Trifluoroacetic acid esters

Scheme 8.—Fragmentation pattern of the trifluoroacetic acid ester of the thiazole of thiamine in the mass spectrometer.

By the way, trifluoroacetaldehyde is a versatile fluoro building block. However the chemical or electrochemical oxidative transformation of trifluoro-ethanol to trifluoroacetaldehyde has been unsuccessful. Trifluoroacetaldehyde is therefore generally produced by the reduction of trifluoroacetic acid ester or acid chloride using an excess of LAH. The anodic substitution at fluoroaikyl phenyl sulfides is a useful alternative because it realizes the transformation of economical trifluoroethanol to highly valuable trifluoroacetaldehyde equivalents as shown in Scheme 6.5. 

The authorswere able to show, however, that the trifluoroacetic acid esters. 111 and 112, differed in stability by approximately 10 kcal mol , with the j8-cyano ester 112 being the more stable. Clearly, in this case the rate of formation of a carbocation is not a... 

Hydrolysis of esters XIV to the acids XVI is considerably slower in aqueous acid than in base. As weak bases, these compounds are sparingly soluble in weak organic acids, such as acetic acid, and in aqueous mineral acids. This contrasts with their solubility in strong non-aqueous acids, such as sulfuric and trifluoroacetic acid. Esters are generally soluble in dilute sodium hydroxide because of the acidic proton at position 3 of the heterocyclic nucleus. 

Simple unactivated esters do not react with TMSCF3. However, activated esters such as trifluoroacetic acid esters do react. Cyclic esters, i.e. lactones, react with TMSCF3 to give the corresponding adducts. An efficient and simple synthesis of tri-fluoropyruvic acid monohydrate has been developed starting from di-f-butyl oxalate. ... 

CF3CO2H. Colourless liquid, b.p. 72-5 C, fumes in air. Trifluoroacetic acid is the most important halogen-substituted acetic acid. It is a very strong acid (pK = o y) and used extensively for acid catalysed reactions, especially ester cleavage in peptide synthesis. 

The blocking and deblocking of carboxyl groups occurs by reactions similar to those described for hydroxyl and amino groups. The most important protected derivatives are /-butyl, benzyl, and methyl esters. These may be cleaved in this order by trifluoroacetic acid, hydrogenolysis, and strong acid or base (J.F.W. McOmie, 1973). 2,2,2-Trihaloethyl esters are cleaved electro-lytically (M.F. Semmelhack, 1972) or by zinc in acetic acid like the Tbeoc- and Tceoc-protected hydroxyl and amino groups. 

In each step of the usual C-to-N peptide synthesis the N-protecting group of the newly coupled amino acid must be selectively removed under conditions that leave all side-chain pro-teaing groups of the peptide intact. The most common protecting groups of side-chains (p. 229) are all stable towards 50% trifluoroacetic acid in dichloromethane, and this reagent is most commonly used for N -deprotection. Only /ert-butyl esters and carbamates ( = Boc) are solvolyzed in this mixture. 

The following acid-catalyzed cyclizations leading to steroid hormone precursors exemplify some important facts an acetylenic bond is less nucleophilic than an olelinic bond acetylenic bonds tend to form cyclopentane rather than cyclohexane derivatives, if there is a choice in proton-catalyzed olefin cyclizations the thermodynamically most stable Irons connection of cyclohexane rings is obtained selectively electroneutral nucleophilic agents such as ethylene carbonate can be used to terminate the cationic cyclization process forming stable enol derivatives which can be hydrolyzed to carbonyl compounds without this nucleophile and with trifluoroacetic acid the corresponding enol ester may be obtained (M.B. Gravestock, 1978, A,B P.E. Peterson, 1969). 

A solution of trifluoroacetic acid in toluene was found to be advantageous for cydization of pyruvate hydrazoncs having nitro substituents[4]. p-Toluene-sulfonic acid or Amberlyst-15 in toluene has also been found to give excellent results in preparation of indole-2-carboxylale esters from pyruvate hydra-zoiies[5,6J. Acidic zeolite catalysts have been used with xylene as a solvent to convert phenylhydraziiies and ketones to indoles both in one-flask procedures and in a flow-through reactor[7]. 

