Within the expansive alkene functionalization toolkit, hydroarylation is a rapidly evolving area of synthetic methodology. Recently, nickel catalysis has emerged as powerful means of effecting alkene hydroarylation of styrenes and 1,3-dienes. Methods for the regioselective hydrofunctionalization of unactivated alkenes still remain underdeveloped. One strategy developed by our group and others is to utilize a removable bidentate directing auxiliary. Given that the bidentate directing group occupies two coordination sites on the nickel center, it diminishes the possibility for an ancillary ligand to play a dominant role in controlling the regioselectivity and enantioselectivity of the reaction. With this in mind, we surmised that use of a weakly coordinating monodentate directing group would create an opportunity for a ligand to have a dominant role in influencing regio- or stereochemical outcomes.<br/>After extensive screening, a novel Pyrox ligand was designed to function as a “toggle switch” in the regiodivergent hydroaylation and alkenylation of alkenyl carboxylates using alcohol solvent as only hydride source. With this method, anti-Markovnikov products can be accessed with a 4,4-dibenzyl substituted Pyrox ligand in excellent yield and &gt;20:1 selectivity. Alternatively, Markovnikov hydrofunctionalization products are obtained under mild ligand-free conditions, with up to 99% yield and &gt;20:1 selectivity.<br/>While anti-Markovnikov hydroarylation of non-conjugated alkenes has developed rapidly during the past several years, markovnikov-selective hydroarylation reactions, on the other hand, are comparatively rare. Building on our results on the regiodivergent hydrofunctionalization of alkenyl carboxylates, we sought to expand the scope of Markovnikov-selective hydroarylation to other classes of alkene starting materials bearing native functionalities, thereby enhancing the preparative utility of this approach. To this end, we explored the hydrofunctionalization reactions of alkenyl sulfonamides, ketones, and amides. The unique coordination environments of each family of alkene substrates requires carefully optimized reaction conditions (particularly with respect to inorganic base and solvent). Despite proceeding via a sterically and electronically disfavored secondary alkylnickel intermediate, high Markovnikov selectivity was achieved, arising from the preference for formation of a 5-membered metallacycle intermediate.

Ligand-controlled regiodivergence in nickel-catalyzed hydroarylation and hydroalkenylation

ACS Spring 2022

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