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

Abstract

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.

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