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

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.

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.

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 ) 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 ).

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 ).

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 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 ) 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 ).

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 ).

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 ). 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 ).

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 ). 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 ).

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 ).

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 ). 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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

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 ). 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 ).

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 ).

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 ).

Scheme 27

InCl3-Catalyzed Synthesis of Pyrazole Derivatives

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 ). 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 ).

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 ). 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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

Scheme 40

InCl3-Catalyzed Oxidation of Hydroxychalcones and Dihydroflavones to Flavone Derivatives

Chen and co-workers[11i] 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 ).

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 ).

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 ).[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 ). 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 ).

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 ).[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 ).

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 ).

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 ).

Scheme 49

InCl3-Catalyzed Synthesis of Pyranoquinolines

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 ).

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 ).

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 ). 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 ). 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-workers[20] 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 ).

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 ). 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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

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 ).

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 ). 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

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.