Alkyl Isocyanates via Manganese-Catalyzed C-H Activation for the Preparation of Substituted Ureas.

Organic isocyanates are versatile intermediates that provide access to a wide range of functionalities. In this work, we have developed the first synthetic method for preparing aliphatic isocyanates via direct C-H activation. This method proceeds efficiently at room temperature and can be applied to functionalize secondary, tertiary, and benzylic C-H bonds with good yields and functional group compatibility. Moreover, the isocyanate products can be readily converted to substituted ureas without isolation, demonstrating the synthetic potential of the method. To study the reaction mechanism, we have synthesized and characterized a rare MnIV-NCO intermediate and demonstrated its ability to transfer the isocyanate moiety to alkyl radicals. Using EPR spectroscopy, we have directly observed a MnIV intermediate under catalytic conditions. Isocyanation of celestolide with a chiral manganese salen catalyst followed by trapping with aniline afforded the urea product in 51% enantiomeric excess. This represents the only example of an asymmetric synthesis of an organic urea via C-H activation. When combined with our DFT calculations, these results clearly demonstrate that the C-NCO bond was formed through capture of a substrate radical by a MnIV-NCO intermediate.