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.

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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 synthesis of 2-epi-pumiliotoxin C was achieved in ten steps from cyclohexadiene oxide, using a challenging Cope-type hydroamination key step. This cyclization was performed on a mixture of two epimeric hydroxylamines, and a boat transition state is proposed to explain the kinetic preference observed for the cyclization of the epimer leading to N-hydroxy-epipumiliotoxin C.Saturated, six-membered nitrogen heterocycles are present in a variety of natural products and medicinally important compounds. Diverse synthetic strategies and methods have been developed to access such motifs, and a variety of general, broadly applicable approaches have emerged. Strategies that involve formation of the heterocyclic ring system include cycloadditions, reductive aminations, iminium-based cyclizations, and ring-closing metathesis (to name a few). Intramolecular hydroaminations also hold the potential to be broadly applicable: 1 the cyclization can occur via formation of the C-N bond between a nitrogen atom and an unsaturated precursor (alkyne, allene, diene, or alkene) and stereoselective variants are possible. 2 However, hydroamination remains an underutilized synthetic strategy in heterocyclic synthesis (Scheme 1). 3 Scheme 1Reported examples of six-membered ring formation via intramolecular alkene hydroamination are especially rare. Most of these examples feature the use of transition-metal catalysts and require terminal alkenes, 4 and it is well established that increased alkene substitution, especially at the distal position (R 2 = H), usually results in significantly decreased hydroamination reactivity. 5 From a synthetic standpoint, such hydroaminations are desirable and could offer a unified approach for the synthesis of various alkaloid families, including 2-alkylpiperidines, benzyl tetrahydroisoquines, and b-carbolines. As such, synthetic efforts addressing this critical requirement for distal alkene substitution in six-membered ring-forming intramolecular hydroaminations are needed. 5 Herein, we report such synthetic studies in the pumiliotoxin C system that resulted in the synthesis of 2-epi-pumilitoxin C (Scheme 2). 6 Scheme 2In line with our current efforts focusing on Cope-type hydroaminations as a concerted, thermal alternative to the use of transition-metal catalysis, 7,8 we selected hydroxylamine 1b (R = OH) as the desired cyclization precursor. Since six-membered forming Cope-House cyclizations have mostly been reported on terminal alkenes (Scheme 3), 9 difficult cyclization was expected. However, based on our intermolecular studies that highlighted the importance of the proton-transfer step of the N-oxide intermediate to the hydroxylamine, 7a we speculated that protic solvents could provide increased efficiency in Cope-House cyclizations, and allow this difficult cyclization despite the distal alkene substituent present in 1. Scheme 3