Trimethylsilyl enol ethers, reaction with

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>. 

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 Mukaiyama version of the aldol reaction is well known a carbonyl-titanium tetrachloride complex reacts with a trimethylsilyl enol ether. Under these conditions there is no titanium enolate involved. Another procedure has been reported a trimethylsilyl enol ether reacts with titanium tetrachloride to give the titanium enolate addition of the carbonyl compound generates the aldol product (although with slightly lower diastereoselectivity than with Mukaiyama s procedure). (Z)-Enolsilanes from acyclic ketones react rapidly and stereospecifically with TiCU to form (Z)-configured CbTi enolates, while the ( )-isomers react slowly to afford low yields of mixtures of ( )- and (Z)-Cl3Ti enolates (Scheme 41). 

Bis(trimethylsiloxy)cyclohexadienes. LDA and related lithium dialkyl-amides appear to be specific for generation of the anion of keto trimethylsilyl enol ethers reaction of these anions with (CHajaSiCI gives the disiloxycyclohexa-dienes 1 and 2, which cannot be prepared directly from the 1,2- and 1,3-dike-... 

Mukaiyama aldol reactions, whereby trimethylsilyl enol ethers react with aldehydes in aqueous solution to form -ketoalcohols, have been promoted by new chiral lanthanide-containing complexes and a chiral Fe(II)-bipyridine complex with 0 outstanding diastereo- and enantio-selectivities. Factors controlling the diastereoselec-tivity of Lewis-acid-catalysed Mukaiyama reactions have been studied using DFT to reveal the transition-state influences of substituents on the enol carbon, the a-carbon of the silyl ether, and the aldehyde. The relative steric effects of the Lewis acid and 0 trimethyl silyl groups and the influence of E/Z isomerism on the aldol transition state were explored. Catalytic asymmetric Mukaiyama aldol reaction of difluoroenoxysilanes with /-unsaturated a-ketoesters has been reported for the first time and studied extensively. ... 

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. 

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... 

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... 

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. 

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. 

Method D TBA-F (26 mg, 0.1 mmol) is added to Me,SiSiMe, (0.2 g, 1.5 mmol) in HMPA (2 ml) and the solution is stirred for 5 min at room temperature. The solution is then added to the aldehyde and the mixture is stirred for 4-5 h. On completion of the reaction, HChMeOH (1 10, 1 ml) is added and the mixture is extracted with Et20 (3 x 35 ml). The extracts are washed with aqueous NH4C1 (sat. soln. 25 ml) and brine (25 ml), and concentrated under vacuum. Chromatography from silica gives the trimethylsilyl enol ether or, in the ease of the aryl aldehydes, the pinacol. 

Regiospecific mono-C-alkylation (60-90%) of trimethylsilyl enol ethers is promoted by benzyltriethylammonium fluoride [34, 35]. A similar alkylation of tin(IV) enolates is aided by stoichiometric amount of tetra-n-butylammonium bromide and has been utilized in the synthesis of y-iminoketones [36]. Carbanions from weakly acidic carbon acids can be generated by the reaction of their trimethylsilyl derivatives with tetra-n-butylammonium triphenyldifluorosilicate [37] (see also Section 6.3). Such carbanions react readily with haloalkanes. Tautomeric ketones in which the enol form has a high degree of stabilization are O-alkylated to form the enol ether, e.g. methylation of anthrone produces 9-methoxyanthracene [26],... 

Ketone and ester enolates have historically proven problematic as nucleophiles for the transition metal-catalyzed allylic alkylation reaction, which can be attributed, at least in part, to their less stabilized and more basic nature. In Hght of these limitations, Tsuji demonstrated the first rhodium-catalyzed allylic alkylation reaction using the trimethly-silyl enol ether derived from cyclohexanone, albeit in modest yield (Eq. 4) [9]. Matsuda and co-workers also examined rhodium-catalyzed allylic alkylation, using trimethylsilyl enol ethers with a wide range of aUyhc carbonates [22]. However, this study was problematic as exemplified by the poor regio- and diastereocontrol, which clearly delineates the limitations in terms of the synthetic utihty of this particular reaction. 

Barani, Fioravanti, Pellacani and Tardella also compared the reactivities of 3k and 3n in their reaction with trimethylsilyl enol ether of cylohexanone in the presence of an inorganic base (Scheme 36) ". The use of triethylamine as a base yielded no aminated product. 

The reaction of 3-benzyloxybutanal with the trimethylsilyl enol ether of acetophenone is stereoselective for the anti diasteromer. 

Simple dienes react readily with good dienophiles in Diels-Alder reactions. Functionalized dienes are also important in organic synthesis. One example which illustrates the versatility of such reagents is l-methoxy-3-trimethylsilyloxy-1,3-butadiene (.Danishefsky s diene) 1 Its Diels-Alder adducts are trimethylsilyl enol ethers which can be readily hydrolyzed to ketones. The /j-mcthoxy group is often eliminated during hydrolysis. 

Mukiayama aldol reactions between silyl enol ethers and various carbonyl containing compounds is yet another reaction whose stereochemical outcome can be influenced by the presence of bis(oxazoline)-metal complexes. Evans has carried out a great deal of the work in this area. In 1996, Evans and coworkers reported the copper(II)- and zinc(II)-py-box (la-c) catalyzed aldol condensation between benzyloxyacetaldehyde 146 and the trimethylsilyl enol ether [(l-ferf-butylthio)vinyl]oxy trimethylsilane I47. b82,85 Complete conversion to aldol adduct 148 was achieved with enantiomeric excesses up to 96% [using copper(II) triflate]. The use of zinc as the coordination metal led to consistently lower selectivities and longer reaction times, as shown in Table 9.25 (Eig. 9.46). 

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. 

The copper-catalyzed conjugate addition of methyl magnesium iodide to cyclohexenone and trapping the enolate as its trimethylsilyl enol ether, followed by a trityl hexachloro-antinomate-catalyzed Mukaiyama reaction, is apphed to / -(—jcarvone. C-2, C-3 functionalized chiral cyclohexanones are converted into their a-cyano ketones, which are submitted to Robinson annulation with methyl vinyl ketone. Highly functionalized chiral decalones are obtained that can be used as starting compounds in the total synthesis of enantiomerically pure clerodanes (equation 70). 

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