In archetypal transition metal-catalyzed cross-coupling reactions, a three step catalytic cycle mechanistically based on 2-electron processes is employed: oxidative addition of a halide at the transition metal, transmetalation of an organometallic nucleophile with an organo transition metal species, and reductive elimination, which releases the coupled product and regenerates the catalyst. Although such methods are highly effective for Csp2-Csp2 coupling, extension to secondary and tertiary Csp3-hybridized organoborons has proven challenging owing primarily to lower rates of transmetalation, which is rate limiting in most cross-coupling protocols operating under the traditional mechanistic manifold. To date, strategies aimed at facilitating the transmetalation of Csp3 the most desirale Suzuki coupling reactions employ excess aqueous base, high temperature, or addition of stoichiometric Cu or Ag salts, thereby eliminating virtually all of the advantages of using organoborons in cross-coupling. Often, the only viable alternative is to abandon the Suzuki approach and utilize more reactive organometallic reagents. The latter not only lack bench stability and severely limit functional group tolerability, but are not configurationally stable and/or are challenging to access in enantiopure form. The limitations of the transmetalation in the more desirable Suzuki couplings are inherent to the mechanism of this process at the most fundamental level, and thus predispose Csp3-hybridized alkylborons for failure. Described is a novel single electron mechanistic paradigm for cross-coupling that avoids this problem. Thus, integrated catalytic cycles are established: a photoredox catalytic cycle, generating radicals from diverse radical precursors, and a cross-coupling catalytic cycle that funnels these radicals into a base-metal catalytic cycle that effects the cross-coupling. In such a manner, methods to forge previously challenging or unexplored bond connections have been developed, allowing such transformations to occur at room temperature within hours.

Single electron transformations to enable cross-couplings via photoredox/Ni dual catalysis

251st National Meeting (2016)

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