Nonvolatile analytes must be chemically converted to a volatile derivative before analysis. For example, amino acids are not sufficiently volatile to analyze directly by gas chromatography. Reacting an amino acid with 1-butanol and acetyl chloride produces an esterfied amino acid. Subsequent treatment with trifluoroacetic acid gives the amino acid s volatile N-trifluoroacetyl- -butyl ester derivative. 

Fluorinated Acids. This class of compounds is characterized by the strength of the fluorocarbon acids, eg, CF COOH, approaching that of mineral acids. This property results from the strong inductive effect of fluorine and is markedly less when the fluorocarbon group is moved away from the carbonyl group. Generally, their reactions are similar to organic acids and they find apphcations, particularly trifluoroacetic acid [76-05-1] and its anhydride [407-25-0] as promotors in the preparation of esters and ketones and in nitration reactions. 

Trifluoroethanol was first prepared by the catalytic reduction of trifluoroacetic anhydride [407-25-0] (58). Other methods iaclude the catalytic hydrogeaatioa of trifluoroacetamide [354-38-1] (59), the lithium aluminum hydride reductioa of trifluoroacetyl chloride [354-32-5] (60) or of trifluoroacetic acid or its esters (61,62), and the acetolysis of 2-chloro-l,l,l-trifluoroethane [75-88-7] followed by hydrolysis (60). More recently, the hydrogenation of... 

Esters derived from the primary alcohols are the most stable and those derived from the tertiary alcohols are the least stable. The decomposition temperature is lower in polar solvents, eg, dimethyl sulfoxide (DMSO), with decomposition occurring at 20°C for esters derived from the tertiary alcohols (38). Esters of benzyl xanthic acid yield stilbenes on heating, and those from neopentyl alcohols thermally rearrange to the corresponding dithiol esters (39,40). The dialkyl xanthate esters catalytically rearrange to the dithiol esters with conventional Lewis acids or trifluoroacetic acid (41,42). The esters are also catalytically rearranged to the dithiolesters by pyridine Ai-oxide catalysts (43) ... 

However, this method is appHed only when esterification cannot be effected by the usual acid—alcohol reaction because of the higher cost of the anhydrides. The production of cellulose acetate (see Fibers, cellulose esters), phenyl acetate (used in acetaminophen production), and aspirin (acetylsahcyhc acid) (see Salicylic acid) are examples of the large-scale use of acetic anhydride. The speed of acylation is greatiy increased by the use of catalysts (68) such as sulfuric acid, perchloric acid, trifluoroacetic acid, phosphoms pentoxide, 2inc chloride, ferric chloride, sodium acetate, and tertiary amines, eg, 4-dimethylaminopyridine. 

The change of mechanism with tertiary alkyl esters is valuable in synthetic methodology because it permits certain esters to be hydrolyzed very selectively. The usual situation involves the use of t-butyl esters, which can be cleaved to carboxylic acids by action of acids such as p-toluenesulfonic acid or trifluoroacetic acid under anhydrous conditions where other esters are stable. 

Aqueous hydrofluoric acid dissolved in acetonitrile is a good catalyst for intramolecular Diels-Alder reactions [9] This reagent promotes highly stereoselective cyclizations of different triene esters (equation 8) The use of other acids, such as hydrochloric, acetic, and trifluoroacetic acid, results in complete polymerization of the starting trienes [9] (equation 8)... 

Conversely, when A-alkyl tryptophan methyl esters were condensed with aldehydes, the trans diastereomers were observed as the major products." X-ray-crystal structures of 1,2,3-trisubstituted tetrahydro-P-carbolines revealed that the Cl substituent preferentially adopted a pseudo-axial position, forcing the C3 substituent into a pseudo-equatorial orientation to give the kinetically and thermodynamically preferred trans isomer." As the steric size of the Cl and N2 substituents increased, the selectivity for the trans isomer became greater. A-alkyl-L-tryptophan methyl ester 42 was condensed with various aliphatic aldehydes in the presence of trifluoroacetic acid to give predominantly the trans isomers. ... 

