Trifluoroacetic acid, methyl ester

A mechanism suggested for Swern-Moffatt oxidation with TFAA is shown in Scheme 8.6. In the first step, DMSO reacts with TFAA to form cationic reactive species I, which is known to be stable only below —At higher temperatures, rearrangement of I takes place to give species II. The reaction of II with an alcohol IQ upon treatment with a base leads to formation of a major by-product, trifluoroacetic acid (TFA) ester VII. Therefore, the first step should be carried out below —50 °C. In the second step, reactive species I is allowed to react with an alcohol HI at or below —50°C to obtain intermediate IV. IV may also undergo the Pummerer rearrangement to give a methyl thiomethyl (MTM) ether VI upon treatment with a base. In the third step, IV is treated with a base (usually triethylamine) to obtain the desired carbonyl compound V and dimethyl sulfide. 

Esterification with diazomethane. Treatment with trifluoroacetic anhydride Methyl esters of N-trifluoroacetylamino acids and N-trifluoroacetyldipep tides 20-22... 

It has been shown that the trifluoroacetates of 3,6,7-trihydroxy bile acids are subject to thermal decomposition in gas chromatographs (30). Oxidation of the bile acids to their keto derivatives and subsequent gas chromatography should also be avoided (31). In our laboratory, we have been unable to gas chromatograph any oxidized 3,6,7 bile acid methyl esters they are either destroyed or will not elute in a reasonable amount of time. 

Trifluroroacetates (100) are prepared by dissolving the bile acid methyl ester (o> the partial silyl ether) in trifluoroacetic anhydride, 15 min, 35 °C (101). The reagent is removed under a stream of nitrogen. Milder conditions yield partial derivatives. Enol esters of 3-keto-J- bile acids may be formed as side products. Trifluoroacetates should be analyzed within 1-2 days since signs of decomposition may appear on storgae for more than 48 hr at room temperature (7, 102). 

In a recent study Hofmann et al. (116) studied the bile acid composition of bile from germ-free rabbits. Deproteinized bile was first analyzed by thin-layer chromatography for a tentative identification of the conjugated bile acids. After alkaline hydrolysis and methylation, bile acid methyl esters were analyzed by thin-layer and gas chromatography. Trifluoroacetate esters and trimethylsilyl ethers of methyl cholanoates were run on QF-1 or Hi-Eff-8B columns, respectively. Gas chromatography-mass spectrometry was used for the final identifications. 

With the procedure of Okishio et al. (24,124) freeze-dried rat liver homogenates are exhaustively extracted with 95% ethanol containing 0.1% ammonium hydroxide, and the extract is taken to dryness. The residue is dissolved in aqueous NaOH, pH 11, and applied to an Amberlyst A-26 anion exchanger. After alkaline or enzymatic hydrolysis the free bile acids are extracted with diethyl ether after acidification. The bile acids are methylated and then purified on aluminum oxide. The bile acid methyl ester fraction eluted from this column is taken to dryness and the residue is trifluoroacet-ylated and analyzed on a triple-component column (QF-1-SE-30-NGS) for quantitative determination. 

In our experience with several different instruments (Atlas CH-4 and LKB 9000) over a period of six years the reproducibility in analyses of bile acid trimethylsilyl ethers is very good also with respect to differences between spectra of stereoisomers. Only once, when the ion source housing was contaminated, were the spectra quite different from normal. Spectra of bile acid methyl esters and particularly of their trifluoroacetates show somewhat larger variations this is assumed to be due to the greater thermal sensitivity of these derivatives. 

Five-membered heterocycles with one nitrogen atom can be prepared from azomethine ylide-type dipoles and alkynes or alkenes. Several solid-supported cycloadditions with maleimide as a dipolarophile have been reported. Trityl resin-bound maleimide captured azomethine ylides that were generated in situ from amino acid methyl esters and aldehydes, and substituted resin-bound pyrrolidines were obtained (Scheme 11.1). Traceless cleavage of the C—N bond between acid-sensitive trityl resin and the IV-unsubstimted cycloadduct was achieved with 50% trifluoroacetic acid. 

Nine substituted hydroxybenzaldehydes were coupled to a Wang resin with a Mitsu-nobu coupling (Scheme 11.4). Treatment of the aldehydes with amino acid methyl esters produced resin-bound azomethine ylides that reacted with maleimide in a 1,3-dipolar cycloaddition. Ether-linked cycloadducts were cleaved from the resin as phenols with 50% trifluoroacetic acid. The compounds were retained as a mixture and were not isolated. 

As fatty alcohols are comparable in structure and molecular weight to fatty acid methyl esters, they are usually subjected to GC on the same stationary phases and under near-identical conditions. It is certainly possible to separate alcohols in the free form by GC, especially on modem WCOT columns of fused silica, but sharper peaks are obtained if less polar derivatives such as the acetates, trifluoroacetates or TMS ethers are prepared. Suitable preparation procedures are described in detail in Chapter 4. Jamieson and Reid [438] studied the relative retention times of many different saturated and unsaturated fatty alcohols in the free form and as the acetates on packed GC columns containing polar polyester phases, and concluded that very similar separation factors applied as with the equivalent fatty acid methyl esters. The order of elution was - methyl ester < alcohol acetate < free alcohol. A TMS ether derivative would be expected to have a lower retention time than an acetate, but the separation factors for double bonds in the alkyl chain in this instance were found to be lower than with the acetates and resolution in general was poorer some changes in retention sequence for specific isomers was noted, depending on the type of derivative [439]. In contrast, the free alcohol eluted before derivatized forms on non-polar phases [944]. It is therefore possible to use equivalent chain-length data for the provisional identification of fatty alcohols in the same way as with methyl ester derivatives of fatty acids (see Chapter 5). 

For example, treatment of imino chloride 144 derived from 7p-(2-phenyl-2-bromo) acetamido-3-methyl 3-cephem benzhydryl ester (143) and phosphorus pentachloride, with an excess of methanolic lithium methoxide in THF at -78°C for 20 min, followed by quenching with acetic acid, afforded 7 -phenylketenimino-7a-methoxy- -lactam (146) in 60% yield. This material was reasonably stable to silica gel chromatography and, when treated with trifluoroacetic acid followed by aqueous quenching, quantitatively afforded 7p-phenylacetamido-7a-methoxy-3-methyl-3-cephem-4-carboxylic acid. Similar treatment of imino chlorides (144) or ketenimines (146) with lithium methoxide at -20 C provided iminoethers (147) in good yield. In the case of the imino chloride formed from 7p-dichloroacetamido-7-deacetoxycephalosporanic acid methyl ester, the corresponding iminoether (147) was obtained in 80% yield with lithium methoxide, even at — 78°C. The same imino chloride reacted... 

Deprotection of Derivatives of Carboxylic Acids.—Methyl esters are demethylated with anhydrous trifluoroacetic acid, in yields ranging from quantitative to 2%. Triarylamine radical cations react with benzyl esters in an oxidative cleavage reaction to give carboxylic acids yields are best with p-methoxybenzyl esters. ... 

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. 

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. 

Upon carefully controlled hydrolysis with hydrochloric acid at room temperature, the corresponding serine methyl esters 4 are obtained in reasonable yields. Higher yields of 4 arc obtained by hydrolyzing with dilute trifluoroacetic acid5. In some cases, the diastereomeric ratio of 4 does not exactly correspond to the d.r. of the adduct 3, which is attributed to different kinetics in the hydrolysis of the diastereomers 4. Subsequent treatment of the methyl ester with excess 5 N hydrochloric acid and methyloxirane as an acid scavenger results in the free amino acid 54,7. 

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