Trimethylsilyl enol ether, preparation

Trimethylsilyl enol ethers prepared in 60-91% yields from ketone enolates and trimethylsilyl chloride are converted into a-hydroxy ketones by chromyl chloride in 62-82% yields (equation 402) [676] (equation 340). 

This procedure illustrates a new three-step reaction sequence for the one-carbon ring expansion of cyclic ketones to the homologous tt,/3-unsaturated ketones. The key step in the sequence is the iron(III) chloride-induced cleavage of the central bond of trimethyl-silyloxycyclopropanes which me obtained by cyclopropanation of trimethylsilyl enol ethers. The procedure for the preparation of 1-trimethylsilyloxycyclohexene from cyclohexanone described in Part A is that of House, Czuba, Gall, and Olmstead. ... 

The cyclopropanation of 1-trimethylsilyloxycyclohexene in the present procedure is accomplished by reaction with diiodomethane and diethylzinc in ethyl ether." This modification of the usual Simmons-Smith reaction in which diiodomethane and activated zinc are used has the advantage of being homogeneous and is often more effective for the cyclopropanation of olefins such as enol ethers which polymerize readily. However, in the case of trimethylsilyl enol ethers, the heterogeneous procedures with either zinc-copper couple or zinc-silver couple are also successful. Attempts by the checkers to carry out Part B in benzene or toluene at reflux instead of ethyl ether afforded the trimethylsilyl ether of 2-methylenecyclohexanol, evidently owing to zinc iodide-catalyzed isomerization of the initially formed cyclopropyl ether. The preparation of l-trimethylsilyloxybicyclo[4.1.0]heptane by cyclopropanation with diethylzinc and chloroiodomethane in the presence of oxygen has been reported. "... 

The composition of the enol ethers trimethylsilyl prepared from an enolate mixture reflects the enolate composition. If the enolate formation can be done with high regio-selection, the corresponding trimethylsilyl enol ether can be obtained in high purity. If not, the silyl enol ether mixture must be separated. Trimethylsilyl enol ethers can be prepared directly from ketones. One procedure involves reaction with trimethylsilyl... 

Trimethylsilyl enol ethers can also be prepared by 1,4-reduction of enones using silanes as reductants. Several effective catalysts have been found,38 of which the most versatile appears to be a Pt complex of divinyltetramethyldisiloxane.39 This catalyst gives good yields of substituted silyl enol ethers (e.g., Scheme 1.2, Entry 7). 

Titanium tetrachloride-catalysed Michael additions of trimethylsilyl enol ethers to artemisitene afforded a neat route to 14-substituted artemisinin derivatives of type 125 (eg. R = allyl) and to 9-epiartemisinin derivatives 126 some of these compounds were more active against Plasmodium falciparum than artemisinin <00BMCL1601>. A series of 11-azaartemisinins also have better activity than artemisinin <00BMC1111>. On the other hand, epiartemisinin, prepared by base-catalysed epimerisation of artemisinin, has been shown to have poor antimalarial activity <00HCA1239>. 

On the contrary, trimethylsilyl enol ethers yield a-fluoroketones when reacting with Xe[ F]F2 [81] or [ F]F2 [101] (Scheme 20). In this way several aryl-a-fn [ F]fluoromethylketones were easily prepared in 22-28% radiochemical yields. 

Folate analogues continue to have importance in chemotherapy, especially heterocyclic analogues other than pteridines which are covered in Chapters 10.15-10.17 and 10.19. 1,3-Dimethyllumazine analogues of folates for use as model compounds have been prepared by side-chain elaboration of 6-bromomethyl-l,3-dimethyllumazine (Scheme 34) <1996JHC341>. More notable in this work, however, was the synthesis of the bromomethyl precursor itself in addition to routine bromination of the 6-methyllumazine 175 prepared by condensation of dihydroxyacetone with 5,6-diamino-l,3-dimethyluracil, a cycloaddition reaction between trimethylsilyl enol ethers and the pyrimidyl bisimine 177, via cycloadducts such as 176, afforded substituted pteridines in moderate to good yields. 

Iron-Catalyzed Reactions of Grignard Reagents TABLE 1. Regioselective preparation of trimethylsilyl enol ether... 

Silylation of 1,7i-dicarbonyl compounds.2 The reagent is particularly useful for preparation of trimethylsilyl enol ethers of 1,3-dicarbonyl compounds. 

House, H. O. Czuba, L. J. Gall, M. Olmstead, H. D. The chemistry of carbanions. XVIII. Preparation of trimethylsilyl enol ethers. 

Accordingly, trimethylsilyl enol ethers are enolate precursors (Figure 10.16). Fortunately, they can be prepared in many ways. For instance, silyl enol ethers are produced in the silylation of ammonium enolates. Such ammonium enolates can be generated at higher temperature by partial deprotonation of ketones with triethylamine (Figure 10.18). The incompleteness of this reaction makes this deprotonation reversible. Therefore, the regioselectivity of such deprotonations is subject to thermodynamic control and assures the preferential formation of the more stable enolate. Consequently, upon... 

