Catalysts 13 00180

catalysts
Review
Catalyzed Methods to Synthesize Pyrimidine and Related
Heterocyclic Compounds
Marcos Díaz-Fernández 1 , Saturnino Calvo-Losada 2 , J.-Joaquín Quirante 2 , Francisco Sarabia 1 ,
Manuel Algarra 3 and M.-Soledad Pino-González 1, *
1 Department of Organic Chemistry, Faculty of Science, University of Málaga, 29071 Málaga, Spain;
marcos_diaz_fernandez@hotmail.es (M.D.-F.); frsarabia@uma.es (F.S.); pino@uma.es (M.-S.P.-G)
2 Department of Physical Chemistry, Faculty of Science, University of Málaga, 29071 Málaga, Spain;
asenruhup@hotmail.com (S.C.-L.); quirante@uma.es (J.-J.Q.)
3 INAMAT2-Institute for Advanced Materials and Mathematics, Department of Science, Public University of
Navarra, 31006 Pamplona, Spain; manuel.algarra@unavarra.es
* Correspondence: pino@uma.es
Abstract: This review covers articles published in the period from 2010 to mid-2022 on synthetic
advances in the formation of pyrimidine and related heterocyclic compounds. Special emphasis
has been given to the different types of cycloadditions, taking into account the number of their
components and leading to the formation of the pyrimidine ring. Due to the large number of
publications on the Biginelli reaction and related reactions, this will be dealt with in a separate review
in the near future.
Keywords: pyrimidines; multicomponent reactions; cycloadditions; N-heterocycles
Citation: Díaz-Fernández, M.; 1. Introduction

Calvo-Losada, S.; Quirante, J.-J.;
Compounds with pyrimidine rings and analogs have attained considerable interest
Sarabia, F.; Algarra, M.;
Pino-González, M.-S. Catalyzed
in the last years because of their properties [1–5]. In this review, we focus on the latest
Methods to Synthesize Pyrimidine
syntheses of these compounds, emphasizing those that use cyclization reactions and cy-
and Related Heterocyclic
cloadditions of two or more components. We are interested in those pyrimidines and
Compounds. Catalysts 2023, 13, 180. analogous compounds such as pyrimidinones, pyrimidinethiones and other pyrimidine-
https://doi.org/10.3390/ related scaffolds. The synthesis of pyrimidines with substituted or decorated rings is
catal13010180 only considered when the principal functionalization is included in the starting compo-
nents and is involved in the cyclization or cyclocondensation processes. Works whose
Academic Editors: Jose A. Sordo,
primary objective is to modify the substitution of an already formed pyrimidine ring are
Chandra M. R. Volla and
not described.
Broggini Gianluigi
In addition, we consider those less well-known reactions with the formation of new
Received: 31 October 2022 rings by expansion or contraction of other types of rings. In this review, we analyze
Revised: 7 January 2023 the synthetic aspect of these compounds as a principal point of view. Their biological
Accepted: 9 January 2023 and medical applications have been well described in a plethora of reviews in the last
Published: 12 January 2023 years [6–12]. We summarize the published findings reported mainly from 2010 to mid-2022.
It is worth noting the growing number of emerging publications in this field in the last
years [13]. Owing to the number of reports about pyrimidine derivatives, we apologize to
researchers whose important publications might be left out.
Copyright: © 2023 by the authors.
The multicomponent approach (MCR) is especially appealing to form the pyrimidine
Licensee MDPI, Basel, Switzerland.
core and other heterocyclic compounds [14–16]. Much diversity can be readily achieved sim-
This article is an open access article
distributed under the terms and
ply by varying the reacting components. The two most known multicomponent reactions
conditions of the Creative Commons
to form N-containing heterocycles are Hantzsch’s (1881) [17] dihydropyridine synthesis
Attribution (CC BY) license (https://
and Biginelli’s (1893) [18] 3,4-dihydropyrimidin-2(1H)-one synthesis to form pyrimidine
creativecommons.org/licenses/by/ frameworks. These reactions were reported a long time ago; however, after years with much
4.0/). interest [19] and later with a discreet number of publications, the Biginelli reaction has been
Catalysts 2023, 13, 180. https://doi.org/10.3390/catal13010180 https://www.mdpi.com/journal/catalysts

Catalysts 2023, 13, x FOR PEER REVIEW 2 of 24
Catalysts 2023, 13, 180 pyrimidine frameworks. These reactions were reported a long time ago; however,2 of after
24
years with much interest [19] and later with a discreet number of publications, the Bigi-
nelli reaction has been intensively studied in the last two decades [20,21]. The principal
reason is the
intensively largeinnumber
studied the last of
twoapplications of synthesized
decades [20,21]. dihydropyrimidinone
The principal and re-
reason is the large number
of applications of synthesized dihydropyrimidinone and related compounds [22]. of
lated compounds [22]. Most of the applications of these products are in the field bio-
Most
chemistry and medicine [23,24]. More information on the Biginelli-type reaction
of the applications of these products are in the field of biochemistry and medicine [23,24]. will be
giveninformation
More in a following review.
on the We now focus
Biginelli-type on will
reaction otherbetypes
givenofinstrategies for review.
a following formingWe the
pyrimidine
now focus oncore.
other types of strategies for forming the pyrimidine core.
2.2.Strategies
Strategiesto
toCompose
Composethe
thePyrimidine
PyrimidineCore
Core
ByByanalyzing
analyzing the
the pyrimidine
pyrimidine framework,
framework, one
one can
can consider
consider diverse
diverse options
options of
of cy-
cy-
cloadditions
cloadditionstotoform
formpyrimidine
pyrimidinerings.
rings. We
Wedistinguish
distinguishthem
themconsidering
consideringthe
thenumber
numberof of
components
components andand the
the atomic composition
composition ofofeach
eachofofthe
thefragments.
fragments.TheThe corresponding
corresponding re-
reactions arerevised
actions are revisedbelow.
below. Figure
Figure 11 depicts the numbers of of the
the schemes
schemes corresponding
correspondingto to
each type, where the reactions are described.
each type, where the reactions are described.
Figure1.1.Formation
Figure Formationofofpyrimidine
pyrimidinecore
corefrom
fromdiverse
diversenumbers
numbersofofcomponents.
components.
2.1. Two-Component Cycloadditions
2.1. Two-Component Cycloadditions
The usefulness of these strategies to form the pyrimidine core can be found in the
The [25].
literature usefulness of these
As a matter strategies
of fact, in the to formconsidered
period the pyrimidine
in thiscore can abelarge
review, found in the
number
literature [25]. As a matter of fact, in the period considered in this review,
of examples have been reported starting from two components [26–65]. In the following a large number
of examples
schemes, have beenisreported
information given onstarting from twowhich
those reactions components
can be [26–65].
includedIninthe following
this group.
The classification has been made according to the four types considered in Figure 1, The
schemes, information is given on those reactions which can be included in this group. for
classification has
two-component been made
reactions, according
starting to the
with the onefour
withtypes considered
the largest in Figure
components 1, for two-
[5+1].
component reactions, starting with the one with the largest components [5+1].
2.1.1. [5+1] Cycloadditions
2.1.1.The
[5+1] Cycloadditions
[5+1] annulation of enamidines 2 with N,N-dimethylformamide dialkyl acetals 4
Thedescribed.
has been [5+1] annulation of enamidines
This process 2 with
leads to the N,N-dimethylformamide
synthesis dialkylpyrim-
of tri- and tetrasubstituted acetals
4 hasderivatives
idine been described. Thiscatalyst-
3 under processand
leads to the synthesis
solvent-free of tri-
reaction and tetrasubstituted
conditions py-
(Scheme 1) [26].
These intermediate
rimidine enamidines
derivatives 2 were prepared
3 under catalyst- from functionalized
and solvent-free silanes,(Scheme
reaction conditions organolithium
1) [26].
compounds and twoenamidines
These intermediate nitriles. Furthermore, the [5+1]
2 were prepared fromannulation of enamidines
functionalized using or-
silanes, organolith-
thoesters 5 with a catalytic amount of ZnBr
ium compounds and two nitriles. Furthermore, 2 was also considered, yielding polysubstituted
the [5+1] annulation of enamidines using
pyrimidines (Scheme 1) [26].
orthoesters 5 with a catalytic amount of ZnBr2 was also considered, yielding polysubsti-
tuted pyrimidines (Scheme 1) [26].
Catalysts 2023, 13, 180 3 of 24
orthoesters 5 with a catalytic amount of ZnBr2 was also considered, yielding polysubsti-
tuted pyrimidines (Scheme 1) [26].
Scheme 1. Synthesis of tri- and tetrasubstituted pyrimidine derivatives 3.
The
Scheme
Scheme 1. diversity
1. Synthesisof
of two-or-more-component pyrimidine
tri- and tetrasubstituted pyrimidine
Synthesis of tri- and tetrasubstituted pyrimidine syntheses
derivatives
derivatives 3. starting from alkynes
3.
has been well documented [27]. Some examples are described below.
Thediversity
The diversityof
of two-or-more-component
two-or-more-componentpyrimidine
pyrimidinesyntheses
synthesesstarting
startingfrom
fromalkynes
alkynes
has been
2.1.2.
has been[4+2]well documented
Cycloadditions
well [27]. Some examples are described
documented [27]. Some examples are described below. below.
An original route to prepare multifunctionalized pyrimidines involved in the in situ
2.1.2.
2.1.2. [4+2]
[4+2] Cycloadditions
generation Cycloadditions
of ketimines from alkynes and sulfonyl azides. Thus, the synthesis of a novel
An
class An original
originalroute
of sulfonamideroute to
toprepare multifunctionalized
preparederivatives
pyrimidine multifunctionalized pyrimidines
pyrimidinesinvolved
10 via a copper-catalyzed involved
tandemin the
theininsitu
inreaction situ
of
generation
generation of ofketimines
ketimines
trichloroacetonitrile, from
fromalkynes
alkynesand
andsulfonyl
sulfonylazides.
1,1,3,3-tetramethylguanidine azides.
(6), Thus, the
the synthesis
Thus,azides
sulfonyl synthesis of
of aanovel
and terminal novel
al-
class
classof
kynes of7sulfonamide
sulfonamide pyrimidine withderivatives
pyrimidine
has been described high yields10
derivatives 10 via aacopper-catalyzed
viato
(up copper-catalyzed
87%) tandem
tandemreaction
[28]. The intermediates 8 andof
reaction of
9
trichloroacetonitrile,
trichloroacetonitrile, 1,1,3,3-tetramethylguanidine
1,1,3,3-tetramethylguanidine (6), sulfonyl
(6), azides
sulfonyl
via a [4+2]-A condensation gave the targeted pyrimidines 10 (Scheme 2). and
azides terminal
and alkynes
terminal al-
has been
7kynes 7 hasdescribed with high
been described withyields
high (up to (up
yields 87%)to[28].
87%)The intermediates
[28]. 8 and 89 and
The intermediates via a9
[4+2]-A condensation gave the targeted pyrimidines 10 (Scheme
via a [4+2]-A condensation gave the targeted pyrimidines 10 (Scheme 2). 2).
Scheme 2.
Scheme 2. Synthesis of sulfonamide
Synthesis pyrimidines
of sulfonamide 10 from 10
pyrimidines trichloroacetonitrile, 1,1,3,3-tetramethyl-
from trichloroacetonitrile, 1,1,3,3-
guanidine (6), sulfonyl(6),
tetramethylguanidine azides and azides
sulfonyl terminal alkynes
and 7. alkynes 7.
terminal
Scheme 2. Synthesis of sulfonamide pyrimidines 10 from trichloroacetonitrile, 1,1,3,3-tetramethyl-
AA methodology
methodology
guanidine [4+2]-A
(6), sulfonyl azides
[4+2]-A to
and prepare
toterminal
prepare 2-trifluoromethylpyrimidines
alkynes 7.
2-trifluoromethylpyrimidines 1414has been
has devel-
been de-
oped based
veloped based onona acyclization
cyclizationreaction
reactionofof 2-trifluoromethyl
2-trifluoromethyl 1,3-diazabutadienes
1,3-diazabutadienes 13 [29].
TheseAintermediates
These methodologywere
intermediates [4+2]-A
were to prepare
prepared
prepared by 2-trifluoromethylpyrimidines
by the
the condensation of
condensation 14 has been11
of trifluoroacetamidine
trifluoroacetamidine devel-
11 and
and
oped based
amide
amide acetals
acetals on
1212a cyclization
or or
with with reaction of 2-trifluoromethyl
chloromethaniminium
chloromethaniminium salt derived
salt derived 1,3-diazabutadienes
from from N,N-dimethylben-
N,N-dimethylbenzamide 13 [29].
These
with
zamide intermediates
phosphorus wereoxychloride.
oxychloride.
with phosphorus prepared
The by thecycloaddition
condensation
cycloaddition
The of trifluoroacetamidine
reactions of these
reactions 11 and
2-trifluoromethyl-
of these 2-trifluorome-
amide acetals
1,3-diazabutadienes12 or
thyl-1,3-diazabutadienes with
13 with chloromethaniminium
dimethyl
13 with salt
acetylenedicarboxylate
dimethyl derived
acetylenedicarboxylate from
and and N,N-dimethylben-
phenylacetyl chloride
phenylacetyl chlo-
zamide
provided
ride with
provided phosphorus oxychloride. The
2-trifluoromethylpyrimidine
2-trifluoromethylpyrimidine cycloaddition
derivatives 14reactions
14 and
derivatives 15 15
and aofaregular
in in these 2-trifluorome-
regular totomoderate
moderate
thyl-1,3-diazabutadienes
overall
overall yield
yield.(Scheme
(Scheme3). 3). 13 with dimethyl acetylenedicarboxylate and phenylacetyl chlo-
ride A
provided
particular2-trifluoromethylpyrimidine
case of [4+2] cycloadditionderivatives 14 and 15
involves triazines in a regular
using to moderate
a Diels–Alder-type
overall yield.
reaction. (Scheme
Recently, 3).
a review on triazines, their syntheses and inverse electron-demand
Diels–Alder reactions, focusing on the application of obtaining heterocycles with nitrogen,
has been published [30]. As an example of their usefulness, a series of 4,5 disubstituted-or
4-monosubstituted-pyrimidine 18 was obtained by an organocatalytic inverse electron-
demand Diels–Alder reaction of a variety of ketones 16 with 1,3,5-triazine 17 through enam-
ine catalysis. Good yields and high levels of regioselectivity were reported (Scheme 4) [31].
Catalysts 2023,13,
Catalysts2023, 13,180
x FOR PEER REVIEW 44 of
of2424
Scheme 3.
Scheme 3. Synthesis
Synthesis of
of 2-trifluoromethylpyrimidines
2-trifluoromethylpyrimidines 14
14 and
and 15.
15.
A particular
A particular case
case ofof [4+2]
[4+2] cycloaddition
cycloaddition involves
involves triazines
triazines using
using aa Diels–Alder-type
Diels–Alder-type
reaction. Recently, a review on triazines, their syntheses and inverse electron-demand
Diels–Alder reactions,
Diels–Alder reactions, focusing
focusing onon the
the application
application ofof obtaining
obtaining heterocycles
heterocycles with
with nitrogen,
nitrogen,
4-monosubstituted-pyrimidine 18
4-monosubstituted-pyrimidine 18 was
was obtained
obtained byby an
an organocatalytic
organocatalytic inverse
inverse electron-
electron-
demand Diels–Alder reaction of a variety of ketones 16 with 1,3,5-triazine
demand Diels–Alder reaction of a variety of ketones 16 with 1,3,5-triazine 17 through 17 through
enamine catalysis. Good yields and high levels of regioselectivity were reported
enamine catalysis. Good yields and high levels of regioselectivity were reported (Scheme (Scheme
4) [31].
4) [31].
Scheme3.3.Synthesis
Scheme Synthesisofof2-trifluoromethylpyrimidines
2-trifluoromethylpyrimidines1414and
and15.
15.
A particular case of [4+2] cycloaddition involves triazines using a Diels–Alder-type

Diels–Alder reactions, focusing on the application of obtaining heterocycles with nitrogen,
4-monosubstituted-pyrimidine 18 was obtained by an organocatalytic inverse electron-
demand Diels–Alder reaction of a variety of ketones 16 with 1,3,5-triazine 17 through
Scheme
enamine
Scheme 4.catalysis.
Synthesis of
of pyrimidines
Good yields and18 from
from ketones
highketones
levels1616 and
of and triazines
triazines 17.
17. were reported (Scheme
regioselectivity
Scheme 4.4.Synthesis
Synthesis pyrimidines
of pyrimidines 18
18 from ketones 16 and triazines 17.
4) [31].
Morerecently,
More
More recently,a asimilar
recently, a similar
similar strategy,
strategy,
strategy, but
butbut
withwith TFA-catalyzed
TFA-catalyzed
with TFA-catalyzed reactions
reactions of electron-defi-
electron-defi-
of electron-deficient
reactions of
cient 1,3,5-triazines
1,3,5-triazines 19 and aldehydes/ketones
19 and19aldehydes/ketones
cient 1,3,5-triazines and aldehydes/ketones 16,
16, was was described
16, described
was described [32].
[32]. [32].
HighlyHighly functional-
functionalized
Highly functional-
ized pyrimidines
pyrimidines
ized pyrimidines 20
20 were were
20 obtained obtained as
as products
were obtained products in fair-to-good
in fair-to-good
as products yields.
yields.yields.
in fair-to-good The
The reaction reaction mech-
mechanism
The reaction mech-
anism
was
anism was carefully
carefully
was carefully
studied studied
by theby
studied by the combination
combination
combination
the of experimental
experimental
of experimental
of and
andand computational
computational
computational stud-
studies.
stud-
ies.
The The reactions
reactions involved
involved a a cascade
cascade of of stepwise
stepwise inverse inverse electron-demand
electron-demand
ies. The reactions involved a cascade of stepwise inverse electron-demand hetero-Diels– hetero-Diels–
hetero-Diels–Alder
Alder reactions,
reactions,
Alder reactions,
followedfollowed by retro-Diels–Alder
retro-Diels–Alder
by retro-Diels–Alder
followed by reactionsreactions and
and theand
reactions the elimination
elimination
elimination
the of water.of water.
of water.
Both
Both Diels–Alder
Diels–Alder
Both Diels–Alderreactionsreactions
reactions required
requiredrequired
TFA. TheTFA.TFA.
yieldsThe
The yields
were higher
yields were
werewhenhigher when
cyclicwhen
higher cyclic
ketones were
cyclic ketones
used.
ketones
were used.
(Scheme
were used.
5). (Scheme 5).
(Scheme 5).
Scheme 4. Synthesis of pyrimidines 18 from ketones 16 and triazines 17.
More recently, a similar strategy, but with TFA-catalyzed reactions of electron-defi-

