Silyl enol 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]. 

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. 

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. 

Carboxonium/oxocarbenium ions that are produced from a silyl enol ether or a silylketene acetal and an electrophile are desilylated in the second step of the reaction. This also produces an a-functionalized carbonyl or carboxyl compound. 

The reactions of silenes with aldehydes and ketones is another area whose synthetic aspects have been particularly well-studied4,6 7 10 12. The favoured reaction pathways for reaction are generally ene-addition (in the case of enolizable ketones and aldehydes) to yield silyl enol ethers and [2 + 2]-cycloaddition to yield 1,2-siloxetanes (equation 44), but other products can also arise in special cases. For example, the reaction of aryldisilane-derived (l-sila)hexatrienes (e.g. 21a-c) with acetone yields mixtures of 1,2-siloxetanes (51a-c) and ene-adducts (52a-c) in which the carbonyl compound rather than the silene has played the role of the enophile (equation 45)47,50 52 98 99. Also, [4 + 2]-cycloadducts are frequently obtained from reaction of silenes with a,/i-unsaturated- or aryl ketones, where the silene acts as a dienophile in a formal Diels-Alder reaction6 29,100-102. 

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. 

The silyl enol ether can be prepared from its parent carbonyl compound by forming a small equilibrium concentration of enolate ion with weak base such as a tertiary amine and trapping the enolate with the very efficient oxygen electrophile MejSiCl. The silyl enol ether is stable enough to be isolated but is usually used immediately without storing. 

The kinetic reprotonation by a series of carbonyl-based acids, of the lithium enolate obtained from 2,4-dimethyltetralone either by LDA-mediated deprotonation or by cleavage of its silyl enol ether, was studied by Eames (Scheme 71)352. The diastereoselective ratio, close to the thermodynamic value, obtained with methanol (pKa = 29 in DMSO) is probably due to equilibration. The difference observed in the presence of an additive was interpreted as the result of a fine balance between the coordinating ability, the intrinsic acidity, and probably the concentration of the enolic form of the cyclic and linear dicarbonyl acidic compounds. 

Phenylthioalkylation of silyl enol ethers. Silyl enol ethers of ketones, aldehydes, esters, and lactones can be alkylated regiospecifically by a -chloroalkyl phenyl sulfides in fhe presence of a Lewis acid. Zinc bromide and titanium(IV) chloride are the most effective catalysts. The former is more satisfactory for enol ethers derived from esters and lactongs. ZnBr2 and TiCL are about equally satisfactory for enol ethers of ketones. The combination of TiCL and Ti(0-f-Pr)4 is more satisfactory for enol ethers of aldehydes. Since the products can be desulfurized by Raney nickel, this reaction also provides a method for alkylation of carbonyl compounds. Of more interest, sulfoxide elimination provides a useful route to a,B-unsaturated carbonyl compounds. 

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