Microwave-assisted Biginelli production

As a suitable model reaction to highlight the steps necessary to successfully translate thermal conditions to microwave conditions, and to outline the general workflow associated with any microwave-assisted reaction sequence, in this section we describe the complete protocol from reaction optimization through to the production of an automated library by sequential microwave-assisted synthesis for the case of the Biginelli three-component dihydropyrimidine condensation (Scheme 5.1) [2, 3],... 

In searching for further expansions of dihydropyrimidine scaffold, Kappe and co-workers [359] immobilized 4-chloroacetoacetate on hydroxymethylpolystyrene resin by a microwave-assisted transesterification in 1,2-dichlorobenzene. The subsequent Biginelli condensation with the aldehyde and the urea components was performed in dioxane at 70 °C in the presence of catalytic amounts of HCl. Low yields, observed in the case of two out of twelve aldehyde building blocks employed, were attributed to the low solubility and reactivity of the bisureide side products. Further manipulations of the BigineUi products, involving thermal, amine-, or hydrazine-mediated cyclizations, gave access to various dihydropyrimidine-condensed heterocycles (461), (462), and (464) respectively (Scheme 95). 

Another procedure for preparation of valuable heterocyclic scaffolds involves the Biginelli condensation on a PEG Support [75, 76]. Polymer-bound acetoacetate was prepared by reacting commercially available PEG 4000 with 2,2,6-trimethyl-4H-l,3-dioxin-4-one in toluene under reflux (Scheme 16.52). The microwave-assisted cyclocondensation was performed with nonvolatile polyphosphoric acid (PPA) as a catalyst in a domestic microwave oven [76]. During microwave heating the PEG-bound substrate melted, ensuring a homogeneous reaction mixture. After the reaction diethyl ether was added to precipitate the polymer bound products. The desired compounds were released by treatment with sodium methoxide in methanol at room temperature. All dihydropyrimidines were obtained in high yield purification was achieved by recrystallization from ethanol. 

---