Rapid Parallel Synthesis of Polymer-Bound Enones Utilizing Microwave-Assisted Solid-Phase Chemistry

A microwave-assisted parallel solid-phase synthesis of a collection of 21 polymer-bound enones has been developed. The two-step protocol involves initial high-speed acetoacetylation of polystyrene Wang resin with a selection of seven common beta-ketoesters. When microwave flash heating at 170 degreesC was employed, complete conversions were achieved within 1-10 min, a significant improvement over the conventional thermal method, which takes several hours for completion. Significant rate enhancements were also observed for the subsequent microwave-heated Knoevenagel condensations with a second set of 13 different aldehydes. Reaction times were reduced to 30-60 min at 125 degreesC in the microwave protocol compared to 1-2 days using conventional thermal conditions. Kinetic comparison studies indicate that the observed rate enhancements can be attributed to the rapid direct heating of the solvent (1,2-dichlorobenzene) by microwaves rather than to any specific microwave effect. All reactions have been carried out in commercially available parallel reactors with on-line temperature measurement, designed specifically for use in multimode microwave cavities.