-assisted continuous flow organic synthe-
sis – MACOS) which looks very promising for generating compounds on a larger
scale without having the need of optimizing the conditions for scale-up.
For all these reasons we are convinced that we will see many more exciting
examples of the application of microwave irradiation to multicomponent chemistry
in the near future.
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DOI: 10.1007/7081_2010_46
Applications of MCR-Derived Heterocycles

in Drug Discovery
Irini Akritopoulou-Zanze and Stevan W. Djuric
Abstract Heterocyclic structures are an integral part of numerous drugs and

natural products and there is a considerable interest in efficient methods for
their synthesis. A variety of multicomponent reactions (MCRs) provide access to
heterocyclic structures such as isocyanide based MCRs, dicarbonyl derivative and
cycloaddition MCRs. MCR-derived heterocycles are typically prepared in few,
versatile and atom efficient synthetic steps and exhibit anticancer, antioxidant and
antimicrobial properties.
Keywords Multicomponent reactions Heterocyles Drug discovery Antimicro-

bial Anticancer Antioxidant Antibacterial Antifungal Antimycobacterial
Dicarbonyl based MCRs Isocyanide based MCRs Knoevenagel based MCR
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
2 Isocyanide-Based MCRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
2.1 Ugi Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
2.2 Bienaymé–Blackburn–Groebke Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
3 Dicarbonyl, Cyanomalonate and Malononitrile Based MCRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
3.1 The Biginelli Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
3.2 The Hantzsch Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
3.3 The Gewald Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
3.4 Knoevenagel/Diels–Alder Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
3.5 Knoevenagel/Michael-Type Sequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
3.6 Knoevenagel/Krohnke Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
3.7 Other Knoevenagel-Based MCRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
4 Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
4.1 Hetero-Diels–Alder Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
I. Akritopoulou-Zanze (*) and S.W. Djuric

Medicinal Chemistry Technologies, Abbott Laboratories, Abbott Park, IL 60064, USA
e-mail: irini.zanze@abbott.com
232 I. Akritopoulou-Zanze and S.W. Djuric
4.2 1,3-Dipolar Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

5 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
5.1 The Döbner Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
5.2 The Bucherer–Bergs Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
5.3 Other Multicomponent Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
Abbreviations
ATP Adenosine 50 -triphosphate

BACE b-Secretase
Boc t-Butoxy carbonyl
Cdc Cyclin-dependent kinase
cGMP Cyclic guanosine monophosphate
DBP Diastolic blood pressure
DDQ 2,3-Dichloro-5,6-dicyano-p-benzoquinone
DEAD Diethyl azodicarboxylate
DIC N,N0 -Diisopropylcarbodiimide
DIEA Diisopropylethylamine
DMAP 4-Di(methylamino)pyridine
DMF Dimethylformamide
DOS Diversity-oriented synthesis
DPPH 2,2-Diphenyl-1-picrylhydrazyl
EDCI N-ethyl-N0 -(3-dimethylaminopropyl)carbodiimide
EDDA Ethylenediammonium diacetate
F Bioavailability
HOBt 1-Hydroxybenzotriazole
Hsp Heat shock protein
HTS High-throughput screening
MDR Multidrug resistance
MIC Minimum inhibitory concentration
MMP Matrix metalloproteinase
MSO L-Methionine-SR-sulfoximine
MtGS Mycobacterium tuberculosis glutamine synthase
NMP 1-Methyl-2-pyrrolidinone
PDE Phosphodiesterase
Pgp P-glycoprotein
PPT Phospinothricin
PTSA p-Toluenesulfonic acid
RCM Ring-closing metathesis
Applications of MCR-Derived Heterocycles in Drug Discovery 233
Red-Al Sodium bis(2-methoxyethoxy)aluminum hydride

ROC Ring-opening metathesis
ROS Reactive oxygen species
RSA Radical scavenging activity
SBP Systolic blood pressure
TFA Trifluoroacetic acid
THF Tetrahydrofuran
1 Introduction
Heterocyclic structures are an integral part of numerous drugs and natural products
[1] and there is a considerable interest in efficient methods for their syntheses [2].
Multicomponent reactions (MCRs) are powerful tools in creating heterocycles in
an atom- and time-efficient manner [3, 4]. MCRs involve the use of multiple
reaction inputs to generate products in a single step. For a reaction to be considered
a multicomponent reaction, most atom parts of each component need to be
incorporated into the final product. The more interesting and highly utilized
MCRs have invariably been the ones that allow for the generation of large numbers
of products by combining highly diverse components. Large libraries of MCR
heterocyclic products are particularly attractive for drug discovery efforts because
they provide rapid access to complex molecules for biological testing. Furthermore,
once biological activity is found, optimization exercises are relatively straight-
forward and expedient. In addition, compounds of interest can be easily scaled-up
for advanced in vivo studies.
2 Isocyanide-Based MCRs
One of the most prominent class of multicomponent reactions involves the use of
isocyanides [5] and many synthetic methods have been developed to access hetero-
cycles from isocyanide-based chemistry [6, 7]. There are a number of reviews
covering the applications of isocyanide-based MCRs in drug discovery [8, 9]. In
this review, we will focus on the most recent developments in the field.
2.1 Ugi Reactions
A high-throughput screening (HTS) campaign to identify b-secretase (BACE-1)

inhibitors provided compound 1 (Fig. 1) as a promising new hit which was quickly
optimized to compound 2 with the aid of an Ugi MCR [10]. Although compound
O O
N N F
N N N N
H H
N N
1 2
BACE 1 IC50 = 22 μM BACE 1 IC50 = 0.11 μM

sAPPβ IC50 = 5.2 μM (cell)
Fig. 1 Initial BACE 1 HTS hit and optimized analog
O O
O N
R1 R2 N R2
a R1
NH2 N N b, c N N
R1 N+ C– H H
R2
KOCN N
R3 N N
R3 R4
Scheme 1 a MeOH, H2O: b HCl (R3 = Boc): c R4CHO, Na(CN)BH3
2 did not show in vivo efficacy because of its weak cellular potency, it was not a
substrate for (P-glycoprotein) Pgp and had high plasma and brain levels validating
this class of compounds for further consideration.
The synthesis of 2 and related analogs proceeded as shown in Scheme 1. The
spiropiperidine iminohydantoin core was obtained in a one-step, four-component
Ugi coupling of piperidones, isocyanides, amines and KOCN, and proceeded in
moderate yields. Deprotection of the piperidine nitrogen and further elaboration
provided the final products.
Numerous heterocyclic structures can be accessed by combining the Ugi reac-
tion with subsequent transformations [11, 12]. In an elegant diversity-oriented
synthesis (DOS) approach, a library of highly complex molecular scaffolds was
prepared and evaluated for its binding affinity against Bcl-xL [13]. Most of the
scaffolds were accessed in few synthetic steps as shown in Scheme 2 by initially
forming versatile intermediates 3 via Ugi-5-center-4-component reactions. When
R1 and/or R4 possessed a double or triple bond, subsequent ring-opening/ring-
closing metatheses (ROM/RCM) of compounds 3 provided compounds 4–6. When
R2 contained an amino group, compounds 7 were prepared. Compounds 6 and 7 can
be further elaborated to compounds 8 and 9 via Diels–Alder and ROM/RCM
transformations, respectively. All compounds were evaluated for their binding
affinity against Bcl-xL by performing docking exercises and by 1H NMR binding
assays and several potential inhibitor core structures were identified for further
evaluation.
R3
O NH
N R2
R3 R3
CO2R4
O NH O NH
O
4
N R2 N R2
O H CO2R4 R5 CO2R4
N O R6 O
R1 O
R2
6 8
CO2H O N R3
O N H
R1
R2 H
CO2R4 3 O
R3 N+ C– O R1 O
R3
R4 OH
N N R3 N N
H O H
R R7
H N 7 NH
O N R O H
3 7 O 9
N R2
O
O
O
5
Scheme 2 Diversity-oriented synthesis of highly complex scaffolds via Ugi-5C-4CR followed by

ROM/RCM cyclizations and Diels–Alder reactions
O HN R3
N a
R1 R3 N+ C – N
NH2 R2 H R1 R2
N
Scheme 3 a MgCl2, EtOH, 160 C, Microwave, 20–30 min
2.2 Bienayme´–Blackburn–Groebke Reactions
The Bienaymé–Blackburn–Groebke reaction [14–16] provides access to a variety

of fused heterocyclic ring systems in one, atom-economical, synthetic step.
The reaction has been recently utilized to prepare functionalized 3-amino-
imidazo[1,2-a]pyridines from aldehydes, 2-aminopyridines and isocyanides, as
shown in Scheme 3 [17].
The compounds prepared were tested for their inhibitory activity against Myco-
bacterium tuberculosis glutamine synthetase (MtGS), an enzyme that plays a key
role in mycobacterial cell-wall biosynthesis and nitrogen metabolism. Compound
10 was identified as a potent inhibitor of the enzyme with favorable inhibitory activity
compared to the most potent inhibitors known, L-methionine-SR-sulfoximine (MSO)
and phosphinothricin (PPT) (Fig. 2).
An interesting variation of the Bienaymé–Blackburn–Groebke reaction employ-
ing 2-formylbenzoic acid, 2-aminopyridines and isocyanides (Scheme 4) resulted
in the production of fused isoquinolinones 11 [18]. The reaction proceeded better
without the presence of a Lewis acid and worked with a variety of different
isocyanides and 2-aminopyridines. Phenyl isocyanide, however, did not give a
satisfactory result. The products were tested against the non-small-cell lung cancer
cell line A549 and three exhibited potent activity (Fig. 3). It was found that the
presence of the 4-methoxybenzyl group was necessary for activity.
HN O O
Br
N HO2C S HO2C P
NH OH
N NH2 NH2
CO2H
10 MSO PPT
Mt GS IC50 = 0.38 μM Mt GS IC50 = 51 μM Mt GS IC50 = 1.9 μM
Fig. 2 MtGS inhibitors
R1
O
R1 N
H a N
R2 N+ C –
CO2H N NH2 N
R2
11
O
Scheme 4 a MeOH, 55 C, 39–82%
N N N Cl
N N N
N N N
O O O
12 13 14
O O O
A549 IC50 = 1.82 μM A549 IC50 = 6.61 μM A549 IC50 = 10.692 μM
Fig. 3 Cytotoxic activity of compounds 12–14 against the A549 cell line
3 Dicarbonyl, Cyanomalonate and Malononitrile Based MCRs
In addition to isocyanide-based MCRs, a wealth of highly functionalized heterocycles

can be obtained from 1,3-dicarbonyl, cyanomalonate and malononitrile based MCRs
[19]. These easily accessible starting materials participate in a variety of multi-
component reactions and have found numerous applications in drug discovery.
3.1 The Biginelli Condensation
The classic Biginelli reaction features the cyclocondensation of an aldehyde, a urea

and an active methylene compound to form dihydropyrimidinones (Fig. 4). The
reaction has been extensively utilized and reviewed [20] and its applications to drug
discovery have also been highlighted [21]. This chapter will focus on some of the
most recent developments and applications of Biginelli reactions to the discovery of
biologically active molecules.
A straightforward synthesis of Biginelli products using p-toluenesulfonic acid
(PTSA) was developed (Scheme 5) [22]. The methodology did not require an-
hydrous conditions and proceeded in high yields at room temperature, although
some reaction mixtures required reflux to go to completion.
The compounds obtained from these reactions were tested for their cytotoxic
and antioxidant activities. It was found that compounds, deriving from cinnamoyl
aldehydes such as 15 and 16 (Fig. 5), had significant cytotoxic activity against
MCF-7 human breast cancer cells. Furan and pyridine moieties in the same position
also imparted potent cytotoxicity, while 3-nitrophenyl substitutions resulted in com-
pounds 17 and 18 with good antioxidant activity. These were the only compounds
with antioxidant activity up to 100 mg.
Several groups have used the Biginelli reaction to search for heat shock protein
70 (Hsp70) modulators. Hsp70 performs essential cell functions such as protein
R
R
E H O E
H+ NH
NH2 heat
Fig. 4 The Biginelli R O R N X
H2N X H
condensation
O O R2
NH2 R1
R1 N R2 a N NH
H HN X H
H O N
O Y X
H
R1 = Me, 2-ClPh X = O, S, NH
Y = H, CN
Scheme 5 a PTSA, EtOH, room temperature or reflux, 24–30 h, 67–81%, for R1 = 2-ClPh,
R2 = Ph, Y = H, X = NH 12%
O2N
O O
N NH N NH
H H
Cl Cl
N X N X
H H
% Cytotoxicity at 10 μg DPPH antioxidant activity

