Cu-Catalyzed Coupling of Aliphatic Amines with Alkylboronic Esters

We report a Cu-catalyzed oxidative coupling of aliphatic amines with benzylic and aliphatic boronic esters to give high value alkyl amines, products found widely in applications from medicinal chemistry to materials science. This operationally simple reaction, which can be performed on gram scale, runs under mild conditions and exhibits broad functional group tolerance. The terminal oxidant of the reaction is O2 from the air, avoiding the need for additional chemical oxidants. Investigation into the reaction mechanism suggests that the boronic ester is activated by an aminyl radical, formed through oxidation of the amine by the Cu catalyst, to give a key alkyl radical intermediate. To demonstrate its utility and potential for late-stage functionalization, we showcase the method as the final step in the total synthesis of a TRPV1 antagonist. We report the Cu-catalysed coupling of alkylboronic esters and aliphatic amines. This mild method is functional group tolerant, and uses O2 from air as the terminal oxidant. Investigation into the mechanism suggest that the boronic ester reacts with an aminyl radical, formed in situ, to generate an alkyl radical intermediate. image