Chapter 1 2014 Multi-Component Reactions in Green Media...

Chapter 1Multi-Component Reactions in Green Media : State of the Art

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1.1. INTRODUCTION

The chemistry of heterocyclic compounds has attracted much

attention in recent times due to its increasing importance in the field of

pharmaceuticals and industrial chemicals. In fact, the development of

simple, elegant and facile methodologies for the synthesis of

heterocycles is one of the most important aspects in organic synthesis.

Multicomponent reactions (MCRs), reactions involving at least three

starting materials in a one-pot reaction, remain the most efficient

method of synthesis of heterocycles.1 Therefore, the design of new

MCRs with green procedure has attracted great attention, especially in

the areas of drug discovery, organic synthesis and material science.2

Moreover, improving already known MCRs is of also a substantial

interest of current organic synthesis.

Recently there has been increasing concern with regard to the

tight legislation on the maintenance of “greenness” in synthetic

pathways and processes.3 Green chemistry strongly influences chemical

research, and there is an insistence on the use of ‘greener’reaction

conditions.4 Volatile organic solvents amount to over 85% of mass

utilization in a typical chemical manufacturing process, and because

recovery efficiency is far from satisfactory, they are major contributors

to environmental pollution.5 In order to remove organic solvents from

the chemical process, an important aspect of green chemistry pertains

to the elimination of volatile organic solvents or their replacement by

non-flammable, non-volatile, non-toxic and inexpensive “green

solvent”.6 In this regard, development of solvent-free alternative

processes is the best solution, especially when either one of the

substrates or the products is a liquid and can be used as the solvent of


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the reaction.7 However, if solvents are crucial to a process, we should

select solvents that will have no or limited impact on health and the

environment.

Indeed, the use of unconventional green solvents in organic

reactions has improved not only the aspect of the reactions from the

point of view green and sustainable properties, but also the synthetic

efficiency by stabilizing the catalyst, changing the reaction selectivity

or facilitating product isolation.8 Particularly, unconventional solvents

also showed a great ability for assisting development of MCRs. Many

new one-pot MCRs have been successfully developed by means of

using an innovative solvent instead of conventional organic solvents.

Moreover, taking advantage of utilizing unconventional solvents as

reaction media, various known MCRs have also been improved in

terms of reaction yield, substrate generality, isolation of products and

catalyst recycling. In view of the emerging importance of this area, in

this review, we will summarize the recent achievements by performing

MCRs in unconventional solvents. Because water and ionic liquids are

main contenders in the area of green solvents, the majority of this

review will be MCRs in these two solvents. Polyethylene glycol

polymers (PGEs) have also been considered as a new class of green

solvents. Recent attempts of using PEGs as reaction media for MCRs

were also described in the present review. Benefited from recent

innovation on utilizing bio-based chemical as green solvents,9 some

MCRs have also been developed in bio-based solvents, which

contributed another part of our review. Because reactions that contain

more than two starting materials are generally classed as MCRs, this


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review will only summarize MCRs that contain at least three different

starting materials.

1.2. MCRs IN WATER

As a reaction medium, water compiles all the current stringent

requirements on sustainable chemistry. Therefore, the development of

synthetically useful reactions in water is of considerable interest.10 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 hydrophobic

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 being involved in hydrogen

bonding.11 The interactions of these unbound hydroxyl groups with

organic substrates and, more importantly, with the transition states,

lower the activation energies, 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) hydrophobic

effect, which leads to high negative volume of activation that means

greater stabilization of activated complexes than hydrophobic reactants

in the reaction; (ii) polarity effect, the high polarity of water results in


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more polar translated states than initial states, so the reaction speed can

be increased.12 However, until now, the exact roles of water in an

organic reaction are However, until now, the exact roles of water in an

organic reaction are still unapprehended. 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 factors.

Because performing a MCR in water combines the synthetic

efficiency of multi-component protocols with the environmental

benefits of using water as the reaction medium, which would lead to

processes close to the ideal synthetic reaction, this topic constitutes thus

a very important challenge for green chemistry. Indeed, many unique

MCRs that cannot be attained in conventional organic solvents have

been developed.13 In 2009, Kumaravel and Vasuki published a

comprehensive review, in which they summarized all the early results

in this area.14 This part of present review will only focus on the results

reported afterward.

1.3. MCRs IN WATER BASED ON KNOEVENAGEL

CONDENSATION

Base-catalyzed condensation of aldehydes with 1,3-dicarbonyl

compounds (Knoevenagel reaction) is widely used to synthesize

various polyfunctionalized organic compounds. Because the product of

Knoevenagel reaction can be easily converted to more complex

molecules in the presence of a suitable reagent, many MCRs have been

developed based on Knoevenagel reaction.15 Importantly, because

Knoevenagel condensation can be conducted under conditions that are

compatible with aqueous environments,16 it was often involved in


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developing MCRs in water. It should be noted that MCRs based on

Knoevenagel reaction are closely related to the reactivity of starting

materials. Because of the high reactivity in aqueous media, the

following three reactions were often adopted: (i) Knoevenagel reaction

between 1,3-dicarbonyl compounds and formaldehyde, (ii)

Knoevenagel reaction of aromatic aldehyde with malononitrile or

cyanoacetic ester; and (iii) Knoevenagel reaction of isatin with

malononitrile. In order to achieve the highest levels of structural

diversity, MCRs based on Knoevenagel reaction are usually combined

with powerful complexity-generating reactions, such as inter- or

intramolecular Diels-Alder, Michael and the formation of heterocycles.

Kumar et al17 described boric acid-catalyzed a three-component

reaction of N, N-dialkylaniline, 1,3-dicarbonyl compound and

formaldehyde in aqueous micelles constructed by SDS and water

(Scheme 1). Although the mechanism of the reaction seems steming

upon a Mannich-type reaction, in which N, N-dialkylaniline plays a

role of a secondary amine, a tandem Knoevenagel/ Michael reaction

pathway might also be operative for the formation of compound (1). It

should be noted that the use of boric acid as a catalyst is the key to

render the reaction possible because a side reaction between N, N-

dialkylaniline and formaldehyde was predominant under catalyst-free

conditions. In an aqueous solution of ethanol, 2-naphthol can also be

used instead of 1,3-dicarbonyl compound to react with N,N-

dialkylaniline and formaldehyde to form diarylmethane derivative 2 in

good yield (Scheme 1).18 However, in this case, an organocatalyst, L-

proline, has to be used in order to inhibit the formation of a

symmetrical product generated from N, N-dialkylaniline and


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formaldehyde. Similarly, a three-component reaction of N,N-

dialkylaniline, formaldehyde and indole was also developed in aqueous

solution of methanol, which providing compound 3 in good yield, by

using a solid acid catalyst, HClO4-SiO2 (Scheme 1).19

NHCHO

EtOO

O

EtOO

O N

OH

NHO

HN

HClO4-SiO2 (2 mol %)

HN

N

Scheme 1. MCRs of N, N-dimethylaniline and formaldehyde in water.

