In situ generation and protonation of the isocyanide/acetylene adduct: a powerful catalyst-free strategy for multicomponent synthesis of ketenimines, aza-dienes, and heterocycles

Abstract

In addition to isocyanide-based Ugi, Passerini, van Leusen, and Orru multicomponent reactions (IMCRs), a new class of isocyanide/acetylene-based multicomponent reactions (IAMCRs), through a zwitterionic adduct, have emerged as powerful and elegant methods for the synthesis of biologically interesting molecules. Coupling reaction between “in situ” generated Huisgen-type zwitterions of the isocyanide/acetylene adduct and CH-, OH- and NH-acids provide a powerful synthetic pathway to obtain ketenimines, aza-dienes, and heterocycles. This review focuses on the chemistry and applications of the isocyanide/acetylene adduct in multicomponent reaction conditions.

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Sadegh Rostamnia

Sadegh Rostamnia attended the Tarbiat Modares University (TMU), Tehran, Iran, and earned his M.Sc. and Ph.D. (honor) under the guidance of Prof. Abdolali Alizadeh. Subsequently, he was a visiting scientist at the Dalian Institute of Chemical Physics (DICP-CAS-China) in Prof. Qihua Yang's group, followed by a short time in the group of Prof. Ali Morsali at TMU. Currently, he is an associate professor at the Department of Chemistry and a director of the knowledge-based association of the Organic and Nano Group (ONG) at the Maragheh University, Maragheh, Iran. His main interests are in green chemistry and nanoporous materials as well as the use of periodic mesoporous organosilicas (PMOs), metal–organic frameworks (MOFs), magnetic nanoparticles, and ionic liquids in catalytic organic processes. He has written more than 75 review/articles on these subjects in international journals and four books/chapters.

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1 Introduction

Isocyanide-based carbon–carbon and carbon–heteroatom bond-forming reactions have been developed in fascinating ways over the past decades.¹ Nowadays, several isocyanide-based multicomponent reactions (IMCRs) have been introduced that allow the preparation of organic molecules.^1,2 After the beginning of isocyanide chemistry in 1838, Mario Passerini discovered the multicomponent reaction of isocyanides, aldehydes and carboxylic acids in 1921.^2b This reaction became what is now called the “Passerini-3CR”. Nowadays, Ugi-MCRs are the modern concept of multicomponent reactions and are also one of the most remarkable examples of MCRs intimately related to the reactions developed with isocyanide reagents.^1–3 In fact, due to the unique reactivity of isocyanides involving the formation of α-adducts with nucleophiles and electrophiles, multicomponent reactions, such as the Ugi,³ Passerini,⁴ van Leusen,⁵ and Orru,⁶ are intimately related to the reactions developed with isocyanide reagents as a part of organic synthesis.

In addition to Ugi, Passerini, van Leusen, and Orru IMCRs, a new class of isocyanide/acetylene-based multicomponent reactions (IAMCRs) has been started by Oakes⁷ and then Yavari,⁸ Nair,⁹ and others. IAMCRs are potent and sophisticated methods for organic synthesis arising from generation of the Huisgen-type zwitterionic adduct 3. Owing to the simplicity of operation, one-pot IAMCRs are preferred to other multi-step and catalytic reactions when a suitable substrate can be envisioned. The intent of this review is to provide an overview of the generation and application of Huisgen-type Oakes–Yavari–Nair (OYN) betaine 3 in organic synthesis and the review focuses on the recent achievements in the in situ generation and protonation of the isocyanide/acetylene adduct in the presence of CH-, NH- and OH-acids in multicomponent reaction conditions (Fig. 1). In particular, the novel and simple catalyst-free approaches to synthesize novel structures of ketenimines, azadienes, and heterocycles (by the reaction of C-, N- and O-nucleophiles (NuH) with a protonated OYN betaine) that are known to be crucial in organic chemistry are discussed in detail.^1–11 We mainly talk about studies done over the past 16 years, but for a more comprehensive discussion, some earlier works are also included. The reader is referred to the references for more applications of isocyanide in multicomponent reactions^1b,1c,2a,10 and the engagement of RNC/DMAD in cyclization reactions.¹¹

Fig. 1 Isocyanide/acetylene-based multicomponent reactions.

2 Background

In 1932, Diels and Alder reported that pyridine (envisioned as an N-heterocyclic diene) condensed with two equivalents of the electron-deficient acetylene in dimethyl acetylenedicarboxylate (DMAD).¹² The product was not identified until Acheson reported it in 1959.¹³ Shortly thereafter, Rolf Huisgen recognized this reaction as the 1,4-dipolar variant of the classical Diels–Alder reaction, involving the zwitterionic adduct of pyridine and acetylene.¹⁴

In fact, Huisgen laid out the classification of many 1,n-dipolar reactions (such as the 1,3-dipolar cycloaddition) and the elaboration of their mechanisms through zwitterion formation by the addition of nucleophiles to activated π systems. Since then, impressive developments have been observed in this field and the mechanism of some organic reactions, such as the Mitsunobu reaction¹⁵ and the Johnson–Tebby adducts,¹⁶ were realized in 1969 and 1962, respectively (Fig. 2).

Fig. 2 Well-known zwitterionic adducts.

