FeCl3-catalyzed alkylation of indoles with 1,3-dicarbonyl compounds: an expedient synthesis of 3-substituted indoles

Indoles undergo smooth alkylation at the 3-position with 1,3-dicarbonyl compounds in the presence of 20 mol % of FeCl₃ under mild reaction conditions to produce a wide range of 3-substituted indoles in excellent yields and with high E-selectivity.     

Direct palladium-catalyzed C-3 alkynylation of indoles

The direct palladium-catalyzed coupling reaction of indoles with alkynyl bromides was described in this paper. In the presence of catalytic amount of PdCl₂(PPh₃)₂ and 2.0 equiv. NaOAc, the coupling reaction of indoles with alkynyl bromides proceeded smoothly at 50 °C to give the corresponding 3-alkynylindoles with high regioselectivity in good to excellent yields.     

Indium trichloride catalyzed three component one-pot route to 1-hydroxymethyl-3-aminomethyl indoles

A one-pot synthesis of 1-hydroxymethyl-3-aminomethyl indoles 3 could be achieved in excellent yield by reacting indoles 1 with formaldehyde and secondary amines 2 in the presence of molecular sieves (3 Å) and catalytic amount of InCl₃ (10 mol %) in 1,4-dioxane at room temperature for 3-5 h.     

First example of FeCl3-catalyzed alkylation of indoles with pinenes

Indoles undergo smooth alkylation with α- and β-pinenes in the presence of 20 mol % of anhydrous FeCl₃ under mild reaction conditions to produce a wide range of the corresponding 3-alkylated indoles in excellent yields with high trans-selectivity. This is the first example of alkylation of indoles with mono-terpenes.     

One-pot oxidative carbon-carbon bond formation of 3-benzylic and 3-allylic indoles with carbon nucleophiles

Indolenines were generated at −78 °C from 3-benzylic or 3-allylic indoles by dehydrogenation with N-tert-butylbenzenesulfinimidoyl chloride, and a carbon-carbon bond was formed at −78 °C in a one-pot manner by treating these indolenines with various carbon nucleophiles such as active methylene compounds or organocuprates.     

Pd(OAc)2-catalyzed C-H activation of indoles: a facile synthesis of 3-cyanoindoles

Indoles undergo smooth cyanation with CuCN in the presence of 20 mol % Pd(OAc)₂ and 40 mol % CuBr₂ in DMF to produce a wide range of the corresponding 3-cyanoindoles in good yields with high regioselectivity.     

An FeCl3-catalyzed highly C3-selective Friedel-Crafts alkylation of indoles with alcohols

The FeCl₃-catalyzed C3-selective Friedel-Crafts alkylation of indoles using allylic, benzylic and propargylic alcohols has been developed. The reaction was performed in the presence of a catalytic amount of inexpensive anhydrous FeCl₃ (10 mol %) in nitromethane under mild conditions. This method can also be used for the alkylation of pyrrole.     

Enantioselective synthesis of (3-indolyl)glycine derivatives via asymmetric Friedel-Crafts reaction between indoles and glyoxylate imines

Chiral phosphoric acid-catalyzed enantioselective Friedel-Crafts reaction of indoles with ethyl glyoxylate imines was developed. With 10 mol % of the catalyst, the Friedel-Crafts reactions between a wide range of indoles and imines have been carried out, affording optically active (3-indolyl)glycine derivatives with excellent yields and high enantioselectivities (up to 87% ee).     

First example of the C-alkylation of indoles with Baylis-Hillman acetates

Baylis-Hillman acetates undergo S_N2′ allylic substitution with indoles in the presence of 20 mol % of indium tribromide under mild conditions to afford a new class of substituted indoles in high yields with (E)-stereoselectivity. The stereochemistry of the products was assigned by various NMR experiments.     

