Isocyanide and Meldrum's acid-based multicomponent reactions in diversity-oriented synthesis: from a serendipitous discovery towards valuable synthetic approaches

Abstract

Multicomponent reactions, which lead to synthesis of target compounds with inherent molecular diversity, greater efficiency and atom economy, are single step types of reactions made from three or more reactants attract the attention of all chemists. The design and discovery of novel multicomponent reactions that are able to generate useful chemical products may be regarded as a preeminent topic in organic chemistry. In this context, isocyanide-based multicomponent reactions are one of the important branches of multicomponent reactions. This review covers and describes our serendipitous discovery of a new isocyanide and Meldrum's acid-based multicomponent reaction in 2001, which created a new vision in synthetic approaches and following contributions by others to the field since then. Isocyanide and Meldrum's acid are the basic components of these discovering multicomponent reactions and have opened new avenues to one-pot synthesis of numerous classes of pharmaceutically and industrially valuable heterocyclic and acyclic organic compounds, such as imino-furopyranones, coumarins, benzodiazepines, benzooxazepines, amidodiesters, functionalized triamides, succinimides, and malonamides, in a three- to six-component condensation reaction strategy.

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Ahmad Shaabani

Ahmad Shaabnai was born in Iran, in 1956. He received his PhD under the supervision of Prof. Issa Yavari from University of Tarbiat Modarres, Tehran, Iran (1994). He was a visiting researcher at University of Regina, Canada, under the guidance of Prof. Donald G. Lee in 2000. He has been a faculty member of Shahid Beheshti University since 1995 and was promoted to Professor in 2002. The Ministry of Science, Research and Technology of Iran selected him as a distinguished Professor of the Iran Universities in 2003 and distinguished Professor selected by the Iran Elite Foundation, (First Festival of Allameh Tabatabaei Award) in 2012. He won a prize at the International Kharazmi Festival in basic science in 2009 and was selected as a leading scientist of OIC Members in 2008. He has published over 320 publications including three chapters and a book. Shaabani's research involves the discovery and design of novel multicomponent reactions based on isocyanides, combinational chemistry, heterocyclic chemistry and the development of new synthetic methods through the synthesis and applications of heterogeneous catalysts. He is also a member of the Editorial Advisory Board of the ACS Combinatorial Science and a member of the editorial board of the Journal of the Iranian Chemical Society.

Seyyed Emad Hooshmand

Seyyed Emad Hooshmand was born in Iran, in 1988. He received his B.Sc. in chemistry from Bu-Ali Sina University, Hamedan, Iran in 2011, and his M.Sc. in organic chemistry from Kharazmi University, Tehran, Iran under the supervision of Dr Azim Ziyaei Halimehjani, in 2013. His research interests include synthesis of novel compounds based on dithiocarbamates and design of acid catalysts for organic transformations. During his studies, he successfully co-authored 8 scientific articles. Currently, he is working as a PhD student under the supervision of Prof. Ahmad Shaabani at Shahid Beheshti University in Tehran, Iran. His present research interests focus on the discovery and development of new isocyanide based multicomponent reactions, synthesis of heterocyclic compounds and green chemistry.

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1 Introduction

The discovery and development of new multicomponent reactions (MCRs) are an intellectually challenging task because one has to consider not only the reactivity match of reactants, but also the reactivity of the intermediate generated molecules in situ and their compatibility and selectivity. Recently, the discovery and development of novel MCRs have received a growing interest from both basic and industrial chemistry point of views. There are various approaches for creating and discovering novel MCRs.^1,2 One highly innovative and efficient strategy for the discovery of new MCRs is a combinatorial reaction finding. Rational design is another method in which the MCRs are planned and are based on the reactivity and mechanistic of the reactant and intermediates. The union of MCRs and chance or serendipity have profound effects on the discovery of the new MCRs.^3,4

Isocyanide-based multicomponent reactions (I-MCRs) are an extremely powerful synthetic strategy for the synthesis of structurally diverse complex compounds, as well as combinatorial libraries of molecules similar to natural product.⁴ The history of isocyanide chemistry goes back to the first synthesis of allyl isocyanide by Lieke in 1859.⁵ During this century, only small amounts of compounds were synthesized and because the known isocyanides smelled very unpleasant, their chemistry was only moderately investigated. In the last years of 1950s' decade, the chemistry of isocyanides, along with the development of combinatorial chemistry in the pharmaceutical industry, eventually led to an outbreak in organic chemistry.⁶ The ability of isocyanides to undergo facile addition with both nucleophiles and electrophiles makes them a popular class of reactants for the development of novel I-MCRs. The chemistry of isocyanides has been the subject of several reviews.^7–17

Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione), is an organic compound, discovered in 1908 by A. N. Meldrum.¹⁸ Meldrum's acid is a white crystalline solid that can be easily prepared by the condensation of malonic acid and acetone in acetic anhydride in the presence of a catalytic amount of concentrated sulfuric acid.¹⁹ Due to its high acidity (pK_a 7.5)²⁰ and tendency to regenerate acetone, Meldrum's acid appears to be an attractive reagent in organic synthesis.²¹ Furthermore, it is susceptible to electrophilic attack at C5 and nucleophilic attack at C4 and C6. In addition, its unique ring-opening reactions makes it a tremendously attractive and useful building block.²² However, the applications of this compound in organic synthesis have received little attention except as an alternative for cyclic malonic esters.^23,24

