Tandem Catalytic Indolization/Enantioconvergent Substitution of Alcohols by Borrowing Hydrogen to Access Tricyclic Indoles

Abstract

An efficient tandem catalysis method is achieved for the direct conversion of alcohol‐containing alkynyl anilines to valuable chiral 2,3‐fused tricyclic indoles. This method relies on a tandem indolization followed by enantioconvergent substitution of alcohols via borrowing hydrogen to construct two rings in one step, enabled by relay and cooperative catalysis of a chiral iridium complex with a chiral phosphoric acid. Highly diastereoselective transformations of the tricyclic indole products also provide efficient access to a diverse array of complex polycyclic indoline compounds.

Cobalt-catalysed CH-alkylation of indoles with alcohols by borrowing hydrogen methodology

“…In this respect, the direct C-alkylation of indoles with alcohols by socalled catalytic 'borrowing hydrogen (BH) methodology' or "hydrogen autotransfer" reaction is a more suitable methodology with water as the only by-product. [18][19][20][21][22][23] In general, the C3-alkylation of indoles with alcohols involves the following steps (Scheme 1): (i) acceptorless dehydrogenation of alcohol to the corresponding aldehyde, (ii) nucleophilic addition of an alkylideneindolenine formation to the aldehyde and elimination of water. Finally, in situ hydro- Following the BH strategy, Grigg pioneered the C3-alkylation of indoles with benzyl alcohols as the alkyl source in the presence of [Cp*IrCl 2 ] 2 .…”

“…In this respect, the direct C-alkylation of indoles with alcohols by so-called catalytic ‘borrowing hydrogen (BH) methodology’ or “hydrogen autotransfer” reaction is a more suitable methodology with water as the only by-product. 18–23…”

Synthesis of C7-Functionalized Indoles through an Aromaticity Destruction–Reconstruction Process

“…2-Alkynyl­anilines are widely used starting materials in the synthesis of heterocyclic compounds. Although a number of cyclization or cascade cyclization/cross-coupling reactions of 2-alkynyl­anilines have been developed in the synthesis of indoles with diverse substitutions on the pyrrole ring (Scheme , paths a and b), a method that allows rapid access to C7-functionalized indoles remains an unmet need in reaction design. Under oxidizing conditions, the dearomatization of 2-alkynyl­anilines forms 2-alkynylcyclo­hexadienimines, and these dearomatized intermediates have been used in the synthesis of C4-functionalized indoles (Scheme , path c) .…”

Transition-Metal-Catalyzed Enantioselective Synthesis of Indoles from 2-Alkynylanilines

“…Very recently, based on the combination of asymmetric relay catalysis and borrowing hydrogen methodology, Zhao and co-workers described an efficient synthesis of tricyclic indoles from alcohol-containing 2-alkynylanilines (Scheme 19). 48 In the presence of [Ir(cod)OMe] 2 /(S)-Segphos as a metal-catalyst and CPA-2 as an organic catalyst, a number of alkyl-substituted tricyclic indoles were prepared in reasonable to high yields and enantioselectivities. However, only a 12% ee and a 50% yield of 105c were obtained in which R was a furan group.…”