Silyl ethers from carbonyl compounds

The other side of the coin is that the S 2 reaction at carbon is not much affected by partial positive [ charge (5+) on the carbon a tom. The Sn2 reaction at silicon is affected by the charge on silicon. The r most electrophilic silicon compounds are the silyl triflates and it is estimated that they react some 108-109 times faster with oxygen nucleophiles than do silyl chlorides. Trimethylsilyl triflate is, in fact, an excellent Lewis acid and can be used to form acetals or silyl enol ethers from carbonyl compounds, and to react these two together in aldol-style reactions. In all three reactions the triflate attacks an oxygen atom. 

A cheap and efficient method for synthesis of 2-triniethylsilyloxy-l,3-butadiene from methyl vinyl ketone was desired. The method had to be practical for molar scale preparations. Although a number of methods for the synthesis of silyl enol ethers from carbonyl compounds are known, none of them were applicable for this conversion. They were either too expensive for use on larger scale, or afforded poor yields on attempted synthesis. 

The preparation of silyl enol ethers from carbonyl compounds represents one of the major uses of TMSOTf. Recently, the stereochemistry and regiospeciflcity of such transformation has been addressed for aldehydes and Q -(lV-alkoxycarbonylamino) ketones, respectively. On the other hand, enantiopure silyl enol ethers can be formed by addition of TMSOTf to zinc enolates, which are obtained from the copper-catalyzed enantioselective conjugate addition of dialkyIzinc reagents to cyclic (eq 36) and acyclic enones. ... 

This reaction sequence of conjugate reduction followed by aldol reaction is known as the reductive aldol reaction. In certain instances, reductive elimination from the M-TM-enolate species may occur to furnish M-enolate, which itself may participate in the aldol reaction (Scheme 3). This detour may be described as the background path or stepwise path in one-pot. Indeed, it has been reported that certain cationic Rh complexes such as [Rh(COD)(DPPB)] (COD = 1,5-cyclooctadiene, DPPB = diphenylphosphinobutane) catalyze the aldol reactions of silyl enol ethers and carbonyl compounds by serving as Lewis acids [5-8]. 

A new, direct route to 0,S-acetals is based in part on the ability of trimethylsilyl triflate to mediate synthesis of 0,0-acetals from carbonyl compounds and silyl ethers (10, 439). Thus reaction of 1 1 mixtures of a silyl ether and phenylthiotrimethylsilane with an aldehyde in the presence of catalytic to stoichiometric amounts of trimethylsilyl triflate can give 0,S-acetals in 37-93% yield. Acetone is amenable to this 0,S-ketalization, but reactions with cyclohexanone result mainly in 0,0-ketals. 

In contrast, the related silyl enol ethers are available by mild selective transformations from carbonyl compounds or other precursors 55). Their stability and that of products derived from these alkenes can easily be regulated by choosing suitable substituents at silicon. Selective cleavage of a Si—O-bond is possible with fluoride reagents under very mild conditions, and this is why cyclopropane ring opening can now be performed with high chemoselectivity. 

Generation of a-Acyl Radicals. As a one-electron oxidant, Ce can promote the formation of radicals from carbonyl compounds. In the presence of interceptors such as butadiene and alkenyl acetates, the a-acyl radicals undergo addition. The carbonyl compounds may be introduced as enol silyl ethers, and the oxidative coupling of two such ethers may be accomplished. Some differences in the efficiency for oxidative cyclization of, s-, and ,f-unsaturated enol silyl ethers using CAN and other oxidants have been noted (eq 14). ... 

Triethylsilane can also facilitate the high yielding reductive formation of dialkyl ethers from carbonyls and silyl ethers. For example, the combination of 4-bromobenzaldehyde, trimethylsi-lyl protected benzyl alcohol, and EtsSiH in the presence of catalytic amounts of FeCls will result in the reduction and benzylation of the carbonyl group (eq 32). Similarly, Cu(OTf)2 has been shown to aid EtsSiH in the reductive etherification of variety of carbonyl compounds with w-octyl trimethylsilyl ether to give the alkyl ethers in moderate to good yields. Likewise, TMSOTf catalyzes the conversion of tetrahydrop)ranyl ethers to benzyl ethers with Ets SiH and benzaldehyde, and diphenylmethyl ethers with EtsSiH and diphenylmethyl formate. Symmetrical and unsymmetrical ethers are afforded in good yield from carbonyl compounds with silyl ethers (or alcohols) and EtsSiH catalyzed by bismuth trihalide salts. An intramolecular version of this procedure has been nicely applied to the construction of cA-2,6-di- and trisubstituted tetrahydropyrans. ... 

We shall be returning to silyl enol ethers and lithium enolates later in the book, but for the moment you should view them simply as enol derivatives that are stable enough to be formed quantitatively from carbonyl compounds before being used in further reactions. 

