Domino Cydoadditions in Parallel Fashion

GlaxoSmithKline Pharmaceuticals in Harlow, UK, investigated domino cydoaddi-tions in a commerdal chip and extended their process development by operation in 

The domino reaction consists of a Knoevenagel condensation giving an intermediate that immediately undergoes an intramolecular hetero-Diels-Alder reaction with inverse electron demand [38]. As aldehydes, rac-citronellal, an aromatic aldehyde, and two commercially available 1,3-diketones, 1,3-dimethylbarbituric acid and Meldrum s acid, were selected. By combinations of these reactants, different cycloadducts were generated. 

Process development was accomplished in single-run reactions [38[. The conversion of the microchannel processing amounted typically to about 50-75%, depending on the nature of cycloadduct and the residence time chosen, and was comparable to the results of batch syntheses [38[. By combinations of aldehydes and 1,3-diketones, different cycloadducts were generated simultaneously in one run on one chip, that is, an undesired transfer of solutions from one channel to another by imperfect sealing between these channels. The conversions were comparable to the single runs, with one exception. Also, cross-contamination was observed. It ranged from a few percent to about 50%. 

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