Bis-TMS-derivatives

The silylation of amino acids with BSTFA was studied in detail by Gehrke and coworkers [254—256]. BSTFA—acetonitrile (1 1) was applied first and fourteen amino acids were silylated at 135°C for 15 min. Glu, Arg, Lys, Trp, His and Cys, however, require up to 4 h, in order for measurable peaks to be obtained in the chromatogram. Despite such a long reaction, Gly and Glu gave two peaks and also it was difficult to separate the tris-TMS derivative of Gly from the derivatives of lie and Pro. The influence of polar and non-polar solvents was demonstrated later and was decisive mainly with respect to uniformity of the products. Only the bis-TMS derivative was produced in hexane, methylene chloride, chloroform and 1,2-dichloroethane bis- and tris-derivatives were produced in six more polar solvents. On the other hand, Arg did not provide any peak in the less polar solvents that were used and only one peak in the six more polar solvents. The best and most reproducible results were obtained when silylating seventeen amino acids with BSTFA—acetonitrile (1 1) at 150°C for 15 min 2.5 h at 150°C were necessary for the reproducible derivatization of Gly, Arg, and Glu. These reaction conditions were recommended for the analysis of all twenty amino acids. The TMS derivatives of amino acids were found to be stable on storing them in a sealed vial at room temperature for 8 days, with no decomposition. 

The most widely used methods of silylation of compounds with an amino group are the use of hexamethyldisilazane (405) or bis(TMS)-acetamide (438). Thus, diamines like trimethylene- (479a) or tetramethylenediamine (479b), respectively, or arylamines such as o-diaminobenzene (481), can be converted into the corresponding bis(TMS)-derivatives in yields of up to 95% by means of 405 (equations 229 and 230)245. 

Dicarbonyl compounds, e.g. quinone (589), can be converted into the bis(TMS) derivative (721) (equation 366)401. Similarly quinone such as naphthoquinone as well as anthraquinone (722) can give the corresponding bis(trimethylsiloxy) derivatives (723) (equation 367)402. 

For the conjugate-addition reactions which produce the prostaglandin skeleton, it is necessary to block all the hydroxy and carboxy functions. The ether blocking groups which we have found useful include tetrahydropyranyl (THP) and trime-thylsilyl (TMS). Both of these ethers are readily cleaved with aqueous acetic acid under conditions compatible with the stability of 11-oxy PGE derivatives. These same two groups also serve to esterify the carboxy function. Thus, a hydroxyacid can be blocked in one operation by conversion to a "bis-THP" or "bis-TMS" derivative. Alkyl esters also may be used, but the alkyl ll-hydroxy-9-ketoprostanoates produced can not be converted to the free acids by chemical means. 

Sometimes the products of carbonyl compounds silylation are not TMS-enols, but bis-TMS derivatives of hydrated carbonyls, RR C = 0 RR C(OH)2 RR C(OTMS)2. More unpredictable products can be formed during silylation of a-ketocarboxylic acids. For example, ketomalonic acid (II) besides the normal bis-JMS ester gives an unusual TMS derivative of the enol-hydrate form (see Fig. 7). 

Incubations were set up as specified in Fig. 3, resulting in the consumption of more than 90 % of the substrates according to n. m. r. analysis of suitable model compounds the methionine produced was isolated by ion exchange technique and subsequently converted into its bis-trimethylsilyl (bis-TMS) derivatives upon reaction with N-(trimethylsilyl)diethylamine. Control experiments, in which the substrates, or homocysteine, were omitted from the incubations, gave no trace of methionine. A non-catalyzed methionine formation, detectable in the absence of the enzyme preparation, proceeded with a rate too low to seriously compete with the enzyme-catalyzed reaction. 

The bis-TMS derivatives of methionine, arising from enzymic transmethylation of the diastereomeric substrates, (8) and (9),... 

The mass spectrum of the bis-TMS-derivative of methionine exhibits a molecular ion at m/e 293 with an intensity of about 5 % of that of the base peak at m/e 176, the latter arising by fission of the Cj-C2-bond ... 

In contrast to the bis-TMS derivative of clenbuterol, its methyl boro-nate analogue generates a comparably abundant molecular ion at m/z 300 and few intense fragments derived from the loss of a methyl radical (-15 Da) and methyl oxoboron (-42 Da) at m/z 285 and 243, respectively. Evidence for their composition was obtained by HRMS, and a suggested dissociation route is illustrated in Scheme 3.11b. 

The advantage of trimethylsilyl (TMS) derivatives lies in the simplicity of the derivatization procedure, which is carried out by the addition of N,0-bis(trimethylsilyl)trifluoroacetamide (BSTFA) in acetonitrile and heating for approximately 2 h at 150 °C under anhydrous conditions in a sealed tube. However, there may be problems owing to the formation of multiple derivatives of each amino acid. Another technique involves the formation of n-butyl esters of the amino acids and their subsequent trimethylsilylation by a similar procedure. The n-butyl esters are formed by heating the amino acids for 15 min in n-butanol and HC1 and these are then converted to the A-TMS-n-butyl ester derivatives. A-acyl amino acid alkyl esters are commonly used. Acetylation of the butyl, methyl or propyl esters of amino acids,... 

The 3-pyridyl O-carbamate affords, under the sec-BuLi/TMEDA conditions, only 4-substituted products. A reinvestigation of LDA metalation (85JOC5436) has shown that high-yield conversion of 320 into the 4-TMS (319) and 2,4-bis-TMS (321) derivatives can be effected (Scheme 97) [90UP1]. Furthermore, LiTMP metalation of 319 followed by electrophile quench leads to derivatives 322, thus demonstrating the TMS protection route to 2-substituted 3-oxygenated pyridines. Another, potentially useful result is the 2-position selective ipso carbodesilylation of 321 with benzoyl chloride, yielding 323. 

In a different pattern, by using silylated acetylenes, substituted pyridazines are obtainable217 from the tetrazine derivative 401 in a diene-type reaction, first introduced by Carboni and Lindsey218. Via this reaction 4-TMS- (402) and 4,5-bis(TMS)-3,6-bis(methoxycarbonyl)pyridazine (403) can be achieved in very high yield, being inert against acid catalyzed desilylation (Scheme 59). 

The thermodynamically controlled reactions between ClCH2GeMe2Cl and O- or N-TMS derivatives of 5-ethyl-3-morpholinone493 and 2,5-piperazinedione489 yield the monochelate 147 and bis-chelate 148a, respectively. 

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