Development of a Protocol for Synthesis of Nitrocinnamonitriles from Nitrotoluenes

A novel protocol for the synthesis of 2- and 4-nitrocinnamonitriles from the corresponding nitrotoluene derivatives has been developed. Condensation of 2- or 4-nitrotoluene derivatives with N,N-dimethylformamide dimethyl acetal (DMF·DMA) afforded the corresponding (2- or 4-nitrophenyl)acetaldehyde enamines. Subsequent Strecker-type hydrocyanation across the enamine moiety, followed by Cope elimination of the N,N-dimethylamino group, furnished the desired nitrocinnamonitriles. This method was broadly applicable to ortho- and para-nitrotoluene derivatives and provided a variety of structurally diverse nitrocinnamonitriles in good to high yields. Notably, the protocol exhibited exclusive site selectivity, functionalizing only the benzylic position ortho or para to the nitro substituent on the nitrotoluene scaffold. Furthermore, it was compatible with polysubstituted aromatic rings and could be readily extended to a broad range of heteroaromatic systems.