15 X = S 71% 17 X = S IC50 = 58 μg
16 X = O 79% 18 X = O IC50 = 63 μg
Fig. 5 Cytotoxic and antioxidant activities of compounds 15–18
folding and trafficking and protects cells from thermal and oxidative stresses.
Although the many roles and mechanisms by which Hsp70 operates are not fully
elucidated, overexpression of Hsp70 in various cancers has made this protein an
interesting target for anticancer therapies. Hybrid peptoid–dihydropyrimidinones
libraries 20 have been prepared by combining the Biginelli and Ugi reactions
(Scheme 6) [23]. Dihydropyrimidone acids 19 have also been used for direct
couplings to provide amides 21 [24]. Alternatively, solid-phase synthesis of dipep-
tides on Wang resin, followed by coupling of the resin bound amines with 19 and
subsequent cleavage from the resin, furnished peptoid-type amides 21 [25].
Several compounds derived from these libraries were identified as Hsp70 modu-
lators and were further evaluated in cell proliferation assays such as the SK-BR-3
and MCF-7 breast cancer cell lines and the HT29 colon cancer cell line (Fig. 6)
[26]. Compounds 22–24 were potent against all three cell lines. The dihydro-
pyrimidinone libraries were also tested for replication inhibition of the malarial
parasite, Plasmodium falciparum, where Hsp70 chaperones are believed to play an
important role in the parasite’s homeostasis [24]. Nine compounds that inhibit
replication of the parasite were identified. Among them, compounds 25 and 26
were the most potent (Fig. 7) and were prepared by direct couplings of dihydro-
pyrimidone acids 19 with a pyrrolo amine.
The activity of numerous peptoid-amides 21 (Scheme 6), deriving from solid-
phase syntheses [25], against two evolutionary distant members of the Hsp70
family, DnaK from Escherichia coli (E. coli) and bovine Hsc70, was also reported.
Several compounds were found to be active against mammalian Hsp70 and some
compounds such as 27 and 28 were found to be active against both Hsp70 isoforms
(Fig. 8).
Copper (II) chloride proved to be a very efficient catalyst for the Biginelli
reaction in the absence of solvent [27]. When ethyl acetoacetate, aldehydes and
urea or thiourea were heated neat in the presence of copper (II) chloride, the
Biginelli products were isolated, after recrystallization from hot ethanol, in high
yields and purities (Scheme 7).
O R3
R1
O NH
R4 NH2 R2 N O
R5 CHO
R6 N+ C – n
O
c
R3 R5 N
O O R3 R4
R1 H O R1
O a or b O NH
HN O
NH2
R2 O R2 N O R6 20
HN O R4 NH2
n O R3
d
n O
R1
O O NH
OH 19
OH R2 N O
n = 1, 3 n
O
NH
R4 21
Scheme 6 a THF, cat HCl, rt, 48 h; b DMF, cat HCl, 55 C, 38 h; c MeOH, Microwave, 70 C,
21–63%; d EDCI, DMAP, CH2Cl2, rt or when R4 is a dipeptide attached to Wang resin, DIC,
HOBt, 60 C, microwave then 1:1 TFA/CH2Cl2
The compounds produced were tested for their antifungal activity against
Trichoderma hammatum, Trichoderma koningii and Aspergillus niger. Radial
growths of the corresponding fungus at 24-, 48- and 72-h time intervals, at various
concentrations of compound, were recorded and inhibition rates over control were
calculated. Most of the compounds exhibited modest antifungal activity. Com-
pound 29 was the most potent against T. hammatum with an MIC of 0.35 mM,
compound 31 against T. koningii (radial growth after 24 and 48 h was completely
inhibited) and compounds 30–33 against A. niger with MIC values of 0.35 mM each
(Table 1).
Fused dihydropyrimidinones of general structure 35, deriving from the combi-
nation of the Biginelli reaction with another one-pot multicomponent reaction as
shown in Scheme 8, exhibited good antifungal as well as antibacterial properties
[28]. The Biginelli product 34 was prepared by a tin dichloride-mediated conden-
sation followed by recrystallization from hot ethanol in 91% yield. It was then
subjected to a one-pot reaction with monochloroacetic acid and an arylaldehyde
or arylfurfuraldehyde in the presence of anhydrous sodium acetate in acetic
acid/acetic anhydride. All the products were tested for antifungal activity against
Aspergillus fumigatus (NCIM No. 524), Aspergillus flavus (NCIM No. 902),
Candida albicans (NCIM No. 3100) and Penicillium marneffei. They were also
O R3 O
O NH O NH
N O N O
O O O O
O O
O O O O
O O
N N
O
HN O HN O
22 R3 = Phenyl 23 R3 = c-Propyl 24
SK-BR-3 GI50 = 6.5 μM SK-BR-3 GI50 = 6.2 μM SK-BR-3 GI50 = 8.8 μM
MCF7 GI50 = 2.4 μM MCF7 GI50 = 6.3 μM MCF7 GI50 = 7.8 μM
HT29 GI50 = 4.8 μM HT29 GI50 = 5.3 μM HT29 GI50 = 3.1 μM
Fig. 6 Antiproliferative activity of hybrid peptoid-dihydropyrimidinones
evaluated for antibacterial properties against E. coli (ATCC 25922), Staphylococ-

cus aureus (S. aureus) (ATCC 25923), Pseudomonas aeruginosa (ATCC 27853)
and Klebsiella pneumoniae. Compounds 36–39 were some of the most potent
compounds with good broad antifungal and antibacterial activities (Table 2).
A variation of the Biginelli condensation in which aldehydes and guanidine
hydrochloride were reacted with ethylcyanoacetate (Scheme 9) under basic condi-
tions provided 2-aminopyrimidines in a one-step synthesis [29]. The products were
tested against E. coli and S. aureus bacteria. Compound 40 was selectively active
against S. aureus.
Another variation of the Biginelli condensation involved the reaction of alde-
hyde 42, guanidine hydrochloride with various pyrazolones 41 to provide pyrazo-
lopyrimidines 43 (Scheme 10) [30]. All the products obtained were tested against
the M. tuberculosis H37 Rv strain and found to be active. In particular, compounds
44–46 had comparable activity (MIC = 1.2 mg/mL) to first-line drugs such as
rifampicin (RIP) (MIC = 1 mg/mL).
The reaction of o-methylisourea hydrogen sulfate with ethyl acetoacetate and
aldehydes provided dihydropyrimidines 47 (Scheme 11) which underwent
NO2
O
O
O NH
O NH
N O
N O
NH
O
O
NH N
O
O
N
O
25 26
P. falsiparum IC50 = 0.05 μM P. falsiparum IC50 = 0.03 μM
Fig. 7 Antimalarial activity of peptoid-dihydropyrimidinones
Br Br
O O
O NH O NH
N O N O
O O
H H H
HO N N NH HO N NH
O O O O O
27 28
NH2
Hsc70 Ec50 = 105 μM Hsc70 Ec50 = 179 μM
Dnak Ec50 = 107 μM Dnak Ec50 = 190 μM
Fig. 8 Hsp70 activity of peptoid-dihydropyrimidinones

O O R1
R1 NH2 a
O O NH
H O H2N X
O N X
X = O, S H
Scheme 7 a 20 mol% CuCl2·2H2O, 100 C, 20 min to 1 h, 85–96%
Table 1 Percentage inhibition of radial growth over control (mm) of dihydropyrimidinones

N
O O OH O
O NH O NH O NH
N X N X N X
H H H
29 X = O 31 X = O 32 X = O
30 X = S 33 X = S
Compound T. hammatum T. koningii A. niger

7% conc. 24 h 48 h 72 h 24 h 48 h 72 h 24 h 48 h 72 h
29 100 100 100 100 100 96 100 79 77
30 100 100 96 91 91 84 100 100 100
31 100 100 97 100 100 97 100 100 93
32 100 96 94 100 87 80 100 100 100
33 100 100 98 100 95 91 100 100 100
S S
S
O
NH2 a b
O O O
H 2N S O
O O NH O N
H O
N S S R
H N
34 35
Scheme 8 a SnCl2·2H2O, EtOH, reflux, 6 h, 91%; b ClCH2CO2H, NaOAc, RCHO, AcOH/Ac2O,

reflux, 3 h, 74–86%
nucleophilic substitution reaction with various phenacyl bromides to provide tetra-

hydropyrimidines 48 [31]. These compounds were evaluated for their antihyper-
tensive, anti-inflammatory, analgesic and acute ulcerogenesis activity. The
antihypertensive activity was measured in Norwegian inbred albino rats (i.p.
dosing, hypertension was induced with deoxycorticosterone acetate salt), first, by
Table 2 Antifungal and antibacterial activity (MIC values in mg/mL) of fused dihydropyrimidi-
nones
S S
O O O O
O N O N
N S N S O
R1 R2
36 R1 = 4-OMe 38 R2 = 4-Br
37 R1 = 4-OH, 3-OMe 39 R2 = 2, 4-diCl
Compound Antifungal activity MIC (mg/mL) Antibacterial activity MIC (mg/mL)

A. fum A. flav C. alb P. marn S. aur P. aer K. pneu E. coli
36 6 12.5 6 12.5 25 6 6 25
37 6 25 12.5 6 12.5 6 12.5 12.5
38 12.5 12.5 6 6 12.5 6 6 12.5
39 12.5 12.5 6 6 12.5 6 6 25
N
Ar
Ar NH2.HCl a NC
N NC
O O H O H2N NH N
HO N NH2
HO N NH2
40
Scheme 9 a NaOH, EtOH, reflux, 1–3 h, 79–95%
Mycobacterium
N N tuberculosis
N Cl
NH2.HCl a
N O N N MIC (μg/mL)
Cl H N NH N
2 N 44 R = 2-Cl 1.2
N N NH2
R O 45 R = 3-Cl 1.2
H
46 R = 4-Me 1.2
41 42 43
R
Scheme 10 a EtOH, reflux, 5 h, 68–100%

R1 R1
R1
O R2
NH O O
a b
O
H2N O O N O N
O O
H O N O N O
H H
47 48
R1 = Cl, OMe, OH, Me R2 = Cl, OMe
Scheme 11 a NaHCO3, DMF, 70 C, 12 h, 64–76%; b Substituted phenyl acetyl bromides,

CH2Cl2, pyridine, reflux, 7 h, 45–81%
Table 3 Antihypertensive and anti-inflammatory activity of tetrahydropyrimidines