In 2001, in continuing our interest in the synthesis of heterocyclic compounds with furan rings via [4 + 1] isocyanide-based reactions (Scheme 1),^25–27 we designed and explored a condensation reaction of isocyanides 1 with substituted-benzylidene Meldrum's acid 2 derivatives for the synthesis of isobenzofurans 3 in methylene chloride without using any activators and catalysts. However, in this reaction, the desired product, isobenzofurans 3, was not produced and instead we found the reaction proceeded with an unexpected and undesired product.²⁸ The structure of the product was deduced from elemental analyses, IR, mass spectra, ¹H and ¹³C NMR spectral data and found the reaction was processed via a new pseudo four-component condensation reaction strategy in which two molecules of ethanol from impurities in the solvent, methylene chloride, participated in this reaction. When this reaction was carried out in ethanol as a solvent, the reaction rate and yield were increased, considerably. This new IM-MCR provides a useful synthetic route to highly functionalized amidodiesters 4 (Scheme 2). Moreover, this discovery became the basis for further synthesis, including three generation approach. The first generation approach is a multicomponent reaction with participation of one or two of the same intermolecular nucleophiles. The second generation is a multicomponent reaction with participation of two different intra and intermolecular nucleophiles. Finally, the third generation approach was included as a multicomponent reaction using a dinucleophile reagent. This review indicates the contributions of a serendipitous discovery of a new isocyanide and Meldrum's acid-based multicomponent reaction (IM-MCR), which was performed in our laboratory in 2001 and all the results of the studies of the next research groups.

Scheme 1 Isocyanides undergo formal [4 + 1] cycloaddition with activated heterodienes.

Scheme 2 The expected and unexpected ways of the reactions.

2 The first generation approach

2.1 Reaction with alcohols

The development of simple synthetic routes for widely used organic compounds from readily available reagents is one of the major tasks in organic synthesis. In 2001, Shaabani et al. first explored the concept of a pseudo four-component reaction to condensation products of Meldrum's acid and 4-nitrobenzaldehyde 2, which reacts smoothly with alkyl isocyanides 1 in the presence of alcohols 5 to produce dialkyl 2-[1-p-nitrophenyl-2-(alkylamino)-2-oxoethyl]malonates 4 in CH₂Cl₂ in good to excellent yields (Scheme 3).²⁸

Scheme 3 Shaabani's pseudo four-component synthesis of functionalized amidodiesters.

A plausible mechanism for the formation of dialkyl 2-[1-p-nitrophenyl-2-(alkylamino)-2-oxoethyl]malonates 4 is proposed in Scheme 4. The first step of this mechanism involves the [4 + 1] cycloaddition reaction of the electron-deficient heterodiene moiety of isopropylidene p-nitrobenzalmalonate 2 with the isocyanides 1 to afford an iminolactone 6 intermediate. As it is known that acylated Meldrum's acids are readily transformed into β-ketoesters by alcoholysis, the subsequent reaction of iminolactone with alcohol leads to the formation of products 4 (see pathway A in Scheme 4). Because the reaction works well with tert-butyl alcohol as the alcohol component, the proposed addition to the vinylogous carbonate in pathway A is expected to be slow. Thus, we prefer to suggest the loss of acetone from 6 first and then the sequential addition of the alcohol to the so-formed ketene and the isourea (see pathway B in Scheme 4). The present method carries the advantage that not only that the reaction is performed under neutral conditions, but also the substances can be mixed without any activation or modification. This group in another paper reported a pseudo five-component reaction approach to the efficient, diversity-oriented synthesis of amidodiesters 4 with alcohols, aldehydes and alkyl or aryl isocyanides in the presence of Meldrum's acid;²⁹ moreover, this research group reported this pseudo four-component reaction by phenols instead of alcohols.³⁰

Scheme 4 Proposed mechanism for the formation of dialkyl 2-[1-p-nitrophenyl-2-(alkylamino)-2-oxoethyl]malonates.

Following pervious reactions, Bazgir et al. synthesized ferrocenyl amidodiesters 7 in good yields by a pseudo five-component reaction of ferrocenecarboxaldehyde 8, isocyanides 1, Meldrum's acid 9 and alcohols 5 in CH₂Cl₂ at room temperature (Scheme 5).³¹

Scheme 5 Pseudo five-component synthesis of ferrocenyl amidodiesters.

Ferrocene derivatives have ever growing applications in many fields, from materials science to medicinal chemistry. The ferrocenyl group is incorporated into the structure of a number of biologically active molecules resulting in enhanced anticancer³² and antimalarial³³ activities, among many others. A number of reasons may be enumerated to explain the success of ferrocenes, among which its unusual stability for an organometallic species; ferrocenes can be handled in the air when solid and often in solution. Thus, formation of ferrocenyl amidoesters via IM-MCRs is useful in functionalizing ferrocenes, because oxidation can be easily avoided, reaction conditions are mild, and ester or amide groups may be transformed into a variety of functional groups.

