Copper-Catalyzed Addition of Alcohols to Carbodiimides: Oxygen as an Accelerant

The use of N,N′-diisopropylcarbamimidate (1) to prepare a tert-butyl ester of a carboxylic acid was required for the synthesis of a key pharmaceutical intermediate. Commercial sources were not adequate to supply this reagent in the quantity and quality required for our campaigns. While developing a process to prepare this compound, we discovered that an aerobic copper-catalyzed reaction between tert-butyl alcohol and N,N′-diisopropylcarbodiimide (DIC) afforded superior reaction rates and conversion compared with the reported conditions under inert atmospheres. Screening and mechanistic studies concluded that CuICl is oxidized in situ by O2 in the atmosphere to a generate a more active CuII(OH)Cl species. Screening studies designed to uncover key catalyst attributes concluded that both chloride and DIC act as ligands on the metal center. The consumption of O2 over the course of the reaction resulted in the low-level production of impurities (notably N,N′-diisopropylurea, which is the stoichiometric byproduct in the ensuing reaction that utilizes 1), but sufficient reaction rates and conversion of DIC were not attainable in the absence of O2. The production of 1 was safely executed using commercially available atmospheres of 4–5% O2/95–96% N2 while still meeting our high-quality product needs. The benefit of aerobic copper catalysis was found to also be useful with less hindered alcohols to form the analogous isoureas.