cient 1,3,5-triazines 19 and aldehydes/ketones 16, was described [32]. Highly functional-
ized pyrimidines 20 were obtained as products in fair-to-good yields. The reaction mech-
anism was carefully studied by the combination of experimental and computational stud-
ies. The reactions involved a cascade of stepwise inverse electron-demand hetero-Diels–
Alder reactions, followed by retro-Diels–Alder reactions and the elimination of water.
Both Diels–Alder
Scheme
Scheme 5.Synthesis
5.5. Synthesisofreactions required
ofpyrimidines
pyrimidines 20from
20 TFA.
from The yields
substituted
substituted were
triazines
triazines higher
19and
19 when
andketones
ketones 16.cyclic ketones
16.
Scheme Synthesis of pyrimidines 20 from substituted triazines 19 and ketones 16.
were used. (Scheme 5).
Amidines
Amidinesare areanother
anothergroup
groupof ofcompounds
compoundsthat thatcan
canbebeused
usedinincyclization
cyclizationreactions
reactions
Amidines are another group of compounds that can be used in cyclization reactions
of
oftwo
two or
or more
more components.
components. Substituted
Substituted amidines
amidines are
are useful
useful intermediates
intermediates in in
the the syn-
synthe-
of two or more components. Substituted amidines are useful intermediates in the synthe-
thesis
sis of of many
of many heterocyclic
many heterocyclic compounds,
heterocyclic compounds,
compounds, not not only
not only for
only for pyrimidines.
for pyrimidines. Consequently,
pyrimidines. Consequently, several
Consequently, severalseveral
sis
reviews have been devoted to the application of amidines as condensation agents to form
heterocyclic rings [33,34].
Amidines can react with malononitrile dimer in a [4+2]-B cyclocondensation, as
reported by Aly’s group [35]. The reaction occurred via an amination process followed by
cyclization to give racemic 6-aminopyrimidine compounds 23, which were catalyzed with
Scheme 5. Synthesis
piperidine of pyrimidines
in DMF. Amidine 20 from substituted
compounds triazines
21 that have 19 and with
aryl groups ketones 16.
electron-donating
or electron-withdrawing substituents on the benzene ring were selected to examine their
Amidines
respective effect are another
on the group
course of theofreaction.
compounds The that
yieldcanwasbehigher
used inin cyclization reactions
the case of electron-
donating substituents, p-methoxy (89%), than for the withdrawing nitro groupsynthe-
of two or more components. Substituted amidines are useful intermediates in the (70%)
sis of many
(Scheme 6). heterocyclic compounds, not only for pyrimidines. Consequently, several
piperidine
ported
cyclizationintoDMF.
by Aly’s Amidine
group
give compounds
reaction 21
[35].6-aminopyrimidine
racemic The thatcompounds
occurred have
viaaryl groups
an aminationwith
23, which electron-donating
process
were followed
catalyzed by
with
or electron-withdrawing
cyclization to give racemicsubstituents on
6-aminopyrimidinethe benzene
compoundsring were
23, selected
which were
piperidine in DMF. Amidine compounds 21 that have aryl groups with electron-donating to examine
catalyzed their
with
respective
piperidine effect on the
in DMF. course
Amidine
or electron-withdrawing of the reaction.
compounds
substituents Thehave
21 that
on the yieldring
benzene wasgroups
aryl higher
were in theelectron-donating
with
selected case of electron-
to examine their
donating
or substituents,
electron-withdrawing p-methoxy
substituents(89%),
on than
the for
benzene the withdrawing
ring were nitro
selected to group
examine
respective effect on the course of the reaction. The yield was higher in the case of electron- (70%)
their
(Scheme
donating6).substituents,
respective effect on the course of the(89%),
p-methoxy reaction. Thefor
than yield
the was higher in the
withdrawing casegroup
nitro of electron-
Catalysts 2023, 13, 180 5(70%)
of 24
donating substituents,
(Scheme 6). p-methoxy (89%), than for the withdrawing nitro group (70%)
(Scheme 6).
Scheme 6. Synthesis of pyrimidines 23 from amidines and malononitrile dimer.

Scheme 6. Synthesis of pyrimidines 23 from amidines and malononitrile dimer.
An6.6.enantioselective
Scheme
Scheme Synthesisof
Synthesis rhodium-catalyzed
ofpyrimidines
pyrimidines 23from
23 [4+2]-B
fromamidines
amidines cycloaddition
andmalononitrile
and malononitrile was performed from
dimer.
dimer.
α,β-unsaturated imines 24rhodium-catalyzed
An enantioselective and isocyanates 25, obtaining
[4+2]-B pyrimidinones
cycloaddition 26 with a high
was performed from
An
An enantioselective
enantioselectivity and
enantioselective rhodium-catalyzed
moderate-to-good
rhodium-catalyzed yields. [4+2]-B
The
[4+2]-B cycloaddition
reaction was
cycloaddition was
catalyzed
was performed
by a aphos-
performed from
α,β-unsaturated imines 24 and isocyanates 25, obtaining pyrimidinones 26 with high
from α,β-unsaturated
phoramidite–Rh
α,β-unsaturated imines
complex,
imines 24 and andaisocyanates
24 isocyanates
affording substitution
25, 25, obtaining
pattern
obtaining pyrimidinones
complementary
pyrimidinones to
26 26 with
that
with of
a a
Big-
high
enantioselectivity and moderate-to-good yields. The reaction was catalyzed by a phos-
high
inellienantioselectivity
adducts (Scheme
enantioselectivity and
and 7) moderate-to-good
[36].
moderate-to-good yields.
yields. The The reaction
reaction was catalyzed
was catalyzed by
by aofphos- a
phoramidite–Rh complex, affording a substitution pattern complementary to that Big-
phosphoramidite–Rh
phoramidite–Rh complex,
complex, affording
affording a a substitution
substitution pattern
pattern complementary
complementary to to that
that of
of Big-
inelli adducts (Scheme 7) [36].
Biginelli adducts
inelli adducts (Scheme
(Scheme 7) [36].
7) [36].
Scheme 7. Synthesis of pyrimidinones 27 from α,β-unsaturated imines 24 and isocyanates 25.

Scheme7.7.Synthesis
Scheme Synthesisof
ofpyrimidinones
pyrimidinones27
27from
fromα,β-unsaturated
α,β-unsaturatedimines
imines24
24and
andisocyanates
isocyanates25.
25.
An 7.
Scheme [4+2]-B condensation
Synthesis starting
of pyrimidinones fromα,β-unsaturated
27 from β-enaminonesimines
was described by Campagne´s
24 and isocyanates 25.
group An
An [37]. These
[4+2]-B
[4+2]-B authors achieved,
condensation
condensation starting
starting withfrom
from (Z)-selectivity,
β-enaminones
β-enaminones several N-Cbz-β-enaminones
wasdescribed
was described byCampagne´s
by Campagne´s 29
through
group An
group[37]. a novel
[4+2]-B
[37].These base-catalyzed
condensation
Theseauthors
authorsachieved, isomerization
starting
achieved,with from from
β-enaminones
with(Z)-selectivity, propargylic
(Z)-selectivity,several was N-hydroxylamines
described by Campagne´s
severalN-Cbz-β-enaminones
N-Cbz-β-enaminones29 28.
29
The
group
throughuse[37].
through aofanovel
NaOH
These
novel as a base achieved,
authors
base-catalyzed wasisomerization
base-catalyzed crucial withto improve
isomerization the
(Z)-selectivity,
from yield of the
several
propargylic
from propargylic reaction. The role
N-Cbz-β-enaminones
N-hydroxylamines
N-hydroxylamines 28.ofThe
the
29
28.
R 2 substituent was also important. In fact, for R2 = tBu, Ph, p-Tol, a propargylic by-product
through
use
The ofuse
NaOHofa NaOH
novel base-catalyzed
as a base was crucial
as a base isomerization
to improve
was crucial to improve thefromthe propargylic
yield of the
yield N-hydroxylamines
ofreaction. The The
the reaction. role role
of the of R28.
2
the
was
The formed
use of NaOH
substituent
R2 substituent in
waswassignificant
asalso
also proportion.
aimportant.
base was crucial
important.In In
fact, The
to
for
fact, usefulness
improve
2 t
R R=2 =Bu,
for tBu, of
thePh, these
yield enaminones
of the
Ph,p-Tol,
p-Tol, reaction.
aapropargylic was
The
propargylic to obtain
role of the
by-product
by-product
2,4,6-trisubstituted
R
was
2 substituent was also pyrimidines
important. 30,
In as
fact, they
for R 2 = tcould
Bu,
was formed in significant proportion. The usefulness of these enaminones wasto
formed in significant proportion. The usefulness Ph,
of be condensed
p-Tol,
these a with
propargylic
enaminones was tovarious
by-product
obtain
obtain
carboxamides,
was formed
2,4,6-trisubstitutedin under basic
significant
pyrimidines conditions,
proportion.
30, as in
The
they gram
could scale,
usefulness
be in moderate-to-good
of these
condensed
2,4,6-trisubstituted pyrimidines 30, as they could be condensed with various enaminones
with variousyields
was (Scheme
to obtain
carboxamides,
8).
2,4,6-trisubstituted
under
carboxamides, underpyrimidines
basic conditions, in gram
basic scale,
conditions,30,ininas they
moderate-to-good
gram could
scale, be condensed
yields (Scheme 8).
in moderate-to-good with (Scheme
yields various
carboxamides,
8). under basic conditions, in gram scale, in moderate-to-good yields (Scheme
8).
Scheme 8. Synthesis
Scheme 8. Synthesis of
of pyrimidines 30 from
pyrimidines 30 β-enaminones 29.
from β-enaminones 29.
Scheme 8. Synthesis of pyrimidines 30 from β-enaminones 29.
Later,
Scheme amino acid-derived
8. Synthesis carboxamides
of pyrimidines were also29.
30 from β-enaminones employed in this reaction, provid-
ing chiral pyrimidine derivatives 34 and 35 in modest yields. The obtained pyrimidines
were studied with NMR and DFT methods (Scheme 9) [38].
Later, amino acid-derived carboxamides were also employed in this reaction, provid-
Catalysts 2023, 13, 180 were studied with NMR and DFT methods (Scheme 9) [38]. 6 of 24
Scheme 9. Synthesis of pyrimidines 34 and 35 from amino acid-derived carboxamides.
Scheme 9. Synthesis of pyrimidines 34 and 35 from amino acid-derived carboxamides.

Anderson and Boger [39] published a systematic study of the inverse electron-de-
mand Diels–Alder
Scheme
Scheme 9. Synthesis
9. reactions
Synthesis of
of of 1,2,3-triazines.
pyrimidines
pyrimidines 34and
34 and3535from The
fromaminostudy
amino revealed
acid-derived
acid-derived not only that the reac-
carboxamides.
carboxamides.
Anderson and Boger [39] published a systematic study of the inverse electron-de-
tivity may be predictably modulated by a C-5 substituent (R = CO2Me > Ph > H), but also
mand Diels–Alder reactions of 1,2,3-triazines. The study revealed not only that the reac-
that Anderson
Anderson
the and
andBoger
application Boger
of [39]
this published
[39] published
methodology a is
systematic
abroadened study
systematic of the
tostudy of inverse electron-demand
the inverse
heterocyclic ring electron-de-
systems as py-
tivity may be predictably modulated by a C-5 substituent (R = CO2Me > Ph > H), but also
Diels–Alder
rimidine reactions
mand Diels–Alder
derivatives. of 1,2,3-triazines.
reactions
In thisofcase, from The
1,2,3-triazines. study revealed
The study
1,2,3-triazines, not only
revealed
pyrimidine not that
only the
formation thatreactivity
the reac-a
follows
that the application of this methodology is broadened to heterocyclic ring systems as py-
may
tivitybe
[4+2]-Bmaypredictably modulated
be predictably
cycloaddition. In amodulatedby a by
subsequent C-5 a substituent
work,C-5amidines (R
substituent
were=(RCO 2 Me
= CO
found Me
2to>undergo
Ph
> Ph> >H),H), but
butalso
also
a powerful
rimidine derivatives. In this case, from 1,2,3-triazines, pyrimidine formation follows a
that
that the application
application
cycloaddition of this methodology
of this methodology
to 1,2,3-triazines is broadened to heterocyclic
is broadened to heterocyclic
bearing electron-donating substituents ringring systems
systems
at C5, as
as py-
to provide
[4+2]-B cycloaddition.
pyrimidine In
derivatives. a subsequent work, amidines were found to undergo a powerful
rimidine derivatives.
2,5-disubstituted InInthis
pyrimidines thiscase,
case,
42 from
infrom 1,2,3-triazines,
1,2,3-triazines,
excellent pyrimidine
pyrimidine
yields (42–99%) (Scheme 10) [40].follows
formation Even se-aa
cycloaddition
[4+2]-B to 1,2,3-triazines
cycloaddition. In bearing electron-donating substituents at C5, toa provide
[4+2]-Bynamines
lected cycloaddition. In a subsequent
and enamines subsequent work,
work, amidines
were capable amidines were
were found
of cycloadditions withto
found undergo
to36,
undergo
but notawithpowerful
powerful
37 or
2,5-disubstituted
cycloaddition pyrimidines 42bearing
in excellent yields (42–99%) (Schemeat10) [40]. Even se-
38, to providetoto
cycloaddition 1,2,3-triazines
1,2,3-triazines
other trisubstituted bearingelectron-donating
in modest substituents
electron-donating
pyridines (37–40%C5,
substituents
yields at
and to33%,
C5, provide 2,5-
to provide
respec-
lected ynamines
disubstituted and enamines
pyrimidines 42 were
in capable
excellent of
yieldscycloadditions
(42–99%) with
(Scheme 36,
10)but
[40].not with
Even 37 or
selected
2,5-disubstituted
tively). pyrimidines 42 in excellent yields (42–99%) (Scheme 10) [40]. Even se-
38, to provide
ynamines other trisubstituted pyridines in modest yields (37–40% and 33%, respec-
lected ynamines and enamines were capable of cycloadditions with 36, but not with 37 to
and enamines were capable of cycloadditions with 36, but not with 37 or 38, or
tively).
provide other trisubstituted pyridines in modest yields (37–40% and 33%,and respectively).
38, to provide other trisubstituted pyridines in modest yields (37–40% 33%, respec-
tively).
Scheme 10. Inverse electron-demand Diels–Alder reactions of 1,2,3-triazines 36–38 with amidines
39.
Scheme
Scheme10.10.Inverse
Inverseelectron-demand
electron-demandDiels–Alder
Diels–Alder reactions 1,2,3-triazines36–38
reactions of 1,2,3-triazines 36–38with
withamidines
amidines39.
39.
2.1.3.
Scheme
2.1.3. [3+3] Cycloadditions
10. Cycloadditions
[3+3] Inverse electron-demand Diels–Alder reactions of 1,2,3-triazines 36–38 with amidines
39. We cannot deal with the synthesis of pyrimidines by [3+3] cycloaddition without de-
We cannot
2.1.3. [3+3] deal with the synthesis of pyrimidines by [3+3] cycloaddition without
Cycloadditions
scribing thethe
describing classical Pinner
classical reaction
Pinner [41].
reaction This
[41]. synthesis
This entails the the
synthesis condensation of 1,3-
We[3+3]
2.1.3. cannot deal with the
Cycloadditions synthesis of pyrimidines by [3+3] entails
cycloadditioncondensation
without de-of
dicarbonyl compounds,
1,3-dicarbonyl compounds, formerly ketones,
formerly with amidines
ketones, (Scheme 11).11).
scribing the classical Pinner reaction [41]. This with amidines
synthesis (Scheme
entails the condensation of 1,3-
We cannot deal with the synthesis of pyrimidines by [3+3] cycloaddition without de-
dicarbonyl compounds, formerly ketones, with amidines (Scheme 11).
scribing the classical Pinner reaction [41]. This synthesis entails the condensation of 1,3-
dicarbonyl compounds, formerly ketones, with amidines (Scheme 11).
Scheme11.
Scheme 11. Classical
Classical Pinner
Pinner synthesis.
synthesis.
Scheme 11. Classical Pinner synthesis.

