Multicomponent Reactions in Unconventional Solvents State of The Art

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Cite this: Green Chem., 2012, 14, 2091

www.rsc.org/greenchem CRITICAL REVIEW
Multicomponent reactions in unconventional solvents: state of the art
Yanlong Gu*a,b
Received 25th April 2012, Accepted 31st May 2012
DOI: 10.1039/c2gc35635j
Simple and green synthetic procedures constitute an important goal in organic synthesis. The combination
Published on 01 June 2012 on http://pubs.rsc.org | doi:10.1039/C2GC35635J
of multicomponent reactions (MCRs) and unconventional solvents has become a new research direction,
which enables simultaneous growth of both MCRs and green solvents toward ideal organic synthesis.
This review summarizes recent results of MCRs obtained in unconventional media including water, ionic
liquids, polyethylene glycol and bio-based solvents.
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1. Introduction manufacturing process, and because recovery efficiency is far

from satisfactory they are major contributors to environmental
The conventional multistep preparation of a complex molecule pollution.6 In order to remove organic solvents from the chemi-
generally involves a large number of synthetic operations, cal process, an important aspect of green chemistry pertains to
including extraction and purification processes in each individual the elimination of volatile organic solvents or their replacement
step. This leads to not only synthetic inefficiency but also gener- by non-flammable, non-volatile, non-toxic and inexpensive
ates large amounts of waste. Multicomponent reactions (MCRs), “green solvents”.7 In this regard, development of solvent-free
defined as one-pot reactions in which at least three different sub- alternative processes is the best solution, especially when either
strates join through covalent bonds, have steadily gained impor- one of the substrates or the products is a liquid and can be used
tance in synthetic organic chemistry. MCRs allow the creation of as the solvent of the reaction.8 However, if solvents are crucial to
several bonds in a single operation and offer remarkable advan- a process, we should select solvents that will have no or limited
tages like convergence, operational simplicity, facile automation, impact on health and the environment.
reduction in the number of workup, extraction and purification Indeed, the use of unconventional green solvents in organic
processes, and hence minimize waste generation, rendering the reactions has improved not only the aspect of the reactions from
transformations green.1 One-pot MCRs often shorten reaction the viewpoint of green and sustainable properties, but also the
periods, giving higher overall chemical yields than multiple-step synthetic efficiency by stabilizing the catalyst, changing the reac-
syntheses, and therefore can reduce the use of energy and man- tion selectivity or facilitating product isolation.9 Particularly,
power. MCRs are useful for the expedient creation of chemical unconventional solvents also showed a great ability for assisting
libraries of drug-like compounds with high levels of molecular development of MCRs. Many new one-pot MCRs have been
complexity and diversity, thereby facilitating identification/ successfully developed by means of using an innovative solvent
optimization in drug discovery programmes.2 Therefore, the instead of conventional organic solvents. Moreover, taking
design of new MCRs with green procedure has attracted great advantage of utilizing unconventional solvents as reaction
attention, especially in the areas of drug discovery, organic syn- media, various known MCRs have also been improved in terms
thesis, and material science.3 Moreover, improving already of reaction yield, substrate generality, isolation of products and
known MCRs also is of substantial interest in current organic catalyst recycling. In view of the emerging importance of this
synthesis. area, in this review we will summarize the recent achievements
Recently there has been increasing concern with regard to the in performing MCRs in unconventional solvents. Because water
tight legislation on the maintenance of ‘greenness’ in synthetic and ionic liquids are the main contenders in the area of green
pathways and processes.4 Green chemistry strongly influences solvents, the majority of this review will cover MCRs in these
chemical research, and there is an insistence on the use of two solvents. Polyethylene glycol polymers (PEGs) have also
‘greener’ reaction conditions.5 Volatile organic solvents amount been considered as a new class of green solvents. Recent
to over 85% of mass utilization in a typical chemical attempts at using PEGs as reaction media for MCRs also will be
described in the present review. Benefiting from recent inno-
a
Institute of Physical Chemistry and Industrial Catalysis, Hubei Key vation in utilizing bio-based chemicals as green solvents,10 some
Laboratory of Material Chemistry and Service Failure, Huazhong MCRs have also been developed in bio-based solvents, which
University of Science and Technology, School of Chemistry and contributes another part of this review. Because reactions that
Chemical Engineering, Hongshan Division, 1037# Luoyu Road, Wuhan, contain more than two starting materials are generally classed as
Hubei Province 430074, PR China. E-mail: klgyl@hust.edu.cn
b
State Key Laboratory for Oxo Synthesis and Selective Oxidation, MCRs, this review will only summarize MCRs that contain at
Lanzhou Institute of Chemical Physics, Lanzhou, 730000, PR China least three different starting materials.
This journal is © The Royal Society of Chemistry 2012 Green Chem., 2012, 14, 2091–2128 | 2091
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2. MCRs in water
As a reaction medium, water complies with all the current strin-
gent requirements on sustainable chemistry. Therefore, the devel-
opment of synthetically useful reactions in water is of
considerable interest.11 It should be noted that a large list of
examples in the recent chemical literature shows that organic
reactions performed at the organic–water interface (“on water”)
are not only typically faster, but also display novel reactivity
profiles and selectivity. In view of the remarkable accelerating
effect of water on various organic reactions, the inherent property
of the water–organic interface has been investigated recently,
which explains, to some extent, the enhanced reactivity of hydro-
phobic organic substrates “on water”. It was found that the

surface of the water, adjoining the oily globules encompassing
the reactants, has as many as 25% of the O–H bonds not
involved in hydrogen bonding.12 The interactions of these
unbound hydroxyl groups with organic substrates and, more
importantly, with the transition states, lower the activation ener-
gies, enabling rate enhancements. The continuous renewal and

reorganization of the hydroxyl groups on the water surface
renders water a powerful “catalyst” for organic reactions of
hydrophobic substances. Besides this hydrogen bond effect,
there are two other effects that have often been adopted for
explaining the observed remarkable performance of water
solvent: (i) the hydrophobic effect, which leads to high negative
volume of activation and greater stabilization of activated com-
plexes than hydrophobic reactants in the reaction; (ii) the polarity
effect, where the high polarity of water results in more polar
translated states than initial states, so the reaction speed can be Scheme 1 MCRs of β-dicarbonyl compound and formaldehyde in
increased.13 However, until now, the exact roles of water in an water.
organic reaction are still not understood. And consequently, in a
reaction, the exact nature of the water influence cannot be
ascribed to a single effect but rather to a superposition of several materials. Because of the high reactivity in aqueous media, the
factors. following three reactions have often been adopted: (i) Knoevena-
Because performing a MCR in water combines the synthetic gel reaction between 1,3-dicarbonyl compounds and formal-
efficiency of multicomponent protocols with the environmental dehyde; (ii) Knoevenagel reaction of aromatic aldehyde with
benefits of using water as the reaction medium, which would malononitrile or cyanoacetic ester; and (iii) Knoevenagel reac-
lead to processes close to the ideal synthetic reaction, this topic tion of isatin with malononitrile. In order to achieve the highest
thus constitutes a very important challenge for green chemistry. levels of structural diversity, MCRs based on Knoevenagel reac-
Indeed, many unique MCRs that cannot be attained in conven- tion are usually combined with powerful complexity-generating
tional organic solvents have been developed.14 In 2009, Kumara- reactions, such as inter- or intramolecular Diels–Alder, Michael
vel and Vasuki published a comprehensive review, in which they and the formation of heterocycles.
summarized all the early results in this area.15 This part of Gu and Jérôme18 have reported a water-mediated three-com-
present review will only focus on the results reported afterward. ponent reaction of 1,3-dicarbonyl compounds, formaldehyde and
α-methylstyrene, which provides 2,5,6-trisubstituted dihydro-
2.1. MCRs in water based on Knoevenagel condensation pyrans, which are useful building blocks for organic synthesis,19
in good yields (Scheme 1). The reaction was performed in water
Base-catalyzed condensation of aldehydes with 1,3-dicarbonyl without the use of any catalyst. The key to this reaction is the
compounds (Knoevenagel reaction) is widely used to synthesize generation of a methylene intermediate (I) through Knoevenagel
various polyfunctionalized organic compounds. Because the reaction of 1,3-dicarbonyl compound and formaldehyde, which
product of Knoevenagel reaction can be easily converted to more can then be trapped by α-methylstyrene by oxo Diels–Alder
complex molecules in the presence of a suitable reagent, many reaction. Investigation of the mechanism revealed that water
MCRs have been developed based on Knoevenagel reaction.16 plays an indispensable role not only in generating the reaction
Importantly, because Knoevenagel condensation can be con- intermediate I but also in enhancing the reaction rate of the oxo
ducted under conditions that are compatible with aqueous Diels–Alder reaction.20 Indole can also be used as a nucleophile
environments,17 it has often been involved in developing MCRs instead of α-methylstyrene. In this case, the intermediate I was
in water. It should be noted that MCRs based on Knoevenagel trapped by a Michael reaction of indole. Because indole can also
reaction are closely related to the reactivity of the starting react with formaldehyde under the reaction conditions, excess
2092 | Green Chem., 2012, 14, 2091–2128 This journal is © The Royal Society of Chemistry 2012
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Scheme 2 Generation and trapping of 2-methylene-1,3-dicarbonyl

intermediate through oxidation of Baylis-Hillman alcohol in water.
amount of 1,3-dicarbonyl compound and formaldehyde have to

be used in order to get a good yield. Remarkably, a novel Scheme 3 MCRs of N,N-dimethylaniline and formaldehyde in water.
pseudo-five-component reaction of N-ethylaniline, acetoacetone
and formaldehyde also occurs selectively, affording a complex

tricyclic skeleton 3 (Scheme 1). This compound might be reaction seems to be a Mannich-type reaction, in which N,N-di-
formed through a cascade of elementary reactions involving (i) alkylaniline plays a role of a secondary amine, a tandem Knoeve-
Friedel–Craft addition of N-ethylaniline to I; (ii) dehydrative nagel–Michael reaction pathway might also be operative for the
cyclization of the adduct II; and (iii) a oxo Diels–Alder reaction formation of compound 6. It should be noted that the use of
between the cyclized product III and I. In aqueous solution of boric acid as a catalyst is the key to render the reaction possible
acetic acid, some phenols, such as 2-naphthol and 6-bromo-2- because a side reaction between N,N-dialkylaniline and formal-
naphthol, can also react with formaldehyde easily to form o-qui- dehyde was predominant under catalyst-free conditions. In an
nones that can then be trapped with α-methylstyrene to form a aqueous solution of ethanol, 2-naphthol can also be used instead
three-component adduct. Some other C–H acids, such as of 1,3-dicarbonyl compound to react with N,N-dialkylaniline and
2-hydroxy-1,4-naphthoquinone, 4-hydroxy-6-methyl-2-pyrone, formaldehyde to form diarylmethane derivative 7 in good yield
barbituric acid, 4,6-dihydroxy-2-mercaptopyrimidine, (Scheme 3).25 However, in this case, an organocatalyst,
4-hydroxy-1-methyl-2-quinolone and 4-hydroxycoumarin, are L-proline, has to be used in order to inhibit the formation of a
also able to react with α-methylstyrene and formaldehyde to symmetrical product generated from N,N-dialkylaniline and for-
form the corresponding three-component adduct in good to maldehyde. Similarly, a three-component reaction of N,N-dialky-
excellent yields.21,22 laniline, formaldehyde and indole was also developed in
However, owing to the fact that the methylene intermediate I aqueous solution of methanol, which provided compound 8 in
was generated through Knoevenagel condensation of formal- good yield, by using a solid acid catalyst, HClO4–SiO2
dehyde, construction of a three-component reaction by means of (Scheme 3).26
trapping of this intermediate sometimes suffers from (i) a side Condensation reaction of an aldehyde with two different
reaction of the trapping reagent with formaldehyde and (ii) a nucleophiles is generally difficult to control. Most of the suc-
Michael-type side reaction of the methylene intermediate and cessful examples deal with the use of nucleophiles that possess a
1,3-dicarbonyl compounds or C–H acids. In order to avoid these specific reactive functional group that allows them fix together
drawbacks, Gu et al.23 reported an alternative method for gener- during the reaction. Without such assisting groups, the selectivity
ating the methylene intermediate by means of oxidation of is notoriously difficult to control. As a result, nucleophiles
Baylis-Hillman alcohol 4 with IBX (iodoxybenzoic acid). without assisting groups are rarely used in the three-component
Because the oxidation could be conducted in pure water, allow- reaction of aldehyde. In order to solve this problem, most of the
ing an easy trapping of the generated methylene intermediate current efforts are devoted toward rational design of a suitable
with many nucleophiles, such as 4-methoxystyrene, indole, 1,3- catalyst that allows the reaction to proceed exclusively. Zhou
dicarbonyl compound and benzamide (Scheme 2). Importantly, et al.27 have developed an efficient three-component reaction of
synthesis of the same dihydropyran 5 through the above-men- indole, aldehyde, and malononitrile that provides 3-indole
tioned three-component reaction of formaldehyde, 4-methoxy- derivative 9 in excellent yield in a simple one-pot procedure by
styrene and β-ketonester was unsuccessful owing to the using a copper(II) sulfonato Salen complex as catalyst in water
extensive formation of side products, indicating the necessity of solvent (Scheme 4). A weak acid, KH2PO4, was used in order to
using a Baylis-Hillman alcohol as substrate for generation of the improve the reaction selectivity, in which KH2PO4 most likely
methylene intermediate. played a role of controlling the pH value of the aqueous solution.
In 2008, Kumar et al.24 described a boric acid-catalyzed three- However, this system was negatively affected by the following
component reaction of N,N-dialkylaniline, 1,3-dicarbonyl com- two points: (i) highly complex catalyst systems, and (ii) the sus-
pound and formaldehyde in aqueous micelles constructed by ceptibility of the reaction to the reaction conditions. Therefore,
SDS and water (Scheme 3). Although the mechanism of the Kleij et al.28 recently suggested use of Zn(salphen) complexes as
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Scheme 6 Three-component reaction of 4-nitrobenzaldehyde, benzyl

Scheme 4 Three-component reaction of indole, aldehyde, and malono- mercaptan and acetylacetone in water.
nitrile in water.
Table 1 Three-component reactions of aromatic aldehydes,

malononitrile and dimedone or 4-hydroxycoumarin in water
Entry Catalyst Solvent Ref.

a
1 Zn(Phen)2Cl2 H2O 32
2 [ADPPY]OHb H2O 33
3 [TETA]TFAc H2O 34
4 Aliquat 336 ([Me(CH2)7]3MeNCl) H2O 35
5 DABCO H2O 36
6 TBABd H2O 37
7a Caro’s acid supported on silica gel H2O 38
8a Poly(4-vinylpyridine) supported on MCM-48 H2O 39
Scheme 5 Three-component reaction of N,N-dimethylbarbituric acid, 9 Piperidine H2O 40, 41
10 Morpholine H2O 42
3-nitrobenzaldehyde and sodium cyanide in water.
11a Nano ZnO H2O 43, 44
12a CuO H2O 45
13 [HOCH2CH2NH3]OAc — 46
catalysts for the three-component reaction of indole, aldehyde, 14 Amberlite IRA-400 H2O 47
and malononitrile, which allowed the reactions to be performed 15a [TEBSA]HSO4e H2O 48
in a homogeneous solution, although an organic solvent, 16 LiBr H2O 49
17 — PEG 50, 51
dichloromethane, was used as solvent.
a
A three-component reaction of N,N-dimethylbarbituric acid, The catalyst is recyclable. b 4-Amino-1-(2,3-dihydroxy propyl)-
3-nitrobenzaldehyde and sodium cyanide has been recently pyridinium hydroxide. c Triethylenetetraammonium trifluoroacetate.
d
Tetrabutylammonium bromide. e N,N,N-Triethyl-N-butanesulfonic acid
developed by Soleimani et al.29 using water as a sole solvent, ammonium hydrogen sulfate.
which generates 10 as a sole product (Scheme 5). Interestingly,
while the reaction proceeded very well in pure water, poor yields
were obtained in other solvents such as toluene and ethanol
under the identical conditions, indicating that water played an Knoevenagel condensation between aldehyde and acetylacetone
indispensable role in this model reaction. Mechanism investi- that led to the formation of an intermediate. The following
gation revealed that the reaction might start from a water- Michael addition of thiol to the intermediate provided the
mediated Knoevenagel condensation between N,N-dimethylbar- desired three-component product. After the reaction was com-
bituric acid and 3-nitrobenzaldehyde that generates an intermedi- pleted, the solid crude products precipitated, which were easy to
ate IV. Following Michael addition of sodium cyanide to the separate just by filtration and drying. Besides, the liquid crude
intermediate IV affords the desired product. Because both N,N- products could be separated simply from water through extrac-
dimethylbarbituric acid and 3-nitrobenzaldehyde are insoluble in tion method.
pure water, the so-called “on water” promoting effect might also In the presence of an assisting group, three-component reac-
exist in this reaction. Meldrum’s acid can also be used in this tions of aldehyde and two different nucleophiles is generally
type of three-component reaction instead of N,N-dimethylbarbi- easy to control. For example, three-component reactions of aro-
turic acid.30 matic aldehydes, malononitrile and dimedone or 4-hydroxycou-
Wu et al.31 reported a catalyst-free, simple and efficient three- marin are typical MCRs that were developed based on
component procedure for the synthesis of β-mercapto diketone Knoevenagel reaction of aldehyde with malononitrile. These
derivative 11 from the corresponding aldehyde, acetylacetone MCRs can also be performed in water by using various catalysts
and thiol in water under reflux conditions (Scheme 6). While the listed in Table 1. Some of the catalysts are recyclable in aqueous
reaction proceeded very well in water, poor yields were obtained conditions.
in some organic solvents, indicating the remarkable promoting A pyrido[2,3-d]pyrimidine derivative 12 was synthesized by a
effect of water solvent in this reaction. The three-component three-component reaction of aromatic aldehyde, malononitrile
reaction was influenced by the electronic and steric factors and 6-amino-4-hydroxy-2-mercaptopyrimidine catalyzed by
associated with substituents on aldehydes and the thiols. Mech- SDS in aqueous media (Table 2, entry 1).52 By using
anism investigation revealed that the reaction started from a H14[NaP5W30O110] as catalyst, three-component reaction of
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Table 2 Three-component reactions of benzaldehyde, malononitrile under aqueous conditions
Entry Nucleophile Condition Product Yield (%)
1 H2O, SDS (10 mol%), 90 °C 12 50
2 H2O, H14[NaP5W30O110] (1 mol%), 100 °C, 1 h 13 89
3 H2O, [BMIm]OH, MWI, 45 °C, 4 min 14 94