Wu et a,l20 reported a catalyst-free, simple and efficient three-

component procedure for the synthesis of β-mercapto diketone

derivative 4 from the corresponding aldehyde, acetylacetone and thiol

in water under reflux conditions (Scheme 2). While the reaction

proceeded very well in water, poor yields were obtained in some

organic solvents, indicating the remarkable promoting effect of water

solvent in this reaction. The three-component reaction was influenced

by the electronic and steric factors associated with substituents on

aldehydes and the thiols. Mechanism investigation revealed that the

reaction started from a Knoevenagel condensation between aldehyde

and acetylacetone that leading to the formation of an intermediate. The

following Michael addition of thiol to the intermediate provided the

desired three-component product. After the reaction was completed, the


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solid crude products precipitated, which were easy to separate just

followed by filtration and drying. Besides, the liquid crude products

could be separated simply from water through extraction method.

Scheme 2. Three-component reaction of 4-nitrobenzaldehyde, benzyl

mercaptan and acetyl acetone in water.

One of research directions of MCRs in water is developing a

heterogeneous catalyst that is notvonly water-compatible but also

capable of keeping a good activity during the recycling. However,

considering the complexicity of MCRs, and taking the purpose of using

a solid catalyst for organic reactions in water into account, which

mainly focuses on emphasizing the catalysis in conjunction of water

solvent, working on a simple MCR is the best choice. On the basis of

this principle, Zahouily et al21 described an efficient catalytic system by

using nanostructured diphosphate Na2CaP2O7, with which, an

environmentally benign synthesis of 2-amino-chromene 5 through a

three-component reaction of 1-naphthol, malononitrile and aldehyde

has been successfully performed in water (Scheme 3). The reaction was

performed in the following reaction pathway: (i) Knoevenagel reaction

between benzaldehyde and malononitrile; (ii) the ortho C-alkylation of

1-naphthol with the generated Knoevenagel intermediate, and (iii)

intramolecular addition of the hydroxyl group of the alkylated 1-

naphthol to α-cyanocinnamonitrile. Intervention of a catalyst on the


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reaction could be observed in the later two steps. It should be noted that

the reaction yield was increased significantly by adding various

volumes of water, and finally, 10 ml of water was used for a 1.0 mmol

reaction. The same reaction has also been evaluated by using a

nanosized magnesium oxide as catalyst in a mixture of water and

PEG.22

Scheme 3. Three-component reaction of benzaldehyde, malononitrile

and 1-naphthol in water.

Mukhopadhyay et al23 described a one-pot three-component

synthesis of 2-amino-5-alkylidenethiazol-4-one 6 from rhodanine,

amine and a methyl ketone in an aqueous solution of ethanol under

reflux condition by using a silica-based substituted pyridine catalyst as

Scheme 4. Three-component reaction of rhodanine, amines and a

methyl ketone in aqueous media.


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catalyst (Scheme 4). This is the first report of a methodology

describing the synthesis of 2-amino-5-alkylidenethiazol-4-ones from

ketones. In this reaction, the silica-based solid catalyst can be recycled

many times without significant loss of its activity.

Gu and Jérôme have reported the synthesis of 2,5,6-trisubstituted

dihydropyrans, a water-mediated three-component reaction of 1,3-

dicarbonyl compounds, formaldehyde and α-methylstyrene. The

reaction was performed through Knoevenagel reaction of 1,3-

dicarbonyl compound and formaldehyde, which can then be trapped by

α-methylstyrene by oxo Diels–Alder reaction.24 Indole can also be used

as a nucleophile instead of α-methylstyrene. In this case, the

Knoevenagel intermediate was trapped by a Michael reaction of

indole.25

Recently a four component reaction reported by Cai et al26 in

which benzaldehyde, malononitrile, 1,3-thiazolidinedione and amine

get react in a mixture of PEG 400 and water, and generated a variety

Scheme 5. MCRs based Knoevenagel/oxo Diels–Alder, and

Knoevenagel/Michael domino reaction in water.


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of dihydrothiophene ureidoformamides 9 in good yields (Scheme

6).The reaction might start from a Knoevenagel condensation between

benzaldehyde and malononitrile that has been ascertained to be well

performed under catalyst-free condition in PEG 400/H2O system. The

generated intermediate underwent the following three steps, which

including (i) a Michael addition of 1,3-thiazolidinedione; (ii) ring-

opening of the formed 4-substituted 1,3-thiazolidinedione with amine,

and (iii) an intramolecular nucleophilic attack of SH group to one of the

cyano groups, to finally form the desired product 9.

Zhou et al. have developed an efficient three-component reaction

of indole, aldehyde, and malononitrile that provides 3-indole derivative

10 via Knoevenagel/Michael domino reaction in excellent yield.27 Use

of copper (II) sulfonato salen complex and a weak acid, KH2PO4, was

Scheme 6. Four-component step-wised sequential reaction of

benzaldehyde, malononitrile,1,3-thiazolidinedione and amine in water.

used in order to improve the reaction selectivity, in which KH2PO4

most likely played a role of controlling the pH value of the aqueous

solution.


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Scheme 7. Three-component reaction of indole, aldehyde, and

malononitrile in water.

A convenient approach to the synthesis of dihydropyrano[2,3-c]-

pyrazoles 11, 12 and 13 via four-component reaction of aromatic

aldehydes, hydrazine, ethyl acetoacetate and malononitrile was also

developed in water with the aid of ultrasound irradiation. This reaction

can also be performed by using piperidine as a catalyst in water.28

Scheme 8. Four-component reactions of hydrazine, ethyl acetoacetate

and malononitrile in water.


