SYNTHESIS OF ALKYL ISOCYANATES VIA MANGANESE- CATALYZED C-H ACTIVATION AND APPLICATION TO THE PREPARATION OF SUBSTITUTED UREAS

Abstract

While the high reactivity of organic isocyanates, driven by their high degree of unsaturation, provides access to a variety of industrially- and biologically-relevant compounds including substituted ureas, urethanes, and amides, known syntheses of isocyanates are hindered by requirement of prior functionalization or use of highly toxic phosgene gas. Here, the first aliphatic and benzylic C-H isocyanation protocol is reported with yields of up to 64% using manganese porphyrin and salen catalysts under relatively mild conditions. This method exhibits wide functional group tolerance, including ketones, amides, esters, ethers, and halides. As proof-of-concept, the organic isocyanates obtained using this method are coupled with several primary and secondary amines with conversions of up to 95% to form di- and tri-substituted ureas. DFT calculations show that rebound of an alkyl radical, generated via hydrogen atom abstraction by a reactive oxo-MnV species, to the nitrogen atom of a HO-MnIV-NCO intermediate to generate the thermodynamically-favored organic isocyanate product occurs with a kinetic barrier of only ~10 kcal/mol. Taken together, these results capitalize on the versatility of the isocyanate functionality and the ubiquity of the C-H bond to expand the synthetic toolbox and provide unprecedented access to the organic isocyanates, encouraging the future development of novel isocyanate-based chemistries.