Yavari et al. reported a one flask synthesis of highly-functionalized amidoester and substituted succinimide by changing the component ratio (Scheme 6).³⁴ The reaction of equimolar amounts of tert-butyl isocyanide, isopropylidene Meldrum's acid 10 and alcohols in dichloromethane at room temperature afforded both dialkyl 2-(1-tert-butylcarbamoyl-1-methyl-ethyl)-malonates 4 and alkyl 1-tert-butyl-4,4-dimethyl-2,5-dioxo-pyrrolidine-3-carboxylate 11, in which the 11 is major products. However, in the case of an excess amount of alcohols, product 4 is the major product (Table 1). It is interesting to note that with n-butanol, only product 11 is obtained in the both conditions. Furthermore, they carried out this reaction by diols 12,³⁵ the results showed the alkyl isocyanides undergo a complex reaction with isopropylidene Meldrum's acid. In the presence of 1,3-propanediol and 1,4-butanediol, hydroxyalkyl 1-(tert-butyl)-4,4-dimethyl-2,5-dioxo-3-pyrrolidinecarboxylates 13 were obtained in good yields in CH₂Cl₂ at room temperature (Scheme 7).

Scheme 6 Synthesis of compounds of 4 and 11.

Table 1 (i) CH₂Cl₂, r.t., 10 : 1 : 5 (1 : 1 : 1); (ii) CH₂Cl₂, r.t., 10 : 1 : 5 (1 : 1 : 3)

Entry	R^1	(i) % yield of 4 + 11	11 : 4	(ii) % yield of 4 + 11	11 : 4
1	Me	65	80 : 20	88	5 : 95
2	Et	68	78 : 23	98	3 : 97
3	Allyl	68	75 : 25	98	3 : 97
4	Bz	65	80 : 20	95	10 : 90
5	Pr	77	93 : 7	65	30 : 70
6	Bu	95	11 only	95	11 only

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Scheme 7 The reaction between alkyl isocyanides and isopropylidene Meldrum's acid in the presence of diols.

Very recently, Teimouri et al. described a diastereoselective synthesis of highly substituted succinimide derivatives 14 with chromone and carboxylic ester functionalities from 3-formylchromones 15, Meldrum's acid 9, and alkyl isocyanides 1 in the presence of alcohols 5.³⁶ The products 14 were obtained in moderate to good yields under catalyst-free conditions in dry dichloromethane (Scheme 8).

Scheme 8 Diastereoselective synthesis of highly substituted succinimide derivatives.

They now disclose a new multicomponent cascade reaction diastereoselectively providing polyfunctionalized succinimide derivatives. Succinimide-substructure-containing compounds show great pharmacological potential acting as enzyme inhibitors, analgesics, antimicrobial agents, anxiolytics, cytotoxic, anticonvulsants, antitumor drugs, and anti-Parkinson's agents, this ubiquitous building block is present in natural products and pharmacologically active molecules.³⁷ A variety of structurally diverse alcohols underwent the one-pot reaction smoothly to afford the corresponding succinimide derivatives, but in the case of the sterically unhindered methanol, the amidodiester fragments were formed instead of the expected formation of succinimide moieties.

A plausible mechanism for the formation of the fully functionalized succinimides is proposed in Scheme 9. The reaction may be rationalized by initial formation of the conjugated electron-deficient heterodiene by the Knoevenagel condensation of the 3-formylchromone 15 and Meldrum's acid 9, followed by a [4 + 1]-cycloaddition reaction with isocyanides to afford an iminolactone intermediate 16. Conjugate addition of the alcohol on the enone moiety of 16, followed by cleavage of the five-membered iminolactone ring obtains 17 and therefore the α-oxoketene 18 by a well precedented electrocyclic ring opening of o-alkylated Meldrum's acids. The α-oxoketene 18 can then undergo an intramolecular reaction between the amide and ketene moieties to obtain a stable carbanion intermediate 19. The resulting enolate 19 undergoes stereoselective reprotonation to yield the thermodynamically favourable isomer of the product 14. Among the alcohols studied, only methanol, as the least sterically hindered alcohol, can compete with the adjacent amide nitrogen atom in attacking the ketene moiety to produce the dimethyl malonate derivative 20.

Scheme 9 Possible mechanisms for the formation of products 14 and 20.

It is important to note that compound 14 has two stereogenic centers and therefore two pairs of diastereoisomers are expected. The relative configuration was determined by X-ray crystal structure analysis.

2.2 Reaction with amines

Shaabani and co-workers reported a novel pseudo five-component reaction approach to the efficient synthesis of triamide derivatives 21 using amines 22, aldehydes 23 and alkyl or aryl isocyanides 1 in the presence of Meldrum's acid 9 as a CH acid, instead of carboxylic acid in an Ugi four-component reaction (Scheme 10).²⁹

Scheme 10 Shaabani's pseudo five-component synthesis of functionalized triamide.

