Terpenoids are an irreplaceable class of natural products. The camphoryl group is an important moiety in the structure of chiral ligands for asymmetric synthesis catalysis or it can be used as an auxiliary group in asymmetric synthesis. The usage of fenchone based molecules for asymmetric catalysis and synthesis is less common because of the difficulty of fenchone modifications due to steric hindrance. Camphor is a readily available starting molecule for the preparation of different compounds with biological activity. For example, camphor diimines demonstrate antiviral activity. Fenchonyl amine-based molecules are potential therapeutic agents for the treatment of Alzheimer’s disease.
Amines are a crucial class of organic compounds with multiple academic and industrial applications. There are a plethora of synthetic approaches towards amines synthesis and modifications, reductive amination being one of the most powerful and useful methods. However, the reductive amination of camphor and fenchone remains a challenge. A standard approach to reductive amination with amines other than ammonia and methylamine includes two steps: preparation of azomethines or Schiff bases in the presence of strong Lewis acids and their reduction with more or less conventional reducing agents. The synthesis of fenchonyl amines is even more challenging. There is no universal approach, and almost every manuscript reports some particular protocol different from others.
In most cases, the first stage of this process requires quite harsh conditions. For example, the preparation of a Schiff base from camphor and 1-phenylethylamine requires 5-10 days of heating at 150°C. Schiff bases of other primary amines could be prepared under similarly harsh conditions. Preparation of enamines is possible using titanium tetrachloride as a catalyst. The reduction also might be challenging. Sodium borohydride or sodium cyanoborohydride was described as suitable for this goal in several reports. To the best of our knowledge, no papers describe any general approach for the direct reductive amination of camphor or fenchone. There is only one example of camphor direct reductive amination without an external hydrogen source using carbon monoxide as a reducing agent. This protocol is very efficient but its application is limited by the necessity of carbon monoxide and high-pressure equipment for the reaction setup.