Consequent to the success of the zwitterionic 1,n-dipolar reactions in organic synthesis, the concept of in situ generation of a variety of zwitterionic species leading to organic molecules appeared as an attractive topic. After the discovery of the Ugi-MCR (isocyanides as the nucleophile) in 1959, the nucleophilic properties of isocyanide in the presence of activated acetylene, was studied by Winterfeldt, wherein he tended to generate zwitterionic species.¹⁷ In 1969, he described the reaction of isocyanide 1 with acetylenes 2. The chemistry of these reactions is based upon the initial formation of a zwitterion 3 from nucleophilic addition of 1 to the acetylene compound 2. The reactions of aliphatic and aromatic isocyanides with acetylenic compounds have been investigated in detail. However, a mixture of the products have been found with no chemoselectivity during spontaneous reactions by potential zwitterionic 1,3- and 1,5-dipolar intermediates (Scheme 1).¹⁸

Scheme 1 1,3- and 1,n-dipolar intermediates from the isocyanides/acetylene adduct.

After the discovery of isocyanide and dimethyl acetylenedicarboxylate (DMAD) reaction, trapping of the corresponding zwitterion 3 by CH-, OH- and NH-acids in multicomponent reaction conditions was started as a synthetic goal. In fact, the reaction between isocyanides, electron-deficient acetylenes, and C-, O- and N-nucleophiles was first documented by Oakes in 1969. He applied dialkyl acetylenedicarboxylates (X = CO₂R) and 1,1,1,4,4,4-hexafluorobut-2-yne (X = CF₃) as acetylenic components and methanol as the NuH (Scheme 2).⁷ Such interesting and promising transformations went nearly disregarded until Yavari in 1996 extended its application to dibenzoylmethane as a NuH.⁸ Afterward, more publications were published differing mostly in the nature of the NuH used.

Scheme 2 Oakes reaction.

It is known that sometimes CH–OH- and NH-based organic acids with nucleophilic behaviour (NuH) can react with zwitterionic adducts of isocyanide 1 and acetylenes 2 in an ABC 3-CR to form ketenimines, aza-dienes, and/or heterocycles. A plausible mechanism for these ABC coupling 3-CR reaction is proposed in Scheme 3. First, zwitterion 3 generates from the reaction of acetylene and isocyanide, and then the protonation of intermediate 3 leads to the formation of ion pair 4 and 4′. Finally, 4′ attack to the active site of 4 produces the procedure A as conjugated addition or B as direct addition (α-addition). Although intermediate 3 is formed in each case, the chemistry and contribution of the NuH building block plays a key role in directing the route of the reaction.

Scheme 3 Proposed mechanism for IAMCRs synthesis of ketenimines, aza-dienes and heterocycles.

3 Isocyanide/acetylene adduct and CH-acids

3.1 Acyclic CH-acids

Yavari et al. in 1996 described the first preparation of stable ketenimines 6 and 7 starting from protonation of zwitterion 3 and CH-acid 5 under multicomponent reaction conditions.⁸ This method is easy to perform and their synthesized stable ketenimines quantitatively converted to their enol tautomer upon refluxing in benzene (Scheme 4). The formation of these ketenimines can be rationalized by the initial generation of 3 by a standard Huisgen reaction of isocyanide 1 and activated acetylene 2, followed by an acid-base protonation reaction with 5 to afford ketenimine 6 that was then isomerized to enolized ketenimine 7 under refluxing conditions in benzene.

Scheme 4 IMCR synthesis of ketenimines.

Based on the mentioned mechanism, adduct 3 undergoes smooth protonation under exposure to β-diesters 8 as the CH-acid to give 2H-pyran-2-one heterocycles 9 at room temperature in CH₂Cl₂ (Scheme 5).¹⁹ The initial event involves the protonation of the zwitterion 3 by 8. Based on the same postulated mechanism for 6, the bromine-containing ketenimine species is annulated after removal of HBr to afford 9.

Scheme 5 MCR synthesis of heterocycle 9.

A novel three-component one-pot synthesis of 1-azadienes 11 and highly functionalized ketenimine 12 was developed by Asghari et al., in which the protonation of 3 and 3-chloropentane-2,4-dione 10 leads to the final products.²⁰ In a typical procedure, equimolar amounts of all starting materials react together in CH₂Cl₂ at room temperature for 24 h. Based on multicomponent studies, 2-pyridone-3,4,5-tricarboxylate 13 and highly functionalized azadiene 14 are synthesized by alternative routes depending on the nature of CH-acid and isocyanide (Scheme 6).^21,22

Scheme 6 Synthesis of aza-dienes and pyridone.

The proposed mechanism involves the formation of zwitterion 3 and then protonation by 10, and the direct O- and C-attack generate the products 11 and 14 via α-addition, respectively. Ketenimine 12 synthesized via conjugated C-attack is not stable herein and converts to 13 over three steps, including removal of HCl from 12′, subsequent π-ring-closing by the formation of sigma-bonds, and finally, water promoted Dimroth-type rearrangement (Scheme 7).

Scheme 7 Proposed mechanism for the formation of 11, 13, and 14.

Trapping of adduct 3 by 2-acetylbutyrolactone 15 afforded the enaminone-butyrolactone skeleton 16. As a plausible explanation for the synthetic mechanism of 16, it is reasonable to assume that after generation of 3 and protonation with 15, the direct C-attack procedure followed by the moisture accelerated AcOH removal gives 17 and 16 (Scheme 8).²³

Scheme 8 MCR synthesis of enaminone 16.

