Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Micro-Flow Reactor.

Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventional lactamization includes acid-mediated approaches and coupling agent-mediated approaches that suffer from a narrow substrate scope, much waste, and/or high cost. Inexpensive, less wasteful and highly electrophilic reagent-mediated approaches are attractive, but there is an imminent risk of side reactions. Herein, we describe methods using highly electrophilic triphosgene in a micro-flow reactor that accomplish lactamization that are rapid (0.5-10 sec), mild, inexpensive, and less wasteful. We developed two methods, referred to here as A and B, using NMM and NMI, respectively. Various lactams as well as a cyclic peptide containing acid- and/or heat-labile functional groups were synthesized in good to high yields without the need for tedious purifications. Undesired reactions were successfully suppressed and the risk in handling triphosgene was minimized by the use of micro-flow technology.