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A three-component reaction of N,N-dimethylbarbituric acid, 3-

nitrobenzaldehyde and sodium cyanide has been recently developed by

Soleimani et al29 by using water as a sole solvent, which generates 14

as a sole product (Scheme 9). Interestingly, while the reaction

proceeded very well in pure water, poor yields were obtained in the

other solvents, such as toluene and ethanol under the identical

conditions, indicating that water played an indispensable role in this

model reaction. Mechanism investigation revealed that the reaction

might start from a water mediated Knoevenagel condensation between

N,N-dimethylbarbituric acid and 3-nitrobenzaldehyde that generates an

intermediate (a). Following Michael addition of sodium cyanide to the

intermediate (a) affords the desired product. Because both N,N-

dimethylbarbituric acid, 3-nitrobenzaldehyde are insoluble in pure

water, the so-called “on water” promoting effect might also exist in this

reaction. Meldrum’s acid can also be used in this type of three-

component reaction instead of N,N-dimethylbarbituric acid.30

Scheme 9. Three-component reaction of N,N-dimethylbarbituric acid,

3-nitrobenzaldehyde and sodium cyanide in water.


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Scheme 10. Four-component reaction of hydrazine hydrate, ethyl

acetoacetate, 2-hydroxybenzaldehyde and malononitrile in water.

Vasuki et al31 reported a catalyst-free four-component reaction of

hydrazine hydrate, ethyl acetoacetate, salicylaldehyde and

malononitrile that generates a novel highly functionalised 4-pyrazolyl-

4H-chromene 15 in water at ambient temperature.

1.4. MCRs BASED ON ACTIVATION OF CARBONYL GROUP

WITH WATER

Electrophilic reaction of aldehyde with two different nucleophiles

is a fundamental strategy for constructing MCRs. Water solvent can

electrophilically activate carbonyl group of aldehyde by hydrogen bond

interaction.32,33 For example, in the absence of catalyst, one-pot

Hantzsch condensation of aromatic aldehyde, dimedone, and

ammonium acetate proceeded very well in an aqueous medium under

microwave irradiation providing various substituted acridinediones in

good yields.34 A MCR of ferrocenecarboxaldehyde, ketone, dimedone

and ammonium acetate proceeded well in water at 100oC with

assistance of microwave irradiation, providing 2-aryl-4-ferrocenyl-

quinoline derivatives 16 as the main product.35

The synthesis of 2, 3-dihydroquinazolin-4(1H)-ones 17 via a three-

component condensation of isatoic anhydride, aromatic aldehydes with

ammonium salts or primary amines was performed in aqueous ethanol


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under reflux condition using SrCl2⋅6H2O as a catalyst (Scheme

12).36The same reaction can also be performed in water by using

magnetically recoverable Fe3O4 nanoparticles as catalyst.37

Ethylenediamine diacetate (EDDA) has also been used as a catalyst in

aqueous media for promoting a three-component reaction of isatins,

isatoic anhydride and amine to give the spiro[indole-thiazolidinone]

libraries 18.38

Scheme 11. Four-component reaction of ferrocene carboxaldehyde,

ketone, dimedone and ammonium acetate in water.

NH

O

O

O

NH2

NH

O

O

EDDA (20 mol %)H2O,reflux, 6h

94 %

CHO

SrCl2.6H2O

H2O/EtOH (3/1)reflux, 1.5 h

94 %

NH

N

O

(17)

NH

N

NH

OO

(18)

Scheme 12. Three-component condensations of isatoic anhydride,

aniline and aromatic aldehydes or isatins in water.


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The one-pot multi-component reaction between primary amines

or linear diamines, 1,1-bis-(methylthio)-2-nitroethene, and ninhydrin

has been investigated by Alizadeh et al under aqueous conditions,

which provides a wide range of dihyroindeno [1,2-b]pyrroles 19 and

indeno[2',1':4,5]pyrrolo[1,2-a]-fused 1,3-diazaheterocycles 20 in fairly

high yields (Scheme 13).3939 Itaconic anhydride can also react with 1,1-

bis-(methylthio)-2-nitroethene and diamines in aqueous solution of

ethanol, generating various pyrido[1,2-a]-fused 1,3-diazaheterocyclic

compounds in good yields.40

Scheme 13. MCRs of ninhydrin, 1,1-bis-(methylthio)-2-nitroethene

with amines in water.

Implementation of a three-component reaction of N-

methylimidazole, methyl propiolate, and butyraldehyde was proved to

be very well in a ‘on water’ conditions, providing compound 21 in

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

propiolate, and butyraldehyde in water.


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good yields.41 The reaction might proceed through the formation of a

water stable nucleophilic imidazole carbene (imidazolium ylide). This

carbene is alkylated by a cascade process involving an efficient

carbene-aldehyde addition, alkoxide-alkynoate addition, and

protonation and hydrolysis set of consecutive reactions.

1.5. ISOCYANIDE-BASED MCRs IN WATER

Since the first documentation of Strecker synthesis of α-amino

cyanides in 1850, MCRs have been extensively investigated. Amongst

all MCRs, isocyanide-based MCRs are most frequently exploited

because the isocyanide is an extraordinary functional group. The

Passerini and Ugi reactions are classical examples. Both reactions stem

upon a unique ability of isocyanide in participating in α-addition with a

nucleophile and an electrophile. In fact, well-known MCRs in organic

synthesis are rather limited in the organic synthesis, and unfortunately,

each MCR affords, in the most cases, compounds with a similar

framework and a few different substituents. In contrast, a much greater

variation of MCRs is known in the chemistry of the isocyanides.

Particularly, in the Ugi 4-CR and Ugi 3-CR reactions and related

MCRs, the skeletons and the substituents can differ. Therefore,

isocyanide-based MCRs have achieved an extensive application. To

expand their utility and also gain access to drug-like heterocyclic

compounds, several research groups are now developing modifications

of these reactions. One of the promising methods is performing

isocyanide-based MCRs in water.

Shaabani et al42 have recently described an efficient approach to

the synthesis of ketenimine sulfonamides derivatives 22 from various


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isocyanides and dialkyl acetylenedicarboxylates in the presence of

alkyl or aryl sulphonamides in water and absence of any catalyst

(Scheme 27). The reaction could be preferably performed in water

rather than the other organic solvents. Generation of a zwitterionic

intermediate through a Michael-type addition of isocyanides to

acetylenic system might be the first step of the reaction. Then,

sulfonamide plays a role of trapping reagent to reaction with the

intermediate to afford the ketenimine sulfonamide. Importantly, the

products could be further hydrolyzed to the corresponding

sulfonamide-butanamide derivatives at 80oC in water in good yields

without using a catalyst. By the same token, the zwitterion that

generated from the reaction of an alkyl isocyanide and a dialkyl

acetylenedicarboxylate, reacts readily with phenacyl halides in water to

produce γ-iminolactone derivatives in high yields.43

Scheme 27. Three-component reactions of isocyanides, diethyl

acetylenedicarboxylate and alkyl or aryl sulfonamides in water.

