InCl₃: A Versatile Catalyst for Synthesizing a Broad Spectrum of Heterocycles

Abstract

This review deals with the recent applications of the indium trichloride (InCl₃) catalyst in the synthesis of a broad spectrum of heterocyclic compounds. Over the years, a number of reviews on the applications of InCl₃-catalyzed organic synthesis have appeared in the literature. It is evident that InCl₃ has emerged as a valuable catalyst for a wide range of organic transformations due to its stability when exposed to moisture and also in an aqueous medium. The most attractive feature of this review is the application of the InCl₃ catalyst for synthesizing bioactive heterocyclic compounds. The study of InCl₃-catalyzed organic reactions has high potential and better intriguing aspects, which are anticipated to originate from this field of research.

1. Introduction

Lewis acid catalysis has brought a radical change in the approach toward the synthesis of a large number of important organic intermediates and heterocyclic compounds having significant biological activity.^1a The common Lewis acids which are generally used for various organic transformations include AlCl₃, BF₃·Et₂O, ZnCl₂, TiCl₄, and SnCl₂. Although indium (In) belongs to the same group in the periodic table as boron (B) and aluminum (Al), the study of indium and its salts was unexplored until recently.^1b Indium and its salts have found applications in the preparation of alloys to be used as medical diagnostic agents for the health sector and equipment for the electronic industry.^2a−2d The ability of indium(III) salts to react with organic compounds to form an in situ organoindium species has largely eliminated the use of sensitive, toxic, and explosive organometallics.^3a The effectiveness of InCl₃ as a Lewis acid catalyst has sustained immense interest due to its moisture compatibility, which enhances its use in a wide range of solvents including water. Moreover, nontoxicity, abundance, recyclability, and excellent catalytic activity^3b of InCl₃ afforded high chemo- and regioselectivity in various organic transformations.^2a−2d These advantages of InCl₃ inspired us to write a review highlighting its catalytic applications in the synthesis of a broad range of heterocycles.

2. Synthesis of N-Heterocycles

N-Heterocycles constitute the core scaffolds of many natural products and pharmaceutical agents. The syntheses of these N-heterocycles are very challenging, and the development of methodologies for their synthesis provided us with unique metal catalysts, but many of them are hazardous and expensive. Among them, InCl₃ was found to be inexpensive, moisture friendly, and reactive even in mild conditions.^{2a−2d,3a,3b}

Nandi et al.^3c accomplished a one-pot synthesis of highly substituted pyrrole 3 directly by reacting propargylic alcohol 1 with β-ketoimide 2 in the presence of InCl₃ catalyst (Scheme 1) in good yields.

Scheme 1. InCl₃-Catalyzed Synthesis of Tetrasubstituted Pyrroles from Propargyl Alcohol and Ketoimide.

In 2011, Meng et al.^3d reported the synthesis of various C-pyrrolyl glycoside 6 in moderate to good yields through a tandem (hemiacetal intermediate) condensation of aminosugar (d-glucosamine and d-galactosamine) 4 and carbonyl compound 5 in water in the presence of InCl₃ (Scheme 2).

Scheme 2. InCl₃-Catalyzed Synthesis of C-Pyrrolyl Glycosides.

Cook et al.^4a disclosed the catalytic activity of InCl₃ to favor an intramolecular Friedel–Crafts reaction of simple arenes incorporated with allylic bromides 8 to give the corresponding arene-fused heterocycle 9 (Scheme 3).

Scheme 3. InCl₃-Catalyzed Synthesis of Substituted N-Tosyl Isoquinolines.

Perumal et al.^4b reported the synthesis of quinoline derivatives 12 and 14. The reaction proceeds via an imino Diels–Alder reaction of N-arylaldimine 10 or 13 with cyclopentadiene 11 in the presence of the InCl₃ catalyst (Schemes 4 and 5). They have also demonstrated that 3,4-dihydro-2H-pyran and indene underwent a Diels–Alder reaction under the same condition.

Scheme 4. InCl₃-Catalyzed Synthesis of Cyclopentane-Fused Hydroquinolines.

Scheme 5. InCl₃-Catalyzed Synthesis of 6,6′-Bishydroquinolinyl Methane.

The tetrahydro-3H-cyclopenta[c]quinoline 14 (Scheme 5) was achieved from the Schiff base 13, which had been derived from 4,4′-diaminodiphenylmethane, and an excess of cyclopentadiene 11.^4b

Menéndez et al.^4c reported the synthesis of C-4-substituted 1,2,3,4-tetrahydroquinoline 17 by reacting aromatic imine 15 and methacrolein dimethyl hydrazone 16 in the presence of 10 mol % of InCl₃ catalyst in acetonitrile (Scheme 6).

Scheme 6. InCl₃-Catalyzed Synthesis of C-4-Substituted 1,2,3-Trihydroquinolines.

Raghunathan et al.^4d disclosed an efficient synthesis of diastereomeric cis-tetrahydroquinoline 20 and trans-tetrahydroquinoline 21 by reacting substituted aromatic amine 18 with N-allyl-indole-2-carbaldehyde 19 in the presence of 20 mol % of InCl₃ catalyst (Scheme 7).

