Oxidative Mizoroki–Heck reaction of unprotected cinnamylamines at ambient temperature under air

Abstract

Cinnamylamines make-up many important drugs that target G protein-coupled receptors. While 3,3-diarylallylamines can be prepared via existing synthetic methods, these often require poorly-selective Wittig addition to unsymmetrical ketones, and multistep sequences thereafter to reach the allylamine product. Methods that make use of direct aryl addition to N-protected cinnamylamines via a Mizoroki–Heck pathway are known, however, unprotected cinnamylamines are sensitive to a mixture of C–H activation and Mizoroki–Heck arylation under Pd-catalysed arylation conditions using aryl iodides. This leads to a decrease in the trans/cis selectivity that can be achieved under these reaction conditions. By reimagining the reaction and using aryl boronic acids, we have herein demonstrated how in many cases the yield and E/Z selectivity can be improved. The in situ-formed active catalyst is more sensitive under these conditions, and was observed to shut down at elevated temperatures.