4 H2O, 100 °C, 35 min 15 97

5 NaN3 H2O, 50 °C, 24 h 16 81
aromatic aldehyde, malononitrile and 3-methyl-1-phenyl-2-pyra-

zolin-5-one could be successfully conducted in water under
reflux, which provided dihydropyrano[2,3-c]pyrazole derivative
13 in high yields (Table 2, entry 2).53 A basic ionic liquid,
[BMIm]OH, has been used for an efficient synthesis of 1H-pyra-
zolo[1,2-b]phthalazine-5,10-dione 14 by one-pot cyclocondensa-
tion reaction of phthalhydrazide, aromatic aldehydes, and Scheme 7 Three-component reaction of benzaldehyde, malononitrile
malononitrile under microwave irradiation in water (Table 2, and 1-naphthol in water.
entry 3).54 In this reaction, the ionic liquid [BMIm]OH could be
recycled up to five times without significant loss of its activity.
Thiopyrano[2,3-b]indole-3-carbonitrile derivative 15 has also choice. On the basis of this principle, Zahouily et al.57 described
been synthesized in water under catalyst-free conditions with an efficient catalytic system by using nanostructured diphosphate
excellent yield through three-component reaction of indoline-2- Na2CaP2O7, with which an environmentally benign synthesis of
thione, aromatic aldehyde and malononitrile (Table 2, entry 4).55 2-amino-chromene 17 through a three-component reaction of
The synthesis was also examined in many other organic solvents, 1-naphthol, malononitrile and aldehyde has been successfully
and it was found that the reaction in water gave the best result. performed in water (Scheme 7). The reaction occurred by the fol-
The reaction proceeds according to a one-pot Knoevenagel con- lowing reaction pathway: (i) Knoevenagel reaction between ben-
densation/Michael addition/cyclization reaction mechanism. zaldehyde and malononitrile; (ii) the ortho C-alkylation of
Sodium azide can also react with benzaldehyde and malono- 1-naphthol with the generated Knoevenagel intermediate; and
nitrile in water without the assistance of any catalyst, providing (iii) intramolecular addition of the hydroxyl group of the alkyl-
5-substituted tetrazole 16 in high yield under mild conditions ated 1-naphthol to α-cyanocinnamonitrile. Intervention of a cata-
(Table 2, entry 5).56 All these MCRs were performed in aqueous lyst on the reaction could be observed in the latter two steps. It
media and started from Knoevenagel reaction of aldehyde with should be noted that the reaction yield was increased signifi-
malononitrile, indicating the fact that water is indeed a solvent cantly by adding various volumes of water, and finally 10 ml of
well suited for developing MCRs based on Knoevenagel water was used for a 1.0 mmol reaction. The same reaction has
reaction. also been evaluated by using nanosized magnesium oxide as cat-
One of research directions of MCRs in water is developing a alyst in a mixture of water and PEG.58
heterogeneous catalyst that is not only water compatible but also One-pot condensation of 2-naphthol, aldehyde and 2-amino-
capable of keeping good activity during recycling. However, benzothiazole that provides 1-(benzothiazolylamino)methyl-2-
considering the complexity of MCRs, and taking the purpose of naphthol has been developed in water by using sodium dodecyl
using a solid catalyst for organic reactions in water into account, sulfate as catalyst.59 In the presence of triethylamine, three-com-
which mainly focuses on emphasizing the catalysis in conjunc- ponent reaction of 5-aminopyrazoles, aromatic aldehydes, and
tion with water solvent, working on a simple MCR is the best dimedone proceeded very well in water with the aid of
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microwave irradiation, providing pyrazolo[3,4-b]quinolin-5-one with hydroxylamine hydrochloride to afford oxime that under-
derivatives in generally good to excellent yields.60 Many MCRs goes a following ring closure to form 3-methyl-isoxazol-5(4H)-
based on three-component condensations of aromatic aldehydes, one; and (ii) the Knoevenagel reaction between 3-methylisoxa-
1,3-dicarbonyl compounds and C–H acids with NH2 or OH zol-5(4H)-one and aromatic aldehyde that produces compound
groups are listed in Table 3.
Liu et al.75 have recently described an efficient method for the
one-pot three-component synthesis of 3-methyl-4-arylmethyl-
ene-isoxazol-5(4H)-one 18 by using sodium benzoate as a
cheap and environmentally benign catalyst in water (Scheme 8).
While the reaction proceeded well in water, the uses of many
other solvents in this reaction led to dramatic decrease of yields.
The reaction under solvent-free conditions also proceeded slug-
gishly. Enhancing the rate of the reaction and purity of the
product in water could be attributed to the increment of sodium

benzoate’s basicity and hydrophobic interactions. This reaction Scheme 8 One-pot three-component condensation of benzaldehyde,
involves the following two steps: (i) ethyl acetoacetate reacts ethyl acetoacetate and hydroxylamine hydrochloride in water.
Table 3 Three-component condensations of aromatic aldehydes, 1,3-dicarbonyl compounds and C–H acids with NH2 or OH groups
Entry Nu (I) Nu (II) Product Condition Ref.

a
1 H2O, TBAC (3 mol%) , 90 °C 61
2 H2O, TBAC (4 mol%), 90 °C 62, 63
3 H2O, 90 °C 64
4 H2O, I2 (5 mol%), rt 65
5 H2O, SDS (10 mol%) 66
6 H2O, SDS (10 mol%) or PEG 400 67, 68
7 p-TSA (20 mol%),b H2O, 90 °C 69
8 70
(10 mol%), H2O, reflux

9 p-TSA (58 mol%),b H2O, reflux 71
10 [BMIm]BF4, rt 72
11 PEG 400, 120 °C or H2SO4, H2O, reflux 73, 74
a
TBAC is triethylbenzylammonium chloride. b p-TSA is p-toluenesulphonic acid.
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Scheme 9 Three-component reaction of rhodanine, amines and a

methyl ketone in aqueous media. Scheme 11 Four-component reaction of hydrazine hydrate, ethyl aceto-
acetate, 2-hydroxybenzaldehyde and malononitrile in water.
Scheme 10 Three-component reactions of salicylaldehyde and

malononitrile.
18. The same type of reaction could also be performed in

aqueous media in the presence of pyridine or sodium silicate Scheme 12 Pseudo-four-component reactions of benzaldehyde and
with or without ultrasonic irradiation.76,77 malononitrile in water.
Mukhopadhyay et al.78 described a one-pot three-component
synthesis of 2-amino-5-alkylidenethiazol-4-one 19 from rhoda- tandem reaction sequence: (i) reaction between hydrazine
nine, amine and a methyl ketone in an aqueous solution of hydrate and ethyl acetoacetate resulting in instantaneous for-
ethanol under reflux by using a silica-based substituted pyridine mation of a pyrazolone intermediate V; (ii) a Knoevenagel con-
catalyst (Scheme 9). This is the first report of a methodology densation between 2-hydroxybenzaldehyde and malononitrile
describing the synthesis of 2-amino-5-alkylidenethiazol-4-ones providing a 2-imino-2H-chromene-3-carbonitrile intermediate
from ketones. In this reaction, the silica-based solid catalyst can VI by 6-exo-dig cyclization of the hydroxyl group with the
be recycled many times without significant loss of its activity. cyano group; and (iii) Michael addition of the intermediate V to
Perumal et al.79 developed a three-component reaction of sali- VI and subsequent rearrangement allows formation of the final
cylaldehyde, malononitrile and indole in water by using product 23 (Scheme 11). This protocol conforms to several green
L-proline as catalyst (Scheme 10). In this reaction, indole reacts chemistry principles coupled with the potential for developing
readily with the 2-imino-2H-chromene-3-carbonitrile intermedi- combinatorial libraries, thus is a typical example which is able to
ate that was generated from salicylaldehyde and malononitrile in show the great power of water as solvent for creation of molecu-
water, providing 2-amino-4-(1H-indol-3-yl)-4H-chromene-3- lar complexity and diversity. A series of 2-aryl-5-methyl-2,3-
carbonitrile derivative 20 in good yield. dihydro-1H-3-pyrazolones have been synthesized by one-pot,
Vasuki et al.80 reported a catalyst-free four-component reac- four-component sequential reactions of phenylhydrazine, methyl
tion of hydrazine hydrate, ethyl acetoacetate, salicylaldehyde and acetoacetate, aromatic aldehydes and β-naphthol in the presence
malononitrile that generates a novel highly functionalised 4-pyr- of p-toluenesulphonic acid in water in good yields.81
azolyl-4H-chromene 23 in water at ambient temperature A one-pot three-component condensation of aldehyde, malono-
(Scheme 11). Generally, the product is separated from the reac- nitrile, and thiophenols has been achieved by using boric acid as
tion mixture and isolated by filtration, and is pure on TLC. Con- catalyst in aqueous medium, with which various 2-amino-3,5-
ventional chromatographic purification or recrystallisation is not dicarbonitrile-6-thio-pyridines 24 were prepared in good yields
required. The reaction might proceed according to the following (Scheme 12).82 This reaction can also be performed in an
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Scheme 13 Possible mechanism for synthesizing compound 26.

aqueous suspension of basic alumina.83 With an analogous strat-

egy, a method for synthesizing 2-amino-4-aryl(alkyl)-6-sulfanyl
pyridine-3,5-dicarbonitrile 25 via a one-pot, three-component
reaction of aldehyde with S-alkylisothiouronium salt and malono-
nitrile has been developed in water in the presence of an inor-

Scheme 14 Pseudo-five-component reaction of methyl ketone, malono-
ganic base (Scheme 12).84 The use of phase transfer catalyst,
nitrile and amine in water.
SDS, was demonstrated to be necessary to improve the reaction
yield. Although the product could be obtained by an alternative
three-component reaction of aldehyde, malononitrile and thiol,
the use of S-alkylisothiouronium salt instead of thiol that has a
strong foul smell allows the reaction to be performed without
special precautions. After the completion of the reaction, the
pure product was conveniently obtained by simple filtration and
then recrystallization from acetonitrile or ethanol. Similarly, Guo
et al.85 synthesized a 3-amino-1-aryl-8-bromo-2,4-dicyano-9H-
fluorene derivative 26 in water under microwave irradiation
(MWI) from aromatic aldehyde, 1,4-bromoindan-1-one and malono-
nitrile by using sodium hydroxide as a base (Scheme 12). The
reaction was assumed to proceed via the following mechanism:
(i) benzaldehyde and 1,4-bromoindan-1-one react initially with
malononitrile in the presence of a base, giving 2-arylidenemalo-
nodinitrile VII and 2-(4-bromo-2,3-dihydroinden-1-ylidene)mal-
ononitrile VIII, respectively; (ii) Michael addition reaction of
Scheme 15 Four-component step-wise sequential reaction of benzal-
VII and VIII affords intermediate IX; (iii) IX undergoes intra- dehyde, malononitrile, 1,3-thiazolidinedione and amine in water.
molecular cyclization, isomerization, and elimination to finally
afford compound 26 (Scheme 13).
Mukhopadhyay et al.86 reported a catalyst-free synthesis of condition. Three-component reaction of aromatic aldehyde,
1,2-dihydro[1,6]naphthyridine 27 through a pseudo-five-com- malononitrile, and 2-(1-(3-chlorophenyl)propylidene)malono-
ponent reaction of methyl ketone, amine, and malononitrile nitrile can also be performed in aqueous media at 90 °C by using
(Scheme 14). The reaction started from Knoevenagel conden- tetraethylbenzylammonium chloride (TEBAC) as a catalyst,
sation of methyl ketone and malononitrile, in which the amine which offers a convenient way for synthesizing 2-amino-6-(3-
acts as a catalyst, generating an intermediate X. This intermediate chlorophenyl)-5-methyl-4-arylcyclohexa-1,5-diene-1,3,3-tricar-
X undergoes a Michael-type reaction with another molecule of bonitrile derivatives.87
X, providing XI by following elimination of a molecule of Cai et al.88 developed a step-wise sequential reaction of ben-
malononitrile. Again the attack of malononitrile on intermediate zaldehyde, malononitrile, 1,3-thiazolidinedione and amine in a
XI triggers the ring closure to yield intermediate XII. mixture of PEG 400 and water, which generated a variety of
Finally, the desired product 27 was formed through a reaction of dihydrothiophene ureidoformamides 28 in good yields
XII and amine, in which a tandem cyclization and aromatization (Scheme 15). The reaction might start from a Knoevenagel con-
reaction was involved. The driving force may be the aromatiza- densation between benzaldehyde and malononitrile that has been
tion in the target compound. This method not only offers an ascertained to be well performed under catalyst-free condition in
expedient synthesis of naphthyridine 27, in which two nitrogen- PEG 400/H2O system. The generated intermediate XIII under-
containing rings are constructed without starting from any nitro- went the following three steps to finally form the desired product
gen-containing heterocycle moiety, but also avoids the use of 28: (i) a Michael addition of 1,3-thiazolidinedione; (ii) ring-
expensive catalysts, toxic organic solvents and anhydrous opening of the formed 4-substituted 1,3-thiazolidinedione with
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Scheme 16 Four-component reaction of dimethyl acetylenedicarboxy-

late, benzylamine, benzaldehyde and malononitrile in water.
amine; and (iii) an intramolecular nucleophilic attack of SH

group to one of the cyano groups. This method not only avoids
the use of an organic amine catalyst that was proved to be

necessary in conventional systems, but also allows us to scale up
the reaction with a simple work-up procedure.
Four-component reaction of dimethyl acetylenedicarboxylate,
benzylamine, aromatic aldehyde, and malononitrile that leads to
polyfunctionalized 1,4-dihydropyridine derivative 29 proceeds
very well at room temperature in aqueous media with the aid of
a catalytic amount (20%) of (NH4)2HPO4 (Scheme 16).89 The Scheme 17 Four-component sequential reaction of phenylhydrazine,
reaction proceeds most likely according to a domino Knoevena- 3-aminocrotononitrile, aromatic aldehydes and 2-hydroxynaphthalene-
gel–Michael addition–cyclization reaction pathway. A new class 1,4-dione in water.
of polysubstituted heterocyclic [3.3.3]propellane derivative 30
could be obtained in pure water when ninhydrin was used
instead of the aldehyde. This four-component reaction might
involve a sequential Knoevenagel condensation/enamine for-
mation/Michael addition/cyclization sequence.90
A four-component sequential reaction of phenylhydrazine,
3-aminocrotononitrile, aromatic aldehydes and 2-hydroxynaphtha-
lene-1,4-dione has also been developed recently in water by
using L-proline as a catalyst (Scheme 17).91 In a typical reaction,
an equimolar mixture of phenylhydrazine and 3-aminocrotono-
nitrile in water was heated to reflux in the presence of L-proline
(40 mol%). This step will generate 5-amino-3-methyl-1-phenyl-
pyrazole in quantitative yield. After 10 min, equimolar amounts
of aromatic aldehyde and 2-hydroxynaphthalene-1,4-dione were
added and reflux was maintained for 1–1.5 hours, which resulted
in the formation of compound 31 in excellent yield. In this
sequential MCR, water was proved to be a superior solvent
when compared with many other organic solvents. Because all
the starting materials are insoluble in water, and considering the
fact that the reaction also proceeds in water in the absence of any Scheme 18 Four-component reactions of hydrazine, ethyl acetoacetate
catalyst (with a low yield, 45% after 10 h), this MCR is a typical and malononitrile in water.
“on-water” process. The use of L-proline was the key to render
the MCR possible, and its important role is mainly exhibited in
(i) activating the aromatic aldehyde to form an iminium A convenient approach to the synthesis of dihydropyrano[2,3-c]-
intermediate XIV, and (ii) controlling the reaction selectivity by pyrazoles 32 via four-component reaction of aromatic aldehydes,
favoring generation of intermediate XV and promoting the hydrazine, ethyl acetoacetate and malononitrile was also devel-
following interaction of 2-hydroxynaphthalene-1,4-dione and oped in water with the aid of ultrasound irradiation
XV to furnish another intermediate XVI. Finally, oxidation of (Scheme 18).92 This reaction can also be performed by using tri-
XVI with molecular oxygen in water provided the desired ethylamine as a catalyst in water.93 The mechanism might also
product 31. involve the formation of a pyrazolone intermediate that
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Table 4 Three-component reactions of isatin and malononitrile in

green solvents
Yield
Entry Nucleophile Condition Product (%)
1 PPL (30 mg for 35 94

0.5 mmol scale of
reaction), EtOH/H2O:
6/1, 30 °C, 3 h
2 L-proline (10 mol%), 36 92
H2O, 80 °C, 15 min
Fig. 1 (a) Reaction mixture of the sodium stearate-catalyzed three-

3 p-TSA (58 mol%), 37 93 component reaction of isatin, malononitrile, and dimedone in water. (b)
H2O, reflux, 24 h Optical micrograph of the reaction mixture (used with agreement of the
publisher).
4 ZnS NPs (10 mol%), 38 95 unfortunately no obvious optical activity could be observed by
H2O, rt, 11 min measuring the enantioselectivity of the product. In spite of this
fact, this lipase-catalyzed multistep conversion method has pro-
vided a new strategy to synthesize spirooxindole derivatives and

