Fluorine-substituted esters

Elucidation of the mechanism of toxicity of fluoroacetate in living organisms led to increased interest into the preparation and properties of a-fluoroesters. More recently, the use of fluorine substituted esters as analytical probes and diagnostic tools in metabolic processes has added to their stature as important compounds in biochemistry(7). In addition, a-fluoroesters have served as useful building blocks to more complex and interesting biological substrates. 

Decarboxylation of (bromodifluoromethyl)malonates (9) reminiscent of Krapcho s deal-koxycarbonylation process, is observed on treatment with potassium fluoride in dimethyl sulfoxide at 170 °C to give 2-(trifluoromethyl)-substituted esters 10.43 The precursors are prepared by reacting diethyl malonates 8 with dibromodifluoromethane in the presence of sodium hydride. The exchange of bromine for fluorine in 9 followed by decarboxylation is an excellent method of introducing a trifluoromethyl group a- to an ester group. 

The data in Table 9 also allows one to reach conclusions regarding the elec-trophilicity vs nucleophilicity of the partially-fluorinated radicals since the three styrene substrates have a considerable range in IP values. /1-Fluorine, and to a lesser extent y-fluorine, substitution would appear to have a small impact on electrophilicity, whereas a single a-fluorine substituent seems to impart slightly nucleophilic properties. In a recent study, Takeuchi et al. have examined both computationally and experimentally radicals which bear both an a-fluorine substituent and an electron withdrawing ester function. They found that the a-fluorine substituent makes such radicals more electrophilic, but that they still add more readily to styrene than they do to acrylonitrile [127],... 

Addition of monosubstituted alkylhydrazines to fluorinated acetylenic esters with either electron-withdrawing groups (e.g.. 12), or sterically bulky /i-substituents, affords 5-substituted 1-alkyl-3-hydroxypyrazolcs (c.g., 13) as the major regioisomeric products. ... 

The effect of substituting fluorine for hydrogen in the methylene halides is to increase the rate of carbanion formation and presumably to stabilize the carbanion and decrease the pK. The effect of fluorine substitution on the acidity of other carbon acids is not so clear. In some cases fluorine substitution leads to a smaller increase in rate than expected from the inductive effect and in other cases results in a decrease in the rate of carbanion formation and an increase in pK values. The results shown in Table 6 were obtained for the rate coefficient (k) for methoxide ion catalysed carbanion formation per hydrogen atom by following the appearance of the MeOH absorbance in the IR spectrum when the esters were allowed to exchange in MeOD [167]. The acidity of the nitro-paraffins in Table 7 is mostly increased by chlorine substitution (p/T... 

We have examined the [2 + 2] photodimerization of the fluorine-substituted benzyl esters of (Z,Z)- and (E,E)-muconic acids in the solid state (Scheme 24.3) [60]. The muconates undergo [2 + 2] cyclodimerization, EZ-isomerization, and... 

It should be noted that selenides 44d and 44e bearing an additional electron-withdrawing group (e.g., ester or chlorine atom) provide fluorinated selenides 45d and 45e in moderate yields, while a-alkyl-ated a-seleno-substituted ester 44f gives only a trace amount of the fluorinated product 45f (run 8). 

Data from kinetic studies on hydrogen-atom abstraction by trifluoromethyl radicals ( nerated by photolysis of hexafluoroacetone) from the esters RpCOaMe (Rf = CFs, C2F5, or n-CaF ) have been presented and discussed. The susceptibilities of the methoxy-groups towards hydrogen abstraction are less by a factor of 2—3 than those found with methyl formate and acetate, which contrasts with the claim (based on a study of the esters FCOaMe and CFa COaMe) that fluorine substitution enhances the ease of abstraction. ... 

Similar results are obtained with fluorine-substituted aUylic esters as reported by Kitazume et al. [21]. Ireland-Claisen rearrangement of the difluoromethylated esters 29 and 31 provided the desired syn- or anti-configured unsaturated acids, which were directly reduced to the corresponding alcohols in overall high yield. 

The inoeased ability of polyfluorinated compounds to undergo fluorine substitution was used for the synthesis of trifluoromethyl-substituted furans. Reaction of perfluorobut-2-ene 131 with acetylacetone or acetoacetic ester furnished 2,3-bis(trifluoromethyl)furans 132 through two sequential fluorine substitutions [97]. Similarly, fluoride-ion catalyzed reaction of fluorinated enol phosphates 133 led to dihydrofurans 134 which treatment with a base produced furans 135 in 44-56 % yields [98]. 

During electrochemical fluorination retention of important functional groups or atoms in molecules is essential. Acyl fluorides and chlorides, but not carboxylic acids and anhydrides (which decarboxylate), survive perfluorination to the perfluorinated acid fluorides, albeit with some cyclization in longer chain (>C4) species [73]. Electrochemical fluorination of acetyl fluoride produces perfluoro-acetyl fluoride in 36-45% yields [85]. Electrochemical fluorination of octanoyl chloride results in perfluorinated cyclic ethers as well as perfluorinated octanoyl fluonde. Cyclization decreases as initial substrate concentration increases and has been linked to hydrogen-bonded onium polycations [73]. Cyclization is a common phenomenon involving longer (>C4) and branched chains. a-Alkyl-substituted carboxylic acid chlorides, fluorides, and methyl esters produce both the perfluorinated cyclic five- and six-membered ring ethers as well as the perfluorinated acid... 

Electrochemical fluorination of a-cyclohexenyl-substituted carboxylic (acetic, propanoic, butanoic, and pentanoic) acid esters (methyl, ethyl, and propyl) results in a series of both perfluoro-9-alkyl-7-oxabicyclo[4 3 OJnonanes and per-fluoro-8-alkoxy-9-alkyl-7-oxabicyclo[4.3.0]nonanes [<8S] (equation 19)... 

An example of cleavage ol the sulfur-oxygen bond in trifluoromethane-sulfonic ester has been reported Tnfluororaethyl triflate reacts with neutral or anionic nucleophiles with elimination of carbonyl difluoride and formation of trifluoromethanesulfonyl fluoride [57] (equation 32) The mechanism of this reaction involves elimination of fluoride ion, which is a chain carrier in the substitution of fluorine for the trifluoromethoxy group... 

Treatment of a- or P hydroxyacids with sulfur tetrafluoride leads to conver Sion of the carboxylic group into the tiifluoromethyl group, but the hydroxyl group undergoes either fluorination, fluorosulfination, esterification, or dehydration to form esters, ethers, or alkenes The ratio of the products depends on P substitution [209, 210] (equations 103 and 104)... 

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