Recent advances in the synthesis of pyrroles via multicomponent reactions using arylglyoxals

Pyrrole is widely known as an active pharmacophore. This core framework plays an important role in several natural and biological products. Due to its properties, developing such scaffolds has attracted much attention. The accessibility of these role-playing heterocyclic motifs via easy, high efficiency and developed methodologies is of interest and value in the creation of new heterocyclic compounds. This review highlights the broad range of applications of arylglyoxals in the synthesis of pyrrole derivatives via multicomponent reactions over the period 2010-2019


Multicomponent and domino reactions
The design and synthesis of hetero-aromatic compounds via a simple, efficient and economical method, with the potential to form several bonds in a single operation, are important factors of a valuable and useful synthetic method.The last few years have seen an enormous increase in the number of applications of multicomponent reactions (MCRs) being reported.MCRs are a convenient route to architecturally complex heterocyclic compounds, [56][57][58][59][60][61][62] and they are powerful synthetic tools for the synthesis of a wide variety of biologically active heterocyclic compounds, providing simple and rapid access to complex structures in a single synthetic operation.
Organic chemists are interested in multicomponent reactions involving domino processes in the synthesis of many organic molecules.4][65][66] These methods have afforded the easy and convenient isolation of products in short reaction times, usually with high atom-economy, high selectivity, and often by environmentally friendly chemical processes without requiring elaborate purification by solvent and chromatographic methods, both in academic laboratories and industrial processes.[69] 1.3 Arylglyoxals: their availability and utility Arylglyoxals are very valuable synthons in the field of heteroaromatic chemistry, owing to these molecules having two active functional groups, aldehyde and ketone, with different reactivities.Therefore, for C-C and C-N bond formation via [3+2] cyclization, they provide two electrophilically active sites (C-O and C=O bonds) as 1,2-acceptors, which can be attacked by the electron-rich β-C atom and the nucleophilic NH group in βenaminones.Various methods have been reported for the synthesis of arylglyoxals in the literature.The most common method is oxidation of aryl methyl ketones by SeO 2 .The various synthetic methods along with reaction conditions are summarized in Table 1. 70,71

Application of active methylene containing compounds in pyrrole synthesis
There are many synthetic methods for the synthesis of pyrrole derivatives and in most of them compounds such as α-diazoketones, α-dicarbonyls, α-hydroxyketones, nitroalkanes, nitroalkenes, isocyanides, 1,4dicarbonyls, and alkynes are used as adaptable precursors.An overview of the syntheses of pyrrole structures by typical cycloaddition methods and using wide range of methylene active compounds is provided in Figures 2 and 3, respectively. 72,73

