Ethyl fluoroacetate reaction

Table 7. Products of the Directed Aldol Reaction of Lithium Enolate of Ethyl Fluoroacetate [/S, 19 ...

B. Reactions.—(/) Halides. Whereas ylides are alkylated in the normal way on treatment with a-bromo- or a-iodo-esters, quite different reactions occur with a-fluoro- and a-chloro-acetates. When salt-free ylides were refluxed in benzene with ethyl fluoroacetate or trifluoroacetate normal Wittig olefin synthesis took place with the carbonyls of the ester groups to give vinyl ethers, e.g. (14). On the other hand, methyl chloroacetate with... 

The Arbuzov reaction has been applied for the synthesis of fluorinated carbohydrates. 1,2 3,4-Di-O-isopropylidene-a-D-galactopyran-ose 6-(N,N-diethyl-P-methylphosphonamidite) was treated with ethyl fluoroacetate, to afford 6-deoxy-6-fluoro-l,2 3,4-di-O-isopropylidene-a-D-galactopyranose in 19% yield.241 The corresponding 6-deoxy-6-fluoride was obtained in 60% yield by treatment of l,2 3,4-di-0-isopropylidene-a-D-galactopyranose 6-(dipropylphosphinite) with hexafluoropropene.242 The mechanism of this reaction has been discussed.243,244 In contrast, treatment of 1,2 -.3,4-di-O-isopropylidene-a-D-galactopyranose 6-(tetraethylphosphorodiamidite) with benzoyl fluoride yielded the corresponding 6-benzoate, not the 6-deoxy-6-flu-oride expected.245... 

N-2-Chloroethylfluoroacetamide was also prepared by the direct action of 2 mol. of fluoroacetyl chloride on ethanolamine, although we carried out this reaction with the intention of preparing 2-(fluoroacetamide)ethyl fluoroacetate,... 

Much more advanced and effective appeared to be the method reported recently by Beaucage et al. [127]. Starting from ( )-2-amino-l-phenylethanol (88) the authors performed chemoselective N-acylation with ethyl fluoroacetate (89) providing 90, followed by its reaction with hexaethylphosphorous triamide (Scheme 23). Cyclic N-acylphosphoramidite 91 has been obtained as a mixture of diastereomeric rotamers. Condensation of AT4-benzoyl-5 -0-DMT-2 -deoxy-cytidine 92 with 91 in the presence of lH-tetrazole gave, after silica gel chromatography, pure Rc,RP-93 and Sc,SP-93.31P NMR studies indicated that when Rp-93 or Sp-93 was reacted with 3 -0-acetyl-AT-benzoylcytidine (94) and A ATjN jN -tetramethylguanidine (TMG), the dinucleoside phosphotriester was formed in nearly quantitative yield with full P-stereospecificity. After subsequent sulfurization, the P-stereodefined dinucleoside phosphorothioate tri-... 

Several routes to this class of compounds have been reported, such as (a) crossed Claisen condensation reactions (50-53) (b) acylation of the anion derived from ethyl fluoroacetate (54) or self-condensation of the anion derived from ethyl bromofluoroacetate (55) (c) electrophilic fluorination of the anion of p-ketoesters (56,57) (d) acylation-hydrolysis of fluoroolefins (58) and (e) acylation of fluorine-containing ketene silyl acetals (Easdon, J.C., University of Iowa, unpublished data). The limitations associated with these methods and the success achieved in the alkylation-hydrolysis of a-fluoro phosphorus ylides prompted us to examine acylation-hydrolysis of these a-fluoro ylides as a general route to 2-fluoro-3-oxoesters. 

Fluorouracil may be prepared by the reaction scheme shown in Figure 7. Ethyl fluoroacetate is condensed in a Claisen condensation with methyl formate. The ethyl sodium fluormalonaldehyde formed is condensed with 2-ethyl-2-thiopseudourea hydrobromide to give 2-ethylmercapto-5-fluor-4(3H)-pyrimidinone which yields fluorouracil on hydrolysis (14). 

Fluoroacetonitrile condenses with carbon disulfide in an interesting aldol-type reaction (Scheme 3.14). The carbanion for ethyl fluoroacetate reacts readily with benzaldehyde in a cross-aldol reaction to give the fluorinated alcohol. a-Fluorinated carbonyl compounds are often very toxic materials because biologically they are converted into fluoroacetate, which is toxic to the Krebs cycle. Thus, extreme care is needed during the use of these compounds. 

First synthesis of 5-FU was accomplished by Heidelberger in 1957 according the methodology [6, 81]. Ethyl fluoroacetate 44 was subjected to Claisen condensation with ethyl formate to give 45. The salt 45 was introduced into reaction with 5 -alkylisothiourea derivatives 46 to give fluoropyrimidines 47, which were hydrolysed to give 5-FU (Scheme 12). 

In 1991, Wright et al. reported a procedure for the preparation of substituted 1-benzyl-1//-1,2,3-triazoles 21 and 23 from benzyl azides 20 under very mild conditions (Scheme 4.7) [9]. Benzyl azides 20 reacted with active methylene compounds in DMSO induced by potassium carbonate at 35-40 C to give 1-benzyl-1//-1,2,3-triazoles 21 and 23 usually in good yield. Acetonitrile derivatives 10 gave 5-amino-l-benzyl-l//-l,2,3-triazoles 21, whereas diethyl malonate gave 5-hydroxy-l-benzyl-l//-l,2,3-triazoles. l//-l,2,3-Triazole-4-carboxylate esters and l//-l,2,3-triazole-4-ketones were obtained from ethyl acetoacetate and P-diketones, respectively. Benzyl methyl ketone reacted to give a 5-methyl-4-phenyl-l//-l,2,3-triazole, but acetone and acetophenone failed to react. Other active methylene compounds that did not react under these reaction conditions included ethyl cyanoacetate, ethyl fluoroacetate, and ethyl nitroacetate. 

Chloroacetate esters are usually made by removing water from a mixture of chloroacetic acid and the corresponding alcohol. Reaction of alcohol with chloroacetyl chloride is an anhydrous process which Hberates HCl. Chloroacetic acid will react with olefins in the presence of a catalyst to yield chloroacetate esters. Dichloroacetic and trichloroacetic acid esters are also known. These esters are usehil in synthesis. They are more reactive than the parent acids. Ethyl chloroacetate can be converted to sodium fluoroacetate by reaction with potassium fluoride (see Fluorine compounds, organic). Both methyl and ethyl chloroacetate are used as agricultural and pharmaceutical intermediates, specialty solvents, flavors, and fragrances. Methyl chloroacetate and P ionone undergo a Dar2ens reaction to form an intermediate in the synthesis of Vitamin A. Reaction of methyl chloroacetate with ammonia produces chloroacetamide [79-07-2] C2H ClNO (53). 

The enolates of fluoroacetate or fluorothioacetate esters are generated either through deprotonation with a lithium amide or by an in situ reduction of ethyl bromofluoroacetate with zinc. These enolates can undergo diverse reactions with electrophiles (Figure 2.7) ... 

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