Mechanistic studies on the enantioselective BINOLAM/titanium(IV)-catalyzed cyanobenzoylation of aldehydes: Part 1

Article abstract of DOI:10.1016/j.tetasy.2011.07.006

The enantioselective titanium(IV)-catalyzed cyanobenzoylation of aldehydes using 1:1 BINOLAM/Ti(OiPr)₄ mixtures as a precatalyst gave O-aroyl cyanohydrins 4 with good enantiomeric excesses. The standard optimization set carried out on the assumption of Curtin-Hammett behavior, led to no amelioration. Extensive experimental and computational studies were carried out with the purpose of identifying the key mechanistic aspects governing enantioselectivity. HCN and isopropyl benzoate were detected in the reacting mixtures. This as well as the reaction response to the presence of an exogenous base, and the failure to react in the presence of Binol/Ti(OiPr)₄ mixtures, led us to propose, not a direct but an indirect process involving an enantioselective hydrocyanation step followed by O-benzoylation. Computational work carried out with mononuclear monomeric M_M and dinuclear mixed dimer D_lMD as catalysts support this mechanistic proposal. On the other hand, cyanobenzoylations carried out with 1:2 or higher 1:n (up to 1:5) BINOLAM/Ti(OiPr)₄ mixtures appear to involve a reversal of the enantioselection. This, together with the fact that the benzoylation of the ligated iPrOH is a slow reaction, has led us to conclude that these cyanobenzoylations do not fit within the standard Curtin-Hammett kinetic scheme. Instead, such BINOLAM/Ti(OiPr)₄ -catalyzed cyanobenzoylations of aldehydes rather behave as non-Curtin-Hammett kinetic schemes. Further computational analysis is needed in order to make a clear distinction between Curtin-Hammett and non-Curtin-Hammett kinetic frameworks.