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Examples of intramolecular alkene hydroaminations forming six-membered ring systems are rare, especially for systems in which the double bond is disubstituted. Such cyclizations have important synthetic relevance. Herein we report a systematic study of these cyclizations using recently developed Cope-type hydroamination methodologies. Difficult intramolecular alkene hydroaminations were used as key steps in syntheses of 2-epi-pumiliotoxin C, coniine, N-norreticuline and desbromoarborescidine A. This effort required the development of optimized hydroamination conditions to improve the efficiency of the cyclizations. Collectively, our results show that Cope-type cyclizations can be achieved on a variety of challenging substrates and proceed under similar conditions for both N-H and N-substituted hydroxylamines.

The condensation of ketones and hydroxylamines to form ketonitrones was reinvestigated by using thermal conditions previously found to minimize hydroxylamine decomposition (t-BuOH, 110 degrees C). This simple approach allows the formation of exocyclic, acyclic, and alpha,beta-unsaturated ketonitrones with benzylic, linear, and branched nitrogen substituents in modest to excellent isolated yields.

The synthesis of ketonitrones from N-alkylhydroxylamines and monosubstituted allenes is accomplished via a Cope-type hydroamination reaction in moderate to good yields. Allenes also undergo a similar reaction with aqueous hydroxylamine to give oximes in excellent yield. DFT calculations support a proposed concerted, five-membered hydroamination process, and calculated transition state energies are in excellent agreement with experimental observations.