Synthesis of Biaryls Having a Piperidylmethyl Group Based on Space Integration of Lithiation, Borylation, and Suzuki-Miyaura Coupling

In a flow microreactor, aryllithiums bearing a piperidylmethyl group were generated using nBuLi by precise residence time control and effective temperature control, and then selectively borylated with boronic esters such as 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (BpinOiPr) and trimethyl borate B(OMe)(3) by fast mixing. Moreover, the direct integration with Suzuki-Miyaura cross coupling were successfully achieved to obtain nitrogen-containing biaryl compounds. The present method could be applied for the straightforward synthesis of the key intermediate of a bioactive component bearing a piperidylmethyl-biphenyl framework.