Ligand-enabled enantio- and site-selective remote C–H arylation of 2-(2-phenpropyl)pyridine derivatives†

Abstract

The great potential of transition metal-catalyzed C–H functionalization lies in its ability to selectively target specific C–H bonds in complex molecules. Therefore, the development of enantio- and site-selective C–H functionalization is a long-term pursuit in this field. Herein, we disclose a ligand-enabled enantio- and site-selective remote C–H arylation of 2-(2-phenylpropyl)pyridine derivatives. The combination of an acetyl-protected aminoethyl phenyl thioether (MPA-thiol) with aryl iodides is found to enable γ-C(sp³)–H arylation, whereas l-pyroglutamic acid (l-pGlu) promotes δ-C(sp²)–H cross-coupling with various aryl-Bpin moieties. Notably, both C–H arylations proceed with high enantioselectivity and good yields. The results of DFT calculations support the enantioselectivity and site-selectivity of these two C–H arylations. Moreover the utility of this transformation was demonstrated by derivatization of a harmane alkaloid, a gram scale reaction and the successful removal of the pyridyl directing group.