Selective Pyridine-Directed C-H Activations Enabled Synthesis of Pyridine-Pyridone Α-Helix Mimics

The search for pyridine directed C-H activation in 2-benzyl-6-phenylpyridine and related systems identified selective bromination at ortho-phenyl instead of ortho-benzyl position via Rh catalysis. In contrast, the failed analogous alkylation suggested that the intermediate rhodacycle likely preferred Rh(III) to Rh(V) pathway to avoid steric congestion amplified by pyridine di-substitutions. This mechanistic understanding facilitated development of improved bromination reactions to provide moderate to good yields of functionalized intermediates that enabled synthesis of pyridine-pyridone α-helix mimics 1b/1c .