Click Mechanochemistry: Quantitative Synthesis of Ready to Use Chiral Organocatalysts by Efficient Two-Fold Thiourea Coupling to Vicinal Diamines

Mechanochemical methods of neat grinding and liquid-assisted grinding have been applied to the synthesis of mono- and bis(thiourea)s by using the click coupling of aromatic and aliphatic diamines with aromatic isothiocyanates. The ability to modify the reaction conditions allowed the optimization of each reaction, leading to the quantitative formation of chiral bis(thiourea)s with known uses as organocatalysts or anion sensors. Quantitative reaction yields, combined with the fact that mechanochemical reaction conditions avoid the use of bulk solvents, enabled solution-based purification methods (such as chromatography or recrystallization) to be completely avoided. Importantly, by using selected model reactions, we also show that the described mechanochemical reaction procedures can be readily scaled up to at least the one-gram scale. In that way, mechanochemical synthesis provides a facile method to fully transform valuable enantiomerically pure reagents into useful products that can immediately be applied in their designed purpose. This was demonstrated by using some of the mechanochemically prepared reagents as organocatalysts in a model MoritaBaylisHillman reaction and as cyanide ion sensors in organic solvents. The use of electronically and sterically hindered ortho-phenylenediamine revealed that mechanochemical reaction conditions can be readily optimized to form either the 1:1 or the 1:2 click-coupling product, demonstrating that reaction stoichiometry can be more efficiently controlled under these conditions than in solution-based syntheses. In this way, it was shown that excellent stoichiometric control by mechanochemistry, previously established for mechanochemical syntheses of cocrystals and coordination polymers, can also be achieved in the context of covalent-bond formation.