Fluorinated CH-acids are used by Baharfar's²⁴ and Asghari's²⁵ groups in one-pot three-component method for protonation of 2-amino-5-trifluoroacetyl-4H-pyran-3,4-dicarboxylate 19. Fluorinated β-diketones 18 with aliphatic or aromatic groups produce chemoselective products, as indicated in Scheme 9.

Scheme 9 Synthetic pathway for the synthesis of 19.

Similarly, zwitterionic protonation of adduct 3 by CH-acids, when alkyl 2-nitroethanoates 20 are used in one-pot reactions as the third component, pentaalkyl 7-[(alkylamino)carbonyl]-2-oxa-1-azabicyclo[3.2.0]hept-3-ene-3,4,5,6,7-pentacarboxylate 21 forms via an unusual 1 : 2 : 1 (isocyanide : acetylene : CH-acid) diastereoselective procedure (Scheme 10).²⁶ The synthetic process along with the 3D structure of 21 have been well demonstrated by Yavari and Moradi.

Scheme 10 IAMCRs synthesis of 2-oxa-1-azabicyclo[3.2.0]hept-3-ene 21.

Shaabani et al., developed a diastereoselective method for the construction of the glutarimide skeleton of N-alkyl-2-triphenylphosphoranylidene 24 using CH-acid 23. Ethoxycarbonylmethyl triphenylphosphonium bromide 23 protonates 3 under one-pot three-component reaction conditions and the reaction undergoes a smooth 1 : 1 : 1 addition of substrates in dichloromethane at room temperature. To raise the applicability of this method, the authors extended the procedure to various dialkyl acetylenedicarboxylates 2 in the presence of cyclohexyl or tert-butyl isocyanide with ¹H and ¹³C NMR studies of the crude reactions. They found only 4-trans diastereoisomer produced from dimethyl- and diethyl acetylenedicarboxylate. However, when di-tert-butyl acetylenedicarboxylates were used, 4-cis and 4-trans diastereoisomers with 37% and 63% yields were obtained, respectively (Scheme 11).²⁷

Scheme 11 Heterocyclic phosphoranylidene glutarimides skeleton 24.

A possible mechanism for the synthesis of glutarimides 24 is proposed in Scheme 12. It is reasonable to assume that protonation of the 1 : 1 zwitterionic intermediate 3 by ethoxycarbonylmethyl triphenylphosphonium bromide 23 as the CH-acid is followed by quenching of the cationic centre caused by the conjugate base of the CH-acid to generate ketenimine. Addition of Br⁻ to the ethyl group of ester may lead to expulsion of the Et-group as EtBr. Then, the residue of molecule isomerizes via a Dimroth-type rearrangement to produce 24.

Scheme 12 Proposed mechanism for synthesis of 24.

Presently, there are a few synthetic methods available for the synthesis of the 7-membered oxadiazepine heterocycles backbone. However, Ramazani et al., used (N-isocyanimino)triphenylphosphorane 25 as a novel and interesting isocyanide in the presence of DMAD and CH-acid 5 for the synthesis of 7-membered 1,3,4-oxadiazepin 26. The one-pot three-component reaction of 5 and 2 with isocyanide 25 in ambient conditions afforded diethyl-(Z)-2-(5,7-diphenyl-1,3,4-oxadiazepin-2-yl)-2-butenedioate 26 via a chemo- and stereoselective aza-Wittig annulation (Scheme 13).²⁸ It is rational to assume that compound 26 could be the result of protonation of the zwitterion adduct 3 by 5. Subsequent attack of the enolate anion on the positively charged ion pair forms iminophosphorane 27, which undergoes an intramolecular aza-Wittig reaction under the conditions employed, to produce 26 as a non-planar 7-membered oxadiazepin skeleton heterocycle.

Scheme 13 Isocyanide 25 for synthesis of oxadiazepin 26.

3.2 Acyclic polycarbonyl CH-acids

Polycarbonyl compounds have interesting chemistry and generate valuable reagents in organic transformations.²⁹ The 1 : 1 zwitterionic intermediate 3 can react with polycarbonyl compounds in three-component reaction conditions to give novel pyran or tetrahydropyranopyrrole annulated heterocyclic systems.

The three-component reaction of tricarbonyl compound 28, isocyanides and activated acetylenes has been reported by Yavari and Nourmohammadian. The products of the reaction are ketenimines 29 (Scheme 14).³⁰

Scheme 14 Three-component synthesis of 29.

Pyrano[4,3-b]pyrrole heterocycles 31 can be prepared by generation and protonation of intermediate 3 with tricarbonyl compound 30. In this method, the efficient synthesis of 1,2,3,6-tetrahydropyrano[4,3-b]pyrrole derivatives 31 was achieved via a one-pot multicomponent reaction of isocyanide 1, acetylene 2, and tricarbonyl compound 30 in CH₂Cl₂ at room temperature.³¹ As shown in Scheme 15, the first step might involve C-attack at the α-carbon of the isocyanide to generate 32 as a tautomer of enaminone 33. Cyclization of 33 by removal of MeOH followed by π-ring-closing sigma-bond cyclization gives corresponding pyranopyrrole 31.

Scheme 15 Fused heterocycle of pyranopyrrole 31.