R1
R2
O
O N
O
N O
H
Compound R1 R2 Average SBP Average DBP Average paw

(10 mg/kg) (mmHg) at 460 min (mmHg) at 240 min volume at 5 h
49 H Cl 122 102 1.10
50 Me H 155 100 1.16
51 OMe H 121 101 0.9
52 OMe Cl 110 102 1.10
Control OMe Cl 225 196 1.86
Nifedipine OMe Cl 120 101 –
Iodomethacin OMe Cl – – 0.93
a noninvasive tail-cuff method to measure the systolic blood pressure (SBP). The
diastolic blood pressure (DBP) was then measured by direct cannulation of the
carotid artery. Most of the compounds exhibited antihypertensive activity compa-
rable to that of nifedipine (Table 3). The compounds were further tested for
their anti-inflammatory activity in the carrageenan-induced rat-paw oedema
model (p.o dosing). Compound 51 was the most efficacious in this model (Table 3).
This compound had also the highest analgesic activity in Swiss albino mice
(59.76% protection) comparable with ibuprofen’s 62.55% at 20 mg/kg p.o. None
of the compounds showed significant ulcerogenic activity.
The antioxidant activity of dihydropyrimidinones was also evaluated. In one
study [32], the compounds were prepared by ultrasound irradiation in the
presence of NH4Cl in good yields. The antioxidant activities were measured in
liver homogenates from male adult albino Winstar rats. The compounds were tested
for their activity against Fe- and EDTA-induced lipid peroxidation at various
O O
N
O NH O NH
N O N O
H H
53 R = H 55
54 R = NO2 ROS levels in 15 min at 400 μM = 11.86

fluorescence emission units (UAF)
Control = 64.14 (UAF)
Fig. 9 Antioxidant activity of dihydropyrimidines
R1 R1
R1
O NH2 Cl HN
a O b
O Cl HN X O NH
O NH
O R2
H O N X
N X
R2 R2
X = O, S
56 57
Scheme 12 a H3BO3, AcOH, reflux, 3 h, 60–90%; b NH3, 10 bar, 250 C, 16 h, 65–90%
concentrations. Compounds 53 and 54 exhibited the best activity with a maximal

effect at 200 mM. Compounds 53 and 55 were the most effective in reducing
reactive oxygen species (ROS) levels in rat liver (Fig. 9).
The free radical scavenging effects of compounds 57 derived from dihydro-
pyrimidines 56 (Scheme 12) was also examined by the DPPH method and by
measuring hydroxyl radical scavenging activity (RSA) [33]. It was found that com-
pounds derived from the thioureas had the best antioxidant activities. Compounds
58 and 59 were the most potent and had comparable activity to quercetol (Table 4).
3.2 The Hantzsch Reaction
The Hantzsch MCR is a well-established tool in the arsenal of contemporary

synthetic organic and medicinal chemists and has, along with many of its variants,
been a subject of past review articles [34]. The material of this chapter briefly
summarizes past contributions and focuses on recent examples of the Hantzsch
reaction in the synthesis of potential medicinal agents. In its original incarnation,
Table 4 Decreasing absorbance DPPH and fluorescence of fused dihydropyrimidines

Cl
HN HN Cl
O NH O NH
N S N S
58 59
Compound (50 mmol/L) % DPPH % Fluorescence

58 9.5 76.5
59 7.7 82.7
Ascorbic acid 36.9 –
Quercetol – 87.9
R1
O O
R1 a
R3O NH3 OR3 R3O2C CO2R3
R2 O H O O R2
R2 N R2
H
60
Nifedipine R1 = 2-NO2, R2, R3 = Me
Scheme 13 a AcOH or EtOH, heat
the reaction utilized 1,3 dicarbonyl compounds, aldehydes and amines to provide
ready access to symmetrically substituted 1,4-dihydropyridines 60 through a four-
component reaction that featured two acetoacetic ester inputs (Scheme 13). A well-
known example of this reaction is the synthesis of Nifedipine, a calcium antagonist,
by Bayer AG in 1977 (Scheme 13) [35].
Cyclic 1,3 diketones could also participate in this MCR allowing for a four-
component Hantzsch synthesis of unsymmetrically substituted 1, 4-dihydropyri-
dines or pyridines depending upon reaction conditions [36, 37] (Scheme 14).
There are numerous variations in the Hantzsch protocol deriving from variations
in the aldehydes, ammonia derivatives and active methylene compounds employed.
The final products are 1,4-dihydropyridine and pyridine derivatives as well as
pyrroles.
Some new substituted tetrahydroacridin-8-ones and diverse derivatives were
synthesized by uncatalyzed multicomponent reaction of dimedone or cyclohexan-
1, 3-dione, a-naphthylamine and various (o, p, m)-substituted benzaldehydes
(Scheme 15) [38]. The in vitro antimicrobial activities of the prepared compounds
O R O
a O
N
O O H
R
O
H O
O O O R O
b
O
Scheme 14 a NH4OH/H2O, 110 C; b microwave, NH4NO3, bentonite
R
O
NH
61
R
NH2
a
R
O
CHO
O
O
NH
62
Scheme 15 a Microwave, 160 W, neat, 2–5 h, 92–98%
were evaluated against some bacteria and fungi strains. The results suggested that
the products 61 and 62 exhibited good inhibitory effect against most of the tested
organisms. Especially, 63–66 were shown to be most effective against E. coli,
Rhodotorula rubra and Aspergillus parasiticus (Table 5).
A one-pot efficient method for the synthesis of derivatives 67 and 68 by
condensation reaction of barbituric acids, 1H-pyrazol-5-amines and aldehydes
under solvent-free conditions has been reported (Scheme 16) [39]. These products
were evaluated in vitro for their antibacterial activities against E. coli (ATCC
25922), P. aeruginosa (ATCC 85327), Enterococcus faecalis (ATCC 29737),
Bacillus subtilis (ATCC 465), Bacillus pumilus (PTCC 1114), Micrococcus luteus
Table 5 Antibacterial and antifungal activities of tetrahydrobenzo-acridinone derivatives

OH OH
NO2
O O O OH O
NH NH NH NH
63 64 65 66
Compound Antibacterial activity Antifungal activity

MIC (mg/mL)
E. coli B. cereus R. rubra A. parasiticus
63 125 62.5 7.8 3.9
64 31.2 31.2 3.9 7.8
65 3.9 15.6 7.8 3.9
66 125 – 7.8 15.6
Ph Ar O
O
HN NH NH
N N N O
O O H H
Ph 67
X
R
N NH2 a
N
O
Ph Ar O
CHO
NH
NH
X O N S
H N N N S
X=H H H
X = NO2
X 68
Scheme 16 a PTSA, neat, 100 C, 4 h, 80–95%
(PTCC 1110), S. aureus (ATCC 25923), Staphylococcus epidermis (ATCC 12228)

and Streptococcus mutans (PTCC 1601). Good antibacterial activity was observed for
most of the compounds against all species of gram-positive and gram-negative
bacteria used in the study (Table 6). Compounds 67 were more potent than com-
pounds 68. The majority of the compounds were found to be more active than
Table 6 Antibacterial activities of select pyrazolo-pyrido-pyrimidine-diones
NO2
Ph O Ph O Ph O Ph O
NH NH NH NH
N N N O N N N O N N N O N N N S
H H H H H H H H
69 70 71 72
MIC (μg/mL) MIC (μg/mL) MIC (μg/mL) MIC (μg/mL)

B. subtilis 2 2 2 4
B. pumilus <2 <2 2 4
M. luteus <2 2 2 8
S. aureus 2 2 2 8
S. epidermis 2 2 2 4
S. mytans <2 <2 <2 <2
E. coli <2 <2 <2 4
E. faecalis 2 2 2 4
P. aeruginosa 2 2 2 32
O O
N
H
73
Fig. 10 Cytotoxic activity of
compound 73 HSC-2 IC50 = 7 μM
Gentamicin against all tested strains and compounds 67 were more potent than
Tetracycline against B. pumilus, M. luteus, S. mutans, E. coli, and P. aeruginosa.
The anticancer properties of a series of dibenzoyl dihydropyrimidines have
recently been reported [40]. In particular, compound 73 (Fig. 10) showed cytotoxic
activity against human oral squamous carcinoma (HSC-2) cells and also inhibited
the Pgp-mediated drug efflux in (multidrug resistant) MDR cells.
The Hantzsch pyrrole synthesis found application in the preparation of a series
of Cdc7 kinase inhibitors (Scheme 17) [41, 42]. Cdc7 is a key regulator of the
S-phase of the cell cycle and its inhibition can cause tumor cell death. SAR studies
of a series of 2-heteroaryl-pyrrolopyridinones 74 identified compound 75 (Fig. 11)
as a potent ATP-competitive inhibitor of Cdc7. This compound had a Ki of 0.5 nM,
O O
O a, b
NR1 NR1
Br Het
Het
O R N R
H
74
Scheme 17 a NH4OAc, EtOH, rt; b TFA where R1 = Boc
(ovarian) A2780 Ic50 = 0.5 μM

(mammary) MCF7 Ic50 = 1.1 μM
O (AML) L363 Ic50 = 1.3 μM
(myeloma) NCI-H929 Ic50 = 1.2 μM
N
NH (myeloma) OPM2 Ic50 = 3.7 μM
N N (human fibroblasts) NHDF Ic50 = 1.6 μM
H2N H Ic50 = 2.5 μM
(human fibroblasts) NIH-3T3
(colon) COL0205 Ic50 = 0.5 μM
75
F (colon) HCT116 Ic50 = 0.4 μM
(colon) HT29 Ic50 = 4.1 μM
(colon) SW403 Ic50 = 0.6 μM
(colon) SW48 Ic50 = 0.9 μM
Fig. 11 Antiproliferative activity against various cancer cell lines of compound 74
OMe OMe
OMe MeO OMe MeO OMe
R2 MeO OMe O
a R2
N O O
O
N NH2 O N O N O
R1 H O N N N N
H H H
R1
76 77
Scheme 18 a Et3N, EtOH, reflux, 45–80%
inhibited cell proliferation in numerous tumor cell lines with an IC50 in the single-
digit micromolar or submicromolar range and exhibited in vivo ovarian tumor
growth inhibition in an A2780 female mice xenograft model.
Other efforts in the anticancer area have focused on the use of heterocyclic
podophyllotoxin analogs 76 as antiproliferative and apoptosis inducing agents
[43, 44] Libraries of analogs were prepared by a one-step multicomponent
Hantzsch-type protocol employing aminopyrazoles (Scheme 18). Apoptosis
OMe OMe
O
R a
O O O
NH2 H O
O HN
N O N N
H H H
78 79
Scheme 19 a AcOH/glycol, 120 C, 4 h, 61–72%
induction was observed with some analogs in Jurkat cells. In particular, analog 77
showed greater than 50% apoptosis induction at 5 mM.
The same group has also reported a multicomponent Hantzsch protocol which
provided access to polycyclic indenoheterocycles 78 utilizing a variety of aromatic
and heterocyclic amines (Scheme 19) [45]. Some of the compounds disclosed
showed apoptosis-inducing activity in a human T-cell leukemia cell line similar
to etoposide. One of the most potent analogs was compound 79 (Scheme 19) which
showed greater than 30% induction of apoptosis at 25 mM, as assessed in a flow
cytometric annexin V/propidium iodide assay in Jurkat cells.
Several papers have been published that highlight the use of the Hantzsch
reaction for the synthesis of compounds that exhibit ion channel modulating
activity. The majority of protocols invoke dihydropyridine synthesis as outlined
in Schemes 13 and 14.
For example, recently new, condensed 1,4-dihydropyridines with variations at the
ester site were synthesized and their calcium channel antagonistic activities were
examined on isolated rabbit sigmoid colon strips[46]. Compounds 80 containing
2-methoxyethyl esters were found to be the most active (Fig. 12). Myorelaxant
activity in isolated rabbit gastric fundal smooth muscle strips was also reported for
7-substituted hexahydroquinoline derivatives such as compounds 81 [47] and 82
[48] (Fig. 12). Imidazolyl dihydropyridines such as 83 exhibited calcium channel
antagonist activity in guinea pig ileal longitudinal smooth muscle [49]. A series of
substituted dihydropyridines was also examined for its KATP channel functional
activity in isolated pig bladder strips and compound 84 (Fig. 12) was found to be a
potent potassium channel opener [50]. Compound 84 also showed efficacy in vivo
inhibiting myogenic bladder contractions in the partial outlet obstructed rat model.
Dihydropyridines were tested for their ability to modulate activity of the heat- and
ligand-gated cation channel vanilloid receptor 1 TRPV1[51]. Compound 85 was the
most efficacious enhancer of this ion channel which has been implicated in pain
sensation.
A variant of the Hantzsch reaction catalyzed by molecular iodine (Scheme 20)
provided N-Aryl dihydropyridine derivatives 86, which were evaluated for their
antidyslipidemic and antioxidant potencies [52]. Several compounds exhibited
promising antidyslipidemic and antioxidant activities (Table 7).
Cl
Cl
F3C Cl NO2
O F O
O Cl
CO2CH2CH2 OMe CO2Me
CO2Me
N N
H N H
H
80 81 82
pD2 = 5.11 pD2 = 5.23 pD2 = 6.87
Emax = 44.99 % Emax = 57.71 % Emax = 96.76 %
F
Br
NH O O
N O O
CH3 O S O
O
CO2Me O N
O O H
N
N H HN
H
83 84 85
Ca Channel IC50 = 0.031 μM (–) enantiomer TRPV1 EC50 = 21.3 μM
KATP pEC50 (% efficacy) = 6.29 Emax = 626%
Fig. 12 Ion channel activities of dihydropyrimidines
R
NH2 R1 O
O
R3 R2 C
a R6
R1 R6
R2 R4 N
O
R5 R3
O H
R4
R5 86
Scheme 20 a I2, MeOH, rt, 1 h, 80–92%
Another application of the Hantzsch reaction involved the identification of

