On-Water Reaction of (Thio)isocyanate: A Sustainable Process for the Synthesis of Unsymmetrical (Thio)ureas

We describe a facile, sustainable, and chemoselective process for the synthesis of unsymmetrical (thio)ureas through the on-water reaction of (thio)isocyanates with amines. Detailed mechanistic studies revealed that the physical nature and solubility of reagents in water are responsible for the observed reaction rate and selectivity. Significant efforts have been made to design a scalable process to achieve the zero waste water-mediated protocol for the synthesis of (thio)ureas from (thio)isocyanates and amines. The decisive advantages of the process are the simple product isolation through filtration and the recycling of the water effluent. It also avoids the use of sensitive anhydrous reaction conditions and toxic volatile organic solvents. The developed process ensures that chemoselectivity and robustness and are successfully scaled-up to produce 100 g of isoproturon in high yield and purity. Green chemistry parameters such as process mass intensity, reaction mass efficiency, and molar efficiency values (with and without solvent) were calculated and compared.

Automated summary

This study presents a facile, sustainable, and chemoselective method for synthesizing unsymmetrical (thio)ureas through the on-water reaction of (thio)isocyanates with amines. Mechanistic investigations reveal that the reaction rate and selectivity are determined by the physical nature and solubility of the reagents in water. The developed protocol achieves zero waste water-mediated synthesis, avoiding the use of toxic volatile organic solvents.