Comprehensive Reinvestigation of Carbodiimide Guanylation: HCl-Initiated Access to Tri- and Tetrasubstituted Guanidines

Abstract

Guanidines are well-known π-electron-conjugated organic bases used widely in synthesis as well as in industry, with more than 150 years of history. Hence, a plethora of synthetic approaches leading to the formation of the central N3C motif has been published, from conventional methods to more sophisticated catalysts. Despite this, some substrates are still not easily obtainable, and the reported procedures lack simplicity and universality. Here, procedures yielding guanidines from carbodiimides and various amines are provided. Thermally conducted reactions of aliphatic amines and carbodiimides led to guanidines, but efforts to extend this method to anilines failed, even with basic or some acidic catalysts. However, when HCl was added to the reaction media at >80 °C, guanidine products were successfully prepared. Thorough mechanistic investigations revealed the complexity of the guanylation, including several proton transfers, the unconventional switch of the reaction mechanism to electrophilic addition, and the regeneration of the catalytically active species. The process was optimized and applicable to a series of various substrates with the use of substoichiometric or even catalytic amounts of HCl. Guanidine structures, the guanylation mechanism, and prototropic tautomerism of aryl-substituted guanidines in solution were investigated by scXRD, NMR spectroscopy, and DFT calculations. An optimized, easy, cheap, and high-yield metal-free procedure catalyzed by HCl was described.