pyridopyrimidine derivatives such as 91 as inhibitors of stable toxin a (STA)
induced cGMP synthesis (Fig. 13) [53].
Table 7 Antidyslipidemic and antioxidant activity of compounds 86
O O O O
C C C C
O O O O
N N N N
87 88 89 90
Compound Total cholesterol- Phospholipid- Triglyceride- Generation of

plus triton lowering lowering lowering hydroxyl radicals
activity (%) activity (%) activity (%) at 200 mg/mL
87 21.9 28.5 25.3 60.92
88 24.8 21.3 10.5 53.35
89 24.1 23.9 25.7 58.57
90 15.5 12.8 11.0 56.05
Gemfibrozil 3.71 39.1 36.1 –
Mannitol – – – 50.24
F3 C CF3
O O
N
O N N
H
Fig. 13 Inhibition of cGMP 91

accumulation in T84 cells IC50 = 2.5 μM
3.3 The Gewald Reaction
The Gewald reaction [54] is one of the most facile methods of preparing
2-aminothiophenes from activated nitriles, active methylene compounds and ele-
mental sulfur (Fig. 14).
Several groups have used this reaction in recent years to prepare biologically
active molecules. Benzothiophene derivatives 93, prepared from Gewald products
92 in three steps via a palladium-mediated aromatization reaction, (Scheme 21)
were tested for their antiproliferative activity and inhibition of tubulin polymeriza-
tion [55]. Several compounds showed inhibitory effects against murine leukemia
(L1210), murine mammary carcinoma (FM3A) and human T-lymphoblastoid
(Molt/4 and CEM) cells. For most of the compounds, there was a positive
R2 O E R2 E
amine
CN NH2
R1 S8 R1 S
Fig. 14 The Gewald reaction
R3 R4 R3 R4
R3 R4
O R2 R2
R2 a b, c, d
S8
O O O
R1
R1 NH2 R1 NH2
CN S S
92 93
Scheme 21 a Morpholine, EtOH, 70 C 1 h then rt 18 h; b Ac2O, pyridine, reflux, 2 h; c 10%Pd/C

(50% wet with water), 130 C, 20 h; d 1 N NaOH, EtOH, reflux, 5 h
O O
O
O O
O
O
NH2
S
HO
94 Combretastatin A-4
L1210 IC50 = 0.76 nM IC50 = 2.8 nM
FM3A IC50 = 0.09 nM IC50 = 42 nM
Molt4 /C8 IC50 = 0.69 nM IC50 = 1.6 nM
CEM IC50 = 0.52 nM IC50 = 1.9 nM
tubuline assembly IC50 = 0.76 μM IC50 = 1.2 μM
colchicine binding at 1 μM = 91% binding at 1 μM = 86%
Fig. 15 Antiproliferative activity and inhibition of tubulin polymerization of thiophene 94 and

combretastatin A-4
correlation between the inhibition of tubulin polymerization and the antiprolifera-

tive effects. Compound 92 stood out as a potent subnanomolar inhibitor of cancer
cell growth and nanomolar inhibitor of tubulin polymerization by binding to the
colchicine site (Fig. 15).
O
R2 O R3 R2 R3 O
a
S8
R1 CN R1 S NH2 S NH2
95
GluR6 IC50 = 0.75 μM
Scheme 22 a Diethylamine or morpholine, EtOH, 50 C, 1–3 h, 60–77%
Table 8 A1AR allosteric and antagonistic activity
Cl
O N N O N N
O O
O O
S NH2 S NH2
96 97
Compound EC50 (mM)a % Inhibitionb pA2c

96 9.75 23 Inactive
97 5.7 100 8.7
a
Concentration of compound producing half-maximal allosteric effect on [125I]-ABA dissociation
b
Percentage inhibition of specific [3H]CPX binding at 50 mM
c
Negative logarithm of concentration of antagonist needed to double the concentration of agonist
necessary to achieve the same response as in the absence of antagonist
The Gewald reaction was also utilized to rapidly assemble 2-aminothiophene-

derived libraries of compounds (Scheme 22) to be evaluated for binding against the
glutamate receptor GluR6 [56]. A calcium influx functional assay was used to
measure antagonistic activity. Compound 95 was identified as a submicromolar
antagonist of GluR6.
Compound 96 was identified as a new lead molecule (Table 8) through screening
for allosteric modulators of the Adenosine A1 receptor (A1AR). A series of related
compounds was prepared and evaluated for activity [57]. It was found that although
the compounds appeared to recognize the allosteric binding site of the receptor their
behavior in the various assays was more consistent with orthosteric antagonism.
Compound 97 was a potent antagonist of A1AR and also exhibited inverse agonism.
Fused thiazolopyridazinones such as 96 and 97 were obtained from anilines
which were converted to phenyl diazonium salts and reacted with ethyl acetoacetate
to prepare phenyl hydrazones 98 (Scheme 23). These compounds participated in a
Knoevenagel-type condensation with ethyl cyanoacetate to provide pyridazinones
R R
R
a, b c d O N N
O N NH O N N
O
O
H2N O
O O
O CN NH2
S
98 99 100
Scheme 23 a 48% HBF4 in H2O, NaNO2, 67–100%; b NaOAc, ethylacetoacetate, EtOH, 58–100%;
c 4-aminobutyric acid, ethyl cyanoacetate, 160 C, 2.5 h, 42–95%; d S8, morpholine, EtOH, reflux,
6–12 h, 55–100% or Microwave, 150 C, 10–20 min, 79–100%
99. Gewald reaction of compounds 99 with sulfur under reflux conditions or with
microwave heating yielded the final products 100.
3.4 Knoevenagel/Diels–Alder Sequences
A domino Knoevenagel/Diels–Alder epimerization sequence followed by Suzuki

coupling provided a library of biphenyl and terphenyl spirocyclic triones
(Scheme 24) [58]. The initial Knoevenagel adducts 103 were formed from either
1,3-indandione or Meldrum’s acid 101 and various bromosubstituted benzalde-
hydes in the presence of catalytic (L)-5,5-dimethyl thiazolidinium-4-carboxylate
(DMTC) in high yields. Diels–Alder cycloaddition of 103 with 104, formed in situ
from 102 and (L)-DMTC, provided exclusively the cis-spiro compounds 105 due to
epimerization of the minor trans isomer to the thermodynamically more stable cis.
Subsequent Suzuki couplings of 105 with various boronic acids afforded the final
compounds 106.
Compounds of general structure 106 were evaluated for their antiproliferative
effects on sensitive acute myelogenous leukemia HL60, Bcr-Abl-expressing K562
cells and normal cells (lymphocytes) [59]. They were also evaluated for their
proapoptotic activity against HL60 and K562 cells. Several compounds showed
activity as illustrated in Table 9. Although the mechanism of action of these
molecules has not been fully understood, it was found that compounds 107 and
109 were able to reduce expression of Bcl-2 in K562 cells. Further mechanistic
studies were under way and they were facilitated by the ease of synthesis by which
the final products could be obtained.
A similar domino sequence in an intramolecular Diels–Alder version of the
previous example provided access to pyrano benzo-[60] and naphtho-[61] quinones
as shown in Scheme 25. Depending on substitution patterns of the aldehyde 111,
para-(112 and 116) or ortho-(113 and 117) adducts or both were obtained. Typi-
cally high diastereoselectivity was observed. Libraries 114 and 115 were tested for
their ability to reverse the multidrug resistance phenotype resulting from over-
expression of drug efflux pumps. The compounds were evaluated in mammalian
O O
H
O S
O
a N CO2H
O
O
R R
R = Br
101 102 103 104
R = 3-Br-Ph
R = 4-Br-Ph
O O
b R = Br A = Ar
O O R = 3-Br-Ph A = 3-Ar-Ph
R = 4-Br-Ph A = 4-Ar-Ph
O O
105 106
R A
Scheme 24 a Cat. (L)-DMTC, MeOH, rt, 72 h, 50–90%; b ArB(OH)2, Pd(Ph3P)4, aq Na2CO3,

toluene, Et3N
Table 9 Antiproliferative and proapoptotic activities of select spiro-triones
O O O O
O O
O O O O
O O
O O O O
OH OH OH
107 108 109 110

OH
Compound HL60 IC50 K562 IC50 Lymphocytes HL60 AC50a K562 AC50
(mM) (mM) IC50 (mM) (mM) (mM)
107 6 8 215 11 25
108 6 14 286 12 80
109 8 9 172 16 33
110 16 8 185 32 >100
a
Concentration to induce apoptosis in 50% of the cells after 48 h
O O
O R O R
R O R O
O O
a
O R
112 114
OH
O O
HO O O O
O a
H
R O R O
111 O O
R
R
113 115
O O
O R O R
O R a O O
OH 116 118
O O O
O O
O H a
111
O O
R
R
117 119
Scheme 25 a EtOH, EDDA, reflux, 57–100%
cancer cell lines overexpressing Pgp, multidrug resistance-associated protein 1

(MDRP1) or breast cancer resistance protein (BCRP) (Fig. 16) [59]. They were
also evaluated in a parasitic Leishmania tropica cell line overexpressing Pgp. From
this series, compounds 120 and 121 were found to be the most potent MDR reversal
agents in human cancer cell lines, while 122 was the most potent in reversing the
MDR phenotype in the parasitic Leismania cells.
Libraries 118 and 119 were evaluated against the a isoform of human topoisom-
erase II (Fig. 17) [60]. Six compounds were found to completely inhibit the enzyme
at 100 mM.
Substituted tetrahydropyridines 134 have been recently prepared via an interest-
ing one-pot transformation involving the Aza Diels–Alder reaction of imines 132
with enamines 133 (Scheme 26) [62]. The enamine adducts were prepared from the
reaction of anilines 129 with the Knoevenagel products of 130 and 131.
The compounds were tested against P. falciparum (3D7) and showed good
antimalarial activity (Fig. 18). In particular, compounds 136 showed much better
potency than chloroquine, a known antimalarial agent (MIC = 0.39 mg/mL).
O
O
O O
O O H H O
H O
H O
O O
H H H
H H O
H O
O O O O
O O
H
H
O
120 121 122
NHI-3T3 MDR1 NHI-3T3 MDR1 MDR L.Tropica
IC50 = 0.09 μM IC50 = 0.07 μM inhibition at 10 μM = 100%
Fig. 16 Daunorubicin resistance reversal in NIH-3T3 MDR1 and L. Tropica MDR cells
O O O
O O O
H H H
H O H H
O O O O O
Br Br
123 124 125
O
O O O
O O O O
H H H
H
O O O O O O
H H
Br 126 127 128
Fig. 17 Inhibitors of hTopoIIa
R1 R1
NH O NH O
NH2 CHO
O
a OR3 OR3
O OR3
N N
R2 R2
R1 R2
R2 R2
133
129 130 131 132 R1 R1 134
Scheme 26 a L-Proline, TFA, MeCN, 20–30 C, 16–24 h, 55–75%

NH O NH O NH O
O O O
N N N
F F F F N N
135 136 137
P. falciparum P. falciparum P. falciparum

