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

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.

Automated summary

Cinnamylamines are important components of many drugs targeting G protein-coupled receptors. Existing methods for synthesizing 3,3-diarylallylamines often involve a multistep process that includes poorly-selective Wittig addition and direct aryl addition to N-protected cinnamylamines using aryl iodides which leads to decreased selectivity. However, by using aryl boronic acids, the yield and selectivity can be improved.