Ji et al44 described an efficient three-component reaction of

isocyanides, heterocyclic thiols and gem-dicyano olefins bearing

electron-withdrawing groups in aqueous solution of acetonitrile, which

produced imino-pyrrolidine-thione scaffold 23 in good yields (Scheme

28). The product may be formed through a typical mechanism

involving a key step of Ugi-Smiles-type rearrangement.


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Scheme 28. Three-component reaction of isocyanides, heterocyclic

thiols and gem-dicyano olefins in water.

Shaabani et al,45 reported A novel isocyanide-based four-

component reaction between a 2-hydroxybenzaldehyde, Meldrum’s

acid, an isocyanide, and an aromatic or an aliphatic alcohol efficiently

provide 3,4-dihydrocoumarin derivatives 24 in good to excellent yields

without using any catalyst or activation. The reaction can be carried out

as a simple one-pot protocol at room temperature.

Scheme 29. Synthesis of 3,4-Dihydrocoumarins from 2-

hydroxybenzaldehydes, meldrum’s acid, isocyanides, and alcohol in

water.

Ugi and Passerini reactions46 reactions consist of the reaction of

three or more starting materials to form a single product, they involve

transition states resulting from the condensation of several molecules

and are therefore predicted to have negative activation volumes. They

initially studied the Passerini reaction of 3-methylbut-2-enoic acid, 3-

methylbutanal and 2-isocyano-2-methylpropane in several solvents


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(Scheme 30). They reported that dichloromethane allowed the

formation of the product with a 50% yield after 18 h, In contrast, the

use of water furnished the expected product 25 quantitatively within 3.5

h.

Scheme 30. Influence of solvent on Passerini reaction.

To demonstrate the value of water as solvent for the high

throughput synthesis of molecules in a combinatorial chemistry

approach, Pirrung and co-workers performed the Ugi reaction of two

isonitriles, four aldehydes and four acids to obtain a library of 26 β-

lactams (Scheme 31).47,48 In most cases, the products were solid and

could be collected by filtration as the only purification.

Scheme 31. Synthesis of β-lactam with water as solvent.

R. K. Srinivas and R. L. Yong49 described a simple and efficient

one-pot synthetic approach for the preparation of biologically

interesting 3,4-dihydroquinoxalin-2-amine derivatives 27 using EDTA-

catalyzed three-component reactions of o-phenylenediamines, carbonyl

compounds, and isocyanides in an aqueous medium.


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Scheme 32. synthesis of β-lactams with water as solvent.

Kumar et al50 developed first boric acid catalyzed Ugi three-

component reaction in water for the synthesis of 2-arylamino-2-

Scheme 33. Synthesis of 2-amino-2-phenylacetamide from aniline,

aldehyde and isocyanide in water.

phenylacetamide 28 using (Scheme 33) aniline, aldehyde and

isocyanide. This work has interesting distinctions of being the first

synthesis of a new class Ugi product in aqueous media.

1.6. MCRs IN WATER BASED ON TRANSITIONAL METALCATALYSIS

Performing a transitional-metal-catalyzed reaction in water offers

an easy approach to use a biphasic system, which two immisible liquid

phases, such that the homogeneous catalyst is soluble in one phase (e.g.

water) and the product in the other phase (organic).51 The product can

then be obtained by a simple phase separation. With this strategy,

industrial applications have been quickly established, such as the

Ruhrchemie AG/Rhone-Poulenc process for the hydroformylation of

propylene. Although hydroformylation of alkenes can also be

considered as a three-component reaction of alkenes, hydrogen and


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CO,52 considering its insufficiency in creation of molecular

complexicity and diversity, this reaction will not be included in this

review. While the recyclable design of homogeneous metal complex

catalysts by means of using water as reaction medium has attracted

great attention, far less effort has been spent on improving the synthetic

efficiency with a rational design of the reactions. In fact, water solvent

also offers an indispensable means to organic chemists who are

interested in developing new MCRs.

Huisgen 1,3-dipolar cycloaddition of organic azides and alkynes

has been extensively investigated since the paramount discovery by the

groups of Meldal and Sharpless.53 However all the methods involve

pre-formed organic azides, for which the use of organic solvents is, in

general, mandatory. In order to further improve the utility and user-

friendliness of this process, a practical multi component variant was

developed. An ideal choice is performing the reaction in water. Li and

Xia183 have recently developed an ammonium salt-tagged

[(SIPr)CuCl] complex (SIPr = N,N'-bis(2,6-diissopropylphenyl)-

Figure 1. Ammonium salt-tagged [(SIPr)CuCl] complex catalyst.

imidazolidin-2-ylidene) 1, which showed a high catalytic activity

toward the three-component click-reaction of a wide arrange of benzyl

bromides and alkynes using water as solvent at room temperature

(Figure 1). Because the catalyst is soluble in water, it could be


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conveniently recycled up to three times without a significant loss of its

activity with catalyst loading as low as 2.0 mol% in the fresh run.

A series of triazolyl methoxyphenyl 1,8-dioxo-decahydroacridine

derivatives 29 have been prepared in aqueous solution of ethanol

through a one-pot pseudo-five-component reaction between aromatic

propargylated aldehyde, various azides, dimedone, and anilines

(Scheme 34).54 In order to get a high yield, a combination of

Cu(OAc)2/sodium ascorbate and 1-methylimidazolium trifluoroacetate

([HMIm]TFA) has to be used as catalyst. In fact, it is a parallel

combination of CuAAC and a pseudo-four-component of aldehyde,

aniline and dimedone. Without [Hmim]TFA, the later reaction cannot

occur, only a CuAAC adduct 30 was formed. A combination of

CuSO4/sodium ascorbate has also been used as catalyst for three-

component reaction of a-bromo ketones, sodium azide and terminal

acetylenes in aqueous solution of PEG 400.55

Scheme 34. Pseudo-five-component reaction of aromatic propargylatedaldehydes, azide, dimedone, and aniline in water.


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By using a cross-linked polymeric ionic liquid material as

support, Xia and Liu56 prepared a supported palladium catalyst (Pd-

CPSIL) that can be used as an effective heterogeneous catalyst for

carbonylative Sonogashira coupling reaction of aryl iodides with

terminal alkynes in water (Scheme 35). In the presence of Et3N, the

three-component carbonylative reactions produce the corresponding

Scheme 35. Carbonylative Sonogashira coupling reaction of aryl

iodides with terminal alkynes in water.

