Experimental and computational insights into the unexpected Type I dyotropic rearrangement within N-Clovanylamides synthetised via Microwave-assisted SnII-catalysis

Abstract

A novel and highly efficient synthesis method for the Ritter reaction of caryophyllene oxide yields N-(hydroxyclovanyl)amides via Sn(OTf)₂ catalysis under dielectric heating by microwave irradiation. This approach not only allows the accommodation of a variety of nitrile substrates, but also outperforms existing methods in terms of yield, selectivity, and reaction time. Notably, under such conditions, prolonged reaction times and elevated temperatures induce a subsequent Wagner-Meerwein rearrangement that modifies the B and C rings of their clovanyl skeleton. To our surprise, both the N-(9α-hydroxyclovan-2β-yl)acetamide and its rearranged derivative react with HBr to form a common brominated product, with retention of configuration at C-9. The mechanistic details of such stereospecific outcome have been elucidated through comprehensive DFT calculations. These show that both species converge into a common intermediate that undergoes a concerted Type I dyotropic rearrangement in the final key step. Herein, the already bound bromo moiety acts as one of the migrating groups, thus leading to a rare case of Type I dyotropic rearrangement.