Exploiting Coordination Behavior of 7‐Azaindole for Mechanistic Investigation of Chan‐Lam Coupling and Application to 7‐Azaindole Based Pharmacophores
Krishanu Mondal, Narottam Mukhopadhyay, Arunava Sengupta, Tanumay Roy, Parthasarathi Das
Abstract
Multiple spectroscopic techniques, along with single-crystal X-ray analysis, have been used to reveal the detailed structural and electronic information on reaction intermediates of a new copper(II)-DBU catalytic system for the N-arylation of 7-Azaindole. The reaction mixture of Chan-Lam cross-coupling yields two dimeric copper(II)-7-azaindole complexes, including one attached with DBU, prior to adding arylboronic acid and are confirmed structurally and spectroscopically. A suitable mechanism has been proposed using the dimeric copper(II) complex as a catalyst for the coupling reactions. The role of DBU as a base and also as an auxiliary ligand in the course of the reaction has been established. The transmetalated monomeric aryl-copper(II) species generated from the dimeric unit is oxidized by another equivalent of copper(II) to yield an aryl-copper(III) intermediate for facile N-arylation, which has been authenticated with UV-vis spectroscopy. The regeneration of the copper(II)-catalyst by aerial oxidation of colorless copper(I) species (generated via reductive elimination and disproportionation step) is confirmed by mass and absorption spectroscopy. Detailed DFT and TD-DFT calculations help to rationalize the proposed reaction intermediates and their corresponding electronic transitions. Moreover, the confirmation of copper(I)-7-azaindole intermediate via HRMS reaffirmed the involvement of Cu(II)/Cu(III)/Cu(I) species in the Chan-Lam type of coupling. A medicinally-important 7-azaindole-based SHP2 inhibitor has been synthesized via sequential arylation.