Methyl fluoroacetate preparation

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... 

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. 

In Report no. 5 on fluoroacetates to the Ministry of Supply2 we described the preparation of methyl 1 Z-difluoroacetoacetate, CH2F CO CHF C02Me, in 10 per cent yield by the action of sodium on methyl fluoroacetate. Later we reported that if the condensation were carried out in the presence of methyl alcohol, the yield of methyl difluoroacetoacetate could be increased to 23 per cent, and allowing for recovered methyl fluoroacetate the overall yield was 35 per cent. 

The preparation of free fluoroacetic acid from methyl fluoroacetate via the barium salt is described on p. 121. An alternative and convenient method1 for preparing the free acid consists in treating fluoroacetamide with nitrous fumes, the pure acid being produced in 90 per cent yield. The two methods may be summarized thus ... 

The group Cl CH2 CH2 N< occurs in the nitrogen mustards which are powerful vesicants, e.g. CH3,N(CH2,CH2C1)2. It was decided therefore to introduce this group into the fluoroacetamide molecule in the hope of combining vesicant properties with the delayed convulsant action of the fluoroacetates. For this purpose N-2 hydroxyethylfluoroacetamide (IV) was prepared by the action of monoethanolamine on methyl fluoroacetate and was readily converted into N-2-chloroethylfluoroacetamide (V) by the action of thionyl chloride ... 

In view of the fact that fluoroethanol is as toxic as methyl fluoroacetate (or as fluoroacetic acid), it seemed worth while preparing a compound in which the active parts of these molecules were combined, in the hope of obtaining a compound of increased potency. Such a compound is 2-fluoroethyl fluoroacetate, first prepared and described by us in 1943.1 This ester was readily prepared by the action of fluoroacetyl chloride on fluoroethanol. It is a stable, mobile liquid possessing an extremely faint odour. 

In view of the biological importance of nicotinic acid, it was decided to prepare a quaternary salt from the acid or ester and bromofluoroethane. S Carbethoxy- N-2-fluoroethylpyridinium bromide (XIX) was therefore prepared and examined. The l.d. 50 for subcutaneous injection into mice was 200 mg. /kg., i.e. it was relatively non-toxic compared with methyl fluoroacetate. 

A pure specimen was prepared as follows.1 Methyl fluoroacetate (39 g.) was shaken with 30 ml. of ammonia solution (sp. gr. = 0-89). Heat was evolved, and on standing overnight the first crop of almost pure crystals was deposited. These were filtered off and dried (yield, 16 g.). By concentrating the filtrate in vacuo a second crop of crystals was obtained (yield, 5 g.). The two crops were united and could be recrystallized from chloroform (fine needles) or acetone (prisms). We used dry chloroform and each recrystallization gave about 76 per cent yield. After recrystallizing three times, the final yield of pure substanoe was 8-7 g., m.p. 108°. The amide can also be purified by sublimation. 

It often suffices for preparation of unsubstituted amides to stir or shake the ester with concentrated aqueous ammonia, but the conditions required vary widely from case to case. For example, ethyl cyanoacetate754 and concentrated aqueous ammonia afford 88% of the amide in 1 hour without external heating, and methyl fluoroacetate reacts equally rapidly (N.B. a potent poison) ... 

Methyl fluoroacetate was first prepared by Swarts in small yield by the action of silver or mercurous fluoride on methyl iodoacetate. The method is impracticable for large-scale work and therefore the preparation was reinvestigated in detail. Methyl chloroacetate was used in place of the expensive iodoacetate, and a variety of fluorinating agents was tried. It was found that fluorination could be effected by heating methyl chloroacetate in a rotating autoclave with potassium fluoride at 220° for 4 hr. Sodium fluoride, on the other hand, was almost without action. 

In view of these facts and of the known toxic action of fluoro-acetates it seemed worth while investigating compounds containing both fluorine and the above-mentioned groups. We prepared the flrst of a series of nitrogen compounds in 1943, namely, ethyl jluoroacetamidoacetate, CHjF CO NH CHg COjEt (XH). It was a colourless crystalline solid which, when injected into mice, had a l.d. 50 of 20 mg./kg. The corresponding figure for methyl fluoroacetate is 6 mg. /kg. The symptoms were similar in each case (delayed convulsant action). 

This reaction was initially reported almost concurrently by McCombie and co-workers in 1946 and Gryszkiewicz-Trochimowski and co-workers in 1947. It is the preparation of methyl fluoroacetate by the treatment of methyl chloroacetate with potassium fluoride at high temperatures (e.g., 190 C) for 10-15 h, with a yield of 60% to 90%. This method has been used to prepare other fluoroacetates" and >-fluoro-alcohols however, sodium fluoride is not suitable for this reaction because of a very low yield." The best conditions for this reaction require a vigorous agitation of completely dried starting materials at high temperature with potassium fluoride in large excess." This reaction has been scaled up in a pilot plant to prepare methyl fluoroacetate in the United States. ... 

Both methyltriethylphosphonium fluoride and methyltributylphospho-nium fluoride have been prepared The latter generates benzyl fluoride from benzyl chloride in 80% yield and ethyl fluoroacetate from ethyl bromoacetate in 53% yield Methyltnbutylphosphonium fluoride converts 1-bromododecane to a 50 50 mixture of 1-fluorododecane and 1-dodecene Methyltnbutylphosphonium fluoride also quantitatively forms styrene from 1-bromo-1-phenylethane [26] Methyl-tnbutylphosphonium fluonde is the reagent of choice for the conversion of N,N dimethylchloroacetamide to its fluoride, but it is not able to convert chloro-acetonitnle to fluoroacetomtrile Methyltnbutylphosphonium fluoride changes chloromethyl octyl ether to the crude fluoromethyl ether in 66% yield The stereoselectivity of methyltnbutylphosphonium fluoride is illustrated by the reac tions of the 2-tert-butyl-3-chlorooxiranes [27] (Table 2)... 

The combination of CsF with Si(OMe)4 58 is an efficient catalyst for Michael additions, e.g. of tetralone 130 to methacrylamide, followed hy cyclization of the addition product to the cyclic enamide 131 in 94% yield [67]. Likewise, addition of the lactone 132 to methyl cinnamate affords, after subsequent cyclization with tri-fluoroacetic acid, the lactam 133 in 58% yield [68] whereas < -valerolactam 134, with ethyl acrylate in the presence of Si(OEt)4 59/CsF, gives 135 in 98% yield [69]. Whereas 10mol% of CsF are often sufficient, equivalent amounts of Si(OEt)4 59 seem to be necessary for preparation of 135 [69] (Scheme 3.11). 

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