A modified Pinner reaction is described by Vidal et al. with a β-keto ester instead of
1,3-diketone. The procedure
Scheme 11. Classical was improved under ultrasound (US) irradiation. Fully substi-
Pinner synthesis.
tuted pyrimidines were obtained by tosylation of the free hydroxyl of the obtained pyrimi-
dine derivatives, which allowed further Suzuki cross-coupling reactions (Scheme 12) [42].
1,3-diketone. The procedure was improved under ultrasound (US) irradiation. Fully sub-
1,3-diketone. ThePinner
A modified procedure was is
reaction improved
describedunder ultrasound
by Vidal (US) irradiation. Fully sub-
stituted pyrimidines were obtained by tosylation of theetfree
al. with a β-keto
hydroxyl ester
of the instead
obtained of
py-
stituted pyrimidines
1,3-diketone. were obtained
The procedure by tosylation
was improved of the free hydroxyl of the obtained py-
rimidine derivatives, which allowed furtherunder
Suzukiultrasound (US) irradiation.
cross-coupling Fully sub-
reactions (Scheme 12)
rimidine
stituted derivatives, were
pyrimidines which allowedby
obtained further Suzuki
tosylation of cross-coupling
the free hydroxylreactions
of the (Scheme py-
obtained 12)
Catalysts 2023, 13, 180 [42]. 7 of 24
[42].
rimidine derivatives, which allowed further Suzuki cross-coupling reactions (Scheme 12)
[42].
Scheme 12. Modified Pinner reaction with β-keto esters 45 and amidines 39.
Scheme 12. Modified Pinner reaction with β-keto esters 45 and amidines 39.
Scheme
Scheme 12. Modified
Other
12. Modified Pinner
variations reaction
of the
Pinner withreaction
original
reaction with β-keto esters
β-keto esters 45been
have45 and amidines
and amidines 39.[43]. Thus, using 1,3-
described
39.
Other variations of the original reaction have been described [43]. Thus, using 1,3-
dicarbonyl equivalents as precursors, several syntheses of pyrimidines have been re-
dicarbonyl
Other
Other equivalents
variations
variations of as
of theprecursors,
the original severalhave
original reaction
reaction syntheses
have been
been of pyrimidines
described
described [43].
[43]. haveusing
Thus, been 1,3-
re-
ported using a Pinner-like synthesis. Cho´s group [44] condensed β-bromo-α,β-unsatu-
ported
dicarbonyl
dicarbonylusing a Pinner-like
equivalents
equivalents synthesis.several
asasprecursors,
precursors, Cho´ s syntheses
several group [44]ofcondensed
syntheses pyrimidines
of β-bromo-α,β-unsatu-
have
pyrimidines been
have reported
been re-
rated ketones with benzamidine or acetamidine under Cu0 catalysis to provide the corre-
using
rated
ported a Pinner-like
ketones
using with synthesis.
benzamidine
a Pinner-like Cho’s
or
synthesis. group
acetamidine
Cho´of [44]
s group condensed
under Cu β-bromo-α,β-unsaturated
0 catalysis
[44] condensed to provide the corre-
sponding pyrimidines in fair yields. Most the samples were fusedβ-bromo-α,β-unsatu-
0 catalysis pyrimidines, which
ketones
sponding
rated with
ketones benzamidine
pyrimidines
with or acetamidine
in fair
benzamidine yields.
or Mostunderof theCu
acetamidine samples
under Cu wereto provide the corresponding
fusedtopyrimidines,
0 catalysis the which
do not fall within the scope of this study. Previously, this group carriedprovide
out the same corre-
syn-
pyrimidines
do
sponding in fair
not fallpyrimidines yields.
within the scope in Most of the
ofyields.
fair samples
this study.
Most were
Previously,
of the fused pyrimidines,
this group
samples were carried
fused which
out thedo
pyrimidines, not
same fall
syn-
which
thesis
within with β-bromo-α,β-unsaturated
the scope ofthe
this study. carboxylic
Previously, acids
this group [45]. One remarkable modification
thesis
do with β-bromo-α,β-unsaturated carboxylic acidscarried
[45]. outcarried
One the same
remarkable synthesis with
modification
wasnot
thefall
usewithin
β-bromo-α,β-unsaturated
scope
of unsaturated of this
ketones
carboxylic
study.
instead
acids
Previously,
of the
[45].
this
dicarbonyl
One
group
remarkable compound out
[46].the
modification
same
Thus,
was
syn-
a [3+3]
the use
was
thesisthe useβ-bromo-α,β-unsaturated
with of unsaturated ketones instead of the acids
carboxylic dicarbonyl
[45]. compound
One remarkable[46]. modification
Thus, a [3+3]
annulation–oxidation
of unsaturated ketones sequenceinstead of between α,β-unsaturated
the dicarbonyl compound ketones
[46]. Thus,and benzamidine
a [3+3] hy-
annulation–
annulation–oxidation
was the use of sequence
unsaturated between
ketones instead α,β-unsaturated
of the dicarbonyl ketones
compound and [46].
benzamidine
Thus, a hy-
[3+3]
drochloride
oxidation was performed
sequence using green andketones
between α,β-unsaturated recyclableandcholine hydroxide
benzamidine as both a cata-
hydrochloride was
drochloride was performed
annulation–oxidation sequence using green and
between recyclable choline
α,β-unsaturated ketoneshydroxide
and as both a cata-
benzamidine hy-
lyst and a reaction
performed using greenmedium. Strong
and recyclable bases,
cholinesuch as NaOH,asKOH
hydroxide bothand CsOH,
a catalyst andcatalyzed the
a reaction
lyst and a reaction
drochloride was medium. using
performed Stronggreen
bases,andsuch as NaOH,
recyclable KOH hydroxide
choline and CsOH,ascatalyzed
both a the
cata-
medium. Strongthan
reaction better bases, suchinorganic
weak as NaOH, KOHtoand
bases, CsOH,
give catalyzed
substituted the reaction
pyrimidine 50 inbetter than
excellent
reaction
lyst
weak and abetter
inorganic than
reaction
bases, weak
medium. inorganic
to give Strong bases,
bases,
substituted to give
such substituted
asrequired
pyrimidine NaOH,
50 in KOH pyrimidine
and
excellent CsOH, 50 in excellent
catalyzed the
yields. However, the optimal reaction conditions the use ofyields.
cholineHowever,
hydroxidethe as
yields.
reaction
optimal However,
better
reaction the
than optimal
weak reaction
inorganic conditions
bases, to giverequired the
substituted use of choline
pyrimidine 50hydroxide
in excellentas
a catalyst, as wellconditions
as reactionrequired
mediumthe at use
60 °C of (Scheme
choline hydroxide
13) [46]. as a catalyst, as well as
ayields.
catalyst,
reaction as wellat
However,
medium as60
the reaction
optimal medium
◦ C (Scheme
reaction at 60 °C (Scheme
13) conditions
[46]. required13)the
[46].
use of choline hydroxide as
a catalyst, as well as reaction medium at 60 °C (Scheme 13) [46].
Scheme 13. Synthesis of pyrimidines 50 from unsaturated ketones 48 and amidine 49.
Scheme 13. Synthesis
Scheme 13. Synthesis of
of pyrimidines 50 from
pyrimidines 50 from unsaturated
unsaturated ketones 48and
ketones48 andamidine
amidine49.
49.
Another of pyrimidines
variation was carried50 out
fromby
unsaturated
Hu et al., ketones 48 and amidine
who reported 49. cycloaddi-
[47] a [3+3]
Another
Anothervariation
variationwas
wascarried
carriedoutoutbyby
Hu Huet et
al.,al.,
who reported
who [47][47]
reported a [3+3] cycloaddition
a [3+3] cycloaddi-
tion
of of polysubstituted
polysubstituted 5-aminopyrimidines
5-aminopyrimidines 52 from52α-azidovinyl
from α-azidovinyl
ketones ketones
51 and 51 and ami-
amidines 39
tion of polysubstituted
Another variation 5-aminopyrimidines
was carried out by Hu 52et from
al., α-azidovinyl
who reported ketones
[47] a 51cycloaddi-
[3+3] and ami-
dines
in the 39 in the presence
presence of a base of aCO
(K base) in
(Kanhydrous
2CO3) in anhydrous DMF (Scheme 14).
DMF (Scheme 14).
dines
tion of39polysubstituted of 2a base
3 (K2CO3) in anhydrous DMF (Scheme 14).
in the presence 5-aminopyrimidines 52 from α-azidovinyl ketones 51 and ami-
dines 39 in the presence of a base (K2CO3) in anhydrous DMF (Scheme 14).
Scheme14.
Synthesis of
of 5-aminopyrimidines
5-aminopyrimidines52
52from
fromα-
α-azidovinyl
azidovinylketones
ketones51
51and
andamidines
amidines39.
39.
Scheme 14. Synthesis of 5-aminopyrimidines 52 from α- azidovinyl ketones 51 and amidines 39.
Amidines wereofalso
5-aminopyrimidines
condensed via 52 fromannulation
[3+3] α- azidovinyl ketones
with 51 and amidines 39.
2,2,2-trichloroethyliden-
acetophenones 53, easily available from chloral and acetophenones, providing novel 2,6-
diaryl-6-hydroxy-4-trichloromethyl-1,4,5,6-tetrahydropyrimidines 54 in good yields.
On the other hand, new intermediate 2,4-diaryl-6-trichloromethyl-1,6-dihydropyrimidines
55 were formed by dehydration and found able to undergo base-induced chloroform elimi-
nation to give 2,4-diarylpyrimidines 56 (Scheme 15) [48].
Amidines were also condensed via [3+3] annulation with 2,2,2-trichloroethyliden-
Amidines were
Amidines were also
also condensed
condensed viavia [3+3]
[3+3] annulation
annulation with
with 2,2,2-trichloroethyliden-
2,2,2-trichloroethyliden-
acetophenones 53, easily available from chloral and acetophenones, providing novel 2,6-
acetophenones
acetophenones 53, easily available from chloral and acetophenones, providing novel
novel 2,6-
diaryl-6-hydroxy-4-trichloromethyl-1,4,5,6-tetrahydropyrimidines 54 in good yields. 2,6-
53, easily available from chloral and acetophenones, providing
diaryl-6-hydroxy-4-trichloromethyl-1,4,5,6-tetrahydropyrimidines 54 in good
diaryl-6-hydroxy-4-trichloromethyl-1,4,5,6-tetrahydropyrimidines 54 in good yields. yields.
On the other hand, new intermediate 2,4-diaryl-6-trichloromethyl-1,6-dihydropyrim-
On the
On the other
other hand,
hand, new intermediate
intermediate 2,4-diaryl-6-trichloromethyl-1,6-dihydropyrim-
2,4-diaryl-6-trichloromethyl-1,6-dihydropyrim-
Catalysts 2023, 13, 180
idines 55 were formed new
by dehydration and found able to undergo base-induced chloro- 8 of 24
idines 55
idines 55 were
were formed
formed by by dehydration
dehydration and
and found
found able
able to
to undergo
undergo base-induced
base-induced chloro-
chloro-
form elimination to give 2,4-diarylpyrimidines 56 (Scheme 15) [48].
form elimination
form elimination to
to give
give 2,4-diarylpyrimidines
2,4-diarylpyrimidines 5656 (Scheme
(Scheme 15)
15) [48].
[48].
Scheme 15. Synthesis of 2,4-diarylpyrimidines 56 from 2,2,2-trichloroethyliden-acetophenones 53

Scheme
15.
and amidinesSynthesis
39. of 2,4-diarylpyrimidines
of 2,4-diarylpyrimidines 56
56 from
from 2,2,2-trichloroethyliden-acetophenones
2,2,2-trichloroethyliden-acetophenones 53
53
Scheme
and 15. Synthesis
amidines 39. of 2,4-diarylpyrimidines 56 from 2,2,2-trichloroethyliden-acetophenones 53
and amidines 39.
and amidines 39.
A bromoenone was used to afford trifluoromethylated pyrimidines 59 through the
A bromoenone
A bromoenone was was used
used to
to afford
afford trifluoromethylated
trifluoromethylated pyrimidines
pyrimidines 59 59 through
through thethe
treatment
A of fluorinated
bromoenone was 2-bromoenones
used to 57 with aryl- and alkylamidines
afford trifluoromethylated pyrimidines 34 59 [49]. The the
through for-
treatment of
treatment of fluorinated
fluorinated 2-bromoenones
2-bromoenones 57 57 with
with aryl-
aryl- and
and alkylamidines
alkylamidines 34 34 [49].
[49]. The
The for-
for-
mation of of
treatment a pyrimidine
fluorinated core proceeded via
2-bromoenones 57 an aza-Michael
with aryl- and addition–intramolecular
alkylamidines 34 [49]. cy-
The
mation of
mation of aa pyrimidine
pyrimidine corecore proceeded
proceeded via
via an
an aza-Michael
aza-Michael addition–intramolecular
addition–intramolecular cy- cy-
clization–dehydrohalogenation/dehydration
formation of a pyrimidine core proceeded via sequence. The influence
an aza-Michael of the trifluorome-
addition–intramolecular
clization–dehydrohalogenation/dehydration sequence.
clization–dehydrohalogenation/dehydration sequence. The
The influence
influence of
of the
the trifluorome-
trifluorome-
thyl group was demonstrated to be necessary to achieve
cyclization–dehydrohalogenation/dehydration selectively
sequence. the target
The influence ofheterocycles
the trifluo-
thyl
thyl group
group was
was demonstrated
demonstrated to
to be
be necessary
necessary to
to achieve
achieve selectively
selectively the
the target
target heterocycles
heterocycles
in high yields
romethyl group(up wasto 99%) under to
demonstrated mild conditions.
be necessary to With other
achieve substituents,
selectively imidazoles
the target hetero-
in high
in high yields
yields (up (up to
to 99%)
99%) under
under mild
mild conditions.
conditions. With
With other
other substituents, imidazoles
imidazoles
cycles in high yields
were obtained (up to
(Scheme 99%) under
16). mild conditions. With othersubstituents,
substituents, imidazoles
were obtained
were
were obtained (Scheme
obtained (Scheme 16).
(Scheme 16).
16).
Scheme 16. Synthesis of trifluoromethylated pyrimidines 59 from bromoenones 57 and aryl- and
Scheme
Scheme
16.
16. Synthesis
alkylamidines 39. of trifluoromethylated
of trifluoromethylated pyrimidines
pyrimidines 59 from bromoenones
59 from bromoenones 57 and aryl-
57 and aryl- and
and
alkylamidines 39.
alkylamidines 39.
Another modification was described by Chu et al. [50], starting from a variety of sat-
Another
Another modification
modificationwas
modification was described
wasdescribed
describedbyby Chu
byChu
Chu etet
et al.al.
al. [50], starting
[50],
[50], starting
starting from
from aa variety
from variety of sat-
a variety
of sat-
of
urated carbonyl compounds: ketones, aldehydes and esters 60. The condensation was pro-
urated carbonyl
saturated
urated carbonyl compounds:
compounds: ketones, aldehydes
ketones, and
aldehydes esters
and 60.
esters The
60. condensation
The condensation was pro-
was
moted carbonyl
by FeSO4compounds: ketones, aldehydes and esters 60.
and 2,2,6,6-tetramethylpiperidin-1-yl)oxyl The condensation
(TEMPO), selectivelywas pro-
favoring
promoted
moted by
moted by FeSO
by FeSO
FeSO 4 and
and
4 and 2,2,6,6-tetramethylpiperidin-1-yl)oxyl
2,2,6,6-tetramethylpiperidin-1-yl)oxyl
2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO),
(TEMPO),
(TEMPO), selectively
selectively
selectively favor-
favoring
favoring
β-functionalization. A mechanism initiated by TEMPO reduction via complexed Fe(II)
4
ing β-functionalization.
β-functionalization.
β-functionalization. A A mechanism
A mechanism
mechanism initiated
initiated
initiated byby
by TEMPOreduction
TEMPO
TEMPO reductionvia
reduction viacomplexed
via complexed Fe(II)
complexed Fe(II)
with ketones was proposed. The total sequence included the formation of intermediate
with ketones
with ketones
with was proposed.
ketones was proposed.
proposed. The total sequence
total sequence included
sequence included
included the the formation
the formation
formation of of intermediate
of intermediate
intermediate
enamine and was finished with aThe total
β-TEMPO elimination, followed by cyclization. The Fe(II)
enamine
enamine
enamine and
and finished
finished
and finished with
with a β-TEMPO
a β-TEMPO
withina situ,
β-TEMPO elimination,
elimination,
elimination, followed
followed
followed by cyclization.
by cyclization.The Fe(II)
The cat-
Fe(II)
catalytic complex, formed could be recycled. More thanby cyclization.
forty pyrimidinic The Fe(II)
deriva-
alytic complex,
catalytic
catalytic complex,
complex, formed
formed
formed in situ,
in could
situ, be
could recycled.
be More
recycled. than
More forty
than pyrimidinic
forty pyrimidinic derivatives
deriva-
tives were obtained (some inof situ,
themcould be recycled. More
with condensated rings),than fortyofpyrimidinic
sixteen which werederiva-
of type
were
tives obtained
tives were
were (some
obtained
obtained of them
(some
(some of withwith
of them
them condensated
with rings),
condensated
condensated sixteen
rings),
rings), of which
sixteen
sixteen of which
of whichwere of type
were
were 61
of type
of type
61 (Scheme 17) [50].
(Scheme
61 17)
(Scheme [50].
17) [50].
61 (Scheme 17) [50].
Scheme17.
Scheme 17.Iron-catalyzed
Iron-catalyzedsynthesis
synthesisofofpyrimidines
pyrimidines6161 from
from carbonyl
carbonyl derivatives
derivatives 60 and
60 and amidines
amidines 39.
Scheme
Scheme
39. 17. Iron-catalyzed
17. Iron-catalyzed synthesis
synthesis of
of pyrimidines
pyrimidines 61
61 from
from carbonyl
carbonyl derivatives
derivatives 60
60 and
and amidines
amidines
39. Subsequently, a condensation with a special type of unsaturated ketone, a substi-
39.
tuted chromone, was carried out by Yu et al. [51]. The strategy was based on a transi-
tion metal-free synthesis of 3-trifluoromethyl chromones via tandem C-H bond trifluo-
romethylation and chromone annulation reactions of o-hydroxyphenyl enaminones. The
addition of K2 S2 O8 made the use of any transition metal catalyst or additive unneces-
sary. The 3-trifluoromethyl chromone products were successfully used for the synthesis
of 3-trifluoromethyl pyrimidines through reactions with guanidine/amidine substrates
(Scheme 18).
Subsequently,
chromone, a condensation
wasofcarried with a special
out by Yu etchromones
al. [51]. Thevia type of was
strategy unsaturated
based ketone, a substituted
ontrifluoromethylation
a transition metal-
free synthesis 3-trifluoromethyl tandem C-H bond
chromone,
free was
synthesis ofcarried out by Yu
3-trifluoromethyl et al. [51].
chromones The
viastrategy
tandem was
C-H based
bond on a transition
trifluoromethylationmetal-
and chromone annulation reactions of o-hydroxyphenyl enaminones. The addition of
free
and synthesis
chromoneofannulation
3-trifluoromethyl
reactionschromones via tandem C-H
of o-hydroxyphenyl bond trifluoromethylation
enaminones. The addition of
K 2S2O8 made the use of any transition metal catalyst or additive unnecessary. The 3-tri-
and
K 2S2Ochromone
8 made theannulation
use of any reactions
transition of o-hydroxyphenyl
metal catalyst or enaminones.
additive The addition
unnecessary. The 3-tri-of
fluoromethyl chromone products were successfully used for the synthesis of 3-trifluoro-
K 2S2O8 made chromone
fluoromethyl the use of products
any transition metal catalyst
were successfully or additive
used unnecessary.
for the synthesis The 3-tri-
of 3-trifluoro-
Catalysts 2023, 13, 180 methyl pyrimidines through reactions with guanidine/amidine substrates (Scheme 18). 9 of 24
fluoromethyl chromone
methyl pyrimidines products
through werewith
reactions successfully used for the
guanidine/amidine synthesis
substrates of 3-trifluoro-
(Scheme 18).
methyl pyrimidines through reactions with guanidine/amidine substrates (Scheme 18).
Scheme 18. Synthesis of F3C-functionalized pyrimidines 63 from chromones 62.

Scheme 18. Synthesis of F3C-functionalized pyrimidines 63 from chromones 62.
Scheme18.
18. Synthesis
Synthesis of
of FF33C-functionalized pyrimidines
pyrimidines 63
63 from
from chromones
Scheme
[3+3] cycloadditions have also been carried out fromchromones 62.
62.
fluorinated building blocks.
[3+3] cycloadditions have also been carried out from fluorinated building blocks.
Thus, an efficient microwave-assisted cyclization reaction was developed to provide
Thus, an cycloadditions
[3+3]
[3+3] efficient microwave-assisted
cycloadditions have
havealso been
also cyclization
carried
been carried reaction
out out
from was
fluorinated
from developed
building
fluorinated to provide
blocks.
building Thus,
blocks.
faster
faster and
and efficient
efficient access to
access to new
new fluoroalkyl
fluoroalkyl pyrimidines
pyrimidines66 66and
and6868from
fromfluorinated
fluorinated
an efficient microwave-assisted cyclization reaction was developed to provide
Thus, an efficient microwave-assisted cyclization reaction was developed to provide faster and
acetoacetates,
acetoacetates, malononitrile, various
malononitrile, various amidines
amidinesand
andfluoroalkyl
fluoroalkylamino
aminoreagents
reagents(Scheme
(Scheme
efficient access to new fluoroalkyl pyrimidines 66 and 68 from fluorinated
faster and efficient access to new fluoroalkyl pyrimidines 66 and 68 from fluorinatedacetoacetates,
19)
19) [52].
[52].
malononitrile,
acetoacetates, various amidines
malononitrile, and fluoroalkyl
various amino
amidines and reagents (Scheme
fluoroalkyl 19) [52].(Scheme
amino reagents
19) [52].

