Guanidium Unmasked: Repurposing Common Amide Coupling Reagents for the Synthesis of Pentasubstituted Guanidine Bases

Abstract

Guanidines make up a class of compounds with important applications in catalysis and medicinal chemistry. In this systematic study, we report on the guanylation of aliphatic amines, anilines, (sulfon)amides, ureas, and carbamates by repurposing HATU, a common amide coupling reagent. The products are 2-substituted 1,1,3,3-tetramethylguanidines (TMGs), a group of sterically hindered superbases. The reaction of a guanidinium salt with aliphatic amines has been regarded as an unwanted side-reaction in amide coupling, yet the exact mechanistic details have been unclear. Our mechanistic investigation shows that the guanylation is highly dependent on the nature of the nitrogen nucleophile. Our findings were applied on two fronts: minimizing guanylation in competing amide coupling reactions as well as maximizing guanylation in a simple one-step synthesis of a broad variety of 2-substituted TMGs, including the late-stage functionalization of pharmaceuticals.