An E-factor minimized protocol for the preparation of methyl beta-hydroxy esters

We report the optimization of the preparation of methyl beta-hydroxy esters (3a- l) in 75-93% yield by a solvent-free aldol reaction of aldehydes (1a-l) with KSA (2) followed by a de-silylation step. Amberlite IRA900F and Dowex 50Wx8 H were found to be the most efficient solid catalysts for the aldol addition and de-silylation steps, respectively. In order to minimize the use of organic solvent and automate the recovery of the catalysts and reaction products, we have developed an automated cyclic continuous-flow reactor operating under solvent-free or highly concentrated conditions. This system, applied to the reactions of 1a-c with 2, avoids the mechanical degradation of the catalysts and allowed reduction of the E-factor of the process to a very low value that ranges from 1.41 to 2.09.