Synthesis of monocyclic pyrroles
The addition reaction of phosphines to electron-deficient carbon-carbon triple bonds is well known to produce a reactive zwitterionic intermediate, which can be trapped by various electrophiles.The reactions of adducts of dialkyl acetylenedicarboxylates with triphenylphosphine in the presence of a variety of organic acidic compounds, have been shown to trap the zwitterionic intermediates, to provide the synthesis of a series of carbocyclic and heterocyclic compounds through an efficient one-pot route.A four-component reaction leading to the substituted pyrroles 5 has been reported by Anaraki-Ardakani et al. with triphenylphosphine 1, a 2-aminopyridine 2, and dialkyl acetylenedicarboxylate 3 in the presence of arylglyoxals 4 at room temperature in dichloromethane, with good yields (Scheme 1). 74 Scheme 1. One-pot synthesis of substituted pyrroles by Anaraki-Ardakani et al. 74 In a recent environmentally benign and efficient contribution to these reactions, an iodine-promoted MCR protocol was described by Musawwer Khan and co-workers for the synthesis of two kinds of pyrrole.In a facile one-pot four-component reaction between dialkyl acetylenedicarboxylate 3, aromatic amines 8 and arylglyoxals 4 catalyzed by 10 mol% of iodine in ethanol at room temperature, the 4-arylaminopyrrole-2,3dicarboxylate esters 9 were formed.Under the same reaction conditions, a three-component reaction between (E)-N-methyl-1-(methylthio)-2-nitroethenamine (NMSM, 7), aromatic amines 8 and arylglyoxals 4 provided the novel dihydro-1H-pyrrole derivatives 6 (Scheme 2). 75heme 2. One-pot syntheses of substituted pyrroles developed by Musawwer Khan et al. 75 Wang's group studied the four-component reaction between 1,3-dicarbonyl compounds 10, arylglyoxals 4, a dialkyl acetylenedicarboxylate 3 and aromatic amines 8 in ethanol as solvent under reflux and catalyst-free conditions; the reaction proceeded especially well, affording the expected products 11 in high yields (Scheme 3).76 Mehrabi and coworkers reported similar reactions but under rather milder conditions.To explore the scope of this transformation a series of pyrrole derivatives 11 was prepared in a one-pot four-component reaction; a mixture of various aromatic amines 8 with arylglyoxals 4, dialkyl acetylenedicarboxylate 3 and Meldrum's acid or dimedone 10 was stirred in ethanol at room temperature (Scheme 4).Again, excellent yields were reported. 77heme 4. Four-component synthesis of polysubstituted pyrroles described by Mehrabi et al. 77 A very efficient synthesis of the polysubstituted pyrroles 12 and 15, was reported by Shi and coworkers.A 1:1:1:1 mixture of arylglyoxals 4, anilines 8, dialkyl acetylenedicarboxylates 3 or alkyl acetoacetates 13, and malononitrile 14 in the presence of the phase-transfer catalyst TEBAC in ethanol as solvent at reflux temperature, was found to lead to pyrroles (Scheme 5).78 Scheme 5. Synthesis of pyrroles developed by Shi and co-workers.78 For the synthesis of polysubstituted pyrroles 17, Dhinakaran and coworkers have developed an efficient domino protocol from the one-pot, three-component domino reactions of arylglyoxals 4, malononitrile 14 and ethyl (E)-3-(4-arylamino)acrylates 16 under solvent-and catalyst-free conditions simply by grinding (Scheme 6).79 Scheme 6. Three-component synthesis of multifunctionalized pyrroles.79 The polysubstituted pyrroles 21 have been synthesized via a coupling reaction involving acetophenone 18, N,N-dimethylformamide dimethylacetal 19, substituted amines 8, arylglyoxals 4 and malononitrile 14 in methanol under reflux, leading to the novel pyrrole cyanoacetamides 21 in good yields (Scheme 7).80 Scheme 7. Synthesis of substituted pyrroles developed by Ambethkar.80 Eftekhary-Sis et al. reported an efficient and facile procedure for the synthesis of pyrrole heterocycles 24 by the reaction of various substituted arylglyoxals 4 and β-dicarbonyl compounds 22 in the presence of ammonium acetate 23 under ultrasound irradiation (US) (Scheme 15).81 Scheme 8. Ultrasound-assisted synthesis of pyrrole derivatives.81 Further research into the synthesis of tetrasubstituted pyrroles 24 by Bhat's group with the reaction of 1,3-dicarbonyls 22, and arylglyoxals 4 with ammonium acetate 23 under solvent-and catalyst-free conditions yielded only one regioisomer (Scheme 16). 