α,β-alkynyl ketones 31 in good to excellent yields. The catalytic system

not only solves the basic problem of homogeneous palladium catalyst

Scheme 36. Pd/Cu-catalyzed four-component reaction of 1,2-

dichloroquinoxaline, hydrazine hydrate, phenylacetylene and aromatic

aldehyde in water.

N

N Cl

Cl+

O2N CHO

+

H2N-NH2

H2O,r.t.crystal-free

N

N

NH

N

NO2

Cu

N

N

NN

NO2

10 % Pd/C (6 mol %)CuI (10 mol %)

H2O, 70oC, 10 h86 %

(Pd (0) catalyst

87 (isolated yield = 89 %)

(32)

(33)


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recovery and reuse but also avoids the use of toxic phosphine ligands,

thus is an environmentally benign system for the three-component

carbonylative reaction of aryl iodides and terminal alkyne.

The one-pot Pd/Cu-catalyzed, four-component reaction of 1,2-

dichloroquinoxaline, hydrazine hydrate, phenylacetylene and aromatic

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]quinoxalines 32 (Scheme

36).57 The reaction might proceed through the following procedure: (i)

formation of 2-(arylhydrazino)-3-chloroquinoxaline 33 that could be

isolated in 89% of yield under catalyst-free conditions in water at room

temperature; (ii) Pd/C-catalyzes the coupling of 33 with copper(I)

acetylide that was generated in situ from phenylacetylene leading to

formation of another intermediate, 2-(arylhydrazino)-3-

alkynylquinoxaline, that was subsequently converted to the desired

product 32 via activation of the triple bond.

Propargylamines are widely used as intermediates for the

synthesis of various nitrogen-containing biologically active compounds

and natural products. Adapa and co-worker58 established a convenient

and efficient route for the synthesis of propargylamines through one-

pot three-component coupling reaction of an aldehyde, amines, and

alkyne using Zn(OAc)2/2H2O zinc salts in a catalytic amount without

any use of additives or base. Aldehydes tolerated with electro-

withdrawing groups required longer reaction time but afforded

propargylamines in good to excellent yields whereas aldehyde bearing

electron-donating groups such as 2- and 3-Hydroxy benzaldehydes also


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furnished the corresponding A3 coupled products under the optimized

conditions. Hetero-aromatic aldehydes such as furfuraldehyde and

thiophene 2-carboxaldehyde gave the corresponding A3 products in

Scheme 37. Synthesis of propargylamines via A3 coupling reaction

using benzaldehyde, piperidine and phenylacetylene by Zn salts in

water.

good yields, on the other hand nitrogen containing aldehyde like

pyridine 2-carboxaldehyde did not furnished desired product 34. The

author also used aliphatic aldehyde with amines and alkyne under same

reaction conditions got good results.

1.7. MCRs IN IONIC LIQUIDS

The attractiveness of ionic liquids as reaction media is attributed

to their unusual physicochemical properties, such as negligible vapor

pressure, low volatility, tunable polarity and miscibility 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 recycled through a biphasic

operation without laborious catalyst modification or work-up, thereby

providing a convenient solution to both the solvent emission and

catalytic recycling problem. Moreover, ionic liquids are able to

generate an internal pressure and promote the association of reactants

in the solvent cavity during the activation process.59 Thus ionic liquids


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are well suited as reaction media for MCRs in which the entropy of the

reaction is decreased in the transition state.60 Rodriguez et al 61

published an excellent review, in which parts of the reported results

were summarized with emphasizing synergistic effect of the combined

use of MCRs and ILs for constructing heterocycles up to the middle of

2010, we intend to particularly focus on the results emerged afterwards.

For MCRs, the issue of selectivity is of particular significance

because of the high probability of several potential parallel reaction

pathways resulted from simultaneous molecular interaction of three or

more components, which might lead to formation of different product

classes. One of the advantages of ionic liquids is their tunable physical

property. By varying the anion and cation, ionic liquids can be prepared

that vary in polarity, viscosity, density, melting point, and

miscibility/solubility properties. This offers a new opportunity for

Scheme 38. Three-component reactions of aromatic aldehyde, 2-(2,3-

dihydrothiochromen-4-ylidene) malononitrile and malononitrile in

ionic liquids.


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controlling the selectivity of MCRs. Wang et a62 have recently reported

a three-component reaction of aromatic aldehyde, 2-(2,3-

dihydrothiochromen-4-ylidene) malononitrile and malononitrile, in

which the reaction product could be changed by altering the anion of

ionic liquid (Scheme 38). In ionic liquid [BMIm]BF4, because of the

hydrolysis of the anion, the medium is acidic, thus allowing formation

of 9-amino-7-aryl-6H-benzo[c]thiochromene-8,8,10(7H)-tricarbonitrile

35. When the anion was replaced by Br-, the same reaction provided

another product, 9-amino-7-phenyl-6H-benzo[c]thiochromene-8,10-

dicarbonitrile 36. This example demonstrated clearly that ionic liquids

indeed have a unique ability to control the selectivity of MCRs.

Scheme 40. MCR of 2-arylidenemalononitrile, 1,3-thiazolidinedione

and aniline.

Kumar et al 63 also synthesized multi-component reaction via a

histidine-based ionic liquid, [BHP-OMe]Br, which can promote

diastereoselective three-component reaction of 2-


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arylidenemalononitrile, 1,3-thiazolidinedione, aliphatic or aromatic

amines, providing dihydrothiophenes 37 in good to excellent yields in

water (Scheme 39). The ionic liquid [BHP-OMe]Br displayed good

reusability at least in four subsequent reactions under the same reaction

conditions without any considerable loss in reaction yield. In addition,

the ionic liquid [BHP-OMe]Br was also utilized in synthesis of tacrine

derivatives hexahydrothieno[2,3-b]quinoline-2-carboxamide 38 from

dihydrothiophenes with the aid of microwave irradiation under aqueous

condition.

