Pyridine N-Oxide vs Pyridine Substrates for Rh(III)-Catalyzed Oxidative C-H Bond Functionalization.

The origin of the high reactivity and site selectivity of pyridine N-oxide substrates in O-pivaloyl hydroxamic acid-directed Rh(III)-catalyzed (4+2) annulation reactions with alkynes was investigated computationally. The reactions of the analogous pyridine derivatives were previously reported to be slower and to display poor site selectivity for functionalization of the C(2)–H vs the C(4)–H bonds of the pyridine ring. The N-oxide substrates are found to be more reactive overall because the directing group interacts more strongly with Rh. For N-oxide substrates, alkyne insertion is rate-limiting and selectivity-determining in the reaction with a dialkyl alkyne, but C–H activation can be selectivity-determining with other coupling partners such as terminal alkynes. The rates of reaction with a dialkyl alkyne at the two sites of a pyridine substrate are limited by two different steps: C–H activation is limiting for C(2)-functionalization, while alkyne insertion is limiting for C(4)-functionalization. Consist...