Iridium and B(C6F5)3 co-catalyzed chemoselective deoxygenative reduction of tertiary amides: application to the efficient synthesis and late-stage modification of pharmaceuticals

The Vaska's complex-tris(pentafluorophenyl)borane combination was found to be a highly efficient cooperative catalysis system for the hydrosilylative reduction of tertiary amides to yield amines under mild conditions. The reaction shows high chemoselectivity, tolerating halide, phenolyl, alkenyl, nitro, nitrile, ester, azido, ketone, and enone functional groups. For unsubstituted cyclohexanone carboxamide, two variations were established to achieve either catalytic concomitant reduction of the two carbonyl groups or selective reduction of the amide carbonyl. The protocol was applied to the efficient synthesis and late-stage modification of several pharmaceuticals and derivatives. Importantly, we showed that by simply prolonging reaction time to 24-28 h, the reaction can reach an exceptionally high efficiency with turnover number (TON) up to 9.8x10(6) and turnover frequency (TOF) up to 408,333 at a quite low catalyst loading of 0.00001 mol% (S/C (Ir) = 10,000,000).

Automated summary

The Vaska's complex-tris(pentafluorophenyl)borane combination is an efficient cooperative catalysis system for the hydrosilylative reduction of tertiary amides to amines. The reaction is highly chemoselective, tolerating various functional groups, and has been applied for the synthesis and modification of pharmaceuticals. By prolonging the reaction time, exceptionally high efficiency with a low catalyst loading can be achieved.