The classic version of the Ugi four-component condensation reaction combines a primary amine, an oxo component (aldehydes or ketones) and an isocyanide in the presence of a carboxylic acid to obtain an amino acylamide containing two amide groups. It is interesting to note that in this reaction three amide groups were produced. The amide functionality is one of the most fundamental chemical building blocks found in nature. It constitutes the backbone of the biologically crucial proteins and it is present in a vast number of synthetic structures.³⁸ For example, the amide bond is found in up to 25% of all pharmaceuticals on the market and it was present in 66% of drug candidates that were surveyed by three leading pharmaceutical companies in 2006.³⁹ It has been estimated that 16% of all reactions involved in the synthesis of modern pharmaceuticals were the acylation of an amine, which makes it the most commonly performed reaction in this field.⁴⁰ Polymers based on the amide linkage are of importance in a wide range of applications, from everyday materials such as nylons, to more advanced uses in drug delivery systems, adhesives and wound healing.⁴¹ In addition, the amide bond is commonly found as a key structural element in agrochemicals and in products from the fine chemicals industry.

Moreover, Yavari et al. with secondary amines, such as pyrrolidine and piperidine, carried out of this reaction for the synthesis of triamide derivatives 21 (Scheme 11).⁴² The mass spectra of these compounds displayed molecular ion peaks at appropriate m/z values. Any initial fragmentation involved the loss of amide moieties.

Scheme 11 Synthesis of triamide derivatives with secondary amines.

Recently, the Safaei-Ghomi group improved the synthesis of tricarboxamides using CuI nanoparticles as a catalyst with excellent yields in short times and mild reaction conditions as some of the important features of this protocol.⁴³

Teimouri et al. reported a pseudo five-component reaction between 3-formylchromones 15, Meldrum's acid 9, isocyanides 1 and primary arylamines 22 to diversity-oriented synthesis of novel chromone-containing peptidomimetics 23 (Scheme 12).⁴⁴

Scheme 12 Synthesis of novel chromone-containing peptidomimetics.

This reaction by an alcohol moiety obtained succinimide derivatives, but unlike the alcohol, when the substrate combination was switched from primary aliphatic alcohols to primary aryl amines, none of the expected succinimide derivatives were obtained. Isocyanides with both sterically hindered and less hindered alkyl or aryl substituents were well tolerated and participated in the clean reactions, obtaining the desired chromone-containing peptidomimetics in good yields.

The chromone moiety forms the nucleus of a class of heterocyclic natural products called flavanoids that occur naturally in fruits, vegetables, nuts, seeds, flowers, and barks.⁴⁵ They are an integral part of the human diet and have been reported to exhibit a wide range of biological effects.^46,47 Chromone is also part of pharmacophores of a large number of molecules of medicinal significance.⁴⁸ Moreover, the aforementioned group reported an efficient one-pot method for the synthesis of novel ferrocene-triamide 24 conjugates via pseudo five-component reactions⁴⁹ (Scheme 13). Conjugates of ferrocene with well-known drugs are reported, for example, with antibiotics such as penicillin and cephalosporin.^50,51

Scheme 13 Synthesis of novel ferrocene-triamide conjugates via a pseudo five-component reaction.

This transformation proceeds through the creation of two C–C bonds, two C–N bonds, and one C=O bond, leading to three peptide bonds, and presumably occurs via a domino sequence involving Knoevenagel condensation, [4 + 1] cycloaddition, deacetonation, and aminolysis reactions. Allylic, benzylic, aromatic, aliphatic, and heteroaromatic amines are used in this protocol with excellent results. A variety of aryl amines carrying different functional groups were subjected to the coupling reactions and in all cases the desired product was obtained in good yields.

The Yavari and Habibi groups reported several articles about the one-pot synthesis of new derivatives of succinimide 25 via three-component reactions of alkylidene Meldrum's acid 10, isocyanides 1 and amines moiety 22 as a nucleophile proceeded slowly at room temperature in CH₂Cl₂ and completed within 24 h to afford the corresponding amidosuccinimides. Allylic, benzylic and aromatic amines 22,⁴² arylhydroxylamines⁵² and 4-(2-phenyldiazenyl)benzenamines⁵³ 26 are used in this method with moderate results (Scheme 14).

Scheme 14 Syntheses of new derivatives of succinimide via a three-component reaction by various amines.

2.3 Reaction with water

Shaabani et al. reported the synthesis of 4-(alkylamino)-3-aryl-4-oxobutanoic acids 27 from the reaction between alkyl isocyanides and substituted-benzylidene Meldrum's acid derivatives in the presence of water.⁵⁴ This reaction proceeded spontaneously at room temperature in CH₂Cl₂ or CH₃CN (Scheme 15).

Scheme 15 Synthesis of 4-(alkylamino)-3-aryl-4-oxobutanoic acids.

2.4 Reaction with thiols

Sulfur-containing architectures serve important functions in general organic synthesis, as well as applications in the pharmaceutical industry and in materials science.⁵⁵ Organosulfur compounds widely exist in drugs and natural products. For example, penicillins are well-known sulfur-containing antibiotics.⁵⁶ Recently, Habibi et al. reported the synthesis of highly functionalized S-alkyl 1-alkyl-4,4-dimethyl-2,5-dioxo-pyridine-3-carbothioates 28 by the reaction of isocyanides 1 with isopropylidene Meldrum's acid 10 in the presence of thiols 29 in dichloromethane at room temperature (Scheme 16).⁵⁷

Scheme 16 Synthesis of highly functionalized S-pentyl 1-benzyl-4,4-dimethyl-2,5-dioxopyrrolidine-3-carbothioates.