MIC = 0.39 μg/mL MIC = 0.09 μg/mL MIC = 0.39 μg/mL
Fig. 18 Antimalarial activity of substituted tetrahydropyridines
3.5 Knoevenagel/Michael-Type Sequences
Knoevenagel condensation of aldehydes with malononitrile under mechanochemi-

cal mixing in the presence of MgO resulted in adducts of general structure 138
(Scheme 27), which were further treated with either ethylacetoacetate or 5,5-
dimethylcyclohexane-1,3-dione to provide products 139 and 140 [63]. The transfor-
mation of 138 and 139 or 140 proceeded via a Michael-type nucleophilic addition of
the enolizable ketoester or dione, followed by intramolecular cyclization.
Several of the compounds synthesized showed antibacterial activity against
E. coli (MTCC 41), S. aureus (MTCC 1144) and the ampicillin-resistant strain
Pseudomonas putida (MTCC 1072) (Table 10).
Tetrahydrochromones have also found applications as inhibitors of excitatory
amino acid transporter Subtype 1(EAAT1) [64]. For example, compound 145
(Fig. 19) was the first reported submicromolar inhibitor of EAAT1 with >400-
fold selectivity over EAAT2 and EAAT3. The subtype selectivity of 145 made
that compound a highly valuable tool to further explore the physiological role of
EAAT1.
The antiproliferative and antitubulin activities of libraries of pyranopyridones
and pyranoquinolones 147 (Scheme 28) derived from aldehydes, malononitrile and
pyridones 146 have been examined [65]. The compounds were evaluated for their
ability to reduce cell viability by 50% after 48 h of treatment relative to control.
The HeLa and MCF-7 cell lines were used as models for human cervical and
breast adenocarcinoma, respectively. Numerous compounds exhibited submicro-
molar antiproliferative activities with the quinolones being more potent than their
pyridine counterparts (Fig. 20). Because of the structural similarity of pyranopyr-
idones with chromene scaffolds known to inhibit tubulin polymerization, com-
pounds 149 and 150 were further evaluated in Jurkat cells for their apoptotic
O O Ar
O CN
O
O NH2
Ar CN Ar
a CN b 139
H O CN
CN O Ar
CN
138
O
O NH2
140
O
Scheme 27 a MgO, rt, grinding, 10 min b MgO, rt, grinding, 15 min 73–94%
Table 10 Antibacterial activity of 2-aminopyrans and tetrahydrochromenes

O NO2
OH
O O O O
CN CN CN CN
O
O NH2 O NH2 O NH2 O NH2
141 142 143 144
Compound E. coli MIC S. aureus MIC P. putida MIC

(mg/mL) (mg/mL) (mg/mL)
141 64 128 128
142 64 >128 128
143 64 64 128
144 128 >128 64
Ampicillin 16 16 >256
Fig. 19 Excitatory amino O

acid transporter activities of
compound 145
EAAT1 IC50 = 0.66 μM
O
CN EAAT2 IC50 = >300 μM
EAAT3 IC50 = >300 μM

O NH2
145
O O Ar
CN CN
N Ar a N
OH H O CN O NH2
146 147
Scheme 28 a Et3N, EtOH, reflux, 50 min, 64–98%
OH O
Br Br O Br O Br
N
O O O O
CN CN CN CN
N N N N
O NH2 O NH2 O NH2 O NH2
148 149 150 151
HeLa GI50 0.74 μM 0.047 μM 0.014 μM 0.013 μM
MCF-7 GI50 0.003 μM 0.39 μM 0.38 μM 0.015 μM
Fig. 20 Antiproliferative activity of pyrano-quinolones
properties and displayed cell cycle arrest in the G2/M phase. They were also found
to block tubulin polymerization in vitro.
A related three-component sequence has been reported, that involved the
reaction of N-(arylsulfonamido)-acetophenones 152 with aldehydes and malono-
nitrile [66] and gave access to functionalized pyrrolidines 153 as shown in
Scheme 29. The compounds were obtained as mixtures of cis and trans diaste-
reomers and evaluated for their antiproliferative properties in HeLa and MCF-7
cells. Compounds 154 and 155, among others, showed antiproliferative effects in
both cells lines and were further evaluated for their apoptotic properties (Fig. 21). It
was suggested that the antiproliferative effects of these compounds might originate
from different mechanisms of action with that of 154 being due to induction of
apoptosis in cancer cells, while for 155 from cancer cell growth inhibition only.
When the Knoevenagel adducts formed from aldehydes with dimedone were
reacted with dihydropyridazine-dione 156 (Scheme 30), pyridazino indazole triones
157 were obtained under solvent-free conditions in moderate yields [67]. The
compounds were tested for their antibacterial properties against E. coli (ATCC
25922), P aeruginusa (ATCC 85327), Bacillus subtilis (ATCC 465) and S. aureus
(ATCC 25923) (Table 11). Compounds 158–160 were found to be more active than
Amoxicillin against E. coli but less potent than Norfloxacin. None of the reported
compounds was active against S. aureus.
O O R3 R3
O CN
R3 CN CN
R1 a R1
O O
HN HN CN R1 N NH2
S O H O CN S O O S
R2 R2 O R2
152 153
Scheme 29 a Et3N, EtOH, reflux, 1.5 h, 90%
O CN O CN
N NH2 N NH2
O S O S
O O
Br Br
154 155
% Apoptosis in Jurkat cells at 50 μM = 30% % Apoptosis in Jurkat cells at 50 μM = 56%
% Live Jurkat Cells at 50 μM = 3% % Live Jurkat Cells at 50 μM = 96%
Fig. 21 Apoptotic and cell-killing properties of pyrrolidines
Ar O
O O
NH Ar O
a N
NH
H O N
O O
O
156 157
Scheme 30 a PTSA, 20–40 min, 46–55%
3.6 Knoevenagel/Krohnke Synthesis
2-Chloro-3-formylquinolines 161 (Scheme 31) were transformed in the presence of

acetic acid to 3-formylquinolones which upon reaction with acetophenones provided
the intermediate a,b unsaturated Knoevenagel adducts. Subsequent Krohnke reaction
of these adducts with pyridinium salts 162 and ammonium acetate provided the final
quinoline-pyridines 163 in excellent yields [68]. All the compounds were tested
N Cl H
Cl– N O
H N+
R1
O R1
161 O 162 a N
O
NH4OAc
163 R2
R2
Scheme 31 a AcOH, Microwave, 180 C, 3–5 min, 80–92%
Table 11 Antibacterial activity of pyridazinoindazole triones

O2N
Br O2N
O O O
O O O
N N N
N N N
O O O
158 159 160
Compound E. coli MIC P. aeruginusa B. subtilis S. aureus

(mg/mL) MIC (mg/mL) MIC (mg/mL) MIC (mg/mL)
158 16 Not active 16 Not active
159 8 64 8 Not active
160 16 60 8 Not active
Amoxycillin 128 – 2 16
Norfloxacin <2 20 2 16
for their antibacterial properties against S. aureus, Bacillus Subtilis, and E. coli and
antifungal properties against A. Niger and phizopus (Table 12).
3.7 Other Knoevenagel-Based MCRs
Reactions of chromene 168 (Scheme 32) with Knoevenagel adducts derived from
aldehydes and ethyl cyanoacetate or malononitrile and ammonium acetate yielded,
after condensation, libraries of general structure 169 and 170, respectively [69].
The products were tested for their anti-inflammatory, analgesic and antipyretic
properties. Anti-inflammatory efficacy was measured in vivo in the rat carrageenan-
Table 12 Antibacterial and antifungal activities of quinolinone-pyridines

H H
N O N O
O
N N
164 165
Cl
H H
N O N O
Cl Cl
N N
166 167
Cl

(1,000 mg/mL) Zone of inhibition in mm
S. aureus B. subtilis E. coli A. niger Rhizopus
164 21 20 25 11 15
165 14 21 21 18 15
166 15 21 26 15 18
167 10 12 23 15 24
Ciprofloxacin 35 37 34 – –
Griseofulvin – – –‘ 28 21
induced paw edema model. Several compounds such as 172–174 showed anti-
inflammatory activity (Table 13). Analgesic activity was measured using the acetic
acid-induced writhing model in mice. Significant protection against writhing was
observed for compound 171. Antipyretic activity was evaluated using the brewer’s
yeast-induced hyperpyrexia model in hyperthermic rats. Compounds 172 and 173
were able to decrease the temperature of pyretic rats as compared to control. In all
the studies, the compounds were administered at doses 1/10 of their LD50s.
The three-component reactions of malononitrile 175, aldehydes 176 and
2-mercaptoacetic acid 177 (Scheme 33), in different molar ratios under microwave
heating, in water, provided thiazolopyridine derivatives 178 and 179 in high yields
[70]. The compounds were evaluated for their cytotoxic activity against the car-
cinoma cell line HCT 116 (ATTC CCL 247) and mice lymphocytes (Table 14).
Compound 183 was the only one with selective cytotoxic activity towards the HTC
116 cells (Fig. 22). The compounds were also evaluated for their antioxidant
CN
Ar
CN
O O OH
N O
H
O
OH O
169
O
Ar a
O Ar
H O
CN
O OH
168 N NH
H
O
CN
O
CN 170
Scheme 32 a Ammonium acetate, EtOH, reflux, 8 h, 55–86%
Table 13 Anti-inflammatory, analgesic and antipyretic activities of chromenone-dihydropyri-

dines
Cl N
HO HO
CN CN CN CN
OH OH OH OH
N O N O N NH N NH
H H H H
O O O O
O O O O
171 172 173 174
Compound Anti-inflammatory Analgesic activity, Antipyretic activity,

activity, paw number of writhes rectal temperature ( C)
size (mm) after 2 h after 2 h
Control 29.54 43.7 39.11
Celecoxib 17.82 – –
Diclofenac sodium – 10.2 –
Paracetamol – – 37.2
171 24.71 41.6 38.84
172 28.26 29.4 38.2
173 23.97 37.4 38.17
174 24.72 38.6 38.91
Ar
NC CN
a
H2N N S
175:176:177 = 2:1:1.5
O
SH
CN Ar
O 178
CN H O Ar
OH
NC CN
175 176 177 b
H2N N S
175:176:175 = 2:2:2.1
O Ar
179
Scheme 33 a Water, microwave, 90 C, 6–9 min, 81–89%; b Water, microwave, 100 C, 6–7 min,
82–89%
Table 14 Cytotoxic and antioxidant properties of thiazolopyridines

OH
F
O2N
S
NC CN
NC CN NC CN
NC CN
H 2N N S
H2N N H2N N S NO2
H2N N S S O
O S O OH
O
180 181 182 183
Compound Cytotoxic activity Antioxidant activity

% Inhibition on % Inhibition on DPPH % OH %
proliferation of proliferation of inhibition inhibition
HCT-116 lymphocytes of free of free
(1 mg/mL) (1 mg/mL) radicals radicals
180 47.77 66.88 880.99 654.55
181 47.42 63.77 858.77 609.85
182 63.81 55.42 717.53 665.91
183 41.22 5.31 108.64 204.52
L-ASCORBIC ACID – – 188.12 108.65
properties by measuring their scavenging DPPH and OH capacity as compared to

control ascorbic acid. Nearly all the compounds showed strong antioxidant proper-
ties, with the most potent being compounds 180–182.
Cl PDE5 IC50 = 0.3 nM

O
IC50 ratio of PDE1,2,3,4 /PDE5 >10,000
IC50 ratio of PDE6/PDE5 = 150

HN N
N ED50 rabbit in vivo model = 100 nmol/kg
N N
N F in rats = 29 %
N N F in dogs = 42 %
NH
188 O t1/2 in rats = 1.2 h
t1/2 in dogs = 2 h
Fig. 22 In vitro and in vivo profile of compound 188
R2 O Cl N
R2 NH R2 N
O
a O b, c
N NH Cl
N N N
N N O N N
R1 N N
R1 R1
184 185 186
R5
Cl N HN N
R2 N R2 N
d R4 e R4
N N
N N
N R3 N R3
N N
R1 R1
187
Scheme 34 a Water or AcOH, rt or 50 C, 24 h, 12–70%; b hydrazine hydrate, EtOH/water, rt, 2 h,

100%; c POCl3, reflux, 3 h, 85%; d R4R5NH, DIEA, NMP, 80 C, 3 h, 40%; e R5NH2, DIEA,
NMP, 110 C, 85%
4 Cycloadditions
4.1 Hetero-Diels–Alder Reactions
Hetero-Diels–Alder reactions have been extensively used in organic synthesis.