An environmentally friendly approach to the diastereoselective

synthesis of (S)-3-phenyl-2,3-dihydro-4H-furo[3,2-c]chromen-4-onein

39 good yields is described by S.M. Rajesh et al.64 The method is based

on the sequential multicomponent reactions of 4-hydroxycoumarin ,

aromatic aldehydes and in situ generated cyanomethylpyridinium,

phenacylpyridinium/(2-ethoxy-2-oxoethyl) pyridinium ylides 1, in the

Scheme 41. Synthesis of furo[3,2-c]coumarins in ionic liquid.

presence of the ionic liquid [BMIm]OH, which functions both as a

catalyst and the reaction medium. This method has several advantages

over previous synthetic protocols, which suffer from the use of either

metal catalysts or large amounts of reactants, catalyst or organic

solvents. In contrast, this protocol requires only the use of 2 molar


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equiv of ionic liquid, which plays twin roles as catalyst as well as

solvent, and which is recyclable.

An unexpected condensation profile was observed by H.

Kefayati et al.65for the three-component reaction of 5,5-dimethyl-1,3-

cyclohexadione (dimidone) , anilines and isatin leading to the

synthesis of novel 2-arylpyrrolo [2,3,4-kl]acridin-1(2H)-ones 40 in the

ionic liquid [HMIm]HSO4. Regeneration of the enamine group after the

initial condensation reaction associated with participation of the

restored amine group in translactonization with the pyrrolidone ring are

suggested as the main differentiating events being favored over

addition of the second dimedone molecule, with respect to similar

reported reactions.

A one-pot synthesis of 6-aminouracils 41 via in situ generated

ureas and cyanoacetylureas (Scheme 43) using an ionic liquid, 1,1,3,3-

Scheme 42. The reaction leading to the synthesis of pyrroloacridones in

ionic liquid.


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tetramethylguanidine acetate ([TMG]Ac), as a recyclable solvent and

catalyst has been recently developed by Degani.66 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 potassium cyanate in the presence of [TMG]Ac at

60°C that resulted in the formation of urea (A); (ii) reaction of (A) with

1 molar equivalent of cyanoacetic acid and 2 molar equivalents of

acetic anhydride at 60 oC afforded cyanoacetylurea (B); (iii) ring

closure of cyanoacetylurea (B) at 90°C gave 6-aminouracil 41

(Scheme 62). After the completion of the reaction, the products were

isolated by filtration after adding cold water into the reaction mixture.

The ionic liquid [TMG]Ac was recovered by removing the water under

reduced pressure and could be reused at least five times without any

Scheme 43. One-pot synthesis of 6-aminouracil in [TMG]Ac.

appreciable decrease in yield. This method offers a simple and

straightforward strategy for the synthesis of 6-aminouracils. In this

report, the same ionic liquid can catalyze different consecutive steps in

a single reaction vessel, which not only reduces the operating time and


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the amount of waste produced, but also provides a means to improve

the economic and environmental aspects of chemical process.

Arya et al,67 described about zeolite supported Brønsted-acid

catalyst system which has been developed by using different Brønsted-

acid ionic liquids supported on ZSM-5 zeolite. Catalytic activity was

tested via aqueous-mediated ultrasound-promoted synthesis of novel

spiro[N-substituted indole-pyrido thiazines] 42,which does not take

place under conventional conditions. The yield of the desired products

was increased in the presence of ultrasonication compared to those of

conventional and MW techniques. In the presence of ultrasonication,

the recyclability of this novel catalyst system was studied. There was

no loss of catalytic activity up to five cycles whereas a significant loss

was observed in the presence of MWs.

Scheme 44. Synthesis of spiro[N-substituted indole-pyrido thiazines].

Z.Chen et al.68 defined a convenient and environmentally green

methodology for the synthesis of 10,11-dihydro-chromeno[4,3-

b]chromene- 6,8(7H,9H)-dione derivatives 42 via the three-component

reactions of 4-hydroxycoumarin, aldehydes, and cyclic 1,3-dicarbonyl

compounds. The attractive features of this protocol are simple reaction

procedure, short reaction time, easy product separation, and

purification, reusability of acidic ionic liquid [DMDBSI].2HSO4, and


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its adaptability synthesis of a broad range of 10,11-

dihydrochromeno[4,3-b]chromene-6,8(7H,9H)- dione derivatives in

moderate to high yields. To the best of our knowledge, the catalyst

[DMDBSI].2HSO4 was synthesized and used in multi-component

reactions for the first time, and this is the first report on the synthesis of

10,11-dihydrochromeno[4,3- b]chromene-6,8(7H,9H)-dione

derivatives.

Scheme 45. [DMDBSI].2HSO4 catalyzed condensation of 4-

hydroxycoumarin, aldehyde and cyclic 1,3-dicarbonyl compound.

Benzopyrano[2,3-d]pyrimidine 43 is a potentially important

pharmacophore that exhibits in vivo antitumor activity, cytotoxic

activity against cancer cell lines and can cause significant perturbation

in cell cycle kinetics.69 An environmentally benign, ionic liquid

promoted multicomponent protocol to benzopyrano(2,3)pyrimidines

and 4H-chromenes has been developed by Gupta et al. at room

temperature. Results of the reaction depend on the nature of the

nucleophile used in the reaction. Secondary amines result in the

formation of benzopyrano(2,3-d)pyrimidines, whereas thiols give rise

to 2-amino-4-arylsulfanyl-4H chromene-3-corbonitriles 44 under the

same set of reaction conditions.


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Scheme 46. Synthesis of benzopyranopyrimidines 43 and 2-amino-4-

arylsulfanyl-4H chromene-3-corbonitriles 44 using [bmim]BF4.

Pyrimidinone 45 derivatives have also been synthesized from the

reaction of aromatic aldehydes, cyclopentanone and urea or thiourea in

the presence of N-(4-sulfonic acid) butyl triethyl ammonium hydrogen

sulphate [TEBSA][HSO4] as the Brønsted acidic ionic liquid as well as

an effective catalyst under thermal and solvent-free conditions.70

Scheme 47. Synthesis of benzopyranopyrimidines 45 and 2-amino-4-

arylsulfanyl-4H chromene-3-corbonitriles using [TEBSA][HSO4].

An efficient pathway for the synthesis of thiopyran derivatives

46 was performed by Fan et al. they describe a multi-component

reaction of aldehydes, cyanothioacetamide, and malononitrile promoted


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35

by ionic liquids without the use of any catalysts, both aromatic and

aliphatic aldehydes participated in this reaction smoothly.71

Scheme 48. Synthesis of 2,6-diamino-4-phenyl-4H-thiopyran-3,5-

dicarbonitrileusing [Bmim]BF4.