2.5 Reaction with activated C–H

Alkyl isocyanides 1 undergo a smooth reaction with isopropylidene Meldrum's acid 10 in the presence of pyrrole or indole 30 to produce 1-alkyl-3,3-dimethyl-4-(1H-pyrrole-2-carbonyl)-pyrrolidine-2,5-diones or 1-alkyl-4-(1H-indole-3-carbonyl)-3,3-dimethylpyrrolidine-2,5-diones 31 in good yields⁵⁸ (Scheme 17). Indole and many of its derivatives are present in many substances commonly found in nature, as well as in many compounds that show pharmacological and biological activities.^59,60 In addition, the pyrrole nucleus is one of the most relevant simple heterocycles found in a large number of natural products, agrochemicals, and pharmaceuticals.⁶¹ Many pyrrole-containing compounds possess potent biological activity.⁶²

Scheme 17 Synthesis of 1-alkyl-4-(1H-indole-3-carbonyl)-3,3-dimethylpyrrolidine-2,5-diones.

2.6 Reaction with isocyanides

Habibi et al. reported the synthesis of imino-furopyranones 32 via an unexpected pseudo four-component [3 + 1] reaction of an alkyl isocyanide 1 with alkylidene-substituted Meldrum's acid 10 in CH₂Cl₂ at room temperature in good yields (Scheme 18).⁶³

Scheme 18 Synthesis of imino-furopyranones via an unexpected pseudo four-component [3 + 1] reaction.

A single crystal X-ray diffraction study confirmed the structure of the compound. The X-ray structure indicated that all the atoms of the furo-pyran ring are in the same plane except for the sp³ carbon atom. On the basis of the well-established chemistry of isocyanides, it is reasonable to assume that the furo-pyran 32 results from an initial [4 + 1] cycloaddition reaction of the electron-deficient heterodiene moiety of isopropylidene Meldrum's acid 10 with cyclohexyl isocyanide 1 to produce an iminolactone intermediate 6. Nucleophilic attack of a second isocyanide on the imine carbon of 6, followed by cleavage of the five-membered ring and subsequent cyclization obtains the di-imino pyran intermediate 33. Addition of a third isocyanide to the carbonyl of intermediate 34 obtains an unstable intermediate 35 that easily loses an acetone molecule and cyclizes to obtain furo-pyran 32 (Scheme 19).

Scheme 19 Possible mechanisms for the formation of furo-pyrans.

2.7 Reaction with carboxylic acids

Habibi et al. reported synthesis of new derivatives of iminofuranone 36 in good yields.⁶⁴ The one-pot multicomponent reaction of alkyl isocyanide 1, alkylidene-substituted Meldrum's acid 10 and arylcarboxylic acids 37 affords the target molecules 36. The iminofuranones 36 was obtained, as depicted in Scheme 20.

Scheme 20 Synthesis of new derivatives of iminofuranone.

An interesting aspect of this reaction is the participation of two molecules of isocyanides 1 and one molecule of alkylidene-substituted Meldrum's acid 10 with arylcarboxylic acids 37. The reaction occurred smoothly at room temperature and was completed within 48 h in CH₂Cl₂/DMSO and led to new derivatives of iminofuranone 36. A proposed mechanism for the reaction is shown in Scheme 21.

Scheme 21 Possible mechanisms for the formation of iminofuranones.

2.8 Reaction with oximes

Habibi's group in 2013 reported an efficient protocol for the synthesis of new isoxazolinedione derivatives 38 with two molecules of isocyanides 1, aliphatic oxime 39, and alkylidene substituted Meldrum's acid 10 (Scheme 22).⁶⁵ This reaction occurred in CH₂Cl₂ as a solvent and at room temperature. After 48 h, the reaction was completed with a moderate yield and the crude products were purified using column chromatography with hexane/ethyl acetate as the eluent.

Scheme 22 Synthesis of new isoxazolinedione derivatives.

3 The second generation approach

Recently, Shaabani et al. reported a novel isocyanide-based four-component reaction with participation of two different intra and intermolecular nucleophiles as a second generation. They reported diversity-oriented synthesis of 3,4-dihydrocoumarin derivatives 40 using 2-hydroxybenzaldehyde 39, Meldrum's acid 9, an isocyanide 1, and an aromatic or an aliphatic alcohol 5 in good to excellent yields without catalysts or activation. The reaction can be carried out as a simple one-pot protocol at room temperature (Scheme 23).⁶⁶ Coumarin (2H-1-benzopyran-2-one) and its derivatives are important compounds due to their presence in naturally occurring aromatic products found in plants⁶⁷ and cinnamon flavoured foods.⁶⁸ It has been reported that coumarin derivatives exhibit anticancer,⁶⁹ anti-HIV,⁶⁹ anti-Alzheimer,⁷⁰ and antimicrobial activities.⁷¹ Moreover, coumarins constitute an important class of organic fluorescent dyes. These fluorescent properties have been used to study proteins and nucleic acids.⁷²

Scheme 23 Shaabani's method for the synthesis of 3,4-dihydrocoumarin derivatives via a novel isocyanide-based four-component reaction.

