Synthesis of Difluoroglycine Derivatives from Amines, Difluorocarbene, and CO2: Computational Design, Scope, and Applications

A three-component reaction (3CR) for the synthesis of difluoroglycine derivatives has been achieved by using amines, difluorocarbene (generated in situ), and the abundant, inexpensive, and nontoxic C-1 source CO2. Various tert-amines and pyridine, (iso)quinoline, imidazole, thiazole, and pyrazole derivatives were incorporated, and the corresponding products were isolated in solid form without purification by column chromatography on silica gel. Detailed reaction profiles of the 3CR were obtained from computational analysis using DFT calculations, and the results critically suggest that simple ammonia is not applicable to this reaction. In addition, as strongly supported by computational predictions, a new reagent that can generate difluorocarbene at 0 degrees C without any additives was discovered. Finally, radical substitution reactions of the obtained difluoroglycine derivatives under photoredox conditions, as well as a synthetic application as an N-heterocyclic carbene ligand are shown.

Automated summary

A three-component reaction for the synthesis of difluoroglycine derivatives was achieved by using amines, in situ generated difluorocarbene, and inexpensive CO2 as the C-1 source. Computational analysis provided detailed reaction profiles of the 3CR, revealing the unsuitability of simple ammonia for this reaction. A new reagent capable of generating difluorocarbene at 0 degrees C without any additives was discovered. Additionally, radical substitution reactions and synthetic applications as an N-heterocyclic carbene ligand were demonstrated for the obtained difluoroglycine derivatives under photoredox conditions.