Scheme 7. InCl₃-Catalyzed Synthesis of Fused Hydroquinolines.

Again, the synthesis of pyrrolo[2,3-d]pyrimidine-annulated tetrahydroquinoline derivatives 24 and 25 were synthesised from aldehyde 22 and amine 18 via intramolecular aza-Diels–Alder cyclization (Scheme 8). The products were obtained as diastereomeric mixtures, which were enriched with the cis-isomer.^4d

Scheme 8. InCl₃-Catalyzed Synthesis of Pyrimidine-Annulated Fused Hydroquinolines.

The same group also reported^4e an excellent catalytic activity of InCl₃ in acetonitrile or impregnated in silica gel toward the synthesis of diastereomeric pyrano/thiopyranoquinoline derivatives 29 and 30 through an intermolecular imino-Diels–Alder reaction (Scheme 9).

Scheme 9. InCl₃-Catalyzed Synthesis of Thiopyranoquinolines via Intramolecular Imino-Diels–Alder Reaction.

An efficient three-component one-pot synthesis of diastereomeric ellipticine derivatives was reported by Nagarajan et al.^4f through an imino-Diels–Alder reaction of 3-aminocarbazole 31 and substituted benzaldehyde 32 with an electron-rich alkene 33, such as 3,4-dihydro-2H-pyran, 2,3-dihydrofuran, or ethyl vinyl ether in the presence of 10 mol % of InCl₃ catalyst in an ionic liquid at 100 °C (Scheme 10). In the case of substituted benzaldehydes, reductive amination was also observed.

Scheme 10. InCl₃-Catalyzed Synthesis of Ellipticine Derivatives.

Ranu et al.^3e demonstrated the InCl₃-catalyzed three-component one-pot synthesis of dihydropyrimidin-2(1H)-one 39 in good to excellent yields by reacting 1,3-dicarbonyl 36, aldehyde 37, and urea/thiourea 38 (Scheme 11).

Scheme 11. InCl₃-Catalyzed Synthesis of Dihydropyrimidines.

Li et al.^4g synthesized diastereoselective tetrahydroquinolines by reacting aromatic amine 40 and cyclic enol ether 41 or 2-hydroxy cyclic ether 42 in the presence of a catalytic amount of InCl₃ in water. The reaction followed an aza-Diels–Alder path to yield cis-selective tetrahydroquinolines as major products (Scheme 12).

Scheme 12. InCl₃-Catalyzed Synthesis of Fused Tetrahydroquinolines.

Juaristi et al.^5a have reported the asymmetric synthesis of R-selective 4-phenyldihydropyrimidinone derivative 50 in a one-pot Biginelli condensation by reacting acetoacetate ester 45 with benzaldehyde 46 and urea 47 in THF in the presence of a catalytic amount of InCl₃ and chiral ligands (Scheme 13). The enantiomeric ratio (er) of the product was found to be 62:38 (for R,R-48) with an excellent yield of up to 93%.

Scheme 13. InCl₃-Catalyzed Synthesis of Aryl-Substituted Chiral Dihydropyrimidinones.

Prajapati et al.^5b have developed an InCl₃-catalyzed neat synthesis of tetra-substituted pyridine derivative 53 via Michael addition of 1,3-dicarbonyl 51 with α,β-unsaturated oxime 52 followed by a ring-closing reaction (Scheme 14).

Scheme 14. InCl₃-Catalyzed Synthesis of Tetrasubstituted Pyridines.

Dobbs et al.^5c reported the cyclization reaction of silylated homoallyl alcohol 54 and aldehyde 55 (even epoxides) in the presence of a catalytic amount of InCl₃ to yield diastereoselective unsaturated heterocycle 56 (Scheme 15).

Scheme 15. InCl₃-Catalyzed Synthesis of Unsaturated Heterocycles from Silylated Homoallyl Alcohols.

Yadav et al.^5d have reported an InCl₃-catalyzed condensation of o-phenylenediamine 57 with 4,6-di-O-alkyl-2,3-dideoxyaldehyde-d-erythro-trans-hex-2-enose 58 followed by cyclization under mild conditions to afford 1,5-benzodiazepine 59 in good yield (Scheme 16).

Scheme 16. InCl₃-Catalyzed Synthesis of 1,5-Benzodiazepine.

A mild, efficient InCl₃-catalyzed multicomponent one-pot synthesis of highly substituted pyrroles was developed by Liu et al.^5e Interestingly, they found that the reaction involved propargylation, amination, followed by cycloisomerization in a single step to afford pyrrole 3 from propargyl alcohol 1, 1,3-dicarbonyl 60, and primary amine 61 in very good yields (Scheme 17).

Scheme 17. InCl₃-Catalyzed Multicomponent Synthesis of Polysubstituted Pyrroles.