Although it is mechanistically different from the Tsuji-Trost allylation, indirect allyla-tions of ketones, aldehydes, and esters via their enolates are briefly summarized here. Related reactions are treated in Sect V.2.1.4. Pd-catalyzed allylation of aldehydes, ketones, and esters with aUyhc carbonates is possible via the Tr-allylpaUadium enolates of these carbonyl compounds. Tr-AUylpalladium enolates can be generated by the treatment of silyl and stannyl enol ethers of carbonyl compounds with allyl carbonates, and the allylated products are obtained by the reductive elimination of the Tr-allylpalladium enolates. 

Although ethereal solutions of methyl lithium may be prepared by the reaction of lithium wire with either methyl iodide or methyl bromide in ether solution, the molar equivalent of lithium iodide or lithium bromide formed in these reactions remains in solution and forms, in part, a complex with the methyllithium. Certain of the ethereal solutions of methyl 1ithium currently marketed by several suppliers including Alfa Products, Morton/Thiokol, Inc., Aldrich Chemical Company, and Lithium Corporation of America, Inc., have been prepared from methyl bromide and contain a full molar equivalent of lithium bromide. In several applications such as the use of methyllithium to prepare lithium dimethyl cuprate or the use of methyllithium in 1,2-dimethyoxyethane to prepare lithium enolates from enol acetates or triraethyl silyl enol ethers, the presence of this lithium salt interferes with the titration and use of methyllithium. There is also evidence which indicates that the stereochemistry observed during addition of methyllithium to carbonyl compounds may be influenced significantly by the presence of a lithium salt in the reaction solution. For these reasons it is often desirable to have ethereal solutions... 

This area of reactivity has been the subject of excellent reviews (J5). Silyl enol ethers are not sufficiently nucleophilic to react spontaneously with carbonyl compounds they do so under the influence of either Lewis acids or fluoride ion, as detailed above. Few clear trends have emerged from the somewhat limited number of definitive studies reported so far, with ambiguities in diastereoisomeric assignments occasionally complicating the issue even further. 

P 55] Before synthesis, a micro-mixing tee chip micro reactor (Figure 4.85) (with two mixing tees and four reservoirs) was primed with anhydrous tetrahydrofuran (THF). A 40 gl volume of a 0.1 M solution of tetrabutylammonium fluoride trihydrate in anhydrous THF is filled into one reservoir of a micro-mixing tee chip reactor [15], 40 gl of a 0.1 M solution of 4-bromobenzaldehyde in anhydrous THF is added to a second reservoir, 40 gl of a 0.1 M solution of the silyl enol ether (masking the enolate of a carbonyl compound such as cyclohexanone) in anhydrous THF is added to a third reservoir and anhydrous TH F is filled into the fourth collection reservoir. Electrical fields of417,455,476 and 0 V cm are applied to transport the reaction species from the respective reservoirs. The reaction is carried out at room temperature. 

The hydrosilylation of carbonyl compounds by EtjSiH catalysed by the copper NHC complexes 65 and 66-67 constitutes a convenient method for the direct synthesis of silyl-protected alcohols (silyl ethers). The catalysts can be generated in situ from the corresponding imidazolium salts, base and CuCl or [Cu(MeCN) ]X", respectively. The catalytic reactions usually occur at room tanperature in THE with very good conversions and exhibit good functional group tolerance. Complex 66, which is more active than 65, allows the reactions to be run under lower silane loadings and is preferred for the hydrosilylation of hindered ketones. The wide scope of application of the copper catalyst [dialkyl-, arylalkyl-ketones, aldehydes (even enoUsable) and esters] is evident from some examples compiled in Table 2.3 [51-53],... 

Silyl enol ethers and silyl ketene acetals also offer both enhanced reactivity and a favorable termination step. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCl4. This reaction provides a method for introducing tertiary alkyl groups a to a carbonyl, a transformation that cannot be achieved by base-catalyzed alkylation because of the strong tendency for tertiary halides to undergo elimination. 

Adapted from Sasidharan and Kumar (257). Reaction conditions catalyst, 150 mg methyl trimethylsilyl dimethylketene acetal (silyl enol ether), 10 mmol a,(3-unsaturated carbonyl compounds, 10 mmol dry THF, 10 mmol reaction temperature, 333 K reaction time, 14 h. Structures of a, p-unsaturated carbonyl compounds (2a-2g) and products (3a-3g) are shown in Scheme 24. 

Studies on the electrochemical oxidation of silyl-substituted ethers have uncovered a rich variety of synthetic application in recent years. Since acetals, the products of the anodic oxidation in the presence of alcohols, are readily hydrolyzed to carbonyl compounds, silyl-substituted ethers can be utilized as efficient precursors of carbonyl compounds. If we consider the synthetic application of the electrooxidation of silyl-substituted ethers, the first question which must be solved is how we synthesize ethers having a silyl group at the carbon adjacent to the oxygen. We can consider either the formation of the C-C bond (Scheme 15a) or the formation of the C-O bond (Scheme 15b). The formation of the C Si bond is also effective, but this method does not seem to be useful from a view point of organic synthesis because the required starting materials are carbonyl compounds. 

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