A new format for the Castagnoli-Cushman reaction of structurally diverse dicarboxylic acids, amines, and aldehydes in the presence of acetic anhydride as dehydrating agent is described. The reaction is distinctly amenable to parallel format: the combinatorial array of 180 reactions delivered 157 products of >85% purity without chromatographic purification (of this number, 143 compounds had >94% purity). The new method offers a convenient preparation of the skeletally and peripherally diverse, lead- and druglike γ- and δ-lactam carboxylic acids with high diastereoselectivity in combinatorial fashion.
Keywords: Castagnoli−Cushman reaction; Schiff bases; cyclodehydration; diversity-oriented synthesis; multicomponent reactions; phase separation; skeletal diversity.