Adimurthy et al.^5f developed a highly efficient and regioselective method for the synthesis of 1,8-naphthyridine 64 directly from substituted 2-aminopyridine 62 and ethyl acetoacetate 63 in the presence of a catalytic amount of InCl₃ in ethanol at 100 °C for 33–48 h (Scheme 18).

Scheme 18. InCl₃-Catalyzed Synthesis of Substituted 1,8-Naphthiridines.

Mahadevan and co-workers^6a reported an advanced efficient method for the synthesis of various cis-2-methyl-4-amido-1,2,3,4-tetrahydroquinoline derivative 67 by reacting aromatic amine 65 and N-vinyl caprolactam or N-vinyl pyrrolidone 66 in the presence of a catalytic amount of InCl₃ in an aqueous medium in good to excellent yields. These 2,4-disubstituted tetrahydroquinolines showed cis diastereoselectivity (Scheme 19).

Scheme 19. InCl₃-Catalyzed Synthesis of Substituted Tetrahydroquinolines.

Khurana et al.^5g reported an appealing synthetic protocol which utilized water as the solvent and InCl₃ as the promoter for the three-component combinatorial synthesis of a variety of bioactive pyrimidine and pyrazole derivatives. The latter derivatives were synthesized from aldehyde 68, electron-rich amino heterocycles such as 6-amino-1,3-dimethyl uracil 69 and 3-methyl-1-phenyl-1H-pyrazol-5-amine, and 1,3-dicarbonyl compound 70 under refluxing conditions. Following the same reaction conditions, the synthesis of a new class of pyrimidine derivative 71 was also reported. The reactions were environmentally benign; the reaction product could be isolated easily, and the catalyst could be recycled (Scheme 20).

Scheme 20. InCl₃-Catalyzed Synthesis of Pyridopyrimidine Derivatives.

A facile and regioselective synthesis of polysubstituted pyrroles 73 have been reported by Muthusubramanian and co-worker^6b from azido chalcones 72 and 1,3-dicarbonyl compounds 60 via an InCl₃ catalyst in water under microwave irradiation (Scheme 21).

Scheme 21. InCl₃ catalyzed synthesis of polysubstituted pyrroles from azidochalcones.

Lavilla et al.^4h achieved a successful InCl₃-catalyzed three-component reaction of dihydropyridine 74, aldehyde 75, and p-methylaniline 76 to afford a diastereomeric mixture of highly substituted tetrahydroquinolines which contained cis-isomer 77 as the major product (Scheme 22).

Scheme 22. InCl₃-Catalyzed Synthesis of Substituted Tetrahydroquinolines.

Li et al.⁴ⁱ reported an intermolecular 1,3-dipolar cycloaddition of methyl α-diazoacetate 79 with alkyne 80 in water in the presence of InCl₃ catalyst to afford substituted pyrazole compounds 81 and 82 in good yields (Scheme 23).

Scheme 23. InCl₃-Catalyzed Synthesis of Substituted Pyrazole Derivatives.

Ranu et al.^3f−3g developed a one-pot synthesis of quinoline 84 by reacting aniline 40 with alkyl vinyl ketone 83 on the solid surface of silica gel impregnated with InCl₃ under microwave irradiation (Scheme 24). The products were obtained in excellent yields.

Scheme 24. InCl₃-Catalyzed Synthesis of 2,3,4-Substituted Quinolines.

An efficient and eco-friendly synthesis of structurally diversified 2-quinolinones 87 from coumarin-3-carboxylic acid 85 and primary amine 86 in the presence of a catalytic amount of InCl₃ in aqueous medium at ambient temperature was reported by Mahadevan et al.^4j (Scheme 25).

Scheme 25. InCl₃-Catalyzed Synthesis of Quinolones from Coumarins.

Gogoi et al.^7a reported an InCl₃-catalyzed condensation of o-phenylenediamine 57 with ketone 88 and 1,2-dicarbonyl 89 to afford various 1,5-benzodiazepine 90 and quinoxaline 91, respectively, with excellent yields (Scheme 26).

Scheme 26. InCl₃-Catalyzed Synthesis of 1,5-Benzodiazepines and Quinoxalines from 1,2-Aminobenzene.

Very recently, Jeong et al.^7b reported a synthesis of novel 3-amino-2-benzoyl-1-aryl-1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivative 94a via a one-pot three-component reaction of phthalhydrazide 92a, aldehyde 32, and arylacetonitrile 93 in the presence of InCl₃ (20 mol %) catalyst under solvent-free environmentally friendly conditions. Similarly, they reported the synthesis of 3-amino-2-benzoyl-1-aryl-1H-pyrazolo[1,2-a]pyridazine-5,8-dione 94b derivatives but used maleic hydrazide 92b instead of 92a (Scheme 27).

Scheme 27. InCl₃-Catalyzed Synthesis of Pyrazole Derivatives.

3. Synthesis of O-Heterocycles

Indium and its salts have been extensively used for alkylation, allylation, and alenylation reactions in water.^8a,8b Therefore, InCl₃-catalyzed synthesis of bioactive compounds in water is the decent choice for researchers for the development of pharmaceutical agents with less or no toxicity. Among various O-heterocycles, chromanes were found in many important natural products and were reported to have significant biological importance.⁹ Synthesis of these compounds in water has been a topic of interest to medicinal chemistry researchers.