This approach was the beginning of a new generation approach based on a four-component reaction with two divergent nucleophiles. 2-Hydroxy benzaldehyde or salicylaldehyde as a reactant has a dual roles: the hydroxyl group acts as an electrophile and the aldehyde group acts as a nucleophile. Mechanistically, the reaction may be rationalized by the initial formation of a conjugated, electron-deficient heterodiene by a standard Knoevenogel condensation of the 2-hydroxybenzaldehydes 39 with Meldrum's acid 9 followed by a [4 + 1] cycloaddition reaction or a Michael-type addition reaction with isocyanides 1 to afford an iminolactone intermediate 6. It is well known that acylated Meldrum's acid is readily transformed into β-ketoesters by alcoholysis. Therefore, it is reasonable to assume that the intramolecular reaction of iminolactone with the hydroxyl group of 2-hydroxybenzaldehyde 39 and subsequently loss of acetone from 6 leads to formation of 41 and then the nucleophilic attack of the alcohol with the activated carbonyl moiety 41 yielded product 40 (Scheme 24).

Scheme 24 Proposed mechanism for the synthesis of 3,4-dihydrocoumarin derivatives.

In 2011, Azuaje et al. used a polymer-supported (polystyrene or silica) p-toluenesulfonic acid as a highly effective, robust, economical and eco-friendly isocyanide scavenger for the abovementioned reaction. The unpleasant odour of isocyanides frequently makes the workup and purification of the reaction products highly tedious and distressing, particularly when applied to high-throughput organic syntheses operating in parallel mode. This group described strategies to circumvent the intense and repulsive odour of volatile isocyanides, enabling simplified and odourless workup and purification.⁷³

Recently, Reddy et al. reported a four-component reaction of sugar hydroxyaldehyde 42, Meldrum's acid 9, isocyanides 1, and a secondary alcohol 5 in dichloromethane, accomplished at room temperature in a highly stereoselective manner to produce a novel class of carbohydrate derivatives, 5-oxo-perhydrofuro[3,2-b]pyrans 43 in good yields with trans-selectivity (Scheme 25).⁷⁴

Scheme 25 Highly stereoselective manner for the synthesis of a novel class of carbohydrate derivatives.

Shaabani and co-workers in an another study reported a new one-pot procedure for the efficient synthesis of novel 3,4-dihydrocoumarin 44 derivatives using commercially available substituted 2-hydroxybenzaldehydes 39, Meldrum's acid 9, and isocyanides 1 by a three-component condensation reaction in dichloromethane at room temperature (Scheme 26). It is interesting to note that the reaction afforded the 2-oxo-2H-chromene-3-carboxylic acid derivatives 45 in CH₃CN as a solvent.⁷⁵

Scheme 26 A one-pot procedure for the efficient synthesis of novel 3,4-dihydrocoumarin 44 and 45.

4 The third generation approach

Benzodiazepines have been an important pharmacophore in the pharmaceutical industry; their derivatives are known to display a wide range of pharmacological activities such as anxiolytics,⁷⁶ HIV reverse transcriptase inhibitors,⁷⁷ antianxiety, analgesic, sedative, antidepressive, hypnotic agents⁷⁸ and anti-inflammatory agents.⁷⁹ Furthermore, 1,5-benzodiazepine-2,4-dione core is a highly efficient pharmacophore and exists in a number of bioactive compounds. Some of them have been clinically used as anxiolytic agents, such as Clobazam, Triflubazam, Razobazam, Lopirazepam and compound 46 as a cholecystokinin-B receptor antagonist (Fig. 1).

Fig. 1 Examples of some biologically active benzodiazepine derivatives.

Accordingly in 2009, Shaabnai and co-workers reported a novel and efficient multicomponent reaction using a dinucleophile reagent as a third generation approach for the synthesis of tetrahydro-2,4-dioxo-1H-benzo[b][1,5]diazepine-3-yl-2-methylpropanamide derivatives 47 using an aromatic diamine 48, Meldrum's acid 9, and isocyanide 1 in CH₂Cl₂ at ambient temperature in high yields without using any catalysts or activation (Scheme 27).⁸⁰ The procedure provides an alternative method for the synthesis of benzo[b][1,5]diazepine derivatives.

Scheme 27 Shaabani's approach for the synthesis of benzo[b][1,5]diazepine derivatives.

This route permits us to introduce great molecular diversity under mild reaction conditions, including substitution and scaffold diversity. A large number of derivatives can be rapidly synthesized in excellent purity and high yield using this method. The reaction is straightforward and treatment of various alkyl, aryl, and alicyclic isocyanides and various o-phenylenediamines with Meldrum's acid in CH₂Cl₂ at room temperature led to the formation of benzo[b][1,5]diazepine derivatives 47.