82cheme 9. Synthesis of fully substituted pyrroles reported by Bhat.82 Anary-Abbasinejad's group has reported a green MCR approach for the synthesis of a series of pyrrole derivatives 26.Thus, the four-component domino reaction between arylglyoxals 4, acetylacetone 22', indole 25 and aliphatic amines in water as a solvent in the absence of any catalyst afforded indole derivatives in excellent yields (Scheme 10).83 Scheme 10.Four-component synthesis of indolyl pyrroles.83 Looking further into this reaction, Anary-Abbasinejad and his group studied the three-component reaction between arylglyoxals 4, acetylacetone 22 and enaminoketones 27 (Scheme 11).84 A mixture of 4 and acetylacetone 22 was stirred in water at 100 °C.Then 27 was added and the mixture was heated at 100 °C, to afford pure 3-acetyl-4-(4-bromobenzoyl)-5-[1-(p-tolylamino)ethylidene]heptane-2,6-dione 28.When the reaction was carried out in 1:1 water-ethanol mixture in the presence of 10 mol% of NaOH under reflux conditions, one of the acetyl groups of an acetylacetone moiety of 28 was removed and the only isolated product was the pyrrole derivative 30.Similar results were obtained when Et 3 N was used as catalyst under reflux condition for the synthesis of pyrrole derivative 29.Scheme 11. Th-component synthesis of multifunctionalized pyrroles.84 The polysubstituted pyrrole derivatives 35-38 were prepared by Choudhury and co-workers in fourcomponent reactions between cyclic 1,3-dicarbonyl compounds 31-34, β-keto esters 22, arylglyoxals 4 and amines 8 under catalyst-free conditions as shown in Scheme 12. 85 Scheme 12. One-pot synthesis of substituted pyrroles.85 A one-pot multicomponent process has been developed by Dommaraju and Prajapati for the formation of poly-functionalized pyrimidin-5-yl-pyrroles 40 and 41 by reacting equimolar amounts of various anilines 8, barbituric acid derivatives 39, arylglyoxals 4 and ethyl acetoacetate 22 or dialkyl acetylenedicarboxylates 3, in ethanol as solvent under reflux conditions (Scheme 13).86 AUTHOR(S) Scheme 13. The-component synthesis of pyrroles.86 In addition, when 1,2-diaminoethane 42 was used as a substrate, the 1,2-bispyrrole derivative 43 was obtained in moderate yield (Scheme 14).When the reaction was performed with the reactants in stoichiometric ratios under same conditions the desired product was obtained in good yield.Scheme 14. Multicomponent syntheses of a bispyrrole derivative.86 Other bispyrroles formed from a diamine are compounds 44, prepared by Choudhury et al. 85 from p-phenylenediamine with ethyl or methyl acetoacetate, phenylglyoxal 4, and 4-hydroxycoumarin 34.
Chen et al. reported a highly efficient one-pot regioselective synthesis of pyrrole derivatives 48 by a sequential reaction of nitriles with -bromoesters and arylglyoxals 4 (Scheme 15). 87The Blaise reaction intermediate 47 was generated in situ from the reaction of benzonitrile 45 with the bromoestert 46 in THF under catalyst-free condition.The tandem reaction of the intermediate 47 with arylglyoxals proceeded smoothly in THF under room temperature for 30 min to afford the corresponding pyrroles 48 in good yields.Scheme 15.Two-step synthesis of pyrroles via the Blaize reaction. 87u et al. have reported the synthesis of indolyl-substituted pyrroles 50 by the reaction of arylglyoxals 4 with the dithioacetal 49, aniline 8 and 2-methylindole 25 in nitromethane using AlCl 3 as catalyst in a fourcomponent reaction (Scheme 16). 88Scheme 16.Four-component synthesis of multifunctionalized pyrroles. 88 convenient method for the synthesis of polysubstituted pyrrole scaffolds has been reported by Kolos and co-workers. 89Refluxing of arylglyoxals 4, acetoacetic ester or its derivatives 52, and substituted anilines 8 in methanol with added catalytic amounts of acetic acid was found to result in precipitation of substituted pyrroles 51 or 53 from the hot reaction mixture after 30 min (Scheme 17).Scheme 17. One-pot reaction of substituted pyrroles. 89u et al. reported the highly efficient annulation of enaminones 27 with arylglyoxals 4 and indoles 25', thiophenol 54 or arylamines 8'', yielding fully substituted pyrroles 55-57 via three-component domino reactions involving indolisation and thiolation processes (Scheme 18). 90Scheme 18. Three-component pyrrole synthesis of Liu et al. 90 The synthesis of pyrrole derivatives 58 was accomplished by Masoudi and Anary-Abbasinejad using the reaction between arylglyoxals 4 with 4-phenylamino-3-pentene-2-one 27 in acetonitrile (Scheme 19). 91riphenylphosphine 1 was added after 10 min of stirring, to form substituted pyrrole 58 and triphenylphosphine oxide.