Catalyst-free,ethylene glycol promoted one-pot three component synthesis of 3-amino alkylated indoles via Mannich-type reaction

A highly efficient and sustainable approach for the multi-component synthesis of biologically important 3-amino alkylated indoles has been investigated via Mannich-type reaction under catalyst-free, ethylene glycol as a recyclable promoting medium. The wide applicability of the present method was examined with various substrates viz substituted aldehydes, indoles and secondary amines. This method will be useful for a large scale synthesis of 3-amino alkylated indoles without the use of column chromatography. The present method provides higher environmental compatibility and sustainability factors such as smaller E-factor (0.433) and higher atom-economy (AE = 93.3%).     

Bromodimethylsulfonium bromide (BDMS)-catalyzed multicomponent synthesis of 3-aminoalkylated indoles

Bromodimethylsulfonium bromide (BDMS)-catalyzed three-component coupling reaction between indoles, aldehydes, and N-alkylanilines is reported to access substituted 3-aminoalkylated indoles at room temperature in high yields (82-96%) within 1.5-3.5 h. The salient features of this protocol are the simplicity of the procedure, the ready accessibility of the catalyst, its cost effectiveness, and higher yields in relatively short reaction times.     

“On-water” synthesis of 3-substituted indoles via Knoevenagel/Michael addition sequence catalyzed by Cu doped ZnS NPs

Cu doped ZnS NPs represent a green catalyst for an ‘on-water’ one-pot rapid synthesis of 3-substituted indole derivatives via Knoevenagel/Michael addition reaction of indane-1,3-dione, aromatic aldehydes, and indole. The catalytic activity of Cu doped ZnS NPs was about sevenfold higher as compared to the ZnS NPs. The Cu doped ZnS NPs catalyst could be recovered and reused for five reaction cycles, giving a total TOF = 201 h⁻¹.     

Palladium-free zinc-mediated hydroamination of alkynes: efficient synthesis of indoles from 2-akynylaniline derivatives

Reaction of 2-phenylethynyl N-tosylanilide prepared by Pd-free procedure with ZnBr₂ (3 equiv) in refluxing toluene gave N-tosyl-2-phenylindole in 93% yield. Treatment of 2-phenylethynylaniline with ZnBr₂ (1 equiv) in refluxing toluene resulted in the formation of 2-phenylindole in 91% yield. Catalytic ZnBr₂ (0.05 equiv) effectively reacted with 2-alkynylanilines to afford 2-substituted indoles in high yields. Thus, complete Pd-free zinc catalyzed hydroamination of 2-alkynylanilines was achieved.     

Nucleus- and side-chain fluorinated 3-substituted indoles by a suitable combination of organometallic and radical chemistry

Regioselectively fluoro-, trifluoromethyl- and trifluoromethoxy-substituted 3-methyleneindolines have been prepared using a four-step procedure involving metalation/bromination of fluorinated Boc-protected anilines, N-propargylation of the resulting o-bromoarylcarbamate and reductive radical cyclization of the product with tributyltin hydride/AIBN. 3-Methyleneindolines, as valuable, versatile intermediates, can be transformed into highly functionalized 3-substituted indoles by ene-type reactions using different enophiles. Thus, fluoro-, trifluoromethyl- and trifluoromethoxy-substituted diethyl 2-hydroxy-2-[(1H-indol-3-yl)methyl]malonates, ethyl 2-hydroxy-3-(1H-indol-3-yl)propionates and ethyl 2-hydroxy-3-(1H-indol-3-yl)-2-trifluormethylpropionates were obtained in 77-86% yield by simply heating the corresponding tert-butyl 3-methyleneindoline-1-carboxylate with an equimolar amount of diethyl ketomalonate, ethyl glyoxalate and ethyl 3,3,3-trifluoropyruvate, respectively, at 100 °C, without solvent, for 0.5-4 h.     