Kang et al.¹⁰ reported an intramolecular allylation of carbonyl/imine 95 to chromane 96 in the presence of In, InCl₃, and Pd(PPh₃)₄ in water with high yield (Scheme 28). The main advantage of using indium along with InCl₃ was to generate active InCl, which was responsible for the generation of an organoindium complex via transmetalation from an organopalladium complex followed by allylation.

Scheme 28. InCl₃-Catalyzed Synthesis of Benzopyran Derivatives.

Li et al.^11a demonstrated InCl₃-mediated highly diastereoselective tandem carbonyl allylation–Prins cyclization of aldehyde 68 with 3-trimethylsilylallyltributylstannane 97 to afford 2,6-dialkyl-5,6-dihydropyran 98 with a cis diastereoselectivity (Scheme 29).

Scheme 29. InCl₃-Catalyzed Synthesis of Substituted Dihydropyrans.

Loh et al.^11b accomplished a one-pot Prins cyclization of aldehyde 68 with allylchlorosilane 99 to afford corresponding 2,4,6-trisubstituted tetrahydropyran 100 in the presence of InCl₃ catalyst (Scheme 30). They also observed that α,β-unsaturated aldehydes also respond to the reaction equally.

Scheme 30. InCl₃-Catalyzed Synthesis of 4-Chlorotetrahydropyrans via Prins Cyclization.

Yadav et al.^12a found that, in the presence of 10 mol % of InCl₃, 1,4-benzoquinone 102 could react with electron-rich alkene 101 to afford the corresponding 2,3-dihydrobenzofuran 103 in excellent yield. It was noted that the reaction underwent a [3 + 2] cycloaddition pathway to produce a trans-selective product (Scheme 31).

Scheme 31. InCl₃-Catalyzed Synthesis of 2,3-Dihydrobenzofuran Derivatives.

Balasubramanian et al.^11c reported the synthesis of 2-(d-glycero-1,2-dihydroxyethyl)furan 105, an optically active furandiol from glucal 104 in the presence of a catalytic amount of InCl₃·3H₂O in acetonitrile at room temperature (Scheme 32).

Scheme 32. InCl₃-Catalyzed Rearrangement of Dihydropyran to Furan.

Ishii et al.^11d have developed a catalytic Baeyer–Villiger oxidation of KA-oil (a mixture of cyclohexanone 106 and cyclohexanol 107) with molecular oxygen. The reaction has been done in the presence of a catalytic amount of InCl₃ and N-hydroxyphthalimide to afford ε-caprolactone 108 (Scheme 33).

Scheme 33. InCl₃-Catalyzed Baeyer–Villiger Oxidation of KA-Oil to ε-Caprolactone.

An efficient InCl₃-catalyzed synthesis of substituted pyran 110 was demonstrated by Lee et al.^11e by reacting 1,3-dicarbonyl 70 with α,β-unsaturated aldehyde 109 in acetonitrile under refluxing conditions with moderate yields (Scheme 34).

Scheme 34. InCl₃-Catalyzed Synthesis of Substituted Pyrans.

Perumal et al.^11f developed InCl₃-catalyzed cyclization of o-hydroxyaldimine 111 with vinyl enol ether 41, resulting in the formation of diastereoselective benzopyran derivatives (syn-112 and anti-113) at ambient temperature with excellent yield and high diastereoselectivity (Scheme 35).

Scheme 35. Diastereoselective Synthesis of Furano/Pyranobenzopyran Derivatives.

Yadav and co-workers^12b also developed the methodology for the synthesis of 2-methyl-3-perhydrofuro[2,3-b]oxepin-4-yl-1H-indole derivative 116 by reacting substituted 2-methylindole 114 with 2,3-dihydrofuran 115 in the presence of a catalytic amount of InCl₃ under mild reaction conditions. The yield and diastereoselectivities of the products were found to be excellent. On the other hand, 5,5-di(1H-3-indolyl)-1-pentanol derivative 118 was formed in high yields when indole 117 and 3,4-dihydro-2H-pyran 33 were reacted under similar reaction conditions (Scheme 36).

Scheme 36. InCl₃-Catalyzed C-Alkylation of Indoles with Cyclic Enol Ether.

Kalyanam et al.^11g synthesized coumarin 121 in a single step with a condensation reaction of substituted phenol 119 and acetylenic ester 120 in the presence of a catalytic amount of InCl₃ under solvent-free conditions (Scheme 37).

Scheme 37. InCl₃-Catalyzed Synthesis of Substituted Coumarins.

Ranu et al.^13a developed an easy and efficient methodology that demonstrated InCl₃-catalyzed masking of carbonyl 122 to 1,3-dioxolane 123 and dialkyl acetal 124 with good to excellent yields (Scheme 38).

Scheme 38. InCl₃-Catalyzed Synthesis of Dioxolanes.

