Silyl esters, of carboxylic acids

After acidification and the addition of an internal standard the extract is reacted with N,0-bis (trimethylsilyl) trifluoroacetamide to produce the silyl ethers of glycols and the silyl esters of carboxylic acids. Gas chromatography of this reaction mixture enables the numbers of acid and glycol units in the polymer to be estimated. 

Danishefsky and coworkers have demonstrated the conversion of lactones to carbocycles by the 3,3-sigmatropic shift of silylketene acetals. Jq the total synthesis of the Fusarium toxin equisetin, for example, keto lactone (138) was converted to its bissilyl derivative (139) by reaction with 2 equiv. of LDA and an excess of TMS-Cl. In situ thermolysis of ketene acetal (1 ) led to a very smooth transformation into ester (140), which was carried on to equisetin (Scheme 26). This methodology was also applied by Schreiber and Smith in the preparation of the cyclohexyl moiety of the immunosuppressive agent FK-506. Ireland-Claisen rearrangement of silylketene acetal (142), prepared by treatment with TBDMS-OTf and triethylamine at low temperature, provided, after hydrolysis of the silyl ester, the carboxylic acid (143) in 71% overall yield (Scheme 27). The strict translation of configuration via a boatlike transition state is typical for this permutation. 

In a number of instances it is also important to solve another problem, viz., the determination of TMS groups in TMS esters of carboxylic acids and N-silyl compounds. The method that has been elaborated is based on desilylation with phenol followed by the GC analysis of the trimethylphenoxysilane formed [383]. The analysis of amino acids was described in a book [9] and a review [10]. 

Allyl derivatives of hydrocarbons with functional group were often used as starting materials. The hydrosilylation of allylperfluoroethers with methyl(chloro)silanes is a frequently used method for synthesis (after hydrolysis and polycondensation) of fluorine-containing polymers (162). Unsaturated esters of unsaturated carboxylic acids in the reaction of hydrosilylation give silyl derivatives of carboxylic acid (e.g., 3-methacryloxypropyltriethoxysilane). 

Alkylation is used in the derivatization of additives and analytes containing active hydrogen atoms, aliphatic or aliphatic-aromatic substituents. This method is also used to modify compounds containing acidic hydrogen, such as carboxylic acids and phenols, which are converted into esters. Alkylation reactions can also be used to prepare ethers, thioethers and thioesters, N-alkylamines, amides, and sulfonamides. Although silyl derivatives of carboxylic acids are easily formed, these compounds suffer from low stability. 

Some of the more common reagents for the conversion of carboxylic acids to trimethylsilyl esters are listed below. For additional methods that can be used to silylate acids, the section on alcohol protection should be consulted since many of the methods presented there are also applicable to carboxylic acids. Trimethylsilyl esters are cleaved in aqueous solutions. 

The use of HMDS (ca. 1.5 mmol) and saccharin (0.01 mmol) per mmol of substrate in refluxing dichloromethane or chloroform has been recommended (5) for easy silylation of carboxylic acids, including azetidin-2-one-4-carboxyIic acids. Clear solutions result, i.e., no ammonium salts are present at completion of the reaction, and consequently the silyl esters can be obtained by direct distillation, or merely by evaporation of solvent. 

N-Silylated peptide esters are acylated by the acid chloride of N-Cbo-glycine to N-acylated peptide bonds [11]. Likewise, acid chlorides, prepared by treatment of carboxylic acids with oxalyl chloride, react with HMDS 2 at 24°C in CH2CI2 to give Me3SiCl 14 and primary amides in 50-92% yield [12]. Free amino acids such as L-phenylalanine or /5-alanine are silylated by Me2SiCl2 48 in pyridine to 0,N-protected and activated cyclic intermediates, which are not isolated but reacted in situ with three equivalents of benzylamine to give, after 16 h and subsequent chro-... 

Carboxylic acids such as acetic acid react with alcohols such as methanol or with methoxytrimethylsilane 13 a in the presence of trimethylchlorosilane (TCS) 14 in THF or 2-methyl-THF to give esters such as methyl acetate in 97% yield and hex-amethyldisiloxane 7. Even methyl pivalate can be readily prepared in 91% yield [111]. Reaction of a variety of carboxylic acids, for example N-benzoylglycine 329, with two equivalents of yS-trimethylsilylethanol 330 and with 14 has been shown to afford esters such as 331 in 98% yield [112, 112 a]. Likewise, silylated carboxylic acids react with silylated alcohols or thiophenols in the presence of 4-trifluoro-methylbenzoic anhydride and TiCl4/AgCl04 to furnish esters or thioesters in high yields [113, 114] (Scheme 4.43). 

