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

Abstract

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 C1 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 °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.

Quantum Chemical Calculations to Trace Back Reaction Paths for the Prediction of Reactants

“…Many of the chemical reactions predicted by this method are difficult to demonstrate experimentally; however, it is an important finding that the experimentally established Strecker and Passerini reactions were included among them. It is also important to note that a new reaction was actually found in the previous application limited to one step, producing a R–CF 2 –COO – skeleton in one-pot from CO 2 -enabled syntheses of a series of compounds that was difficult to synthesize . In the future, we would like to systematically apply this method to various compounds to discover unknown chemical reactions.…”

“…It is also important to note that a new reaction was actually found in the previous application limited to one step, 20 producing a R−CF 2 −COO − skeleton in one-pot from CO 2 -enabled syntheses of a series of compounds that was difficult to synthesize. 30 In the future, we would like to systematically apply this method to various compounds to discover unknown chemical reactions.…”

In silico reaction screening with difluorocarbene for N-difluoroalkylative dearomatization of pyridines

“…Bromo(trimethylsilyl)difluoromethane (Me 3 SiCF 2 Br) and tetrabutylammonium difluorotriphenylsilicate (Ph 3 SiF 2 •NBu 4 )-which have been proven to be effective for the multicomponent reaction of tert-amines, difluorocarbene and CO 2 -were used to generate difluorocarbene in situ 13,14 . However, the reactions using 1a and 1b did not provide the desired cyclic products when using benzaldehyde 3a.…”

“…The reaction of aromatic aldehydes including heterocycles proceeded smoothly to give the dearomative products in synthetically useful yields (6)(7)(8)(9)(10)(11). Alkenyl and enolizable aliphatic aldehydes were also employed to afford the desired cyclic products (12)(13)(14)(15)(16). Even sterically hindered pivalaldehyde could react to provide 17.…”

“…This method is potentially applicable not only for mechanistic studies of known chemical reactions, but also for predictions of reactions in which the products or pathways are uncertain. As an example of the latter, we recently reported a synthetic method for α,α-difluoroglycine derivatives that was discovered using computational retrosynthetic disconnection and a subsequent search for the reaction pathways to the possible products (which included not only the target molecule but also the other possible side products) using the AFIR method 13,14 . The computationally proposed multicomponent reaction of amines, difluorocarbene and CO 2 towards the target compound was then successfully demonstrated experimentally.…”