Shi et al. synthesized new 3,3’-benzylidenebis(4-hydroxy- 6-

methylpyridin-2(1H)one) derivatives 47 in 82–89% yields by a three-

Scheme 49. Three-component Synthesis of 3,3’-benzylidenebis(4-

hydroxy- 6-methylpyridin-2(1H)one using [bmim]Br.

component reaction of an aldehyde, an amine, and 6-methyl-4-

hydroxypyran-2-one in an ionic liquid at 95°C.72 The resulting

heterocyclic products can be conveniently separated from the reaction

mixture without the use of any volatile organic solvents and the ionic

liquid cab be readily reused without losing efficiency after simple

treatment.


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1.8. MCRs UNDER SOLVENT-FREE CONDITION

Because of the increasing concern of the harmful effects of

organic solvents on the environment and human body, organic

reactions that are operated with green solvents or without conventional

organic solvents have aroused the attention of organic and medicinal

chemists. In the past decade, interest in solvent-free MCRs has

expanded and it now encompasses wide areas of the chemical

enterprise. For reasons of economy and pollution prevention, solvent-

free methods73 are used to modernize classical procedures by making

them cleaner, safer, and easier to perform. The demand for both clean

and efficient chemical syntheses is becoming more urgent.74 Among the

proposed solutions, solvent free conditions are becoming more popular

and it is often claimed that the best solvent is no solvent.75

A pressing challenge facing organic chemists, therefore, is to

advance new processes that are not only efficient, selective, and high

yielding but also eco-compatible.76,77 Although steps toward

sustainability can be made by reusing solvents, recycling is rarely

accomplished with complete efficiency. An alternative strategy is to

reduce the E factor (the E factor, introduced by Sheldon,78 is defined as

the ratio of the weight of waste to the weight of product) of reactions

and their impact on the environment is to conduct them under solvent-

free conditions.79,80 The benefits of solvent-free processes are cost

savings, decreased energy consumption, reduced reaction times, a large

reduction in reactor size and capital investment. It has been an

interesting observation that due to demerits associated with reactions

carried out in conventional organic solvents, synthetic chemists are

paying more attention to the development of new methodologies based


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37

on solvent-free reactions, clearly shown by the graphical representation

of the growing number of solvent free synthetic methodologies against

years. Several research groups are now developing modifications of

these reactions. One of the promising methods is performing MCRs

under solvent-free conditions.

Scheme 50. Three-component reaction of 5-methyl-2-hydroxyphenyl

sulphide, 2-aminopyrimidine and aromatic aldehyed under solvent-free

condition.

A novel one-pot three-component Mannich condensation

between an electron-rich aromatic compound such as 5-methyl-2-

hydroxyphenyl sulphide, 2-aminopyrimidine, and aromatic aldehydes

for the preparation of a series of new unsymmetrical multidentate

aminophenol 48 ligands has been described in high yields under

solvent-free conditions at 125°C.81

Dawane, et. al82 have developed an efficient and solvent-free

synthesis of thiazole 49 derivatives by a three-component one-pot

reaction of thiourea, α-haloketone and substituted pyrazolones under

environmentally solvent-free conditions in good yields has been

developed.


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H2N

S

NH2

ClO

NN O

Grind,r.t.N

N N N

S

+(49)90%

Scheme 51. Three-component one-pot reaction of thiourea, haloketone

and pyrazolones under solvent-free condition.

Yavari and co-workers83 have synthesized thiazolidine-4-ones 50

in 70–83% yields through one-pot three-component reaction under

solvent-free conditions at room temperature. Various 4-

phenylthiosemicarbazides, DMAD and aldehydes or ketones were

tolerated well under solvent-free conditions.

Scheme 52. Multi-component reaction of 4-phenylthiosemicarbazides,

DMAD and aldehydes or ketones under solvent-free condition.

Very recently, the synthesis of highly functionalized pyridine

derivatives 51 has been reported by the domino coupling of readily

available malononitrile and cyclic ketones in the presence of

ammonium acetate in one-pot under microwave irradiation and solvent-

free conditions in high yields. The proposed mechanism involves a

novel sequence consisting of deprotonation/imine formation/anionic

carbonyl addition. The reaction was also performed in different


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solvents like AcOH, DMF, ethyl alcohol and water but the solvent-free

method was found to be most efficient.84

Scheme 53. Multi-component reaction of malononitrile, cyclic ketones

and ammonium acetate under solvent-free conditions.

The reported methods for the synthesis of phthalazine derivatives

show varying degrees of success, and limitations include harsh reaction

conditions, expensive catalysts/ reagents, toxic organic solvents, low

product yields, long reaction times, and co-occurrence of several side

products. Therefore, there still remains a high demand for the

Reaction conditions : (1) CSA (20 mol%), 80°C, solvent-free

(2) CSA (20 mol%),r.t.,solvent-free

Scheme 54. Three-component reaction of phthalhydrazide, 1,3-

diketones and aldehydes under solvent-free conditions as well as under

solvent-free ultrasound irradiation at rt.


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development of more general, efficient, economically viable, and eco-

compatible protocols to assemble such scaffolds. Very recently, we

reported a facile one-pot synthesis of 2H-indazolo[2,1-b]phthalazine-

1,6,11-triones and 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 52 via

the three-component coupling of phthalhydrazide, 1,3-diketones, and

aldehydes under solvent-free conditions at 80oC as well as under

solvent-free ultrasound irradiation at room temperature.85

As above, in connection with our continuing studies on the

development of one-pot multi-component reactions, here we described

our lab work on MCR under solvent-free condition. β-Aryl-β-

mercaptoketones 53 are valuable synthetic scaffolds for both medicinal

and synthetic organic chemists. They have been utilized as precursors

for the synthesis of various biologically active compounds, such as

thiochromans,86 thiopyrans,87 benzothiazapines,88 4,5-

dihydroisoxazoles89, 4,5-dihydropyrazoles90 etc. Traditionally their

synthesis has been performed by a sequence of two separate reaction

steps, (i) synthesis of an α, β unsaturated ketone via an aldol reaction,

(ii) 1,4-conjugate addition of a thiol to an α,β-unsaturated ketone via

thia-Michael addition. Michael addition of a thiol to chalcone is an

efficient approach to prepare β-aryl-β-mercaptoketones. Zirconium

chloride (40 mol%) efficiently catalyzes the one-pot three-component

reaction of an aryl aldehyde, cyclic or acyclic enolizable ketones and

thiols under solvent-free conditions at room temperature to afford the

corresponding β-aryl-βmercaptoketones 54 via an aldol–Michael

addition reaction.91


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Scheme 55. One-pot three-component reaction of aldehyde, ketones

and thiols under solvent-free condition for the synthesis of β-aryl-

βmercaptoketones.

