Ethers trimethylsilyl enol

In the past two decades, investigations of the enol ether condensation have concentrated almost exclusively upon this alternative, the history and development of which were rather different from those of the alkyl enol ether method. Whereas the work in the field of alkyl enol ethers concentrated mostly on the C2- and Ca-building blocks 77-75, with which significant results were achieved particularly in the chemistry of polyenes and carotenoids, the C. 5-reagents 75 and 16 were applied less frequently, because of the problem of side 

The most popular promoter for the reaction of acetals with siloxy enol ethers is the universal typical aprotic Lewis acid TiCU [17,44] which acts in stoichiometric amounts and at very low temperatures. 

The dienoxysilanes however, are highly sensitive towards TiCU and polymerize instantaneously in solvents that are stable to TiCU e.g. dichloromethane) instead of reacting with the acetal. On the other hand, in THF, which forms a coloured complex with TiCU, the reaction proceeds at low temperature with a good yield. The problem with dichloromethane as solvent was solved by decreasing the effect of TiCU by addition of Ti[OCH(CH3)2]4, both being added in stoichiometric amounts [24,45]. The order of addition of the reactants determines whether or not the 5-alkoxy group in the resulting aldehyde is replaced by the isopropyl moiety [45]. 

The conversion of 6-alkoxy-a,p-unsaturated aldehydes into polyenes is performed under acidic conditions identical to those used for the elimination and hydrolysis reactions of alkoxy acetals prepared by alkyl enol ether condensations the yields and diverse reaction conditions have been compared [45]. Elimination under basic conditions, in the presence of DBU or DBN (l,5-diazabicyclo[4.3.0]non-5-ene) and a molecular sieve, was found to be superior to the above methods [45]. 

Examples of carbon chain lengthening by enol ether condensation are summarized in Tables 1 to 4. As interesting and useful results have also been achieved in another connection, the choice of reactions listed has not been limited strictly to the chemistry of polyenes and carotenoids. The reactions in the Tables are listed according to the increasing number of carbon atoms of the target compound. 

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Two techniques have been described for producing trimethylsilyl enol ethers from aldehydes or ketones (10) reaction of (CH2)2SiCl and (C2H3)2N in DMF and reaction of LiN(C2H3)2, which generates enolate ions in the presence of... 

Me3SiI, CH2CI2, 25°, 15 min, 85-95% yield.Under these cleavage conditions i,3-dithiolanes, alkyl and trimethylsilyl enol ethers, and enol acetates are stable. 1,3-Dioxolanes give complex mixtures. Alcohols, epoxides, trityl, r-butyl, and benzyl ethers and esters are reactive. Most other ethers and esters, amines, amides, ketones, olefins, acetylenes, and halides are expected to be stable. 

Trimethylsilyl enol ethers can be used to protect ketones, but in general are not used for this purpose because they are reactive under both acidic and basic conditions. More highly hindered silyl enol ethers are much less susceptible to acid and base. A less hindered silyl enol can be hydrolyzed in the presence of a more hindered one. ... 

Me3SiCH2C02Et, cat. Bu4N F, 25°, 1-3 h, 90% yield. This reagent combination allows the isolation of pure products under nonaqueous conditions. The reagent also converts aldehydes and ketones to trimethylsilyl enol ethers.The analogous methyl trimethylsilylacetate has also been used. " ... 

Methoxyethoxymethyl, 365 Enamino Derivatives, 365 4-Methyl-1,3-dioxolanyl Enol Acetate, 365 Pyrrolidinyl Enamine, 365 Benzyl Enol Ether, 366 Butylthio Enol Ether, 366 Protection of Tetronic Acids, 366 Trimethylsilyl Enol Ether, 367... 

By using the directed aldol reaction, unsymmetrical ketones can be made to react regioselectively. After conversion into an appropriate enol derivative (e.g. trimethylsilyl enol ether 8) the ketone reacts at the desired a-carbon. 

For example in the so-called Mukaiyama aldol reaction of an aldehyde R -CHO and a trimethylsilyl enol ether 8, which is catalyzed by Lewis acids, the required asymmetric environment in the carbon-carbon bond forming step can be created by employing an asymmetric Lewis acid L in catalytic amounts. 

