Synthesis and Lewis Base-Catalyzed Functionalization of Carbamoyl Fluorides

Abstract

Amides are extremely prevalent in the pharmaceutical, agrochemical and materials industries. Typically, amides are prepared by the combination of amines and carboxylic acids in the presence of an amide-coupling reagent. This dissertation describes the synthesis and reactivity of carbamoyl fluorides, a unique electrophilic class of molecules that form amides when treated with carbon-based nucleophiles.

A synthesis of carbamoyl fluorides directly from secondary amines is described. This method relies on the reaction of difluorocarbene with an oxidant to generate difluorophosgene (COF2) in-situ. Several carbamoyl fluorides were prepared with this method, and the mechanism was supported by kinetic analysis and nuclear magnetic resonance (NMR) spectroscopy experiments.

To prepare alkynamides, carbamoyl fluorides were paired with alkynyl silanes and the common laboratory reagent tetrabutylammonium fluoride (TBAF) was found to be the optimal catalyst. This reaction proceeded efficiently due to the thermodynamic driving force of forming extremely strong Si-F bonds in the by-products. A selection of alkynamides were synthesized using this method, including those bearing functional groups that may be problematic in other modern alkynamide syntheses.

Using silyl ketene imine nucleophiles, α-cyanoamides were prepared from carbamoyl fluorides using either fluoride, phenanthrolines or P(V) compounds as catalysts. As the amide produced in this method contains a chiral quaternary carbon centre, this project was focused on identifying a chiral Lewis base for asymmetric catalysis. It is suspected that the fluoride released in this reaction acts as the active catalyst, outcompeting the chiral compounds and limiting asymmetric induction.