Scheme 19.
Scheme Synthesis of
of fluoroalkyl
of fluoroalkyl pyrimidines
fluoroalkyl pyrimidines66
pyrimidines 66and
66 and68
and 68under
68 underMW
under MWirradiation.
MW irradiation.
irradiation.
Scheme 19. Synthesis of fluoroalkyl pyrimidines 66 and 68 under MW irradiation.
Veryrecently,
Very recently,in
in2022,
2022,Xiang
2022, Xiang andandYang
Yangreported
reported[53]
reported [53]aaaphotoredox-catalyzed
[53] photoredox-catalyzedamina-
photoredox-catalyzed amina-
tion of
tion ofo-hydroxyarylenaminones
o-hydroxyarylenaminones
o-hydroxyarylenaminoneswith withtert-butyl
with tert-butyl[(perfluoropyridin-4-yl)oxy]carbamate,
tert-butyl [(perfluoropyridin-4-yl)oxy]carbamate,
[(perfluoropyridin-4-yl)oxy]carbamate, a
Very recently, in 2022, Xiang and Yang reported [53] a photoredox-catalyzed amina-
a versatile
versatile amidyl
amidyl radical
radical
radical precursor.
precursor.
precursor. This
ThisThis method
method
method allows
allows
allows 3-aminochromones
3-aminochromones
3-aminochromones to betoto bebeob-
ob-
obtained
tion of o-hydroxyarylenaminones with tert-butyl [(perfluoropyridin-4-yl)oxy]carbamate,
tainedmild
under under mild conditions,
conditions, with anwith
conditions, with an
anadditional
additional
additional application
application
application ininthe
thesynthesis
in the synthesis synthesisofofa aseries
of a series ofof
ofseries
amino
a versatile amidyl radical precursor. This method allows 3-aminochromones to be ob-
amino pyrimidines
pyrimidines (Scheme (Scheme
20) [53].20)
(Scheme 20) [53].
[53].
tained under mild conditions, with an additional application in the synthesis of a series of
amino pyrimidines (Scheme 20) [53].
Scheme 20.
Scheme
20. Synthesis of
Synthesis of 3-aminochromones
3-aminochromones71
of 3-aminochromones 71and
71 andamino
and aminopyrimidines
amino pyrimidines72.
pyrimidines 72.
72.
Scheme
Not20. Synthesis
many of 3-aminochromones
examples 71 andare
of bis-pyrimidines amino pyrimidines
found 72.
in the literature. With the aim
of obtaining new biological active pyrimidine derivatives 75, 76 and 77, Dabholkar and
Ansari [54] proposed this synthesis starting from bis-α,β-unsaturated esters 74 and car-
bamide C, thiocarbamide (T) and guanidine (G) as efficient substrates under ultrasound
(US) irradiation in aqueous media (Scheme 21).
Not many examples of bis-pyrimidines are found in the literature. With the aim of
obtaining new biological
Not many examplesactive pyrimidine derivatives
of bis-pyrimidines are found75,in 76
theand 77, Dabholkar
literature. With theandaimAn-of
sari Not many examples of bis-pyrimidines are found in the literature. With
obtaining new biological active pyrimidine derivatives 75, 76 and 77, Dabholkar and car-
[54] proposed this synthesis starting from bis-α,β-unsaturated esters the
74 aim
and of
An-
obtaining new biological active pyrimidine
bamide
sari [54]C,proposed
thiocarbamide (T) and
this synthesis starting derivatives
guanidine (G) as
from 75, 76 substrates
efficient and 77, Dabholkar
bis-α,β-unsaturated under 74
esters and An-
ultrasound
and car-
sari
(US) [54] proposed
irradiation this synthesis
in aqueous(T) media starting from
(Scheme 21). bis-α,β-unsaturated esters 74 and car-
Catalysts 2023, 13, 180 bamide C, thiocarbamide and guanidine (G) as efficient substrates under ultrasound10 of 24
bamide C, thiocarbamide (T) and guanidine (G) as efficient substrates under ultrasound
Scheme 21. Synthesis of bis-pyrimidines 75, 76 and 77 under US irradiation.

Scheme 21.
Synthesisof
ofbis-pyrimidines
bis-pyrimidines75,
75, 76and
and 77under
underUS
US irradiation.
Scheme Synthesis of
The21.effectiveness bis-pyrimidines 75, 76
of the cyclization and 77
77 under
76reactions USirradiation.
irradiation.
involving alkynes and nitrogen com-
pounds Thefor the synthesis
effectiveness of
thepyrimidines,
of the cyclizationreactionsusing a variety
reactions involvingof promoters
alkynesand andnitrogen
and catalysts,com-has
The
The effectiveness
effectiveness of the cyclization
cyclization reactions involving
involving alkynes
alkynes and nitrogen
nitrogencom-com-
been demonstrated.
pounds for for thethe More
synthesis ofspecifically,
pyrimidines, the Cu(II)-catalyzed
using cycloaddition reaction of al-
pounds
pounds the synthesis
synthesisof ofpyrimidines,
pyrimidines, using
using aavariety
variety
a variety ofofpromoters
promoters
of promoters andcatalysts,
and catalysts,
and hashas
catalysts,
kynes
beenbeenis considered
demonstrated. a powerful
MoreMore tool
specifically, for the construction
theCu(II)-catalyzed
Cu(II)-catalyzed of pyrimidines
cycloaddition using nitrogen-
reaction
been
has demonstrated.
demonstrated. More specifically,
specifically,the the Cu(II)-catalyzed cycloaddition reaction
cycloaddition ofofal-al-
reaction
containing
kynes is molecules,a such
considered powerfulas amidines,
tool for guanidines
the constructionand sulfonyl
of azides [27].
pyrimidines usingMüller and
nitrogen-
kynes
of is considered
alkynes is considered a powerful
a powerful tooltool
forfor thethe
construction
construction of of
pyrimidines
pyrimidines using
using nitrogen-
nitrogen-
colleagues [55]
containingmolecules, planned
molecules,such a versatile
suchas copper-catalyzed
asamidines,
amidines,guanidines
guanidinesand synthesis
andsulfonyl of 2,6-disubstituted
sulfonylazides
azides[27].
[27].Müller
Müllerpyrim-
and
containing
containing molecules, amidines, guanidines and sulfonyl azides [27]. Müller and
and
idones 79 from
colleagues terminal
plannedaaalkynes
[55]planned versatile7, CO 2 and amidine hydrochloride 34 in DMF. Although
copper-catalyzed synthesisof of2,6-disubstituted
2,6-disubstituted pyrim-
colleagues
colleagues [55]
[55] versatile copper-catalyzed
copper-catalyzed synthesis
synthesis of 2,6-disubstituted pyrim-
pyrimi-
the total79reaction
idones from involved
terminal three 7,
alkynes components,
CO and the formation
amidine of a pyrimidine
hydrochloride 34ininDMF.
DMF. ring can be
Although
idones
dones 7979from
from terminal
terminal alkynes
alkynes 7,7,CO
CO 2 2and
2 and amidine
amidine hydrochloride
hydrochloride 3434in DMF. Although
Although the
considered
the total
total a
reaction
reaction
[3+3] cycloaddition
involved
involved three strategy.
components, After an initial
theformation
formation carboxylation/methylation
ofofa apyrimidine
pyrimidine ring can of
bebe
total reaction involved threethree components,
components, the
the formation of a pyrimidine ring
ring can becan
consid-
terminal
considered
considered
ered a [3+3] alkynes
a [3+3]tocycloaddition
[3+3] produce
cycloaddition
acycloaddition the methyl
strategy. After arylpropiolates
strategy.
strategy. After
anAfter an
initialan 78,carboxylation/methylation
initial
initial a Michael additionofcyclocon-
carboxylation/methylation
carboxylation/methylation terminalofof
densation
terminal
alkynes led
terminaltoalkynes
alkynes to
produce pyrimidones
tothe
to produce
produce
methyl 79
the
the with
methyl moderate-to-good
methylarylpropiolates
arylpropiolates arylpropiolates
78, a Michael yields
78, (Scheme
78,a aMichael
Michael
addition 22) [55].
addition
addition cyclocon-
cyclocon-
cyclocondensation
densation
densation
led led to
led to pyrimidones
to pyrimidones pyrimidones 79with
79 withmoderate-to-good
moderate-to-good
79 with moderate-to-good yields
yields
yields (Scheme (Scheme
(Scheme
22) 22)[55].
[55]. 22) [55].
Scheme 22. Copper-catalyzed synthesis of 2,6-disubstituted pyrimidones 79 with MW.

Scheme
Scheme 22.
Scheme22. Copper-catalyzed
Copper-catalyzedsynthesis
22.Copper-catalyzed synthesisof
synthesis of2,6-disubstituted
of 2,6-disubstitutedpyrimidones
2,6-disubstituted pyrimidones79
pyrimidones 79with
79 with
with MW.
MW.
MW.
Lin et al. [56] described the use of Cu(II) triflate (20 mol%) as an efficient catalyst to
synthesize
Lin
Linet
Lin et 2,4-disubstituted
al.
etal. [56]
al.[56] described
[56]described
described or
the
thethe2,4,6-trisubstituted
use
use ofofof
use Cu(II)
Cu(II)
Cu(II) triflate pyrimidines
triflate
triflate (20(20
(20 mol%)
mol%) mol%)as as
an83
asan from
an propargyl
efficient
efficient
efficient toalco-
catalyst
catalyst
catalyst toto
syn-
hols and
synthesize
synthesize
thesize amidine. The synthesis
2,4-disubstituted
2,4-disubstituted
2,4-disubstituted or started with
2,4,6-trisubstituteda
or 2,4,6-trisubstituted
or 2,4,6-trisubstituted Cu(II) activation
pyrimidines
pyrimidines
pyrimidines 83of propargyl
from
83 from83propargyl alcohol
propargyl
from propargyl alco-80,
alcoholsalco-
and
followed
hols and
hols andThe
amidine. by a [3+3]
amidine.
amidine. addition
The
Thestarted
synthesis combined
synthesis
synthesis started
withstarted with
with
a Cu(II) ring
with a closure
Cu(II) in a
activation
a Cu(II)ofactivation
activation 6-endo-dig
of mode.
propargyl
propargylofalcoholpropargyl The authors
alcohol 80,
alcohol by
80, followed 80,
aproposed
followed the
by
[3+3] addition
followed by initial
aa[3+3] formation
addition
combined
[3+3] addition with of
combined
ring
combinedtheclosure
propargyl
with
withring
ring cationin81,
in aclosure
6-endo-dig
closure which
ina a6-endo-dig
mode. triggers
The
6-endo-dig mode.
mode. the
The
authors attack
authors
proposed
The on
authors
amidine
the initialtoformation
proposed
proposed complete
the
the initial the
of pyrimidine
initial formation
the of
ofthe
propargyl
formation theskeleton,
propargyl
cation as which
81,
propargyl acation
key step
cation 81, of
81,which
triggers the
whichthereaction
triggers mechanism.
attack the
triggers on attack A
attackonto
amidine
the on
subsequent
amidine
amidine to
complete the
to aromatization
complete
pyrimidine
complete the by
thepyrimidineoxidation
skeleton,
pyrimidine asskeleton,was
askeleton,
key step the
asasaakey
of last
the step
step
stepofofthe
keyreaction leading
thereactionto pyrimidines
reactionmechanism.
mechanism. A subsequent
mechanism. AA83
(Scheme
subsequent 23)
aromatization [56].
aromatization
by oxidation by
was oxidation
the last was
step the
leading last
to step leading
pyrimidines
subsequent aromatization by oxidation was the last step leading to pyrimidines 83 83to pyrimidines
(Scheme 23) 83
[56].
(Scheme
(Scheme 23) 23) [56].
[56].
Scheme 23. Mechanistic proposal for Cu(II)-catalyzed tandem synthesis of pyrimidines 83.
A series of 4-iminopyrimidines 86 using the strategy of [3+3]-A cycloaddition was

synthesized from intermediate β-alkynyl-N-sulfonyl ketenimines 85 with a copper catalyst.
The sequence started with the reaction of butadiynes 84 and sulfonylazides and continued
with the addition of hydrazides or imidamides (Scheme 24) [57]. The best reaction condi-
tions to first form ketenimine 85 with subsequent cycloaddition were with CuCl (10 mol%)
Scheme 23. Mechanistic proposal for Cu(II)-catalyzed tandem synthesis of pyrimidines 83.
A series
Scheme of 4-iminopyrimidines
23. Mechanistic 86 using the
proposal for Cu(II)-catalyzed strategy
tandem of [3+3]-A
synthesis cycloaddition
of pyrimidines 83. was
A series of
synthesized 4-iminopyrimidines
from 86 using the strategyketenimines
intermediate β-alkynyl-N-sulfonyl of [3+3]-A cycloaddition
85 with a copperwas
synthesized
catalyst. The from
A series sequenceintermediate
started with
of 4-iminopyrimidines β-alkynyl-N-sulfonyl
the reaction
86 using theofstrategyketenimines
butadiynes 84 and
of [3+3]-A 85 with a copper
sulfonylazides
cycloaddition wasand
catalyst.
continued
synthesizedThewith
sequence started with
fromtheintermediate
addition the reactionorofimidamides
of β-alkynyl-N-sulfonyl
hydrazides butadiynes 84 and 85
(Scheme
ketenimines sulfonylazides
24) [57].
with a The and
copperbest
Catalysts 2023, 13, 180 continued
catalyst.
reaction The with the to
sequence
conditions addition
started
first formof hydrazides
with the reaction
ketenimine or imidamides
85 of butadiynes
with (Scheme
subsequent84 and 24) [57]. The
sulfonylazides
cycloaddition were 11 of 24
best
and
with
reaction
CuCl (10conditions
continued with the
mol%) astoaddition
a first form
catalyst ketenimine
ofwith NEt3 in85
hydrazides or with
DCE subsequent
imidamides
at cycloaddition
(Scheme
room temperature. 24) [57].were
The with
Although best
three
CuCl (10
reaction mol%)
conditions as a
to catalyst
first form with NEt
ketenimine in DCE
85 withat room temperature.
subsequent Although
cycloaddition
components are involved in this reaction, in two sequential steps, the atoms of the starting
3 were three
with
components
CuCl
as (10
a catalyst
azide notare
are mol%)with involved
asNEt
integrated 3 ininDCE
a catalyst
in thiswith
the reaction,
NEt3 in
at room
pyrimidine intwo
DCE sequential
inat
theroom
temperature.
core steps, thethree
atoms
temperature.
Although
cycloaddition of the
24)starting
Although
components
(Scheme three
[57]. are
azide are
components
involved not integrated
are involved
in this reaction, inin the
inthispyrimidine
tworeaction,
sequential core
in two in the cycloaddition
sequential
steps, the atomssteps, (Scheme
the starting
of the 24)
the[57].
atoms ofazide starting
are not
azide are not
integrated integrated
in the pyrimidinein thecore
pyrimidine core in the cycloaddition
in the cycloaddition (Scheme 24) [57].
(Scheme 24) [57].
Scheme 24. Copper-catalyzed synthesis of 4-iminopyrimidines 86.

Scheme 24. Copper-catalyzed synthesis of 4-iminopyrimidines 86.
Scheme
Scheme 24. Copper-catalyzed
24.
Sharma et al. [58] tooksynthesis
synthesis
advantageof
of 4-iminopyrimidines
4-iminopyrimidines 86.
86.ability to regioselectively func-
of the Selectfluor’s
Sharma et al. [58] took advantage of the Selectfluor’s ability to regioselectively func-
tionalize a variety of methylthio-substituted β-enaminones 87, which were transformed
tionalize
Sharmaa variety of methylthio-substituted
et al. [58] took advantage
took advantage ofthe
of β-enaminones
theThe
Selectfluor’s
Selectfluor’s 87, which
ability were transformed
toregioselectively
regioselectively func-
into α-fluoro-β-enaminones in acetonitrile. resultingability
crudetoreaction func-
was condensed
into α-fluoro-β-enaminones
tionalize
tionalize aavariety
varietyofof in acetonitrile.
methylthio-substituted
methylthio-substituted The resulting
β-enaminones
β-enaminones crude reaction
which
87,87, which were was
were condensed
transformed
transformed into
with guanidinium nitrate under basic conditions. The corresponding 6-aryl- or 6-alkyla-
with guanidinium nitrate
α-fluoro-β-enaminones
into α-fluoro-β-enaminones inunder
in basic conditions.
acetonitrile. The The
acetonitrile. Thecrude
resulting corresponding
resulting reaction
crude 6-aryl-
was
reaction or 6-alkyla-
condensed
was condensedwith
mines-2-amino-5-fluoropyrimidines 88 were obtained in good overall yields (Scheme 25)
mines-2-amino-5-fluoropyrimidines
guanidinium
with guanidiniumnitratenitrate
underunder 88conditions.
were The
basic conditions.
basic obtained
The in good overall
corresponding yields
6-aryl-6-aryl-
corresponding (Scheme 25)
or 6-alkylamines-2-
or 6-alkyla-
[58].
[58].
amino-5-fluoropyrimidines
mines-2-amino-5-fluoropyrimidines 88 were obtained in good overall
88 were obtained in goodyields
overall(Scheme 25) [58]. 25)
yields (Scheme
[58].
Scheme 25.
Scheme 25. Sequential synthesisofof4-amino-5-fluoropyrimidines
4-amino-5-fluoropyrimidines 88.
Scheme 25. Sequential synthesis
synthesis of 4-amino-5-fluoropyrimidines88.
88.
Scheme 25. Sequential synthesis of 4-amino-5-fluoropyrimidines 88.
Sulfur derivatives
Sulfur derivativesare
derivatives arefrequently
are frequentlycompounds
frequently compoundsofof
compounds ofinterest
interestinin
interest inbiomedical
biomedicalapplications.
biomedical applications.
applications.
With
With the
the
WithSulfur aim
theaim
aim of obtaining
ofofobtaining
obtaining
derivatives are sulfur-functionalized
sulfur-functionalized
sulfur-functionalized
frequently compounds pyrimidines,
pyrimidines, a practical
of interesta practical
pyrimidines, microwave-as-
microwave-assisted
ina biomedical
practical microwave-as-
applications.
sistedthe
protocol
sisted
With protocol
for
aimthe
protocol for
offor thesynthesis
synthesis
the
obtainingsynthesis
of ofof2,6-disubstituted
2,6-disubstituted
2,6-disubstituted
sulfur-functionalized pyrimidinones
pyrimidinones
pyrimidinones
pyrimidines, a91 9191was
was was developed.
developed.
practical developed. It It
It was
microwave-as-
was based
based
was
sistedbased
on aonon
protocol aadomino
dominodomino
for the Michael
Michael
Michael
synthesis addition/cyclocondensation
addition/cyclocondensation
addition/cyclocondensation
of reaction
reaction
2,6-disubstituted pyrimidinones between
between
between
91 substituted
substituted
substituted
was developed. It
thioureas/guanidines
thioureas/guanidines
thioureas/guanidines and
and acetylencarboxylates
acetylencarboxylates (Scheme
(Scheme 26).
26). Following
Following
was based on a domino Michael addition/cyclocondensation reaction between substituted this
this strategy,
strategy,
strategy, the
the
the
subsequent
subsequent
subsequent synthesis
synthesis of
synthesis and
thioureas/guanidines of
not not
easily
of not easily accessible
accessible N-DABON-DABO
easily accessible N-DABO
acetylencarboxylates (dihydro-alkoxyl-benzyl-oxopy-
(dihydro-alkoxyl-benzyl-oxopyrimidine)
(Scheme (dihydro-alkoxyl-benzyl-oxopy-
26). Following this strategy, the
rimidine) derivatives
derivatives
rimidine)
subsequent derivatives
was reported
synthesis was
was
of reported
[59].
reported
not [59].
easily [59].
accessible N-DABO (dihydro-alkoxyl-benzyl-oxopy-
rimidine) derivatives was reported [59].
Scheme 26.
Scheme
Scheme 26. Microwave-assisted
26. Microwave-assisted
Microwave-assisted tandem
tandem
tandem Michael addition–cyclocondensation
Michael
Michael toto
addition–cyclocondensation
addition–cyclocondensation form sulfur-func-
to sulfur-func-
form form sulfur-
tionalized
tionalized pyrimidines
26.pyrimidines
functionalized
Scheme 91. 91. tandem Michael addition–cyclocondensation to form sulfur-func-
91.
pyrimidines
Microwave-assisted
tionalized pyrimidines 91.
A direct
A direct
directand single-stepprocedure
andsingle-step
single-step procedure
procedure towards
towards
towards substituted
substituted
substituted pyrimidine
pyrimidine and
pyrimidine and pyridine
pyridine
and pyridinede-
de-
derivatives
rivatives
rivatives viavia
via
A direct Lewis-acid-promoted
Lewis-acid-promoted
Lewis-acid-promoted
and [3+3]
[3+3]
[3+3]
single-step procedure annulation
annulation
annulation
towards between
between
between
substituted 3-ethoxycyclobutanones
3-ethoxycyclobutanones
pyrimidine and pyridineand
3-ethoxycyclobutanones and
de-
and enamines
rivatives or amidines is presented.
via Lewis-acid-promoted These 3-ethoxycyclobutanones
[3+3] annulation act as 1,3-di-
between 3-ethoxycyclobutanones and
carbonyl surrogates. Choosing the right reaction conditions, diverse substituted pyrimidine
95 and pyridine derivatives 94 were obtained in good-to-high yields with a wide substrate
scope (Scheme 27) [60].
enamines or amidines is presented. These 3-ethoxycyclobutanones act as 1,3-di-carbonyl

surrogates.
enamines
enamines orChoosing
or amidinesthe
amidines is right reaction
is presented.
presented. conditions,
These
These diverse substituted
3-ethoxycyclobutanones
3-ethoxycyclobutanones act pyrimidine
act 95 and
as 1,3-di-carbonyl
as 1,3-di-carbonyl
pyridine derivatives
surrogates.
surrogates. Choosing94
Choosing thewere
the rightobtained
right reactionin
reaction good-to-high
conditions,
conditions, yields
diverse
diverse with a wide
substituted
substituted substrate95
pyrimidine
pyrimidine 95scope
and
and
Catalysts 2023, 13, 180 (Scheme 27) [60]. 12 of 24
pyridine derivatives
pyridine derivatives 94
94 were
were obtained
obtained in
in good-to-high
good-to-high yields
yields with
with aa wide
wide substrate
substrate scope
scope
(Scheme 27)
(Scheme 27) [60].
[60].
Scheme 27. Synthesis of pyrimidines 94 and 95 from 3-ethoxycyclobutanones 92.

