Theoretical Underpinning of Synergetic Ir/Cu-Metallaphotoredox Catalysis in Multicomponent C-N Cross-Coupling Reactions

Abstract

Recent years have witnessed a growing interest in multicomponent reactions (MCRs) as environmental benign and reliable synthetic strategies for drug discovery. Though MCRs have been significantly explored in photoredox-transition metal dual catalysis, photocatalyst-copper dual catalysis is quite underdeveloped due to an unclear mechanistic basis. Herein, we discuss theoretical investigations unraveling the mechanistic avenues in IrIII-CuII dual catalyzed MCRs of a carboxylic acid (as an alkyl radical precursor X•), [1.1.1]propellane and a N-nucleophile leading to three component C-N coupled products, experimentally reported by MacMillan. We investigated the radical formation pathway, defined the favored photoredox catalytic cycle, and found the favorable reaction pathway within the Cu-catalytic cycle, and finally we elucidated the origin of selectivity between three-component and two-component coupling products. Our computations suggest that the N-H bond activation is the rate-limiting step. The preference for a two-component coupling product over a three-component product is governed by the relative stabilities of the CuII-X• intermediates. Energy decomposition analysis reveals a fairly strong correlation existing between the energy span for the three-component product generation and stabilizing electrostatic interaction within the CuII and X• fragments in CuII-X•.