Silylation activation

After silylation-amination in situ transsilylation (cf Section 2.3) of the intermediate persilylated cytidines 5 with excess boiling methanol for 3-5 h gives the desired free cytidines 6 and methoxytrimethylsilane 13a (b.p. 57°C) [13]. Thus protection of the alcohohc hydroxyl groups of the ribose moiety and silylation-activation of the 4-position in the pyrimidine moiety in persilylated uridine 3, and the concomitant amination of 3, aU in one reaction step, to 5 is followed finally by in situ transsilylation (cf. Section 2.3) with excess boihng methanol in one reaction vessel. 

All these steps proceed to afford free or N -substituted crystalline cytidines 6 in high yields [11] (cf. the preparation of N (tetramethylene)cytidine 6b in 95.4% yield in Section 1.1.). This simple one-pot reaction is also very easy to perform on a technical scale, as are the subsequently discussed analogous silylation-aminations of purine nucleosides and other hydroxy-N-heterocycles (cf. Sections 4.2.4 and 4.2.5). The concept of silylation-activation while simultaneously protecting hydroxyl groups in alcohols, phenols, or phosphoric acids by silylation was subsequently rediscovered and appropriately termed transient protection [16-18]. 

Most of the other silylation-activation-substitution reactions reported in this review are mechanistically related. Several new reactions (such as those discussed in Sections 7.1, 7.2, and 7.4) have been discovered by following these hnes of thinking about activation of functional groups by O-silylation and subsequent or concomitant reaction with nucleophiles giving the expected products and hexamethyldisiloxane 7. It can thus be expected that current and new silylation-activation reactions will be more commonly used in preparative chemistry in the future. 

Thus we hope that these O-silylations-activations with the readily available HMDS (MesSiNHSiMes), TCS (MesSiCl), dimethyldichlorosilane (Me2SiCl2), hexa-methylcyclotrisilazane (HNSiMe2)s, OMCTS (HNSiMe2)4, tetra(alkoxy) silane (Si(OR)4) or sihcon tetrachloride (SiCL ), most of which can also effect the transient protection of any present hydroxyl group, and the subsequent or concomitant reaction with nucleophiles accompanied by formation of silylated water as HMDSO (MesSiOSiMes), (OSiMe2)n or Si02 will be applied more often in the fu-... 

P, P] Tin(II) enolates of propionyl imides do not undergo uncatalyzed reactions with enones. Lewis acid catalysis results in the construction of 1,4-addition products. The stereoselectivity of this reaction has been examined by Mukaiyama and co-workers (87,88) and is summarized in Scheme 41 and Table 14. The tin(II) enolates were generated by the action of tin(II) triflate with N-ethylpiperidine on the propionyl imide. Although not examined, it is likely that this procedure results in the generation of a Z enolate (89). A process can be envisioned whereby transmetallation occurs to yield a silyl ether and a tin(II) species capable of Lewis acidic behavior. Hence, either direct conjugate addition of the tin enolate to a silyl-activated acceptor or transmetallation to... 

If a Michael reaction uses an unsymmetrical ketone with two CH-groups of similar acidity, the enol or enolate is first prepared in pure form (p. llff.). To avoid equilibration one has to work at low temperatures. The reaction may then become slow, and it is advisable to further activate the carbon-carbon double bond. This may be achieved by the introduction of an extra electron-withdrawing silyl substituent at C-2 of an a -synthon. Treatment of the Michael adduct with base removes the silicon, and may lead as well to an aldol addition (G. Stork, 1973, 1974 B R.K. Boeckman, Jr., 1974). 

Silyl enol ethers are other ketone or aldehyde enolate equivalents and react with allyl carbonate to give allyl ketones or aldehydes 13,300. The transme-tallation of the 7r-allylpalladium methoxide, formed from allyl alkyl carbonate, with the silyl enol ether 464 forms the palladium enolate 465, which undergoes reductive elimination to afford the allyl ketone or aldehyde 466. For this reaction, neither fluoride anion nor a Lewis acid is necessary for the activation of silyl enol ethers. The reaction also proceed.s with metallic Pd supported on silica by a special method[301j. The ketene silyl acetal 467 derived from esters or lactones also reacts with allyl carbonates, affording allylated esters or lactones by using dppe as a ligand[302]... 

