Journal of the American Chemical Society, Vol.142, No.11, 5117-5125, 2020
Iridium(I)-Catalyzed alpha-C(sp(3))-H Alkylation of Saturated Azacycles
Saturated azacycles are commonly encountered in bioactive compounds and approved therapeutic agents. The development of methods for functionalization of the alpha-methylene C-H bonds of these highly privileged building blocks is of great importance, especially in drug discovery. While much effort has been dedicated toward this goal by using a directed C-H activation approach, the development of directing groups that are both general as well as practical remains a significant challenge. Herein, the design and development of novel amidoxime directing groups is described for Ir(I)-catalyzed alpha-C(sp(3))-H alkylation of saturated azacycles using readily available olefins as coupling partners. This protocol extends the scope of saturated azacycles to piperidines, azepane, and tetrahydroisoquinoline that are incompatible with our previously reported directing group. A variety of olefin coupling partners, including previously unreactive disubstituted terminal olefins and internal olefins, are compatible with this transformation. The selectivity for a branched alpha-C(sp(3))-alkylation product is also observed for the first time when acrylate is used as the reaction partner. The development of practical, one-step installation and removal protocols further adds to the utility of amidoxime directing groups.