Reversal of Regioselectivity in Catalytic Arene-Ynamide Cyclization: Direct Synthesis of Valuable Azepino[4,5‑b]indoles and β‑Carbolines and DFT Calculations

Ynamides are important building blocks in organic synthesis, and a variety of versatile synthetic methods have been developed in the past decade. Among these, catalytic cyclizations of π-tethered ynamides are particularly attractive, since this approach enables facile access to a diverse array of synthetically useful nitrogen heterocycles. However, due to the fact that the nitrogen atom is able to impose an electronic bias, these cyclizations exclusively occur on the α position of ynamides. Herein, we report the reversal of regioselectivity in arene-ynamide cyclization by copper catalysis, which represents the first catalytic π-tethered ynamide cyclization involving the reversal of regioselectivity. This strategy allows the expedient and practical synthesis of valuable azepino­[4,5-b]­indoles and β-carbolines in generally high yields under mild conditions. Moreover, the relevant mechanistic rationale for this cyclization, especially for the observed high regioselectivity, is strongly supported by density functional theory (DFT) calculations. The synthetic utility of this chemistry is also indicated by the synthesis of several biologically active compounds and natural product bauerine A.