Heterobiaryl synthesis by contractive C-C coupling via P(V) intermediates.

ABSTRACT: Heterobiaryls composed of pyridine and diazine rings are key components of pharmaceuticals and are often central to pharmacological function. We present an alternative approach to metal-catalyzed cross-coupling to make heterobiaryls using contractive phosphorus C-C couplings, also termed phosphorus ligand coupling reactions. The process starts by regioselective phosphorus substitution of the C-H bonds para to nitrogen in two successive heterocycles; ligand coupling is then triggered via acidic alcohol solutions to form the heterobiaryl bond. Mechanistic studies imply that ligand coupling is an asynchronous process involving migration of one heterocycle to the ipso position of the other around a central pentacoordinate P(V) atom. The strategy can be applied to complex drug-like molecules containing multiple reactive sites and polar functional groups, and also enables convergent coupling of drug fragments and late-stage heteroarylation of pharmaceuticals.

SUBMITTER: Hilton MC 

PROVIDER: S-EPMC6814017 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature