DMAP Catalyzed One-Pot Curtius Rearrangement Using 1,1-Dimethyl-2,2,2-trichloroethoxycarbonyl Azide

We report our development of a controllable, base-free, one-pot Curtius rearrangement using 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl azide (DMTN3) with 4-(dimethylamino)pyridine (DMAP) as a catalyst. The scope of this catalytic process covers a range of primary, secondary, and tertiary alkyl and aryl carboxylic acids that allow the efficient stereospecific construction of alkyl or aryl isocyanates. Examples are reported of late-stage decarboxylative isocyanation of natural products and drug molecules, the rapid synthesis of several drugs, and the utilization of in situ generated DMTN3. Detailed studies of the mechanism indicate that the reaction rate depends on the concentration of the DMAP catalyst, and this ensures that the reaction is a mild and controllable process.