Fluoroacetic acid, ethyl ester

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). 

It was obviously of interest to determine whether other esters of fluoroacetic acid would prove to be more or less toxic than the methyl ester. In the phosphorofluoridate series, for example, we found that esters of secondary alcohols were far more potent than those of primary alcohols for instance, di-isopropyl fluorophosphonate (I) was a compound of considerable activity. Accordingly ethyl, ra-propyl and isopropyl fluoroacetates were prepared by heating the corresponding esters of chloroacetic acid in the rotating autoclave with potassium fluoride. The toxicity figures of these esters were very similar to those of methyl fluoroacetate. 

From a study of the fluoroacetates so far mentioned, it appears that any compound which can give rise to fluoroacetic acid (or the fluoroacetate ion), either by hydrolysis or by oxidation (or both), is toxic. The toxic grouping is thus F-CH2-CO, and any substitution in this radical destroys the toxicity as far as relatively simple compounds are concerned. We had reached this conclusion by May 1943.1 We subsequently showed that esters of / -fluoropropionic acid were non-toxic, whereas esters of y-fluorobutyric acid were shown by American workers to be toxic. In 19442 we reported the synthesis of ethyl 5-fluoro-pentanecarboxylate, F,[CH2]g C02Et (I). This is a stable, colourless liquid and we showed that it possessed very potent toxic properties of the fluoroacetate type. By subcutaneous injection of the propylene glycol solution into mice the l.d. 50 was 4 mg./kg. Methyl fluoroacetate (II) may be taken as a convenient standard (p. 115) and has a l.d. 50 of about 6 mg./kg. for saline solutions, and 15 mg./kg. for propylene glycol solution.3 Therefore ethyl 5-fluoropentanecarboxylate was about 7 times as toxic as methyl fluoroacetate (molecule for molecule).4... 

Fluorouracil Fluorouracil, 4-fluorouracil (30.1.3.3), is made by condensing the ethyl ester of fluoroacetic acid with ethylformate in the presence of potassium ethoxide, forming hydroxy-methylenfluoroacetic ester (30.3.1), which cyclizes by reacting it with S-methyl-isothiourea to 2-methylthio-4-hydroxy-5-fluoropyrimidine, which is subsequently hydrolyzed by hydrochloric acid to fluorouracil (30.1.3.3) [21,22]. An alternative method of synthesizing... 

Acid sensitivity is a feature of 2-(trimethylsilyl)ethyl esters that has not yet been much exploited but a synthesis of Epoxysorbicillinol serves as a harbinger of a new vein in protecting group chemistry. Care must be taken in a synthesis of Epoxysorbicillinol to prevent aromatisation. Wood and co-workers were able to deprotect the 2-(trimethylsilyl)ethyl ester 94.1 [Scheme 6.94] with excess tri-fluoroacetic acid whereupon decarboxylation ensued to give the iketone derivative 94.2 in 81% yield. The conjugated dienone was then installed by a DDQ oxidation of 94.2 to give Epoxysorbicillinol in a modest 30-40% yield. If the ester deprotection-decarboxylation is attempted with the dienone in place, the yield is very poor. With dilute trifluoroacetic acid. yV-Boc groups can be cleaved in the presence of 2-(trimethylsilyl)ethyl esters. 

Many cellulose derivatives form lyotropic liquid crystals in suitable solvents and several thermotropic cellulose derivatives have been reported (1-3) Cellulosic liquid crystalline systems reported prior to early 1982 have been tabulated (1). Since then, some new substituted cellulosic derivatives which form thermotropic cholesteric phases have been prepared (4), and much effort has been devoted to investigating the previously-reported systems. Anisotropic solutions of cellulose acetate and triacetate in tri-fluoroacetic acid have attracted the attention of several groups. Chiroptical properties (5,6), refractive index (7), phase boundaries (8), nuclear magnetic resonance spectra (9,10) and differential scanning calorimetry (11,12) have been reported for this system. However, trifluoroacetic acid causes degradation of cellulosic polymers this calls into question some of the physical measurements on these mesophases, because time is required for the mesophase solutions to achieve their equilibrium order. Mixtures of trifluoroacetic acid with chlorinated solvents have been employed to minimize this problem (13), and anisotropic solutions of cellulose acetate and triacetate in other solvents have been examined (14,15). The mesophase formed by (hydroxypropyl)cellulose (HPC) in water (16) is stable and easy to handle, and has thus attracted further attention (10,11,17-19), as has the thermotropic mesophase of HPC (20). Detailed studies of mesophase formation and chain rigidity for HPC in dimethyl acetamide (21) and for the benzoic acid ester of HPC in acetone and benzene (22) have been published. Anisotropic solutions of methylol cellulose in dimethyl sulfoxide (23) and of cellulose in dimethyl acetamide/ LiCl (24) were reported. Cellulose tricarbanilate in methyl ethyl ketone forms a liquid crystalline solution (25) with optical properties which are quite distinct from those of previously reported cholesteric cellulosic mesophases (26). 

Ethyl, n-propyl and isopropyl fluoroacetates were also readily prepared by heating the corresponding esters of chloroacetic acid with potassium fluoride in the rotating autoclave. Their toxicities were similar to that of methyl fluoroacetate. (It... 

The product, a nearly white oil, settles out as the lower layer. It is separated, washed until free of acid with three 25-ml. portions of saturated sodium bicarbonate solution (Note 2) then with four 25-ml. portions of water, and dried over 10 g. of Drierite. The weight of crude dried ester is 200-210 g. (68-71%). Fractional distillation gives 190-200 g. (65-68% yield) of pure ethyl chloro-fluoroacetate, b.p. 129-130°, d 1.3925 (Note 3). 

Esters of monofluoroacetic acid. e.g. I98 and 2,101 are synthesized from the corresponding chloro or bromo derivatives with potassium fluoride.98 103 The yield for the synthesis of ethyl fluoroacetate (1) ranges from 20 to 75%. Similarly, chloroacetamide and chloroacetonitrile... 

Allmendinger, T. (1991) Ethyl phenylsulfinyl fluoroacetate, a new and versatile reagent for the preparation of a-fluoro-a,P-unsaturated carboxylic acid esters. Tetrahedron, 47, 4905-4914. 

We developed a new method utilizing the previously unknown ethyl phenylsulfinyl fluoroacetate (entry 4). Its alkylation followed by thermal elimination of phenylsulfinic acid give rise to a-fluoro-a,p-unsaturated esters with high stereoselectivity, scheme 2 shows an example (Allmendinger, T. in preparation). For the first time easy accessible and stable alkyl halides (e.g. 5, X=H,Br) instead of aldehydes (e.g. 5, X=0) may be used for this purpose. 

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