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.

[reaction: see text] The combination of the intramolecular Schmidt reaction with the Diels-Alder reaction provides expedient access to a variety of heterocycles. Two different modes of reaction planning are presented. In one, the azide and ketone moieties necessary for the intramolecular Schmidt reaction originate on different molecules that are reacted and subsequently undergo a ring-adjustment step. Alternatively, an azido ketone can be used provided the ketone is deactivated by its presence in an enone.

A synthetic sequence was developed in which a diene containing an attached secondary amine was reacted with maleic anhydride to afford the title structures in one step. The reaction involves a Diels-Alder reaction combined with a transacylation reaction of the imide group. A series of six scaffolds was constructed using this methodology. Each scaffold was subsequently reacted with 12 amines to afford a library containing 72 compounds.

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.

Ring closure reactions O 0130 Domino Reactions that Combine an Azido-Schmidt Ring Expansion with the Diels-Alder Reaction. -Two conceptually different ways concerning the title reaction are investigated, 1. an olefinic azide reacts with unsaturated carbonyl compounds, 2. a substrate containing double bonds, azide and keto function reacts with dienes. A variety of heterocyclic structures is obtained including skeletons of natural products. In the case of azidoketones (XIV) and cyclohexadiene, only the Diels-Alder adducts (XX) are observed. -(ZENG, Y.; REDDY, D. S. D.; HIRT, E.; AUBE*, J.; Org. Lett. 6 (2004) 26, 4993-4995; Dep. Med. Chem., Univ. Kans., Lawrence, KS 66045, USA; Eng.) -Steudel 17-042