Cooperative Phosphine-Photoredox Catalysis Enables N–H Activation of Azoles for Intermolecular Olefin Hydroamination
Kassandra Sedillo, Flora Fan, Robert R. Knowles, Abigail G. Doyle
Abstract
Catalytic intermolecular olefin hydroamination is an enabling synthetic strategy that offers direct and atom-economical access to a variety of nitrogen-containing compounds from abundant feedstocks. However, despite numerous advances in catalyst design and reaction development, hydroamination of N–H azoles with unactivated olefins remains an unsolved problem in synthesis. We report a dual phosphine and photoredox catalytic protocol for the hydroamination of numerous structurally diverse and medicinally relevant N–H azoles with unactivated olefins. Hydroamination proceeds with high anti-Markovnikov regioselectivity and N -site selectivity. The mild conditions and high functional group tolerance of the reaction permit the rapid construction of molecular complexity and late-stage functionalization of bioactive compounds. N–H bond activation is proposed to proceed via polar addition of the N–H azole to a phosphine radical cation, followed by P–N α-scission from a phosphoranyl radical intermediate. Reactivity and N -site selectivity are classified by azole N–H BDFE and nitrogen-centered radical spin density, respectively, which can serve as a useful predictive aid in extending the reaction to unseen azoles.