Hydrogen-Bonding as a Factor to Determine the Regioselectivity for Pd-mediated C-H Activation of Pyridine

摘要

Direct and regioselective functionalization of pyridine is a topic of high scientific and technological importance. In spite of extensive efforts, the regioselective functionalization of pyridine still remains a significant challenge due to their low reactivity and presence of Lewis-basic sp(2) nitrogen. Here, we studied the effect of hydrogen bonding interactions on the regiochemical outcome of Pd-mediated C-H activation of pyridine by utilizing DFT calculations. We demonstrated that hydrogen bonding can act as a second independent factor to override the inherent regioselectivity of pyridine. This novel approach complements previously reported strategies, such as: (a) coordination of pyridine to transition metal center via its N-center, (b) installation of directing group (DG) and then coordination of pyridine to the transition metal center via this DG (i. e. chelation assistant strategy), (c) protection of its nitrogen lone pair with N-oxide or N-imino groups or with Lewis acids, (d) the inherent positional reactivity of C-H bonds based on the electronic or steric properties of the substituents, and (e) by the identity of the oxidant used. We have also demonstrated that the oxidation state of the Pd catalyst has impact on the regiochemical outcome of the C-H activation step in pyridine. The implications of our study for regioselective C-H functionalization catalyst design of heteroarenes are twofold: It demonstrates (1) hydrogen bonding as a viable design principle, and (2) Pd(IV) as a catalyst for C-H functionalization.