Scheme27.
Synthesis of
of pyrimidines
pyrimidines 94
94and
and95
95from
from3-ethoxycyclobutanones
3-ethoxycyclobutanones92.
3-ethoxycyclobutanones 92.
92.
A new [3+3] strategy was carried out by El-Sayed et al. [61], preparing pyrimidine
derivatives
AA new via
[3+3]anstrategy
new [3+3] epoxy was
strategy ketone. Pyrimidinic
was carried
carried out
out by compounds
by El-Sayed
El-Sayed et al.98
et al. andpreparing
[61],
[61], 99 were pyrimidine
preparing
preparing synthesized
pyrimidine
pyrimidine
starting from
derivatives
derivatives viaunsaturated
via an
an epoxy
epoxy carbonyl
epoxy ketone.
ketone.
ketone. compound
Pyrimidinic
Pyrimidinic 96, which,
compounds
compounds 98 with
98 and 99
and hydrogen
99 were peroxide,
were synthesized
synthesized
synthesized
yieldedfrom
starting
starting
starting epoxy
from ketone
fromunsaturated 97. carbonyl
unsaturated
unsaturated After a reaction
compound
carbonyl
carbonyl with
compound
compound 96,urea
96,orwhich,
which,
96, thiourea
which, by epoxide
with hydrogen
with
with opening,
peroxide,
hydrogen
hydrogen the
yielded
peroxide,
peroxide,
corresponding
epoxy ketone
yielded epoxy
yielded 97.derivatives
After
epoxy ketone a
ketone 97. 98
reaction
97. Afterwere
withformed.
urea
After aa reaction or
reaction with Compound
thiourea
with urea
urea or by 99 was
epoxide
or thiourea
thiourea by prepared
opening,
by epoxide by
thethe treatment
correspond-
epoxide opening,
opening, the
the
of epoxy
ing ketone
derivatives
corresponding
corresponding 98with
werethiosemicarbazide.
derivatives
derivativesformed. Compound
98 were
98 were formed.
formed. The anticancer
99
Compound
Compound 99activity
was prepared
99 wasby
was of
thethese
prepared
prepared by
byderivatives
treatment was
of epoxy
the treatment
the treatment
studied
ketone
of
of epoxy
epoxy against
with
ketone
ketone the
with
withMCF-7
thiosemicarbazide. human Thebreast
thiosemicarbazide.
thiosemicarbazide. cancer
anticancer
The
The cell lineof
activity
anticancer
anticancer (Scheme
activity
activity of28)
of [61].derivatives
these derivatives
these
these was studied
derivatives was
was
against
studiedthe
studied MCF-7
against
against thehuman
the MCF-7breast
MCF-7 human
human cancer
breast
breast cell line (Scheme
cancer
cancer cell line
cell 28) [61]. 28)
line (Scheme
(Scheme 28) [61].
[61].
Scheme 28. Synthesis of oxo and thio pyrimidine derivatives 98 and 99 via epoxyde 97.
Scheme28.
Synthesis of
of oxo
oxo and
and thio
thiopyrimidine
pyrimidinederivatives
derivatives98
98and
98 and99
and 99via
99 viaepoxyde
via epoxyde97.
epoxyde 97.
97.
Modified nucleobases and nucleic acids have found many biological and pharmaceu-
ticalModified
applications.
Modified Burgulaand
Modifiednucleobases
nucleobases
nucleobases et
and
and al.nucleic
[62] have
nucleic
nucleic acids
acids
acids reported
have
havefound
have a [3+3]
found
found green
many
many
many procedure
biological
biological
biological and
and
and for the single-
pharmaceuti-
pharmaceu-
pharmaceu-
step
cal
tical
tical preparation
applications.
applications.
applications. of a
Burgulaseries
Burgula
Burgula of
et et
al. uracil
[62]
et al.
al. have
[62]
[62] and
have
have cytosine
reported
reported
reported nucleobases
a [3+3] green
aa [3+3]
[3+3] green
green100 and
procedure 101.
procedure
procedure Uracil
for the theanalogs
forsingle-step
for the single-
single-
100 preparation
step
step were
preparation synthesized
of a series
preparation ofthrough
uracil
of aa series
of series and
of uracil
of uracilthecytosine
treatment
and
and cytosine
cytosine ofnucleobases
the respective
nucleobases 100 and
nucleobases β-ketoesters
101.
100 and
100 Uracil
and 101.
101. Uracil
Uracil oranalogs
analogs β-alde-
100
analogs
hydoesters
were
100
100 were
were 102 with
synthesized
synthesized
synthesized urea,
through whereas
the
through
through thethe
treatment
the cytosine
of
treatment
treatment ofderivatives
the respective
of 101 were
β-ketoesters
the respective
the respective orobtained
β-ketoesters
β-ketoesters from
β-aldehydoesters
or
or ben-
β-alde-
β-alde-
zoylacetonitriles
102 with urea,
hydoesters
hydoesters 102
102 103urea,
whereas
with
with or
theN,N-diethylamide
urea, cytosine
whereasderivatives
whereas the cytosine
the precursors
cytosine were(Scheme
derivatives 10129).
obtained
101derivatives 101 from
were
were Abenzoylacetonitriles
Lewis acid
obtained
obtained from
fromcatalyst
ben-
ben-
(BF
103 or:EtN,N-diethylamide
O) and
zoylacetonitriles 103
zoylacetonitriles
3 2 MW103 or precursors
irradiation improved
or N,N-diethylamide (Scheme
N,N-diethylamide precursorsthe 29). A
reaction, Lewis
with
precursors (Scheme acid
higher
(Scheme 29). catalyst
yields
29). A
A Lewis (BF
and
Lewis acid :Et
lower
acid
3 O) and
reac-
catalyst
2catalyst
MW
tion
(BF33:Et
(BF irradiation
times.
:Et22O) The
O) and
and MW improved
crystal
MW irradiation the
structuresreaction,
irradiation improved of with higher yields
5-isopropyl-6-methyluracil
improved the the reaction,
reaction, with and lower
with higher and reaction
6-phenyluracil
higher yields
yields and times.
and lower The
were
lower reac-
reac-
crystal
tion structures
also times.
tion determined.
times. The of 5-isopropyl-6-methyluracil
The crystal
crystal structures of
structures and 6-phenyluracil
of 5-isopropyl-6-methyluracil
5-isopropyl-6-methyluracil and
andwere also determined.
6-phenyluracil
6-phenyluracil were
were
also determined.
also determined.
Scheme29.
Scheme 29.Green
Greensynthesis
synthesisof
ofuracil
uraciland
andcytosine
cytosineanalogs
analogs(100
(100and
and101).
101).
Scheme 29.
Scheme 29. Green
Green synthesis
synthesis of
of uracil
uracil and
and cytosine
cytosine analogs
analogs (100
(100 and
and 101).
101).
A good synthetic design was reported by Tejedor and García-Tellado [63] to obtain
pyrimidine derivatives 105 with an oxy-functionalized acetate chain at the ring. Amidines
32 with electrophilic diynes 104 interacted in two consecutive aza-Michael additions,
followed by a second domino process involving sequential [H]-shift and a [3,3]-sigmatropic
rearrangement, giving pyrimidine derivatives 105 (Scheme 30).
32 with electrophilic diynes 104 interacted in two consecutive aza-Michael additions, fol-
A good synthetic design was reported by Tejedor and García-Tellado [63] to obtain
lowed by a second domino process involving sequential [H]-shift and a [3,3]-sigmatropic
32 with electrophilic diynes 104 interacted in two consecutive aza-Michael additions, fol-
Catalysts 2023, 13, 180 13 of 24
lowed by a second domino process involving sequential [H]-shift and a [3,3]-sigmatropic
Scheme 30. Synthesis of functionalized pyrimidines from electrophilic diynes 104 and amidines
39.
Scheme 30.
30. Synthesis
Synthesis of
Scheme
Hosamani et al.ofreported
functionalized pyrimidines
functionalized pyrimidines from
the MW-assisted from electrophilic
electrophilic diynes
synthesis diynes 104
104 and
and amidines
amidines 39.
of 3-(2-(4-fluorobenzyl)-4-(sub-
39.
stituted phenyl) pyrimidin-6-yl)-2H-chromen-2-ones 108 [64]. The reactions proceeded
Hosamani et al. reported the MW-assisted synthesis of 3-(2-(4-fluorobenzyl)-4-(substituted
through a [3+3] cyclic condensation of substituted chalconated coumarins 106 with 2-(4-
Hosamani
phenyl) et al. reported the MW-assisted
pyrimidin-6-yl)-2H-chromen-2-ones 108synthesis
[64]. The of 3-(2-(4-fluorobenzyl)-4-(sub-
reactions proceeded through a
fluorophenyl) acetamidine hydrochloride 107 in DMF. Improved yields and shortened
stituted phenyl) pyrimidin-6-yl)-2H-chromen-2-ones 108
[3+3] cyclic condensation of substituted chalconated coumarins 106 with[64]. The reactions proceeded
2-(4-fluorophenyl)
reaction times, when using MW irradiation compared to conventional heating, were ob-
through a [3+3]
acetamidine cyclic condensation
hydrochloride of substituted
107 in DMF. Improvedchalconated coumarinsreaction
yields and shortened 106 withtimes,
2-(4-
served (Scheme 31). Although we do not focus on the biological activities of the com-
fluorophenyl)
when using MW acetamidine hydrochloride
irradiation compared 107 in DMF.
to conventional Improved
heating, were yields
observedand(Scheme
shortened
31).
pounds in this review, this work is of interest because it evaluates the role of the substit-
reaction times,
Although we dowhen usingonMW
not focus irradiationactivities
the biological compared to conventional
of the compounds in heating, were this
this review, ob-
uents in the pharmacological activities and it evaluates the obtained products against can-
work
servedis (Scheme
of interest31).
because it evaluates
Although we do thenot role of on
focus the the
substituents
biologicalinactivities
the pharmacological
of the com-
cer lines.
activities
pounds inand thisitreview,
evaluates the
this obtained
work products
is of interest againstitcancer
because lines.
evaluates the role of the substit-
uents in the pharmacological activities and it evaluates the obtained products against can-
cer lines.
Scheme31.
Scheme 31. MW-assisted
MW-assistedsynthesis
synthesisof
offluorinated
fluorinatedcoumarin–pyrimidine
coumarin–pyrimidinehybrid
hybridmolecules
molecules108.
108.
Very
Veryrecently,
recently,in in2022,
2022,the
theeffective
effectiveandandaccessible
accessible synthesis
synthesis ofof (E,E)-4,6-bis(styryl)-
(E,E)-4,6-bis(styryl)-
Scheme 31. MW-assisted
pyrimidines synthesis of fluorinated coumarin–pyrimidine hybrid molecules 108.
pyrimidineswaswascarried
carriedout
outwith
withTFA
TFAas asaacatalyst
catalystand
andwater
wateras asaa solvent.
solvent. The
The pyrimidine
pyrimidine
ring
ring formation was
was achieved
achievedfrom
fromacetylacetone
acetylacetoneand and urea
urea byby [3+3]
[3+3] cycloaddition.
cycloaddition. A of A
sub-
Catalysts 2023, 13, x FOR PEER REVIEW Very recently, in 2022, the effective and accessible synthesis 14
of (E,E)-4,6-bis(styryl)-24
subsequent aldol condensation with differently substituted aromatic aldehyde
sequent aldol condensation with differently substituted aromatic aldehyde gave the de- gave the
pyrimidines
desired was carried out with TFA
(E,E)-4,6-bis(styryl)-pyrimidines as a catalyst and water as a solvent. The pyrimidine
sired (E,E)-4,6-bis(styryl)-pyrimidines 110 inin
110 moderate-to-good
moderate-to-good yields
yields (Scheme32)
(Scheme 32)[65].
[65].
ring formation was achieved from acetylacetone and urea by [3+3] cycloaddition. A sub-
sequent aldol condensation with differently substituted aromatic aldehyde gave the de-
sired (E,E)-4,6-bis(styryl)-pyrimidines 110 in moderate-to-good yields (Scheme 32) [65].
Scheme 32.
Scheme 32. Synthesis of (E,E)-4,6-bis(styryl)-pyrimidines
(E,E)-4,6-bis(styryl)-pyrimidines 110.
110.
2.2.
2.2. Three-Component
Three-Component Cycloadditions
Cycloadditions
There
There is a plethora ofofthree-component
is a plethora three-componentcondensations
condensations leading
leading to to pyrimidine
pyrimidine andand
re-
related products. We start by describing an example of a [4+1+1] reaction and continue
lated products. We start by describing an example of a [4+1+1] reaction and continue with
with [3+2+1]
[3+2+1] reactions.
reactions.
2.2.1. [4+1+1] Cycloadditions

Yuan et al. [66] developed a base-promoted formal [4+1+1] annulation of aryl alde-
hyde 109, N-benzyl arylamidines 111 and DMSO to access to a series of 2,4,6-triaryl py-
rimidines 112 in moderate-to-good yields, with molecular O2 as the sole eco-friendly oxi-
Scheme 32. Synthesis of (E,E)-4,6-bis(styryl)-pyrimidines 110.
Scheme 32. Synthesis of (E,E)-4,6-bis(styryl)-pyrimidines 110.
2.2. Three-Component Cycloadditions