Tocco et al.^13b reported that 2,2′-dihydroxybiphenyl 125 and bis(2-hydroxyphenyl)methane 127 reacted with carbonyl 122 to afford dibenzo(d,f)-(1,3)dioxepine 126 and 12H-dibenzo(d,g)-(1,3)dioxocin 128, respectively, in the presence of a catalytic amount of InCl₃ (Scheme 39).

Scheme 39. InCl₃-Catalyzed Synthesis of Dibenzodioxepines and -dioxocins.

van Lier et al.^11h have shown a facile oxidation of 2′-hydroxychalcone 129 and hydroflavanone 130 to afford the corresponding flavone 131 in the presence of silica gel impregnated with 15–20 mol % of InBr₃ or InCl₃ under solvent-free conditions (Scheme 40).

Scheme 40. InCl₃-Catalyzed Oxidation of Hydroxychalcones and Dihydroflavones to Flavone Derivatives.

Chen and co-workers¹¹ⁱ reported an InCl₃-catalyzed three-component reaction of arylglyoxal monohydrate 132, phenol 133, and p-toluenesulfonamide 134 to afford 2-aryl-3-aminobenzofuran 135 in good to excellent yields (Scheme 41).

Scheme 41. InCl₃-Catalyzed Synthesis of Substituted Benzofurans.

Raghunathan et al.^13c reported the InCl₃-catalyzed synthesis of 1,3,5-trioxane 136 by the cyclotrimerization of aldehyde 68 in excellent yields under solvent-free conditions (Scheme 42).

Scheme 42. InCl₃-Catalyzed Cyclotrimerization of Aldehydes to Trioxanes.

Prajapati and Gohain have synthesized a cis–trans mixture of pyrano[2,3-d]pyrimidines 140 and 141 from a multicomponent domino Knoevenagel/hetero-Diels–Alder reaction of 1,3-dimethyl barbituric acid 137 and an aromatic aldehyde 138 followed by vinyl ether 139 addition, in the presence of 1 mol % of InCl₃ (Scheme 43).^13d

Scheme 43. InCl₃-Catalyzed Synthesis of Pyranopyrimidines.

Yadav et al.^12c also reported that hexose sugar 142 underwent a coupling reaction with 1,3-dicarbonyl 143 in the presence of 10 mol % of InCl₃ in water at 80 °C to afford C-furyl glycosides 144 in high yields (Scheme 44). The pentose sugars with 1,3-dicarbonyls gave the corresponding furan derivatives, and reaction of cyclic ketones with hexose sugars gave the corresponding tetrahydrobenzofuranyl glycoside derivatives.

Scheme 44. InCl₃-Catalyzed Synthesis of Furyl Glycosides.

Perumal et al.^2a developed an InCl₃-catalyzed three-component one-pot synthesis of spirooxindoles under both conventional and solvent-free microwave irradiation conditions. Isatin 145 first condenses with malononitrile 146a or ethyl cyanoacetate 146b to form α,β-unsaturated nitrile or acetate derivatives which undergo a C-alkylation reaction with 1-naphthol 147c or 2-naphthol 147d followed by nucleophilic addition of the phenolic OH group onto the cyano moiety, affording spirooxindoles 148 and 149, respectively (Scheme 45).

Scheme 45. Synthesis of Spirooxindoles from Isatin and Malonitriles.

The same group further reported a convenient three-component one-pot synthesis of 2-aminochromene 153 from salicylaldehyde 150, malononitrile 151, and Hantzsch dihydropyridine ester 152 in aqueous ethanol using InCl₃ catalyst (Scheme 46).^13e

Scheme 46. InCl₃-Catalyzed Synthesis of Amino Chromenes.

Singh et al.¹⁴ have reported an InCl₃-catalyzed three-component one-pot coupling of β-naphthol 154, aldehydes 155, and 6-amino-1,3-dimethyluracil 156 under solvent-free conditions to give 8,10-dimethyl-12-aryl-12H-naphtho[1′,2′:5,6]pyrano[2,3-d]pyrimidine-9,11-dione 157 in high yields (Scheme 47).

Scheme 47. InCl₃-Catalyzed Synthesis of Naphthapyranopyrimidines.

Reddy et al.¹⁵ reported a novel three-component one-pot synthesis of dihydropyrano[3,2-β]chromenedione derivative 160 from kojic acid 158, aldehyde 159, and dimedone 70 in the presence of 10 mol % of InCl₃ under solvent-free conditions at 120 °C. The product 2-(hydroxymethyl-7,7-dimethyl-10-phenyl-7,8-dihydroxypyrano[3,2-β]-chromene-4,9(6H,10H)-dione (160) was obtained in 90% yield (Scheme 48).

Scheme 48. InCl₃-Catalyzed Synthesis of Dihydropyranochromenediones.

Balalaie et al.¹⁶ reported an efficient approach for the synthesis of pyranoquinoline 162 through InCl₃-catalyzed activation of alkyne 161. Intramolecular hydroamidation of alkynes can proceed through alkyne activation by indium(III) chloride and then 6-exo-dig cyclization, leading to a fused pyran ring with high selectivity, high atom economy, and good yields (Scheme 49).