Nasiri et al., used dimethyl 1,3-acetonedicarboxylate 34 as the polycarbonyl CH-acid for protonation of in situ generated 3. The three-component reaction of 1 and 2 in the presence of 34 in ambient conditions afforded enaminone 35 and 2-amino-4H-pyrans 36.³² A possible explanation is proposed in Scheme 16. It is reasonable to assume that 35 and 36 are produced by an initial protonation of 3. Then, the positively charged ion 4 might be attacked from two positions by the enolate anion of the CH-acid; direct C-attack produces azadiene, which isomerizes to corresponding enaminone 35. Conjugate addition leads to the intermediate ketenimine. Such an addition product may be isomerized under the reaction conditions to produce aminopyran 36.

Scheme 16 IAMCRs synthesis of 35 and 36.

3.3 Cyclic CH-acids

Yavari and Maghsoodlou in 1998 used cyclic CH-acids for the protonation of 3. The reaction of 1 and 2 in the presence of N,N′-dimethylbarbituric acid 37 afforded the isomeric products of dimethyl 7-(2,6-dimethylphenylamino)-1,3-dimethyl-2,4-dioxo-4H-pyrano[3,2-d]pyrimidine-5,6-dicarboxylate 38 and dimethyl (E)-2-((2,6-dimethylphenylamino)-(1,3-dimethyl-2,4,6-trioxopyrimidine-5-ylidene)-methyl)-but-2-enedioate 39 (Scheme 17).³³

Scheme 17 One-pot synthesis of 38 and 39.

As shown in Fig. 3, trapping of 3 by cyclic CH-acids leads to highly functionalized fused 4H-pyrans heterocycles (mechanism illustrated in Scheme 9). Trapping of zwitterion 3, under three-component reaction conditions, with various cyclic CH-acids have been reported for the synthesis of 5-oxo-4,5-dihydroindeno[1,2-b]pyrans 40,³⁴ dialkyl 7-methyl-2-(alkylamino)-5-oxo-4H,5H-pyrano-[4,3-b]pyran-3,4-dicarboxylates 41,³⁵ 4H-benzo[g]chromene-3,4-dicarboxylates 42,³⁵ 4H-furo[3,4-b]pyrans 43,³⁷ dimethyl 2-alkylamino-5-oxo-4,5,6,7-tetrahydrocyclopenta[b]pyran-3,4-dicarboxylates 44,³⁸ pyrano[2,3-c]pyrazoles 45,³⁹ 4H-pyrano[3,2-d]isoxazoles 46,⁴⁰ dialkyl 10-(alkylamino)-7-oxo-7H,8H-naphtho[1,8-gh]chromene-8,9-dicarboxylates 47,⁴¹ pyrano-pyrido-quinoxalines 48, and benzo[a]pyrano[2,3-c]phenazines 49.^42,43 For competition of NH- and OH-acid protonation of 3-amido 2-naphthol, in an interesting work by Hassanabadi et al., it was found that 50 is the final product.⁴⁴

Fig. 3 Products obtained from the cyclic CH-acids.

It is reported that adduct 3 reacts with 5-methyl-Meldrum's acid 51 to afford highly functionalized ketenimines of dialkyl 2-(alkylimino-methylene)-3-(2,2,5-trimethyl-4,6-dioxo-1,3-dioxan-5-yl)-succinates 52 in good yields (Scheme 18).⁴⁵

Scheme 18 Synthesis of ketenimine 52.

Tetrahydrocyclopenta[b]pyran derivatives 54 were synthesized by 3-methylcyclopentane-1,2,4-trione 53 CH-acid in the presence of in situ generated 3 via a chemo- and diastereoselective IAMCRs method over 12 hour at room temperature (Scheme 19). The authors did not report 55 as either a main product or a side product.⁴⁶

Scheme 19 Tetrahydrocyclopenta[b]pyrans 54.

Nair et al.⁴⁷ and then Teimouri et al.³⁵ used 4-hydroxycoumarin 56 as a CH-acid to yield pyrano[4,3-b]pyran 57 as a pyrano-coumarin heterocycle skeleton (Scheme 20). Prajapati et al. also synthesized pyranocoumarin 57 by a green method in water.⁴⁸ Shaabani also reported a novel pseudo-five-component reaction and efficient approach for the synthesis of highly functionalized bis-chromene 59 based on the reactivity of 3 with 2,5-dihydroxy-para-benzoquinone 58 (Scheme 20).³⁶

Scheme 20 IAMCRs synthesis of chromene 57 and bis-chromene 59.

Protonation of reactive intermediate 3 in a reaction between alkyl(aryl) isocyanides and dialkyl acetylenedicarboxylates 2 in the presence of indan-1,3-dione 60 as a cyclic CH-acid leads to 5-oxo-4,5-dihydroindeno[1,2-b]pyrans 40 and methyl 2-[(aryl)imino]-3-(2-methoxy-2-oxoethyl)-4-oxo-3,4-dihydro-2H-indeno[1,2-b]furan-3-carboxylates 61 (Scheme 21).³⁴

Scheme 21 Protonation of 3 by indan-1,3-dione.

In situ generation of the zwitterionic adduct from the unsymmetric, electron deficient, acetylene of ethynylphenylketone 62 and isocyanides 1 followed by protonation with N,N′-dimethylbarbituric acid 37 yields 1,3-dimethyl-2,4-dioxo-7-phenyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-5-carboxamide 63.⁴⁹ Under the same conditions, Maghsoodlou et al., reported a cross-conjugated push–pull enaminone system 64 (Scheme 22).⁵⁰

Scheme 22 Isocyanide/propiolate adduct for synthesis of 63 and 64.

