Dearomatization strategies for the synthesis of azaspirocycles

Construction of spirocyclic centers is a challenging problem in organic synthesis. The synthesis of spirocycles can be accomplished from arene compounds via the process of nucleophilic aromatic addition. While this is normally an unfavorable reaction pathway, coordination of arene ligands to transition metal fragments renders the arenes electrophilic; hence nucleophilic substitution and addition reactions become feasible. As part of efforts aimed at expanding the synthetic utility of arene metal complexes, a stereocontrolled approach to 2-azaspiro[4.5]decanes from arene ruthenium precursors has been developed. It has been found that beta-amido phosphonate groups tethered to arene ruthenium fragments participate in tandem spirocyclization/Horner-Wadsworth-Emmons olefination reactions upon treatment with base and aldehyde. The reaction is compatible with various aldehydes and with functional groups on the arene ring. This process is inherently stereoselective and cyclohexadienyl ruthenium complexes are obtained as readily isolable products. The spirocyclic complexes are air and moisture stable materials that are isolated in generally good yields. Oxidative demetalation of these complexes using copper salts then affords spiroheterocyclic building blocks. Demetalation performed under an atmosphere of CO permits recovery of the ruthenium fragment as a form of its dicarbonyl adduct. Certain cyclohexadienyl complexes undergo skeletal rearrangement upon demetalation to give fused ring tetrahydroisoquinoline derivatives. Chiral non-racemic azaspirocycles can be conveniently prepared starting from alpha substituted benzyl amines. As a complement to Ru-mediated synthesis, oxidative cyclization manifolds mediated by hypervalent iodine reagents were also explored. beta-Keto amide derivatives functionalized with phenol ether substituents were found to participate in oxidative cyclization to afford dearomatized spirocyclic products. The scope of this last reaction type, however, appears to be limited.