Scheme 49. InCl₃-Catalyzed Synthesis of Pyranoquinolines.

4. Synthesis of S-Containing Heterocycles and Others

Muthusamy et al.¹⁸ reported an InCl₃-catalyzed synthesis of 1,3-dithiolane 164 by reacting carbonyl 122 with 1,2-ethanedithiol 163 in methanol at room temperature in excellent yields (Scheme 50).

Scheme 50. InCl₃-Catalyzed Synthesis of Dithiolanes.

Ranu et al.¹⁷ also developed a method for trans-thioacetalization of O,O-acetal 165 by thiol 166 in 1,2-dichloroethane (DCE) to afford 167 in the presence of a catalytic amount of InCl₃ in good yields (Scheme 51).

Scheme 51. InCl₃-Catalyzed Thioacetalization of Ketals.

Muthusamy et al.¹⁸ reported an InCl₃-catalyzed atom-economical diastereoselective synthesis of indenodithiepines and indenodithiocines via a domino reaction of propargylic alcohol 168 and dithioacetal 169 (Scheme 52). The reaction works efficiently with remarkable accessibility of a wide variety of indene-fused sulfur heterocycles 170 (e.g., functionalized dithiepines and dithiocines) with good to excellent yields (up to 96%).

Scheme 52. InCl₃-Catalyzed Synthesis of Indenodithiepines and Dithiocines.

Sakai et al.¹⁹ reported the direct conversion of lactone 171 into thiolactone 172 with elemental sulfur (S8) catalyzed by InCl₃/PhSiH₃ in a one-pot reaction (Scheme 53). This catalytic system was successfully applied to the novel preparation of selenolactones from lactones and selenium.

Scheme 53. InCl₃-Catalyzed Conversion of Lactones to Thiolactones.

Gharpure and co-workers²⁰ reported an inter- as well as intramolecular thia-Pictet–Spengler cyclization of N-tethered thiol 173 and carbonyl compound 174 to yield nitrogen-fused thiazinoindole derivative 175 in excellent yields (Scheme 54).

Scheme 54. InCl₃-Catalyzed Synthesis of Nitrogen-Fused Thiazinoindole Derivatives.

The strategy was extended to a one-pot, sequential Friedel–Crafts alkylation/Pictet–Spengler cyclization and the synthesis of thiazinooxepinoindole.²⁰

Perumal et al.^2a have discovered the intramolecular imino Diels–Alder reaction of aldimines derived from aromatic amines 40 and O-allyl salicylaldehydes 176 to give a diastereomeric mixture of tetrahydrochromano[4,3-b]quinolines in the presence of InCl₃ catalyst in excellent yields under mild reaction conditions (Scheme 55). The products were obtained as a mixture of cis177 and trans178 isomers in 1:1 ratio.

Scheme 55. InCl₃ catalyzed synthesis of tetrahydrochomanoquinolines.

Pak et al.²¹ reported an InCl₃ catalyzed Beckmann rearrangement of 3-acyl-4-quinolinone ketoximes 179 to obtain predominantly an oxazoloquinoline 180 as the major product; an isooxazoloquinoline 181 was isolated as a minor product without rearrangement (Scheme 56).

Scheme 56. InCl₃ catalyzed synthesis of oxazoloquinolines.

Yadav et al.^12d developed a synthetic methodology for the synthesis of oxa-aza bicyclononene scaffolds which have presumed importance in the field of drug discovery. They have demonstrated a three-component coupling (3CC) of glycal 182, 1,3-dicarbonyl compound 51, and arylamine 40 in the presence of 10 mol % of InCl₃ in DCE under refluxing conditions. This reaction afforded oxa-aza bicyclononene 183 in 93% isolated yield and high stereoselectivity (Scheme 57).

Scheme 57. InCl₃-Catalyzed Synthesis of Oxa-Aza Bicyclononene Derivatives.

For more than a decade, our group also worked on the InCl₃-catalyzed synthesis of heterocycles.²² We explored the use of the InCl₃ catalyst in the synthesis of four different types of heterocyclic compounds, which included substituted furans, pyrroles, bipyrroles, and pyrones. We reacted 1,2-diaroylethylene 184 with various β-dicarbonyls 51 in the presence of a catalytic amount of InCl₃, which resulted in the formation of tetra-substituted furan 186. In the presence of ammonium acetate (NH₄OAc), the reaction between 51 and 184 yielded substituted pyrrole 187. The treatment of diaroylacetylene 185 with 51 and NH₄OAc yielded (±)-3,3′-bipyrrole 188. In the absence of NH₄OAc, 51 reacted with 185 to afford substituted 2-pyrone 189 in very good yield and not the expected(±)-3,3′-bifuran 190 (Scheme 58).

Scheme 58. InCl₃-Catalyzed Synthesis of Broad Spectrum of Heterocycles.