A plausible mechanism for the synthesis 63 can be started by initial formation of the zwitterionic intermediate 65, produced from isocyanide 1 and acetylenic ester 62. Protonation of 62 by 37 produces intermediate 66 via annulation and ring-closing steps, and finally 66 is converted to 63 by a proton transfer (Scheme 23).

Scheme 23 Proposed mechanism for the synthesis of 64.

4 Isocyanide/acetylene adduct and OH-acids

4.1 Aromatic OH-acids

Phenol and its derivatives as aromatic OH-acids are other alternatives for the synthesis of stable ketenimines and heterocycles based on the IAMCRs method. Protonation of the reactive intermediates produced in the reaction between isocyanide 1 and acetylene 2 or dibenzoylacetylene (DBA) 67 and α-naphthol 68 leads to highly functionalized fused-benzochromenes 69 (Scheme 24). The chemical structure of 69 was distinct from 70, 71 and 72 by ¹³C NMR chemical shift of the methine group.⁵¹

Scheme 24 IAMCRs synthesis of 69.

It is conceivable that the initial ionic pair 73 results from the proton transfer of 1-naphthol 68 to intermediate 3. Then, 73 is attacked by the enolate anion of naphthol (C-attack) to produce the active ketenimine 74. Such an addition product may tautomerize and cyclize under the reaction conditions employed to produce 69 (Scheme 25).

Scheme 25 Proposed mechanism for the synthesis of 69.

The authors using in situ protonation of 3 with aromatic phenolic substrates, such as 2-naphthol, 2,7-dihydroxynaphthalene, 2,3-dihydroxynaphthalene, and 4-methyl-8-hydroxycoumarin or phenols, synthesized compounds 75, 76, 77, 78, and 79, respectively (Fig. 4).

Fig. 4 Examples of IAMCR-based fused-benzochromenes.

The reaction of alkyl isocyanides 1 and dibenzoylacetylene 67 in the presence of resorcinol 80 effectively produced 1H-furo[3,4-b]chromene-1,6-diol 81. It can be noted that the reaction proceeds by a one-pot 3-CR condition (Scheme 26). A rational mechanism can be speculated to this reaction in which the zwitterion 3, from isocyanide 1 and dibenzoylacetylene 67, is protonated by resorcinol to furnish ketenimine and then the aminochromene intermediate 82. H-Migration occurs later and thus, the final product 81 is produced.⁵²

Scheme 26 IAMCR-based synthesis 81.

Baharfar et al. investigated the reactivity of 1 and 2 with 2,4-dihydroxyacetophenones 83.⁵³ The addition of 83 to 2 under neutral conditions in the presence of isocyanide 1 leads to 2-amino-4H-chromene derivatives 84 and 85 in high yields. The authors did not report the 1,3-dipolar cyclization of 3 with 83, in which the protonation of 3 is the director of the reaction progress in comparison with a cyclization factor to produce Nair's product⁹ 86 (Scheme 27).

Scheme 27 Synthesis of amino-chromenes 84 and 85.

In situ generated intermediate 3 can undergo smooth protonation at room temperature with salicylaldehyde 87 in IAMCRs conditions. In this reaction, an aromatic OH-acid is used to give coumarin (2H-chromen-2-one) 88 with an interesting heterocycle structure. The proposed mechanism is shown in Scheme 28. Similar to 83, aminofuran 89 as Nair's product was not reported.⁵⁴

Scheme 28 IAMCRs strategy for the synthesis of 2H-chromen-2-one 88.

Synthesis of 4H-chromene 94 and 95 and ketenimines 96 can be produced through one-pot three-component reactions under mild conditions by a reaction between alkyl isocyanide 1 and acetylenedicarboxylate 2 in the presence of 6-hydroxyquinoline 90 and 8-hydroxyquinoline 91. For the reaction of isocyanides 1, acetylenes 2, and 1-hydroxy isoquinoline 93 (or 2-hydroxy pyridine as an NH acid), 1-azadienes 98 are the final products. However, in the case of 2-hydroxyquinoline 92, ketenimine 97 is the final product (Scheme 29).^54–57

Scheme 29 IAMCRs synthesis of heterocyclic compounds 94–98.

Azizian and Ramazani et al. reported a fused pyrano-tropolone heterocycle based on the IAMCRs method (Scheme 30). Dialkyl 2-(alkylamino)-4,9-dihydro-9-oxocyclohepta[b]pyran-3,4-dicarboxylates 100 were prepared in a one-pot three-component reaction of alkyl isocyanide 1, dialkyl acetylenedicarboxylate 2, and α-tropolone (2-hydroxycyclohepta-2,4,6-trienone) 99. The reaction proceeds smoothly at room temperature and under neutral conditions to afford pyrano-tropolone heterocycles in high yield.⁵⁸ Again, the corresponding cyclization (Nair's product) was not reported.

Scheme 30 Pyrano-tropolone 100.

4.2 Carboxylic (sulfonic) acids and oximes

In traditional Passerini or Ugi multicomponent reactions, isocyanides react with aldehyde or imine and carboxylic acids. In contrast, it was of interest to investigate the reactivity of the isocyanide/acetylene zwitterion towards carboxylic acids 101, in comparison with aldehydes or imines of Passerini or Ugi reactions.¹ With this in mind, in 2006 we designed a new class of isocyanide-based Oakes–Yavari–Nair multicomponent reaction, in which activated acetylene was used instead of the carbonyl component of Ugi and Passerini 3-CRs. When we reacted isocyanides and activated acetyls in the presence of aromatic carboxylic acids, the final product was unsaturated linear imides 103, while the amido-aminofuran 104 synthesized aliphatic and heterocyclic aromatic carboxylic acids (Fig. 5).^59,60

Fig. 5 Component comparison of the Passerini and Ugi reactions with the designed reaction of Alizadeh and Rostamnia.

