Mechanism and Origins of Enantio- and Regioselectivities in Catalytic Asymmetric Minisci-Type Addition to Heteroarenes

Abstract

This work presents a density functional theory (DFT) study on the mechanism and origins of enantio- and regioselectivities in dual photoredox/chiral Brønsted acid-catalyzed asymmetric Minisci-type addition of carbon-centered radicals to N-heteroarenes [<i>Science</i>, <b>2018</b>, <i>360</i>, 419-422]. The previously proposed mechanism has been partially revised. First, photoexcited *[Ir^III] is reductively quenched by TRIP anion rather than the experimentally proposed neutral radical generated from the chiral Brønsted acid cycle. Second, final product formation involves a hydrogen-atom transfer (HAT) from a neutral radical intermediate to the TRIP radical, instead of single-electron transfer (SET) to *[Ir^III]. The TRIP catalyst has been shown to play a triple role by reductively quenching *[Ir^III] with its anion form, activating the substrate, and inducing asymmetry. The calculated results rationalize the experimentally observed enantio- and regioselectivities and reveal that the enantioselectivity of the reaction originates from the hydrogen-bond interaction between TRIP and the N-H group of the carbon-centered radical, and the regioselectivity arises from the electron-withdrawing inductive effect from the protonated N-atom and the intramolecular hydrogen-bond interaction between the acetylamino group and the protonated pyridine ring. We also provide explanations for the experimentally observed a dramatic decrease in enantioselectivity when changing substrate or radical precursor and rationalize the solvent-controlled switch of regioselectivity.