Then, 1-(3-acetylthio-2-methylpropanoyl)-L-proline is produced. The 1-(3-acetylthio-3-methyl-propanoyl)-L-proline tert-butyl ester (7.8 g) is dissolved in a mixture of anisole (55 ml) and trifluoroacetic acid (110 ml). After one hour storage at room temperature the solvent Is removed in vacuo and the residue is precipitated several times from ether-hexane. The residue (6.8 g) is dissolved in acetonitrile (40 ml) and dicyclohexylamine (4.5 ml) is added. The crystalline salt is boiled with fresh acetonitrile (100 ml), chilled to room temperature and filtered, yield 3 g, MP 187°C to 188°C. This material is recrystallized from isopropanol [ttlo -67° (C 1.4, EtOH). The crystalline dicyclohexylamine salt is suspended in a mixture of 5% aqueous potassium bisulfate and ethyl acetate. The organic phase is washed with water and concentrated to dryness. The residue is crystallized from ethyl acetate-hexane to yield the 1-(3-acetylthio-2-D-methylpropanoyl-L-proline, MP83°Cto 85°C. 

A) A solution of (SMI (320 mg) in trifluoroacetic acid (7 ml) was kept under nitrogen at room temperature for 15 minutes. Ether (100 ml) was added and the precipitate filtered, washed thoroughly with ether and dried. This material (280 mg) was added to concentrated sulfuric acid (20 ml), cooled at -20°C. The solution was kept in the dry ice-acetone bath at -20°C for 75 minutes. The sulfuric acid solution was poured into ice water (80 ml). The precipitate was centrifuged, resuspended in ice water (30 ml) and 4N sodium hydroxide was added until a clear solution was obtained. After reacidification to pH 4 with dilute sulfuric acid, the precipitate formed was centrifuged, washed twice with ice water and dried. Yield 155 mg. Chromatograph of DEAE Sephadex (with ammonium carbonate buffer) yielded the desired octa-peptide sulfate ester 30 mg. 

This approach is only restricted by the accessibility of the tripyrranes 1. To avoid constitutional isomers it is also necessary that at least one of the building blocks should be symmetric. Since trifluoroacetic acid is used for the condensation step, /rvV-butyl ester moieties can be used in the x-positions of the tripyrrane which are cleaved prior to the decarboxylativc condensation. 

The cyclization of 1,19-dideoxybilene-i-dicarboxylic acid esters has been widely used for the synthesis of porphyrins. In this case, the use of tert-butyl esters which can be hydrolyzed with trifluoroacetic acid prior to the cyclization step is necessary. The cyclization step also requires trifluoroacetic acid and orthoformates. However, attempts to prepare porphyrins with /f-acceptor substituents can give rise to problems with side products and yields. 

A completely different concept13 makes use of a highly reduced bilane 5 which is oxidatively cyclized to an isobacteriochlorin 6 with copper(II) acetate. The ring closure is initiated by ester cleavage with trifluoroacetic acid and decarboxylative formylation with trimethyl orthoformate to yield a dialdehyde. One of the aldehyde functions forms the desired methine bridge whereas the other is lost during cyclization. 

Studies on Trifluoroacetic Acid. Part I. Trifluoroacetic Anhydride as a Promotor of Ester Formation between Hydroxy-Compounds and Carboxylic Acids, E. J. Bourne, M. Stacey, J. C. Tatlow, and J. M. Tedder, J. Chem. Soc., (1949) 2976-2979. 

Acid derivatives that can be converted to amides include thiol acids (RCOSH), thiol esters (RCOSR), ° acyloxyboranes [RCOB(OR )2]. silicic esters [(RCOO)4Si], 1,1,1-trihalo ketones (RCOCXa), a-keto nitriles, acyl azides, and non-enolizable ketones (see the Haller-Bauer reaction 12-31). A polymer-bound acyl derivative was converted to an amide using tributylvinyl tin, trifluoroacetic acid, AsPh3, and a palladium catalyst. The source of amine in this reaction was the polymer itself, which was an amide resin. 

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