Reformatsky reactions, 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]. 

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 ... 

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>. 

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]. 

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

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... 

Fluorinated L-nucleosides have also been reported. Compounds 47 (B=Ade, Cyt) have been prepared from L-xylose," and the same team have also made 2, 2 -difluorocompounds of type 48, the sugar being assembled using a Reformatsky reaction between ethyl bromodifluoroacetate and isopropylidene-L-glyceraldehyde. The adenosine analogue showed good anti-HIV activity with no cytotoxicity. ... 

An enantioselective difluoro Reformatsky reaction with imines was disclosed recently by Ando and coworkers. According to this valuable procedure, , -difluoro-P-lactams are obtained directly due to an in situ condensation following the addition of the zinc enolate. For this purpose, ethyl bromodifluoroacetate 324b was allowed to react with Af-benzyl-protected imines 391 that are derived from aromatic aldehydes. Diethyl zinc was used to generate the zinc enolate. When the reaction was mediated by the amino alcohol 323, required in equimolar amounts, P-lactams 392 were obtained in fair chemical yields and remarkably... 

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