In traditional cross-coupling reactions, a three step catalytic cycle mechanistically based on 2-electron processes is employed: oxidative addition of a halide at Pd0 or Ni0, transmetalation of an organoboron nucleophile with an organometallic(II) species, and reductive elimination, which releases the coupled product and regenerates the Pd0 or Ni0 catalyst. Although such methods are highly effective for Csp2-Csp2 coupling, extension to 2o and 3o Csp3-hybridized organoboron reagents in particular has proven challenging owing primarily to lower rates of transmetalation, which is rate limiting in many alkylmetallic cross-coupling protocols operating under the traditional mechanistic manifold. To date, strategies aimed at facilitating the transmetalation of Csp3 cross-coupling reactions employ harsh reaction conditions or highly reactive organometallic reagents. The latter not only lack bench stability but also severely limit functional group tolerability. The limitations of the transmetalation in cross-coupling reactions are inherent to the mechanism of this process at the most fundamental level, and thus predispose many Csp3-hybridized alkylmetallic reagents for failure. Described is a novel, single electron mechanistic paradigm for cross-coupling that avoids this problem. Thus, dual catalytic cycles are established: a photoredox catalytic cycle, generating radicals from appropriate precursors, and a cross-coupling catalytic cycle that funnels these radicals into a base metal catalytic cycle that effects the cross-coupling. The nature of the cross-coupling cycle, in which high-energy radical intermediates engage the cross-coupling catalyst, insures a cascade of low energy events leading to product, avoiding the high energy of activation associated with previous cross-coupling protocols. Described will be our efforts to develop a suite of radical precursors for cross-coupling, emphasizing the tolerability of the developed conditions to an unprecedented array of functional groups.

Photoredox/nickel dual catalytic cross-coupling and related processes

253rd National Meeting (2017)

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