Novel cleavage reaction of the C16-N17 bond in naltrexone derivatives

A dealkylation reaction of tertiary amines using chloroformate was a useful method for synthesizing morphinan derivatives without 17-substituents; however, the reaction has been applied to only the 14-hydromorphinans. In the course of the investigation of the 17-dealkylation reaction in 14-hydroxymorphinan, the novel cleavage reaction of the C16-N17 bond in the naltrexone derivative was found. A plausible reaction mechanism based on the stereoelectronic effect is presented. The examinations of dealkylation reactions in general tertiary amines ranked the tendency of cleavage as follows: benzyl > cyclopropylmethyl (CPM) ≈ allyl > methyl, ethyl. The preferable cleavage of the CPM group may be explained by the polarization of CPM-N17 bond due to a postulation of extreme stability of the cyclopropylcarbinyl cation.