A possible mechanism for the formation of products is shown in Scheme 28. It is conceivable that the initial event is the formation of 1H-benzo[b][1,5]diazepine-2,4(3H,5H)-dione 49 from a condensation reaction between o-phenylenediamine 48 and Meldrum's acid 9. Then, intermediate 1H-benzo[b][1,5]diazepine-2,4(3H,5H)-dione 49 under a Knoevenagel condensation reaction with in situ liberated acetone produces the intermediate 50. On the basis of the well-established chemistry of the reaction of isocyanides with electron deficient α,β-unsaturated carbonyl compounds, intermediate 51 was produced by the nucleophilic attack of an isocyanide to 3-(propan-2-ylidene)-1H-benzo[b][1,5]diazepine-2,4(3H,5H)-dione 50 via a Michael-type addition reaction, followed by nucleophilic attack of a H₂O molecule on the nitrilium moiety to produce compound 52. Finally, tautomerization of compound 52 produces the 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2-carboxamide derivatives 47 (Scheme 28).

Scheme 28 Possible mechanism for the formation of products 47.

To clarify the mechanism, the reaction of 4,5-dimethylbenzene-1,2-diamine 48, Meldrum's acid 9, and cyclohexyl isocyanide 1 in the presence of 1,1,1,3,3,3-hexafluoropropan-2-one 53 under the same reaction conditions was checked. As can be observed in Scheme 29, the desired product 54 was obtained. On the other hand, this result shows that 1,1,1,3,3,3-hexafluoropropan-2-one 53 was replaced with liberated acetone from Meldrum's acid.

Scheme 29 Clarification of the mechanism.

A highly efficient catalyst, such as ZnO nanoparticles (ZnO NPs),⁸¹ CuI nanoparticles⁸² and magnetite (Fe₃O₄) nanoparticle,⁸³ was used for the one-pot preparation of tetrahydro-2,4-dioxo-1H-benzo[b][1,5]diazepine-3-yl-2-methylpropanamide by Ghasemzadeh et al. This methodology afforded a number of benzo[b][1,5]diazepine derivatives with excellent yields and short reaction times by good reusability of catalysts.

Li et al. investigated and reported a series of 1,5-benzodiazepine-2,4-dione derivatives with C-6 amide substituents 55, which were designed and synthesized using Shaabani's approach. The preliminary assays showed that most of them displayed moderate to good antitumor activity against human lung carcinoma, human breast epithelial carcinoma, human colon carcinoma, human cervical carcinoma and Lewis lung carcinoma. In a model reaction, o-phenylenediamine containing amide 56, Meldrum's acid 9 and benzyl isocyanide 1 in 1,2-dichloroethane at reflux under Ar produced the target compounds in 25–45% yields after column chromatography or recrystallization (Scheme 30).⁸⁴

Scheme 30 Synthesis of novel 1,5-benzodiazepine-2,4-dione derivatives with C-6 amide substituents.

In another study, the Bazgir research group reported an efficient method for the synthesis of new 2-aryl-2-(2,3,4,5-tetrahydro-2,4-dioxo-1H-1,5-benzodiazepin-3-yl)acetamides 57 via a five-component condensation reaction of benzene-1,2-diamine 48, Meldrums acid 9, benzaldehyde derivatives 23, isocyanides 1, and H₂O in CH₂Cl₂ at room temperature (Scheme 31). These products were evaluated in vitro for their antibacterial activities.⁸⁵

Scheme 31 Synthesis of 2-aryl-2-(2,3,4,5-tetrahydro-2,4-dioxo-1H-1,5-benzodiazepin-3-yl)acetamides via a five-component reaction.

Recently, Rahmati et al. reported the synthesis of a new series of 1,2,4,5-tetrahydro-2,4-dioxobenzo[b][1,4]diazepine 58 and malonamide derivatives 59 using aromatic 1,2-diamine 48, Meldrum's acid 9, isocyanide 1 and arylidene malononitrile 60 (or an aldehyde and malononitrile instead of an arylidene malononitrile) in CH₂Cl₂ at ambient temperature⁸⁶ (Scheme 32). Synthesis of 1,2,4,5-tetrahydro-2,4-dioxobenzo[b][1,4]diazepines 58 proceeded via four- and five-component reactions, whereas the synthesis of malonamide derivatives 59 was performed using five- and six-component reactions. In addition, a new series of malonamide derivatives has been prepared using an aldehyde, malononitrile, Meldrum's acid, an isocyanide and two molecules of 1,4-diamine via a six-component reaction. These procedures provide alternative methods to the synthesis of 1,2,4,5-tetrahydro-2,4-dioxobenzo[b][1,4]diazepine and malonamide derivatives.

Scheme 32 Synthesis of a new series of 1,2,4,5-tetrahydro-2,4-dioxobenzo[b][1,4]diazepine and malonamide derivatives.

