Fluoroacetate formation

Rearrangements. Ireland-Claisen rearrangement of allyl fluoroacetates, formation of /3-(W-acylamino)aldehydes from 0-vinyl-N,0-acetals, 1,2-group migra-tion/trapping are some of the useful transformations initiated by TMSOTf. ... 

Eluoropyridine derivatives can be constmcted from fluoroaUphatic feedstocks. 5-Eluoro-2,6-dihydroxynicotinamide [655-15-OJ, a precursor to the anti-bacterial, enoxacin [74011-58-8] was prepared in 63% yield from ethyl fluoroacetate [459-72-3] ethyl formate [109-94-4], and malonamide [108-13-4] (394). 

Specifically, it has recently been found 149) that diarylthallium tri-fluoroacetates may be converted into aromatic iodides by refluxing a solution in benzene with an excess of molecular iodine. Yields are excellent (74-94%) and the overall conversion represents, in effect, a procedure for the conversion of aromatic chlorides or bromides into aromatic iodides via intermediate Grignard reagents. The overall stoichiometry for this conversion is represented in Eq. (10), and it would appear that the initial reaction is probably formation of 1 mole of aromatic iodide and 1 mole of arylthallium trifluoroacetate iodide [Eq. (8)] which subsequently spontaneously decomposes to give a second mole of aromatic iodide and thallium(I) trifluoroacetate [Eq. (9)]. Support for this interpretation comes from the... 

The first electrochemical H2 generation catalyzed by a hetero-nuclear Fe-Ni complex [Ni(L)Fe2(CO)g] (27) [L - = (CH3C6H3S2)2(CH2)3 ] (Fig. 9) with tri-fluoroacetic acid was reported by Schoder and coworkers in 2006 [211]. Based on their electrochemical behavior, spectroscopic data, and DFT calculations of 27, an EECC mechanism was mled out and therefore an ECCE or ECEC mechanism involving the formation of Fe°-H and Ni -H intermediates is likely. In this cycle, six catalytic turnovers were achieved. This value is comparable to those for... 

There are several examples in which metabolites that toxify the organism responsible for their synthesis are produced. The classic example is fluoroacetate (Peters 1952), which enters the TCA cycle and is thereby converted into fluorocitrate. This effectively inhibits aconitase—the enzyme involved in the next metabolic step—so that cell metabolism itself is inhibited with the resulting death of the cell. Walsh (1982) has extensively reinvestigated the problan and revealed both the complexity of the mechanism of inhibition and the stereospecihcity of the formation of fluorocitrate from fluoroacetate (p. 239). It should be noted, however, that bacteria able to degrade fluoroacetate to fluoride exist so that some organisms have developed the capability for overcoming this toxicity (Meyer et al. 1990). 

Secondary Alkyl Alcohols. Treatment of secondary alkyl alcohols with tri-fluoroacetic acid and organosilicon hydrides results only in the formation of the trifluoroacetate esters no reduction is reported to occur.1,2 Reduction of secondary alkyl alcohols does take place when very strong Lewis acids such as boron trifluoride126 129 or aluminum chloride136,146 are used. For example, treatment of a dichlo-romethane solution of 2-adamantanol and triethy lsilane (1.3 equivalents) with boron trifluoride gas at room temperature for 15 minutes gives upon workup a 98% yield of the hydrocarbon adamantane along with fluorotriethylsilane (Eq. 10).129... 

The formation of iminium ions of 20-epipandoline occurred only under Polo-novski-Potier conditions. Thus on treatment of the TV-oxide of 165 with tri-fluoroacetic anhydride followed by an aqueous solution of KCN, the iminium ion 329 was obtained, readily isolated as the corresponding a-amino nitrile 331 (Scheme 17). The reaction was completely regioselective and no traces of the enamine 332 could be obtained. This made the synthesis of spiroketone 333... 

Injection of (V) into mice showed that the l.d. 50 was similar to that of fluoroacetamide or of fluoroacetic acid, and the symptoms produced appeared to be similar in each case (V), however, showed no vesicant action. It is probable then that hydrolysis of the molecule occurs in vivo, resulting in the formation of fluoroacetic acid and the relatively harmless 2-chloroethylamine. 

The formation of fluoroacetate in the plant is of very great interest and the question arises how the plant enzymes build up the C—F link. Equally interesting is the mechanism by which fluoroacetate is destroyed. Throughout the aeons of time, in which the plant has built up fluoroacetic acid, the accumulation... 

