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Recent Patents on Catalysis, 2012, 1, 137-158 137

Organic Domino Reactions Catalyzed by Molecular Iodine

Gunasekar Ramachandran and Kulathu I. Sathiyanarayanan*

Chemistry Division, School of Advanced Sciences, VIT University, Vellore-632014, Tamilnadu India

Received: May 8, 2012; Revised: June 15, 2012; Accepted: June 30, 2012

Abstract: Molecular iodine has established itself as an efficient catalyst in organic synthesis to attain several organic
transformations. Domino reactions involve the synthesis of a target molecule in a single step where three or more compo-
nents are reacting simultaneously. Thus these types of domino reactions are carried out in the presence of iodine as a cata-
lyst. They have more significance and are fascinating in organic synthesis. The use of molecular iodine as catalyst in vari-
ous domino reactions along with the recent patents is discussed in this review.
Keywords: Biginelli reaction, domino reaction, imino-Diels-Alder (Povarov) reaction, Mannich reaction, Michael reaction and
molecular iodine.

INTRODUCTION one-pot in which at least three functional groups join through

Iodine was discovered by Bernard Courtois during the
process of making saltpeter in 1811 [1, 2]. During this proc-
ess, an excess of sulphur compounds were created. In order
to clean the sulphur compounds from their saltpetre, acciden-
tally Courtois added excess of sulphuric acid to the mixture
thereby a violet vapor cloud erupted from the mass and
forms lustrous crystals on metal object. Later Gay-Lussac
and A.M. Ampere reported that this was either an element or
a compound of oxygen. Finally, Davy found that it was a
new element and named it Iodine from a Greek word for
"violet color" [3-5]. Lewis acidity is the leading factor for
the behavior of iodine as a catalyst. Molecular iodine in syn-
thetic organic chemistry possesses many applications. In
recent years, in organic chemistry the use of molecular io-
dine has been received much considerable attention due to
the less toxic, readily available, inexpensive, easy workup
and a moisture-stable mild Lewis acid [6, 7]. The elemental
iodine is emerging as an effective Lewis acid catalyst which
enhances utility in organic synthesis to achieve numerous
organic transformations [8, 9].
The scientific research of organic synthesis is continu-
ously enriched by the development of synthetic methodol-
ogy. In order to achieve a target molecule in synthetic or-
ganic chemistry, a usual procedure will be followed by step-
wise formation of individual bonds. If the reaction could
form several bonds in one sequence without isolating the
intermediates, such reaction would be more efficient; it
causes the minimum of waste; it also utilizes minimum
amount of solvents and reagents in the reactions [10, 11].
Energy utilization would be significantly decreased when
compared to stepwise reaction. This type of transformation is
a domino reaction. Domino reaction is a synthesis of com-
plex molecules by combining three or more components in a
*Address correspondence to this author at the Chemistry Division, School
of Advanced Sciences, VIT University, Vellore-632014, Tamilnadu India;
Tel: 914162244520; Fax: 914162243092;
E-mail: sathiya_kuna@hotmail.com
covalent bonds and this has been steadily gaining importance
in synthetic organic chemistry [10-12].
Domino reaction has wide significant importance in sev-
eral reactions which are emerging as useful tools for the
formation of carbon-carbon and carbon-heteroatom bonds in
synthetic chemistry to create interesting and novel drug like
scaffolds [12, 13]. Several research groups had established
the individuality of domino reaction as a powerful tool for
the preparation of unique therapeutic scaffolds which is the
most challenging objective in modern organic synthesis [14,
15]. This type of reactions had numerous advantages like
low cost, lower reaction time, use of simple precursors to
synthesize complex molecules and the use of commercial
catalysts [15-17].
Several organic domino reactions were carried out in the
presence of iodine as catalyst. The importance and utility of
this process are more attractive in recent organic synthesis.
This review provides information on the use of molecular
iodine as catalyst in various domino reactions.
BIGINELLI REACTION
In 1891 Pietro Biginelli first reported the synthesis of
tetrahydropyrimidinones via a one-pot synthesis using three
components namely benzaldehyde,
-ketoesters and urea in
the presence of acids or Lewis acids catalyst [18].
Das et al. reported the synthesis of 4-aryl-3,4-dihy-
dropyrimidin-2(1H)-ones (DHPMs) by combining three
components aldehyde, 1, 3-dicarbonyl compounds and urea
or thiourea in the presence of iodine as catalyst under reflux
condition in nitrogen atmosphere (Scheme 1) [19]. Several
improvements and modifications had resulted in milder reac-
tion condition and more efficient use of catalyst. To get
maximum yields of the products they had used 40 mmol% of
iodine as minimum amount with respect to the aldehydes.
Zubaida et al. also reported the synthesis of DHPMs by
mixing heterocyclic aromatic aldehydes,
-ketoesters and

2211-548X/12 $100.00+.00 © 2012 Bentham Science Publishers

138 Recent Patents on Catalysis, 2012, Vol. 1, No. 2 Ramachandran and Sathiyanarayanan

O R'

O O X
O 40 mmol% Iodine R'' NH

R'' H2 N NH2 , 6-8 h

R' H CH3CN, N X
H
R' = Alkyl or Aryl R'' = Alkyl-O or Alkyl X=O, S
Yield: 71-93 %

Scheme 1.

O
N O
HN CHO O O
N O 5 mol% Iodine N
RHN N O O HN
O NH
O H2N NH2 Toluene, reflux RHN N HN
RO O O
OR 3-5 h
RO
RO OR
R = (CH3)2CHCO RO
Yield: 69-95%

Scheme 2.

O R'
O O O
O Iodine, Ultrasound
EtO NH
OEt H2N NH2
R' H CH3CN, 1.5 - 8 h
N O
R' = Alkyl or Aryl H
Yield: 19-95%

Scheme 3.

O Ph
O O O
O
5 mol% Iodine
NH
OEt H2N NH
Ph H EtOH, rt
R N O
R = Substituted Phenyl R
Yield: 78-90%

Scheme 4.

urea in different solvent (toluene). These reaction mixtures
were refluxed for 3-5 h (Scheme 2) [20]. The reaction was
found to be very sluggish and iodine worked as an excellent
catalyst for this reaction.
Li et al. described the synthesis of DHPMs via Biginelli
reaction under ultrasound irradiation using iodine as catalyst
with high yields in shorter reaction time (Scheme 3) [21].
Synthesis of DHPMs was carried out under solvent free con-
dition via Biginelli reaction. The reaction time varied from
1.5 to 8 hr.
Joshi et al. developed one-pot Biginelli reaction from
aromatic aldehydes, 1,3-dicarbonyl compounds and N-
substituted urea in the presence of catalytic amount of iodine
in ethanol to give moderate yield and the authors had studied
in-vitro antimycobacterial activity for the synthesized com-
pounds (Scheme 4) [22]. Hence, most of the molecules
obtained using iodine as catalyst in the domino reaction
possesses bioactivity [15]. Besides thiourea, N-methylurea
had also been employed to furnish the corresponding dihy-
dropyrimidinones.
Cai et al. reported the synthesis of 5-unsubstituted-3, 4-
dihydropyrimidin-2(1H)-ones using molecular iodine as
catalyst for the reaction of aldehydes, acetophenones and
urea under solvent-free conditions (Scheme 5) [23]. Besides

-ketoesters and
-diketone, ketone was also employed to
form the corresponding dihydropyrimidinones, which are
also of much interest from biological activity point of view.
Synthesis of 4,6-diarylpyrimidin-2(1H)-ones using mo-
lecular iodine as catalyst was reported by Pasha et al. under
solvent-free conditions (Scheme 6) [24]. While carrying out
the same reaction using other Lewis acids such as indium
(III) chloride, gadolinium (III) chloride and cerium (III)
chloride, the reaction had revealed that iodine was superior
in terms of conversion and reaction time.
Organic Domino Reactions Catalyzed by Molecular Iodine Recent Patents on Catalysis, 2012, Vol. 1, No. 2 139

