Over 80% of the top-selling small molecule drugs contain at least one phenyl ring, and in addition 80% of small molecule drugs contain nitrogen. Incidentally, cinnamylamines, which contain at least one phenyl ring and one nitrogen, are of great importance in natural products, as well as in medicinal, agricultural, and even in materials chemistry. Palladium-catalyzed organometallic transformations, though a powerful tool for synthetic chemistry, are difficult to perform on free amine-containing substrates due to the substrates’ susceptibility to side reactions such as oxidation via β-hydride elimination, allylic deamination, intramolecular cyclization, and even N-functionalization. However, it is critical to develop methods that are compatible with amines without the need for protection and deprotection of the reactive nitrogen, particularly in pharmaceuticals, where the protecting group can interfere with the physical and chemical properties of the drug targets. As a result, a Pd-catalyzed regioselective functionalization of unprotected allylamines was sought. Previous work has shown that for allylamines it is possible to achieve selective γ-arylation by use of CO2 as a transient protecting group, however, stereoselectivity was poor due to competing pathways between a C–H activation and a nanoparticle-catalyzed Mizoroki-Heck reaction which stereospecifically gave Z and E-products respectively. To improve the use of this chemistry for pharmaceutical production, there is a need to develop a method to obtain selective products. A better understanding of the controlled Pd-catalyzed reactions of allylamines can also be used to access new bond disconnections.

Selective Mizoroki–Heck reactions on allylamines

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