Scheme 19.
Anary-Abbasinejad's three-component synthesis of polyfunctionalized pyrroles. 91nsidering the significance of iodine-mediated oxidation of methyl ketones, Jalani et al. investigated the one-pot synthesis of substituted pyrroles under the influence of a co-product promoted Povarov reaction of acetophenone 18, arylamines 8, and a-keto esters 59.They used enamine such as methyl-3-aminobut-2enoate instead of a-keto esters to permit the nucleophilic addition of enamines to the C-acylimine ion, which could then be followed through intramolecular cyclization to the formation of 4-aminopyrroles 60 (Scheme 20). 92Scheme 20.Multicomponent syntheses of pyrroles reported by Jalani et al. 92

Synthesis of 1,5,6,7-dihydro-4H-indol-4-ones and other indoles
Recently, a four-component reaction leading to the fused pyrrole derivatives 61 and 64 was reported: the reaction of dimedone 31 and various anilines 8 proceeds by one-pot reaction under solvent-free conditions at 80 o C to produce the enaminone adduct intermediate 63.The sequential addition of arylglyoxals 4 and malononitrile 14 or ethyl cyanoacetate or methyl cyanoacetate 62 in ethanol successfully gave the desired product in good yields.It is noteworthy that when malononitrile 14 was used, the reaction led to the formation of 64 in excellent yield, whereas using and using ethyl or methyl cyanoacetate 62 led to product 61 (Scheme 21). 93Scheme 21.Four-component synthesis of fused pyrroles developed by Bayat et al. 93 Recently, Indian researchers have reported that the domino condensation of arylglyoxals 4, enaminones 63, and malononitrile 14 can produce highly substituted pyrrole and tetrahydroindole derivatives, e.g.64', in high yield by a one-pot reaction (Scheme 22). 94Scheme 22. Synthesis of tetrahydroindoles from arylglyoxals, enamines and malononitrile. 94ng and Shi studied the three-component reaction of 1,3-dicarbonyl compounds 10, arylglyoxals 4, and enaminone 63 (Scheme 23) for the synthesis of functionalized dihydro-1H-indol-4(5H)-ones 65 via one-pot three-component reactions under catalyst-free conditions. 95The reaction mixture was tested under a variety of different conditions to study the effects of solvent and temperature.Scheme 23.Three-component synthesis of 6,7-dihydroindol-4(5H)-ones. 95ring another study of this topic, there was reported the three-component domino [3+2] heterocyclization of arylglyoxals 4, N-arylenaminones 63, and 4-hydroxy-6-methyl-2H-pyran-2-one 66, providing fused pyrroles 65 on microwave irradiation in the presence of acetic acid (Scheme 24). 96The attractive aspect of this reaction is the fact that the construction of the pyrrole skeleton and the direct C3 pyranation were readily achieved in an intermolecular fashion in a single process.Scheme 24.Three-component synthesis of fused pyrroles. 96urther, Jiang et al. developed related novel domino reactions for the synthesis of polyfunctionalized fused pyrroles 67 and 68 that allows the incorporation of nucleophilic moieties into the pyrrole C-4 position.This method is based on the microwave-promoted reaction between various N-substituted enaminones 63 and arylamines 8 with arylglyoxals 4 in the presence of acetic acid (Scheme 25). 97Scheme 25.Jiang's synthesis of polyfunctionalized fused pyrroles. 97cently, Jiang's group has reported a series of three-component reaction between arylglyoxals 4, enamonones 63, and an arylamine 8 to form 3-arylaminoindole derivatives 68 (Scheme 26). 98.Three-component dihydroindolone synthesis of Jiang et al. 98 The pseudo-four-component reaction between one equivalent of enaminones 63 with arylglyoxals 4, phenylhydrazine 70, and dialkyl acetylenedicarboxylates 3 was reported by Tu et al. to afford multifunctionalized fused indole derivatives 71 selectively in good yields (Scheme 27). 99The mixture of enaminones 63 and arylglyoxals 4 in HOAc was firstly heated at 120 o C under microwave irradiation, and then phenylhydrazine 70 and dialkyl acetylenedicarboxylates 3 were added into the mixed system at 150 o C, to form substituted pyrrole 71.Scheme 27.Tu's synthesis of polysubstituted tetrahydroindol-4-ones. 99 The three-component reaction of enamonones 63, arylglyoxals 4, and indoles 25, in HOAc under microwave irradiation to give 72 and 73 in high yields has also been reported (Scheme 28). 100 Scheme 28.Three-component synthesis of pyrroles starting from enaminones, arylglyoxals and indoles. 100cently a new, green protocol was investigated for the construction of bis-isoxazolylamino dihydro-1Hindol-4(5H)-one derivatives 74, 78, and 80.The generality of the reaction was established by employing Nisoxazolyl enaminone 76 with arylglyoxals 4 and a series of isoxazoles 75, 77, and 79 in the reaction process to produce the desired products in good to excellent yields in water and AcOH as catalyst under metal-free and refluxing conditions (Scheme 29). 101Scheme 29.The synthesis of bis-isoxazolyl-1H-indol-4(5H)-one derivatives of Reddy and Kumar. 101ity's group has reported the simple reaction of arylglyoxals 4 and enaminones 63, for the synthesis of fused pyrrole derivatives 81 through microwave-assisted reactions under neutral conditions and in a nonnucleophilic solvent, without the use of any catalyst (Scheme 30). 102Scheme 30.Maity's synthesis of fused pyrroles. 102ontinuing these investigations, Maity observed that heating a mixture of 3-arylaminocyclohex-2-enones 63 and arylglyoxals 4 at reflux in a non-nucleophilic solvent such as acetonitrile produced indol-4-ol derivatives 82 within 6-8 h in moderate-to-good yields.Surprisingly, completely different products were formed in a nucleophilic solvent such as ethanol; heating arylglyoxals 4 and enamine 63 in ethanol at reflux produced tetrahydroindol-4-one derivatives 81 in 6-8 h in good yields (Scheme 31). 103In this case a solvent molecule is incorporated into the product.Scheme 31.The synthesis of indole derivatives. 103n's group found that when anilines 8, arylglyoxals 4, and cyclic 1,3-dicarbonyl compounds 10 in a mixture of ethanol and water were subjected to microwave irradiation (MW), a regioselective domino reaction proceeded to give 3-functionalized indole derivatives 83 (Scheme 32). 104heme 32.Three-component synthesis of multifunctionalized indoles. 104aidu has developed an efficient method for the synthesis of highly functionalized indoles 84 and bisindoles 85 by reductive alkylation of α-keto imines, followed by cyclization process (Scheme 33). 105Similarly the one-pot reaction of aniline 8, arylglyoxals 4, and cyclic diketones 10/indoles 25 gave a large number of compounds (Scheme 33).Scheme 33.Three-component syntheses of substituted indoles described by Naidu. 105