5 NiCl2 (20 mol%), PEG 39 90 expanded the application of biocatalysts. It should be noted that
600, 100 °C, 1.3 h multi-component reaction relying on catalysis with enzyme
suffers from, at this moment, low activity and high cost of
enzyme catalyst. Therefore developing new multi-component
reactions that cannot be attained by conventional methods will
be the main goal for using enzyme catalyst.
A Lewis base-surfactant combined catalyst, sodium stearate,
undergoes a condensation with aromatic aldehyde and malono- has been recently applied as a catalyst in a one-pot three-com-
nitrile to generate the final dihydropyrano[2,3-c]pyrazole deriva- ponent reaction of isatin, malononitrile, and 1,3-dicarbonyl com-
tive. Replacing aromatic aldehyde with isatine in the above- pounds that generates the corresponding spirooxindoles
mentioned four-component reaction results in an extensive derivatives in good yields under aqueous micellar media.96
formation of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-5′-carbo- Sodium stearate shows the favorable activity as a surfactant
nitrile 33 with the aid of piperidine catalyst in water (Fig. 1) in this system, and thereby it would act as both a base to
(Scheme 18).94 The newly developed four-component reaction activate the substrate molecules and a surfactant to form stable
of β-ketoesters, hydrazine hydrate, malononitrile, and isatines colloidal dispersion with water-insoluble substrates.
was done at room temperature, and, interestingly, in most cases Shi et al.97 described an efficient one-pot three-component
the generated products exhibited good to excellent antibacterial reaction of isatin, malononitrile and tetronic acid for the syn-
activity against all species of the selected Gram positive and thesis of spirooxindole derivatives 36 catalyzed by L-proline in
Gram negative bacteria. In addition, acenaphthylene-1,2-dione aqueous medium (Table 4, entry 2). Because L-proline is soluble
can also be used in this four-component reaction instead of in the reaction medium and the desired products are less soluble
isatine (Scheme 18). in water, the products can be directly separated by cooling to
Zhang et al.95 have recently demonstrated that lipase from room temperature and filtering after the reaction was completed.
porcine pancreas (PPL) has an unique catalytic activity for one- The filtrate containing L-proline can directly be recovered and
pot synthesis of spirooxindole derivatives 35 in aqueous solution reused. The authors suggested that the catalytic effect of
of ethanol under the mild conditions from isatin, 1,3-dicarbonyl L-proline might mainly present in the initial step of the reaction,
compound and malononitrile (Table 4, entry 1). In this reaction, Knoevenagel condensation between isatin and malononitrile. A
PPL combines three types of catalytic activities for the Knoeve- similar MCR, three-component reaction of isatin, tetronic acid
nagel condensation, Michael addition and cyclization, and there- and 1,3-diphenyl-1H-pyrazoles-5-amine, has also been accom-
fore is capable of catalyzing the model three-component plished in aqueous solution by using L-proline as catalyst.98 A
reaction. The effect of the water concentration on the PPL-cata- three-component reaction of isatins, malononitrile and 2-hydro-
lyzed one-pot synthesis of spirooxindoles was also found to be xynaphthalene-1,4-dione or 2-methylpyrimidine-4,6-diol has
crucial. When the water content was between 10–20%, high also been reported recently by using p-TSA as a catalyst in water
yields could be obtained. However, once the water content sur- (Table 4, entry 3), which provides a simple way to access 37.99
passed 30%, the yield of spirooxindole product declined sharply A three-component reaction of isatin, malononitrile and
due to the insolubility of the substrates. In pure water, spirooxin- 3-hydroxy-1H-phenalen-1-one also proceeded well in water by
dole product was obtained only in 23% yield. All these results using p-TSA as a catalyst.100
indicated obviously that water was essential in this promiscuous Dandia et al.101 described an efficient protocol for the syn-
biocatalysis reaction. Although many substrates were success- thesis of spirooxindole derivatives 38 through three-component
fully applied in this three-component reaction with PPL catalyst, reaction of isatin, malononitrile and 3-methyl-1-phenyl-2-
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pyrazolin-5-one or dimedone catalyzed by ZnS nanoparticles in catalyst.102,103 Isatin has also been used to construct many other
aqueous medium under ultrasonic irradiation (Table 4, entry 4). MCRs in water in conjunction with 1,3-dicarbonyl compounds
A conceivable mechanism is that ZnS NPs first facilitate the and C–H acid containing NH2 or OH groups. Table 5 collects
Knoevenagel-type coupling through Lewis acid sites (Zn2+) some of the recent results.
coordinated to the oxygens of carbonyl groups. By the same New multicomponent domino reactions have been recently
token, ZnS NPs then can also activate methylene compounds so established for the synthesis of spiropyrazolo[1,3]-dioxanopyri-
that deprotonation of the C–H bond occurs in the presence of dine}-4,6-diones 40 and spiro{isoxazolo[1,3]dioxanopyridine}-
Lewis basic sites (S2−). As a result, formation of the spirooxin- 4,6-diones 41 (Scheme 19).111,112 The multicomponent domino
dole derivatives proceeds by activation of reactants through both reactions were conducted by condensations of aldehydes, pyra-
Lewis acidic and basic sites of ZnS NPs. It is noted that ZnS zolo-amines or isoxazoloamines, and Meldrum’s acid in aqueous
NPs can be easily recycled in these three-component reactions, solution under microwave irradiation in the absence of any acid,
thus endowing an important characteristic of green chemistry to metal catalyst, or promoter. The ratio of substrates is quite impor-
this system. These results also address the problem posed by the tant, and finally it was found that an optimal ratio should be
use of homogeneous catalysts that have to be treated and then aldehyde/amine/Meldrum’s acid = 2/1/1. Interestingly, the
disposed of. Three-component reaction of isatin, molononitrile N-phenyl-based spiro{pyrazolo[1,3]-dioxanopyridine}-4,6-diones
and dimedone has also been investigated in water by using can only be generated in aqueous solution. Other polar solvents,
TBAB (tetrabutyl ammonium bromide) or KAl(SO4)2·12H2O as such as DMF, acetic acid and glycol resulted in predominant
Table 5 Three-component reactions of isatin and 1,3-dicarbonyl compounds for construction of heterocyclic compounds
Entry Nu (I) Nu (II) Product Condition Ref.
1 H2O, p-TSA (29 mol%),a reflux 104
3 H2O, p-TSA (58 mol%), reflux 105
8 PEG-SO3H (10 mol%), solvent-free, 80 °C 110
a
p-TSA is p-toluenesulphonic acid.
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Scheme 20 Four-component reaction of ferrocenecarboxaldehyde,

ketone, dimedone and ammonium acetate in water.
Scheme 21 Three-component reaction of β-ketoester, arylglyoxal and

hydrazine in water.
Scheme 19 Multicomponent condensations of aldehydes, pyrazolo-
amines or isoxazoloamines, and Meldrum’s acid in aqueous solution.
formation of pyrazolo[3,4-b]pyridines. The reaction might start

from a Knoevenagel reaction of Meldrum’s acid with aromatic
aldehyde to form an intermediate XVII. And at the same time,
the condensation of aromatic aldehyde with aromatic amine
occurs to form an imine XVIII. The key step is the hetero-
Diels–Alder reaction of the Knoevenagel adduct XVII with the
aromatic imine XVIII, resulting in pyridine ring formation and
intermediate XIX that can form the desired product 40 through a
proton transfer step.
Scheme 22 Three-component condensations of isatoic anhydride,
aniline and aromatic aldehydes or isatins in water.
2.2. MCRs based on activation of carbonyl group with water
Electrophilic reaction of aldehyde with two different nucleo-

philes is a fundamental strategy for constructing MCRs. Water 100 °C with assistance of microwave irradiation, providing
solvent can electrophilically activate the carbonyl group of alde- 2-aryl-4-ferrocenyl-quinoline derivatives 42 as the main product
hydes by hydrogen bond interaction.113,114 For example, in the (Scheme 20).120
absence of catalyst, one-pot Hantzsch condensation of aromatic A novel method for preparing alkyl 6-aryl-3-methylpyrida-
aldehyde, dimedone, and ammonium acetate proceeded very zine-4-carboxylate 43 from β-ketoester, arylglyoxal and hydra-
well in an aqueous medium under microwave irradiation provid- zine was also developed in water (Scheme 21).121 The key step
ing various substituted acridinediones in good yields.115 of the three-component reaction is generation of a 3-hydroxy-
Ammonium chloride, or Zn(OAc)2·2H2O or L-proline has also 1,4-dicarbonyl compound intermediate XX that can undergo a
been used as a catalyst in this three-component reaction.116 A Paal-Knoor condensation with hydrazine to form the cyclized
similar three-component reaction between a variety of aromatic product. This reaction protocol provides a very efficient and
aldehydes, dimedone, and a variety of primary arylamines also straightforward route to construct various trisubstituted pyrid-
proceeded very well in water with assistance of either microwave azines without using an acidic condition or metal catalysts.
irradiation or SDS.117,118 Based on a similar mechanism, Shi The synthesis of 2,3-dihydroquinazolin-4(1H)-ones 44 via a
et al. developed a four-component reaction of an aldehyde, three-component condensation of isatoic anhydride, aromatic
aniline, Meldrum’s acid and dimedone in aqueous medium by aldehydes with ammonium salts or primary amines was per-
using benzyltriethylammonium chloride (TEBAC) as catalyst, formed in aqueous ethanol under reflux condition using
with which a series of N-substituted-3-aryl-3-(2-hydroxy-4,4- SrCl2·6H2O as a catalyst (Scheme 22).122 The same reaction can
dimethyl-6-oxocyclohex-1-enyl)propanamides were synthesized also be performed in water by using magnetically recoverable
in good yields.119 A MCR of ferrocenecarboxaldehyde, ketone, Fe3O4 nanoparticles as catalyst.123 Ethylenediamine diacetate
dimedone and ammonium acetate proceeded well in water at (EDDA) has also been used as a catalyst in aqueous media for
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Scheme 23 Three-component reaction of isatin, 4-amino antipyrine

and 2-mercaptopropionic acid in water. Scheme 25 MCRs of isatin, 1,1-bis(methylthio)-2-nitroethylene and
hydrazine hydrate in water.
Scheme 26 Three-component reaction of N-methylimidazole, methyl

propiolate, and butyraldehyde in water.
nitroethylene, which was then trapped by two equivalents of

isatin derivatives to form the final products.
Implementation of a three-component reaction of N-methyl-

Scheme 24 MCRs of ninhydrin, 1,1-bis(methylthio)-2-nitroethene imidazole, methyl propiolate, and butyraldehyde was proved to
with amines in water. occur very well in ‘on water’ conditions, providing compound
50 in good yields (Scheme 26).130 The reaction might proceed
through the formation of a water-stable nucleophilic imidazole
promoting a three-component reaction of isatins, isatoic anhy- carbene (imidazolium ylide). This carbene is alkylated by a
dride and amine (Scheme 22).124 When 2-aminobenzothiazole cascade process involving an efficient carbene–aldehyde
was used as substrate instead of the primary amine, the three- addition, alkoxide–alkynoate addition, and protonation and
component reaction proceeded very well in aqueous solution of hydrolysis set of consecutive reactions.
ethanol without the use of any catalyst.125
Quite recently, an ultrasound-promoted synthesis of spiro
[indole-thiazolidinone] libraries 46, which are medically impor-
2.3. MCRs in water based on imine formation
tant, through a tandem reaction of isatin, 4-amino antipyrine and
2-mercaptopropionic acid using cetyltrimethylammonium Tanaka et al.131 have observed an easy formation of imine from
bromide (CTAB) as a phase transfer catalyst has been developed aldehyde and aniline in water. Based on this fact, Mannich-type
in water (Scheme 23).126 Conventional methods for the synthesis three-component reaction of aldehyde, aniline and ketone has
involve either azeotropic removal of water or the use of dehydrat- been extensively investigated in water, and these works have
ing agent. In addition, the use of ultrasound irradiation was been well summarized by Aziz et al.132 in a recent paper. In this
proved to be the key for the reaction to proceed toward com- part, we will only summarize the results reported within the last
pletion. The mechanical effect of cavitation from ultrasound three years.
irradiation and the resulted efficient mixing of reactants was Rafiee et al.133 reported a new type of magnetically-recover-
expected to be responsible for increasing the rate and yield of able catalyst that was synthesized by immobilizing H3PW12O40
the reaction. on the surface of silica-encapsulated γ-Fe2O3 nanoparticles.
The one-pot multi-component reaction between primary Physicochemical characterizations of the catalyst revealed that
amines or linear diamines, 1,1-bis(methylthio)-2-nitroethene, the obtained material has an average size of approximately
and ninhydrin has been investigated by Alizadeh et al. under 94 nm, and possesses a very strong solid acid with an excellent
aqueous conditions, which provides a wide range of dihyroin- distribution of acid sites. Compared to its homogeneous
deno [1,2-b]pyrroles 47 and indeno[2′,1′:4,5]pyrrolo[1,2-a]- H3PW12O40, the solid catalyst possesses also a higher number of
fused 1,3-diazaheterocycles 48 in fairly high yields surface active sites. These unique properties allow the catalyst
(Scheme 24).127 Itaconic anhydride can also react with 1,1-bis- show an excellent performance for a one-pot three-component
(methylthio)-2-nitroethene and diamines in aqueous solution of Mannich-type reaction of aldehyde, amine and ketone in water at
ethanol, generating various pyrido[1,2-a]-fused 1,3-diazahetero- room temperature. After the reaction, the catalyst/product separ-
cyclic compounds in good yields.128 ation could be easily achieved with an external magnetic field,
A pseudo-five-component reaction of isatin, 1,1-bis- and the recovered catalyst could be reused at least five times
(methylthio)-2-nitroethylene and hydrazine hydrate could also be without any loss of its high catalytic activity (Fig. 2).
performed under a catalyst-free aqueous condition, providing The same reaction could also be performed in water at room
very a complex spirooxindolepyrazoline 49 in good yields temperature by using some homogeneous acids such as trifluoro-
(Scheme 25).129 In the beginning of the reaction, a 1,1-bishydra- methanesulfonic acid and Ga(OTf )3 as catalyst.134,135 A base-
zino-2-nitroethylene intermediate might be generated in situ catalyzed Mannich reaction has also been realized in water by
from the addition of aqueous hydrazine to 1,1-bis(methylthio)-2- using derivatives of Tröger’s base as catalysts.136 A neutral
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Fig. 2 Separation of the γ-Fe2O3@SiO2-PW catalyst from the reaction Scheme 27 MCRs of benzaldehyde and aniline in water or ionic
mixture using an external magnet (used with agreement of the liquid.
publisher).
system, AgNO3 and p-TSA showed a synergistic promoting

catalyst, triethylbenzylammonium chloride (TEBAC), has been effect on the stereoselectivity and the reaction yield. By means
proved to be efficient for three-component reaction of aromatic of this synergistic effect, the stereoselectivity of the reaction
aldehyde, 2-naphthalenamine and 1,2-diphenylethanone in reached to 100% that cannot be attained with conventional
aqueous media, which gave 3-aryl-3-(naphthalen-2-ylamino)- heterogeneous catalytic systems. Furthermore, water solvent also
1,2-diphenylpropan-1-one derivatives in good yields.137 plays an important role in this reaction because of the fact that
However, difficulty in recycling the expensive acid catalyst low yields were obtained in other solvent systems. But even in
restricts its application in practical synthesis. In order to recycle some organic solvents, the stereoselectivity of the reaction still
the homogeneous catalyst, Lin et al.138 combined Yb(OTf )3 and remains at 100%, indicating a unique ability of the present
a PEG-supported quaternary ammonium salt, and then utilized it system for the synthesis of β-amino ketones in an exclusive
in a three-component Mannich reaction of cyclohexanone with stereoselectivity. A three-component reaction of aromatic alde-
aromatic aldehyde and aromatic amine in water. This reaction hyde, amine and allyltributylstannane has also been investigated
afforded the corresponding β-amino carbonyl compounds in by using phosphomolybdic acid or FeCl3 as catalyst.142,143 The
good yields with high anti selectivity, and the catalyst system reaction went smoothly in water to afford the corresponding
was recyclable. A novel functionalized ionic liquid 3-(N,N- homoallylic amine in high yields at room temperature. Among
dimethyldodecylammonium)propanesulfonic acid hydrogen the screened solvent systems, water led to the highest yield, indi-
sulfate ([DDPA]HSO4) has been used as an alternative Brønsted cating the great ability of water solvent for assisting progress of
acid–surfactant combined catalyst to DBSA for Mannich-type the reaction.
reaction in water. In the reaction, the catalyst could be reused at Three-component reaction of aldehydes, amines, and triethyl
least six times without noticeably decreasing the catalytic or diphenyl phosphate (Kabacknik–Fields reaction) in water was
activity.139 Mannich three-component reaction has also been effectively catalyzed by magnesium dodecyl sulfate (10 mol%)
examined in a mixture of water and acetic acid by using Zn[(L)- to give various α-amino phosphonates 52 in high yields
proline]2 as catalyst. Interestingly, because Zn[L-proline]2 is well (Scheme 27).144 The catalyst is easily available from inexpensive
soluble in water, it can be recycled after the reaction with a sodium dodecyl sulfate and magnesium bromide, and the reac-
slight decrease of catalytic acitivity.140 tion can be performed in water at room temperature. Probably,
Palaniappan et al.141 have recently prepared a polyaniline con- magnesium dodecyl sulfate forms stable dispersion systems with
taining the dual dopants, silver nitrate and p-TSA, (PANI– organic substrates in water and the magnesium cation combines
AgNO3–p-TSA) by an aqueous polymerization pathway, which aldehydes and amines to form the corresponding imines, which
was then demonstrated successfully as a reusable solid acid cata- react with phosphites. The same reaction can also be performed
lyst for the stereoselective synthesis of 100% anti-β-amino in water by using a SO3H-functionalized ionic liquid as a recycl-
ketones 51 through three-component Mannich reaction of able catalyst.145 Kabacknik–Fields three-component reaction can
aniline, benzaldehyde and cyclohexanone (Scheme 27). The even be performed under neutral conditions in water by using
reaction was performed in aqueous medium at room temperature SDS as a catalyst.146 However, in this system, only one phos-
with short reaction time, and the desired products were obtained phite, diethyl phosphite, was examined. The catalytic effect of
generally in excellent yields. In the PANI–AgNO3–p-TSA micellar SDS in these reactions can be explained by the
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following factors: (i) molecules of aldehydes, amines and diethyl