Scheme 56. Synthesis of β-aryl-βmercaptoketones.

A convenient approach to the synthesis of 1,4-dihydropyridines

55 via domino four-component reaction of aromatic aldehydes, anilne,

DEAD, and malanonitrile proceed very well without catalyst under

“solvent-free” condition at room temperature. The reaction proceeds

most likely according to a domino Knoevenagel/aza-Michael

reaction/cyclization reaction pathway. Initially, coupling of the

aldehyde with the active methylene compound, and the aza-Michael

reaction of DEAD(diethyl acetylenedicarboxylate) and aniline occur.

The mechanism might also involve the rearrangement of intermediate

to generates the final product and observed that the aza-Michael

product as an oily compound after 1 min of grinding, but no

hydroamination or Knoevenagel products were isolated.92


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Scheme 57. Synthesis of 1,4-dihydropyridines under solvent-free

condition.

Zhu and co-workers have reported that upon heating a mixture of

2-aminopyridine (2-aminopyrazine or 2-aminopyrimidine), aromatic

aldehyde, and imidazoline-2,4,5-trione under solvent-free conditions

Scheme 58. Synthesis of imidazo[1,2-a]pyridine derivatives under

solvent-free condition.

afforded imidazo[1,2-a]pyridine derivatives 56 in excellent yields. The

one-pot multi-component reaction was performed at 200°C for 5 min,

producing the desired compounds in 92–97% yields.93

An interesting synthesis of the heterocycles by MDRs has been

recently achieved by reacting fumaryl chloride with primary amines

and alkyl acetoacetate as reported by Alizadeh and co-workers.94 This

multicomponent cyclocondensation was performed under solvent-free

conditions at room temperature to afford penta substituted pyrroles 57

in 70-85% chemical yields.


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Scheme 59. Synthesis of pyrrole under solvent-free condition.

Koszelewski et al.95 have studied the effects of the substrate

structure and concentration on the yield of the Passerini reaction. They

have developed a new and convenient solvent free methodology for the

preparation of α-cyloxyamides 58 by the coupling of aldehyde,

carboxylic acid, and isocyanide. The reaction was performed in solvent

as well as under solvent-free conditions, but the yield of the product

was greatly enhanced (86%) under solvent-free conditions compared to

when using solvent (22%). When aromatic isocyanide was used, an

increment of the yield (almost 50%) was observed under solvent-free

conditions compared to the classical procedure. On the other hand, the

products derived from aliphatic aldehydes were obtained in good yields

(88–90%) when the reaction was performed in DCM. Reactions with p-

anisaldehyde, p-methoxybenzoic acid, and isocyanoacetic acid ethyl

ester did not give any desired product.

Scheme 60. Multi-component reaction of aldehyde, aniline and

carboxylic acid under solvent-free condition.


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Khalilzadeh et al 96 described an efficient three-component

reaction for the synthesis of 2H-pyran-3,4-dicarboxylates 59 using the

three-component reaction of dithiocarbamates, dialkyl acetylenedicarb-

Scheme 61. Three-component condensation reactions of isocyanides,

activated acetylenes, and dithiocarbamates under solvent-free

condition.

oxylates, and isocyanides in solvent-free conditions is described. In

these reactions, synthesis of dithiocarbamates 60 is possibly based on

the one-pot reaction of secondary amines, CS2, and alkyl halides in

solvent-free conditions without using a catalyst.

Scheme 62. Three-component reactions of phenacyl bromides,

disulfide carbon, and secondary amines.

Jida et al.97 described three-component reaction for the synthesis

of the five- and six-membered lactams 61 via a 3C-Ugi reaction under

solvent-free condition in microwave. These reactions are performed


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neat at 100°C for 3 min under 75 W. A set of structurally different

amines and isocyanides were combined with either levulinic or 5-keto-

Scheme 63. U-3CR from ketoacid, isocyanide and amine undersolvent-free condition.

hexanoic acid under optimized conditions to give different lactams.

Interestingly, this procedure was successfully applied to the synthesis

of lactam 61 from the bulkier 3-benzoylpropionic acid isocyanide, and

benzylamine in 70% yield in 3 min.

1.9. CONCLUSION

Heterocycles play an important role in our everyday life and are

of immense importance in organic chemistry, natural products, and

pharmaceutical and agrochemical industries. We have demonstrated

here extensive efforts to produce these heterocyclic compounds by new

and efficient synthetic transformations. As illustrated in this review, a

wide variety of heterocycles of different sizes and ring systems can be

readily synthesized through MCR strategies that often result in a broad

scope of applications. MCRs were considered as an important

instrument to perform an “ideal synthesis” that was defined by

Wender,98 where the target molecules were synthesized in one step, in

quantitative yield from easily available and inexpensive starting

materials in resource effective and environmentally acceptable process.

On the other hand, to combat the harmful effect of organic solvents


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frequently used in large quantities for organic transformations, many

liquid substances (or fluids) have been recently proposed as alternative

green reaction media. Combination of MCRs and unconventional green

solvents has originated a new research direction that has emerged as an

important facet of green chemistry, from which both MCRs and green

solvents can simultaneously benefit. These researches not only offered

facile preparation of various highly functionalized organic molecules

with environmentally benign route, but also opened an avenue to

further strengthen the current innovation of green solvents.

Many new MCRs have been developed by using water, ionic liquids,

and under solvent-free condition. Modification of known MCRs with

green characteristics remains a challenge, but the utilization of

unconventional media offers researchers an important vehicle to realize

this idea. Although some of them can be performed in conventional

solvents or under solvent-free conditions,9999 the use of unconventional

solvents often endowed the system some concomitant advantages that

cannot be attained by other ways. Using water and ionic liquids in

metal-catalyzed MCRs also facilitates the recovery of metal catalysts.

Some unique properties of unconventional solvents also allow the use

of assisting technique, such as microwave irradiation. Looking back the

past decades, endeavours of performing MCRs in unconventional

solvents are mostly driven by the concept of using an unusual solvent

as reaction medium. However, the catalogues of MCRs that can be

performed in these solvents are rather limited. This can be partially

ascribed to the deficiency on the diversity of unconventional green

solvents. Therefore, development of new green media will be beneficial

for the chemistry of MCRs.


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