Pyridines silylation

Early reviews on the mass spectra of nucleotides, more particularly of mononucleotides, " covered trimethylsilyl and methyl derivatives of nucleotides. The silylation of nucleotides, for instance, takes place on the base, on the sugar hydroxyls, and on the free phosphate hydroxyls under mild (room temperature) and basic (pyridine) silylation conditions (BSTFA/TMCS). The fragmentation of derivatives obtained from both procedures has been well studied. Several typical fragments ([M — CHj]", [base -I- 2H], silylated and desilylated sugar, S-TMSOH, etc.), as well as a weak M+ ion have been recorded. The FD spectrum of an underivatized... 

The formation of stable iV,0-acetal TMS ethers, which are excellent precursors of V-acyliminium ions, is easily achieved by DIBAL reduction of V-acylamides followed by in situ protection with TMSOTf/pyridine (eq 39). 2,6-Lutidine has also been used as base. The DIBAL reduction-TMSOTf/pyridine silylation sequence has also been applied to the formation of monosilyl... 

Silyl Ethers. The preparation of per- O-trimethyl silyl ethers of sucrose is generally achieved by reaction with chi orotrimethyl sil ane and/or hexamethyldisila2ane in pyridine (25,26). However, this reaction is not selective and in general per-trimethyl silyl ethers are only used as derivatives for gas chromatographic studies. 

Sdylation of sucrose with 0.65 equivalents of ferZ-hutyl dimethyl silyl chloride in pyridine gives the corresponding 6 -, 6,6 -di-, and... 

Selective fluonnation in polar solvents has proved commercially successful in the synthesis of 5 fluorouracil and its pyrimidine relatives, an extensive subject that will be discussed in another section Selective fluonnation of enolates [47], enols [48], and silyl enol ethers [49] resulted in preparation of a/phn-fluoro ketones, fieto-diketones, heta-ketoesters, and aldehydes The reactions of fluorine with these functionalities is most probably an addition to the ene followed by elimination of fluonde ion or hydrogen fluoride rather than a simple substitution In a similar vein, selective fluonnation of pyridmes to give 2-fluoropyridines was shown to proceed through pyridine difluondes [50]... 

Enolizable compounds can be used for Meerwein reactions provided that the keto-enol equilibrium is not too far on the side of the ketone for example, P-dicar-bonyl compounds such as acetylacetone are suitable (Citterio and Ferrario, 1983). The arylation of enol esters or ethers (10.12) affords a convenient route for arylating aldehydes and ketones at the a-carbon atom (Scheme 10-48). Silyl enol ethers [10.12, R = Si(CH3)3] can be used instead of enol ethers (Sakakura et al., 1985). The reaction is carried out in pyridine. 

Ketones and carboxylic esters can be a hydroxylated by treatment of their enolate forms (prepared by adding the ketone or ester to LDA) with a molybdenum peroxide reagent (MoOs-pyridine-HMPA) in THF-hexane at -70°C. The enolate forms of amides and estersand the enamine derivatives of ketones can similarly be converted to their a hydroxy derivatives by reaction with molecular oxygen. The M0O5 method can also be applied to certain nitriles. Ketones have also been Qc hydroxylated by treating the corresponding silyl enol ethers with /n-chloroperoxy-... 

In order to ameliorate the problem of solvolytic degradation, compound 109 was treated with TIPSOTf, to provide silyl ether 113 in 72% yield (Scheme 19). The acetonides were removed with PPTS in warm MeOH to provide a mixture of compounds in which the TBS groups were also partially removed. Exposure of this mixture to HF-pyridine successfully generated filipin III (114), in 39 % overall yield from 113. 

Last but not least HMDS 2 is, in the laboratory and in pilot plants, quite stable when stored in a normal closed vessel whereas trimethylchlorosilane (TCS) 14 should be stored in a hood, because it reacts with humidity to hexamethyldisilox-ane 7 and HCl. Because HMDS 2 is a very non-polar compound, the silylation of very polar compounds, e.g. purines or pteridines, with HMDS 2 wiU often proceed only on addition of a polar solvent such as pyridine which is, however, readily removed after silylation, with excess HMDS 2, on codistillation with abs. xylene. Interestingly, it was recently reported that addition of catalytic amounts of iodine dramatically accelerates the silylation of alcohols, in particular tertiary alcohols, with HMDS 2 in CH2CI2 at room temperature [63]. 