The synthetic problem is now reduced to cyclopentanone 16. This substance possesses two stereocenters, one of which is quaternary, and its constitution permits a productive retrosynthetic maneuver. Retrosynthetic disassembly of 16 by cleavage of the indicated bond furnishes compounds 17 and 18 as potential precursors. In the synthetic direction, a diastereoselective alkylation of the thermodynamic (more substituted) enolate derived from 18 with alkyl iodide 17 could afford intermediate 16. While trimethylsilyl enol ether 18 could arise through silylation of the enolate oxygen produced by a Michael addition of a divinyl cuprate reagent to 2-methylcyclopentenone (19), iodide 17 can be traced to the simple and readily available building blocks 7 and 20. The application of this basic plan to a synthesis of racemic estrone [( >1] is described below. 

An important stage in the synthesis has been reached. It was anticipated that cleavage of the trimethylsilyl enol ether in 18 using the procedure of Binkley and Heathcock18 would regiospecifically furnish the thermodynamic (more substituted) cyclopentanone enolate, a nucleophilic species that could then be alkylated with iodo-diyne 17. To secure what is to become the trans CD ring junction of the steroid nucleus, the diastereoisomer in which the vinyl and methyl substituents have a cis relationship must be formed. In the... 

Enantioselective deprotonation of prochiral 4-alkylcyclohexanones using certain lithium amide bases derived from chiral amines such as (1) has been shown (73) to generate chiral lithium enolates, which can be trapped and used further as the corresponding trimethylsilyl enol ethers trapping was achieved using Corey s internal quench described above. 

A solution of the trimethylsilyl enol ether of propionyl trimethylsilane (5 mmol) (Chapter 12) and benzaldehyde diethyl acetal (5 mmol) in dichloromethane (10ml) was added to a solution of BF3.OEt2 (5 mmol) in dichloromethane (5ml), cooled to —78 C. After being stirred for lh at -78°C and 2h at -30°C, the mixture was quenched with excess saturated sodium hydrogen carbonate solution, and extracted with ether. Concentration and distillation gave the product -ethoxy acylsilane, (4.6mmol, 95%). b.p. 105-106 C/2mmHg. Treatment of this alkoxy... 

Trimethylsilyl enol ethers, 94,133 Trimethylsilyl ketene acetals, 112-113 3-Trimethylsilyl -lactam, 71 Trimethylsilyl lithium, 51-2... 

Trimethylsilyl trimethylsilyl enol ethers, 15 Trimethylsilyl (45,)-N-ftrimethylsilyl)-... 

The few exceptions to this general rule arise when the a-carbon carries a substituent that can stabilize carbonium-ion development well, such as oxygen or sulphur. For example, 1-trimethylsilyl trimethylsilyl enol ethers give products (72) derived from electrophilic attack at the /J-carbon, and the vinylsilane (1) reacts with a/3-unsaturated acid chlorides in a Nazarov cyclization (13) to give cyclopentenones such as (2) the isomeric vinylsilane (3), in which the directing effects are additive, gives the cyclopentenone (4) ... 

The addition of sulphinyl chlorides to trimethylsilyl enol ether 138 affording a-ketosulphoxides 139 (equation 76) represents an extension of the reaction of sulphinyl chlorides with ketones. This reaction has attracted attention only recently. Sergeev and coworkers192 reported that treatment of sulphinyl chlorides with acyclic enol ethers afforded a-ketosulphoxides 139 in good to excellent yields. Meanwell and Johnson193 observed that in the case of cyclic enol ethers the corresponding sulphoxides were formed only in very low yields. They found, however, that the introduction of an equivalent amount of a Lewis acid into the reaction mixture markedly promotes the desired reaction, whereas the use of catalytic amounts of a Lewis acid led to a substantial reduction in the yield. This is most probably due to the formation of a complex, between the a-ketosulphoxide and the Lewis acid. 

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. "... 

Because the trimethylsilyl enol ether of cyclohexanone 107 a is considerably more bulky than the corresponding dimethylsilyl enolate 107b, only the latter reacts with the N-tosyhmine 108 in the presence of catalytic amounts of diisopropylamine in DMF/H2O at 78°C or at room temperature to give the Mannich type compounds 109 in high yields [39] (Scheme 3.4). 

