A method for carrying out the intramolecular Schmidt reaction of alkyl azides and ketones using a substoichiometric amount of catalyst is reported. Following extensive screening, the use of the strong hydrogen bond donating solvent hexafluoro-2-propanol was found to be consistent with low catalyst loadings, which range from 2.5 mol% for favorable substrates to 25 mol% for more difficult cases. Reaction optimization, broad substrate scope, and preliminary mechanistic studies of this improved version of the reaction are described.

The tricyclic core of the cylindricine or lepadiformine families of alkaloid natural products was assembled via a Prins addition/intramolecular Schmidt rearrangement under Lewis acid conditions. Both single-pot and two-stage variations of this process were examined, with particular attention to the stereochemical outcome of the processes. This technology has been applied to a formal total synthesis of lepadiformine A and a total synthesis of lepadiformine C.

The intramolecular Schmidt reaction of ketones and tethered azides is an efficient method for the generation of amides and lactams. This reaction is catalyzed by Lewis acids, which tightly bind the strongly basic amide product and result in product inhibition. We report herein conditions to achieve a catalytic Schmidt reaction using substoichiometric amounts of the heat-stable Lewis acid Sc(OTf)3. This species was shown to effectively release products of the Schmidt reaction in a temperature-dependent fashion. Thus, heat was able to promote catalyst turnover. A brief substrate scope was conducted using these conditions.