2.2. Three-Component Cycloadditions
There is a plethora of three-component condensations leading to pyrimidine and re-
There is a plethora of three-component condensations leading to pyrimidine and re-
Catalysts 2023, 13, 180 lated products. We start by describing an example of a [4+1+1] reaction and continue14with
of 24
lated products. We start by describing an example of a [4+1+1] reaction and continue with
[3+2+1] reactions.
[3+2+1] reactions.
2.2.1. [4+1+1]
Cycloadditions
Yuan et al. [66] developed a base-promoted formal [4+1+1] annulation of aryl alde-
Yuanetetal.
Yuan al.[66]
[66]developed
developedaabase-promoted
base-promotedformal
formal[4+1+1]
[4+1+1] annulation
annulation of aryl
aryl alde-
alde-
hyde 109, N-benzyl arylamidines 111 and DMSO to access to a series of 2,4,6-triaryl py-
hyde 109, N-benzyl arylamidines 111 and DMSO to access to a series of 2,4,6-triaryl
hyde 109, N-benzyl arylamidines 111 and DMSO to access to a series of 2,4,6-triaryl pyrim- py-
rimidines 112 in moderate-to-good yields, with molecular O2 as the sole eco-friendly oxi-
rimidines
idines 112moderate-to-good
112 in in moderate-to-good yields,
yields, withwith molecular
molecular O2 asOthe
2 as sole
the sole eco-friendly
eco-friendly oxi-
oxidant
dant (Scheme 33). It is to be noted that DMSO served as a methine source, which was
dant (Scheme
(Scheme 33). It33). It be
is to is to be noted
noted that DMSO
that DMSO servedserved as a methine
as a methine source,source,
whichwhich was
was pro-
promoted by a base rather than either a Lewis acid or electrophile. A detailed mechanism
promoted
moted by aby a base
base rather
rather than
than either
either a Lewis
a Lewis acid
acid oror electrophile.AAdetailed
electrophile. detailedmechanism
mechanism
was proposed.
wasproposed.
was proposed.
Scheme 33. Base-promoted synthesis of 2,4,6-triaryl pyrimidines 112 from aryl aldehyde 109, N-
Scheme33.33. Base-promoted
Base-promoted synthesis
synthesis of 2,4,6-triaryl pyrimidines 112 from aryl aldehyde 109, N-
Scheme
benzyl arylamidines 111 and DMSO. of 2,4,6-triaryl pyrimidines 112 from aryl aldehyde 109, N-
benzyl arylamidines 111 and DMSO.
benzyl arylamidines 111 and DMSO.
2.2.2. [3+2+1]
One of the classical multicomponent strategies for synthesizing dihydropyrimidines
Oneof
One ofthe
theclassical
classicalmulticomponent
multicomponentstrategies strategies forfor synthesizing
synthesizing dihydropyrimidines
dihydropyrimidines is
is the Biginelli three-component condensation (type [3+2+1]-A, Figure 1) of an aldehyde,
is the
the Biginelli
Biginelli three-component
three-component condensation
condensation (type(type [3+2+1]-A,
[3+2+1]-A, Figure
Figure 1)an
1) of of aldehyde,
an aldehyde, an
an α-keto ester and a urea or thiourea that gives a 3,4-dihydropyrimidin-2(1H)-(thi)one
an α-keto
α-keto esterester
and anda ureaa urea or thiourea
or thiourea that gives
that gives a 3,4-dihydropyrimidin-2(1H)-(thi)one
a 3,4-dihydropyrimidin-2(1H)-(thi)one [18].
[18]. Due to the vast information and literature on this type of multicomponent reaction
Due
[18].to
Duetheto vast
theinformation and literature
vast information on this on
and literature type thisof type
multicomponent reactionreaction
of multicomponent (MCR),
(MCR),
we will wesoon will soon provide
provide a furthera further
reviewreview
of this of this reaction.
reaction. Now, Now, we detail
we detail otherother strat-
strategies,
(MCR), we will soon provide a further review of this reaction. Now, we detail other strat-
egies,
although although
a number a number
of themof them may be considered by other authors as modifications of
egies, although a number of may
thembe considered
may be considered by other authors
by other as modifications
authors as modifications of the
of
the Biginelli
Biginelli reaction.
reaction.
the Biginelli reaction.
Thus, in
Thus, in the following,
following, we look look at otherpossibilities
possibilities withthe the [3+2+1] combination
combination
Thus, inthe the following,we we lookatatother other possibilitieswith with the[3+2+1]
[3+2+1] combination
that differ
that differ from the classical Biginelli
Biginellireaction.
reaction.In pyrimidine synthesis, thethe
in situ oxyda-
that differ from
from the classical Biginelli reaction. InInpyrimidine
pyrimidine synthesis,
synthesis, the inin situ
situ oxy-
oxyda-
tion
dationof alcohols to provide the formyl component in MCRs is a good option. Thus, a com-
tion of of alcohols
alcohols to to provide
provide thethe formyl
formyl component
component in MCRs
in MCRs is a is a good
good option.
option. Thus,Thus,
a com- a
parative study
comparative of nickel-catalyzed
study of nickel-catalyzedsyntheses
syntheses of pyrimidines
of pyrimidines via theviadehydrogenative
the dehydrogenative mul-
parative study of nickel-catalyzed syntheses of pyrimidines via the dehydrogenative mul-
ticomponent coupling
multicomponent of alcohols
coupling and and
of alcohols amidinesamidinesusingusing two typestypesof nickel complex cata-
ticomponent coupling of alcohols and amidines using two two of nickel
types of nickel complexcomplex
cata-
lysts has
catalysts been
has reported
been [67].
reported Catalyst
[67]. CatalystI dehydrogenates
I dehydrogenates alcohols via
alcohols a
viatwo-electron
a two-electron hy-
lysts has been reported [67]. Catalyst I dehydrogenates alcohols via a two-electron hy-
dride transfer
hydride transferpathway,
pathway, while in the
while presence
in the presence of II,oftheII, dehydrogenation
the dehydrogenation of alcohols pro-
of alcohols
dride transfer pathway, while in the presence of II, the dehydrogenation of alcohols pro-
ceeds viavia
proceeds a one-electron
a one-electron hydrogen
hydrogen atomatom transfer
transfer(Scheme
(Scheme 34).34).
ceeds via a one-electron hydrogen atom transfer (Scheme 34).
Scheme 34.
34. syntheses of
of pyrimidines 115
115 from alcohols
alcohols and amidines.
amidines.
Scheme 34.Nickel-catalyzed
Scheme Nickel-catalyzedsyntheses
syntheses ofpyrimidines
pyrimidines 115from
from alcoholsand
and amidines.
With the aim of obtaining 2-(N-alkylamino)pyrimidines, heterocycles widely found

in various pharmaceutically drugs, a new ruthenium-catalyzed synthesis was reported in
a [3+2+1] fashion [68]. The method consisted of a new cooperative ruthenium-complex-
catalyzed, multicomponent tandem synthesis of 2-(N-alkylamino)pyrimidines directly
from guanidine salt and alcohols. The reactions proceeded through the dehydrogenation
of alcohols, followed by C–C coupling and sequential C–N coupling with guanidine and
primary alcohol, with the elimination of three equivalents of hydrogen gas. Several Ru
catalysts were tested, Ru catalyst I (2 mol %) being that which provided the best results
(Scheme 35). The viability of this method was demonstrated through the preparative-scale
synthesis of a few products. Mechanistic studies and DFT calculations were subsequently
performed (Scheme 35) [68].
of alcohols,
of alcohols,
from followed
guanidine by alcohols.
salt and
followed by C–C coupling
C–C coupling and sequential
sequential
The reactions
and C–Nthrough
proceeded
C–N coupling
coupling with
thewith guanidine and
dehydrogenation
guanidine and
primary
of alcohol,
alcohols, followedwithby the
C–C elimination
coupling of
and three equivalents
sequential C–N of hydrogen
coupling with
primary alcohol, with the elimination of three equivalents of hydrogen gas. Several Ru gas. Several
guanidine and Ru
primary
catalysts alcohol,
catalysts were with
were tested,
tested, Ruthe elimination
Ru catalyst
catalyst II (2 of
(2 molthree
mol %) equivalents
%) being
being that of
that which hydrogen
which provided gas.
provided the Several
the best Ru
best results
results
catalysts
(Scheme were
(Scheme 35).
35). tested,
The
The Ru catalyst
viability
viability of this
of I (2 molwas
this method
method %) demonstrated
was being that which
demonstrated provided
through
through the best results
the preparative-scale
the preparative-scale
(Scheme
synthesis35).
synthesis of aaThe
of fewviability
few products.
products. of this method was
Mechanistic
Mechanistic demonstrated
studies
studies and DFT
and through thewere
DFT calculations
calculations preparative-scale
were subsequently
subsequently
Catalysts 2023, 13, 180 15 of 24
synthesis
performedof(Scheme
performed a few products.
(Scheme [68].Mechanistic studies and DFT calculations were subsequently
35) [68].
35)
performed (Scheme 35) [68].
Scheme 35.
Synthesis of
of 2-(N-alkylamino)pyrimidines
2-(N-alkylamino)pyrimidines 119
119 directly
directly from
from guanidine
guanidine salt
salt and
and alcohols.
alcohols.
Scheme 35.
Synthesis of
of 2-(N-alkylamino)pyrimidines
2-(N-alkylamino)pyrimidines119
119directly
directlyfrom
fromguanidine
guanidinesalt
saltand
andalcohols.
alcohols.
A series
A series of of [3+2+1]
[3+2+1] three-component
three-component annulations
annulations of of amidines
amidines 39, 39, ketones
ketones and
and N,N-
N,N-
AA series
series ofof [3+2+1]
dimethylaminoethanol
dimethylaminoethanol [3+2+1] 120
three-component
three-component
120 to obtain
to annulations
annulations
obtain pyrimidine
pyrimidine ofofamidines
amidines
derivatives
derivatives 121 was
121 39, ketones
ketonesand
39,reported.
was reported. andN,N-
This
This N,N-
pro-
pro-
ductive and eco-friendly 120
120 to
to obtain
obtain
method pyrimidine
pyrimidine
showed the derivatives
derivatives
oxidation of 121
121 was
wasreported.
reported.This
This
N,N-dimethylaminoethanol pro-
pro-
ductive and eco-friendly method showed the oxidation of N,N-dimethylaminoethanol
ductive
ductive
throughandand eco-friendly
C(speco-friendly
)−H activation
33)−H activationmethod showed
showed
to provide
provide onethe
the oxidation
donorof
oxidation
carbon toN,N-dimethylaminoethanol
oftoN,N-dimethylaminoethanol
be the
the principal
principal action.
action. It
It isis
through C(sp 3
to one carbon donor be
through
through C(sp
C(sp 3
worth mentioning, ) −
)−H
mentioning, in Hactivation
activation
in this to
to provide
provide
this strategy,
strategy, the one
one carbon
the goodcarbon donor
donor
good tolerance
tolerance tototobebethe
to many
manytheprincipal
principalaction.
important action.ItItisis
functional
worth important functional
worthmentioning,
worth mentioning,ininthis this strategy,
strategy, the the good tolerance to many important functional
groups in
groups in air,
air, with
with improvements
improvements to good
to the
tolerance
the existing
existing to many
methods
methods ofimportant
of 4-aliphatic
4-aliphatic
functional groups
pyrimidine
pyrimidine for-
for-
groups
in air, in air,
with with improvements
improvements to the to the existing
existing methods methods
of of 4-aliphatic
4-aliphatic pyrimidine
pyrimidine for-
formation
mation (Scheme
mation (Scheme 36) 36) [69].
[69].
mation (Scheme
(Scheme 36) [69].36) [69].
Scheme 36.
Scheme 36. Copper-mediated synthesis
synthesis of
of 4-aliphatic
4-aliphatic pyrimidines
pyrimidines 121
121 from
fromketones,
from ketones,amino
ketones, aminoalcohol
amino alcohol
alcohol
Scheme 36. Copper-mediated
Scheme 36. Copper-mediated synthesis of 4-aliphatic pyrimidines 121 from ketones, amino alcohol
120and
120
120 andamidines
and amidines39.
amidines 39.
39.
120 and amidines 39.
2.2.3.
2.2.3. [2+2+2]
2.2.3. Cycloadditions
[2+2+2] Cycloadditions
[2+2+2] Cycloadditions
2.2.3. [2+2+2]
A
AA copper
copper acetate-catalyzed
copper tandem
acetate-catalyzed tandem
acetate-catalyzed Blaise/Pinner-type
tandemBlaise/Pinner-type
tandem reaction with
Blaise/Pinner-typereaction
Blaise/Pinner-type reaction with nitriles
nitriles and
anda aaa
nitrilesand
and
A copper acetate-catalyzed with nitriles
Reformatsky
Reformatsky reagent
Reformatsky reagent
reagent was
reagentwas
was performed
wasperformed
performedto
performed to
to obtain
toobtain
obtain pyrimidinones
obtainpyrimidinones 125.
pyrimidinones125.
pyrimidinones Nitrile
125.Nitrile
125. 122
Nitrile122
Nitrile reacted
122reacted
122 reacted
reacted with
with
with
Reformatsky with
Reformatsky
Reformatsky
Reformatsky reagent
reagent
reagent 123
123
123 to
to
to form
form
form aaa Blaise
Blaise
Blaise intermediary
intermediary
intermediary 124,
124,
124, and
and
and then,
then,
then, aaa second
second
second nitrile
nitrile
nitrile 122
122
122
Reformatsky reagent 123 to form a Blaise intermediary 124, and then, a second nitrile 122
was
was
was added
added
added to
to
to complete
complete
complete the
the
the targeted
targeted
targeted ring
ring
ring (Scheme
(Scheme
(Scheme 37)
37)
37) [70].
[70].
[70].
was added to complete the targeted ring (Scheme 37) [70].
Scheme
Scheme 37. Zinc-mediated
Scheme 37.
37. Zinc-mediatedsynthesis
Zinc-mediated
Zinc-mediated synthesis
synthesis
synthesis of
ofof
of pyrimidinones
pyrimidinones 125
pyrimidinones
pyrimidinones 125
125
125 from
from
from
from nitriles
nitriles 122
nitriles
nitriles 122
and
122
122 and
and
and ethyl
ethyl
ethyl
ethyl bromoacetates
bromoacetates 123.
bromoacetates
bromoacetates
123.
123.
The multicomponent condensation [2+2+2] (C-C+N-C+N-C) of oxygenated arylacetic
acids with electron-donating trimethoxybenzene provided o-diaryl pyrimidines in acetoni-
trile at 60 ◦ C. On the other hand, electron-withdrawing nitroarylaldehydes followed the
annulation route (C-C-C-C+C+N) to give 1-aryl isoquinolinones. The uses of various metal
triflates and reaction conditions were investigated in these one-pot reactions, highlighting
bismuth triflate Bi(OTf)3 , which acted in mild conditions in open vessels (Scheme 38). The
reaction mechanisms were proposed [71].
The
acidsThewithmulticomponent
multicomponent
electron-donating condensation
condensation [2+2+2] (C-C+N-C+N-C)
[2+2+2]
trimethoxybenzene (C-C+N-C+N-C) of oxygenated
of
provided o-diaryl oxygenated
pyrimidinesarylacetic
arylacetic
in ace-
acids with
acids with
tonitrile electron-donating
electron-donating
at 60 trimethoxybenzene
°C. On the othertrimethoxybenzene provided o-diaryl pyrimidines
provided nitroarylaldehydes
hand, electron-withdrawing o-diaryl pyrimidines in ace-
in ace-
followed
tonitrile
tonitrile
the at 60 °C.
at 60 °C.
annulation On the other
On (C-C-C-C+C+N)
route hand,
the other hand, to electron-withdrawing
electron-withdrawing nitroarylaldehydes
nitroarylaldehydes
give 1-aryl isoquinolinones. followed
The uses offollowed
various
the
the annulation
annulation route
route (C-C-C-C+C+N)
(C-C-C-C+C+N) to
to give
give 1-aryl
1-aryl isoquinolinones.
isoquinolinones. The
The
metal triflates and reaction conditions were investigated in these one-pot reactions, uses
uses of
of various
various
high-
metal triflates
metal
lightingtriflates
bismuth and
and reaction
reaction
triflate conditions
conditions
Bi(OTf) 3, which
were
were investigated
investigated
acted in these
in thesein
in mild conditions one-pot
one-pot reactions,
reactions,
open vessels high-
high-
(Scheme
Catalysts 2023, 13, 180 lighting bismuth triflate Bi(OTf) 3, which acted in mild conditions in open vessels (Scheme16 of 24
lighting
38). bismuth mechanisms
The reaction triflate Bi(OTf) 3, which
were acted[71].
proposed in mild conditions in open vessels (Scheme
38). The
38). The reaction
reaction mechanisms
mechanisms were were proposed
proposed [71].
[71].
Scheme 38. Bismuth-mediated synthesis of pyrimidinones 128 from arylacetic acids 126 with tri-
Scheme 38.
38. Bismuth-mediated
Bismuth-mediated
methoxybenzene
Scheme 127. synthesis of
synthesis of pyrimidinones 128
128 from
from arylacetic
arylacetic acids
acids 126
126 with
with tri-
tri-
Scheme Bismuth-mediated synthesis ofpyrimidinones
pyrimidinones 128 from arylacetic acids 126 with
methoxybenzene 127.
methoxybenzene 127.
trimethoxybenzene 127.
Gold complexes have been used to catalyze different cycloadditions to give pyrim-
idines. Gold complexes
Karad
Gold have
and Liuhave
complexes reportedbeenthe
been used
used to catalyze
catalyze different
intermolecular
to different cycloadditions
[2+2+2] cycloaddition
cycloadditions to
ofto give pyrim-
give pyrim-
ynamides 129
idines.
idines.
idines.
(R 2 Karad
Karad
= Ms, and Liu
and Liu
Ts) with reported
reported
reported
nitriles the
the
to give intermolecular
the4-aminopyrimidines
intermolecular [2+2+2]
intermolecular [2+2+2]
130cycloaddition of ynamides
of ynamides
[72]. The reaction 129
129
129
conditions
(R2
were
2
2 = Ms, Ts) with nitriles to give 4-aminopyrimidines 130 [72]. The reaction conditions
(R = studied
(R Ms, Ts) with
with nitriles
nitriles
in detail, to give
to give 4-aminopyrimidines
indicating 4-aminopyrimidines
that the use of Ph3PAuNTf 130 [72].
130 [72]. The
2 (5 The
mol%)reaction
reaction
in DCEconditions
conditions
at 75 °C
werethe
were studied
studied indetail,
in detail, indicating
indicating thatthe
that theuseuse ofPh
of Ph 3PAuNTf2 (5 mol%) in DCE at 75 ◦°C
were
was studied in detail,
best option indicating
to obtain that
the products the use
in of
good Ph 33PAuNTf
PAuNTf
yields 22 (5 mol%)
(Scheme 39). in DCE at 75 C
75 °C
wasthe
was
was thebest
the bestoption
best optionto
option toobtain
to obtainthe
obtain theproducts
the productsin
products ingood
in goodyields
good yields(Scheme
yields (Scheme39).
(Scheme 39).
39).
Scheme 39. Gold-complex-mediated synthesis of 4-aminopyrimidines 130 by [2+2+2] cycloaddition