Trimethylsilyl enol ethers can also be cleaved by tetraalkylammonium fluoride (Entry 2) The driving force for this reaction is the formation of the very strong Si-F bond, which has a bond energy of 142 kcal/mol.31 These conditions, too, lead to enolate equilibration. 

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 enolates can also be used under conditions in which the titanium exists as an ate species. Crossed aldehyde-aldehyde additions have been accomplished starting with trimethylsilyl enol ethers, which are converted to lithium enolates and then to ate species by addition of Ti(0- -Bu)4.26 These conditions show only modest stereoselectivity. 

Conditions for effecting conjugate addition of neutral enolate equivalents such as silyl enol ethers in the presence of Lewis acids have been developed and are called Mukaiyama-Michael reactions. Trimethylsilyl enol ethers can be caused to react with electrophilic alkenes by use of TiCl4. These reactions proceed rapidly even at -78° C.308... 

Danishefsky s diene).46 The two donor substituents provide strong regiochemical control. The D-A adducts are trimethylsilyl enol ethers that can be readily hydrolyzed to ketones. The (3-methoxy group is often eliminated during hydrolysis, resulting in formation of cyclohexenones. 

The use of oxygen-containing dienophiles such as enol ethers, silyl enol ethers, or ketene acetals has received considerable attention. Yoshikoshi and coworkers have developed the simple addition of silyl enol ethers to nitroalkenes. Many Lewis acids are effective in promoting the reaction, and the products are converted into 1,4-dicarbonyl compounds after hydrolysis of the adducts (see Section 4.1.3 Michael addition).156 The trimethylsilyl enol ether of cyclohexanone reacts with nitrostyrenes in the presence of titanium dichloride diisopropoxide [Ti(Oi-Pr)2Cl2], as shown in Eq. 8.99.157 Endo approach (with respect to the carbocyclic ring) is favored in the presence of Ti(Oi-Pr)2Cl2. Titanium tetrachloride affords the nitronates nonselectively. 

More traditional carbon nucleophiles can also be used for an alkylative ring-opening strategy, as exemplified by the titanium tetrachloride promoted reaction of trimethylsilyl enol ethers (82) with ethylene oxide, a protocol which provides aldol products (84) in moderate to good yields <00TL763>. While typical lithium enolates of esters and ketones do not react directly with epoxides, aluminum ester enolates (e.g., 86) can be used quite effectively. This methodology is the subject of a recent review <00T1149>. 

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>. 

The scope of the acid-catalyzed formation of C-glycosyl compounds has been greatly expanded with the finding that enol ethers and ketene acetals can be used as the carbon source in electrophilic substitution reactions at the anomeric center.126 Treatment of 198 with the trimethylsilyl enol ether derived from cyclohexanone, in the presence of stannic chloride, led to 2-(2,3,5-tri-0-benzoyl-/J-D-ribofuranosyl)cyelohexanone (206), presumably by way of the inter-... 

Palladium-catalyzed bis-silylation of methyl vinyl ketone proceeds in a 1,4-fashion, leading to the formation of a silyl enol ether (Equation (47)).121 1,4-Bis-silylation of a wide variety of enones bearing /3-substituents has become possible by the use of unsymmetrical disilanes, such as 1,1-dichloro-l-phenyltrimethyldisilane and 1,1,1-trichloro-trimethyldisilane (Scheme 28).129 The trimethylsilyl enol ethers obtained by the 1,4-bis-silylation are treated with methyllithium, generating lithium enolates, which in turn are reacted with electrophiles. The a-substituted-/3-silyl ketones, thus obtained, are subjected to Tamao oxidation conditions, leading to the formation of /3-hydroxy ketones. This 1,4-bis-silylation reaction has been extended to the asymmetric synthesis of optically active /3-hydroxy ketones (Scheme 29).130 The key to the success of the asymmetric bis-silylation is to use BINAP as the chiral ligand on palladium. Enantiomeric excesses ranging from 74% to 92% have been attained in the 1,4-bis-silylation. 

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