A green protocol for the synthesis of spirobicyclic het-
erocycles from benzaldehydes, cyclic 1,3-diketone and urea
using iodine as catalyst via Biginelli type reaction under sol-
vent-free conditions in good to excellent yield was described
by Prajapati and co-workers under solvent-free conditions
(Scheme 7) [25]. The yield varied from 50 - 96%.
Sarma et al. reported the synthesis of 3,4-dihy-
dropyrimidin-2(1H)-ones using iodine-alumina as a catalyst
under microwave irradiation from three components namely
aldehyde, urea/ thiourea and a 1,3-dicarbonyl compound
(Scheme 8). In the reaction they have utilized 10 mol% of
iodine adsorbed on neutral alumina. The reaction was irradi-
ated in a microwave reactor at 90ºC for 1 min. The yield
varied from 58-90% [26].
From the above (schemes 1-8) Biginelli reactions it is
clear that the reactions carried out under solvent-free condi-
tions using iodine as catalyst, yield lower amount of the
product, in comparison with the same reactions conducted in
solvents [19-26]. When Biginelli reaction is carried out in
the presence of solvent like EtOH, CH3CN and toluene
(Scheme 1-4), the completion of the reaction takes longer
time and yields are lower than under solvent-free condition
(Scheme 5-8).
CHICHIBABIN (TSCHITSCHIBABIN) PYRIDINE
SYNTHESIS
In 1905 Chichibabin et al. first reported the pyridine syn-
thesis; they synthesized 2, 3, 5-trisubstituted pyridines [27].
It is a condensation reaction of aldehyde and ketone in the
presence of ammonium acetate or ammonia.
The detailed reaction mechanism for Chichibabin pyri-
dine synthesis involves three steps namely, imine synthesis,
aldol condensation by a base-catalysis and Michael reaction.
Cai et al. reported the synthesis of 2, 4, 6-triphenyl-
pyridine using iodine as catalyst under solvent-free condi-
tions (Scheme 9) [23]. This reaction also undergoes the same
mechanism as Imino-Aldol-Michael reaction. Initially imine
is formed by the condensation of acetophenone with ammo-
nium acetate followed by aldol condensation between aceto-
phenone and aromatic aldehyde. Finally these two interme-
diates get fused by Michael addition in order to form 2, 4, 6-
triphenylpyridine using iodine as catalyst.
DEBUS-RADZISZEWSKI IMIDAZOLE SYNTHESIS
In 1858, Debus et al. and Radziszewski et al. first re-
ported the synthesis of imidazole from diketone, aldehyde
and ammonia or ammonium acetate [28].

Ar1
O O O
Iodine, 140oC
NH
Ar1 H Ar2 H2N NH2 Solvent-free
20-40 min Ar2 N O
Ar, Ar' = Substituted Phenyl H

Yield: 68-80%

Scheme 5.

O O O Ar2 Ar1
5 mol%Iodine
Ar1 H Ar2 H2N NH2 N NH
Neat, 80oC
Ar, Ar' = Substituted Phenyl 5-15 min O
Yield 90-96%

Scheme 6.
O Ar

O O O Iodine, solvent-free
O NH

H 2N NH2 Microwave
Ar H N O
1.5-4.5 min H
Ar = Substituted Phenyl Yield: 50-96%

Scheme 7.

CHO O R
X Iodine-Al2O3
O O
EtO NH
H2N NH2 MW, Solvent-free
OEt
90oC for 1 min N X
H
X= O, S
58-90%
Scheme 8.
140 Recent Patents on Catalysis, 2012, Vol. 1, No. 2 Ramachandran and Sathiyanarayanan

Ar
O
Iodine
2 NH4OAc Ar CHO
Solvent-free N
Ar = Substituted Phenyl 120oC, 6h

48-61%

Scheme 9.

Ph OH NH2 10 mol% Iodine Ph N

NH4OAc Ar CHO
EtOH, reflux Ar
Ph O
20-30 min N
Ph
Ar = Substituted Phenyl
Yield 94-98%

Scheme 10.

Ph OH
10 mol% Iodine Ph
2 NH4OAc Ar CHO N
EtOH, 70 C o Ar
Ph O
Ar = Substituted Phenyl N
15-30 min Ph H

93-98%

Scheme 11.

Ph O 5 mol% Iodine Ph
N
2 NH4OAc Ar CHO Ar
EtOH, 70oC
N
Ph O Ar = Substituted Phenyl 15-25 min Ph H

Scheme 12.

H
O 5 mol% Iodine
Ar CHO N
NH4OAc
EtOH, Heat Ar
O Ar = Substituted Phenyl N
45-60 min

83-92%
Scheme 13.

Synthesis of imidazole from benzoin, benzaldehydes,
aniline and ammonium acetate was developed by Kidwai et
al. using iodine as catalyst (Scheme 10). The yield varied
from 94-98% and the reaction time varied from 20 - 30 min
[29]. In general diketone is used as a precursor for the syn-
thesis of imidazole, but Kidwai et al. used benzoin. The
author reported the synthesis of highly functionalized N-
phenyl imidazoles.
The same group (Kidwai et al.) reported the synthesis of
imidazole from benzoin, benzaldehydes and 2 equivalents of
ammonium acetate using iodine as catalyst (Scheme 11)
[30].
Kidwai et al. presented the synthesis of imidazoles start-
ing with benzil and iodine as catalyst (Scheme 12) [31]. The
yield varied from 97-99% and the reaction time varied from
15 - 20 min.
Behmadi et al. synthesized 1H-phenanthro [9, 10] imida-
zole using molecular iodine as catalyst from aldehydes, phe-
nanthraquinone and ammonium acetate (Scheme 13) [32].
The yield varied from 83-92% and the reaction time varied
from 45 to 60 min.
One pot synthesis of 2-phenylimidazo [4, 5-f] [1, 10]
phenanthroline derivatives under solvent-free conditions
using iodine catalyst was developed by Shahed et al.
(Scheme 14). The yield varied from 89-95% [33].
DOEBNER QUINOLINE SYNTHESIS
In 1883, Bottinger synthesized methylquinolinecarbox-
ylic acid from pyruvic acid and aniline, but no effort was
taken to determine the position of either the methyl or car-
boxylic group. After four years, Doebner found that the first
Organic Domino Reactions Catalyzed by Molecular Iodine Recent Patents on Catalysis, 2012, Vol. 1, No. 2 141

H
N O 10 mol% Iodine N N
NH4OAc Ar CHO
NH4OAc Ar
N O N N
Ar = Substituted Phenyl

89-95%

Scheme 14.

R
NH2 O
5 mol% Iodine
Ar CHO
R THF, reflux, 10-48 h
Ar = Substituted Phenyl N Ar
R = Me, Substituted Phenyl
79-90%

Scheme 15.

Me
COOR

NH2
O O
5 mol% Iodine N Ar
Ar CHO
R THF, reflux CH2COOR
Ar = Substituted Phenyl R = Me, Et
6-8 h

N Ar

80-94%
Scheme 16.

