Reaction Of Ethyl Bromodifluoroacetate Research Articles

The preparative synthetic approach to α,α-difluoro-γ-aminobutyric acid

Aim . To develop a convenient synthetic approach for the preparation of multigram amounts of 2,2-difluoro-γ-aminobutyric acid, which is pharmacologically promising analog of γ-aminobutyric acid (GABA). Results and discussion . α,α-Difluoro-γ-aminobutyric acid (2,2-difluoro-GABA, 53 g) has been synthesized using the reaction of ethyl bromodifluoroacetate (EBDFA) addition to benzyl acrylate in the presence of copper as a key stage. Experimental part . The reaction of EBDFA with benzyl acrylate in the presence of copper and tetramethylethylenediamine (TMEDA) was carried out; the resulting product was transformed to the target α,α-difluoro-γ-aminobutyric acid (in the form of hydrochloride) by consecutive debenzylation, Curtius rearrangement and treatment with hydrochloric acid to remove protecting groups. The synthesis was scaled up for the preparation of 53 g of α,α-difluoro-γ-aminobutyric acid. The ethyl ester of α,α-difluoro-γ-aminobutyric acid was also prepared and further transformed to 3,3-difluoropyrrolidine-2-one. The structure of the compounds synthesized was confirmed by 1 Н, 13 C and 19 F NMR spectroscopy, mass spectrometry and elemental analysis. Conclusions . It has been shown that the synthetic approach developed can be used for the preparation of α,α-difluoro-γ-aminobutyric acid in multigram amounts. The pathway is much more convenient, cheaper and safer compared to the method earlier described. Received: 30.07.2020 Revised: 19.08.2020 Accepted: 27.08.2020

Copper-Catalyzed N-Formylation of Amines through Tandem Amination/Hydrolysis/Decarboxylation Reaction of Ethyl Bromodifluoroacetate.

Ethyl bromodifluoroacetate (BrCF2COOEt) was first used as the N-formylating reagent in the copper-catalyzed N-formylation of amines. A range of primary, secondary, cyclic arylamines, and aliphatic amines underwent the N-formylation smoothly to furnish the N-formamides in moderate-to-excellent yields.

Stereoselective Synthesis of α‐Fluorinated Amino Acid Derivatives

AbstractThis account concentrates on our new methodologies for the synthesis of fluorine analogues of amino acids and their derivatives using the Reformatsky‐type reactions of ethyl bromodifluoroacetate and ethyl dibromofluoroacetate with imines promoted by the Wilkinson catalyst. First, we present the rhodium‐catalyzed Reformatsky‐type reaction of ethyl bromodifluoroacetate with imines using diethylzinc for the chemoselective synthesis of α,α‐difluoro‐β‐lactams and non‐cyclized products, 3‐alkylamino‐2,2‐difluorocarboxylates. This reaction was expanded to the asymmetric synthesis of difluoro‐β‐lactams using two types of chiral auxiliaries. To develop another methodology for the synthesis of monofluoro analogues of amino acids and their derivatives, we investigated the reaction of ethyl dibromofluoroacetate with imines using diethylzinc, and found that this Reformatsky‐type reaction proceeded without a rhodium catalyst in diethyl ether to give syn‐α‐bromo‐α‐fluoro‐β‐lactams stereoselectively. Interestingly, by changing the solvent to acetonitrile, the Reformatsky‐type aza‐Darzens products, syn‐2‐fluoroaziridine‐2‐carboxylates, were obtained chemo‐ and stereoselectively.

ChemInform Abstract: Synthesis of 14,14-Difluoro-4-demethoxydaunorubicin.

The title compound, (+)-14,14-difluoro-4-demethoxydaunorubicin hydrochloride (9), was prepared starting from the readily available (−)-hydroxy ester (10). This synthesis featured the efficient synthetic route to (−)-14,14-difluoro-4-demethoxy-7-deoxydaunomycinone (20) employing the Reformatsky reaction of ethyl bromodifluoroacetate with the (−)-siloxy aldehyde (14) and previously developed glycosylation method in which trimethylsilyl trifluoromethanesulfonate was used as an activator. In P388 in vitro test, 9 was found to be fifty times more active than adriamycin (1). Prominent antitumor activity was also observed for 9 in P388 in vivo test.

Rhodium‐Catalyzed Reformatsky‐Type Reaction of Ethyl Bromodifluoroacetate.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Radical Reaction Using an Organocopper Reagent Derived from Ethyl Bromodifluoroacetate.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Radical Reaction Using an Organocopper Reagent Derived from Ethyl Bromodifluoroacetate

In our previous work, reaction of ethyl bromodifluoroacetate (1) in the presence of Cu powder with olefins activated by an electron-withdrawing group gave the Michael-type adducts through an anionic intermediate. The same reaction with non-activated olefins was found to give addition products by a radical mechanism. The radical intermediate from α-methylstyrene was stabilized by a benzene ring and gave novel dimerization products. This reaction with 1-decene provided a convenient route to 2,2-difluorododecanoic acid.

ChemInform Abstract: Michael-Type Reaction of Ethyl Bromodifluoroacetate with α,β-Unsaturated Carbonyl Compounds in the Presence of Copper Powder.

We have reported that the reaction of ethyl bromodifluoroacetate (1) with alkenyl iodides in the presence of copper powder gives ethyl alkenyldifluoroacetates. As an extension of this reaction, reaction of 1 with Michael acceptors in the presence of copper powder was examined and found to give 1,4-addition products selectively, unless the acceptor has a group stabilizing a radical intermediate, such as a phenyl group.