(407d) Development of New Flow Reactors and Their Application for Rhodium-Catalyzed C-H Activation in Organic Synthesis

C-H functionalization is an emerging synthetic strategy allowing for innovation in total synthesis and new methodologies for drug development. One particularly useful C-H functionalization procedure has been the C-H insertion chemistry of transient metal carbenes, which are typically generated from diazo compounds. As an example, rhodium-stabilized donor/acceptor carbenes have been shown to be highly effective in a wide range of intermolecular C-H functionalization reactions, in which the site selectivity and stereoselectivity are dominated by catalyst control. However, a potential drawback of the use of diazo compounds as carbene precursors is the issue of safe handling of large quantities of these high-energy compounds. Additionally, Rh catalysts can be quite expensive, and methodologies of maximizing catalyst turnover number and potentially recovering Rh for reprocessing are needed.

Three advances will be described in this lecture, all developed in the Center for C-H Functionalization (CCHF). First, a new type of microfluidic flow reactor was developed based on polymeric hollow fibers that have been deployed large scale gas separations. Second, modified Rh₂complexes that are can be grafted onto solid supports have been developed. Third, the utilization of the Rh catalysts in several enantioselective coupling reactions has been demonstrated in flow, including in conjunction with on-demand, flow synthesis of the reactive diazonium compounds.