product was 2-methylquinoline-4-carboxylic acid and the
second product was 2-methylquinoline [34].
Wang et al. synthesized the 3-arylbenzoquinoline deriva-
tives using iodine as catalyst from aryl aldehydes, napthalen-
2-amine and acetone or acetophenone. The aliphatic alde-
hydes failed to react (Scheme 15). The yield varied from 82-
94%, and the transformation took place on refluxing in THF
[35]. They examined the reaction with various aromatic al-
dehydes, with naphthalen-2-amine and straight chain ketones
like pentan-2-one and hexan-2-one, giving 3-arylbenzo[f]
quinoline derivatives, in good to high yields and high selec-
tivity [35, 36].
The same reaction was carried out by the same group
with
-lactoester and one product was selectively formed of
the yield varied from 80-94% and reaction time varied from
6-8 h (Scheme 16) [35]. Initially, the reaction was carried out
with 4-chlorobenzaldehyde, naphthalen-2-amine, and ace-
tone in THF in the absence of I2. No product was obtained at
room temperature and under reflux condition. Reactions took
place well in refluxing THF and in the presence of 5 mol%
of I2. These types of reactions are considered as green chem-
istry transformations due to economical reaction condition
and easy isolation of the product. The normal multi-step syn-
theses create extensive amounts of waste in the isolation of
product often consuming expensive and toxic chemical after
each step.
Wang et al. reported a method for the synthesis of
benzo[f]quinoline and benzo[a]phenanthridine derivatives
from a three-component benzaldehydes, naphthalen-2-amine,
and cyclic ketone using iodine as catalyst. The same reaction
conditions have been extended to other cyclic ketones like
cyclohexanone, cycloheptanone, cyclooctanone and cyclo-
dodecanone to afford the corresponding benzo[a] phenan-
thridines, benzo[f]cyclohepta[c]quinolines, and benzo[f] cy-
cloocta[c]quinolines, benzo[f]cyclododeca[c]quinolines in
good to high yields. Mechanism for the formation of Benzo
[a]phenanthridines has been investigated by the authors by
performing each step individually (Scheme 17). Initially the
Schiff base N-arylidenenaphthalen-2-amine was obtained
from 2-chlorobenzaldehyde and naphthalen-2-amine in THF
at ambient temperature. The Schiff base reacted with
cyclopentanone to give the corresponding
benzo[f]cyclopenta [c]quinoline in the presence of 5 mol%
of iodine at reflux. The yield varied from 71-96% and the
reaction time was varied from 6-20 h [37].
O ( )n
NH2
5 mol% Iodine
Ph CHO
( )n THF, reflux
N Ph
6-20 h
n = 0, 1, 2, 3, 7
71-96%
Scheme 17.
Same authors have reported the same method for the syn-
thesis of pyranoquinoline, thiopyranoquinoline, thienoquino-
line, and naphtha [2, 7] naphthyridine derivatives using io-
dine as catalyst from benzaldehydes, naphthalen-2-amine,
and heterocycloketones like tetrahydropyran-4-one, tetrahy-
142 Recent Patents on Catalysis, 2012, Vol. 1, No. 2 Ramachandran and Sathiyanarayanan

drothiopyran-4-one, pyridinone, and thiophenone. The yield cycloadduct. The exact mechanism for this reaction is still
varied from 68-92% and the reaction time varied from 8-17 h not clear.
(Scheme 18) [37, 38].
HANTZSCH PYRIDINE SYNTHESIS
O X
NH2 ( )n In 1882, Arthur Hantzsch reported the first synthesis of 1,
5 mol% Iodine
Ph CHO ( )n
4-dihydro-2, 6-dimethylpyridine-3, 5-dicarboxylates from
-
X THF, reflux
N Ph ketoester, aldehyde and ammonia solution in ethanol [41].
X = O, S 8-17 h
n = 0, 1 68-92% Synthesis of 4-substituted-1, 4-dihydropyridine deriva-
tives via Hantzsch reaction using molecular iodine catalyst
Scheme 18. was presented by Yao et al. (Scheme 20). The yield varied
from 85-99% and the reaction time varied from 25 min to 6 h
DOMINO KNOEVENAGEL/6
ELECTROCYCLIZA- [42].
TION REACTION
Initially, the reaction with benzaldehyde, 1,3-cyclo hex-
One-pot synthesis of 2H-pyrans by domino Knoeve- anedione, ethyl acetoacetate and ammonium acetate under
nagel/6 Electrocyclization was reported by Rok Lee et al. stirring condition at room temperature in the presence of few
using iodine as catalyst from cyclic 1,3-dicarbonyl com- drops of ethanol was tested. After 4 hours 56% conversion
pound, 3-methyl-2-butenal in dichloromethane (Scheme 19) was achieved. Products were obtained in excellent yields
[39]. under the optimized reaction conditions (15 mol% of Io-
This work has been patented by Lee et al. entitled dine).
“METHOD FOR PREPARATION OF 2H-PYRANS US- Joshi et al. described the synthesis of 1,4-dihy-
ING IODINE CATALYST” [40]. The reaction was carried dropyridines from aromatic aldehydes,
-ketoester and am-
out with diverse range of cyclic 1,3-dicarbonyls. monium acetate using iodine as catalyst (Scheme 21) [43].

O
O O
H 20 mol% Iodine
DCM, reflux, 24 h
OH
66-99%
Scheme 19.
It was established that iodine was used as a catalyst for
this cyclization. They had carried out the reaction between
cyclic 1,3-dicarbonyls and 3-metyl-2-butenal to form 1-
cyclohexene-1-carboxaldehyde. The dimedone then attacked
activated aldehyde to yield intermediate, which then dehy-
drated on heating to give other intermediate. The latter in-
termediate further underwent 6-electrocyclization to give
The experiment was carried out using 30 mol% of iodine
as catalyst. Two equivalents of a 1,3-dicarbonyl compound,
one equivalent of aromatic aldehydes and ammonium acetate
were stirred at room temperature using molecular iodine as a
O catalyst in a little amount of ethanol giving the correspond-
ing 1,4-DHPs (dihydropyridines) in 88-95% yield. In a simi-
lar fashion, reaction of 1,3-dicarbonyl compound, methyl
acetoacetate and ammonium acetate with various aldehydes
under the same reaction conditions gave the corresponding
unsymmetrical 1,4-DHPs derivatives in 88-94% yield under
ambient conditions.
Wang et al. reported a green method for the synthesis of
Benzo[f]pyridmido[4,5-b]quinoline derivatives using iodine
as catalyst in aqueous media (Scheme 22) [44].

O O Ar O
O O 15 mol% Iodine
O
NH4OAc
Ar CHO EtOH, 25-40oC
O
O 25-360 min N
H
Ar = Substituted Phenyl 85-99%
Scheme 20.
O Ar O
O O
Iodine, EtOH
Ar CHO NH4OAc R' R
R' R r.t., 2.5-5 h
Ar = Substituted Phenyl R' = OMe, OCH(CH3)2 N
H
R = Me, CH(CH3)2
88-95%
Scheme 21.

O Ar
NH2 O O 5mol% Iodine
Ar CHO HN
HN NH H2O, r.t., 6-8 h
Ar = Substituted Phenyl O N N
O H H
Scheme 22.
Organic Domino Reactions Catalyzed by Molecular Iodine Recent Patents on Catalysis, 2012, Vol. 1, No. 2 143

R
O O O

OEt N N OEt
N
3-5 h N N
10 mol% Iodine H
H NH2 CHO 39-77%
N i-PrOH, reflux
N
N R
N 5-70 min
R O
O O N N
N
N N
H
63-92%

Scheme 23.

H H
NH2 O O
30 mol% Iodine
Ar CHO H H
NH NH
O CH3CN, r.t.
H H
3-6 h Ar
Ar = Substituted Phenyl Ar

58-96%

Scheme 24.

O
O H

NH2
Iodine H
Ar CHO N Ar
ether, r.t., 1-5 h H
Ar = Substituted Phenyl

52-95%

Scheme 25.