Cycloadditions of imines 184 with maleimide 185 (Scheme 34) generated pyrazo-
lopyridines 186 [71]. These compounds were further elaborated as shown in
Scheme 34 to provide pyrazolopyridopyridazines 187 which were potent and
selective PDE5 inhibitors [72]. Compound 188 was selected for further evaluation.
This compound had superior selectivity towards other PDE isoenzymes and was
found to be efficacious in an anesthetized rabbit model of erectile function.
H2N a
N
O R R
H N
N
O
b c
N R N R N R
HN N N
189 190 191
Scheme 35 a BF3·OEt2, MeCN, 80 C, 2–10 h, 32–98%; b S8, 220–240 C, 5–10 min, 76–96%;
c KMnO4, Na2CO3, acetone, heat, 26–45%
Furthermore, its pharmacokinetic profile in rats and dogs was favorable and there
were no major safety concerns. Although the compound was reported to enter Phase
I clinical trials and was well tolerated at the highest dose in healthy volunteers, no
further information has been disclosed for its development.
A three-component Grieco condensation [73] of anilines, aldehydes and indene
resulted in libraries of tetrahydroindenoquinolines 189 (Scheme 35), which were
heated with powdered sulfur to provide indenoquinolines 190 [74]. Subsequent
oxidation with potassium permanganate yielded indeno-quinolinones 191. Com-
pounds 189–191 were evaluated for their cytotoxic properties against the breast
MCF-7, lung H-460 and central nervous system SF-268 human cancer cell lines
(Table 15). They were also tested for their antifungal activities against a panel of ten
pathogenic fungi: C. albicans (ATCC 10231), Candida tropicalis (C 131), Crypto-
coccus neoformans (ATCC 32264), Saccharomyces cerevisiae (ATCC 9763),
A. niger (ATCC 9092), A. flavus (ATCC 9170), A. fumigatus (ATCC 26934),
Microsporum gypseum (C115), Trichophyton rubrum (C113), Trichophyton men-
tagrophytes (ATCC 9972). Almost all the compounds showed cytotoxic activity
(GI < 10 mg/mL). None of the compounds was active against the yeast fungi and
Aspergillus species. However, several compounds from the 189 and 190 series
showed modest activity against dermatophytes. None of compounds 191 had any
antifungal activity.
4.1.1 The Povarov Reaction
A subset of imino-Diels–Alder cycloadditions involving reactions between N-aryl

imines and electron-rich dienophiles is the Povarov reaction [75].
Table 15 Cytotoxic and antifungal activities of select indenoquinoline derivatives
O
N N
N N
HN N N Cl N
192 193 194 195
Compound Cytotoxic activity Antifungal activity

MCF-7 IC50 H-460 IC50 SF-268 IC50 M. gyp T. rub T. men
(mg/mL) (mg/mL) (mg/mL)
192 2.4 2 4.3 >250 >250 >250
193 4.8 6.5 >10 31 31 31
194 4.9 4.7 6.7 31 31 31
195 2.3 2.4 2.7 >250 >250 >250
Adriamycin 0.16 0.18 0.14 – – –
Terbinafine – – – 0.04 0.01 0.04
R3
N
R1 N
R3
HN
R2
196
R1 O H2N a
R2 O
H
n n n n
R1 O R1 O R1 O
n = 1, 2 b c
HN N N+
R2 R2 I– R2
197 198 199
Scheme 36 a Sc(OTf)3, MeCN, rt, 12 h; b DDQ, CH2Cl2, rt, 24–48 h; c MeI, acetone/water,
rt, 72 h
The reaction has been used to synthesize libraries of benzonaphthyridines 196,

in high diastereoselectivity, from the cycloaddition of 1,4-dihydropyridines with
imines formed from aldehydes and anilines. When cyclic enol ethers were used as
dienophiles, mixtures of diastereomers 197 were obtained. These compounds were
oxidized to the corresponding quinolines 198 and were further transformed to the
quinolinium salts 199 as shown in Scheme 36 [76]. Compounds 196 and 198 were
tested for their ability to inhibit human propyl oligopeptidase (POP) and were found
to have modest potencies. Much better results were obtained when the quinoline
nitrogen was methylated to provide adducts 199. The cationic center improved the
inhibitory activity of these compounds (Fig. 23).
Cl Cl
O O O
+ +
N N N+
I–
CO2Et CO2Et CO2Et
200 201 202
POP IC50 = 75 μM POP IC50 = 133 μM POP IC50 = 124 μM
Fig. 23 POP inhibition of quinolinium salts
Cl
O
N
N
H
N
N
H
O
203
hAChE IC50 = 14 nM
Inhibition of AChE-induced Aβ1-40 aggregation = 45.7 %
Inhibition of self-induced Aβ1–40 aggregation = 47.3 %
BACE-1 % inhibition at 2.5 μM = 77.8 %
Fig. 24 In vitro profile of compounds 203
Following similar procedures, compound 203 (Fig. 24) and related analogs
were prepared from couplings of Povarov products with 6-chlorotacrine tethered
diamines [77]. The hybrid molecules were designed as dual AChE active-site/
peripheral-site binders. In particular, 203 emerged as a promising anti-Alzheimer
candidate because of its strong inhibitory potency against human AChE, AChE-
induced and self-induced b-amyloid peptide (Ab) aggregation and BACE1.
Furthermore, compound 203 was predicted based on the PAMPA-BBB assay to
have good CNS penetration.
4.2 1,3-Dipolar Cycloadditions
A highly atom-efficient azomethine ylide 1,3-dipolar cycloaddition of compound

204 (Scheme 37) with ylides formed in situ from either proline, phenylglycine or
H
N CO2H N
O Ar
N
O
Ar 206
H2N CO2H
Ar H
O O N
a
N O O Ar
N
O
Ar
204 205 Ar 207
H N
N CO2H
O Ar
N
O
Ar 208
Scheme 37 a MeOH, reflux, 1 h, 95–98%
sarcosine and acenaphthenequinone 205 yielded libraries of spiro pyrrolidines

206–208 [78]. The compounds were tested against M. tuberculosis, MDR M. tuber-
culosis and M. smegmatis. Most of the compounds exhibited some antimycobacter-
ial activity (Table 16). Compounds 209 and 211 were very potent against the
multidrug-resistant M. tuberculosis strain.
5 Miscellaneous
5.1 The Döbner Synthesis
The one-step Döbner reaction of aldehyde 213, anilines and pyruvic acid
(Scheme 38) was used to prepare, after oxidation of the methylthio substituent to
Table 16 Antimycobacterial activities of spiro pyrrolidines
H N
N N N Cl
Cl Cl
O
O O O
N
N N N O
O O O Cl
Cl
Cl Cl
Cl
209 210 211 212
Compound M. tuberculosis MDR M. tuberculosis M. smegmatis

MIC (mg/mL) MIC (mg/mL) MIC (mg/mL)
209 0.4 0.4 25
210 1.56 Not tested 3.13
211 0.78 0.4 25
212 0.78 0.78 12.5
Isoniazid 0.05 1.56 6.25
Ciprofloxacin 1.56 12.5 0.78
O
HO O
213 S HO O
HO O
a b
R2 N
O R2 N
R1
R1 S
S O
O
R2 NH2 214
R1
Scheme 38 a EtOH, reflux, 12 h, 16–27%; b oxone, THF/water, rt, 12 h, 40–89%
the methyl sulfone, quinoline derivatives 214 as cyclooxygenase-2 (COX-2) inhi-

bitors [79]. Most compounds were potent COX-2 inhibitors and compound 215 had
better selectivity over COX-1 than Celecoxib (Fig. 25).
Quinolines 216–218, prepared in a similar manner via a microwave-assisted
Döbner synthesis, were found to have moderate antiparasitic activities (Table 17) [80].
5.2 The Bucherer–Bergs Reaction
The Bucherer–Bergs hydantoin synthesis has been employed to build spiro com-
pounds 221 as 5-HT1A modulators [81]. The compounds were prepared from
HO F 3C
O
N
N
N S
O
O
S
O
O
215 Celecoxib
COX-1 IC50 = 22.1μM COX-1 IC50 = 24.3 μM

COX-2 IC50 = 0.0432 μM COX-2 IC50 = 0.060 μM
Fig. 25 COX-1 and COX-2 inhibitory activity of compound 215 and Celecoxib
Table 17 Antiparasitic and cytotoxic activities of 2-phenylquinoline-4-carboxylic acid derivatives

HO O HO O HO O
N N F3C N
O
216 217 218
Compound P. falciparum P. cruzi P. T. b. rhodesiense L. infantum L6 cells

IC50 (mg/mL) IC50 (mg/mL) IC50 (mg/mL) IC50 (mg/mL)
216 >5 13.8 >90 Not tested 35.6
217 3.1 >30 35.25 Not tested 75.6
218 >20.3 Not tested 2.2 8.6 >20.3
O O
a NH b, c N N
O N
N O N O R
H H
219 220 221
Scheme 39 a KCN, (NH4)2CO3, 50% EtOH/water, reflux, 20 h, 51–66%; b Br(CH2)3Cl, K2CO3,

acetone, reflux, 30 min, 70–98%; c 1-phenylpiperazine derivatives, anhydrous EtOH, reflux,
28–30 h, 31–72%
ketones 219 upon reaction with KCN and (NH4)2CO3 in refluxing EtOH/water
(Scheme 39). Further derivatization of the Bucherer–Bergs adducts 220 with alkyl
tethers and attachment of phenylpiperazines provided the final products 221. These
compounds were tested for their 5-HT1A and 5-HT2A activity (Table 18) and
compounds 222–224 exhibited antagonistic, partial agonistic and agonistic activity,
respectively, towards the 5-HT1A receptor. These compounds were evaluated in a
four-plate mouse anxiolytic model and only compound 224 showed efficacy at
10 mpk. This compound was further profiled in the forced swim mouse model for
Table 18 5-HT1A, 5-HT2A and D2 affinities and 5-HT1A/5-HT2A functional activitiesa of spiro-
hydantoins
O O
N N N N
Cl Cl
N N
N O N O
H H
222 223
O
N O
N
N
N O
H
224
Compound 5-HT1A 5-HT2A D2 5-HT1A 5-HT2A

Ki (nM) Ki (nM) Ki (nM) functional activity functional activity
222 13 78 Ndb antagonist Nd
223 38 53 6,200 Partial agonist Antagonist
224 23 284 965 Agonist Nd
a
Conclusions were based on the following in vivo experiments: hypothermia model in mice, lower
lip retraction in rats, heat-twitch response in mice
b
Not determined
Table 19 Porcine TACE and MMP-1, -2, -9 and -13 activities of hydantoins
O
O O
NH
NH NH
N HN
O
N H N O
H O H
O O O
HN NH HN
O O O
N N
N
225 226 227

racemic mixture (5R,6S) (5R,6R)
Compound pTACE MMP-1 MMP-2 MMP-9 MMP-13

IC50 (nM) IC50 (nM) IC50 (nM) IC50 (nM) IC50 (nM)
225 64 >4,946 >3,333 >2,128 >5,025
226 11 >4,946 >3,333 >2,128 >5,025
227 25 >4,946 >3,333 >2,128 >5,025
Table 20 M3 and M2 binding affinities and intrinsic clearance (rat and human) of select hydantoin
derivatives
F
N N N
O O O
N N N
S S
N N N
H H H
S S
232 233 234
Compounds M3 Ki (nM) M2 Ki (nM) r Clint_L h Clint_L

mL/min/g liver mL/min/g
232 1.9 80.1 4.7 1.1
233 2.7 96.8 23.7 2.3
234 2.75 187 13.8 0.95
depression and was found to be efficacious at 10 and 20 mpk doses without an effect
on the locomotor activity of mice.
Spiro hydantoins such as 225–227 (Table 19) were tested for their inhibitory
activity against tumor necrosis factor a (TNF-a) converting enzyme (TACE) [82].
The compounds exhibited strong inhibitory activity against porcine TACE and
excellent selectivity over MMPs (Table 11). For compound 226, the (5S, 6R) enan-
tiomer was more than 80-fold less active against pTACE. Boc or isopropylacetyl
pyrrolidine derivatives of 227 were also equipotent with 227.
Bucherer–Bergs products were also the starting points for the preparation
of potent and selective muscarinic M3 receptor antagonists (Table 20) [83].
Hydantoins of general structure 228 (Scheme 40) participated in Mitsunobu reac-
tions with alcohols to provide derivatives 229, which were reduced with sodium bis
(2-methoxyethoxy)aluminum hydride (Red-Al) to afford imidazolidinones 230.
Removal of the benzyl group allowed for further functionalization of the secondary
amines to yield compounds 231.
5.3 Other Multicomponent Reactions
The one-pot, three-component synthesis of 1,2,4-triazoles from primary amines,