phosphite are accumulated inside the droplet vesicles of micellar
SDS; in these micellar droplets, the distance between the reactive
species decreases drastically, thus facilitating the progress of the
reaction and consequently enhancing the reaction rate; (ii) high
hydrophobicity of the α-aminophosphonate reaction products,
which is comparable with the hydrophobic core of the micellar
droplet, also helps progress of the reaction.
A one-pot three-component condensation of aldehydes,
amines, and trimethylsilyl cyanide could be performed at room
temperature in the presence of a heterogeneous acidic ionic Scheme 29 Three-component reactions of nitroarenes, formaldehyde,
liquid, silica-supported N-(3-silicapropyl)imidazolium hydrogen and dialkyl acetylenedicarboxylate in water.
sulfate, which generated α-aminonitriles in good yields.147 By
using K2PdCl4 as catalyst, the same three-component reaction

could also be performed in water.148 In these cases, both the
acidic ionic liquid and K2PdCl4 act as efficient acids to furnish
the formation of imines by condensation of aldehyde and amine.
The activated imine reacts thereafter with TMSCN to generate
the desired product.
A one-pot tandem reactions of 1,3-dicarbonyl compounds, Scheme 30 Strecker reaction of ketones and aniline using acetyl
aromatic aldehydes and various amines in ethanol containing a cyanide in water.
small amount of water proceeded well in the presence of cataly-
tic amount of Bi(NO3)3 at room temperature (Scheme 28), pro-
viding a simple and straightforward way for diastereoselective
synthesis of a series of pharmaceutically interesting functiona-
lized piperidine derivatives 54.149 To form the final functiona-
lized piperidine scaffold, the mechanism of this pseudo-five- Scheme 31 Strecker reaction of benzaldehyde, benzylamine, and
component reaction involves: (i) imine formation from aniline acetone cyanohydrin in water.
and aldehyde; (ii) enamine formation from aniline and β-keto-
ester; (iii) attack of enamine on the activated imine, and (iv)
inter- and intra-molecular Mannich-type reactions. Bismuth nitroarenes, aldehydes, and phenylacetylene in dilute hydro-
nitrate likely enhances the rate of this multi-step reaction. The chloric acid also produce the corresponding quinoline derivatives
same reaction can also be performed in ethanol by using under reflux.152 The reaction in this one-pot synthesis involves
PEG-embedded potassium tribromide ([K+PEG400]Br3−) as the following four steps: (i) reduction of the nitroarenes to ani-
catalyst.150 lines by indium; (ii) three-component coupling of the anilines,
A distinct approach for the synthesis of 1,3,3-trisubstituted aldehydes, and phenylacetylene; (iii) cyclization of the resulting
4,5-dioxopyrrolidine and 1,3,4,5-tetrasubstituted 1,2,3,6-tetrahy- species; and (iv) dehydrogenation of the cyclic intermediates.
dropyrimidine has been developed at room temperature in dilute The three-component reaction of an aldehyde or ketone, a
aqueous HCl with the aid of indium, in the form of a three-com- primary amine and a cyanide ion (Strecker reaction) constitutes
ponent reaction of nitroarenes, formaldehyde, and dialkyl acety- one of the most efficient manifolds for the synthesis of α-amino-
lenedicarboxylates (Scheme 29).151 The molar ratios of these nitriles, versatile precursors of α-amino acids. During the last
substrates are 1 : 4 : 1 and 2 : 4 : 1 for the preparation of dioxo- two years, some interesting advances that target the use of new
pyrrolidines 55 and tetrahydropyrimidines 56, respectively. The types of cyanide source were reported. Particularly, water as the
products are formed in good to excellent yields in water solvent. reaction solvent showed an additional advantage in developing
In the present conversions, nitro compounds were initially environmentally benign systems. García-Tellado et al.153 devel-
reduced to amines, which then reacted with dialkyl acetylene- oped a Strecker reaction of ketones and aniline using acetyl
dicarboxylates and formaldehyde to form the desired hetero- cyanide as a cyanide source and utilizing N,N-dimethylcyclo-
cycles. In the presence of indium, three-component reactions of hexylamine as a Lewis base catalyst in brine (Scheme 30). Remark-
ably, the reaction did not produce N-acylated α-aminonitriles,
which indeed constituted the main products in organic media
using this cyanide source. Generation and following activation of
a ketimine intermediate by means of hydrogen bond networks
were expected to be the key to render the reaction toward for-
mation of 57.
A simple and practical method for the synthesis of α-amino
nitriles 58 through a one-pot, three-component Strecker reaction
of a carbonyl compound, amine, and acetone cyanohydrin in
Scheme 28 Pseudo-five-component reaction of β-ketonester, benzal- water has been recently developed (Scheme 31).154 The protocol
aldehyde and aniline in water. is particularly efficient for both aliphatic and aromatic aldehydes,
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Scheme 33 Three-component vinylogous Mukaiyama–Mannich reac-

Scheme 32 Mannich reaction of 3-substituted oxindoles, formalin, and tion of pyrrole ketene silyl-N,O-acetal, aniline, and aldehydes in water.
various secondary amines.
and cyclic ketones, in combination with primary and secondary

amines. Because of the immiscibility of the substrates and pro-
ducts with water, the reactions were performed in a hetero-

geneous condition that endowed the system with an additional
advantage in some cases in which the expected α-amino nitriles
could be directly obtained in high purity without silica column
chromatography.
Scheme 34 Three-component reaction of aromatic aldehyde, thiosemi-
A three-component Mannich reaction of 3-substituted oxi-
carbazide and phenacyl bromide in different solvents.

ndoles, formalin, and various secondary amines, which produces
aminomethylation products of 3-substituted oxindoles 59, was
component reaction of a wide range of chalcones, ethyl acetoace-
developed in aqueous media by using formaldehyde as a C1
tate and ammonium acetate utilizing cellulose sulfuric acid
source (Scheme 32).155 Although the best result was obtained in
(CSA) as a catalyst.162 After the reaction, CSA catalyst could be
ethyl acetate by using paraformaldehyde as C1 unit, the reaction
easily recovered, and the catalyst can be reused at least three
required a long reaction time, 24 hours. In order to decrease the
additional times in subsequent reactions without significant loss
reaction time, an aqueous formalin solution was then used in
in product yield.
conjunction with a catalyst, SDS. And interestingly, within a
A Biginelli-type three-component reaction of dimedone, urea
shortened reaction time, 3 hours, the yield obtained is quite com-
and aromatic aldehydes has also been selected as a model reac-
petitive, demonstrating the effectiveness of water for this reac-
tion for evaluating the catalytic activity of MoO3–ZrO2 nano-
tion. In aqueous media, a non-ionic surfactant, triton X-100, has
composite oxides, and finally a MoO3 (10 mol%)–ZrO2 catalyst
been proven to be an efficient catalyst for multicomponent syn-
was found to be highly active for the transformation under
thesis of benzylamino coumarin derivatives via Mannich-type
aqueous conditions.163 A dicationic SO3H-functionalized ionic
reaction by using secondary amines, aromatic aldehyde and
liquids has also been used in Biginelli condensation of various
4-hydroxy coumarin as substrates.156 It is speculated that, in this
aldehydes, 1,3-dicarbonyl compounds, and urea under aqueous
Mannich-type reaction, triton X-100 forms stable colloidal
condition.164
medium to stabilize iminium ion which undergoes nucleophilic
Zanardi et al.165 reported an uncatalyzed aqueous and solvent-
addition of 4-hydroxy coumarin to give benzylamino coumarin
free three-component vinylogous Mukaiyama–Mannich reaction
in very good yields. The synthesis of 1-( phenyl( piperidin-1-yl)-
of a pyrrole ketene silyl-N,O-acetal, anilines, and various alde-
methyl)naphthalene-2-ol through a special case of the Mannich
hydes (Scheme 33). The reactions of both hydrophobic alde-
reaction, Betti reaction of benzaldehyde, β-naphthol, and piper-
hydes and hydrophilic aldehydes proceeded well, furnishing
idine, was attempted in water using various dual metal cyanide
γ-substituted δ-aminopyrrolinone units 60 in high yields, with
catalysts that were prepared from potassium ferrocyanide, metal
excellent γ-site selectivity and chemoselectivity, and moderate to
chloride.157 The reaction proceeded smoothly at room tempera-
high diastereoselectivity in favour of anti-configured adducts.
ture to give the corresponding product in good yields. A
A facile one-pot three-component reaction of aromatic alde-
Mannich-type three-component reaction of formaldehyde,
hyde, thiosemicarbazide and phenacyl bromide that providing
amines and phenols could also be performed in water without
N-(4-arylthiazol-2-yl) hydrazones 61 has been recently carried
the use of any catalyst, providing dihydrobenzo- and naphtho[e]-
out in water without any catalyst under ultrasound irradiation
1,3-oxazines in good yields.158 The reaction condensation could
(Scheme 34).166 The reaction in water was completed in 50 min
be completed in a short time (30 min to 1 h) at 25 °C in water,
with yield of 90%. It is very interesting that one-pot synthesis
reactions in other organic solvents take several hours to days for
under ultrasound condition was more efficient than the tra-
complete consumption of starting materials.
ditional two-step approach. Under the same condition, water was
2,4,5-Triarylimidazoles could be obtained in good yields by a
found to be more effective than organic solvents, such as
one-pot three-component condensation of benzil/benzoin, alde-
ethanol, 2-propanol, acetonitrile and dichloromethane.
hydes and ammonium acetate in the presence of catalytic
amount of IV ammonium nitrate (CAN) or boric acid in aqueous
media under ultrasound at room temperature.159,160 Sulfated tin 2.4. Synthesis of dithiocarbamate through MCRs in water
oxide has also been used as a catalyst in aqueous media for this
three-component synthesis.161 C5-unsubstituted 1,4-dihydropyri- It is well known that amines can react readily with carbon
dines were obtained in good to excellent yields by three- disulfide to afford zwitterion species that can then be trapped by
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Scheme 35 Three-component reaction of fumarylchloride, carbon

disulfide and benzylamine in water.
Fig. 3 Comparison of the reaction time for the synthesis of rhodanine

65 in water using ultrasound and high-speed stirring (used with agree-
ment of the publisher).
Scheme 37 Three-component reaction of amine, carbon disulfide and

alkyl vinyl ether in water.
Scheme 36 Three-component reactions of amine and carbon disulfide.

Three-component reaction of dimethyl acetylenedicarboxylate,
carbon disulfide and benzylamine, which generates rhodanine
65, was carried out in water with assistance of ultrasonic
various electrophiles. This strategy has been used for construc- irradiation or high-speed stirring (rpm = 1500) (Scheme 36).170
tion of various MCRs in water. For example, a three-component The one-pot three-component reaction using ultrasonic
synthesis of 2-thioxothiazolidin-4-one 62 from fumarylchloride, irradiation was completed in three minutes, but the high-speed
carbon disulfide and benzylamine was also reported stirring method required a reaction time of one hour to go to
(Scheme 35).167 The reaction was performed in water without completion (Fig. 3). Unfortunately, in this reaction CS2 has to be
any catalyst at room temperature. After 12 hours of reaction, used in great excess in order to get a high reaction yield.
2-(3-alkyl-4-oxo-2-thioxo-1,3-thiazolan-5-yl)acetic acid deriva- A one-pot and three-component reaction of amines and
tives were obtained in good to excellent yields. The reaction pre- carbon disulfide with alkyl vinyl ethers has been carried out in
sumably proceeds through initial addition of benzylamine to pure water under catalyst-free conditions at room temperature
carbon disulfide to afford a zwitterion species XXI, which then (Scheme 37).171 Various primary and secondary amines could be
attacks the conjugated double bond of fumarylchloride to applied in this type of reaction, generating the corresponding
produce an intermediate that undergoes intramolecular cycliza- dithiocarbamates 66 in good to excellent yields. The reaction
tion followed by loss of an HCl molecule to form the thiazoli- proceeded through the following two steps involving (i) for-
dine XXII. Finally, hydrolysis of intermediate XXII leads to the mation of a dithiocarbamic acid species XXIII via a reaction of
corresponding 2-thioxo-1,3-thiazolidin-4-one. amine and CS2, and (ii) Markovnikov addition reaction of XXIII
Sun et al.168 described an efficient method for the synthesis of to the electron-enriched alkyl vinyl ethers. Although good per-
multisubstituted thiazolidine-2-thione derivatives 63 via a three- formance of water solvent was observed in this reaction, it
component reaction of amine, carbon disulfide, and α-bromo- cannot be ascribed to an accelerating effect of water on the reac-
ketone (Scheme 36). By using water as the reaction medium and tion because other solvents, such ethanol and THF, can also
K2CO3 as base, the reaction proceeds smoothly to give corre- produce the desired product in the same yield. In addition, an
sponding products in good to excellent yields. When 2-chloro- efficient three-component method for the synthesis of organic
1,3-dicarbonyl compounds were used instead of α-bromoketone, dithiocarbamates from acrylates, amines and carbon disulfide has
N-alkylthiazoline-2-thiones 64 were obtained in good to excel- also been achieved at room temperature using basic nanocrystal-
lent yields (Scheme 36).169 line MgO catalyst in aqueous conditions.172
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Scheme 39 Four-component reaction of p-hydroxybenzaldehyde, ben-

zylamine, fumaric acid monoethyl ester, and tert-butyl isocyanide in
water.
Scheme 38 One-pot condensation of aryl diazonium fluoroborate,
carbon disulfide and amine.
Although this method is quite satisfactory for the synthesis of

alkyl dithiocarbamates, it is not applicable in the synthesis of
aryl dithiocarbamates. In order to solve this problem, Ranu
et al.173 have recently reported a new method for synthesis of
S-aryl dithiocarbamates 67, which was realized by a one-pot con-
densation of aryl diazonium fluoroborate, carbon disulfide and

amine in the absence of any transition metal catalyst in water at
Scheme 40 Three-component reactions of isocyanides, diethyl acetyle-
room temperature (Scheme 38). Compared with some earlier
nedicarboxylate and alkyl or aryl sulfonamides in water.
methods for the synthesis of S-aryl dithiocarbamates, the salient
features of Ranu’s method can be summarized as the following
three points: (i) the use of phenyl diazonium tetrafluoroborates, like heterocyclic compounds, several research groups are now
which are stable solid compounds and easy to prepare and developing modifications of these reactions. One of the promis-
handle, as starting materials not only avoids dealing with a toxic ing methods is performing isocyanide-based MCRs in water.
reagent, diazonium chloride, but also allows utilization of CS2 Santra and Andreana174 realized a novel Ugi-type four-com-
that is much cheaper than the other S-reagents, such as sodium ponent reaction of p-hydroxybenzaldehyde, benzylamine,
salt of dithiocarbamic acid (XXIII); (ii) exclusion of using of a fumaric acid monoethyl ester, and tert-butyl isocyanide in pure
metal-containing material as catalyst in the synthetic system, water with the aid of microwave irradiation, which gave rise to a
which thus minimizes the possibility of product contamination natural-product-like molecule, 5,5,6-fused azaspiro tricycle 68,
with toxic metal species; and (iii) using water as a solvent that as the main product (Scheme 39). In order to avoid the formation
endows this method an additional merit in fitting the environ- of unwanted by-products, the reaction was performed by a step-
mentally friendly requirements of current organic synthesis. It wise protocol in which the mixture was first treated at 70 °C
was found that the initial event of the reaction is also the for- under microwave irradiation for 1 hour at 10 bar, and then the
mation of a dithiocarbamic acid via a reaction of amine and CS2, resulting mixture was subjected to the next reaction condition,
which can then attack at C-1 of ArN2+ in a pathway of SN2Ar, 190 °C, 19 bar and 30 min. With this procedure, the yield of 68
generating an intermediate (XXIV) that can then be converted to could be improved to 85%. The reaction might proceed through
the desired S-aryl dithiocarbamate 67. a unique Ugi/Michael/aza-Michael cascade reaction pathway. It
should be noted that this cascade process generates a quaternary
2.5. Isocyanide-based MCRs in water center, four stereogenic centers, and six contiguous bonds in a
one-pot reaction, indicating the great ability of water as a solvent
Since the first documentation of the Strecker synthesis of for creating molecular complexity.
α-amino cyanides in 1850, MCRs have been extensively investi- Shaabani et al.175 have recently described an efficient
gated. Amongst all MCRs, isocyanide-based MCRs are most fre- approach to the synthesis of ketenimine sulfonamide derivatives
quently exploited because the isocyanide is an extraordinary 69 from various isocyanides and dialkyl acetylenedicarboxylates
functional group. The Passerini and Ugi reactions are classical in the presence of alkyl or aryl sulfonamides in water and
examples. Both reactions stem from the unique ability of isocya- absence of any catalyst (Scheme 40). The reaction could be pre-
nide to participate in α-addition with a nucleophile and an elec- ferably performed in water rather than other organic solvents.
trophile. In fact, well-known MCRs in organic synthesis are Generation of a zwitterionic intermediate through a Michael-type
rather limited in the organic synthesis, and unfortunately each addition of isocyanides to the acetylenic system might be the
MCR affords, in the most cases, compounds with a similar first step of the reaction. Then, sulfonamide plays a role of trap-
framework and a few different substituents. In contrast, a much ping reagent to react with the intermediate to afford the keteni-
greater variation of MCRs is known in the chemistry of the iso- mine sulfonamide. Importantly, the products could be further
cyanides. Particularly, in the Ugi four-component reactions and hydrolyzed to the corresponding sulfonamide-butanamide
related MCRs, the skeletons and the substituents can differ. derivatives at 80 °C in water in good yields without using a cata-
Therefore, isocyanide-based MCRs have achieved extensive lyst. By the same token, the zwitterion that was generated from
application. To expand their utility and also gain access to drug- the reaction of an alkyl isocyanide and a dialkyl
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Fig. 4 Ammonium salt-tagged [(SIPr)CuCl] complex catalyst.