Synthesis of substituted indoles using continuous flow micro reactors

Continuous flow micro fluidic devices for organic synthesis (‘micro reactors’) are becoming established in a number of facets of modern applied chemistry. As part of a concurrent research project with a pharmaceutical company for generation of materials of pharmaceutical interest within continuous flow environments, we present here, for the first time a series of indoles that have been produced within micro reactor systems. We have developed three different approaches to the synthesis, which are compared with traditional batch synthesis as well as each other in terms of ease of optimization, chemical suitability and versatility, and implications as to throughput. Typical throughputs of approach 1 (simulated classical synthesis) were in the region of 2 mgh⁻¹ of indoles such as tetrahydrocarbazole and cyclopentaindole. The second approach (based on Elk's modification of Fischer indole synthesis) gave throughputs of 5.7-8.9 mgh⁻¹ and the final approach (using heterocatalytic flow reactors) gave the highest throughputs of 12.7-20.1 mgh⁻¹. All throughputs are per single channel reactor system (i.e., one single reactor set up), and the latter two approaches produce viable output quantities for the syntheses of radiolabelled materials (where typically minute amounts of high purity materials are required from a rapid and safe production environment).     

Synthesis of 1,2,3,4-tetrahydrocarbazoles and related tricyclic indoles

Reduction of 2-(2-nitrophenyl)-2-cyclohexene-1-ones using palladium on carbon under 1 atm of hydrogen gas at ambient temperature affords 1,2,3,4-tetrahydrocarbazoles in excellent isolated yields. The starting materials were prepared by intermolecular Stille coupling of 2-iodo-2-cyclohexen-1-ones with 2-(tributylstannyl)-1-nitrobenzenes.     

Thorpe-Ingold effect in copper(II)-catalyzed formal hydroalkoxylation-hydroarylation reaction of alkynols with indoles

The use of Cu(OTf)₂ as a catalyst for tandem hydroalkoxylation-hydroarylation reaction of alkynes tethered with hydroxyl group is reported. The reaction proceeds at 60 °C or even at room temperature with 5 mol % catalyst loading and produces C-3-substituted indoles in good to high yields. The method was shown to be applicable to a broad range of indoles, containing electron-withdrawing and electron-donating substituents, and alkynol substrates bearing sterically demanding substituents in the tether. Interestingly, it was found that Thorpe-Ingold effect is operating for this cyclization reaction. Easy availability and low cost of Cu(OTf)₂ make this method attractive and amenable for large-scale synthesis compared to known literature methods.     

Gallium(III) triiodide catalyzed conjugate addition of indoles with α,β-unsaturated ketones

Reactions of indoles and α,β-unsaturated ketones could be effectively catalyzed by using 10 mol % gallium triiodide to give the corresponding Michael adducts in good to excellent yields.     

Gallium(III) halide-catalyzed coupling of indoles with phenylacetylene: synthesis of bis(indolyl)phenylethanes

Indoles undergo smooth coupling with phenylacetylene in the presence of 10 mol % of gallium(III) chloride or gallium(III) bromide under mild conditions to afford the corresponding 1,1-bis(1H-3-indolyl)-1-phenylethanes in high yields and with high selectivity.     

3-β-D-ribofuranosides (C-nucleosides) of indoles

The possibilities of the direct glycosylation of indoles with glycosyl halides that do not contain participating groups in the 2 position were studied. The and anomers of the corresponding C-ribofuranosides were obtained by the reaction of indole or its 5-bromo and 5- or 6-nitro derivatives with 2,3-O-isopropylidene-5-O-p-nitrobenzoyl-D-ribofuranosyl bromide in refluxing benzene in the presence of silver oxide and molecular sieves. O-Substituted 3--D-ribofuranosides of indoles undergo isomerization to the 3--anomers. Mixtures of anomeric 3,2-deoxy-D-ribofuranosyl-6-nitroindoles and 1,2-deoxy-D-ribofuranosyl-6-nitroindoles were synthesized. The structures of the compounds obtained were confirmed by data from PMR, IR, UV, and circular dichroism spectroscopy and mass spectrometry.See [1] for our preliminary communication.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 767–778, June, 1981.