Temperature and steric hindrance-regulated selective synthesis of ketamine derivatives and 2-aryl-cycloketone-1-carboxamides via nucleophilic substitution and Favorskii rearrangement†

Abstract

A selective temperature and steric hindrance-regulated method for nucleophilic substitution or Favorskii rearrangement reactions of 2-aryl-2-bromo-cycloketones with aliphatic amines has been developed to prepare ketamine derivatives and 2-aryl-cycloketone-1-carboxamides. In the presence of secondary amines or ortho-substituted 2-aryl-2-bromocycloketones, steric hindrance directs the Favorskii rearrangement to occur. Conversely, with primary amines, the product ratio of nucleophilic substitution to Favorskii rearrangement is temperature-dependent, with higher temperatures favoring the Favorskii rearrangement. At lower temperatures (−25 °C or below), nucleophilic substitution predominates, yielding ketamine derivatives in yields of 60% to 85%. This method effectively utilizes temperature and steric hindrance to control the reaction pathway and optimize product formation.