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Updated: May 29, 2025

Facile Preparation of 4-Substituted Quinazoline Derivatives
Published on: February 15, 2016
Development of a Highly Selective Synthesis of 4-Substituted Tetrahydroquinolines: Substrate Scope and Mechanistic
Jeanette Piña1, Lupita S Aguirre1, Levi T Litwiller1
1Department of Chemistry, Texas A&M University, 580 Ross St, College Station, TX, USA, 77843 1.
None:
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.
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