Scheme 41 Three-component reaction of isocyanide and dimethyl

acetylenedicarboxylate in water or PEG 400.
Scheme 43 Three-component of alkyl halide, sodium azide, and
alkyne in water catalyzed by copper(I) isonitrile complex.
phase separation. With this strategy, industrial applications have

been quickly established, such as the Ruhrchemie AG/Rhône-
Poulenc process for the hydroformylation of propylene.
Although hydroformylation of alkenes can also be considered as
a three-component reaction of alkenes, hydrogen and CO,180
Scheme 42 Three-component reaction of isocyanides, heterocyclic considering its insufficiency in creation of molecular complexity
thiols and gem-dicyano olefins in water. and diversity, this reaction will not be included in this review.
While the recyclable design of homogeneous metal complex cat-
alysts by means of using water as reaction medium has attracted
acetylenedicarboxylate reacts readily with phenacyl halides in
great attention, far less effort has been spent on improving the
water to produce γ-iminolactone derivatives in high yields.176
synthetic efficiency with a rational design of the reactions. In
In the presence of a phase-transfer catalyst, tetrabutylammo-
fact, water solvent also offers an indispensable means to organic
nium bromide (TBAB), a three-component reaction of an isocya-
chemists who are interested in developing new MCRs.
nide, dialkyl acetylenedicarboxylate and 4-hydroxycoumarin
Huisgen 1,3-dipolar cycloaddition of organic azides and
proceeded well in water at 80 °C, which generated a pyrano[3,2-c]-
alkynes has been extensively investigated since the discovery by
coumarin 70 in good yields (Scheme 41).177 The reaction also
the groups of Meldal and Sharpless.181 However all the methods
proceeded smoothly when 4-hydroxy-6-methyl-2H-pyran-2-one
involve pre-formed organic azides, for which the use of organic
was employed in place of 4-hydroxycoumarin. The reaction
solvents is, in general, mandatory. In order to further improve
might proceed according to the following steps: (i) formation of
the utility and user-friendliness of this process, a practical multi-
a zwitterionic intermediate by means of reaction of isocyanide
component variant was developed. An ideal choice is performing
and dialkyl acetylenedicarboxylate; (ii) addition of 4-hydroxy-
the reaction in water.182 Li and Xia183 have recently developed
coumarin to the zwitterionic intermediate providing a three-com-
an ammonium salt-tagged [(SIPr)CuCl] complex (SIPr = N,N′-
ponent adduct that was then further cyclized to generate 70.
bis(2,6-diissopropylphenyl)-imidazolidin-2-ylidene) 73, which
Ji et al.178 described an efficient three-component reaction of
showed a high catalytic activity toward the three-component
isocyanides, heterocyclic thiols and gem-dicyano olefins bearing
click reaction of a wide arrange of benzyl bromides and alkynes
electron-withdrawing groups in aqueous solution of acetonitrile,
using water as solvent at room temperature (Fig. 4). Because the
which produced imino-pyrrolidine-thione scaffold 72 in good
catalyst is soluble in water, it could be conveniently recycled up
yields (Scheme 42). The product may be formed through a
to three times without a significant loss of its activity with cata-
typical mechanism involving a key step of Ugi-Smiles-type
lyst loading as low as 2.0 mol% in the fresh run.
rearrangement.
Reiser et al.184 synthesized a structurally well-defined copper(I)
isonitrile complex 74 and then utilized it as an efficient catalyst
2.6. MCRs in water based on transition metal catalysis in a three-component of alkyl halide, sodium azide, and alkyne
in water that generates 1,4-disubstituted 1,2,3-triazole 75 in high
Performing a transition-metal-catalyzed reaction in water offers yield (Scheme 43). Liu and Xia185 prepared three solid Cu
an easy approach to use a biphasic system, with two immiscible catalysts including a cross-linked polymeric ionic liquid
liquid phases, such that the homogeneous catalyst is soluble in material-supported copper (Cu-CPSIL), imidazolium-loaded
one phase (e.g. water) and the product in the other phase Merrifield resin-supported copper (Cu-PSIL) and silica-dispersed
(organic).179 The product can then be obtained by a simple CuO (CuO/SiO2) that were then used as efficient catalysts for the
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Scheme 45 Three-component reaction of azetidinone 80, sodium azide

and terminal alkyne in water catalyzed by CuI.
Scheme 44 Multicomponent Huisgen 1,3-dipolar cycloaddition in

water catalyzed by CuNPs/C.
one-pot synthesis of 1,4-disubsituted-1,2,3-triazoles by the reac-

tion of alkyl halides with sodium azide and terminal alkynes in
water at room temperature. In these catalyst systems, water was
proved to be more suitable than other solvents due perhaps to its Scheme 46 Pseudo-five-component reaction of aromatic propargylated
proton-providing ability. Physicochemical characterization aldehydes, azide, dimedone, and aniline in water.
revealed that the valence state of the Cu species changed from
Cu(II) to Cu(I) by reductive elimination via alkyne–alkyne homo-
coupling. Thus a mechanism was then proposed as follows: (i) trans-β-lactam. Inspired by this observation, a three-component
the alkyne–alkyne homocoupling proceed on the Cu(II) site to reaction of azetidinone 80, sodium azide and terminal alkyne
form the catalytically active Cu(I) species; and (ii) the cyclo- was examined in water by using various Cu catalysts. It was
addition proceeded then over the active Cu(I) species generated. found that CuI was the best choice of catalyst, with which 81
Varma et al.186 report a nano-ferrite-supported Cu catalyst that was obtained in 95% of yield (Scheme 45). It is speculated that
can efficiently catalyze three-component Huisgen 1,3-dipolar water appears to be an ideal solvent capable of supporting a
cycloaddition reactions in water under microwave irradiation. Cu(I) acetylide species that was generated during the reaction.
The catalyst was prepared by sonicating nano-ferrites with gluta- Therefore, this three-component reaction performed smoothly in
thione in water for 2 h, followed by the addition of CuCl2 in water in high yields.
basic aqueous conditions. In a two-component Huisgen 1,3- A series of triazolyl methoxyphenyl 1,8-dioxo-decahydroacri-
dipolar cycloaddition reaction, the nano-ferrite-supported Cu cat- dine derivatives 83 have been prepared in aqueous solution of
alyst could be reused at least three times without any change in ethanol through a one-pot pseudo-five-component reaction
activity. Contrastive analysis of the fresh and the used samples between aromatic propargylated aldehyde 82, various azides,
with ICP-AES (inductively coupled plasma-atomic emission dimedone, and anilines (Scheme 46).189 In order to get a high
spectroscopy) confirms the fact that glutathione provides enough yield, a combination of Cu(OAc)2/sodium ascorbate and
binding sites on the surface of Fe3O4 nanoparticles to serve as a 1-methylimidazolium trifluoroacetate ([HMIm]TFA) has to be
pseudo-ligand for anchoring Cu. This minimizes deterioration used as catalyst. In fact, it is a parallel combination of CuAAC
and metal leaching and facilitates efficient catalyst recycling. and a pseudo-four-component reaction of aldehyde, aniline and
Yus et al.187 have recently reported a new heterogeneous cata- dimedone. Without [Hmim]TFA the latter reaction cannot occur,
lyst that consists of oxidized copper nanoparticles on activated and only a CuAAC adduct 84 was formed. A combination of
carbon (CuNPs/C) for the multicomponent Huisgen 1,3-dipolar CuSO4/sodium ascorbate has also been used as catalyst for
cycloaddition in water (Scheme 44). The catalyst, CuNPs/C, is three-component reaction of α-bromo ketones, sodium azide and
reusable and seemingly operates under heterogeneous con- terminal acetylenes in aqueous solution of PEG 400.190
ditions. At a low catalyst loading (0.5 mol%), CuNPs/C mani- By using a cross-linked polymeric ionic liquid material as
fested a high versatility as not only organic halides, but also support, Xia and Liu191 prepared a supported palladium catalyst
other azide precursors, including epoxides, diazonium salts, ani- (Pd-CPSIL) that can be used as an effective heterogeneous cata-
lines, or alkenes, could be successfully transformed into the lyst for carbonylative Sonogashira coupling reaction of aryl
corresponding 1,2,3-triazoles 77 to 79. Particularly, a haloalk- iodides with terminal alkynes in water (Scheme 47). In the pres-
yne, 6-chlorohex-1-yne, can also be utilized in this type of three- ence of Et3N, the three-component carbonylative reactions
component reaction in water, providing a bicyclic triazole 76 that produce the corresponding α,β-alkynyl ketones 85 in good to
is generally difficult to access in high yields with other methods. excellent yields. The catalytic system not only solves the basic
Lei et al.188 have recently found that an azetidinone 80 can problem of homogeneous palladium catalyst recovery and reuse
react readily with alkyl azide in water to form 4-azide-substituted but also avoids the use of toxic phosphine ligands, and thus is an
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Scheme 47 Carbonylative Sonogashira coupling reaction of aryl

iodides with terminal alkynes in water.
Scheme 48 Pd/Cu-catalyzed four-component reaction of 1,2-dichloro-

quinoxaline, hydrazine hydrate, phenylacetylene and aromatic aldehyde
in water.
environmentally benign system for the three-component carbo-

nylative reaction of aryl iodides and terminal alkyne.
The one-pot Pd/Cu-catalyzed, four-component reaction of 1,2-
dichloroquinoxaline, hydrazine hydrate, phenylacetylene, aro-
matic aldehydes has been recently developed in water in the
presence of K2CO3, which provides an efficient and a direct
method for the preparation of N-substituted pyrrolo[2,3-b]qui-
noxalines 86 (Scheme 48).192 The reaction might proceed
through the following procedure: (i) formation of 2-(arylhydra-
zino)-3-chloroquinoxaline 87 that could be isolated in 95% of
yield under catalyst-free conditions in water at room temperature;
(ii) Pd/C-catalyzes the coupling of 87 with copper(I) acetylide
that was generated in situ from phenylacetylene leading to for- Scheme 49 Multicomponent domino reaction of benzene-1,2-di-
mation of another intermediate, 2-(arylhydrazino)-3-alkynylqui- amines, tetronic acid and 2,2-dihydroxy-2H-indene-1,3-dione in water.
noxaline, that was subsequently converted to the desired product
86 via activation of the triple bond. Wong et al.193 reported an
efficient modular approach for single-site incorporation of controlling the chemo- and regioselectivity of the multicomponent
amines and alkynes into aldehyde-containing oligosaccharides, reaction. And the optimal ratio of benzene-1,2-diamine/
such as D-raffinose, concurrently by using a one-pot gold- tetronic acid/2,2-dihydroxy-2H-indene-1,3-dione was found to be
mediated three-component coupling reaction in aqueous medium 2/1/1. The reaction might involve the following three steps:
under mild conditions. While high aldehyde conversion was (i) condensation of benzene-1,2-diamine and tetronic acid generat-
obtained with [Au(C^N)Cl2] (HC^N = 2-benzylpyridine) cata- ing a 4-(2-aminophenylamino)furan-2(5H)-one XXV; (ii) 2,2-
lyst, the hydroxyl groups of the oligosaccharides remained dihydroxy-2H-indene-1,3-dione with benzene-1,2-diamine pro-
intact. viding corresponding 11H-indeno[1,2-b]quinoxalin-11-one
XXVI; and (iii) attack of XXV to XXVI affording an intermediate
2.7. Other MCRs in water XXVII that can then undergo an acid-catalyzed intramolecular
nucleophilic substitution to form the final product 88. It should be
A multicomponent domino reaction of benzene-1,2-diamines, noted that when the ratio of substrate is 1/1/1 the two nucleophilic
tetronic acid and 2,2-dihydroxy-2H-indene-1,3-dione was also centers of XXV can also attack 2,2-dihydroxy-2H-indene-1,3-
reported in an aqueous solution of acetic acid under microwave dione to form XXVIII. Interestingly, when two types of benzene-
irradiation, which generated spiro-substituted benzo[b]furo[3,4-e]- 1,2-diamines (1.0 equiv for each) were subjected to this reaction
[1,4]diazepine derivatives 88 in good to excellent yields under similar conditions by controlling their addition sequence,
(Scheme 49).194 In this reaction, five σ bonds including four the corresponding products 89 were also formed in good to excel-
C–N bonds and a quaternary amine functionality were estab- lent yields (Scheme 49). Similarly, a three-component reaction of
lished in one step. The ratio of reactants plays a crucial role in benzene-1,2-diamines, tetronic acid and aldehydes can also be
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Scheme 52 Three-component reaction of 2-picoline, α-bromoaceto-

phenone and dimethyl acetylenedicarboxylate.
conditions in comparison to microwave heating, suggesting that

Scheme 50 Three-component reaction of 2-arylidenemalononitrile, a synergistic effect between water solvent and microwave radi-
1,3-thiazolidinedione and aniline. ation plays a key role in promoting the reaction toward com-
pletion. The reaction proceeds according to (i) the initial
formation of the corresponding Tschitschibabin indolizine XXX,
(ii) generation of XXXI through a [3 + 2] cycloaddition with a

triple bond of dialkyl acetylenedicarboxylate or alkyl propiolate,
and (iii) a concomitant aerial oxidation of XXXI toward com-
pound 94.
A three-component domino reaction of 2-hydroxy-1,4-
naphthoquinone, aromatic aldehydes and a 1-(2-oxo-2-phenyl-
Scheme 51 Three-component condensation reaction of acid chloride, ethyl)pyridinium bromide salt has been developed in the pres-
dimethyl acetylenedicarboxylates and amino acid. ence of ammonium acetate under microwave irradiation and
using water as solvent (Scheme 53).199 Although other solvents,
such as methanol, ethanol, acetonitrile, ethylene glycol and
DMF, are also able to generate the same product, highest yield
performed under the identical condition, providing a wide range was obtained in water. This reaction afforded a library of
of XXIX-type benzo[f]azulen-1-ones.195 According to a similar novel 2-arylcarbonyl-3-aryl-4,9-dihydronaphtho-[2,3-b]furan-4,9-
mechanism, the product XXIX was generated, apparently, by diones 95 in good yields. To explain the formation of the final
attacking of XXV to the carbonyl of the aldehyde. product, a sequential transformation is proposed that involves (i)
Kumar et al.196 synthesized a histidine-based ionic liquid, generation of α,β-unsaturated triketone XXXII, (ii) Michael
[BHP-OMe]Br 90, which can promote diastereoselective three- addition of XXXIII to XXXII, (iii) intramolecular cyclisation of
component reaction of 2-arylidenemalononitrile, 1,3-thiazolidi- XXXIV and (iv) oxidation of XXXV with air to afford 95.
nedione, aliphatic or aromatic amines, providing dihydrothio- Singh et al.200 reported sequential one-pot three-component
phenes 91 in good to excellent yields in water (Scheme 50). The reaction of isoquinoline, phenacylbromide and styrene oxide in
ionic liquid 90 displayed good reusability in at least four sub- an aqueous micellar system constructed by CBAB. Under opti-
sequent reactions under the same reaction conditions without mized conditions, the reaction afforded the desired product 96
any considerable loss in reaction yield. In addition, the ionic with 95% of yield (Scheme 54). Replacing water with many
liquid 90 was also utilized in synthesis of tacrine derivatives 92 other solvents, such as hexane, THF, acetonitrile and toluene,
from dihydrothiophenes with the aid of microwave irradiation resulted in significant decreases of the reaction yield, indicating
under aqueous conditions (Scheme 50). that water plays an indispensable role in accelerating the three-
Synthesis of tetrasubstituted pyrroles 93 by the three-com- component reaction. A stepwise one-pot three-component re-
ponent condensation reaction of acid chlorides, dialkyl acetylene- action of isoquinoline, phenacyl bromide and thiocyanate that
dicarboxylates and amino acids in the presence of catalytic leads to imidazo[2,1-a]isoquinoline derivatives 97 in good yields
amount of a basic ionic liquid, butyl methyl imidazolium was described by Kianmehr (Scheme 54).201 The reaction was
hydroxide [BMIm]OH, was reported by Yavari et al. preferably performed in water as compared with other solvent
(Scheme 51).197 The [BMIm]OH/H2O catalyst system could be systems when K2CO3 was used as a base. Dimethyl acetylene-
reused for at least five recycles without appreciable loss of dicarboxylate can also react with phenacyl bromide and
efficiency. quinoline or isoquinoline under the identical conditions to afford
A microwave-promoted and base-catalyzed synthesis of cycl pyrrolo[2,1-a]isoquinoline 98 and pyrrolo[1,2-a]quinoline
[3.2.2]azines 94 was accomplished in water via a three-com- derivatives in high yields (Scheme 54).202
ponent reaction of 2-picoline, α-bromoacetophenone and dialkyl A simple synthesis of 1,4-benzoxazepin-2-one derivative 100
acetylenedicarboxylate or alkyl propiolate (Scheme 52).198 It has been realized via a three-component reaction of isoquinoline
should be noted that the model three-component reactions in or quinoline, activated acetylenes, and 1-(6-hydroxy-2-isoprope-
water were found to be sluggish when carried out under thermal nyl-1-benzofuran-yl)-1-ethanone (99) in water without using any
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Scheme 55 Three-component reaction of isoquinoline, activated acetyl-

enes, and 99 or isatin in water.
Scheme 53 Three-component domino reaction of 2-hydroxy-1,4-

naphthoquinone, benzaldehyde and 1-(2-oxo-2-phenylethyl)pyridinium
bromide salt in water.
Scheme 56 Three-component reaction of alkynyl bromide, amine and

water.
these reactions, it was suggested that the mechanism proceeded

via the initial formation of a 1 : 1 zwitterionic intermediate
XXXVI between isoquinoline and the activated acetylenes. This
intermediate is protonated by 99 to provide XXXVII, and then
the conjugate base of 99 attacks the iminium carbon of XXXVII
to form another intermediate XXXVIII. Finally, the intermediate
XXXVIII undergoes cyclisation to produce the desired product
100. A one-pot three-component reaction of isoquinoline, acti-
Scheme 54 Three-component reaction of isoquinoline and phenacyl vated acetylenes and NH-acids has also been developed in water
bromide under aqueous conditions. at 70 °C without using any catalyst, which generated 1,2-di-
hydroisoquinolines 101 in good yields (Scheme 55).204
Jiang and his co-workers205 described an effective method for
catalyst (Scheme 55).203 The reactions were completed after synthesis of amide 102 by means of a three-component reaction
approximately 12 h at room temperature. To explain the result of of alkynyl bromide, amine and water (Scheme 56). The reaction
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was conducted in pure water without the use of any catalyst.

