Mechanistic study of copper-catalyzed intramolecular ortho-C-H activation/carbon-nitrogen and carbon-oxygen cyclizations

Intramolecular ortho-C-H activation and C-N/C-O cyclizations of phenyl amidines and amides have recently been achieved under Cu catalysis. These reactions provide important examples of Cu-catalyzed functionalization of inert C-H bonds, but their mechanisms remain poorly understood. In the present study the several possible mechanisms including electrophilic aro- matic substitution, concerted metalation-deprotonation （CMD）, Friedel-Crafts mechanism, radical mechanism, and proton- coupled electron transfer have been theoretically examined. Cu（II）-assisted CMD mechanism is found to be the most feasible for both C-O and C-N cyclizations. This mechanism includes three steps, i.e. CMD with Cu（II）, oxidation of the Cu（II） inter- mediate, and reductive elimination from Cu（III）. Our calculations show that Cu（II） mediates the C-H activation through an six-membered ring CMD transition state similar to that proposed for many Pd-catalyzed C-H activation reactions. It is also in- teresting to find that the rate-limiting steps are different for C-N and C-O cyclizations： for the former it is concerted metalation-deprotonation with Cu（II）, whereas for the latter it is reductive elimination from Cu（III）. The above conclusions are consistent with the experimental kinetic isotope effects （1.0 and 2.1 for C-O and C-N cyclizations, respectively）, substituent effects, and the reactions under O2-free conditions.

Intramolecular ortho-C-H activation and C-N/C-O cyclizations of phenyl amidines and amides have recently been achieved under Cu catalysis. These reactions provide important examples of Cu-catalyzed functionalization of inert C-H bonds, but their mechanisms remain poorly understood. In the present study the several possible mechanisms including electrophilic aromatic substitution, concerted metalation-deprotonation (CMD), Friedel-Crafts mechanism, radical mechanism, and protoncoupled electron transfer have been theoretically examined. Cu(Ⅱ)-assisted CMD mechanism is found to be the most feasible for both C-O and C-N cyclizations. This mechanism includes three steps, i.e. CMD with Cu(Ⅱ), oxidation of the Cu(Ⅱ) intermediate, and reductive elimination from Cu(Ⅲ). Our calculations show that Cu(Ⅱ) mediates the C-H activation through an six-membered ring CMD transition state similar to that proposed for many Pd-catalyzed C-H activation reactions. It is also interesting to find that the rate-limiting steps are different for C-N and C-O cyclizations: for the former it is concerted metalation-deprotonation with Cu(Ⅱ), whereas for the latter it is reductive elimination from Cu(Ⅲ). The above conclusions are consistent with the experimental kinetic isotope effects (1.0 and 2.1 for C-O and C-N cyclizations, respectively), substituent effects, and the reactions under O2 -free conditions.