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.