Scheme
Scheme
of
Scheme 39.129
39.
alkynes
39. Gold-complex-mediated
Gold-complex-mediated
with nitriles 122.
Gold-complex-mediated synthesisof
synthesis
synthesis of4-aminopyrimidines
of 4-aminopyrimidines130
4-aminopyrimidines 130by
130 by[2+2+2]
by [2+2+2] cycloaddition
cycloaddition
of
of alkynes
alkynes 129
129 with
with nitriles
nitriles 122.
122.
of alkynes 129 with nitriles 122.
A zirconium-mediated reaction of silyl-butadiynes with two molecules of aryl nitriles
AA zirconium-mediated reaction of silyl-butadiynes with
withtwo molecules
moleculesof aryl
A zirconium-mediated
zirconium-mediated
was described, which provided reaction
reaction
rapid ofaccess
of silyl-butadiynes
silyl-butadiynes with
to polysubstituted two
two molecules
pyrimidines of
of innitriles
aryl
aryl
132 nitriles
nitriles
a regi-
was
was described,
described,
was described, which
which provided rapid
rapid access
access to
to polysubstituted
polysubstituted pyrimidines
pyrimidines 132
132 in a re-
in aa regi-
in regi-
oselective manner andprovided
in a one-potrapidfashion.
access toOnpolysubstituted
the other hand,pyrimidines
employing 132aliphatic ni-
gioselective
oselective mannerand
manner andinina aone-pot
one-pot fashion.
fashion. On On
the the other
other hand,
hand, employing
employing aliphatic
aliphatic ni-
oselective
triles manner
resulted in theand in a one-pot
coupling of only fashion. On the
one nitrile, other to
leading hand, employingofaliphatic
the formation enynyl ke-ni-
nitriles resulted
triles resulted
resulted in the
in the coupling
the coupling
coupling of only
of only
only one nitrile,
oneextended leading
nitrile, leading
leading to
to the the formation
the formation
formation of of
of enynylenynyl
enynyl ke-
triles
tones in
after hydrolysis. of
The reaction wasone nitrile, to
to a zirconocene–monoyne complex,ke-
ketones
tones afterhydrolysis.
after hydrolysis.TheThereaction
reactionwaswasextended
extended to to a zirconocene–monoyne complex,
tones after
which hydrolysis.
underwent Thereactions
similar reactionwithwas nitriles
extended to a zirconocene–monoyne
to form complex,
highly substituted pyrimidines
which
which underwent
underwent similar
similar reactions
reactions with
with nitriles
nitriles to
to form
formhighly
highlysubstituted
substituted pyrimidines
pyrimidines
which
(Scheme underwent
40) [73]. similar reactions with nitriles to form highly substituted pyrimidines
(Scheme
(Scheme40) 40)[73].
[73].
(Scheme 40) [73].
Scheme 40.40.Zirconium-mediated
Zirconium-mediated synthesis
synthesis of polysubstituted
of polysubstituted pyrimidines
pyrimidines 132silyl-butadiynes
132 with with silyl-bu-
Scheme or
tadiynes
Scheme 40.other
40. Zirconium-mediated
alkynes 131 and
with two
polysubstituted
molecules
of of aryl pyrimidines
nitriles 122.
pyrimidines 132 with
132 with silyl-bu-
silyl-bu-
or other alkynes 131 and with two molecules of aryl nitriles 122.
tadiynes or other alkynes 131 and with two molecules of aryl nitriles 122.
tadiynes or other alkynes 131 and with two molecules of aryl nitriles 122.
In a similar strategy [2+2+2], Low et al. reported the synthesis and reactivity of Zr
complexes Zr(IV)L(THF)3 , which display a two-electron-reduced anthracene moiety. Mech-
anistic studies suggest that selectivity to form pyrimidines 133 originates from the preferred
formation of an azazirconacyclopentadiene intermediate, which reacts preferentially with
nitriles over alkynes (Scheme 41) [74]. Previously, Sato et al. reported a similar synthesis
catalyzed by NbCl5 [75].
In
In aa similar
similar strategy
strategy [2+2+2],
[2+2+2], Low
Low et
et al.
al. reported
reported the
the synthesis
synthesis and
and reactivity
reactivity ofof Zr
Zr
complexes
In a Zr(IV)L(THF)
similar strategy , which
[2+2+2], display
Low et a
al. two-electron-reduced
reported the synthesis
complexes Zr(IV)L(THF)3, which display a two-electron-reduced anthracene moiety.
3 anthracene
and moiety.
reactivity of Zr
Mechanistic
complexes studies
studies suggest
MechanisticZr(IV)L(THF) that
that selectivity
3, which
suggest display ato
selectivity form
form pyrimidines
pyrimidines 133
totwo-electron-reduced originates
originates from
133 anthracene moiety.
from the
the
preferred
preferred formation
Mechanistic of
of an
an azazirconacyclopentadiene
studies suggest
formation intermediate,
that selectivity to form pyrimidines
azazirconacyclopentadiene 133which
intermediate, reacts
originates
which prefer-
from
reacts prefer-the
entially
entially with
preferred nitriles
formation
with over
nitriles of analkynes
over (Scheme
(Scheme 41)
41) [74].
[74]. Previously,
azazirconacyclopentadiene
alkynes Sato
Sato et
intermediate,
Previously, al.
al. reported
which
et aa sim-
reacts prefer-
reported sim-
Catalysts 2023, 13, 180 17 of 24
ilar synthesis
entially with catalyzed
nitriles by
over NbCl
alkynes
ilar synthesis catalyzed by NbCl5 [75].5 [75].
(Scheme 41) [74]. Previously, Sato et al. reported a sim-
ilar synthesis catalyzed by NbCl5 [75].
Scheme
Scheme 41.
synthesis of
of polysubstituted
pyrimidines 133
133 with
with alkynes
alkynes 131
131 and
and
two
two molecules
Scheme
molecules
Scheme of
of nitriles
nitriles 122.
122.
Zirconium-mediated synthesis of
pyrimidines133
133 with
with alkynes
alkynes 131
131 and
and
two molecules
two molecules of
of nitriles
nitriles 122.
122.
In
In the
the following
following synthesis
synthesis ofof diversely
diversely functionalized
functionalized pyrimidines
pyrimidines with
with aa [2+2+2]
[2+2+2]
strategy,
In the
strategy, the
the cyclization
following
following
the of
of ketones
synthesis
synthesis
cyclization of
ketones with
with nitriles
of diversely
diversely was
was carried
functionalized
functionalized
nitriles out
out under
under basic
pyrimidines
carriedpyrimidines withconditions
with
basic aa [2+2+2]
[2+2+2]
conditions
with
with aa copper
strategy,
strategy, the
copper catalyst.
catalyst. The
thecyclization
cyclization ofof
The reaction
ketones
ketones
reaction proceeded
with nitriles
with via
was
nitriles
proceeded aa pathway
carried
viawas involving
out under
carried
pathway basicthe
out under
involving nitriles
conditions
basic
the acting
with
conditions
nitriles acting
awith
ascopper
a catalyst.
electrophiles,
copper The
with
catalyst. reaction
consecutive
The proceeded
C–C
reaction bondsvia
proceeded a
andpathway
viatwo
a C–N involving
pathway bond the nitriles
formations.
involving
as electrophiles, with consecutive C–C bonds and two C–N bond formations. The method the The acting
nitrilesmethodas
acting
electrophiles,
shows
as aa broad
electrophiles,
shows with consecutive
broad substrate scope
scope and
with consecutive
substrate C–C
andC–C bonds
aa good
bonds
good and two
tolerance
and two
tolerance C–N
for
forC–N bond
many
many formations.
important
bond The
functional
formations.
important method
groups
The method
functional groups
shows
(Scheme
shows
(Scheme a broad
42) substrate
substrate scope
42) [76].
broad [76]. scope and
and a good tolerance for many important functional groups
(Scheme
(Scheme 42) 42) [76].
[76].
Scheme 42.
Scheme 42. Copper-catalyzed
42. Copper-catalyzed synthesis
Copper-catalyzed synthesis of
synthesis of pyrimidines
of pyrimidines 134
pyrimidines 134 from
134from ketones
fromketones and
ketonesand nitriles
andnitriles 122.
nitriles122.
122.
Scheme
Scheme 42. Copper-catalyzed synthesis of pyrimidines 134 from ketones and nitriles 122.
Babaoglu
Babaogluetet
Babaoglu al.
etal. described
describeda aasequential
al.described sequential
sequential three-component,
three-component,
three-component, one-pot
one-pot
one-pot reaction
reaction
reaction sequence
sequence
sequence for
for the formation
Babaoglu
for formation
the et
the formation al.of 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates
described a sequential three-component, one-pot following
reaction
of 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates
of 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates following a [2+2+2]a
sequence
following a
[2+2+2]
for the strategy
[2+2+2]
strategy (Scheme(Scheme
formation
strategy of[77].
(Scheme
43) 43)
43) [77].
2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates
[77]. following a
[2+2+2] strategy (Scheme 43) [77].
Scheme 43. Indium-mediated

Scheme 43.
Scheme 43. Indium-mediatedBlaise-type
Indium-mediated Blaise-typesynthesis
Blaise-type synthesisofof
synthesis ofpyrimidines
pyrimidines
pyrimidines138 viavia
138
138 thethe
via reaction
the of bromoma-
reaction
reaction of
of bromo-
bromo-
malonates
lonates
Scheme 135 135
with
43.135
malonates with nitriles
nitriles 136
136 136
Indium-mediated
with nitriles and isocyanates
andBlaise-type
isocyanates
and 137. of pyrimidines 138 via the reaction of bromo-
137.137.
synthesis
isocyanates
malonates 135 with nitriles 136 and isocyanates 137.
Jadah
Jadah and
Jadah and Singh
and Singh planned
Singh planned an
planned anoxidative
an oxidativeannulation
oxidative annulationpromoted
annulation promotedby
promoted byKK
by K2S S2 22O
22S O888,,, involving
O involving
involving
anilines,
anilines,
Jadah
anilines, aryl
aryl ketones
and
aryl Singhand
ketones
ketones and DMSO
DMSO
planned
and DMSO anasasaa
amethine
methine
oxidative
as methine (=CH-)
(=CH-)equivalent.
annulation
(=CH-) promotedInby
equivalent.
equivalent. Inthe
In K2process,
the
the process,
Sprocess,
2O8, involvingaa asulfe-
sul-
sul-
nium
fenium ion
anilines, was
ion
aryl formed.
was formed.
ketones This
and methodology
This
DMSOmethodology
as a was
methineapplied
was to
applied
(=CH-) the
tosynthesis
the of
synthesis
equivalent. In 4-arylpyrimidines
the
fenium ion was formed. This methodology was applied to the synthesis of 4-arylpyrim- of 4-arylpyrim-
process, a sul-
139 from
idines
fenium
idines aryl
139
ion
139 ketones,
from
was
from aryl
formed.viaThis
the activation
aryl ketones,
ketones, via
via the
methodology of acetophenone–formamide
the activation
was of
activation of conjugates
acetophenone–formamide
applied to the synthesis
acetophenone–formamide 141. The
conjugates
of 4-arylpyrim-
conjugates
proposed
141.
141. The
idines
The 139mechanism
proposed
from aryl
proposed is depicted
mechanism
ketones,
mechanism is in
is
via Scheme
depicted
the in44Scheme
in
activation
depicted [78]. 44
44 [78].
of acetophenone–formamide
Scheme [78]. conjugates
141. The proposed mechanism is depicted in Scheme 44 [78].
Scheme 44.
Synthesis of
of pyrimidines
pyrimidines 139
139 and
and proposed
proposed mechanism
mechanismfrom
fromaryl
arylketones
ketones140.
140.
2.3. Four-Component Cycloadditions

A regioselective, iridium-catalyzed [3+1+1+1] synthesis of alkyl or aryl pyrimidines
142 from amidines and up to three (different) alcohols was carried out. The reaction pro-
ceeded via a sequence of condensation and dehydrogenation steps, which gave rise to
Catalysts 2023, 13, 180 Scheme 44. Synthesis of pyrimidines 139 and proposed mechanism from aryl ketones 140. 18 of 24
Scheme 44. Synthesis of pyrimidines 139 and proposed mechanism from aryl ketones 140.
A regioselective,
2.3. Four-Component iridium-catalyzed [3+1+1+1] synthesis of alkyl or aryl pyrimidines
Cycloadditions
A regioselective, iridium-catalyzed [3+1+1+1] synthesis of alkyl or aryl pyrimidines
142 from amidines and up to three (different) alcohols was carried out. The reaction pro-
A regioselective,
142 from amidines and iridium-catalyzed
up to three (different)[3+1+1+1] synthesis
alcohols of alkyl
was carried or The
out. aryl reaction
pyrimidines pro-
ceeded via a sequence of condensation and dehydrogenation steps, which gave rise to
142 fromvia
ceeded amidines
a sequence andofupcondensation
to three (different) alcohols was carried
and dehydrogenation out. The
steps, which gave reaction
rise to
selective C–C and C–N bond formations. PN5P–Ir–pincer complexes (cat. [Ir]) efficiently
proceeded
selective C–Cvia and
a sequence
C–N bond of condensation and dehydrogenation
formations. PN5P–Ir–pincer steps,(cat.
complexes which[Ir])gave rise to
efficiently
catalyzed the regioselective process. A total of thirty-eight different pyrimidines were syn-
selective C–C and C–N bond formations. PN5P–Ir–pincer complexes (cat.
catalyzed the regioselective process. A total of thirty-eight different pyrimidines were syn- [Ir]) efficiently
thesized in isolated yields of up to 93% (Scheme 45). The authors pointed out that the
catalyzed
thesized inthe regioselective
isolated yields ofprocess.
up to 93%A total of thirty-eight
(Scheme different
45). The authors pyrimidines
pointed out that were
the
combinationinofisolated
synthesized this novel protocol with established methods for converting alcohols to
combination of this novel protocol with established methods for converting alcoholsthe
yields of up to 93% (Scheme 45). The authors pointed out that to
amidines
combination could allow
of this the
novel selective assembly of pyrimidines from four alcohol building
amidines could allow the protocol
selective with
assemblyestablished methodsfrom
of pyrimidines for converting
four alcohol alcohols
buildingto
blocks
amidines and two equivalents of ammonia [79]. Later, a similar approximation using an Mn
blocks andcould allow the selective
two equivalents of ammoniaassembly of pyrimidines
[79]. Later, from four alcohol
a similar approximation usingbuilding
an Mn
complex
blocks andstabilized
two by a PN5P–pincer
equivalents of ammonia ligand
[79]. (cat. a[Mn])
Later, as approximation
similar a catalyst gaveusing pyrimidines
an Mn
complex stabilized by a PN5P–pincer ligand (cat. [Mn]) as a catalyst gave pyrimidines
from amidines
complex and by
stabilized up atoPN5P–pincer
three (different) alcohols.
ligand (cat. The
[Mn]) consecutive
as a four-component
catalyst gave pyrimidines reac-
from amidines and up to three (different) alcohols. The consecutive four-component reac-
tion combines
from amidinesthe the
and concept
up to of of borrowing
three (different)hydrogen
alcohols.or hydrogen auto transfer
The consecutive with dehy-
four-component
tion combines concept borrowing hydrogen or hydrogen auto transfer with dehy-
drogenation–condensation
reaction combines the concept to permit selective
of borrowing C–N and C–C bond formation, as in the
drogenation–condensation to permit selectivehydrogen
C–N andor hydrogen
C–C auto transfer
bond formation, as inwith
the
previous work (Scheme 45) [80].
dehydrogenation–condensation
previous work (Scheme 45) [80].to permit selective C–N and C–C bond formation, as in the
previous work (Scheme 45) [80].
Scheme 45. Iridium- or manganese-mediated four-component synthesis of pyrimidines 142 from

Scheme
Scheme 45.
amidines45.
andIridium-
Iridium- or manganese-mediated
or
alcohols. manganese-mediated four-component
four-component synthesis
synthesis of
of pyrimidines
pyrimidines 142
142 from
from
amidines and
amidines and alcohols.
alcohols.
Using β-cyclodextrin (β-CD) as a catalyst, pyrimidine derivatives were synthesized
β-cyclodextrin (β-CD) as a catalyst, pyrimidine derivatives were synthesized
synthesized
fromUsing β-cyclodextrin
a variety of substituted phenyl and heterocyclic aldehydes in aqueous medium. The
from aa variety
from variety of
of substituted
substituted phenyl
phenyl and
and heterocyclic
heterocyclic aldehydes
aldehydes in in aqueous
aqueous medium.
medium. TheThe
advantage of this [3+1+1+1] method is that β-CD is a recyclable, inexpensive, economically
advantage of
advantage of this
this [3+1+1+1]
[3+1+1+1] method is that β- CD is
β-CD isaarecyclable,
recyclable, inexpensive,
inexpensive, economically
viable, non-toxic and readily available material. Thus, the reaction of a series of aromatic
viable, non-toxic
viable, non-toxic and
and readily
readily available
available material.
material. Thus, the reaction of a series of aromatic
aldehydes with ammonium acetate and 1,3-diketones afforded a series of pyrimidine de-
aldehydes with
with ammonium
ammoniumacetate
acetateand
and1,3-diketones
1,3-diketones afforded
afforded a series
a series of pyrimidine
of pyrimidine de-
rivatives 143. The method worked well with both electron-withdrawing and electron-re-
derivatives
rivatives 143.143.
TheThe method
method worked
worked well
well with
with both
both electron-withdrawing
electron-withdrawing andand electron-
electron-re-
leasing substituents in the aromatic groups, giving pyrimidines 143 in good-to-excellent
releasing substituentsininthe
leasing substituents thearomatic
aromaticgroups,
groups,giving
giving pyrimidines
pyrimidines 143 in good-to-excellent
good-to-excellent
yields (Scheme 46 [81].
yields
yields (Scheme
(Scheme 46 46 [81].
[81].
Scheme 46. β-cyclodextrin (β-CD)-catalyzed synthesis of pyrimidine derivatives 143 from a variety
of substituted phenyl and heterocyclic aldehydes in aqueous medium.
2,4,6-Triarylpyrimidines 144 were synthesized via a simple, one-pot, four-component