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-... 

In the reactivity scale of Scheme 4.25 the reactivity of any of these heterocycles is substantially increased by annellation with a conjugated aromatic ring. Thus 2-quinolone is much more reactive than pyridine-2-one 245, which is the least reactive hydroxyheterocycle and requires reaction temperatures higher than 190-200 °C for silylation-amination [27]. To achieve these temperatures at normal pres-... 

A large range of aromatic and heteroaromatic aldehydes, for example benzalde-hyde 462a or pyridine-2-aldehyde 462b, condense with two equivalents of N-silyl-ated dimethylamine 463, piperidine, or morpholine 294 in the presence of... 

N-silylated imines 509 react with the Li salts of tosylmethylisonitriles to give 4,5-disubstituted imidazoles in moderate yields [93]. Acetylation of N-trimethylsilyl imines 509 with acetyl chloride and triethylamine affords 72-80% of the aza-dienes 510 these undergo readily Diels-Alder reactions, e.g. with maleic anhydride at 24 °C to give 511 [94] or with dimethyl acetylenedicarboxylate to give dimethyl pyridine-3,4-dicarboxylates [94] (Scheme 5.29). 

It is interesting to note that condensation of the N,N-bis(silylated) enamine 538 with a variety of chalcones such as benzalacetophenone 735 proceeds, via 539 and subsequent cyclization and oxidation, to pyridines such as 540 [106, 108] whereas persilylated co-amino ketones such as the 2-substituted pyridine 541 cyclize, via 542, in 29% yield, to the pyrrole 543 [109] (Scheme 5.36). 

Normal yS-dicarbonyl compounds such as ethyl acetoacetate 723 a or acetylace-tone 723 b are converted, as the free yS-dicarbonyl compounds or as their sodium salts, by TCS 14, 14/pyridine, or HMDS 2/TCS 14 into their enol silyl ethers 724a [216, 217, 219] and 724b [218]. Yet treatment of / -triketones such as 2-acetyl-dimedone 725 with HMDS 2 results, via the corresponding 2-enol trimethylsilyl... 

Treatment of the allylic sulfoxide 1227 a with diisopropylethylamine (DIPEA) or of 1227 b with N-trimethylsilyldiethylamine 146 and TMSOTf 20 leads in ca. 90% yield to the quaternary amino derivatives 1228 and 1229 and HMDSO 7 [36] (Scheme 8.15). Tetramethylene sulfoxide 1230 reacts with silylated thymine 1231 in the presence of three equivalents of TMSOTf 20 to give the 4 -thio-nucleoside analogue 1232 and HMDSO 7 [37]. Other silylated pyrimidine, pyridine, and purine bases react analogously with cyclic sulfoxides to give 4 -thio-nucleoside analogues [37, 37a, 38]. 

The N-silylated enol acetate 1523 is cyclized by TMSOTf 20 in CHCI3, in 95% yield, giving the oxazole 1524 [57]. The dimeric derivative 1525 affords the 2,2 -bis-oxazole 1526 in 46% yield [57]. 2-Benzoylamino-3-chloropyridine 1527 is cyclized by polyphosphoric acid trimethylsilyl ester (PPSE) 195 on heating for 15 h in boiling 1,2-dichlorobenzene to give 40-60% 2-phenyloxazolo[5,4-f)]pyridine 1528 [58] (Scheme 9.34). 

The N-silylated amide 1558 reacts with diketene vio the O-silylated intermediate 1559 to give the pyrone 1560, which rearranges when treated with 10% HCl to give pyridin-2-one 1561 [74] (Scheme 9.43). 

Epoxides such as cyclohexene epoxide are converted by MesSiSiMes 857/12 or TMS 14/NaI, via O-silylated-2-iodocyclohexanol 1777 [26], into cyclohexene [27, 28] (cf also Ref. [33]). Pyridine-N-oxides such as 2-, 3-, or 4-methylpyridine-N-oxides 1778 are reduced by Me3SiI 17/Zn in acetonitrile, probably via 2-iodopyridines 1779, to picolines in 80-92% yield [29] (Scheme 12.8). 

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