In their initial study they had used the reaction of 2,3-
dichlorobenzaldehyde, naphthalen-2-amine, and barbituric
acid as a model reaction to optimize the conditions. In order
to avoid a ring-opening reaction they had carried out the re-
action in water at room temperature. Same reaction condi-
tions were followed in the presence of I2 as catalyst. Benzal-
dehydes bearing either electron-withdrawing groups or elec-
tron-donating groups gave the expected products in good
yields under the same reaction conditions.
Cai et al. reported the synthesis of Tetrazolo[1,5-
a]pyrimidine derivatives using iodine as catalyst from three
components namely benzaldehyde, 5-aminotetrazole and
ethylacetoactate/ dimedone. This reaction was carried out in
the presence of 10 mol% of iodine in isopropanol at reflux
temperature (Scheme 23) [45].
IMINO-DIELS-ALDER (POVAROV) REACTION
In 1963, Povarov et al. reported the cycloaddition be-
tween an alkene and an aromatic imine (condensation of
aldehydes and aniline, Schiff base) [46].
Xia et al. presented the synthesis of pyrano [3, 2-
c]quinolines via Imino-Diels-Alder reaction by iodine cata-
lyst from benzaldehydes, aniline and 2,3-dihydropyran
(Scheme 24) [47]. With the optimum condition they had car-
ried out the reaction with diverse aldehydes and anilines. The
products thus obtained were cis/trans isomers without any
other isomer detected.
Yao et al. reported stereoselective synthesis of trans-
endo-Decahydroquinolin-4-one derivatives from aldehydes,
aniline and acetylcyclohexene by iodine catalyst (Scheme
25). The yield varied from 52-95% and the reaction time
varied from 1-5 h [48].
For the one-pot preparation of trans-endo-N-phenyl-2-
phenyldecahydroquinolin-4-one the reaction was initially
carried out with benzaldehyde, aniline and 1-
acetylcyclohexene at room temperature in the presence of
iodine. Optimization of the reaction conditions by varying
the amount of benzaldehydes and iodine afforded reasonable
yields of trans-endo-N-phenyl-2-phenyldecahydroquinolin-
4-ones with high diastereoselectivity (>20:1) [49].
Synthesis of tetrahydroquinolines from aromatic alde-
hyde, aniline and dihydrofuran using iodine catalyst was
reported by Yan Ming et al. (Scheme 26). The yield varied
from 35-74% [49].
The reaction in the absence of iodine didn’t proceed. The
transformation was carried out in different solvents and yield
144 Recent Patents on Catalysis, 2012, Vol. 1, No. 2
was not changed significantly, but the cis/trans ratio of the
product was highly dependent on the solvent polarity. In
general, less polar solvent favored the formation of cis-
isomer and more polar solvent favored the formation of
trans-isomer. The electronic effects of the substituent on the
aldehyde and aniline exerted profound effect on the cis/trans
ratio. When the substituent was changed from NO2 to H, and
to OMe, the cis/trans ratio of product changed from 4/96, to
32/68, and to 47/53 [49].
CHO
NH2
15 mol% Iodine
O DCM, r.t., 12 h
Scheme 26.
The synthesis of tetrahydroquinolines by molecular io-
dine-catalysed domino reaction of anilines with cyclic enol
ethers was developed by Wang et al. (Scheme 27). The yield
varied from 77-93% and the endo/exo ratio varied from
27:73 - 57:43 [50]. Utilization of 2 equivalents of 2, 3-
dihydrofuran for the condensation reaction with anilines
gave tetrahydroquinolines.
NH2 O
Iodine
2
NH
O DCM, r.t., 5 min
endo
Scheme 27.
Ji et al. reported the Imino-Diels-Alder reaction of N-
vinyl-2-pyrrolidone with benzaldehydes and aniline using
iodine catalyst under solvent-free conditions (Scheme 28).
The yield varied from 42-90% and the endo/exo ratio varied
from 100:0 - 78:22 [51]. Under the optimized reaction condi-
tions the corresponding aza-Diels-Alder products were
formed in the similar cis/trans ratio.
CHO NH2
Scheme 28.
NH2
R CHO
R = 1-Ethylpropyl, Cyclopropyl
Scheme 29.
Ramachandran and Sathiyanarayanan
Synthesis of 3, 4-dihydro-2H-pyran from aldehydes, ani-
line and 3,4-dihydro-2H-pyran by iodine catalyst was de-
scribed by Shashikanth et al. (Scheme 29) [52]. They had
found that the reaction proceeded smoothly to afford the
corresponding pyrano [3,2-c]quinoline as a mixture of
cis/trans isomers in ratio of 30:70. In the case of cyclopro-
pane substituted compound, good trans-selectivity was ob-
served.
Zhu et al. reported the synthesis of 2-perflurophenyl tet-
rahydroquinoline derivatives using iodine catalyst (Scheme
O 30). The overall yield varied from 42-65% and cis/trans ratio
varied from 20/80 to 57/43 [53].
NH
IMINO-MICHAEL-CYCLISATION
Chen et al. reported the synthesis of 1,5-benzodiazepine
derivatives under solvent-free conditions using molecular
35-74%
iodine catalyst (Scheme 31). The yield varied from 83-97%
and the reaction time varied from 5-10 min. The reaction was
carried out simply by mixing of o-phenylenediamine with a
ketone using catalytic amount of iodine under solvent-free
conditions. The mixture was ground together in a mortar
with a pestle at room temperature for several minutes, they
purified the 1,5-benzodiazepine derivatives by column
chromatography and obtained in excellent yields [54].
Wang et al. synthesized the 3,4-dihydroquinazolin-4-
O ones from amines, ortho esters and anthranilic acids using
OH
NH OH iodine catalyst under solvent-free condition (Scheme 32).
The yield varied from 92-99% and the reaction time varied
exo from 3-10 min [55]. Authors have established the optimal
77-93% condition for the synthesis of quinazolones by carrying out
the reaction between anthranilic acid, triethyl orthofomate
and aniline and also investigated the effect of the amount of
iodine on the reaction. The reaction did not proceed in the
absence of iodine even after a long reaction time [55].
MANNICH REACTION
In 1912, C. Mannich first reported the synthesis of ami-
nomethylated products (Mannich base) by a reaction of
compounds having active hydrogen with non-enolizable al-
O
N O
5 mol% Iodine N
O H
H
N solvent-free, r.t. H
10-240 min H
N
H N
H
37-90%
H H
O O
30 mol% Iodine
H H
NH NH
O CH3CN, r.t., 20-30 min
H H
R R
57-75%
Organic Domino Reactions Catalyzed by Molecular Iodine Recent Patents on Catalysis, 2012, Vol. 1, No. 2 145

O
CHO H2 N
F F NH
15 mol% Iodine

CF3CH2 OH, r.t., 12 h F F

F F O
F
F F
F

11-56%

Scheme 30.

NH2 R
O Iodine, 5-10 min N
2
R Solvent-free, r.t.
NH2 N
H R
R = Me, Et, iPr, C6H5.
83-95%

Scheme 31.

NH2 O
COOH
5 mol% Iodine N
HC(OR')3
Solvent-free, r.t.
NH2 N
R' = Me, Et 3-10 min
92-99%

Scheme 32.

OTMS R
10 mol% Iodine NH O
Ph CHO R NH 2
Ph CH3CN, r.t. Ph Ph
Ph = substituted phenyl R' = Ph, Bn, n-Bu
30-180 min
81-100%

Scheme 33.

O 10 mol% Iodine O NHCbz

Ph CHO CbzNH2
R CH3CN, r.t. R Ph
R, Ph = substituted phenyl 24 h 42-86%

Scheme 34.

dehydes and ammonia or primary or secondary amine [56,
57].
Janda et al. developed a three components, nucleophilic
addition reaction for the synthesis of
-amino ketones from
aldehydes, aniline and silyl enol ethers using iodine catalyst
(Scheme 33) [58].
Initially they tested a two-component reaction by the
condensation of N-benzylideneaniline with nucleophiles like
silyl enol ether or trimethylsilyl cyanide in the presence of
catalytic amount of iodine. Then they carried out three com-
ponents reaction of anilines, aldehydes and nucleophiles like
silyl enol ether or trimethylsilyl cyanide. For few of the
products a mixture of syn/anti diastereomers was obtained.
The reaction did not proceed with aliphatic amines or alde-
hydes.
Phukan et al. described the direct synthesis of benzyl
carbamate (Cbz) protected
-amino ketones from aldehydes,
ketones and benzyl carbamate using iodine as catalyst
(Scheme 34). The yield varied from 42-86% and the reaction
time is 24 h at room temperature [59].
The same group (Phukan et al.) reported the synthesis of
the Cbz protected
-amino ketones form aldehydes, benzyl
146 Recent Patents on Catalysis, 2012, Vol. 1, No. 2 Ramachandran and Sathiyanarayanan

O Cbz
NH O
H OTMS 10 mol% Iodine
CbzNH 2 OMe
OMe MeCN, r.t.
2-5 hr
32-73%

Scheme 35.

O O
O
10 mol% Iodine
R'' R''
R' AcCl R'
R H CH3 CN, r.t.
R, R', R'' = substituted phenyl R NHAc
4-6 h
75-89%

Scheme 36.