[2+2+1+1] annulation among aryl methyl ketones, benzaldehydes, aromatic nitriles and hy-
droxylamine under microwave irradiation and solvent-free conditions in good-to-excellent
yields (Scheme 47) [82].
of substituted phenyl and heterocyclic aldehydes in aqueous medium.
2,4,6-Triarylpyrimidines
of substituted 144 were
phenyl and heterocyclic synthesized
aldehydes via amedium.
in aqueous simple, one-pot, four-component
[2+2+1+1] annulation among aryl methyl ketones, benzaldehydes, aromatic nitriles and
2,4,6-Triarylpyrimidines 144 were synthesized via a simple, one-pot, four-component
2,4,6-Triarylpyrimidines
hydroxylamine 144 were
under microwave synthesized
irradiation via a simple,conditions
and solvent-free one-pot, four-component
in good-to-ex-
[2+2+1+1] annulation among aryl methyl ketones, benzaldehydes, aromatic nitriles and
[2+2+1+1] annulation among aryl
cellent yields (Scheme 47) [82]. methyl ketones, benzaldehydes, aromatic nitriles and
Catalysts 2023, 13, 180 hydroxylamine under microwave irradiation and solvent-free conditions in good-to-ex- 19 of 24
hydroxylamine under microwave irradiation and solvent-free conditions in good-to-ex-
cellent yields (Scheme 47) [82].
cellent yields (Scheme 47) [82].
Scheme 47. Synthesis of 2,4,6-triarylpyrimidines 144 by [2+2+1+1] annulation from aryl methyl ke-
tones, benzaldehydes, aromatic nitriles and hydroxylamine under MW irradiation.
Scheme 47. Synthesis of 2,4,6-triarylpyrimidines 144 by [2+2+1+1] annulation from aryl methyl ke-
Scheme 47.
Synthesis of
of 2,4,6-triarylpyrimidines
2,4,6-triarylpyrimidines 144
144by
by[2+2+1+1] annulation
[2+2+1+1] from
annulation arylaryl
from methyl ke-
methyl
tones, benzaldehydes, aromatic nitriles and hydroxylamine under MW irradiation.
tones,Guo
ketones, et al. [83] designed
benzaldehydes,
benzaldehydes,aromatic an effective
aromaticnitriles and
nitriles four-component
andhydroxylamine
hydroxylamine underreaction
underMW methodology for the
MWirradiation.
irradiation.
synthesis of pyrimidine carboxamides 145 from three different starting compounds:
Guo et al. [83] designed an effective four-component reaction methodology for the
Guoetetstyrene
Guo
amidines, al.[83]
al. [83]designed
designed
and anan effective
effective four-component
four-component
N,N-dimethylformamide reaction
reaction
(DMF). methodology
methodology
Regarding forsyn-
for the
this Pd-catalyzedthe
synthesis of pyrimidine carboxamides 145 from three different starting compounds:
synthesis
thesis of of pyrimidine
pyrimidine carboxamides
carboxamides 145 from145 from
three three
different different
starting
oxidative process, the versatility of DMF as a dual synthon ought to be mentioned, starting
compounds: compounds:
amidines,
amidines, styrene and N,N-dimethylformamide (DMF). Regarding this Pd-catalyzed
amidines,
styrene
providing styrene and N,N-dimethylformamide
N,N-dimethylformamide
andboth a one-carbon atom and (DMF).amide (DMF).
Regarding
synthons. thisRegarding
rolesthis
Pd-catalyzed
These Pd-catalyzed
oxidative
were provenpro-by
oxidative process, the versatility of DMF as a dual synthon ought to be mentioned,
oxidative
cess, the
isotope process,
versatility
labeling the versatility
of DMF
experiments, as a of showed
dual
which DMF asthe
synthon a dual
ought synthon
to be
usefulness ought
mentioned,
of this to be from
mentioned,
providing
reaction both
easily
providing both a one-carbon atom and amide synthons. These roles were proven by
aavailable
one-carbon
providing atom
both
starting and amide
amaterials
one-carbon synthons.
atom
(Scheme and[83].
48) These synthons.
amide roles wereTheseproven by isotope
roles labeling
were proven by
isotope labeling experiments, which showed the usefulness of this reaction from easily
experiments,
isotope labelingwhich showed the
experiments, usefulness
which showed of this reaction from
the usefulness easily
of this available
reaction fromstarting
easily
available (Scheme
materials starting materials
48) [83]. (Scheme 48) [83].
available starting materials (Scheme 48) [83].
Scheme 48. Pd-catalyzed synthesis of pyrimidine carboxamides 145 from amidines, styrene and
N,N-dimethylformamide (DMF).
Scheme 48.
Scheme 48. Pd-catalyzed
Pd-catalyzed synthesis
synthesis of
of pyrimidine
pyrimidine carboxamides
carboxamides 145
145 from
from amidines,
amidines, styrene
styrene and
and
Scheme 48. Pd-catalyzed synthesis of pyrimidine carboxamides 145 from amidines, styrene and
N,N-dimethylformamide(DMF).
N,N-dimethylformamide (DMF).
2.4. Pseudo Five--Component-
N,N-dimethylformamide (DMF).Cycloadditions
2.4.
2.4. Pseudo
Pseudo Five-Component
Five--Component- Cycloadditions
Cycloadditions
2.4. Pseudo Five--Component-
[2+1+1+1+1]
[2+1+1+1+1] Cycloadditions Cycloadditions
Cycloadditions
Ding et
[2+1+1+1+1]
Ding et al.
al. reported
reportedaa[C-C+C+N+C+N]
Cycloadditions [C-C+C+N+C+N] multicomponent cyclocondensation between
multicomponent cyclocondensation between
[2+1+1+1+1]
methyl aryl Cycloadditions
ketone, two equivalents of aromatic aldehyde and two of ammonium acetate
methyl aryletketone,
Ding two equivalents
al. reported of aromatic
a [C-C+C+N+C+N] aldehyde and two
multicomponent of ammonium acetate
cyclocondensation betweento
to give
give Ding et al.
pyrimidines
pyrimidines reported
146.146.
Thata [C-C+C+N+C+N]
That
is toissay,
to five multicomponent
say, components
five componentswere cyclocondensation
were involved
involved in the in the
ring between
ring for-
formation,
methyl aryl ketone, two equivalents of aromatic aldehyde and two of ammonium acetate
methyl
but witharyl
mation, but ketone,
onlywith
threeonlytwo equivalents
three
different differentof
molecules. aromatic
molecules.
Thus, aldehyde
Thus, the andittwo
authors of ammonium
called acetate
itfive-component
a pseudo five-
to give pyrimidines 146. That is to say, fivethe authors
components called
were ainvolved
pseudo in the ring for-
to give
component
reaction. pyrimidines
reaction.
Thewith
process 146.
The That
processis to
was say, five
catalyzed components
by triflic were
acid involved
(Scheme 49) in the
[84]. ring for-
mation, but onlywas catalyzed
three differentbymolecules.
triflic acidThus,
(Scheme 49) [84]. called it a pseudo five-
the authors
mation, but with only three different molecules. Thus, the authors called it a pseudo five-
component reaction. The process was catalyzed by triflic acid (Scheme 49) [84].
component reaction. The process was catalyzed by triflic acid (Scheme 49) [84].
Scheme 49.
Synthesisofofpyrimidines
pyrimidines146
146via
via the
the multicomponent
multicomponent cyclocondensation
cyclocondensation between
between me-
methyl
thyl ketone,
aryl aryl ketone, two equivalents
two equivalents of aromatic
of aromatic aldehyde
aldehyde andof
and two two of ammonium
ammonium acetate.
acetate.
Scheme 49. Synthesis of pyrimidines 146 via the multicomponent cyclocondensation between me-
Scheme 49. Synthesis of pyrimidines 146 via the multicomponent cyclocondensation between me-
thyl Miscellaneous
2.5. aryl ketone, two equivalents of aromatic aldehyde and two of ammonium acetate.
thyl Miscellaneous
2.5. aryl ketone, two equivalents of aromatic aldehyde and two of ammonium acetate.
In
In this
this section,
section, we
we have
have highlighted
highlighted several
several reactions
reactions due
due to
to their
their peculiarity.
peculiarity. For
For
2.5. Miscellaneous
2.5. Miscellaneous
example, a multifunctionalized pyrimidine 149 was synthesized from 3,4,4,5-tetrachloro-
example, a multifunctionalized pyrimidine 149 was synthesized from 3,4,4,5-tetrachloro-
In this section,(147)
4H-1,2,6-thiadiazine we have highlighted
through several
the treatment withreactions
Ph3 P. Andue to their peculiarity.
intermediate For
spirocycle 148
In this section, we have highlighted several reactions due to their peculiarity. For
example,
was a
obtained multifunctionalized pyrimidine
with a 66% yield, and 149 was
its degradation synthesized from 3,4,4,5-tetrachloro-
example, a multifunctionalized pyrimidine 149 was with BnEt3 NCl
synthesized from(0.5 equiv.) afforded
3,4,4,5-tetrachloro-
4,5,6-trichloropyrimidine-2-carbonitrile (149) in an 81% yield. Rational mechanisms to
explain the intermediate and product formation were proposed (Scheme 50) [85].
4H-1,2,6-thiadiazine (147) through the treatment with Ph3P. An intermediate spirocycle
148 was obtained with
4H-1,2,6-thiadiazine a through
(147) 66% yield,
theand its degradation
treatment with Ph3P.with
An BnEt 3NCl (0.5spirocycle
intermediate equiv.) af-
148 was
forded obtained with a 66% yield, and its
4,5,6-trichloropyrimidine-2-carbonitriledegradation
(149) in with
an 81%BnEt 3NCl Rational
yield. (0.5 equiv.)
4H-1,2,6-thiadiazine (147) through the treatment with Ph3P. An intermediate spirocycle af-
mecha-
forded
nisms 4,5,6-trichloropyrimidine-2-carbonitrile
to obtained
explain the intermediate andand
product (149) in an 81%
formation were yield. Rational mecha-
148 was with a 66% yield, its degradation withproposed
BnEt3NCl(Scheme 50) [85].
(0.5 equiv.) af-
Catalysts 2023, 13, 180 nisms to explain the intermediate and product formation were proposed (Scheme 50) 20 [85].
of 24
forded 4,5,6-trichloropyrimidine-2-carbonitrile (149) in an 81% yield. Rational mecha-
nisms to explain the intermediate and product formation were proposed (Scheme 50) [85].
Scheme 50. Ph3P-mediated pyrimidine 149 synthesis from 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine

Scheme
(147). 50. Ph3P-mediated pyrimidine 149 synthesis from 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine
(147).
Scheme 50.
Scheme 50. Ph
Ph33P-mediated
P-mediatedpyrimidine
pyrimidine 149
149 synthesis
synthesis from
from 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine
3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine (147).
A straightforward synthesis of pyrimidines 153 or 154 via Au(III) or Au(I)/Lewis-
(147).A straightforward synthesis of pyrimidines 153 or 154 via Au(III) or Au(I)/Lewis-
acid-catalyzed cascadesynthesis
A straightforward reactionsofofpyrimidines
propargyl alcohols
153 or 154150
viawith 3-amino-benzo[d]isoxa-
Au(III) or Au(I)/Lewis-acid-
acid-catalyzed
zoles 151 has cascade
very reactions
recently been of propargyl
carried out. alcohols
The 150 with
propargyl amine 3-amino-benzo[d]isoxa-
intermediates 152 were
catalyzed
A151 cascade reactions
straightforward of propargyl
synthesis alcohols 150
of pyrimidines 153with 3-amino-benzo[d]isoxazoles
or 154 via intermediates
Au(III) or Au(I)/Lewis- 151
zoles
readily has very recently
generated in situ been
via carried
oxophilic out. The propargyl
activation by Au(III)amine
or a Lewis acid. 152 were
After the in-
has very recently
acid-catalyzed been carried
cascade reactionsout.
of The propargyl
propargyl amine
alcohols 150intermediates
with 152 were readily
3-amino-benzo[d]isoxa-
readily generated
termediate in situ via oxophilic activation by Au(III) or a Lewis theacid. Afterproducts
the in-
generated
zoles in cyclization/1,2-H
151 has situ
veryvia oxophilic
recently beenorcarried
group
activation migration/aromatization,
by
out.Au(III) or a Lewis
The propargyl desired
acid.intermediates
amine After the intermediate
152 were
termediate cyclization/1,2-H
were delivered. The selective or group migration/aromatization,
migratory aptitudeby was the desired products
cyclization/1,2-H
readily generated or
in group
situ migration/aromatization,
via oxophilic thedependent
desired on the were
or a products stericdelivered.
and elec-
were delivered. The selective migratoryactivation
aptitude wasAu(III)
dependent Lewis
on theacid.
stericAfter
and the
elec-in-
tronic
The properties
selective
termediate of the propargylic
migratory aptitude
cyclization/1,2-H or was groups used on
dependent
group (Scheme 51) and
the steric
migration/aromatization,[86].electronic properties of
tronic properties of the propargylic groups used (Scheme 51) [86]. the desired products
the
werepropargylic
delivered.groups used (Scheme
The selective 51) [86].
migratory aptitude was dependent on the steric and elec-
tronic properties of the propargylic groups used (Scheme 51) [86].
Scheme 51. Gold-mediated pyrimidine 153 and 154 synthesis from propargyl alcohols 150 with 3-
Scheme 51.
Scheme 51. Gold-mediated
Gold-mediatedpyrimidine
pyrimidine153 and
153 154
and synthesis
154 from
synthesis propargyl
from alcohols
propargyl 150 150
alcohols withwith
3-
amino-benzo[d]isoxazoles 151.
amino-benzo[d]isoxazoles 151.
3-amino-benzo[d]isoxazoles 151.
Scheme 51. Gold-mediated pyrimidine 153 and 154 synthesis from propargyl alcohols 150 with 3-
Dofe et al. reportedaaconvenient
convenient andfacile
facile methodologyfor for thesynthesis
synthesis of a new
Dofe et al. reported a convenientand
reported151.
amino-benzo[d]isoxazoles and facilemethodology
methodology forthe the synthesisofofa anew
new
series of pyrazole and
series and pyrimidine
pyrimidine derivatives156 156 fromchromenones
chromenones 155and and thiourea
series of pyrazole pyrimidine derivatives
derivatives 156fromfrom chromenones155 155 andthiourea
thiourea
under
under ultrasound
ultrasound irradiation.
irradiation. With
With regard
regard to pyrimidine
andtofacile
pyrimidine derivatives,
derivatives, they
they have
have been syn-
underDofe et al. reported
ultrasound a convenient
irradiation. With regard methodology
to pyrimidine for the
derivatives, they been
synthesis of asyn-
have new
been
thesized
thesized in better
in better yields
yields and
and shorter
shorter reaction
reaction times
times compared
compared with
with the conventional
series of pyrazole
synthesized and
in better pyrimidine
yields and derivatives
shorter reaction156 from
times compared withthe
chromenones theconventional
155 and thiourea
conventional
method
method
under
method (Scheme52)
ultrasound
(Scheme 52) [87].
[87].
irradiation. With regard to pyrimidine derivatives, they have been syn-
thesized in better yields and shorter reaction times compared with the conventional
method (Scheme 52) [87].
Scheme52.
Scheme
Scheme 52.Synthesis
52. Synthesisofof
Synthesis ofpyrimidines
pyrimidines
pyrimidines 156
156
156 from
from
from chromones
chromones
chromones 155and
155155
and andthiourea
thiourea
thiourea under
under
under ultrasound
ultrasound
ultrasound irra-
irra-
irradiation.
diation.
diation.
Pyrimidine N-oxides 158 were prepared from β-keto enamides 157 and hydroxy-
Scheme 52. Synthesis of pyrimidines 156 from chromones 155 and thiourea under ultrasound irra-
lamine Pyrimidine
Pyrimidine N-oxides
hydrochloride 158
by a158
N-oxides werein
reaction
were prepared from
r.t. for 5–19
prepared from β-keto
days 70–75 ◦ C
atenamides
or enamides
β-keto 157157
forandandhydroxyla-
hydroxyla-
4.5–6.5 h under
diation.
MW
mineirradiation.
mine hydrochloride
hydrochlorideThebyrequired
by aareaction
reaction in r.t.enamides
inr.t.
β-keto for
for5–19
5–19days were
157 or
days prepared
oratat70–75 by
70–75°C°Cfor the MCR
for4.5–6.5 of ni-
h hunder
4.5–6.5 under
triles, trichloroacetic
MW irradiation.
irradiation. The
The acid andβ-keto
required
required lithiated
β-keto methoxyallene.
enamides
enamides 157
157were
were N-oxides
prepared
prepared bybythe
158 were
theMCR
MCR obtained
ofof in
nitriles,
nitriles,
Pyrimidine N-oxides 158 were prepared from β-keto enamides 157 and hydroxyla-
moderate-to-excellent
trichloroacetic
trichloroacetic acid
acid and
andchemical
lithiatedyields
lithiated (28–61% and
methoxyallene.
methoxyallene. 71–96%),
N-oxides
N-oxides 158 together
158were
were a pyridine
obtained
obtained inin side prod-
moderate-
moderate-
mine hydrochloride by a reaction in r.t. for 5–19 days or at 70–75 °C for 4.5–6.5 h under
uct (2%). The acetylation of the methyl group of the pyrimidine N-oxides 158 was achieved
MW irradiation. The required β-keto enamides 157 were prepared by the MCR of nitriles,
with Ac2 O at 130 ◦ C through Boekelheide rearrangement to provide the acetylated 159
trichloroacetic acid and lithiated methoxyallene. N-oxides 158 were obtained in moderate-
(Scheme 53) [88].
to-excellent chemical yields (28–61% and 71–96%), together a pyridine side product (2%).
The acetylation of the methyl group of the pyrimidine N-oxides 158 was achieved with
Catalysts 2023, 13, 180 21 of 24
Ac2O at 130 °C through Boekelheide rearrangement to provide the acetylated 159 (Scheme
53) [88].
Scheme 53.
Synthesis of
of pyrimidine
pyrimidine N-oxides
N-oxides 158
158 from
from β-keto
β-keto enamides
enamides 157
157 and
andhydroxylamine
hydroxylamine
hydrochloride under MW irradiation.
hydrochloride under MW irradiation.
3.
3. Conclusions
Conclusions
The
The MCR is is aavaluable
valuablesynthetic
syntheticapproach
approach to to obtain
obtain new new pyrimidine
pyrimidine derivatives
derivatives and
and related
related compounds,
compounds, not by
not only only by using
using the Biginelli
the Biginelli reaction.
reaction. Catalysis
Catalysis is of
is of great great
value in
value in this
this type type of reaction,
of reaction, andnumber
and a large a largeof number of new have
new catalysts catalysts
beenhave been developed.
developed. New per-
New perspectives
spectives for knownforcatalysts
known catalysts have
have also been also been discovered.
discovered. In addition,
In addition, the use ofthevarious
use of
various technologies, such as microwave and ultrasound irradiation, also helps
technologies, such as microwave and ultrasound irradiation, also helps to improve reac- to improve
reaction conditions
tion conditions andand yields.
yields. In In general,
general, in in
thethe periodofoftime
period timeconsidered
consideredinin this
this review,
review,
increasingly
increasinglymoremoreimportance
importancehashasbeen
beengiven
givento toeco-friendly
eco-friendlyreactions.
reactions.
Author Contributions:Conceptualization,
AuthorContributions: Conceptualization,M.-S.P.-G.; methodology,
M.-S.P.-G.; methodology, M.-S.P.-G. and and
M.-S.P.-G. M.A.; writing—
M.A.; writ-
review and editing, M.-S.P.-G., M.A., S.C.-L., M.D.-F., F.S. and J.-J.Q.; supervision, M.-S.P.-G. and
ing—review and editing, M.-S.P.-G., M.A., S.C.-L., M.D.-F., F.S. and J.-J.Q.; supervision, M.-S.P.-G.
M.A.; project administration, M.-S.P.-G. All authors have read and agreed to the published version
and M.A.; project administration, M.-S.P.-G. All authors have read and agreed to the published ver- of
the manuscript.
sion of the manuscript.
Funding: Supported
Funding: Supported by
by grant
grant RTI2018-098296-BI00
RTI2018-098296-BI00(MINECO
(MINECOand
andFEDER).
FEDER).
Data
DataAvailability Statement:Not
AvailabilityStatement: Notapplicable
applicablehere.
here.
Conflicts
Conflictsof Interest:The
ofInterest: Theauthors
authorsdeclare
declareno
noconflict
conflictofofinterest.
interest.
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Keywords: pyrimidines; multicomponent reactions; cycloadditions; N-heterocycles

Citation: Díaz-Fernández, M.; 1. Introduction

Catalysts 2023, 13, 180. https://doi.org/10.3390/catal13010180 https://www.mdpi.com/journal/catalysts

Catalysts 2023, 13, x FOR PEER REVIEW 3 of 24

Scheme 1. Synthesis of tri- and tetrasubstituted pyrimidine derivatives 3.

A particular case of [4+2] cycloaddition involves triazines using a Diels–Alder-type

More recently, a similar strategy, but with TFA-catalyzed reactions of electron-defi-

Scheme 6. Synthesis of pyrimidines 23 from amidines and malononitrile dimer.

Scheme 7. Synthesis of pyrimidinones 27 from α,β-unsaturated imines 24 and isocyanates 25.

Scheme 9. Synthesis of pyrimidines 34 and 35 from amino acid-derived carboxamides.

Scheme 9. Synthesis of pyrimidines 34 and 35 from amino acid-derived carboxamides.

Scheme 11. Classical Pinner synthesis.

Scheme 15. Synthesis of 2,4-diarylpyrimidines 56 from 2,2,2-trichloroethyliden-acetophenones 53

Scheme 18. Synthesis of F3C-functionalized pyrimidines 63 from chromones 62.

Scheme 19. Synthesis

Scheme 21. Synthesis of bis-pyrimidines 75, 76 and 77 under US irradiation.

Scheme 22. Copper-catalyzed synthesis of 2,6-disubstituted pyrimidones 79 with MW.

A series of 4-iminopyrimidines 86 using the strategy of [3+3]-A cycloaddition was

Scheme 24. Copper-catalyzed synthesis of 4-iminopyrimidines 86.

enamines or amidines is presented. These 3-ethoxycyclobutanones act as 1,3-di-carbonyl

Scheme 27. Synthesis of pyrimidines 94 and 95 from 3-ethoxycyclobutanones 92.

2.2.1. [4+1+1] Cycloadditions

2.2. Three-Component Cycloadditions

With the aim of obtaining 2-(N-alkylamino)pyrimidines, heterocycles widely found

Scheme 39. Gold-complex-mediated synthesis of 4-aminopyrimidines 130 by [2+2+2] cycloaddition

Scheme 43. Indium-mediated

2.3. Four-Component Cycloadditions

Scheme 45. Iridium- or manganese-mediated four-component synthesis of pyrimidines 142 from

2,4,6-Triarylpyrimidines 144 were synthesized via a simple, one-pot, four-component

Scheme 50. Ph3P-mediated pyrimidine 149 synthesis from 3,4,4,5-tetrachloro-4H-1,2,6-thiadiazine

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