E-Diastereomers of unsaturated linear imide 103 were produced with 61–98% yields via protonation of 3 with aromatic carboxylic acids at room temperature. At that time, these results encouraged us to investigate the generality of our method. To our surprise, when we used aliphatic carboxylic acids, the product was amido aminofurans 104 that was coupled through a serendipitous pseudo four-component procedure.

The mechanism can be proposed as follows. First, protonation of the 1 : 1 zwitterion adduct of 3 with the carboxylic acid occurs. Then, 103 can be formed by a Mumm rearrangement [1,3(O–N) acyl transfer] of imidoylcarboxylate 105. For aromatic acids, 103 is the final product, which is isolatable from the reaction mixture. However, for aliphatic and heteroaromatic acids, amido aminofuran 104 is formed by attachment of 103 into the second equivalent of isocyanide containing [4 + 1] and then aromatization of the product through a H-shift process (Scheme 31).

Scheme 31 Proposed mechanism for the synthesis of 103 and 104.

In the following year, reactivity of the zwitterion intermediate 3 was investigated in the presence of hetero-aromatic nicotinic and isonicotinic acids. The final products were aminofurano-nicotinamide and isonicotinamide molecules.⁶¹ The reaction was then explored with biochemically interesting bicinchoninic acid (BCA) and the bis(aminofuryl)bicinchoninic amide product was yielded in 37–52%.⁶² In 2009, Huang et al., discovered a new chemistry for this reaction, both in regio- and stereo-selectivity during the synthesis of (Z)- or (E)-N-acryl butenedioic monoimides.⁶³ Bayat and co-workers could also synthesize both 103 and 104 products from the reaction of 1 and 2 with anhydrides.⁶⁴

A simple synthesis of uracil based aminofurans 106 via an IAMCR method was reported by Baharfar and Baghbanian.⁶⁵ The reaction was achieved with fairly good yields (Scheme 32).

Scheme 32 IAMCR synthesis of uracil-based aminofurans 106.

The synthesis of 2-(alkylamino)-5-{alkyl[(2-oxo-2H-chromen-3-yl)carbonyl]amino}-3,4-furandicarboxylates 108, which was simply accomplished via a IAMCR strategy, was reported by Adib et al. The in situ generated adduct of isocyanides/acetylenedicarboxylates was efficiently reacted with coumarin-3-carboxylic acids 107, at room temperature (Scheme 33).⁶⁶

Scheme 33 Simple synthesis of chromen-aminofurans 108.

For the first time in 2007, following our previous experience in using trivalent phosphines such as triphenylphosphine as a special nucleophile in reactivity of activated acetylenes,⁶⁷ we began a comparative study on nucleophilicity of isocyanides and phosphines (see Fig. 6).^68,69 Our research led to the introduction a novel bi-nucleophilic system in IAMCRs.

Fig. 6 Examples of binucleophilic multicomponent reactions.¹⁰

We investigated the reaction of acetylene 2 and carboxylic acid 101 in a binucleophilic system with triphenylphosphine and alkyl isocyanide, which led to highly functionalized aminofuran 109 (Scheme 34). The reaction was also found to be effective with other trivalent organophosphorus compound such as trialkyl phosphites and triaryl phosphites. Formerly, Nair and co-workers had reported 109 by the cycloaddition reaction of 3 in the presence of aldehydes.^9,11

Scheme 34 IAMCRs synthesis of aminofurans 109.

A possible mechanism can be proposed as follows. First, the formation of zwitterion adducts occurs from the addition of triphenyl phosphine to acetylene 2. The product is protonated by 101 and is then attacked by carboxylate to produce Ph₃PO. The obtained intermediate 110 loses Ph₃PO through a Wittig-type reaction and finally, 109 forms by reaction of the isocyanide through a [4 + 1] reaction followed by an aromatization induced H-shift (Scheme 35).

Scheme 35 Proposed mechanism for the synthesis of 109.

In another binucleophilic system, related to the chemical importance of fluorinated compounds, we designed a similar reaction (see Scheme 34) for the synthesis of the corresponding fluorinated aminofurans 111, using trifluoroacetic acid (TFA) as the carboxylic acid.⁷⁰ The reaction of phosphine/isocyanide binucleophilic system and activated acetylene in the presence of TFA did not afford the desired fluorinated aminofurans 111. Surprisingly, the product λ⁵-phosphanylidene bis(dioxotetrahydro-1H-pyrrole-3-carboxylates) 112 was produced via a pseudo-seven-component (7-CR) procedure. We found that the influence of atmospheric moisture was responsible for the observed modification, and hence, the aforementioned reaction in the presence of H₂O also furnished the main product 112 (Scheme 36).

Scheme 36 7-CR synthesis of λ⁵-phosphanylidene bis-pyrrolidine 112.

When the structure was clearly demonstrated by X-ray, we were able to perform the reaction based on formation of 112. We found that stoichiometric amounts of TFA were needed; moreover, [(1R,2S,3R) or (1S,2R,3S)] stereoisomers of λ⁵-phosphanylidene bis-pyrrolidine are the main products, which shows diastereoselectivity for three chiralgenic centres (Fig. 7). We note that the ylide functional group of 112 is stable in moisture and room temperature for several months.