Ph NHCOR
OH
5 mol% Iodine
OH
Ph CHO RCONH2
DCM, r.t., 125oC
Ph = substituted phenyl R = NH2, Me, Ph,CH=CH2
70-91%

Scheme 37.

Ar NHAc
OH
4 mol% Iodine
Ph CHO AcCl OH
MeCN, r.t.
Ph = substituted phenyl
3-6 h
62-90%

Scheme 38.

O
O
5 mol% Iodine
N
5h H
28-92%
CHO
Solvent-Free
Ph NH2
r.t.
O
1 mol% Iodine O
Ph = substituted phenyl
0.5-8 h N
H

83-97%

Scheme 39.

carbamate and 1-methoxy-2-methyl-1-(trimethylsilyloxy)-1-
propene using iodine catalyst (Scheme 35) [60].
Das et al. described the synthesis of
-acetamido ketones
from aldehydes, ketones or ketoesters and acetonitrile in the
presence of acetyl chloride using iodine catalyst (Scheme
36). The yield varied from 75-89% and the reaction time
varied from 4-6 h [61]. Propiophenones instead of acetophe-
nones furnished both anti and syn products. The anti isomers
were the major products formed and diastereoselectivity was
high.
The same group (Das et al.) and Shinde et al. extended
the Mannich reaction by preparing a series of amidoalkyl
napthols from
-napthol, aldehydes and amides using iodine
catalyst in dichloromethane (Scheme 37). The yield varied
from 70-90% and the reaction time varied from 10-26 h [62,
63].
Perumal et al. presented the synthesis of amidophenols
from phenols, aldehydes and acetyl chloride in acetonitrile
using iodine catalyst (Scheme 38). The yield varied from 62-
90% and the reaction time varied from 3-6 h [64].
Iodine-catalyzed Mannich reaction under solvent-free
conditions from aldehydes, aniline and acetophenone at
room temperature was presented by Gang et al. (Scheme 39).
The temperature varied from room temperature to 50ºC and
the reaction time varied from 5-24 h. The yield varied from
28-92%. Instead of acetophenone, cyclohexanone was used
Organic Domino Reactions Catalyzed by Molecular Iodine Recent Patents on Catalysis, 2012, Vol. 1, No. 2 147

H
OH Iodine Ph N O
solvent-free, 5 min
Ph CHO NH 2CONH 2 O
Hot plate, 80oC
Ph = substituted phenyl

90-96%
Scheme 40.

H CHO SH

O N Iodine (15 mol%) N

O
DCM, 120 min S
R1 R2 r.t.
R2
R1 = H, 2-Me, 4-Me, 2-OMe, 4-OMe, 4-Cl, R1
2F, 2-OEt, 4-Br, 1-napth-, terephth-, 45-95%
4-benzyloxy,
R2 = 4-OMe, 4-Br

Scheme 41.

and the yield was varying from 74-96%. Time taken varied
from 1-3 h and the temperature varied from room tempera-
ture to 50ºC [65].
Synthesis of 1,2-dihydro-1-arylnaphtho[1,2e][1,3] oxaz-
ine-3-ones from
-napthol, benzaldehydes and urea was re-
ported by Pasha et al. under solvent-free condition by iodine
catalyst (Scheme 40). The yield varied from 90-96% [66].
Synthesis of 1-((phenylthio) (phenyl) methyl) pyrrolidin-
2-one derivatives from 2-pyrrolidone, benzaldehydes and
thiophenols was reported by Sathiyanarayanan et al. using
15 mol% of iodine as efficient catalyst (Scheme 41). N-
acyliminium cation intermediate is formed in the initial step
by the attack of iodine to the carbonyl oxygen of aldehyde
thereby carbonyl carbon gets bonded with nitrogen of 2-
pyrrolidone. Finally to the N-acyliminium cation nucleo-
philic attack of thiophenol takes place to yield the pyrrolidin-
2-one derivatives. The yield varied from 45-95% [67].
Synthesis of
-amino ketone from acetone, benzaldehyde
and aniline using 5 mol% of iodine as catalyst was reported
by Xia et al. The authors have developed an efficient method
for a Mannich reaction between acetone, benzaldehyde and
aniline at room temperature (Scheme 42). The yield varied
from 61-95% and the reaction time varied from 0.5 to 6 h
[68]. Similarly, the synthesis of
-amino ketone from ace-
tone, benzaldehyde and aniline was reported by Tallapally
Swamy and his co. workers. The author used 10 mol% of
iodine in ethanol as a catalyst in order to prepare good to
excellent anti selective
-amino ketone in high yields [70].
CHO NH2
O 5 mol% Iodine O bazole derivatives via N-alkylation, N-arylation, azocou-
r.t., 0.5-6 h
R R'
61-95%
R = R' = H, 4-Cl, 4-CF3, 4-F,
3-F, 4-CH3, 3-CF3
Scheme 42.
MICHAEL REACTION
In 1887, A. Michael et al. developed the base-promoted
addition of carbon nucleophiles to activated-unsaturated sys-
tems [69].
Xia et al. reported the solid-state synthesis of 4-[(Indol-3-
yl)-arylmethyl]-1-phenyl-3-methyl-5-pyrazolones from alde-
hydes, indole and 1-phenyl-3-methyl-5-pyrazolone using
molecular iodine as catalyst (Scheme 43). The yields varied
from 72-93% [71]. They had carried out a model reaction
between 4-chlorobenzaldehyde and indole with 1-phenyl-3-
methyl-5-pyrazolone in the presence of iodine to optimize
the reaction condition. They used a green method to synthe-
sise the desired product by grinding the reactants with iodine
as a catalyst in a mortar.
Ph OH
10 mol% Iodine
O N
N N N
Ph CHO
solvent-free, N N
H r.t. 2 h H HO Ph
Ph
Ph = substituted phenyl 72-93%
Scheme 43.
Dehaen et al. presented a facile efficient three-stage one-
pot approach for the synthesis of 6-monosubstituted and 6,
12-disubstituted 5, 11-dihydroindolo-[3, 4-b]carbazoles (ICZs)
via Michael reaction using iodine catalyst (Scheme 44) [72].
They had reported an extension of their method for the syn-
thesis of both 6-monosubstituted and asymmetrically 6, 12-
disubstituted ICZs. Besides they synthesized a variety of
functionalized 6-pentyl-5, 11-dihydroindolo [3, 2-b]car-
pling, formylation, and bromination [72].
N
H
Bandgar et al. developed an efficient method for the syn-
thesis of bis(indolyl)methanes from indole and benzalde-
hydes using 20 mol% of iodine as catalyst. The authors have
proposed a possible mechanism for the formation of bis (in-
dolyl)methanes where iodine initiates the reaction to proceed
further (Scheme 45). The desired product was obtained im-
148 Recent Patents on Catalysis, 2012, Vol. 1, No. 2 Ramachandran and Sathiyanarayanan

mediately after a few seconds of stirring the reaction mixture
containing iodine in acetonitrile with excellent yield (81-
100%) [73].
Ji et al. reported the synthesis of bis(indolyl)methanes
from indole and benzaldehydes in the presence of iodine as
catalyst under solvent-free conditions at room temperature
(Scheme 46). Dehaen et al., [72] and Bandgar et al. [73]
have synthesized same bis(indolyl)methanes by a conven-
tional method but Ji et al. have proposed a new synthetic
methods to synthesis bis(indolyl)methanes using microwave
oven. The yield varied from 62-91% and the reaction time
varied from 7-10 min [74].
Kidwai et al. described iodine-catalyzed for the synthesis
of bis(4-hydroxycoumarin)methanes in water from alde-
hydes and 4-hydroxycoumarin (Scheme 47). The yield was
varied from 91-99% and the reaction time varied from 20-34
min [75].
Efficient method for the synthesis of bisindolyl oxindoles
analogs from isatin and indoles/pyrrole using iodine as cata-
lyst was developed by Mondal et al. Only 5 mol % of iodine
is used to catalyze this reaction to synthesise 3,3-
diheteroaromatic oxindole derivatives (Scheme 48). The
yield varied from 85-98% and the reaction time varied from
15-120 min [76].
A simple and efficient method for the synthesis of both
symmetrical and unsymmetrical triindolylmethanes from
indole-3-carboxaldehyde and substituted indoles using io-
dine as a Lewis acid catalyst was reported by Mondal et al.
(Scheme 49). When the reaction was carried out at elevated
temperatures 65 - 70ºC it took less time compared to those at
room temperature but gave lower yield, so all the reactions
were carried out in the room temperature. The yield varied
from 75-95% and the reaction time varied from 5 min to 48 h
[77].
Jun et al. reported the synthesis of symmetrical triin-
dolylmethanes from indole and triethyl orthoformate under
solvent-free condition catalyzed by iodine (Scheme 50). This
reaction was carried out in the presence of 5 mol% iodine
and the desired product was formed in moderate to excellent
yields 79 – 99% at room temperature. The reaction time var-
ied from 2-300 min [78].

