Phosphine-mediated azine C-H couplings with water and ammonia

The unique reactivity of transition metals has advanced C-H functionalization chemistry, enabling practitioners to directly modify drug and agrochemical compounds during Structure Activity Relationship (SAR) studies. These metals are particularly adept at transforming the C-H bonds of arenes and aromatic heterocycles, generating new reactions that form C-C and C-heteroatom bonds. However, among the many potential coupling partners, (hetero)arene C-H coupling reactions with water and ammonia are rare.^1-5 Despite being two of the most abundant chemicals on Earth, their reactivity can be at odds with transition metal complexes and the elementary steps associated with C-O/C-N bond formation.⁶ We suspected that elements outside of the transition metal block might instead facilitate these reactions. Here, we show that simple triarylphosphines enable selective azine C-H coupling with water and ammonia. The reactions proceed via a distinct mechanism where pendant aldehyde and imine functional groups interconvert to acetal- and aminal-type forms, studied here both experimentally and computationally. This unusual example of neighboring group participation effectively delivers water and ammonia molecules into a P(V) coordination environment, promoting C-O and C-N bond formation via ligand-coupling reactions.⁷ A broad range of pyridines are compatible, as well as quinolines and diazines, and the chemistry functions as a late-stage tactic for hydroxylation and amination of complex pharmaceuticals and agrochemicals.