Reddy et al.²³ developed a novel one-pot synthesis of oxa-aza bicycle 194 from the δ-hydroxy-α,β-unsaturated sugar aldehyde (Perlin aldehyde) 191, arylamine 192, and 1,3-dicarbonyl compound 193 in the presence of 10 mol % of InCl₃ in acetonitrile at 80 °C. Initially, the aryl amine reacted with the 1,3-dicarbonyl to form β-enamino ketones, which subsequently coupled with the Perlin aldehyde to produce oxa-aza bicycles in good yields with high selectivity (Scheme 59).

Scheme 59. InCl₃-Catalyzed Synthesis of Oxa-Aza Bicycles.

Yadav et al.^12e found that in the presence of a catalytic amount of InCl₃ a tandem Michael addition and intramolecular Friedel–Crafts-type cyclization occurred under mild conditions between δ-hydroxy-α,β-unsaturated aldehyde 195 and arylamine 196 to afford fused heterocycle 197 in good yield and excellent stereoselectivity (Scheme 60).

Scheme 60. InCl₃-Catalyzed Synthesis of Fused Tetrahydroquinolines.

A systematic and comprehensive study on the synthesis of 3H-(pyrrol-1-yl)indolin-2-one 200 was reported by Ji et al.²⁴ Various isatin derivatives 198 and 4-hydroxyproline 199 were reacted in the presence of 10 mol % of InCl₃ under ambient reaction conditions to afford the products in excellent yields up to 99% (Scheme 61).

Scheme 61. InCl₃-Catalyzed Synthesis of 3-Pyrrolylindolones.

Yadav et al.^12f described a cycloaddition reaction of aryl amine 40 with 3,4-dihydro-2H-pyran 33 in the presence of the InCl₃ catalyst under mild reaction conditions to afford the corresponding pyrano[3,2-c]quinoline 201 with high diastereoselectivity (Scheme 62).

Scheme 62. InCl₃-Catalyzed Synthesis of Pyranoquinolines.

Raghunathan et al.²⁵ demonstrated the synthesis of tetrahydropyrazolo[4′,3′:5,6]thiopyrano[4,3-b]quinolines catalyzed by InCl₃ under mild conditions (Scheme 63). The products were obtained as a diastereomeric mixture of cis-isomer 204 as the major product and the trans-isomer 205 as the minor product.

Scheme 63. InCl₃-Catalyzed Synthesis of Pyrazole-Fused Thiopyranoquinolines.

5. Conclusions

This review encompasses catalytic applications of InCl₃ for synthesizing a wide range of heterocycles. It is evident from the above discussion that InCl₃ is a valuable Lewis acid catalyst for the synthesis of many heterocyclic scaffolds. The most attractive feature of this review is the application of InCl₃ to catalyze reactions in both organic and/or aqueous media with almost equal feasibility. It exhibits unique activity in this area owing to its high coordination number and fast coordination–dissociation equilibrium maintenance. In contrast, the application of InCl₃ along with a chiral auxiliary in asymmetric synthesis is still largely unexplored. Thus, the future of this area lies in the development of an enantioselective InCl₃ catalyst which may be air- and water-insensitive. Hence, InCl₃-catalyzed reactions have a huge potential for application in organic synthesis and green chemistry.

Biographies

Sanjit K. Mahato completed his Ph.D. (Organic Chemistry) from Jadavpur University in 2012 under the supervision of Prof. Parasuraman Jaisankar at the CSIR-Indian Institute of Chemical Biology, India, in the area of heterocyclic synthesis using catalysts. During his doctoral program, he also worked with Prof. Marek Zaidlewicz on borane-based oxazaborolidine asymmetric catalysis. He did postdoctoral training (November 2012 to October 2013) with Prof. K. Mallick at the University of Johannesburg on catalysis. Further postdoctoral training was with Prof. Emeritus Eli Breuer (November 2013 to January 2014) at the Institute for Drug Research, School of Pharmacy, Hebrew University of Jerusalem, Israel, where he worked on the design and synthesis of carbamoylphosphonic-based autotoxin inhibitors. He also worked at the Career Point University Hamirpur, India (August 2014 to July 2016) as an Assistant Professor in organic chemistry, and on deputation from this University, he served as a position of visiting scientist at Council for Scientific and Industrial Research in Pretoria, South Africa, and the Indian Institute of Technology in Bombay, India, under the joint supervision of Prof. A. Maity and Prof. Debabrata Maiti on catalysis funded by UNISA, South Africa (March 2015 to March 2016). This was followed by as a position of Research Scientist at TCG Lifesciences Pvt. Ltd. Kolkata, India (July 2016 to August 2018). Currently, he is working on the C–H activation reaction in the laboratory of Professor Naoto Chatani as a Specially Appointed Researcher (since September 2018) at the Department of Applied Chemistry, Osaka University, Japan.

Chiranjit Acharya obtained his B.Sc. in 2005 and his M.Sc. in 2007 from Vidyasagar University, Midnapore, West Bengal, India. He then moved to the CSIR-Indian Institute of Chemical Biology, Jadavpur, Kolkata, India, in 2009 and joined the group of Prof. Parasuraman Jaisankar as a junior research fellow (JRF) in the field of synthetic organic chemistry and chemical biology. He was also awarded a Senior Research Fellowship (SRF) in 2011 by the University Grant Commission (UGC). He also had an opportunity to work with Prof. Hiroshi Sugiyama at Kyoto University in Japan during his Ph.D. internship program in the field of DNA-catalyzed asymmetric Diels–Alder reactions in 2013. He was awarded the Ph.D. (Chemistry) degree by Jadavpur University in 2015 followed by a Research Associate (RA) award from CSIR in 2017. In the same year, he was also awarded the National Postdoctoral Fellowship (N-PDF) from DST in chemical science for continuing his postdoctoral research at the CSIR-Indian Institute of Chemical Technology, Hyderabad. He was recently awarded the prestigious Royal Society–SERB Newton International Fellowship by the Royal Society, UK, to pursue postdoctoral research at Liverpool John Moores University, UK.

Kevin W. Wellington obtained his Ph.D. (Chemistry) degree from Rhodes University, Grahamstown, South Africa, in 1999 under the supervision of Prof. Perry T. Kaye with whom he was also a postdoctoral fellow in 2000 in the area of asymmetric synthesis. He then joined the group of Prof. Kelly Chibale as a postdoctoral fellow at the University of Cape Town, South Africa, where he conducted research on the discovery of antimycobacterial agents with GlaxoSmithkline (2001–2002). In the USA, he worked as a postdoctoral associate with Prof. Steven A. Benner at the University of Florida and the Foundation of Applied Molecular Evolution in Gainesville, Florida, USA (2003–2006) in the area of nucleic acid chemistry for application in synthetic biology. He joined the Biosciences unit at the Council for Scientific and Industrial Research, Pretoria, South Africa, in January 2007. His research has been on the development of green methods (biocatalysis) for the synthesis of anticancer and antimicrobial agents and on the discovery of bioactive natural products from plants for application in human and animal health.

Pinaki Bhattacharje completed his B.Sc. in 2010 and M.Sc. in 2012 from North Bengal University, Darjeeling, West Bengal, India. He received “State Fellowship” from the Govt. of West Bengal to carry out research in the department of chemistry, North Bengal University, in the year of 2012. In September 2013, he moved to join the research group of Prof. Parasuraman Jaisankar at CSIR-Indian Institute of Chemical biology, Kolkata, India, to pursue his Ph.D. He was awarded CSIR-Senior Research Fellowship (Direct) in Organic Chemistry in April 2018. His research work is based on the design and synthesis of novel heterocycles and the study their photophysical, chiroptical, and biological properties.

Parasuraman Jaisankar was born on May 20, 1966 in Vinayagapuram Village, Tiruvannamalai Dist. Tamil Nadu, India, and did his M.Sc. (Chemistry) degree from Presidency College, Madras University, in 1989 and the Ph.D. degree from Jadavpur University, Kolkata, in 1995. He pursued his postdoctoral research (DAAD Fellowship; 1996–1998) on antisense oligonucleotides in association with Prof. Seliger of Ulm University, Germany, and has achieved a rare accomplishment of having worked with the group of Nobel Laureates, Prof. Ryoji Noyori and Prof. Masato Kitamura of Nagoya University, Japan, in the field of asymmetric catalysis. His research career started by joining CSIR-Indian Institute of Chemical Biology (January 1990), Kolkata, and presently he is the head of the department and holding permanent position as “Chief Scientist and Professor of Chemical Sciences, AcSIR, New Delhi”. He was the visiting Scientist to the Laboratory of Prof. Marek Zaidlewicz of Nicolaus Copernicus University in Toruń, Poland, during 2007–2008. He was awarded the “Raman Research Fellowship (RRF)” by CSIR for the year 2010 to visit Prof. Masato Kitamura’s Laboratory of Nagoya University, Japan, and again the DAAD fellowship (German Academic Exchange Service) under a reinvitation program in 2013 to the laboratory of Prof. Lukas Hintermann, Technical University of Munich (TUM), Germany. He is the recipient of the prestigious “Bharat Seva Ratan GOLD MEDAL” Award by Global Economic Progress & Research Association (GEPRA), New Delhi, for the year 2014. Recently, he was awarded the INSA International Fellowship award to NCUE, Taiwan, in the year 2015. He is the elected Fellow of West Bengal Academy of Science and Technology (FAScT) and Fellow of Institution of Chemists India (FIC). He is one of the founders and Secretary of Chemical Biology Society (CBS), India. He has supervised 21 Ph.D. and more than 26 masters and bachelor theses. Currently, he is continuing his research on catalysis and chemical biology with a 10-member team. Prof. Jaisankar has published over 100 research articles, filed 13 national and international patents, and is the author of three book chapters.

Author Present Address

^⊥ Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan.

Author Present Address

^# School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, United Kingdom.

The authors declare no competing financial interest.