Unstrained difluorotetramethyldisilane (84) gives the 1 1 adduct 85 as the main product and the 1 2 adduct 86 as a minor product[78,79]. On the other hand, the dimerization and double silylation of conjugated dienes with (Me3Si)2 catalyzed by PdCl2(PhCN)2 take place at 90" C[80]. Pd(dba)2 without phosphine is an active catalyst for the reaction, which proceeds in DMF to give 87 at room temperature[81], A five-membered ring is formed by the application of the reaction to the di-(2,4-pentadienyl)malonate (69)[82]. 

Dimethylaminopyridine [1122-58-3] (DMAP) (24) has emerged as the preferred catalyst for a variety of synthetic transformations under mild conditions, particularly acylations, alkylations, silylations, esterifications, polymeri2ations, and rearrangements (100). POLYDMAP resin [1122-58-3], a polymeric version of DMAP, is available, and is as effective as DMAP as a catalyst for acylation reactions. Furthermore, it can be recycled without regeneration more than 20 times with very Htde loss in activity. POLYDMAP is a trademark of Reilly Industries, Inc. 

Trimethylsilyloxazolidinone. This reagent can be used to silylate most active hydrogen compounds. 

A similar procedure has been employed to silylate the dianion of 3-methyl-3-buten-2-ol (67% yield).In systems where such internal activation is not possible (e.g. 2-raethyl-2-cyclohexen-l-o1), dianion formation can be performed in hexane to give a 75% yield of the corresponding disilyl compound. 

Systems usually fluonnated by electropositive fluorine reagents include acti-vated alkenes (enol ethers, enol acetates, silyl enol ethers, and enamines), activated aromatic systems, certain slightly activated carbon-hydrogen bonds, and selected organometallics. 

Benzyloxy-2-fluoro-2-methylpropionaIdehyde was prepared in optically active form from (5)-monoethyl 2-fluoro-2-methylmalonate, which had itself been prepared by enzymatic hydrolysis A number of enol silyl ethers or enolates were added to the aldehyde in processes that occur with fair to good diastereoselectivity [6] (equation 6) (Table 2)... 

Darzens reaction can be used to efficiently complete the stereoselective synthesis of a"-substituted epoxy ketones. As an example, Enders and Hett reported a technique for the asymmetric synthesis of a"-silylated a,P-epoxy ketones. Thus, optically active a -silyl a-bromoketone 38 was treated with LDA followed by the addition of benzaldehyde to give a"-silyl epoxyketone 40 in 66% yield with good... 

Replacement of heterocyclic rings in nucleosides by ring systems which do not occur in nature represents another approach to compounds which may have activity against viral and neoplastic diseases. One of the early successes in this category involves replacement of a pyrimidine ring by a triazine. The synthesis starts with a now classical glycosidation of a heterocycle as its silylated derivative (146) with a protected halosugar (145), in this case a derivative of arabinose... 

Later, Kricheldorf and coworkers [93,94] extensively demonstrated the use of 0-silylated bifunctional monomers, such as diphenols, for synthesis of a wide variety of polycondensation polymers. The silylated oxygen of difunctional phenols may be condensed with activated... 

Condensation with activated chloroaromatics with O-silylated bisphenols in NMP in presence of K2CO3 has also been reported by Kricheldorf and Jahnke [103]. The... 

Merck s thienamycin synthesis commences with mono (V-silylation of dibenzyl aspartate (13, Scheme 2), the bis(benzyl) ester of aspartic acid (12). Thus, treatment of a cooled (0°C) solution of 13 in ether with trimethylsilyl chloride and triethylamine, followed by filtration to remove the triethylamine hydrochloride by-product, provides 11. When 11 is exposed to the action of one equivalent of tm-butylmagnesium chloride, the active hydrogen attached to nitrogen is removed, and the resultant anion spontaneously condenses with the electrophilic ester carbonyl four atoms away. After hydrolysis of the reaction mixture with 2 n HC1 saturated with ammonium chloride, enantiomerically pure azetidinone ester 10 is formed in 65-70% yield from 13. Although it is conceivable that... 

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