Ph

Iodine
2 Ph CHO
N CH 3CN, r.t. N N
H H H
Ph = substituted phenyl 14 h

Scheme 44.

Ph
20 mol% Iodine
2 Ph CHO
N immediately
H CH3CN, r.t. N N
H H
81-100%

Scheme 45.

Ph
Iodine, r.t.
2 Ph CHO
N Solvent-free
H N N
7-10 min H H
62-91%

Scheme 46.
O O O O O
10 mol% Iodine O
2 Ph CHO
H2 O, 1 atm, 100o C
Ph = substituted phenyl
OH 20-34 min
OH Ph
91-99%

Scheme 47.
Organic Domino Reactions Catalyzed by Molecular Iodine Recent Patents on Catalysis, 2012, Vol. 1, No. 2 149

R1
N
R2
O R3
R3 R3
Iodine, (CH3 )2 CHOH
O
N R2
N r.t., 15-120 min N R2 N
H H
R1 R1
85-98%

Scheme 48.

CHO
R1 R1 )2
5 mmol% Iodine
R2 R2
N N CH3CN/MeOH, r.t. N
N H
H H H
5 min - 48 h
75-95%

Scheme 49.

H
N
R1
R1
R1 O O 5 mol% Iodine
R1
O Solvent-free, r.t. N
N N
H 2 - 300 min H H
79-99%%

Scheme 50.

Ph
2 mol% Iodine
Ph CHO
N CH3CN, Heat NH
H N
5-45 min H Ph
20-85%

Scheme 51.

Synthesis of 6,12-disubstituted 5,7-dihydroindolo[2,3-
b]carbazoles from indole and benzaldehydes using molecular
iodine as catalyst was developed by Bhuyan et al. (Scheme
51). The authors have investigated the mechanism for the
formation of product. Initially bis(indol-3-yl)methane was
formed which in turn reacted with the second aldehyde in the
presence of iodine and eliminated water molecule to give the
intermediate which then subsequently oxidized to the fully
aromatized 6,12-disubstituted 5,7-dihydroindolo[ 2,3-b] car-
bazole [79].
NIEMENTOWSKI QUINAZOLINE SYNTHESIS
In 1895, Niementowski first reported the formation of
3,4-dihydroquinazolines by reaction of anthranilic acid and
amides and the product obtained in the first step had under-
gone a cyclization to form the final product [80].
Rostamizadeh et al. carried out the reaction with isatoic
anhydride, an aromatic aldehyde, ammonium acetate, and a
catalytic amount of I2 under solvent-free conditions under
stirring at 115ºC and the corresponding 2,3-dihydroquinazo-
lin-4(1H)-ones (1) were obtained in excellent yield (Scheme
52). Thus they had presented an easy and green method for
the synthesis of a new class of the quinazolinone family. In
the absence of I2 the reaction did not proceed and also when
instead of ammonium acetate other amines like ethylamine,
methylamine, and aniline were used the products were not
achieved [81]. The yields varied from 94-99% and the reac-
tion time varied from 4-25min.
Dabiri et al. also reported the synthesis of quinazolinones
(2) from isatoic anhydride, aromatic aldehyde and aniline
instead of ammonium acetate (Scheme 52). The yields varied
from 40-74% and the reaction time varied from 5-10 [82].
The yield is moderate.
SAKURAI-HOSOMI REACTION
In 1976, Hosomi and Sakurai reported the nucleophilic
addition of allylic silanes to carbon electrophiles accompa-
nied by regiospecific transposition of the allylic moiety using
Lewis acid as catalyst [83, 84].
150 Recent Patents on Catalysis, 2012, Vol. 1, No. 2 Ramachandran and Sathiyanarayanan

Iodine, 115o C NH

NH 4OAc Solvent free N Ph

O H
4-25 min
(1) 94-99%
Or
O Ph CHO Or
NH 2
O
N O
H Iodine, AcOH Ph
Ph = substituted phenyl N
CH3CN : H2O (1:1)
Reflux 5-10 h N Ph
H
(2) 45-74%

Scheme 52.

Iodine (catalyst)
2 Me3SiCH2CH =CH2 PhCHO MeOH PhCH2CH2CH =CH2
CH2Cl2, 40oC, 1hr
Ph = substituted phenyl
77-94%

Scheme 53.

O
OSiMe3 10 mol% Iodine O
SiMe3
Ph H
DCM, 0oC Ph
Ph = substituted phenyl 40-90 min
65-86%

Scheme 54.

O 10 mol% Iodine O
HO TMSX
R H DCM, r.t.
R X
R = substituted phenyl X = N 3, CH 2-CH=CH2 10-20 min
70-80%

Scheme 55.

Sakurai et al. reported the allylation reaction of carbonyl
compounds into homoallyl ethers using an allylsilane by
iodine catalyst. This was the first report of the three compo-
nents domino reaction using iodine as catalyst in 1984 and
more publications were reported only after 2004 (Scheme
53) [85].
They carried out a reaction by combining three consecu-
tive reactions namely, silylation, acetalization and allylation.
Synthesis of homoallyl ether can be achieved using iodine as
catalyst from a mixture of methanol, benzaldehyde and allyl-
trimethylsilane.
Phukan et al. presented the synthesis of homoallyl benzyl
ethers from aldehydes using iodine catalyst (Scheme 54).
The yields ranged from 65-86% and the reaction time varied
from 40-90 min [86].
Optimal condition for the synthesis of homoallyl benzyl
ethers was developed by considering several parameters like
catalyst concentration, solvents and the amount of benzy-
loxytrimethylsilane & allyltrimethylsilane.
Jhillu et al. prepared
-alkoxy azides and homoallyl
ethers from aldehydes, alcohols and TMSN3/allyltrimethylsi-
lanes using iodine catalyst (Scheme 55). The yields ranged
from 70-80% and the reaction time varied from 10-20 min
[87].
SAKURAI-PRINS-RITTER REACTION
Sabitha et al. described the diastereoselective synthesis
of 4-amido tetrahydropyrans by molecular iodine catalyst
from aldehydes, allyltrimethylsilane in acetonitrile (Scheme
56). The yields ranged from 60-98% and the reaction time
varied from 0.4-3 h [88]. Initially they studied the reaction
with 1.0 eq of n-butyraldehyde and 0.6 eq of allyltrimethylsi-
lane using iodine catalyst in acetonitrile by means of a Sa-
kurai-Prins-Ritter reaction sequence. The presented reaction
was highly diastereoselective as determined from the NMR
spectra of the crude products.
STRECKER SYNTHESIS
In 1850, Strecker synthesized
-amino acids by hydroly-
sis
-aminonitriles which were obtained from aldehydes,
ammonia and hydrogen cyanide. The scope of the reaction
was extended to the primary or secondary amines instead of
ammonia [89].
Organic Domino Reactions Catalyzed by Molecular Iodine Recent Patents on Catalysis, 2012, Vol. 1, No. 2 151

NHCOCH3

10 mol% Iodine
RCHO Si(CH 3)3
CH 3CN
CH3 CN, r.t.
R = Alkyl or Aryl R O R
0.4-3 h
60-98%

Scheme 56.

