Synthesis of 3-(Quinazolin-4-yl)propionic Acids via an Acid-Catalyzed Rearrangement of 4-Oxobutyronitriles

Abstract

4-(2-Aminophenyl)-4-oxobutyronitriles in the presence of formic acid (HCOOH) and p-toluenesulfonic acid (TsOH) undergo an unusual rearrangement providing access to a range of 3-(quinazolin-4-yl)propionic acids that have been poorly represented in the literature, with only a few isolated examples known to date. The reaction demonstrates a new route to the quinazoline core through transfer of the nitrile group nitrogen, mediated through the formation of a pyrrolidine cycle. The availability of 4-oxobutyronitrile precursors—2′-aminochacones—provides high variability of substituents in the required positions of product. The transformation is general and can be extended to the preparation of 2-substituted 3-(quinazolin-4-yl)propionic acids through preliminary acylation or to the synthesis of 4-(quinazolin-4-yl)butyric acids.