Cobalt-Catalyzed, Aminoquinoline-Directed Functionalization of Nonactivated C(sp3)-H Bonds under Mild Conditions

Abstract

Abstract Second- and third-row transition metal catalysis in C(sp3)-H bond functionalization is well-established and is currently used in the synthesis of complex natural products, which can be considered the ultimate test of new synthetic methodologies. However, readily available and abundant first-row metals have been mostly employed in the functionalization of C(sp2)-H bonds. Their use in transformations of nonactivated (not benzylic or α to a heteroatom) C(sp3)-H bonds is rare and typically limited by the inability to functionalize secondary C–H bonds, high reaction temperatures, and the need to employ multiple equivalents of silver(I) oxidants. We report here a new approach to cobalt-catalyzed carbon–hydrogen bond functionalization by using a double-directing group strategy, enabling efficient activation of primary and secondary C(sp3)-H bonds under mild conditions to form β- or γ-lactams. Barium manganate is employed as an oxidant. Several Co(III) intermediates have been isolated and their reactivity is explored, supporting their involvement in the catalytic cycle. The reaction shows unusually high KIE kH/kD (>11) for C–H functionalization, allowing the use of deuterium as a blocking group, which enables amplified or switchable site selectivity. Mechanistic studies suggest a possible contribution of quantum tunneling in the C–H activation step.