Among different solvents tested in the reaction, water clearly
stood out, producing the amide product with the highest yield
(ca. 92% yield), with 1,4-dioxane in a distant second place
(ca. 70% yield). The reaction might proceed according to the fol-
lowing procedure: (i) alkynyl bromide reacts with diethylamine
to afford a ynamine XXXIX, and (ii) the oxygen atom of water
then attacks the triple bond and forms the intermediate XL,
which is then subsequently converted to the amide 102.
Although this method showed a diverse substrate scope, owing
to the fact that alkynyl bromide is generally obtained from
alkyne that can also be used for preparation of amide, the advan- Scheme 57 Three-component reactions of aromatic aldehyde, 2-(2,3-
tages of Jiang’s method are not very significant from the view- dihydrothiochromen-4-ylidene) malononitrile and malononitrile in ionic
point of cost-effective synthesis. Fortunately, the use of water as liquids.

solvent endowed this system with some green parameters, such
as transition-metal-free method and operationally simple pro-
cedure, which made the system a valuable complement method
to the traditional synthesis of amides.
3. MCRs in ionic liquids

The attractiveness of ionic liquids as reaction media is attributed
to their unusual physicochemical properties, such as negligible Scheme 58 Pseudo-four-component condensation of aldehydes, thio-
vapor pressure, low volatility, tunable polarity and miscibility phenols, and malononitrile in an ionic liquids.
with organic or inorganic compounds. The ionic nature of ionic
liquid ensures that catalysts that are ionic or possess polar or
ionic fragments can be readily immobilized, separated and benzo[c]thiochromene-8,10-dicarbonitrile 104. This example
recycled through a biphasic operation without laborious catalyst demonstrated clearly that ionic liquids indeed have a unique
modification or work-up, thereby providing a convenient solu- ability to control the selectivity of MCRs.
tion to both the solvent emission and catalytic recycling Heravi et al.210 described a ZrOCl2·8H2O/NaNH2-catalyzed a
problem. Moreover, ionic liquids are able to generate an internal pseudo-four-component condensation of aldehydes, thiophenols,
pressure and promote the association of reactants in the solvent and malononitrile in [BMIm]BF4 under ultrasound irradiation at
cavity during the activation process.206 Thus ionic liquids are room temperature, which generated 2-amino-6-(arylthio)-4-aryl-
well suited as reaction media for MCRs in which the entropy of pyridine-3,5-dicarbonitrile derivatives 105 in high yields
the reaction is decreased in the transition state.207 Rodriguez (Scheme 58). Interestingly, in the absence of ZrCl2, NaNH2,
et al.208 published an excellent review, in which parts of the [BMIm]BF4 and sonication, or elements of these, no reaction
reported results were summarized, emphasizing the synergistic occurred. The reactions were generally completed within 20 min
effect of the combined use of MCRs and ILs for constructing and the products were easily isolated by extraction with ethyl
heterocycles, covering up to the middle of 2010, we intend to acetate. The remaining [BMIm]BF4 containing the catalyst was
particularly focus on the results that have emerged afterwards. recovered and reused in subsequent reactions with only a gradual
For MCRs, the issue of selectivity is of particular significance decrease in the activity being observed. Three-component reac-
because of the high probability of several potential parallel reactions of salicylaldehyde, malononitrile and thiophenols also pro-
tion pathways resulting from simultaneous molecular interaction ceeded very well in [BMIm]BF4, providing 4H-chromenes 22 in
of three or more components, which might lead to formation of good yields (Scheme 10).211
different product classes. One of the advantages of ionic liquids An efficient one-pot three-component reaction of ketone, malono-
is their tunable physical properties. By varying the anion and nitrile and carbon disulfide has been described by Esmaeili
cation, ionic liquids can be prepared that vary in polarity, vis- et al.,212 which generated a variety of 2-thioxo-2H-thiopyran
cosity, density, melting point, and miscibility/solubility proper- derivatives 106 in fairly good yields (Scheme 59). The reaction
ties. This offers a new opportunity for controlling the selectivity was performed in an ionic liquid, [BMIm]Br, in conjunction
of MCRs. Wang et al.209 have recently reported a three-com- with a base, EtONa. Initially, Knoevenagel reaction of ketone
ponent reaction of aromatic aldehyde, 2-(2,3-dihydrothiochro- and malononitrile provides arylidenemalononitrile, which under-
men-4-ylidene) malononitrile and malononitrile, in which the goes a cyclization with carbon disulfide to generate the desired
reaction product could be changed by altering the anion of ionic 2-thioxo-2H-thiopyran 106. Interestingly, [BMIm]Br was proved
liquid (Scheme 57). In ionic liquid [BMIm]BF4, because of the to be the best solvent for this three-component reaction, even
hydrolysis of the anion, the medium is acidic, thus allowing for- [BMIm]OH is ineffective.
mation of 9-amino-7-aryl-6H-benzo[c]thiochromene-8,8,10(7H)- A four-component, one-pot reaction of aromatic aldehyde,
tricarbonitrile 103. When the anion was replaced by Br−, the cyclohexanone, malononitrile, and amines could be performed in
same reaction provided another product, 9-amino-7-phenyl-6H- a basic ionic liquid [BMIm]OH, providing N-methyl- or N-aryl-
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Scheme 59 Three-component reaction of ketone, malononitrile and

carbon disulfide in different solvents. Scheme 62 One-pot synthesis of 6-aminouracil 111 in [TMG]Ac.
Scheme 60 Four-component, one-pot reaction of aromatic aldehyde,

cyclohexanone, malononitrile, and amines in ionic liquid.
Scheme 63 Synthesis of 1,2,4,5-substituted imidazoles from benzil,

aldehydes, amines and ammonium acetate in ionic liquid.
A one-pot synthesis of 6-aminouracils 111 via in situ gener-

ated ureas and cyanoacetylureas (Scheme 62) using an ionic
Scheme 61 Four-component cyclocondensation of hydrazine mono- liquid, 1,1,3,3-tetramethylguanidine acetate ([TMG]Ac), as a
hydrate/phenyl hydrazine, ethyl acetoacetate, aldehydes, and malononi- recyclable solvent and catalyst has been recently developed by
trile in ionic liquid. Chavan and Degani.218 The synthetic reaction was performed in
a one-pot manner and involved the following sequential three-
steps: (i) a reaction of equi-molar amounts of benzylamine and
substituted 2-amino-4-aryl-5,6,7,8-tetrahydroquinoline-3-carbo- potassium cyanate in the presence of [TMG]Ac at 60 °C that
nitriles 107 in good to excellent yields (Scheme 60).213 During resulted in the formation of urea 109; (ii) reaction of 109 with
this transformation, at least 11 bonds were cleaved and 7 new 1 molar equivalent of cyanoacetic acid and 2 molar equivalents
bonds were constructed. The ionic liquid could be recovered of acetic anhydride at 60 °C afforded cyanoacetylurea 110; (iii)
easily after the reaction, and reused up to five cycles as a reaction ring closure of cyanoacetylurea 110 at 90 °C gave 6-aminouracil
medium with a slight decrease in yields. An efficient one-pot 111 (Scheme 62). After the completion of the reaction, the pro-
multicomponent synthesis of 2,4-diamino-5-pyrimidinecarbo- ducts were isolated by filtration after adding cold water into the
nitrile derivatives has been developed by the condensation of reaction mixture. The ionic liquid [TMG]Ac was recovered by
aromatic aldehydes, malononitrile, and guanidine using ionic removing the water under reduced pressure and could be reused
liquid [BMIm]OH as base under microwave irradiation (100 W) at least five times without any appreciable decrease in yield. This
at 60 °C.214 method offers a simple and straightforward strategy for the syn-
A highly efficient synthesis of 4H-pyrano[2,3-c]pyrazoles 108 thesis of 6-aminouracils. In this report, the same ionic liquid can
has been realized via four-component cyclocondensation of catalyze different consecutive steps in a single reaction vessel,
hydrazine monohydrate/phenyl hydrazine, ethyl acetoacetate, which not only reduces the operating time and the amount of
aldehydes, and malononitrile by using L-proline as catalyst in waste produced, but also provides a means to improve the econo-
ionic liquid [BMIm]BF4 (Scheme 61).215 The ionic liquid could mical and environmental aspects of chemical process.
be recycled without significant loss in the reaction yields. Three- A catalyst-free one-pot four-component methodology for the
component reactions of 1,3-diketones, substituted hydrazines synthesis of 1,2,4,5-substituted imidazoles 112 from benzil, alde-
and benzaldehydes have also been performed in [BMIm]BF4 by hydes, amines and ammonium acetate under conventional
using Yb(OTf )3 as catalyst.216 This method provided an efficient heating and microwave irradiation using [BMIm]Br as an
and eco-friendly route to access the 2-substituted tetrahydroinda- efficient promoting reaction medium has been recently described
zolone derivatives. Yb(OTf )3/[BMIm]BF4 is also effective for by Hasaninejad et al. (Scheme 63).219 Parallel reactions in other
the synthesis of β-acetamido ketones from corresponding organic media, such as DMSO, DMF, CH3CN and toluene, gave
ketones, aldehydes, acetonitrile, and acetyl chloride.217 no or a small amount of product, indicating the existence of a
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Scheme 64 Four-component condensation of 3-methyl-1H-pyrazol-5-

(4H)-one, ammonium acetate, aromatic aldehydes, and Meldrum’s acid Scheme 65 Two-step synthesis of 4(1H)-quinolones 115 in ionic
in ionic liquid. liquids.
great promoting effect of [BMIm]Br in this reaction. The authors

suggested that [BMIm]Br might play the following two func-

tions: (i) electrophilically activating the aldehyde carbonyl
through hydrogen bonding to the carbonyl oxygen; and (ii)
enhancing the nucleophilicity of the amine through deprotona-
tion of the N–H bond. Kumar et al.220 developed a straightfor-
ward and an efficient method for the synthesis of quinolines 53
by the Yb(OTf )3-catalyzed three-component reaction of alde-

hydes, alkynes, and amines under microwave irradiation in an
ionic liquid [BMIm]BF4 (Scheme 27). The catalyst as well as the
ionic liquid can be recycled up to four cycles without significant
loss of its catalytic activity. Scheme 66 Four-component reaction of aldehyde, phthalic anhydride,
A one-pot, four-component condensation of 3-methyl-1H- hydrazinium hydroxide and dimedone in different solvents.
pyrazol-5(4H)-one, ammonium acetate, aromatic aldehydes, and
Meldrum’s acid has been developed by means of using [BMIm]-
BF4 as a recyclable medium by Lei and Hu,221 which generated of dialkyl acetylenedicarboxylates, formaldehyde and 3-amino-
3-(5-amino-3-methyl-1H-pyrazol-4-yl)-3-arylpropanoic acid carbazoles can also be performed in [BMIm]BF4, generating
derivatives 113 in good to excellent yields (Scheme 64). A three- various carbazolyltetrahydropyrimidine derivatives in good
component reaction of aldehyde, 5-amino-3-methyl-1-phenyl- yields.227
pyrazole and Meldrum’s acid or dimedone has also been studied A one-pot four-component reaction of aldehyde, phthalic
in some ionic liquids, such as [BMIm]BF4 and [BMIm]Br, anhydride, hydrazinium hydroxide and dimedone under ultra-
which provides pyrazolo[3,4-b]pyridinone or pyrazolo[3,4-b]qui- sonic irradiation in ionic liquid [BMIm]Br has been described,
nolin-5(6H)-one derivatives in high yields.222,223 The same ionic which generated various 2H-indazolo[2,1-b]phthalazinetriones
liquid [BMIm]BF4 was also proved to be a suitable medium for 118 in good yields under neutral and catalyst-free conditions
synthesis of a spiro[4H-pyran-oxindole] heterocycle 39 by (Scheme 66).228 Reactions in other solvents under the identical
means of three-component reactions between isatins, malono- conditions are also able to afford the same product, but the
nitrile, and 1,3-dicarbonyl compounds (Table 4, entry 5).224 A yields are rather low. The reaction mechanism might involve: (i)
three-component reaction of aldehydes, 1-naphthylamine and formation of phthalhydrazide through reaction hydrazinium
barbituric acid proceeded very well in ionic liquid [BMIm]BF4, hydroxide and phthalic anhydride; (ii) Knoevenagel conden-
providing 7-aryl-11,12-dihydrobenzo[h]pyrimido-[4,5-b]quino- sation of dimedone and aldehyde that generated an α,β-unsatu-
line-8,10(7H,9H)-diones in good to excellent yields.225 Three- rated intermediate; and (iii) Michael-type addition of the
component reaction of aromatic aldehyde, 2-hydroxy-1,4- phthalhydrazide to the α,β-unsaturated intermediate and sub-
naphthoquinone and 2-naphthylamine could also be performed sequent cyclization to afford the corresponding product. Both
in ionic liquid [BMIm]BF4 at room temperature, which generated cation and anion of [BMIm]Br might play a key role in assisting
a series of 14-aryl-1,6,7,14-tetrahydrodibenzo[a,i]-acridine-1,6- this reaction. Three-component reaction of 5,5-dimethyl-
dione derivatives in good yields (Table 3, entry 10). 3-aminocyclohex-2-enone, aromatic aldehyde, and acyl aceto-
Yadav et al.226 described a two-step synthesis of 4(1H)-quino- nitrile could be performed in [BMIm]Br, which provided a series
lones 115 in ionic liquids. First, a three-component condensation of hexahydroquinoline derivatives in high yields.229
of aniline, Meldrum’s acid and trimethylorthoformate was Constantieux and Plaquevent230 investigated a three-com-
carried out in [BMIm]Br under nitrogen atmosphere at 40 °C, ponent reaction of β-ketoamide, acrolein and 2-aminophenol in
which generated compounds 114 in excellent yields. Then, the various ionic liquids, with which a novel heterocyclic compound
resulting compounds 114 were treated in [BMIm]OTf at 80 °C, 119 could be synthesized (Scheme 67). Previously, the same
providing the desired 4(1H)-quinolones 115 in excellent yields reaction has been performed in toluene solvent in conjunction
(Scheme 65). When 2-aminothiazole and 2-aminobenzenethi- with the use of a large amount of 4 Å molecular sieves. Repla-
azole were used instead of aniline, 5H-thiazolo[3,2-a]pyrimidin- cing toluene with ionic liquid [BMIm]NTf2 not only gave com-
5-one 116 and 4H-pyrimido[2,1-b]benzothiazol-4-one 117 were petitive yields but also increased the reaction rate. In some cases,
obtained in good yields (Scheme 65). Three-component reaction the use of 4 Å MS could be totally excluded thanks to the
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Scheme 67 Three-component reaction of β-ketoamide, acrolein and 2-

aminophenol in ionic liquid. Scheme 69 Chemoselective synthesis of 2,2-dimethyl-6-substituted 4-
piperidones 123 in ionic liquid.
Fig. 5 Reaction procedure in PEG1000-DAIL/toluene. (a) PEG1000-

