Development of a Highly Selective Synthesis of 4-Substituted Tetrahydroquinolines: Substrate Scope and Mechanistic Study

Herein, we describe a general and selective deprotonation functionalization reaction of tetrahydroquinolines at the 4–position using organolithiums and phosphoramide ligands. In addition to the development of a direct deprotonation alkylation reaction with primary and secondary alkyl halides, a Negishi cross–coupling protocol was realized to afford products with a range of aromatic halides. These methods were applied to the late-stage installation of tetrahydroquinolines into a variety of substrates including pharmaceuticals as well as natural product analogues. The use of thorough mechanistic investigations revealed the aggregation state of the newly formed tetrahydroquinoline anion to be a separated ion pair, which proved critical to optimizing the reaction conditions.