CS2 and acetone. The increases of 1.3-2.0 Hz depending on the temperature were about half the size of the temperature effects. Both were attributed to self association of the ethyl formate. Dhingra et al. 28> reported that /13 of tri-fluoroacetic acid increases with decreasing concentration in CC14, dioxane, acetone, water and acetonitrile. The change was apparently in order of the di-... 

Delayed respiratory distress, fibrosis, and atelectasis Gastrointestinal, liver, and kidney toxicity Formation of reactive oxygen species Block tricarboxylic acid cycle (fluoroacetates)... 

Finally, recent developments on research into the first C-F bond forming enzyme are summarized. The fluorinase enzyme isolated from Streptomyces cat-tleya catalyzes the formation of 5 -fluoro-5 -deoxyadenosine from S-adenosyl-L-methionine and fluoride. The substrate specificity and subsequent transformation of the fluorinated nucleoside to fluoroacetic acid and to fluoro threonine are discussed. 

The toxicity of fluoroacetic acid and of its derivatives has played an historical decisive role at the conceptual level. Indeed, it demonstrates that a fluorinated analogue of a natural substrate could have an activity profile that is far different from that of the nonfluorinated parent compound. The toxicity of fluoroacetic acid is due to its ability to block the citric acid cycle (Krebs cycle), which is an essential process of the respiratory chain. The fluoroacetate is transformed in vivo into 2-fluorocitrate by the citrate synthase. It is generally admitted that aconitase (the enzyme that performs the following step of the Krebs cycle) is inhibited by 2-fluorocitrate the formation of aconitate through elimination of the water molecule is a priori impossible from this substrate analogue (Figure 7.1). 

Fluorocitrate is therefore a pseudosubstrate. As well as inhibiting cellular respiration, inhibition of the TCA cycle will also reduce the supply of 2-oxoglutarate. This may decrease the removal of ammonia via formation of glutamic acid and glutamine, and this might account for the convulsions seen in some species after exposure to fluoroacetate. The toxicity is manifested as a malfunction of the CNS and heart, giving rise to nausea, apprehension, convulsions, and defects of cardiac rhythm, leading to ventricular fibrillation. Fluoroacetate and fluorocitrate do not appear to inhibit other enzymes involved in intermediary metabolism, and the di- and trifluoroacetic acids are not similarly incorporated and therefore do not produce the same toxic effects. 

Fluoroacetate causes inhibition of aconitase, an enzyme in the tricarboxylic acid cycle. This is due to the formation of fluorocitrate, which binds to aconitase and inhibits the enzyme. This is because the fluorine atom cannot be removed from the fluorocitrate unlike the hydrogen atom in the normal substrate, citrate. The result is complete blockade of the cycle and this means tissues become starved of ATP and other vital metabolic intermediates. This causes adverse effects in the heart as the organ is particularly sensitive to deficiency of ATP. 

Few of these have been found so far, the first not until 1944, in a poisonous South African plant, Gifblaar . The toxic principle of this was identified44 as fluoroacetic acid. A recent summary45 indicates that some 10 fluorinated natural products have now been isolated (in small amounts) largely from other plant sources, their formation being rationalized from the metabolism of fluoroacetate. The exception is nucleocidin (1), an antibiotic from a microbial source (Streptomyces calvus), originating in an Indian soil sample, and which has a ribose moiety carrying fluorine at C4. 

Derivative formation prior to chromatographic analysis has been used successfully. An unidentified component of urine was found which had a retention time very close to that of pregnanediol and which could not be separated from it by thin layer chromatography. The trimethylsilyl ether derivatives and the tri-fluoroacetate derivatives of the two compounds would not provide resolution only the acetate derivatives could be separated. 

Polymerization of styrene initiated by trifluoro-acetic acid (3) is another example of the same phenomenon. Addition of styrene to tri-fluoroacetic acid yields polystyrene of M. W. 20,000 to 30,000 while the addition of trifluoro-acetic acid to styrene does not produce any polymer Trifluoro-acetate counter ions, formed in the first process, are strongly stabilized by the solvent (trifluoro-acetic acid) through powerful hydrogen bonds, and hence their capacity to recombine with the growing carbonium ion is greatly reduced. In the second process, the counter ions are formed in a hydrocarbon millieu (styrene) of low solvation power. Their recombination with carbonium ions remains therefore unhindered and consequently the formation of a polymer is prevented. 

Sect. 3.1.13 (Simple Organofluorines)), several reviews are available (895, 914, 915, 2390, 2391, 2395). Based on the available evidence, a proposed biosynthetic pathway for the formation of fluoroacetic acid and 4-fhiorothreonine is shown in Scheme 4.7. Fluorinase has also served as a catalyst for the incorporation of [18F]-fluoride into nucleosides (2396, 2397). 

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