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

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.