DAIL/toluene at room temperature; (b) after addition of substrates; (c)
homogeneous phase at 80 °C; (d) phase-separation along with cooling;
(e) complete phase-separation after being cooled to room temperature
(used with agreement of the publisher).
Scheme 68 Three-component reaction of 2-aminobenzophenones,
ammonium acetate with isatin, 1,2-diketone or aromatic aldehydes in
ionic liquid [HMIm]ATF. chemoselective synthesis of 2,2-dimethyl-6-substituted 4-piperi-
dones 123 via a L-proline catalyzed four-component tandem
promoting properties of the ionic liquid solvent. Furthermore, Mannich reaction of ammonia, aldehydes and acetone
the ionic liquid in this three-component reaction could be (Scheme 69). The ionic liquid [BMIm]PF6 not only serves as a
recycled and reused up to five times without significant decrease reaction medium, but also significantly enhances the chemo-
of the reaction yield. selectivity. The authors speculated that [BMIm]PF6 may favor
4-Substituted-spiro-1,2-dihydroquinazolines 120 and 121 were the formation of imine and consequently result in the preferential
synthesized by direct reaction of 2-aminobenzophenones, isatin, occurrence of Mannich reaction over aldol reaction. In addition,
or 1,2-diketone derivatives and ammonium acetate in the pres- the ionic phase containing L-proline catalyst could be easily
ence of dual role catalyst/solvent ionic liquid, 1-methylimidazo- recycled for several times without loss of reactivity and
lium trifluoroacetate [HMIm]TFA (Scheme 68).231 In the chemoselectivity.
presence of the same ionic liquid, [HMIm]TFA, a three-com- The introduction of Brønsted-acidic functional groups into the
ponent condensation reaction between 2-aminobenzophenone cations or anions of the ionic liquids, especially SO3H functional
derivatives, aromatic aldehydes, and ammonium acetate group, obviously enhanced their acidities and water solubilities.
efficiently provides substituted quinazolines 122 in a one-pot Therefore, Brønsted-acidic ionic liquids can be used as highly
reaction in conjunction with aerobic oxidation (Scheme 68). The efficient acid catalysts and have attracted extensive interest as
ionic liquid was separated from the reaction mixture by simple green substitutes for H2SO4, HF, and AlCl3 as catalysts in chemi-
extraction and was recycled three times without considerable cal processes.236 Luo et al.237 developed a PEG1000-based
loss in activity.232 Preparation of benzo[b][1,4]oxazines through dicationic acidic ionic liquid (PEG1000-DAIL) that can be used for
a three-component reaction of 2-aminophenole, aldehyde and constructing a temperature-dependant phase-separation system in
isocyanide has been performed in [BMIm]Br at ambient temp- conjunction with toluene (Fig. 5). A one-pot three-component
erature. High reaction yields, recyclable medium and mild con- condensation reaction of aromatic aldehydes, malononitrile and
ditions are the features of this synthetic system.233 In the 5,5-dimethyl-1,3-cyclohexanedione could be performed in this
presence of [BMIm]BF4, one-pot three-component condensation system, which produced a various of 5-oxo-5,6,7,8-tetrahydro-
of anthranilic acid, carboxylic acid and aniline proceeded well 4H-benzo[b]pyrans in excellent yields. PEG1000-DAIL could be
with the aid of ultrasound irradiation, providing 4(3H)-quinazoli- efficiently recovered by simple decantation after reaction without
nones in high yields.234 any apparent loss of catalytic activity and little loss of weight
Ionic liquid [BMIm]PF6 has been demonstrated by Xu even after 10 times recycling. The same system can also be used
et al.235 to be an efficient and recyclable medium for highly in the synthesis of 2,4,5-trisubstituted imidazoles via one-pot
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Scheme 70 Three-component reaction of aromatic aldehydes, urea or

thiourea, and 3,4-dihydro-2H-pyran in ionic liquid.
three-component condensation with various aldehydes, benzil

and ammonium acetate.238 Analogous three-component reaction
of aromatic aldehydes, malononitrile and 2-hydroxy-1,4-
naphthoquinone can also be performed in ethanol by using a

basic ionic liquid, [BMIm]OH, as catalyst.239,240 Scheme 71 The synthesis of monastrol 125 and enastron 126 in ionic
liquid [BMIm]MeSO4.
By using common SO3H-functionalized Brønsted acidic di-
alkylimidazolium ionic liquids as catalyst, one-pot condensation
of 2-naphthol, aldehydes and 1,3-cyclohexanediones proceeded reexamined the organocatalytic potential of [BMIm]-based ionic
very well, generating thus a variety of 8,9,10,12-tetrahydrobenzo liquids in Biginelli reaction of aldehydes, β-keto ester or
[a]xanthen-11-one derivatives in good yields.241,242 The same β-diketone, and urea or thiourea. It was found that both countera-
reaction can also be performed in a neutral ionic liquid in the nion and 1,3-disubstituted imidazolium moiety played a key role
presence of IBX or p-TSA.243,244 A one-pot three-component in determining the catalytic activity of the ionic liquid. The best
condensation of aldehydes, amides and 2-naphthol has also been ionic liquid was proved to be [BMIm]MeSO4, and very small
investigated by using either a polyethylene glycol (PEG)-based amount of the ionic liquid (1 mol%) was sufficiently enough to
dicationic acidic ionic liquid or SiO2-supported SO3H-functiona- finish the Biginelli reaction at 100 °C for 30 min, affording dihy-
lised benzimidazolium-based ionic liquid as catalyst under dropyrimidinones in good yields. Mechanism investigation
solvent-free conditions.245,246 An analogous one-pot conden- revealed that the reaction proceeded according to the following
sation reaction of aromatic aldehydes, 2-naphthol and methyl steps: (i) formation of the imine or iminium intermediate from
carbamate or acetamide can also be promoted by using the aldehyde and the urea; (ii) subsequent nucleophilic attack of
Brønsted-acidic ionic liquids [(CH2)4SO3HMIm]HSO4 and the active methylene carbon of the β-dicarbonyl compound
[(CH2)4SO3HPy]HSO4 as catalysts.247,248 through its enol form to the intermediate; and (iii) intramolecular
A Biginelli-type three-component reaction of aromatic alde- cyclocondensation of the generated intermediate in the second
hydes, cyclopentanone and urea or thiourea has been developed step to afford the Biginelli product. The catalytic effect of
by using N-(4-sulfonic acid) butyl triethyl ammonium hydrogen [BMIm]MeSO4 on the reaction was displayed mainly in the later
sulfate ([TEBSA]HSO4), which is a Brønsted acidic ionic liquid, two steps. Finally, this method was successfully extended to the
as an effective and recyclable catalyst under thermal and solvent- synthesis of monastrol 125 and its analogue enastron 126, which
free conditions, which generates various pyrimidinone deriva- are both biologically active, and these molecules were formed in
tives in good to excellent yields.249 The same reaction can also excellent yields in a short reaction time (Scheme 71). It should
be performed in ionic liquid [BMIm]Br in conjunction with be noted that this mechanism postulated in [BMIm]MeSO4
TMSCl as an additive.250 However, in these systems, the ionic system might be different from the reactions in aqueous media in
liquids were all used in large amounts. Mirzai and Valizadeh which the interaction between 1,3-dicarbonyl compound and
reported a novel nitrite-functionalized dialkylimidazolium ionic aldehyde might preferentially occur, and urea acts as a
liquid (IL-ONO) that can be used as a weak Lewis base catalyst catalyst.256
for the Biginelli reaction, with which good to excellent yields A geminal dicationic ionic liquid, N,N,N′,N′-tetramethyl-N,N′-
were obtained.251 An analogous phosphinite ionic liquid dipropanesulfonic acid ethylenediammonium hydrogen sulfate
(IL-OPPh2) can also efficiently catalyze Biginelli reactions.252 ([TMEDAPS]HSO4), could be used as efficient and recyclable
Recently, a series of 1H-pyrano[2,3-d]pyrimidin-2(8aH)-one catalyst for the synthesis of α-aminophosphonates at room temp-
derivatives 124 have been synthesized via one-pot three-com- erature via a one-pot three-component reaction of benzaldehyde,
ponent reaction of aromatic aldehydes, urea or thiourea, and 3,4- aniline, and trimethylphosphite.257 Recently, a choline-based Zn-
dihydro-2H-pyran using a Brønsted acidic ionic liquid, containing deep eutectic mixture (choline chloride·2ZnCl2) has
1-methyl-2-pyrrolidinone hydrosulfate ([HNMP]HSO4), as also been applied as an efficient and eco-friendly catalyst for the
catalyst under solvent-free conditions (Scheme 70).253 A Biginelli- one pot three-component synthesis of α-aminophosphonates
like three-component reaction of aldehydes, 5-aminotetrazole and under solvent-free conditions at room temperature.258 Synthesis
ethyl 4,4,4-trifluoro-3-oxobutanoate or 4,4,4-trifluoro-1-phenylbu- of 2,4,6-triarylpyridines (Kröhnke pyridines) through a one-pot
tane-1,3-dione can also be performed in ionic liquid [BMIm]BF4, three-component reaction of acetophenones, aromatic aldehydes,
providing 5-(trifluoromethyl)-4,7-dihydrotetrazolo[1,5-a]pyrimi- and ammonium acetate using a Brønsted acidic ionic liquid,
dine derivatives in good yields.254 3-methyl-1-(4-sulfonylbutyl)imidazolium hydrogen sulfate [HO3S-
In order to find an efficient ionic liquid for this type of three- (CH2)4MIm]HSO4, as a reusable catalyst under solvent-free con-
component reaction, recently Chakraborti et al.255 have ditions has been described.259 The ionic liquid catalyst can be
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Scheme 73 Willgerodt-Kindler reaction in PEG 600.

Scheme 72 Mannich-type reaction catalyzed synthesis of 128 in ionic
liquid [BMIm]PF6.
reused after simple work-up, with a slight decline of its activity

being observed. The same three-component reaction of 2-acetyl-
naphthalene or 2-acetylthiophene, aromatic aldehydes, and
ammonium acetate has also been investigated by using
[(CH2)4SO3HPy]HSO4 as catalyst.260
Scheme 74 Povarov reaction in PEG-400.
A three-component Mannich-type reaction of aromatic alde-
hydes, aromatic amines, and ketones was catalyzed by a novel
functionalized ionic liquid, 3-(N,N-dimethyldodecylammonium)
propanesulfonic acid hydrogen sulfate ([DDPA]HSO4), at room transfer catalyst (PTC) in organic synthesis,266,267 none of these
temperature to give various β-amino carbonyl compounds in articles has focused on MCRs developed by using PEG as an
good yields.261 In [BMIm]PF6, an asymmetric direct three-com- alternative reaction media. This part of the present review will
ponent Mannich reaction of aromatic aldehyde, aniline and summarize, for the first time, the results of performing MCRs in
ketone proceeded well in the presence of a siloxy-L-serine orga- PEG media or over a PEG-functionalized catalyst.
nocatalyst 127, (2S)-2-benzyloxycarbonylamino-3-(tert-butyl- In the past decade, various named reactions have been evalu-
diphenyl-silanyloxy)-propionic acid, furnishing the β-amino car- ated by using PEG as solvent or catalyst. For example, in 2007
bonyl scaffold 128 in high enantio- and diastereoselectivities PEG-400 was proved to be an essential promoter for Biginelli
(Scheme 72). The siloxy serine organocatalyst in [BMIm]PF6 reaction by Sain et al., and was able to produce 3,4-dihydropyri-
can be recycled up to three times with comparable enantio- midinones in high yields under neutral conditions.268 While
selectivities.262 An amino acid-based ionic liquid, 1-ethyl-3- good yields was obtained in the presence of PEG, the reaction
methylimizazolium 2-pyrrolidinecarboxylate [EMIm][Pro], has did not proceed under the identical conditions in different sol-
also been employed in the same asymmetric Mannich reaction. vents. Addition of some solvents, such as water, toluene and
Although good yields were obtained with excellent ee value, acetonitrile is also detrimental for this reaction. Bandgar et al.269
because the reaction has to be carried out in an organic solvent, described an efficient protocol for the three-component conden-
DMSO, the green effect arising from the use of ionic liquid as sation of aryl alkyl ketones, sulfur and morpholine in PEG-600
catalyst was diminished.263 Silica-supported boric acid, H3BO3– (Willgerodt-Kindler reaction), which produced thiomorpholides
SiO2, has also been examined as a catalyst for Mannich-type 129 generally in high yields (Scheme 73). In the classical
three-component reaction in [BMIm]PF6.264 Although high Willgerodt-Kindler reaction, morpholine was generally used in
yields were obtained, the real catalyst in this system might be HF large excess amount because it also acted as solvent. The use of
that was generated by a boric acid-mediated hydrolysis of PEG 600 as a solvent not only gives this system many salient
PF6 anion. features of green processes, but also minimizes the quantity of
morpholine to one equivalent amount.
Three-component imino Diels–Alder reactions between trans-
4. MCRs in PEGs isoeugenol or trans-anethole, anilines, and benzaldehyde
(Povarov reaction) could be performed in PEG-400 in the pres-
Polyethylene glycol polymers (PEGs) have recently emerged ence of 1 equivalent of BF3·OEt2, which give polyfuncionalized
also as environmentally benign reaction media as well as new 2,4-diaryl-1,2,3,4-tetrahydroquinoline derivatives 130 in fairly
vehicles for the immobilization of homogeneous molecular cata- good yields (Scheme 74).270 Although the yields of the Povarov
lysts.265 The reasons why PEGs have been widely used as green reactions were slightly lower than in MeCN, reaction time and
solvents are multifold: (i) PEGs are nonvolatile, recyclable, and volume of solvent were reduced considerably. Moreover, iso-
stable to acid, base and also to high temperature; (ii) PEGs are lation of the reaction products was simplified by avoiding basic
easily available in the market with low prices; (iii) data of PEGs treatment and extraction steps.
concerning their toxicity and biocompatibility are well known, The reaction of acetophenone, aldehyde, ethyl cyanoacetate
and, importantly, the low toxicity of PEGs allowed them to be and ammonium acetate has been performed in PEG-600, which
used in many areas; and (iv) PEGs are readily soluble in rela- provided polyfunctionalized 2-pyridones 131 in good yields
tively polar solvents like DMF, methanol, and water but are inso- (Scheme 75).271 Several solvents, like ethanol, H2O, and PEG–
luble in diethyl ether and isopropanol; this unique property H2O, were tested but very low yields were obtained. The MCR
allows the recovery of PEGs by precipitation and filtration, might proceed through formation an intermediate XLI that can
which is extremely important in soluble polymer-supported further react with acetophenone to afford the final product 131.
chemistry. Although some excellent reviews have covered the PEG-400 was found to be a cost-effective medium for the
topic of using PEG and its derivatives as solvent and phase one-pot synthesis of N-substituted decahydroacridine-1,8-diones
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Scheme 75 Four-component reaction of acetophenone, aldehyde, ethyl

cyanoacetate and ammonium acetate in PEG-600.

Scheme 77 Three-component reaction of 2-aminobenzimidazole, aro-
matic aldehydes and 1,2-diphenylethanone in PEG-300.
oxazines. This type of three-component reaction can also be per-

formed in PEG. While good yield was obtained in PEG-400,

reaction in other solvents, such as water, DMF, acetonitrile and
THF afforded the desired product only in moderate yields under
the identical conditions, indicating the essential role of PEG
solvent in rendering the reaction toward completion.279
PEG-400/CAN system was also used as a catalytic system for
one-pot, three-component Mannich reaction of acetophenone,
aromatic aldehydes and aromatic amines. However, a slight
decrease in reactivity was observed during the reuse of this
system. Also, an approximately 5% weight loss of PEG was also
Scheme 76 Three-component reactions of aniline and dialkyl acetylene-
dicarboxylate in PEG-400. observed.280 Mannich-type three-component one-pot reactions of
cyclohexanones, aromatic aldehydes and aniline could be per-
formed in PEG-400 in conjunction with 2,4,6-trichloro-1,3,5-
by means of three-component reaction of aromatic aldehyde, triazine as catalyst.281 Lei and Hu282 observed that a Biginelli-
1,3,-cyclohexadione, and aniline in the presence of catalytic like three-component condensation reaction of aromatic alde-
amount of ceric ammonium nitrate (CAN) in high yields.272 hyde, β-dicarbonyl compound and 2-aminobenzimidazole could
After reaction, PEG solvent as well as CAN catalyst can be be performed in water by using thiamine hydrochloride (VB1),
recovered and reused, thus making this protocol economically which is a nonflammable, inexpensive, and non-toxic reagent, as
and potentially viable. Some substituted pyrazolo[3,4b:4′,3′e] catalyst (Scheme 77). This method offers a straightforward and
pyridine can be prepared through multicomponent reaction of eco-friendly method for synthesizing benzo[4,5]imidazo[1,2-a]-
pyrazolone, aldehyde and ammonium acetate in PEG-400 under pyrimidine derivatives 134. Many other solvents, such as THF,
microwave irradiation by using basic bleaching earth catalyst.273 DMF, toluene, acetonitrile, ethanol and dichloromethane, were
Some acridines were also synthesized by the one-pot conden- also used in this reaction, but the yields obtained are inferior as
sation of 3,4,9,10-tetrahydroacridine-1(2H)-one, substituted alde- compared with water. Furthermore, water solvent also enables a
hyde and liquid ammonia in an alkaline PEG-400.274 A series of good recyclability of VB1 catalyst. Heating equimolar amounts
Hantzsch 1,4-dihydropyridines were also synthesized by one-pot of 2-aminobenzimidazole, aromatic aldehydes and 1,2-dipheny-
condensation of aldehyde, β-dicarbonyl compound and lethanone under microwave in PEG-300 in the presence of
ammonium acetate or ammonia in PEG-400 with or without K2CO3 resulted in formation of benzo[4,5]imidazo[1,2-a]pyrimi-
assistance of microwave irridiation.275,276 dines 135 (Scheme 77).283 The PEG/K2CO3 system could be
Polyethylene glycol (PEG) was proved to be an effective reused three times without significant loss of the reaction yield.
medium for one-pot synthesis of N-substituted azepines 132 However, a weight loss of 10% PEG was observed from cycle to
from aniline, dialkylacetylene dicarboxylate, and 2,5-dimethoxy- cycle.
tetrahydrofuran under mild conditions and catalyst-free con- He et al.284 developed an efficient and environmentally
ditions by Yeramanchi et al. (Scheme 76).277 The synthesis of benign method for the synthesis of organic carbamates through
polysubstituted pyrrole derivatives 133 through three-component three-component amines, CO2, and alkyl halides in the presence
reaction of phenacyl bromides, amine, and dialkyl acetylene- of K2CO3 by using PEG-400 as both solvent and catalyst under
dicarboxylate could be carried out in PEG-400 without the ambient conditions. Notably, the use of PEG could also depress
addition of any additive or organic co-solvent (Scheme 76).278 the alkylation of both the amine and the carbamate, thus result-
Mannich reaction of β-naphthol, formaldehyde and primary ing in enhanced selectivity toward the target carbamate. A one-
amines was known to be the best method for synthesizing 1,3- pot synthesis of polysubstituted-tetrahydropyrimidines through
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phosphonates 21 from salicylaldehydes, malononitrile or ethyl