Fig. 7 Main stereoisomers and single crystal X-ray structure of 112 (reproduced with permission from Elsevier).

The addition of triphenylphosphine (TPP) to acetylenedicarboxylates 2 followed by protonation with TFA yields 1,5-dipole 113. 1 : 2 zwitterionic adduct 113 is protonated by TFA and then by reacting with 1 and water, 112 is produced. In this reaction, stoichiometric amounts of TFA are needed. Otherwise, when the reaction was performed using less than the stoichiometric quantity of TFA, fumarate and maleate were observed as the by-products (Scheme 37).

Scheme 37 Proposed mechanism for the synthesis of 112.

After these successful discoveries in new IAMCRs by carboxylic acids, the next question to ask was, “what is the situation with sulfonic acids in IAMCRs?” Synthesis of sulfonamide 115 was recorded when we reacted isocyanide and activated acetyls with the monohydrate of p-toluenesulfonic acid (PTSA) 114 as an aromatic sulfonic acid. The mechanism can be proposed as follows. First, protonation of the 1 : 1 zwitterion adduct of 3 with the sulfonic acid occurs. Then, sulfonamide 115 can be formed by a Mumm-type rearrangement. By changing PTSA to camphorsulfonic acid, product 116 was produced without incorporation of acetylene (Scheme 38).⁷¹

Scheme 38 Sulfonic acid mediated IAMCRs for sulfonamide 115.

2-[(Alkylimino)methylene]-3-{(E)-[(1-phenylalkylidene)amino]oxy}succinates as thermally stable ketenimines 118 were synthesized by the reaction of alkyl isocyanides 1 and acetylenedicarboxylates 2 in the presence of aryl oximes 117. The reaction underwent a smooth 1 : 1 : 1 conjugated addition (O-attack) of substrates in dichloromethane under ambient conditions (Scheme 39).⁷²

Scheme 39 IAMCRs synthesis of stable ketenimine 118.

The addition of pyridine-2-carboxaldoxime or α-furyldioxime to dialkyl acetylenedicarboxylates under neutral conditions in the presence of isocyanides leads to ketenimines 119 and bis-ketenimines 120 in good yields (Fig. 8).⁷³

Fig. 8 IAMCR synthesis of ketenimines 119 and 120.

5 Isocyanide/acetylene adduct and NH-acids

Similar to CH- and OH-acids, it has been known that NH-acids can react with zwitterion 3 to form azadienes and ketenimines. The reaction between 1 and acetylenic esters 2 in the presence of different NH-acids affords azadienes and ketenimines. Carbazole or indole affords the isomeric 1-azadienes 121 based on direct N-attack and yields highly functionalized ketenimines 122, which is the result of conjugated addition of N-nucleophiles (Scheme 40). Using pyrrole or 2-aminobenzothiazole, direct addition of the nucleophile occurs, leading to the formation of 1-azadiene derivative 121 as the sole product.^74,75

Scheme 40 IAMCRs of NH-acids.

As shown in Fig. 9, reaction of NH-acids affords interesting ketenimines (123,⁷⁶ 124,⁷⁷ 125,⁷⁸ 126,⁷⁹ 127,⁸⁰ 128,⁸¹ 129 and 130,⁸² 131,⁸³ 132,⁸⁴ and 133 (ref. 74)), including sulfonamide, hydantoins, α-chlorocarbonyl, and active carbonyl skeletons. All reactions are reported to be carried out under ambient conditions without using any acids, bases, or other additives. For some of these NH-starting materials, the authors applied a multi-step procedure.⁷⁹

Fig. 9 Products obtained from the IAMCRs of NH-acids.

In continuation of isocyanide/acetylene-based MCRs, pseudo four-component reactions of isocyanides and acetylenes were explored in the presence of cyclic NH-acids such as succinimide or maleimide 134. Depending on isocyanide hindrance, the reaction could proceed through two different pathways. For the unhindered isocyanides, such as cyclohexyl isocyanide and 2,6-dimethylphenyl isocyanide, formation of reactive intermediate 3 followed by further reactions with isocyanide to form the bis-ketenimine intermediate 135 is predictable. The subsequent reaction of 135 with compound 134 and cyclization under the reaction conditions produces 136 (pathway A). However, the reaction with tert-butyl isocyanide (pathway B), as a hindered isocyanide, produces ketenimine 137 by the conjugated base of the NH-acid (Scheme 41).⁸⁵

Scheme 41 IAMCR synthesis of 137 and 136.

In the reaction of dibenzoylacetylene (DBA) with isocyanides 1 in presence of the phthalimide 138, the corresponding aminofurans 139 are produced. Product 140 is then yielded via the crystallization process. The reaction with various NH-acids provides excellent yields. The products showed atropisomerism (141–143) at room temperature due to restrictions in rotation around the new Ar–N bond (Scheme 42).^86,87

Scheme 42 Isocyanide/DBA protonation.

There are several reactions in which ketenimines are assumed to be the main products and do not undergo further cyclization or addition. However, there are also some examples (e.g. 144) in which a reaction would occur between dialkyl acetylenedicarboxylates and isocyanide with NH-acids. The mechanism of this reaction is consistent with the abovementioned reactions (Scheme 43).⁸⁸

Scheme 43 IAMCRs diastereoselective synthesis of pyrimidine 144.

