Ru-catalyzed room-temperature alkylation and late-stage alkylation of arenes with primary alkyl bromides

Abstract

The C–H alkylation of arenes with N-based directing groups typically requires high temperatures and/or harsh reaction conditions, which has traditionally reduced its functional group compatibility and applicability for late-stage functionalization. We report that a cyclometallated Ru complex is able to perform the C–H alkylation of arenes bearing a variety of N-directing groups with primary alkyl bromides at room temperature and under mild reaction conditions. We demonstrate this with an extended substrate scope, which includes several examples of late-stage alkylation of drug molecules, thus showcasing the “real-world” capabilities of this method. Mechanistic studies show that, in contrast to previous mechanistic proposals, the reaction proceeds via a bis-cyclometallated Ru intermediate, followed by an S N 2-type oxidative addition. • Mono-cyclometallated ruthenium complex enables room-temperature alkylation • Late-stage alkylation of pharmaceutical molecules • Detailed mechanistic studies, including kinetic analysis and NMR studies The formation of Csp 2 –Csp 3 bonds is one of the most fundamental synthetic transformations enabling the construction of a target molecule's “skeleton.” Classical methods can be limited by issues such as harsh conditions, the need for highly specialized reagents, and restricted functional group tolerance. C–H activation is a key enabling approach in organic synthesis, allowing for the streamlining of syntheses and improved atom economy. However, these processes often require harsh conditions, preventing their application to the late-stage alkylation of pharmaceutical and other highly functionalized compounds. We report a mild new method for the alkylation of arenes directed by a variety of nitrogen-containing functionalities. The reaction, which proceeds at room temperature, shows exquisite functional group tolerance and has been applied to the direct functionalization of several pharmaceutical molecules, showcasing its power for the functionalization of “real-world” molecules. We report a new method for the C–H alkylation of arenes using a cyclometallated ruthenium catalyst. This method shows significant functional group tolerance and has been applied to the late-stage alkylation of several pharmaceutical compounds. Mechanistic studies point toward a mechanism proceeding through a bis-cyclometallated intermediate.