The aim of this study was the synthesis of product 58 or 59 in a pure form based on the model reaction. Optimization of the reaction conditions to obtain only product 58 showed that altering temperature and solvent did not affect the selectivity of products, but changing the quantity of reaction components along with the amount of solvent volume changed the product ratio significantly. Results showed that by decreasing 1,2-diamines and increasing the solvent volume, the amount of 58 is increased. Moreover, no obvious changes were observed with varying the quantity of the other reaction components. In addition, decreasing solvent volume was not effective on the amount of product ratios and yields. Furthermore, this group in another study reported the synthesis of malonamide derivatives 59 via a pseudo five-component condensation reaction of isocyanide 1, Meldrum's acid 9, arylidene malononitrile 60, and two amine molecules 48 in CH₂Cl₂ at ambient temperature.⁸⁷

Benzoxazepine derivatives are important scaffolds in medicinal chemistry with various biological activities^88,89 and attractive compounds of growing pharmaceutical interest as documented by many publications. Among compounds containing this fragment are a non-nucleoside HIV-1 reverse transcriptase inhibitor,⁹⁰ a histamine receptor agonist⁹¹ and calcium antagonists,⁹² as well as an anticancer agent with activity against breast cancer cells.⁹³ Malonamide derivatives have some important applications such as excellent ionophores for the construction of alkali and alkaline-earth cations-selective electrodes,⁹⁴ effective liquid–liquid extractants for the separation of actinide ions from acid media, as an alternative to carbamoylmethylphosphine oxide (CMPO) systems in the nuclear waste management process, as bidentate chelates especially for uranium(VI) and plutonium(IV) ions,⁹⁵ as monomers in the nylons' family and as components in peptidomimetic substances.⁹⁶

Recently, Shaabani et al. discovered and reported the novel one step synthesis of tetrahydrobenzo[b][1,4]oxazepine 61 or malonamide derivatives 62.⁹⁷ In this study, a multicomponent reaction of 2-aminophenols 63 instead of benzene-1,2-diamine 48, Meldrum's acid 9, and isocyanides leads to the synthesis of compounds 61 or 62 derivatives using 1 or 2 equivalent of 2-aminophenols 63, respectively, in good to excellent yields at ambient temperature (Scheme 33).

Scheme 33 Synthesis of tetrahydrobenzo[b][1,4]oxazepine or malonamide derivatives.

A new and reusable heterogeneous catalytic system is reported for the one-pot, three-component synthesis of a series of tetrahydrobenzo[b][1,4]oxazepine 61 and malonamide derivatives 62 in the presence of a heterogeneous material composed of MCM-48/H₅PW₁₀V₂O₄₀ in aqueous media and at room temperature.⁹⁸

Moreover, Habibi et al. reported an efficient method for the synthesis of new barbituric acid derivatives 64 via a one-pot three-component reaction of alkylidene-substituted Meldrum's acid 10, alkyl isocyanide 1 and urea 65 that leads to the production of the target molecule in CH₂Cl₂/DMSO stirred for 24 h (Scheme 34).⁹⁹

Scheme 34 Syntheses of new barbituric acid derivatives.

5 Miscellaneous

Very recently, Shaabani et al. designed and developed an efficient and straightforward method for the diversity-oriented synthesis of trifunctional coumarin-amide-triazole containing compounds 66 (Scheme 35). A wide variety of pharmacologically significant and structurally interesting compounds were synthesized via a one-pot, six-component, tandem Knoevenagel/Ugi/click reaction sequence from readily available starting materials, such as salicylaldehydes 39, Meldrum's acid 9, aromatic propargyloxy aldehydes 67, amines 22, isocyanides 1, and azides 68, in the presence of catalytic amounts of Cu(OAc)₂ (10 mol%) and sodium ascorbate (20 mol%) as a reducing agent for the reduction of Cu(II) to Cu(I) in ethanol at room temperature in excellent overall yields.¹⁰⁰

Scheme 35 Syntheses of trifunctional coumarin-amide-triazole containing compounds.

Substituents could be independently varied at five different positions. It is important to note that the existence of amide groups in coumarin-3-carboxamides improves the biological activity of these compounds.^101,102 The potential uses of this route in synthetic and medicinal chemistry may be significant because the products share structural and functional group properties with biologically active molecules.

6 Conclusion

The driving force of multicomponent reactions arise from the reactivity embedded in one or more of reactants. In this study, it has been shown that the rich chemistry accessible through the compound isocyanide in organic and biomolecular synthesis along with the unique chemical properties of Meldrum's acid as the two major components has led to the development of a variety of synthetically useful reactions, including MCRs. These MCRs have opened new avenues to the one-pot synthesis of numerous classes of pharmaceutically and industrially valuable heterocyclic and acyclic organic compounds, such as imino-furopyranones, coumarins, benzodiazepines, benzooxazepines, amidodiesters, functionalized triamides, succinimides, and malonamides, in a three- to six-component condensation reaction strategy starting from simple and readily available precursors. We believe that this study will be interesting for scientists from different categories of chemistry such as design and discovery of novel multicomponent reactions, combinatorial chemistry, catalysis and inorganic chemistry; in addition, it will be interesting for scientists from medicinal chemistry, syntheses of biologically active molecules, biochemistry and biology. Finally, we propose future perspectives in the development of isocyanide and Meldrum's acid-based multicomponent reactions (IM-MCRs) such as applications in computational chemistry, polymerization processes, and pharmaceutical.

Acknowledgements

We gratefully acknowledge financial support of the Iran National Elites Foundation (INEF) and the Research Council of Shahid Beheshti University.

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Footnote

† This research is dedicated to Professor Issa Yavari, who is a pioneer in the field of isocyanides chemistry in Iran.

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