Trimethylsilyl enol ethers.8 Kinetic enol ethers can be obtained by trimethylsilyl triflate-catalyzed rearrangement of p-keto silanes, which can be prepared in high yield by reaction of acid chlorides with trimethylsilylmethylcopper. 

Another regiospecific preparation of trimethylsilyl enol ethers involves treatment of acyltrimethylsilanes with the lithium anions of alkyl sulfones or nitriles. In this case, the sulfone or nitrile group is eliminated during the silyl alkoxide rearrangement (e.g., 5 — 6). Mixtures of olefin stereoisomers are obtained. Note that 4 and 8 give complementary regiochemical results. 

Alkylation of fl-aryleyclopentanones. Addition of 10 mole% of CuCN to the lithium enolate prepared from /3-arylcyclopentanones and LDA increases the amount of the less stable product of alkylation. Polyalkylation is also suppressed. Similar results are obtained when methyl- or phenylcopper is added to the enolate prepared by alkyUithium cleavage of trimethylsilyl enol ethers. The mechanism by which Cu(I) influences these alkylations is not as yet understood. The regiospecificity of enolate formation in the example Illustrated in equation (I) has been attributed to a directing efiect of the proximate phenyl group. This effect is also observed in the deprotonation of -arylcyclohexanones. Quantitative, but not qualitative, differences exist between five- and six-membered rings, probably because of conformational differences. ... 

Cycloheptane annelation (7, 212). The mixed cuprate 1 reacts with acid chlorides to afford vinylcyclopropyl ketones. Previously these ketones were prepared from aldehydes by condensation with l-lithio-2-vinylcyclopropane followed by oxidation (7, 192-193). These compounds are rearranged to 4-cycloheptenones on conversion to trimethylsilyl enol ethers, thermolysis, and hydrolysis. ... 

Stereo- and regiospecific synthesis of trimethylsilyl enol ethers. Addition of vinylmagnesium bromide to acyltrimethylsilanes, R COSifCH,), affords 1-tri-mclhylsilylallylic alcohols (1), Lithium alkoxides of 1, prepared by treatment with... 

Trimethylsilyl enol ethers proved to be unsuitable substrates due to the ease of hydrolysis to the ketone. Presumably, for the same reason, the yield of the a-azido ketone prepared from 17 dropped to less than 50% on reaction scales larger than 100 mg125. 

Recently, Armstrong and Tsuchiya have prepared the chiral tetrahydropyranone 56 and examined its use in asymmetric epoxidation reactions. Phenylcyclohexene oxide was formed in excellent yield and high ee however, low enantioselectivity was observed with a trimethylsilyl enol ether (Scheme 21) <2006T257>. 

This is a mild, simple and practical procedure for 1,4-addition of an aldehyde to methyl vinyl ketone, without converting the aldehyde into an enamine or a silyl enol ether. The products, substituted 5-ketoaldehydes, are important compounds, especially for the preparation of substituted 2-cyclohexen-1-one derivatives, which have been versatile starting materials for syntheses of natural products such as terpenoids. These 5-ketoaldehydes have been prepared previously by the 1,4-addition of modified aldehydes, i.e., morpholinoenamines of aldehydes,trimethylsilyl enol ethers of aldehydes in the presence of a Lewis acid, or diethylallylamine in the presence of a catalytic amount of a Ru complex, to methyl vinyl ketones. 

Trapping. The enolate generated from the enone shown below reacts at oxygen with chlorotrimethylsilane in the presence of triethylamine to produce the trimethylsilyl enol ether. Silyl enol ethers are valuable intermediates for the preparation of regiode-fmed enolates (see Chapter 6). 

The enolate that is required for the aldol reaction can be generated in other ways, too. For example, trimethylsilyl enol ethers react with TBAF (tetrabutylammonium fluoride, BU4ISD F ) to give the corresponding enolates. Enolates may also be prepared by the dissolving metal reduction of a.jS-unsaturated ketones (see Chapter 5). 

The TiCLrmediated Mukaiyama aldol reactions between 7r-allyltricarbonyliron lactone complexes and chiral aldehydes were well documented by Ley and coworkers [37]. (/ )-Trimethylsilyl enol ether 23 (>96% ee) was prepared from the methyl ketone complex 22 by treatment with MesSiOTf/EtsN in CH2CI2 and this was then reacted with (R)- and (5)-2-benzyloxypropanal 24 under the influence of TiCl4 in CH2CI2 at -78 °C. Although the reactions proceeded very slowly and apparent hydrolysis of the silyl enol ether occurred, the aldol products 25 and 26 were isolated in excellent diastereoselectivity in both cases (Scheme 1-8). Interest-... 

Trimethylsilyl enol ethers continue to be useful synthons for various aldol typeis,lb and Michael1 18 reactions. Their utility in part is due to their ease of regiospecific preparation, ease of cleavage and high reactivity. Danishefsky and coworkers have shown that silyl enol ethers react with dimethyl(methylene)ammonium iodide yielding Mannich bases.19 Otherwise inaccessible Mannich bases are accessible via the series below. 

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