Synthesis of other fused pyrrole heterocycles
In some very interesting reactions related to those of the previous subsection, but where an additional ring fused to the indole [hi] bonds is formed, Jiang and coworkers established a new three-component domino reaction for the synthesis of fused indole derivatives.The reaction is performed simply by mixing N-aryl enaminones and arylglyoxal 4 in acetic acid as solvent and applying microwave irradiation.Under such conditions, 1,2-diaryl dihydroindolones are formed, but with the aminoacid-derived enaminones 86 the tricyclic 1,4-oxazine-fused indole derivatives 87 are formed (Scheme 34). 106cheme 34.Synthesis of oxazino-indoles. 106ng, Zhong and coworkers described a method for the synthesis of polysubstituted fused pyrroles 88 and 90 in moderate to high yields (Scheme 35). 107The synthetic strategy was based on a one-pot procedure involving condensation of 3-aminocoumarins 89 and arylglyoxasl 4 in refluxing ethanol in the presence of catalytic p-TSA to give 88, or in toluene to give 90.Scheme 35.Zhong's synthesis of polysubstituted pyrroles. 107 another study by this group, the synthesis of polyfunctionalized fused pyrroles 92 was accomplished by intermolecular cycloaddition of arylglyoxals 4 with 4-aminocoumarins 91 and cyclic diketones 10 as the key step using readily available starting materials.Various arylglyoxals 4 were found to be compatible in this reaction and their electronic nature and substitution pattern had little influence on the reaction efficiency; the corresponding products 92 were formed in moderate to good yields (Scheme 36). 108cheme 36.Yang's three-component synthesis of polyfunctionalized fused pyrroles. 108 et al. studied the three-component reactions of 4-aminocoumarins 91, arylglyoxals 4, and anilines 8 in toluene at reflux using KHSO 4 as a catalyst, to give the products 93 in moderate to excellent yields (Scheme 37). 109heme 37. Synthesis of fused pyrroles from 4-aminocoumarins, arylglyoxals and anilines. 109vahershenas and Khalafy reported a new method for the synthesis of pyrrolo [2,3-d]pyrimidine derivatives 95 through the one-pot, the three-component reaction of 4-hydroxycoumarin 34, arylglyoxals 4 and 6-aminouracil or 1,3-dimethyl-6-aminouracil 94 catalyzed by L-proline (Scheme 38). 110cheme 38.Javahershenas and Khalafy's three-component synthesis of polyfunctionalized fused pyrroles. 110 another study, this group reported an efficient procedure for the reaction of arylglyoxals 4 with 6amino-1,3-dimethyluracil 94 and barbituric acid derivatives 39 in the presence of TBAB (5 mol%) in ethanol at 50 °C, affording polyfunctionalized pyrrolo [2,3-d]pyrimidine derivatives 96 in high yields (Scheme 39). 111Scheme 39.Three-component pyrrolopyrimidine synthesis developed by Javahershenas and Khalafy. 111cently, the synthesis of polyfunctionalized pyrrolo [2,3-d]pyrimidine derivatives was reported in a review. 70hen and coworkers have reported the multicomponent synthesis of N-bridgehead-fused pyrroles 98 and 99 by reaction of arylglyoxals 4, cyclohexane-1,3-diones 31, and heterocyclic ketene aminals (HKA) 97 under two different reflux conditions in high yield (Scheme 40). 112 further work of Chen et al., the reaction between one equivalent of an HKA 97 with arylglyoxals 4 and 1,3-diphenylpropane-1,3-dione 100 is reported to proceed selectively, providing multifunctionalized fused pyrrole derivatives 101 in high yields, as shown in Scheme 41. 113

Figure 2 .
Figure 2. Typical cycloaddition methods for the synthesis of pyrroles.

Figure 3 .
Figure 3.The syntheses of pyrroles using methylene active compounds

Table 1 .
Methods for the synthesis of arylglyoxals