Synthesis of 2‐Substituted Indoles by Pd‐Catalyzed Reductive Cyclization of 1‐Halo‐2‐nitrobenzene with Alkynes

Abstract

An effective process for synthesizing 2-substituted indoles in a one-pot tandem reaction of 1-halo-2-nitrobenzene and terminal alkynes through addition/reductive cyclization is presented. This protocol involves a Sonogashira-type coupling reaction followed by reductive cyclization employing dppf (1,1'bis(diphenylphosphino)ferrocene) ligated Pd dithiolate complex as a catalyst and Zn as an inexpensive reductant. This efficient and tandem process tolerates broad functional groups with moderate to good yields. The gram-scale synthesis of 2substituted indole has also been demonstrated. This protocol provides an alternative route for the synthesis of 2-substituted indoles.

Synthesis of Indoles via Domino Reactions of 2-Methoxytoluene and Nitriles

“… , Consequently, numerous synthetic methods have been developed to access the 2-arylindole substructure. Classic routes include the Fischer indole synthesis while contemporary approaches employ transition-metal catalysts, including direct C-2 arylation of pre-existing indoles, − and intramolecular cyclization of functionalized anilines, − and many others. − Some of these approaches employ harsh reagents, highly functionalized precursors, or cryogenic temperatures that are challenging to access on scale. Therefore, more straightforward, efficient, and practical synthetic methods without addition of transition metals for the assembly of 2-arylindoles remain in demand.…”

Recent Advances in the Synthesis of Five‐membered Nitrogen Heterocycles Induced by Palladium Ions and Complexes

“…2-Nitroiodobenzenes in combination with alkynes were also used in indole synthesis. [85] The catalyst, dppf-ligated Pd dithiolate complex 15 [Pd 2 (dppf) 2 (4,4'-SC 12 H 8 S)] 2 (OTf) 4 ], was employed in combination with trimethylamine as base, Zn as reductant, and Me 3 SiCl as additive in acetonitrile. Data collected in Scheme 61 show a very low to high yield range.…”

Recent Progress in Pd-Catalyzed Tandem Processes

“…Cyclization is another type of reaction widely used in fine synthesis [67][68][69][70][71][72][73][74][75][76]. Such reactions can proceed with the in situ-generated active species as a part of tandem catalytic transformations.…”