Joint Experimental/Theoretical Investigation of the Chemoselective Iridium(III) Metallacycle-Catalyzed Reduction of Substituted γ-Lactams by Et3SiH

Abstract

This study addresses the chemoselectivity of the catalyzed reduction of a series of variously substituted γ-lactams by Et₃SiH mediated by a pentamethylcyclopentadienyl iridacyclic acetonitrilo salt derived from benzo[h]quinoline. Introduction of an unsaturation within the 5-membered ring of the γ-lactam annihilates the precedence of the amide function over the capture of the silylium cation, which results in a lower chemoselectivity. Monitoring over time the catalyzed reduction of a γ-lactam bearing a carboxylic ester appendage by ¹H NMR spectroscopy revealed pseudo-zero-order kinetics for the prior hydrosilylation of the lactam’s amide. This primary hydrosilylation reaction is followed by the full conversion of the formed intermediate into a pyrrolidine following a pseudo-first-order rate law. Under anhydrous conditions, the hydrosilylation of the pendant ester function occurs only in a late stage once the γ-lactam’s amide function has underwent full reduction of the carbonyl function. DFT investigations show that chemoselectivity is governed (1) by the affinity of the organic substrate for the triethylsilylium cation produced by the electrophilic activation of Et₃SiH by the Ir(III) catalyst and (2) by the ability of the in situ-formed hydrido-iridium(III) intermediate to transfer hydride to the activated substrate.