Palladium(II)-Catalyzed 1,4-Oxidation of 2-Aryl-1,3-cyclohexadienes. Application to the Synthesis of (±)-Epibatidine and Analogues

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Abstract

Palladium(II)-catalyzed 1,4-chloroacetoxylation of 2-aryl-1,3-cyclohexadienes 2a and 2b resulted in a highly regio- and stereoselective reaction to give cis-1-acetoxy-3-aryl-4-chloro-2-cyclohexenes 7a and 7b, respectively. The phenyl adduct 7a was subjected to the synthesis of exo- and endo-2-phenyl-7-azabicyclo[2.2.1]heptanes (exo-1a and endo-1a). Stereoselective allylic nucleophilic substitution of the chloro group in 7a by tosylamide with either retention or inversion and hydrolysis to give 9a and 14a, respectively, followed by hydrogenation, cyclization, and deprotection afforded the target molecules. Interestingly, stereoselective hydrogenation of intermediates 9a and 14a afforded the required 1,2-cis and 1,2-trans relationships, respectively, between the nitrogen and the phenyl group. In an analogous manner, 7b was transformed to exo-12b, which previously has been converted to epibatidine.

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