Enolates from trimethylsilyl enol ethers

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... 

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. 

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. 

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) ... 

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 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... 

The method can be further improved using trimethylsilyl (TMS) enol ethers, which can be prepared in situ from aldehydes and ketones [49]. TMS enol ethers of cyclic ketones are also suitable, and diversity can be enhanced by making either the kinetic or thermodynamic enol ether, as shown for benzyl methyl ketone. Thus, reaction of the kinetic TMS enol ether 10-133 with the amino aldehyde 10-134 and dimethylbarbituric acid 10-135 yielded 10-136, whereas the thermodynamic TMS enol ether 10-137 led to 10-138, again in excellent purity, simply by adding diethyl ether to the reaction mixture (Scheme 10.33). 

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. 

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. 

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. 

Trimethylsilylation of enolizable carbonyl compounds and alcohols has also been accomplished by the fluoride ion promoted reaction with hexamethyldisilane and ethyl trimethylsilylacetate [48, 49], with high stereospecificity giving Z-enol ethers from ketones [50]. l-Trimethylsilyl-(l-trimethylsilyloxy)alkanes, produced from the reaction of aldehydes with hexamethyldisilane, undergo acid-catalysed hydrolysis during work up to yield the trimethylsilylcarbinols [51]. In the case of aryl aldehydes, the initially formed trimethylsiloxy carbanion produces the pinacol (Scheme 3.1). 

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],... 

The aryl aldehyde (1.1 mmol) and trimethylsilyl enol ether (1 mmol) are added sequentially to TBA-F (16 mg, 0.06 mmol) in THF (2 ml) at -78°C. The mixture is stirred at -78°C for 3-5 h, then warmed to room temperature, and H,0 (25 ml) is added. The aqueous mixture is extracted with Et,0 (3x15 ml) and the dried (MgS04) extracts are fractionally distilled to yield the aldol product (e.g. from PhCHO and 1-trimethylsilyl-oxycyclohexene, 84%, 6-methyl- 1-trimethylsilyloxycyclohexene, 68% 1 -trimethylsilyl-oxycycloheptene, 80%, 3-trimethylsilyloxypent-2-ene, 70%]. 

Monoalkyl ethers of (R,R) 1,2-bis[3,5-bis(trifluoromethyl)phenyl]ethanediol, 24, have been examined for the enantioselective protonation of silyl enol ethers and ketene disilyl acetals in the presence of SnCU (Scheme 12.21) [25]. The corresponding ketones and carboxylic acids have been isolated in quantitative yield. High enantioselectivities have been observed for the protonation of trimethylsilyl enol ethers derived from aromatic ketones and ketene bis(trimethylsilyl)acetals derived from 2-arylalkanoic acids. 

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. 

From singlet oxygen reaction with silyl enol ethers When a carbon tetrachloride solution of 1-methoxy-l-trimethylsiloxy-l-alkene in the presence of tetraphenylporphyrin and bubbling oxygen is irradiated with a 400-W Na lamp, a-trimethylsilyl peroxyesters were obtained in good yield (equation 11) . ... 

Azlactone oxidation Azlactones derived from dipeptides are more readily dehydrogenated than the dipeptides. This route to dehydropeptides has been examined with several reagents. Halogenation dehydrohalogenation is possible, but yields at best are 50%. Various oxidation procedures are about as effective. The most satisfactory method is oxidation of the corresponding trimethylsilyl enol ether with DDQ. However, this oxidation is limited to aryl azlactones. 

Trimethylsilylpyrimidinium triflate, derived from pyrimidine and trimethylsilyl triflate, adds silylated enol ethers to form 1,4-dihydropyrimidines. /V-Acylpyrimidinium tetrafluoroborates undergo analogous reactions (85H(23)207). 

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