Iodine
TMSCN NHR'
RCHO RNH2 or CH3CN, r.t. R CN
Bu3SnCN
R = Substituted Phenyl

Scheme 57.
R5
R3 R O
2
R4
R1 O O
O HO
3 mol% Iodine R4 R4
O
tandam Michael, r.t. R1 iodine cyclization R R3
3
R1 C(O)R5 O r.t., 5 h R2 O R2
O R2
R2 R3 H R1 R1
R 3 R4 L-proline, DMSO R5
R 4 OH
O
3d

Scheme 58.

OH R
Iodine, 2-5 h
2 RCHO
Neat,
R = Substituted Phenyl
O
82-95%
Scheme 59.

De et al., Hong-She et al. and Janda et al. had synthe-

sized
-aminonitriles by a three component condensation of MISCELLANEOUS DOMINO REACTION
aldehydes/ketones, amines and trimethylsilyl cyanide/ tribu- Das et al. presented an efficient synthesis of 14-aryl or
tyltin cyanide using iodine catalyst (Scheme 57) [90, 91, 58]. alkyl-14-H-dibenzo [a,j]xanthenes from -napthols and ben-
They carried out the reaction between benzaldehyde and zaldehydes using iodine catalyst (Scheme 59) [93].
benzyl amine with TMSCN using catalytic amount of iodine Synthesis of substituted 2-amino-2-chromenes using io-
giving 2-(N-benzylamino)-1-phenylacetonitrile. In the same dine and K2 CO3 as catalyst in aqueous medium from benzal-
manner they synthesised a variety of
-aminonitriles in good dehydes, -napthols and malononitrile was reported by Cai
to excellent yields using diverse range of aldehydes, a wide et al. (Scheme 60) [94]. The reaction was carried out in
range of amines and trimethylsilyl cyanide in a one-pot fash- aqueous medium.
ion at room temperature using catalytic amount of iodine.
NH2
OH
CN
TANDEM MICHAEL-CYCLIZATION CN Iodine/K2CO3 O
RCHO
Cravero et al. reported the synthesis of 9-Substituted-1,8- KI/H 2O, 100oC R
CN
dioxooctahydroxanthenes from 1,3-cyclohexanediones using R = Substituted Phenyl
5-25 min
iodine as catalyst. Synthesis of octahydroxanthene has been 89-97%
carried out from the Knoevenagel reaction between dime-
Scheme 60.
done and benzaldehydes in the presence of a catalytic
amount of 3 mol % of iodine (Scheme 58). The authors have Synthesis of 12-aryl-8,9,10,12-tetrahydro-benzo[a]xan-
developed a simple, efficient, and practical method for the then-11-one derivatives was developed by Wang et al. under
synthesis of oxooctahydroxanthenes in high yields by em- solvent-free conditions using iodine catalyst (Scheme 61)
ploying a sequential tandem Michael–iodine-catalyzed cycli- [95]. In an initial endeavor the authors had synthesized 12-
zation [92]. aryl-8,9,10,12-tetrahydro-benzo[a]xanthen-11-one from a
152 Recent Patents on Catalysis, 2012, Vol. 1, No. 2 Ramachandran and Sathiyanarayanan

mixture of 2-naphthol, 4-chlorobenzaldehyde, and 5,5- Synthesis of unsymmetrical meso-substituted porphyrins

dimethyl-1,3-cyclohexanedione under reflux conditions us-
ing iodine catalyst in 1,2-dichloroethane. Reaction yields
were improved under the solvent-free reaction conditions.
Rawat et al. developed the synthesis of 3, 6-diphenyl [1,
2, 4, 5]tetraoxanes using iodine as catalyst (Scheme 50) and
he also studied its antimalarial activity [96].
In most of the cases bishydroperoxide has been used as
an intermediate for the synthesis of tetraoxanes.
Tu et al. developed iodine promoted Domino reaction
leading to N-substituted 2-aminoquinoline-3-carbonitriles
under microwave irradiation (Scheme 51) [97].
Iodine-promoted domino reaction of 2-aminochromene-
3-carbonitrile with isocyanate under microwave irradiation
led to the highly regioselective formation of N-substituted 2-
aminoquinoline-3-carbonitriles. Initially the reaction of
arylidenemalononitrile, dimedone and aromatic amine in
DMF under microwave heating, instead of the desired N-
aryl-2-aminoquinoline-3-carbonitriles, led to chromene-3-
carbonitriles in high yields. A new mechanism involving
ring-opening/recyclization was proposed for this reaction.
using iodine as catalyst was reported by Zerrouki et al.
(Scheme 52) [98].
They had used the same method for the synthesis of un-
symmetrical porphyrins especially 5-(4-nitrophenyl)-10, 15,
20-triphenylporphyrin.
Sobhani et al. reported an efficient synthesis of primary
1-aminophosphonates using molecular iodine as catalyst
(Scheme 65). The yield varied from 70-96% and the reaction
time varied from 10 min - 4 h [99].
A new synthetic route for the one-pot synthesis of pri-
mary 1-aminophosphonates (1-functionalized phosphonates)
was developed from aldehydes/ketones, HMDS, diethyl
phosphite and molecular iodine as catalyst under solvent-free
conditions.
Khan et al. reported the synthesis of highly functional-
ized piperidines in five-component reaction using iodine as
catalyst (Scheme 66) [100]. Synthesis of highly functional-
ized piperidine was developed from 4-methylbenzaldehyde,
aniline and methyl acetoacetate using 10 mol % of iodine at
room temperature. Khan et al. targeted synthesis of highly
functionalized piperidines using diethyl malonate as a reac-
tant but while using acetylacetone as a reactant they got
-
amino carbonyl compound.

O O
OH
10 mol% Iodine
ArCHO
Solvent-free, 60oC
O
Ar O
Ar = Substituted Phenyl 45-95 min

82-94%

Scheme 61.

CHO O O
Iodine, MeCN, r.t.
2 2 H2O2
HBF4.Et2O O O

25-54%

Scheme 62.

O O Ar
Iodine CN
Ar CN
ArNH 2 R-N=C=O
DMF, MW R
CN O N N
20-36 min H
R, Ar = Substituted Phenyl 150 oC 62-85oC

Scheme 63.
Ar

H
N NH N
1 ) Iodine, DCM, MW
4 4 Ar CHO Ar Ar
2) p-chlor anil, r.t
N HN
Ar = Substituted P henyl

Ar
Scheme 64.
Organic Domino Reactions Catalyzed by Molecular Iodine Recent Patents on Catalysis, 2012, Vol. 1, No. 2 153

R1 O R1 O
10 mol% Iodine
O HMDS P OEt R2 P OEt
H
R2 OEt Solvent-free, 80oC NH2 OEt
10-210 min
R1=alkyl, aryl, heteroaryl 70-96%
R2=alky, H

Scheme 65.

O O O O NH O
NH O NH2 CHO

EtO OEt Me OEt OEt

OEt
Iodine, MeOH, r.t. Iodine, MeOH, r.t.
N
O OEt
8-48 h

Scheme 66. 36-88%

O O R2 O O
Iodine, CuO
O
R R1 R OR 1
H DMSO, 70oC 6 h
O
R 2 = (hetero)aryl, alkenyl
R, R1 = (hetero)aryl, alkenyl, alkyl, alkoxyl
R2

74-86%

Scheme 67.

CHO HN N
N
Iodine N
NaN3 NH3
100oC, 7-12 h
65-90%

Scheme 68.

R O
O O
O N
R 10 mol% Iodine
HN
O N
HN EtOH, reflux
H
O O
15-30 min
R = Substituted Phenyl O
86-96%

Scheme 69.

