Copper-Catalyzed (4+1) Cascade Annulation of Terminal Alkynes with 2-(Tosylmethyl)anilines: Synthesis of 2,3-Disubstituted Indoles

Abstract

A novel strategy based on Cu-catalyzed (4+1) cascade annulation of terminal alkynes as one-carbon synthons with 2-(tosylmethyl)­anilines has been developed for the expeditious synthesis of 2,3-disubstituted indoles, in which in situ generations of aza-o-quinone methides and alkynyl-copper­(I) species are involved. This annulation provides an effective method for the assembly of synthetically and structurally interesting 2,3-disubstituted indoles.

Recent Advances in Indole Synthesis and the Related Alkylation

“…(19) Fan reported a novel strategy for the expeditious synthesis of 2,3-disubstituted indoles, in which in situ generations of azao-quinone methides and alkynyl-copper(I) species were involved. [24] This protocol was based on Cu-catalyzed (4 + 1) cascade annulation of terminal alkynes as one-carbon synthons with 2-(tosylmethyl)anilines, providing an effective method for the assembly of synthetically and structurally interesting 2,3disubstituted indoles [Eq. (20)].…”

“…[27] A broad range of substituents were found to be tolerated for the synthesis of the target products in high yields and high regio-selectivities [Eq. (23)(24)].…”

“…(23) (24) Ding demonstrated the Ag(I)-catalyzed regioselective cyclization, affording indole N-carboximidamides or N-carboximidoates which were obtained by aza-Wittig reaction and further reaction of the carbodiimides with amines or alcohols [28] [Eq. ( 25)].…”

Recent Advances in Nonprecious Metal Catalysis

“…One novel strategy employed to prepare indoles involves a [4 + 1] cascade between terminal alkynes and 2-tosylmethylanilines (Scheme ). In this process, catalytic DBU and stoichiometric Cs 2 CO 3 promote deprotonation to liberate the tosyl group, which yields an aza- o -quinone methide species that undergoes addition to a Cu acetylide followed by insertion of the amide into the alkyne. This cascade results in an exo -olefin that isomerizes to the indole.…”

Cobalt-catalyzed C(sp3)–H bond functionalization to access indole derivatives

“…4 However, most of these elegant works focus on precious metal-based catalysts (Pd, Rh, Ru, etc . ), 5 and first-row transition metal-catalyzed C–H bond activation to construct indole derivatives, 6 especially for cobalt catalysts, has been reported very rarely.…”