Mechanistic studies of the zirconium-triisopropanolamine-catalyzed enantioselective addition of azide to cyclohexene oxide

The mechanism of the enantioselective ring-opening of cyclohexene oxide by Me3SiN3, catalyzed by zirconium complexes of the C-3-symmetric ligand (+)-(S,S,S)-triisopropanolamine, has been investigated. Measurements of molecular weights of precatalyst species show that complexes are formed with average trimeric aggregation. Kinetics measurements reveal the overall process to be approximately half order in total zirconium, epoxide, and Me3SiN3 components. The reaction also shows a strong nonlinear relationship between enantiomeric excess of product azido ether vs the incorporation of (R,S,S)-triisopropanolamine ligand in the catalyst mixture. On the basis of these and other results, a preequilibrium interconversion of dimeric and tetrameric zirconium-triisopropanolamine species is proposed to occur rapidly with respect to the rate of epoxide ring-opening, with the dimeric form being the active catalyst. The reaction is accelerated by silyl ethers or by small amounts of water or alcohol, whereas larger amounts of protic additives inhibit the reaction. Enantioselectivity is eroded at catalyst concentrations less than 1 mole-percent and at high concentrations of cyclohexene oxide. Both enantioselectivity and rate are influenced to a small extent by the nature of the silyl azide employed for the first catalytic turnover, suggesting that a silyl fragment becomes irreversibly incorporated in the catalyst structure. It is proposed that catalytic activity requires the cooperative action of two zirconium centers for the binding and delivery of azide to epoxide.