Wu et al. described the formation of the unsymmetrical
1, 4-enediones via a domino strategy by cross coupling of
1,3-dicarbonyl compounds and methyl ketones or terminal
aryl alkenes using iodine catalyst (Scheme 67) [101].
The feasibility of the strategy was examined by carrying
out a reaction between acetophenone and ethyl benzoylace-
tate at 70ºC. The reaction was carried out in DMSO for 12 h
in the presence of copper (II) oxide and iodine as catalyst.
The yield varied from 74-86%. In most of the cases they
found that the reaction delivers a mixture of E/Z isomers and
the thermodynamically stable E-isomers were the major
products.
Pasha et al. presented the conversion of arylaldehydes
into 5-aryl-1H-tetrazoles using iodine as catalyst without
isolating the corresponding 4-methoxybenzonitrile at 100ºC
(Scheme 68). The yield varied from 67-90% and the reaction
time varied from 7-12 h [102].
Ma et al. developed the synthesis of 2H-indazole [2, 1-b]
phthalazine-1, 6, 11, (13H)-trione derivatives using molecu-
154 Recent Patents on Catalysis, 2012, Vol. 1, No. 2 Ramachandran and Sathiyanarayanan

NH2 R1

R Iodine, r.t.
O
Air, MeNO2
H R1 N R
12 h
R = Substituted Phenyl 32-82%

Scheme 70.

I
R R2
OH R1
NH Iodine, MeCN
R2 N
0oC, 30 min R
N O
H R1
N O
R = Ph, Benzyl, iPr R 1, R2 = Substituted Phenyl H
52-72%

Scheme 71.

lar iodine catalyst in ethanol (Scheme 69). The yield varied R1 O

from 87-96% and the reaction time varied from 10-30 min COOR HN
1-4 h
[103]. N R2
R 1 NH 2
ROOC
Lin et al. described the synthesis of quinolines from COOR I2 (10 mol%) 68-85
amines, aldehydes and alkynes using iodine as catalyst MeOH
(Scheme 70). The yield varied from 32-82% and the reaction ROOC
N
R2
time was 12 h [104]. This work has been patented by Lin R 2 NH 2 HCHO X
ROOC N
et al. entitled “METHOD FOR PREPARING QUINOLINE”
R1
[105]. Exhaustive studies of the reaction conditions had been R = Me/Et
carried out for the synthesis of quinoline using molecular
iodine as catalyst from p-methoxyaniline with benzaldehydes Scheme 72.
and phenylacetylene. The solvent of choice was found to be
Phukan et al. reported a simple method for the synthesis
MeNO2 in the presence of 10 mol% of iodine at room tem-
of Cbz-protected homoallylamines from a three component
perature.
aldehydes, benzyl carbamate and allyltrimethylsilane using
Kundu et al. reported the synthesis of Iodo- iodine as a catalyst (Scheme 73). The author has utilized 10
Indoloazepinones in an iodine-mediated domino reaction via mol% of iodine as catalyst in acetonitrile at 25ºC and the
a regioselective 7-endo-dig Iodo-cylization pathway using reaction time varied from 10-20 min [108].
iodine as catalyst (Scheme 71). The yield varied from 52- NHCbz
O 10 mol% Iodine
72% and the time taken to complete the reaction was 30 min Cbz NH2
SiMe 3
o R
[106]. A novel three-component strategy involving an elec- R H CH3CN, 25 C
10-20 min 66-82%
trophilic 7-endo-dig cyclization pathway was developed by
treating bifunctional indole-2-carboxamide with the three-
carbon 1,3-disubstituted propargyl alcohol derivatives. Use Scheme 73.
of molecular iodine as catalyst for this domino reaction was
carried out instead of metal catalyst. Sessler et al. developed an efficient method for the syn-
thesis of cyclononatripyrroles from ethyl 3,3-dimethyl-5,7-
Abu et al. developed the synthesis of substituted dihydro- dihydro[1,3] dioxepino[5,6-c]pyrrole-6-carboxylate using
2-oxypyrrole catalyzed by molecular iodine by One-pot four- iodine as a catalyst in methanol (Scheme 74). The author had
component domino reaction (Scheme 72). The yield varied utilized 1 mol% of iodine as catalyst and the reaction mix-
from 68-83% and the reaction time was 1 - 4 h [107]. ture was gently heated to obtain the desired product [109].
Optimal reaction condition for these reactions was found Synthesis and straightforward construction of tetrasubsti-
by varying the solvent and loading the amount of catalyst. tuted hydantoins from simple 1, 3-dicarbonyl compounds,
The reaction was carried out using dimethyl acetylenedicar- ureas, and methyl ketones or terminal aryl alkenes via an
boxylate, aniline and formaldehyde in 10 mol % of iodine at integration of two coupled domino processes in a one-pot
room temperature. reaction was developed by Wu et al. (Scheme 75). The
authors have investigated the reaction mechanism and found
Organic Domino Reactions Catalyzed by Molecular Iodine Recent Patents on Catalysis, 2012, Vol. 1, No. 2 155

to contain six mechanistically different reactions: iodination, Bhosale et al. reported the synthesis of Tetrahydro-
Kornblum oxidation, Knoevenagel condensation, dinucleo- benzo[b]pyrans from cyclic dimedones, benzaldehyde and
philic addition, oxidative dehydrogenation, 1, 2-rearrangement malononitrile using 10 mol% of iodine as efficient catalyst in
reaction [110]. a simple and convenient method (Scheme 77). The author
had utilized DMSO solvent at 120ºC to get higher yield. The
EtOOC reaction time varied from 3-4 h [112].
NH
O O 1 mol% Iodine Wu et al. developed a concise and efficient method for
HN the synthesis of polyenic diones from
, -unsaturated
gentle heating
methyl ketones using copper (II) oxide and iodine as a cata-
COOEt MeOH, 16 h EtOOC COOEt
N lyst (Scheme 78). The author has investigated and proposed
H NH the reaction mechanism. During the reaction process, precur-
Scheme 74. sor
, -unsaturated methyl ketone presents a self-sorting
property [113].
Rong et al. reported the synthesis of xanthenedione from
Wu et al. has developed the convergent and linear dom-
Imines, 5,5-Dimethyl-1 and 3-cyclohexandione using 2
ino reactions for the synthesis of indole-furan conjugates
mol% of iodine as catalyst. The authors have investigated the
from indoles, methyl ketones, and 1,3-dicarbonyl com-
mechanism for the formation of xanthenedione using iodine
pounds using CuO and iodine as catalyst in DMSO (Scheme
as catalyst; here iodine acts as a weak Lewis acid (Scheme
79). The author has investigated and proposed the reaction
76). At initial stage molecular iodine became polarized by
mechanism which undergoes linear domino FriedeleCrafts
the influence of zinc powder thereby it initiates the reaction
alkylation/PaaleKnorr cyclization to afford the expected 3-
to form the desired product. The yield varied from 84-97%
(furan-3-yl or 4 -yl)indole derivatives [114].
[111].

O
R4
OO N R4
O R1 N
R2
O O Domino O R1
R1 Domino O
R3 Process II O
G

R2 R3 Process I O R2
R1 I2 R3
O
CuO, I2 R4 R4
N N
or IBX, CuO, I2 H H

Scheme 75.

CHO NH2 O O O
2 mol% Iodine
2
Zn, MeOH, 70oC
O O
84-97%

Scheme 76.

O CHO O
CN 5 mol% Iodine CN
CN DMSO,
O O NH2
3-4 h
80-92%

Scheme 77.

O O SMe
CuO, Iodine
R
R DMSO, 65oC R
20 h O
49-80%

Scheme 78.
156 Recent Patents on Catalysis, 2012, Vol. 1, No. 2
O O O O
(i) CuO, I2, DMSO, 70oC
O
(ii)
CH3SO3H, CH3CN, reflux
Scheme 79.
CURRENT & FUTURE DEVELOPMENTS
Domino reaction using iodine catalyst provides one-pot
fashion to synthesize exciting target molecules in organic
chemistry which otherwise would require multi-step synthe-
ses and it quickly became a powerful and efficient tool in
organic chemistry. We have illustrated the development and
utility of molecular iodine as a Lewis acid catalyst in domino
reaction, knowing the potential of molecular iodine in sev-
eral organic syntheses. With this tremendous potential utility
of molecular iodine in domino reaction, we are sure that this
reagent still has a long way to go as a catalyst in organic
synthesis concerned. We hope that this review will contrib-
ute to the discoveries of new synthesis in organic chemistry.
The authors regret if any omissions had occurred in this re-
view.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flicts of interest.
ACKNOWLEDGEMENTS
The authors thank the management of VIT University,
Vellore, India, for carrying out this study.
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