Hydrolysis of Iminium Ethers Derived from the Reaction of Ketones with Hydroxy Azides:  Synthesis of Macrocyclic Lactams and Lactones

The hydrolysis of iminium ether intermediates formed by a nitrogen insertion sequence involving azido alcohols 1 or 2 and ketones was investigated. Ketones containing 6−12-membered rings were surveyed and shown to provide lactams and lactones in good to excellent overall yield. Reactions employing acetone or 5-nonanone gave similar results, generating analogous amides and esters. The relative amounts of lactone vs lactam produced in a given reaction were found to depend on the structures of the reactants and the pH of the basic media used to hydrolyze the iminium ethers. A mechanism accounting for the formation of each product is discussed in terms of ring strain and the protonation state of ortho ester aminal intermediates.