Transition-metal-free silylboronate-mediated cross-couplings of organic fluorides with amines

Abstract

C–N bond cross-couplings are fundamental in the field of organic chemistry. Herein, silylboronate-mediated selective defluorinative cross-coupling of organic fluorides with secondary amines via a transition-metal-free strategy is disclosed. The cooperation of silylboronate and potassium tert-butoxide enables the room-temperature cross-coupling of C–F and N–H bonds, effectively avoiding the high barriers associated with thermally induced SN2 or SN1 amination. The significant advantage of this transformation is the selective activation of the C–F bond of the organic fluoride by silylboronate without affecting potentially cleavable C–O, C–Cl, heteroaryl C–H, or C–N bonds and CF3 groups. Tertiary amines with aromatic, heteroaromatic, and/or aliphatic groups were efficiently synthesized in a single step using electronically and sterically varying organic fluorides and N-alkylanilines or secondary amines. The protocol is extended to the late-stage syntheses of drug candidates, including their deuterium-labeled analogs.