Protection of—COOH.1 Trimethylsilyl esters are useful for temporary protection of carboxylic acid groups during hydroboration of an unsaturated acid. The silyl esters need not be isolated and deprotection occurs spontaneously during the oxidation or iodination step. 

Like the silyl ethers, the stability of the silyl esters parallels the steric bulk of the substituents on the silicon atom. Tris(2,6-diphenylbenzyl)siiy1 esters confer extraordinary steric protection upon the carboxyl group.234 For example, the tris(2,6-diphenylbenzyl)silyl ester of 4-phenylbutanoic acid 104.1 [Scheme 6.104] does not react with butyllithium (2.5 equiv) after 5 h at -78 °C or methylmag-nesium bromide (2,5 equiv) at room temperature. Nor did it react with lithium aluminium hydride after 30 min at 0 °C l M HC1 in THF at 40 °C, or aqueous sodium hydroxide at 50 °C after 5 h. Ester 104.1 was reduced with diisobutyl-aluminium hydride in 99% yield to give the 4-phenyl-l-butanol (99%) and HF pyridine in THF (1 2) at 50 aC cleaved it back to the acid after 5 h. Unfortunately, the penalty for such unusual stability is high the tris(2 6-diphenyl-... 

These derivatives of carboxylic acids behave analogously to ester silyl ketene acetals (Sedion... 

These derivatives of carboxylic acids behave analogously to ester silyl ketene acetals (Section 2.3.2.4.3.i). Thus treatment with peracid in hexane followed by acidic work-up allows isolation of good yields of the a-hydroxy acids. 

A third possibility of chemical modification is conversion into an acylsilane which reduces the oxidation potential of the corresponding ketone by approximately 1 V. A peak potential of 1.45 V (relative to Ag/AgCl) for the oxidation of undecanoyltrimethylsilane has been reported. Preparative electrochemical oxidations of acylsilanes proceed in methanol to give the corresponding methyl esters. A two-step oxidation process must be assumed because of the reaction stoichiometry —oxidation of the acylsilane results in the carbonyl radical cation which is meso-lytically cleaved to give the silyl cation and the acyl radical, which is subsequently oxidized to give the acyl cation as ultimate electrophile which reacts with the solvent. A variety of other nucleophiles have been used and a series of carboxylic acid derivatives are available via this pathway (Scheme 49) [198]. 

Transesterification has been carried out with phase-transfer catalysts, without an added solvent. Nonionic superbases (see p. 365) of the type P(RNCH2CH2)3N catalyze the transesterification of carboxylic acid esters at 25°C. ° Silyl esters (R C02SiR3) have been converted to alkyl esters (R C02R) via reaction with alkyl halides and tetrabutylammonium fluoride. Thioesters are converted to phenolic esters by treatment with triphosgene-pyridine and then phenol. 

Silyl enol ethers of carboxylic acid esters can be alkylated by means of (CH3)3CC1 in the presence of ZnCl2 to give a-butylated products.The... 

Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched P-amino ketones or esters [48a, 48b]. For the most part, these methods involve the use of chirally modified enolates or imines. Only a handful of examples has been reported on the reaction of imines with enolates of carboxylic acid derivatives or silyl ketene acetals in the presence of a stoichiometric amount of a chiral controller [49a, 49b, 49c]. Reports describing the use of a substoichiometric amount of the chiral agent are even more scarce. This section contains some of the most recent advances in the field of catalytic enantioselective additions of lithium enolates and silyl enol ethers of esters and ketones to imines. 

An extremely interesting development is the intramolecular silyl group migration from a silyl ester of thiophene-3-carboxylic acid to position 2 of the ring (Equation (54)) <9lSL33>. The yields are moderate. 3-Thienyllithium has been converted to 3-(tri- -butylsilyl)thiophene by reaction with n-BUjSiCl <94TL3673>. 

As a-alkylated products are thermodynamically more stable, it is significant to note that these ester carbanions undergo both C-silylation and enol silyl-ation (155) the 0,a-dianions of carboxylic acids furnish bistrimethylsilyl enol ethers (156). 

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