Practical Access to <i>meta</i>‐Substituted Anilines by Amination of Quinone Imine Ketals Derived from Anisidines: Efficient Synthesis of Anti‐Psychotic Drugs
Naveen Yadav, Neha Taneja, Dulal Musib, Chinmoy Kumar Hazra
Abstract
Reversing the conventional site-selectivity of C-H activation provides efficient retrosynthetic disconnections to otherwise unreactive bonds. Described herein is the Brønsted acid-catalyzed reaction that selectively performs meta-amination of anisidines with aliphatic-, heterocyclic- and aromatic amines in a one-pot procedure. In addition to dramatically simplifying the synthesis of meta-substituted anilines, our approach has the advantage of the scalability and remarkable functional group tolerance, including late-stage functionalization of pharmaceutical compounds and natural products. The control experiments and detailed computational analysis provide insight into the reaction mechanism and the origin of meta-selectivity. The protocol extended to the synthesis of challenging tri-aminated arenes and successfully applied for the efficient synthesis of 5-HT6 receptor antagonists, the anti-psychotic drugs viz.. SB-214111, SB-258510, and specifically, anti-schizophrenic drug SB-271046.