Improved Synthetic Methodology, Substrate Scope and X-ray Crystal Structure for N, N’-disubstituted Guanidines

Guanidine is a privileged scaffold in drug discovery. Herein we report our investigations into the acid promoted amination of pyrimidine-bearing cyanamide to produce N, N’-disubstituted guanidines. Hydrochloric acid was found to be a suitable catalyst, and the substrate scope using conventional heating was investigated with 23 aniline derivatives. The highest yield was obtained with anilines having pKa in the range of 2–4. Further, a microwave synthesis was developed using 3-chloroaniline as a model substrate increasing the yield from 68 to 93 %. The microwave method was especially suited for increasing yields with anilines having pKa > 3. The structure of the pyrimidine-bearing guanidines was confirmed by NMR spectroscopy, and one representative compound has been evaluated by X-ray crystallography, showing the trans-isomer as the only tautomer in solid form.