Ethyl bromodifluoroacetate

Kitazume and Kasai [55] have investigated the Reformatsky reaction in three ionic liquids. This reaction involves treatment of an a-bromo ester with zinc to give an a-zinc bromide ester, which in turn reacts with an aldehyde to give an addition product. An example is given in Scheme 5.1-26. Moderate to good yields (45-95 %) were obtained in ionic liquids such as [EDBU][OTf] for the reactions between ethyl bro-moacetate or ethyl bromodifluoroacetate and benzaldehyde [55]. 

The radicals generated from esters of halogenodifluoroacetic acid or halogenodi-fluorophosphonic acid add onto olefins and enolates. When these reactions are intramolecular, they afford tetrahydrofurans. In the presence of copper dust, ethyl bromodifluoroacetate can couple with aromatic and vinyl halides or can add onto Michael acceptors (Figure 2.13). ... 

Condensation of the Reformatsky reagent of ethyl bromodifluoroacetate with an imine affords difluoroazetidinone. This latter compound is a precursor of 2,2-difluoro-2-deoxyaminopyranoses. ... 

Ethyl bromodifluoroacetate lc was also used in the rhodium-catalysed Reformatsky protocol the reaction was optimized in acetonitrile as solvent and worked particularly... 

In 1984, Fried et al. reported the reaction of bromodifluoroacetate with carbonyl substrates in the presence of zinc. The a,a-difluoro /1-hydroxyester was obtained in good yield without isolation of the Reformatsky reagent [240, 241] (Scheme 80) Later, this zinc reagent has also been prepared via reaction of ethyl bromodifluoroacetate with zinc amalgam in triglyme [242] or reaction of methyl iododifluoroacetate with zinc in acetonitrile [243]. 

Ethyl bromodifluoroacetate is one of the fluorinated building blocks used most widely. There are scores of examples of the important Reformatsky reaction with aldehydes which occurs in THF/ether solvent mixtures, sometimes under sonication conditions (Eq. 62). 

Electron-withdrawing fluorine atoms are introduced on the methylenic a-carbon by the Reformatsky reaction of Boc-leucinal with ethyl bromodifluoroacetate in the presence of activated zinc dust with no diastereoselection. Under thermodynamic control, the y -isomer is obtained almost exclusively (Scheme 16)J15 The use of additives such as diethylaluminium chloride-silver(II) acetate enhances the chemical yield of the reaction, but also presents the disadvantage of being nonstereoselectiveJ78 ... 

Treatment of imines with ethyl bromodifluoroacetate and Et2Zn, in the presence of RhCl(PPh3)3 in anhydrous medium, has been reported to give via Reformasky-type reaction difluoro-(3-lactams and 3-amino-2,2-difluorocarboxylic esters, [105]. Different product ratios were observed changing the reaction conditions (solvent, reaction time, addition of MgSCL). 

In 2007, Boyer and coworkers developed a complete study of the parameters that can influence the selective synthesis of p-lactam or p-aminoester during Refor-matsky reaction between ethyl bromodifluoroacetate and various imines. It clearly appeared that by modifying the nature of the amine or the reaction conditions, it was always possible to inverse the p-aminoester/p-lactam ratio (Scheme 55). 

Scheme 55 Synthesis of gem-difluoro-P-aminoesters and gem-difluoro-P-lactams from ethyl bromodifluoroacetate...

Add the ethyl bromodifluoroacetate and THF (33 mL) to the pressure-equalizing addition funnel. With stirring, add the ethyl bromodifluoro-acetate/THF solution dropwise. After addition is complete, continue to stir the mixture at reflux for 3 h. 

In this section, the cyclodimerization reaction leading to dioxocinone 661 from the reaction of 4-pentenoic acid with ethyl bromodifluoroacetate in Zn-THF, likely through the indermediate 662, will be reported. The retro-cyclodimerization 661 was reported in Section 14.07.5.4 (Scheme 132) <1997H(46)275>. 

Reformatsky reaction of ethyl bromodifluoroacetate with Ay9-(dibenzyl)-l//-benzotriazolyl-1-methylamine 174 gave the fully protected a,a-difluoro-p-alanine 175 <03TL2375>. Hydrogenolysis and hydrolysis furnished a,a-difluoro-p-alanine 176. This methodology was also applied to the synthesis of A-protected 3,3-difluoroazetidin-2-ones <03S2483>. 

Access to 2-difluoro-2-deoxy-D-sugars and their derived nucleosides was realized by Reformatsky condensation of the reagent with ethyl bromodifluoroacetate. The resulting difluoro ester was obtained as a 2.5 1 antUsyn mixture. Following separation, the ma-... 

Oxazolidine 130 is a masked aldimine bearing a chiral N-(2-hydroxy-l-phenyl)ethyl moiety and is readily available from (R)-phenylglycinol. Mannich reaction of 130 with Reformatsky reagent of ethyl bromodifluoroacetate produces difluorolactam 131 in high diastereoselectivity, which is then transformed to enantio-enriched (S)-3-amino-2,2-difluoro-3-phenylpropanoic acid 133 (see Scheme 9.28) [55]. 

Marcotte, S., Pannecoucke, X., Feasson, C. and Quirion, J.-C. (1999) Enantioselective synthesis of a,a-difluoro-P-amino acid and 3,3-difluoroazetidin-2-one via the Reformatskii-type reaction of ethyl bromodifluoroacetate with chiral 1,3-oxazolidines. J. Org. Chem., 64, 8461-8464. 

A 1 M solution of chlorotrimethylsilane in THF (11 mb, 11 mmol) was diluted with further dry THF (80 mb) and heated under reflux. Zn (720 mg, 11 mmol) was then added and the mixture was vigorously stirred, and then ethyl bromodifluoroacetate (1.410 mb, 11 mmol) was added dropwise, followed by the resin-bound benzotriazolyl derivative (10 tea bags , 1.1 mmol). After refluxing for 2 h, the resin was washed as follows ... 

Scheme 2.203 Example of the synthesis of gem-difluorinated carbohydrate analogs via a Reformatsky reaction with ethyl bromodifluoroacetate [41c].

Sato, K. Tarui, A. Matsuda, S. Omote, M. Ando, A. KumadaM, I. The simple and selective synthesis of 3-amino 2,2-difluoro carboxylic esters and difluoro 3-lactams using ethyl bromodifluoroacetate in the presence of rhodium catalyst. Tetrahedron Lett. 2005, 46(45), 1619-1 eu. 

Boyer, N. Gloanec, R De Nanteuil, G. Jubault, R Quirion, J.-C. Chemoselective and stereoselective synthesis of gcm-difluoro-P-aminoesters or gcm-difluoro-P-lactams from ethyl bromodifluoroacetate and imines during Reformatsky reaction. Tetrahedron 2007, 65(50), 12352-12366. 

Wilkinson s catalyst mediates the Reformatsky-type reaction of ethyl bromodifluoroacetate with various carbonyl confounds (eq 84).124... 

When the 2 -thionucleoside derivatives 54 (R = Me, p-methoxyphenyl), made by opening of the 2,2 -anhydronucleoside with thiolate anion, were treated with xenon difluoride or with DAST in the presence of SbCls, the 2 -disubstituted compounds 55 could be obtained after deacetylation. In work reminiscent of an earlier report (Vol.22, p. 210), the difluorolactone 56 was obtained by means of a sequence involving a Reformatsky reaction between isopropylidene-D-glyceraldehyde and ethyl bromodifluoroacetate. The D-r/treo-epimer of 56 was removed by... 

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