acyl hydrazines and dimethoxy-N-N-dimethylmethanamine [84] was utilized for
the preparation of compounds 235 (Scheme 41), which were evaluated for their
anticonvulsant and neurotoxic properties [85]. The anticonvulsant activity was
measured in mice by the maximal electroshock test (MES) and the neurotoxicity
in mice by the rotarod neurotoxicity test (Tox). The majority of the compounds
O HO N O N
O
a R1 NH R1 N c
R1 R2 b
R2 N O R2 N O
H H
228 229
O N O N R3
d,e R1 N
R1 N
R2 R2 N
N
H H
230 231
Scheme 40 a KCN, (NH4)2CO3, 50% EtOH/water, 120 C stainless steel sealed tube, 24 h; b PPh3,
DEAD, THF, 0 C-rt, 24 h; c Red-Al, THF, 0 C then 85 C, 4 h; d H2, Pd/C, MeOH/water, HCl,
20 psi, 8 h; e R3Cl, K2CO3, CH2Cl2, rt, 5 h
R C6H13O
C6H13O O R
a
N O NH N N
NH2 O
NH2
N
235
Scheme 41 MeCN, 120 C, 3 h, 69.5–87.5%
Table 21 Anticonvulsant and neurotoxic activities of 1,2,4-triazoles in mice
C6H13O C6H13O C6H13O C6H13O
N N N N N N N N
N N N N
236 237 238 239
Compounds ED50 (mg/kg) TD50 (mg/kg) PI (TD50/ED50)

236 9.8 112.3 11.4
237 13.2 62.1 4.7
238 5.7 65.7 11.5
239 11.4 101.2 8.8
Phenyltoin 9.5 65.5 6.9
exhibited strong anticonvulsant potencies (Table 21) and lower neurotoxicity.

Compound 238 had better overall profile than the antiepileptic drug phenyltoin.
The domino three-component reaction of isatins, aminoacids and cyclic ketones
provided novel dispiropyrrolidines 240–243 (Scheme 42) [86]. The compounds were
O
O
n
R1 n N
n = 1, 2, 3 O
N
H
R2
O
240
CO2H O
N
HN N
X X
R1 N
X = Me, N = O
a O
N
O H
R2
R1
O 241
O
N
H O Ph Ph
R2
n
R1 n NH
b n = 1, 2, 3
NH2 O
N
CO2H H
R2
O 242
O Ph
N Ph
X N
X NH
X = Me, N = O R1
O
N
H
R2
243
Scheme 42 a MeOH, reflux, 6–10 h, 37–52%; b MeOH, reflux, 24 h, 32–42%
evaluated for their antimycobacterial activity against M. tuberculosis H37Rv. Several

compounds showed good antimycobacterial activity (Fig. 26), with compound 246
having better potency than fluoroquinolone Ciprofloxacin (MIC ¼ 4.71 mM) but is
less potent than Isoniazid (MIC = 0.36 mM).
A three-component synthesis of di- and tetrahydroisoquinolines via the Ritter
reaction yielded compounds 248 and 249 (Scheme 43), which were tested for their
anticoagulant properties using citrated dog blood [87]. An increase in coagulation
time (CT) for all the tested compounds was observed, with compounds 250–252
O O O O Ph
Ph
N N O NN N
Br Br N Br NH
Br
O O O O
N N N N
H H H H
244 245 246 247
M. tuberculosis M. tuberculosis M. tuberculosis M. tuberculosis
MIC = 4.13 μM MIC = 4.29 μM MIC = 1.98 μM MIC = 6.06 μM
Fig. 26 Antimycobacterial activity of dispiropyrrolidines
O O
O
a b
ArCN N NH
O O O
O
Ar Ar
248 249
Scheme 43 a Conc. H2SO4, 5–10 C, 30 min, 33–76%; b LiAlH4, Et2O, 15 h, 35–79%
O O O
N NH NH
O O O
F
NO2
250 251 252
% increase in CT over control – 44.9 – 30.5 – 34.3
Fig. 27 Anticoagulant activity of dihydroisoquinolines and tetrahydroisoquinolines
having percent increases in coagulation times greater than Heparin (% increase in

CT = 22.4) (Fig. 27). Dihydroisoquinolines such as 253 were prepared in a
similar manner to compounds 248 and were tested for their hypotensive properties
in anesthetized cats as shown in Fig. 28 [88].
The four-component reaction of arylthioacetones, arylaldehydes, and methyl-
amine or ammonium acetate resulted in the productions of piperidinones of general
structure 254 (Scheme 44) which were evaluated for their antibacterial and antifun-
gal properties [89]. The compounds were tested against gram-positive bacteria
S. Aureus, K. pneumoniae, Vibrio cholerae and Salmonella typhi, the gram-negative
E. coli and also the fungi C. albicans and A. niger. None of the compounds were
active against K. pneumoniae. Several compounds showed strong antibacterial and
antifungal properties as shown in Table 22.
Hypotensive activity
253 Extent of effect at 5 mg/Kg = 72.4 mmHg

Cl
Fig. 28 Hypotensive activity of 253
R1
O O O O
S a S
H H NH2R
R1 R2 R2 N
R = H, Me R
R2 R2
254
Scheme 44 a EtOH, heat, 32–50%
Table 22 Antibacterial and antifungal activities of piperidinones

Cl Cl Cl
O O O
S S S
Cl
N N N
H H
Cl Cl Cl Cl Cl
255 256 257

(200 mg/mL) Zone of inhibition in mm
S. aureus V. cholerae S. typhi E. coli C. albicans A. niger
255 11 11 10 11 11 10
256 12 12 12 12 12 12
257 13 12 11 13 11 12
Streptomycin 13 12 12 13 – –
Nystatin – – – – 12 12
The four-component, two-step synthesis of tetrasubstituted imidazoles 259 is

described in Scheme 45 [90]. Initially, all the four components were heated together
resulting, however, in lower yields because of the competing formation of
O
HO
R1 NH2 R2 H N
a N
O R2 N
b
CH3CO2NH4 N R2
O R1 N CO2H
R1
258 259 260

CTC50 = 94.63 mg/mL
Scheme 45 a glacial AcOH, reflux, 6 h or Microwave, activated silica gel, 8 min b reflux, 12–15 h,
58–90% or Microwave, 14–23 min, 81–92%
O
O
R3 R3
R1 O
a HN HN
O NH3 Br
R2 Cl
R2
N R4 N
R4 R1 H H H
261 262 HO
Scheme 46 a MeOH, ultrasonic irradiation, 90 min, 75–95%
trisubstituted adducts. When imines 258 were preformed, the final products were
obtained in much higher yields particularly using microwave irradiation. The
imidazoles were tested for their antibacterial (S. aureus, B. subtilis, E. coli,
K. pneumoniae), antimycobacterial (M. tuberculosis H37Rv) and anticancer
(Dalton’s lymphoma ascites cells) properties. None of the compounds showed
any antibacterial or antimycobacterial properties, with the exception of com-
pound 260 (Scheme 45) which demonstrated moderate activity against S. aureus
(MIC = 250 mg/mL). Several compounds exhibited good anticancer activity as
measured by the concentration that inhibited 50% growth of total cells, with the
most potent being 260.
The three component reaction of a,b unsaturated ketones with aldehydes or
ketones and ammonia, under ultrasound irradiation, provided tetrahydropyrimi-
dines 261 in high yields (Scheme 46) [91]. The compounds were tested against
M. tuberculosis H37Rv (ATCC 27294) at a single concentration of 6.25 mg/mL.
Most of the compounds exhibited inhibitory activity between 50 and 80%. The
most potent compound was 262 (Scheme 46), with inhibitory activity of 98%.
Reactions of amines, aldehydes and mercaptoacetic acid in ionic liquids
(Scheme 47) resulted in the formation of thiazolidinones 263 in moderate to high
yields [92]. The reaction was used to create a library of nucleoside thiazolidinones
AcO
AcO
O
O
N
NH
Cl
R2
H R2 OH R1
a O
R1 NH2 SH N
O O S N
S
O
O
263 264

Scheme 47 a [bmim] [PF6] , 60–80 C, 5–9 h, 47–92%
+
employing 5-formyl-20 -deoxyuridine as the aldehyde component. The compounds

were tested against Trypanosoma brucei brucei GVR35 and against Leishmania
donovani LV9. While none of the compounds was active against the latter, several
compounds showed moderate activity against T. brucei brucei. The most potent was
compound 264 (Scheme 47) with an IC50 = 25 mM.
6 Conclusions
In recent years multicomponent reactions have been extensively utilized to pro-

duce libraries of heterocyclic molecules with biological activity against a variety
of targets. The majority of these compounds were tested for their anticancer,
antioxidant and antimicrobial properties and numerous promising compounds
were identified and were further evaluated. With the continuous development of
new multicomponent reactions and combinations of MCRs with subsequent trans-
formations, this area of research holds great promise for the discovery of novel
therapeutic agents.
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Index
A Antimycobacterial activity, 231

