Synthesis of β- and γ-Carbolines by the Palladium/Copper-Catalyzed Coupling and Cyclization of Terminal Acetylenes

Abstract

A variety of 3-substituted beta- and gamma-carbolines have been synthesized from N-substituted 3-iodoindole-2-carboxaldehydes and 2-bromoindole-3-carboxaldehydes, respectively. The coupling of these aldehydes with various terminal acetylenes with PdCl(2)(PPh(3))(2)/CuI as the catalyst readily affords the corresponding alkynylindole carboxaldehydes, which have subsequently been converted to the corresponding tert-butylimines and cyclized to beta- and gamma-carbolines by either copper-catalyzed or thermal processes.

Copper-Catalyzed Tandem Imine Formation, Sonogashira Coupling and Intramolecular Hydroamination: A Facile Synthesis of 3-Aryl-γ−carbolines

“…This is particularly significant because unprotected 2‐bromo‐indole‐3‐carbaldehydes reacted sluggishly under these conditions to produce, for instance 3fa , in <10%. Our findings along with the literature reports further substantiate that unprotected 2‐halo‐indole‐3‐carbaldehydes are poor substrates for the direct synthesis of N ‐unsubstituted γ‐carbolines under metal catalysis.…”

“…Because of their importance in biological and medicinal field, development of simple and efficient protocols for the construction of carbolines and their derivatives under mild conditions is a continued area of research. In the pioneering work, the Larock group described the synthesis of γ‐carbolines using combination of Pd−Cu catalysts in two steps via iminium intermediate . Very recently, the Verma group reported the synthesis of γ‐carboline by a three‐component tandem approach from o‐ haloindole‐3‐carboxaldehydes, alkynes and tert ‐butylamine using a bimetallic Pd/Cu catalytic system .…”

“…All currently known synthetic methods of γ‐carbolines involving alkynes utilize Pd catalysis in combination with Cu. The overall strategy is based on first attaining Sonogashira coupling between o ‐halo aldehydes and alkynes mediated by the combination of Pd/Cu catalytic system followed by Cu‐catalyzed electrophilic cyclization in the presence of tert ‐butylamine . Although, traditionally Sonogashira coupling reactions have been carried out in the presence of combination of Pd and Cu catalysts, reports in the literature exist where Sonogashira coupling reactions have been achieved using Cu‐based catalysts as the sole catalyst system .…”

Domino Benzylic‐Amination–Sonogashira–Heterocyclisation Reaction: Direct Access to Dipyrido[1,2‐a:3′,4′‐d]imidazole Salts

“…This transformation can be promoted by both metals used in the domino process 19. But in the presence of both copper and palladium, Larock et al proposed a copper(I) catalyst for this transformation 20. The coordination of the copper catalyst to the triple bond allowed N‐cyclisation, leading to vinyl‐copper species F , which is transformed into G in the presence of the base.…”

A Straightforward Synthesis of Benzofuran- and Indole-Substituted 1,2,3-Triazoles via Click Chemistry

“…To realize this goal, we decided to use in situ deprotection and the click approach starting from 2-(silylalkynyl)-substituted benzofuran derivatives. Indeed, we easily performed the synthesis of compound 4, as reported in the literature 18 and of compound 5, that, when subjected to the reactions with several azides (Table 3) led to the desired compounds 2 and 6 in fair to high yields (55-89%). The overall results are reported in Table 3.…”