cyanoacetate, and alkyl phosphites. The reaction was carried out
in PEG-400 under mild conditions without the use of any cata-
lysts (Scheme 10).
An efficient and a convenient three-component coupling reac-
tion of aldehyde, amine and alkyne has been developed in
Scheme 78 Three-component reaction of 2-chloro-3-formyl quinoline, PEG-400 by using CuI as the catalyst, providing a wide range of
piperidine and 2,4-thiazolidinedione in PEG-400. propargylamines in moderate to excellent yields.296 PEG solvent
as well as the metal catalyst could be recovered and reused
several times without evident loss in activity. Ag nanoparticles
four-component reaction of diethyl acetylenedicarboxylate, were prepared in PEG with simple bubbling of H2, and were
aniline, formaldehyde and primary amine has also been evalu- then used to catalyze a one-pot three-component reaction of
ated in PEG-400, and good yields were obtained within 45 min aldehyde, alkyne, and amine. This PEG-assisted process pro-
under mild conditions.285 vided a diverse range of propargylamines in high yields.297 Pas-
A three-component reaction of benzil, aldehyde and serini three-component reaction of isocyanide, aldehyde and
ammonium acetate or aromatic primary amines proceeded well carboxylic acid could also be efficiently carried out under mild
in PEG-400, providing various 2,4,5-triaryl-1H-imidazoles and conditions using PEG-400 as a green reaction medium, provid-
1,2,4,5-tetraaryl-1H-imidazoles in good yields with or without ing various α-acyloxy carboxamides in high yields.298 Conden-
assistance of microwave irradiation.286,287 One-pot synthesis of sation between isocyanides, dialkyl acetylenedicarboxylates and
2,4-diaryl pyrido[3,2-c]coumarins could be realized by reacting α,β-unsaturated aldehydes proceeded also very well in PEG-400,
4-hydroxy-7-methyl-coumarin with α,β-unsaturated ketones in affording the corresponding styrylfuran derivatives 71 in good
the presence of ammonium acetate in PEG-400.288 yields (Scheme 41).299 An Ugi-type multicomponent reaction of
An efficient one-pot three-component cyclocondensation of heterocyclic amidines with aldehydes and isocyanides catalyzed
4-( p-toulylsulfonoxy)benzaldehyde, aryl amines, and mercapto- by ZrCl4 in PEG-400 was also reported.300
acetic acid has also been conducted in PEG-400 to synthesize
various 2,3-disubstituted-4-thiazolidinone derivatives.289
A 5-[(2-( piperidin-1-yl)quinolin-3-yl)methylene]-2,4-thiazolidi-
nedione 136 could be obtained by exposing a mixture of 5. MCRs in bio-based solvents
2-chloro-3-formylquinoline, piperidine and 2,4-thiazolidinedione
to microwave irradiation in PEG-400 (Scheme 78).290 It should One of the important criteria of green solvents is the question of
be noted that piperidine was used in excess amount in this where the solvent comes from. Because solvents were used gen-
reaction, which also acted as a base to trap the generated HCl. erally in large quantity, how to access industrially the solvent is
The one-pot condensation of aldehyde, 3-methyl-1-phenyl- of course a key issue that needed to be solved before its appli-
1H-pyrazol-5(4H)-one and malononitrile in PEG-400 afforded cation. However, most of the green solvents, except water, were
the corresponding substituted pyrano-[2,3-c]-pyrazole derivatives prepared from fossil oil. For example, Jessop has recently
in good yield.291 One-pot three-component reaction of isatin, depicted a general route for synthesizing a commonly used ionic
malononitrile or cyanoacetic ester, and phthalhydrazide has been liquid, [BMIm]BF4, in which all the starting materials are finally
developed by using NiCl2 as catalyst in PEG-600, which gener- derived from fossil resource.301 Although supercritical CO2
ates various pyrazolophthalazinyl spirooxindoles 36 in good to (scCO2) seems to be an ideal green solvent, considering the fact
excellent yields (Scheme 20).292 Interestingly, reactions in many that the injected highly pure CO2 has to be industrially prepared
other organic solvents or water gave low yield or even no from heavy oil by combustion at low temperature, recognition of
product, indicating importance of PEG solvent for realization of scCO2 as a perfect sustainable solvent is still under dispute. Fur-
this MCR. Recently, Meshram et al.293 have reported a PEG- thermore, widespread application of scCO2 in R&D is also ham-
mediated synthesis of spiro-oxindoles under mild conditions by pered by the demand for advanced apparatus. With the predicted
means of three-component reaction of isatin, malononitrile, and disappearance of fossil resource, exploration of new solvents that
dimedone or 4-hydroxycoumarin. come from alternative resources to fossil oil and coal has
Synthesis of tetrahydrobenzo[α]-xanthen-11-one from dime- become an urgent topic of green chemistry. An ideal choice for
done, aldehyde and 2-naphthol can also be carried out in us, at this moment, is utilizing bio-based chemicals as a new
PEG-400 without the use of any catalyst (Table 2, entry 10).62 generation of green solvents. Because bio-based chemicals are
An efficient method has been developed for the synthesis of tri- prepared from renewable biomass, utilization of these chemicals
azolo[1,2-a]indazole-triones and spiro triazolo[1,2-a]indazole- as solvents does not consume any fossil resource. For many bio-
tetraone derivatives via a one-pot three-component condensation based chemicals, the profiles about toxicity and biocompatibility
reaction of 4-phenylurazole, dimedone with aromatic aldehyde, are well known. And importantly, the use of various bio-based
acenaphthenequinone or isatin derivatives, using PEG-SO3H as chemicals has been approved by governmental legislations.
an eco-friendly degradable polymeric catalyst (Table 3, entry Therefore, exploration of bio-based solvents is now an important
8).98 The same catalyst has also been used in Kabachnike-Field’s topic for sustainable chemistry. Over the past five years, many
reaction.294 However, in this case, the reaction was performed in bio-based chemicals were proposed as green solvents, such as
an organic solvent, toluene. Das et al.295 developed a convenient glycerol,302 ethyl lactate,303 amphiphilic carbohydrates304 and
method for the synthesis of (2-amino-4H-1-benzopyran-4-yl) gluconic acid aqueous solution.305 Interestingly, synergistic
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Fig. 6 Imagined procedure of the model reaction in glycerol (reused

with agreement of the publisher).
Scheme 79 Three-component of dimedone, formaldehyde and styrene

in glycerol.
effects have also been observed by performing MCRs in these

bio-based solvents.
Gu et al.306 described a three-component reaction of dime-
Scheme 80 One-pot two-step sequential reaction of arylhydrazines,
done, formaldehyde and styrene, which can be preferably per-
β-ketone esters, formaldehyde and styrenes.
formed in glycerol. While good yield of 137 was obtained in
glycerol, the same reactions in the other solvents gave the
desired product in low yield. The positive effect of glycerol (Scheme 80).307 In the first step of the reaction, phenylhydrazine
could be attributed to the following two factors: (i) a restricted and ethyl 4-methoxybenzoylacetate were heated at 110 °C in gly-
formation of a oxo-diene intermediate XLII (Scheme 79), result- cerol for 4 hours, allowing exclusive formation of 1,3-diphenyl-
ing from the initial Knoevenagel reaction of dimedone and for- 5-pyrazolone 139. And then paraformaldehyde and α-methyl-
maldehyde, and (ii) promoting effect of glycerol on the rate of styrene were added into the reaction vial. After 10 hours of re-
the subsequent oxo Diels–Alder reaction of XLII with styrene action at 110 °C, the desired product 140 was finally obtained in
due to its polar and protic character. During the reaction, the good yield. With the same strategy, another one-pot four-com-
authors observed an unusual formation of a white solid in gly- ponent reaction involving indoles, arylhydrazine, β-ketone esters
cerol, which cannot be observed when water and other organic and paraformaldehdye has been developed in glycerol. Although
solvents were used as reaction media. By means of 1H NMR examples using glycerol as solvent for designing new MCRs are
analysis, it was found that the solid was mainly composed of not popular at this stage, these examples discussed here clearly
paraformaldehyde and an insoluble by-product 138 was gener- demonstrate that glycerol can indeed be used as an indispensable
ated during the reaction. It has also been found that paraform- medium for developing new MCRs.
aldehyde decomposed quickly in glycerol in the absence of Glycerol solvent has recently been applied in the one-pot
dimedone in contrast to toluene for which many hours were three-component synthesis of 4H-pyrans under catalyst-free con-
necessary in order to decompose paraformaldehyde. On the basis ditions.308 In fact, the synthesis benefited by the unique ability
of these observations, the authors deduced that 138 was gener- of glycerol solvent for promoting an electrophilic alkylation of
ated quickly at the beginning of the reaction, resulting in for- carbonyl functional group, which has been well documented by
mation of a core–shell-type solid in which paraformaldehyde Gu and his co-workers in 2009.309 But in this work the capacity
was coated by 138 in glycerol. This not only prevents the of glycerol solvent was extended very much, and a wide range of
decomposition of paraformaldehyde, but also inhibits the for- carbonyl-containing compounds including aromatic and hetero-
mation of the intermediate XLII, thus avoiding accumulation of aromatic aldehydes, isatine derivatives, acenaphthenequinone
XLII in glycerol. Therefore, once XLII was released, it was and ninehydrine are condensed successfully with 1,3-dicarbonyl
immediately consumed in the oxo Diels–Alder step without time compounds or another type of reactive α-methylene groups in
to evolve into 137. By these synergistic effects, the three-com- glycerol solvent, providing the corresponding 4H-pyrans in good
ponent reaction can proceed in glycerol with greater selectivity yields.
than in other systems (Fig. 6). A mixture of two bio-based chemicals, meglumine and gluco-
Recently, glycerol was proved to be an indispensable solvent nic acid aqueous solution (GAAS, 50 wt%), was recently
in establishing a one-pot two-step sequential reaction involving demonstrated by Gu et al.310 to be a task-specific bio-based
arylhydrazines, β-ketone esters, formaldehyde and styrenes solvent for performing hydroxymethylation of β-ketosulfone
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with formaldehyde. While the desired products were obtained in proved to be an effective medium for this Pd-catalyzed system.
good yields in GAAS/meglumine system, the synthesis cannot The low viscosity of scCO2 allows the products to diffuse away
be performed well in other solvent systems, indicating the great from Pd catalyst and CsOAc, while the proper amounts of
ability of the GAAS/meglumine system. The formed hydroxy- MeOH make Pd catalyst and NaOAc partially dissolve in scCO2.
methylation product 141 could further react with a nucleophile, Replacing scCO2 with other solvents, such as THF, H2O, EtOH,
which allowed development of some one-pot stepwise three- DMSO, CH3CN, toluene, DMF, and dioxane, resulted in dra-
component reactions of β-ketosulfone and formaldehyde in this matic decrease of the reaction yields, indicating the indispensa-
binary mixture (Scheme 81). These results not only demonstrate ble effect of scCO2 in promoting the reaction.
that it is possible to develop a new bio-based system by mixing Fluorous separation technology has also been examined in
two or more bio-based chemicals together, but also provide a some multicomponent reactions, which improve the MCRs in
convenient means for controlling the selectivity of some MCRs terms of energy efficiency, atom economy, easy purification, and
of formaldehyde. Because GAAS and meglumine are both reduced amount of waste solvents.314 However, in these cases,
highly hydrophilic, the mixed solvent system could thus be fluorous substances mainly play the role of liquid supports but
recovered after extraction of organic products. In a three-com- not solvents. Therefore our review will not discuss these
ponent reaction of β-ketosulfone, paraformaldehyde and examples in detail.
α-methylstyrene, GAAS/meglumine system could be reused at
least four times without significant loss of activity. A one-pot
two-step sequential four-component reaction of α-bromoketone, 7. Conclusions and perspectives
sodium benzenesulfinate, thiophenol and formaldehyde was also
MCRs were considered as an important instrument to perform an

developed in this binary bio-based solvent system.309 “ideal synthesis” that was defined by Wender et al.,315 where the
Glycerol has also been used as an alternative green solvent in target molecules were synthesized in one step, in quantitative
combination with PS-PEG-supported sulfonic acid catalyst; the yield from easily available and inexpensive starting materials in
resulting system is able to promote some three-component resource effective and environmentally acceptable process. On
reactions, such as Biginelli reaction, the reaction of amide,
2-naphthol, and aldehydes.311 A one-pot three-component Cu-
catalysed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) was
investigated by using D-sorbitol/urea/NH4Cl melt as the reaction
medium.312 The three-component CuAAC reaction can be per-
formed in one step in the D-sorbitol melt, giving an excellent
overall yield.
6. MCRs in other green solvents

Jiang et al.313 have developed an efficient protocol for the Pd-
catalyzed three-component coupling of aryl iodides, internal
alkynes, and arylboronic acids in scCO2 using CsOAc as base,
which produced tetrasubstituted olefins 145 in good yields Scheme 82 Pd-catalyzed three-component coupling of aryl iodides,
(Scheme 82). With the aid of methanol co-solvent, scCO2 was internal alkynes, and arylboronic acids in scCO2.
Scheme 81 One-pot stepwise three-component reaction of β-ketosulfone and formaldehyde in binary bio-based solvent composed of GAAS and
meglumine.
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the other hand, to combat the harmful effect of organic solvents Acknowledgements
frequently used in large quantities for organic transformations,
many liquid substances (or fluids) have been recently proposed The author thanks for National Natural Science Foundation of
as alternative green reaction media. Combination of MCRs and China for the financial support (20903042 and 21173089). The
unconventional green solvents has originated a new research author is also grateful for Ms Ping Liang and all the other staff
direction that has emerged as an important facet of green chem- members in the Analytical and Testing Center of HUST for their
istry, from which both MCRs and green solvents can simul- supportive and constant contributions to our works. The
taneously benefit. These researches not only offered facile Program for new Century Excellent Talents in the University of
preparation of various highly functionalized organic molecules China (NCEJ-10-0383) and Chutian Scholar Program of the
by environmentally benign routes, but also opened an avenue to Hubei provincial government are also acknowledged. The
further strengthen the current innovation of green solvents. authors also thank the Specialized Research Fund for the
Many new MCRs have been developed by using water, ionic Doctoral Program of Higher Education (20090142120081).
liquids, polyethylene glycol and some bio-based chemicals as
alternative media to conventional organic solvents. Indeed, these

solvents have an indispensable role in the development of many
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Multicomponent Reactions in Unconventional Solvents State of The Art

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Cite this: Green Chem., 2012, 14, 2091

1. Introduction manufacturing process, and because recovery efﬁciency is far

phobic organic substrates “on water”. It was found that the

gies, enabling rate enhancements. The continuous renewal and

Scheme 2 Generation and trapping of 2-methylene-1,3-dicarbonyl

amount of 1,3-dicarbonyl compound and formaldehyde have to

and formaldehyde also occurs selectively, affording a complex

Scheme 6 Three-component reaction of 4-nitrobenzaldehyde, benzyl

Table 1 Three-component reactions of aromatic aldehydes,

Entry Catalyst Solvent Ref.

Table 2 Three-component reactions of benzaldehyde, malononitrile under aqueous conditions

Entry Nucleophile Condition Product Yield (%)

1 H2O, SDS (10 mol%), 90 °C 12 50

2 H2O, H14[NaP5W30O110] (1 mol%), 100 °C, 1 h 13 89

3 H2O, [BMIm]OH, MWI, 45 °C, 4 min 14 94

4 H2O, 100 °C, 35 min 15 97

5 NaN3 H2O, 50 °C, 24 h 16 81

aromatic aldehyde, malononitrile and 3-methyl-1-phenyl-2-pyra-

product in water could be attributed to the increment of sodium

Entry Nu (I) Nu (II) Product Condition Ref.

2 H2O, TBAC (4 mol%), 90 °C 62, 63

5 H2O, SDS (10 mol%) 66

6 H2O, SDS (10 mol%) or PEG 400 67, 68

7 p-TSA (20 mol%),b H2O, 90 °C 69

(10 mol%), H2O, reﬂux

11 PEG 400, 120 °C or H2SO4, H2O, reﬂux 73, 74

Scheme 9 Three-component reaction of rhodanine, amines and a

Scheme 10 Three-component reactions of salicylaldehyde and

18. The same type of reaction could also be performed in

Scheme 13 Possible mechanism for synthesizing compound 26.

aqueous suspension of basic alumina.83 With an analogous strat-

nitrile has been developed in water in the presence of an inor-

Scheme 16 Four-component reaction of dimethyl acetylenedicarboxy-

amine; and (iii) an intramolecular nucleophilic attack of SH

the use of an organic amine catalyst that was proved to be

Table 4 Three-component reactions of isatin and malononitrile in

1 PPL (30 mg for 35 94

Fig. 1 (a) Reaction mixture of the sodium stearate-catalyzed three-

vided a new strategy to synthesize spirooxindole derivatives and

Entry Nu (I) Nu (II) Product Condition Ref.

1 H2O, p-TSA (29 mol%),a reﬂux 104

2 H2O, p-TSA (58 mol%),a reﬂux 92

3 H2O, p-TSA (58 mol%), reﬂux 105

4 H2O, p-TSA (58 mol%),a reﬂux 106

5 H2O, p-TSA (58 mol%),a reﬂux 107

6 H2O, p-TSA (58 mol%),a reﬂux 108

7 H2O, p-TSA (58 mol%),a reﬂux 109

8 PEG-SO3H (10 mol%), solvent-free, 80 °C 110

Scheme 20 Four-component reaction of ferrocenecarboxaldehyde,

Scheme 21 Three-component reaction of β-ketoester, arylglyoxal and

formation of pyrazolo[3,4-b]pyridines. The reaction might start

Electrophilic reaction of aldehyde with two different nucleo-

Scheme 23 Three-component reaction of isatin, 4-amino antipyrine

Scheme 26 Three-component reaction of N-methylimidazole, methyl

nitroethylene, which was then trapped by two equivalents of

Implementation of a three-component reaction of N-methyl-

system, AgNO3 and p-TSA showed a synergistic promoting

following factors: (i) molecules of aldehydes, amines and diethyl

using K2PdCl4 as catalyst, the same three-component reaction

Scheme 33 Three-component vinylogous Mukaiyama–Mannich reac-

and cyclic ketones, in combination with primary and secondary