In a similar manner, 5H-imidazo[2,1-b]1,3oxazine 146 derivatives were synthesized by an IAMCR method involving the reaction of isocyanides, dialkyl acetylenedicarboxylates, and 4,5-diphenyl-1,3-dihydro-2H-imidazol-2-one 145. Isomerization of the ketenimine intermediate led to the production of fused heterocyclic system 146 (Scheme 44).⁸⁹

Scheme 44 Synthesis of the fused system of imidazo-oxazine 146.

Baharfar et al. reported the synthesis of pyrimido[2,1-b]1,3oxazine 148 and pyrimido[2,1-b]1,3thiazine 149 and 150 by the reaction of isocyanides with dialkyl acetylenedicarboxylates in the presence of uracils (or thiouracils) 147 (Scheme 45).^90,91

Scheme 45 Synthesis of the fused system of pyrimido-oxazine 148, pyrimido-thiazine 149 and 150.

Anary-Abbasinejad et al., reported a novel isocyanide-based four-component cascade reaction of benzoyl hydrazine (BHZ), acetylene 2, and isocyanide 1, which lead to highly functionalized 1H-pyrazoles 151 in excellent yields.⁹² Highly functionalized 2-dihydropyridine derives 152 are a result of the 1 : 1 : 1 addition reaction of isocyanide and dialkyl acetylenedicarboxylates in the presence of in situ generated enaminone (Scheme 46).⁹³

Scheme 46 Tandem synthesis of pyrazoles 151 and dihydropyridine 152.

Adib et al. reported the synthesis of pyrazole-pyrazoles l53,⁹⁴ pyrazolo-triazoles 154,⁹⁵ highly functionalized pyrazoles 155,⁹⁶ and dialkyl 5-(alkylamino)-1-aryl-1H-pyrazole-3,4-dicarboxylates 156 ⁹⁷ based on in situ generation of the 1 : 1 zwitterion 3 and its subsequent protonation by the substituted hydrazines. These reactions proceeded in acetone at room temperature (Scheme 47).

Scheme 47 IAMCR synthesis of pyrazoles 153, 154, 155, and 156.

Pyrazolo[1,2-b]phthalazines 157 were synthesized by Teimouri in 2006.⁹⁸ In an independent work by Shaabani et al., the synthesis of pyrazolo-phthalazine and pyrazolo-pyridazine were done by in situ synthesis of NH-acids. This protocol has been developed for the synthesis of structurally diverse 1H-pyrazolo[1,2-b]phthalazine-1,2-dicarboxylates and 1H-pyrazolo[1,2-a]pyridazine-1,2-dicarboxylates via a four-component reaction of hydrazine hydrate, acetylene 2, isocyanides, and various cyclic anhydrides such as succinic anhydride, maleic anhydride, and phthalic anhydride in good to moderate yields (Scheme 48).⁹⁹

Scheme 48 IAMCR synthesis of pyrazolo-phthalazine 157.

The reaction of acetylenic esters and isocyanides in the presence of N-(2-pyridyl)amides 158 and N-(1,3-thiazol-2-yl)amides 159 proceeded spontaneously in dry DCM at ambient temperature. The authors utilized these NH-acids for the protonation of the in situ generated zwitterion 3. However, ketenimine was not the main product. It could also undergo further intramolecular cyclization to form the bicyclic 4H-pyrido[1,2-a]pyrimidines 160 and thiazolo[3,2-a]pyrimidines 161 (Scheme 49).^100–102

Scheme 49 IAMCRs synthesis of 160 and 161.

In this process, formation of the corresponding ketenimines is followed by an intramolecular cyclization to produce bicyclic zwitterion 162. The last product undergoes facile intramolecular nucleophilic addition of nitrogen to the neighboring carbonyl group, which obtains the tricyclic compound 163. Finally, the ring opening process yields the fused heterocyclic system 160 or 161 (Scheme 50).

Scheme 50 Proposed mechanism for the synthesis of 160 and 161.

6 Summary

We tried to summarize in this review the major developments for the in situ generation of the isocyanide/acetylene zwitterionic adduct and its protonation by CH-, OH- and NH-acids for the syntheses of ketenimines, aza-dienes, and heterocycles, in which the resulting protonated OYN zwitterions will react further with a variety of C-, O- and N-nucleophiles under IAMCRs conditions.

In general, these reactions start with commercially available compounds and are used in multicomponent reaction strategies without any catalysts and additives. The basis for most of today's known methodologies was laid by I. Yavari already in the mid-1990s and then V. Nair in their work on one-pot protonation of various trivalent phosphine-based zwitterions and other reactive intermediates. This review gives a comprehensive survey regarding the isocyanide/acetylene-based multicomponent (IAMCRs) synthesis of extremely useful organic backbones.

Although developments of more general and efficient protocols are highly warranted, the progress achieved so far in this area holds promise for extensive applications for the isocyanide/acetylene adduct towards one-pot multicomponent syntheses.

Acknowledgements

Dedicated to Professors A. Alizadeh, I. Yavari, A. Heydari and M. Z. Kassaee from the Tarbiat Modares University (TMU) for their great contributions in the area of organic chemistry of Iran. The author thanks the helpful discussion and suggestions of Professor Issa Yavari from the Tarbiat Modares University, Dr Mohammad Sharifian Gh. (Temple University), Dr Farhad Mazlum, Esmail Doustkhah, and Nasrin Nouruzi (Maragheh University) for editing this paper.

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