Acenaphthenequinone, 272 Antioxidant activity, 171, 231, 251, 265
Acetamidoamide, 5 Arndtsen pyrrole synthesis, 156
4-N-Acetylamino-2-methyl-cis-3a,4,7,7a- 4-Aryl-8-arylidene-5,6,7,8-tetrahydro-
tetrahydroisoindole-1,3-dione, 217 2-quinolinones, 193
Acridines, 207 Aspergillus niger, 239
Acroyl chlorides, 59 Aspergillus parasiticus, 247
5-Acyl dihydropyrid-2-ones, 60 2-Azafluoranthene, 131
Alkenones, 25 1-Azapyrene, 131
Alkenylzirconocene chlorides, 140 2-Azaspiro[4.5]deca-6,9-diene-3,8-
Alkyne activation, cross-coupling, 30 diones, 218
– Sonogashira coupling, 31 N-(4-Azidobutyl)-N-benzyl-2-isocyano-
Alkynones, 25, 30, 43 3-phenylpropanamide, 11
2-Alkynyl 5-nitrothiophenes, 31 Azines, 127, 152
Allenes, 25 Aziridine, 9
Allylboration, pyridine, 139
Amidinium salts, 46
1-Amidoalkyl-2-naphthols, 215 B
b-Amino acid, 6 BACE 1 HTS, 233
5-Amino-3-phenylpyrazole, 197 Barbituric acids, 247
3-Aminoimidazo[1,2-a]pyridines, 235 Barrenazines, 145
Aminoimidazoles, N-fused, 205 Benzimidazoles, 131
2-Aminothiophenes, 221 Benzodiazepines, 51, 209
Aminovinylation, 31 Benzoheteroazepine, 66
b-Aminovinyl nitrothiophenes, 31 Benzonaphthyridines, 270
Anilines, ortho-thio substituted, 66 Benzothiazepines, 53
Antibacterial activity, 46, 53, 63, 76, 192, Benzothiophenes, 253
206, 231 Bienaymé–Blackburn–Groebke
Anticancer activity, 39, 173, 231, 250, 281 reactions, 235
Antifungal activity, 46, 53, 231, 239, Biginelli condensation, 100, 237
243, 264 Biindolizines, 41
Antimicrobial activity, 46, 53, 63, 208, Bis-amino oxazole, 114
231, 246 Bucherer–Bergs reaction, 273
289
290 Index
C Dimethoxy-N,N-dimethylmethanamine, 276
Carbamoylation, 161 Dimethyl acetylenedicarboxylate, 109
Carbo-Reissert-type processes, 137 Dipole formation, 147
Cerivastatin, 173 Dispiropyrrolidines, 277
Chalcones, 36, 64 – antimycobacterial, 279
2-Chloro-3-formylquinolines, 263 Diversity oriented synthesis (DOS), 95,
3-Chloro-4-iodo furans, 57 98, 234
Chromenone-dihydropyridines, 266 Döbner synthesis, 272
Chromeno[3,4-b][4,7]phenanthrolines, 212 Domino Knoevenagel/hetero-Diels–Alder
Chromens, 211 reaction (DKHDA), 207
Ciprofloxacin, 278 Domino reactions, 25, 28, 147
Combinatorial chemistry, 98 Drug discovery, 97, 231
Combretastatin, 255
Complexity, 95, 97
Condition-based divergence, 115 E
Coupling-addition, 31 Enaminones, 34
Coupling-isomerization, 25, 34 Enimines, 38
Cross-coupling, 25
Cyanomalonate, 237
F
Cycloadditions, 268
Ferrocene, 194
– 1,3-dipolar, 271
3-Formylquinolones, 263
Cyclodimerization, 3
Furans, 212
Cyclopeptides, 7
Furo[3,4-b]quinolines, 195
Cyclophanes, 18
Cyclopropane-1,1-dicarboxylic acid, 15
Cyclopropylvinylboronic acid, 106 G
Gentamicin, 249
Gewald reaction, 253
D Guanidinium salts, 48
Daunorubicin, 259
1,3-Diaryl propenones (chalcones), 30
Diarylamines, 218 H
Dibenzoyl dihydropyrimidines, 249 Halo furans, 54
Dicarbonyl, 231, 237 Hantzsch reaction, 245
Diethyl a-aminomalonate, 116 Hemicryptophane, 15
Dihydroazine, N,a-disubstituted, 127 Hept-6-ynal, 11
Dihydrofuropyrrolone, 114 Heteroarenes, 48
Dihydroisoquinolines, 279 Heteroaryl enones, 37
3,4-Dihydro-3-oxo-2H-1,4- Heteroaryl halides, 47, 64
benzoxazines, 216 2-Heteroaryl-pyrrolopyridinones, 249
2,3-Dihydropyrans, 212 Heterocycles, 231
Dihydropyridines, 171 – coupling–addition–
Dihydropyrimidines, 183 cyclocondensation, 43
– ion channel activities, 252 – coupling–cycloaddition, 38
Dihydropyrimidinones, 237 – coupling–isomerization–
Dihydropyrimidone, 113 cyclocondensation, 64
Diisopropylethylamine (DIPEA), 11 – domino synthesis, coupling-
1,4-Diketones, 66 isomerization, 75
2,5-Diketopiperazines, 218 Hetero-Diels–Alder reactions, 268
Index 291
Horner–Wadsworth–Emmons (HWE) Macrocylopeptide, 1

reaction, 111 Malononitrile, 237
Hydantoin, 273 Meridianins, 47
Hydrazines, 44, 64 4-Methoxypyridines, 146
2-Hydrazolyl-4-thiazolidinones, 206 Michael addition, 43
Hyperaspine, 145 Microwave-assisted organic synthesis
(MAOS), 152
Modular reaction sequences, 111
I Molecular diversity, 102
Igloo-shaped macrotetracycles, 21 Morpholine, 11, 254
Imidazoles, 203 Multiple multicomponent
Imidazolines, 119 macrocyclization, 11, 19
Imidazolyl dihydropyridines, 251 Mumm rearrangement, 5
Iminium ion, 102 Mycobacterium tuberculosis 240, 272
Indenoquinolines, 269 – glutamine synthetase (MtGS), 235
Indole-3-glyoxylyl chlorides, 50
Indolizines, 41
Indolopyridine alkaloids, 134 N
3-Iodo pyrroles, 58 Naphthyridines, 220
Irbesartan, 205 Nifedipine, 246
Isatins, 277 Nitrile oxides, 39
Isocyanides, 1, 127, 152, 231, 233 Nucleophiles, 135
Isocyanoacetamides, 11
Isoquinolinephosphonates, 137
O
Isoquinolines, 131, 199
Organocatalysis, 103
Isoquinolinobutyrolactones, 139
Ortho-amino thiophenols, 53
Isoquinolinones, fused, 236
Ortho-phenylene diamines, 51
Isoxazoles, 39
Oxalyl chloride, 48
Oxazepines, 209
K Oxazoles, 1, 57
Knoevenagel, 231
– /Diels–Alder, 256 P
– /Krohnke synthesis, 263 Palladium catalysis, 25
– /Michael-type sequences, 260 Passerin-3CR, 1
Passerini 3-component reaction
L (P-3CR), 101
b-Lactames, 6 Penicillium marneffei, 239
Lasubine II, 145 Peptoid-dihydropyrimidinones,
Lavendamycin, 173 antimalarial, 241
Leishmania donovani, 282 2-Phenylquinoline-4-carboxylic acids, 274
Leishmania tropica, 258 Phosphinothricin, 236
Leukotriene, 173 Phospho-Reissert-type processes, 137
Levulinic acid, 122 Piperidinones, 279
Piperidones, 234
Plasmodium falciparum, 238, 260, 274
M Podophyllotoxin, 250
Macrocyclization, 1, 5, 19 Polyhydroquinolines, 194
– in situ generated functional groups, 5 Povarov reaction, 269
292 Index
Propargyl alcohols, 64 Silyloxyfurans, 139

Propargyl amides, 58 Single reactant replacement (SRR), 108
Propargyl amines, 57, 213 Spiro hydantoins, 276
Propargyl ethers, 54 Spiro-benzofuranones, domino synthesis, 76
Propyl oligopeptidasen, 270 Spiro-benzoindolones, domino synthesis, 76
Pyrans, 212 Spiroimidazolinones, 204
Pyrazoles, 44, 64, 206 Spiro-triones, 257
Pyrazolo[4,3-f]quinolin-7-ones, 194 Staudinger reaction, 1
Pyrazolopyridines, 268 Streptonigrin, 173
Pyrazolopyridopyridazines, 268 Streptonigrone, 173
Pyrazolo-pyrido-pyrimidine-diones, 249
Pyrazolopyrimidines, 240
T
Pyridazinoindazole triones, antibacterial, 264
Target oriented synthesis (TOS), 98
Pyridazinones, 255
Tetracyanoethylene, 149
Pyridine, allylboration, 139
Tetrahydro-b-carbolines, 59, 61
Pyridines, 171, 173
Tetrahydrochromones, 261
– annelated/substituted, 4CR 69
Tetrahydroindenoquinolines, 269
Pyridinium ylids, 41
Tetrahydroisoquinolines, 279
3-Pyrimidin-5-ylpropanamides, 218
Tetrahydropyridines, antimalarial, 260
Pyrimidines, 46, 65, 183
Tetrahydropyrimidines, 244
– fused, 187
Tetraponerine T4, 139
Pyrimido[1,2-a]quinolines, 195
Thiazapines, 209
Pyrrolidines, 263
Thiazolidinones, 206, 281
Pyrroloisoquinolines, 150
Thiazolines, 206
Thiazolopyridazinones, fused, 255
Q Thiazolopyridines, 265
Quinazolines, 131, 200 – cytotoxic/antioxidant, 267
Quinoline-pyridines, 263 Thiochromenones, 63
Quinolines, 191 Thiopyranones, annelated, 62
– 2-substituted, domino synthesis, 75 Transition metal catalysis, 29
Quinolino[1,2-a]quinazolines, 195 Triazadibenzoazulenones, 220
Quinolizines, 202 Triazoles, 276
o-Quinone methide, 215 Trichoderma hammatum, 239
Quinoxalines, 203 Trichoderma koningii, 239
Trichophyton rubrum, 269
Trimethylsilyl alkynones, 33
R
Trypanosoma brucei brucei, 282
Reissert reaction, 127
Tryptamines, 59
– activating agents, 132
Tryptanthrin, 203
– asymmetric, 142
– nucleophiles, 134
Reissert–Henze reaction, nucleophiles, 136 U
Rhodotorula rubra, 247 Ugi reactions, 101, 233
– 4CR, 1, 5, 102
S
Salmonella typhi, 279 V
Scaffold diversity, 95, 99, 107 Vancomycin, 2
Secretase (BACE-1), 233 Variolins, 47
Sequential Reissert–lactonization, 140 Vibrio cholerae, 279

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25

Topics in Heterocyclic Chemistry

Series Editor: Bert U. W. Maes

R. Noyori L.E. Overman A. Padwa S. Polanc

Recently Published and Forthcoming Volumes

Synthesis of Heterocycles via Synthesis of Heterocycles via

Anion Recognition in Supramolecular Synthesis of Heterocycles via

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Topics in Heterocyclic Chemistry ISSN 1861-9282

# Springer-Verlag Berlin Heidelberg 2010

Cover design: WMXDesign GmbH, Heidelberg, Germany

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Prof. G. Mehta FRS

Prof. Ryoji Noyori NL Prof. Albert Padwa

Topics in Heterocyclic Chemistry is included in Springer’s eBook package Chemistry

Aims and Scope

The series Topics in Heterocyclic Chemistry presents critical reviews on

Synthetic sophistication has increased to an impressive level in the past two

(chemo)-selective, convergent, and atom-efficient processes of high exploratory

VU University, Amsterdam Romano V.A. Orru & Eelco Ruijter

Multicomponent Syntheses of Macrocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Palladium-Copper Catalyzed Alkyne Activation as an Entry

Multicomponent Reaction Design Strategies: Towards Scaffold

Recent Developments in Reissert-Type Multicomponent Reactions . . . . . 127

Microwave Irradiation and Multicomponent Reactions . . . . . . . . . . . . . . . . . . 169

Applications of MCR-Derived Heterocycles in Drug Discovery . . . . . . . . . . 231

Multicomponent Syntheses of Macrocycles

Géraldine Masson, Luc Neuville, Carine Bughin, Aude Fayol,

Abstract How to access efficiently the macrocyclic structure remained to be a

Keywords Isocyanide Macrocycle Macrocyclization Macrocylopeptide

Macrocycles, by virtue of their widespread occurrence in nature and their intrinsic

G. Masson, L. Neuville, C. Bughin, A. Fayol, and J. Zhu (*)

cyclosporine, macrolides (erythromycin) and the vancomycin family glycopep-

Fig. 1 Structure of vancomycin

Scheme 1 Cyclization and

Scheme 2 Linear sequence a

Indeed, addition reactions are susceptible to generate new reactive functionalities

Scheme 3 Synthesis of macrocycles by multicomponent reactions

2 Macrocyclization Involving In Situ Generated (Activated)

The Ugi four-component reaction (4CR) produced a-acetamidoamide by simply

Scheme 4 Multicomponent synthesis of macrocycles: potential competitive reaction pathways

Scheme 5 The Ugi four-component reaction

Scheme 6 Three-component four-center Ugi reaction to b-lactam

Scheme 8 Synthesis of cyclohexapeptide by Ugi reaction

Scheme 9 Synthesis of cyclopentapeptide by Ugi reaction

Scheme 10 Synthesis of macrocycles using amphoteric amino aldehyde

Scheme 11 Synthesis of macrocycles using amphoteric amino aldehyde: examples

Scheme 12 Ring opening of aziridine

Scheme 13 Synthesis of cyclodimers by a double Ugi reaction

substituted lithocholic acid derivative 38, formaldehyde and tert-butyl isocyanide

Scheme 14 Synthesis of heterocycles by Ugi reaction

components of the Ugi reaction. As shown in Scheme 14, stirring a methanol

3 Multiple Multicomponent Macrocyclization Using

The Ugi four-component reaction is currently the most investigated MCRs in

Scheme 15 Tandem Ugi-[3þ2] cycloaddition to macrocycle

Scheme 16 Structural diversity of macrocycles by tandem Ugi-[3þ2] cycloaddition process

four-component reaction, it is also the most exploited one in developing multicom-

FG1 FG3 FG3 FG3

FG1 FG2 FG1 FG2

3rd Ugi 4th Ugi

Scheme 17 Synthesis of macrocycles by multiple multicomponent reactions including bifunctional

Using Ugi-4CR as prototypical reaction, a possible reaction leading to twofold