Methyllithium, with enol acetates

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... 

Methyllithium (4.0 mmol, 1.0 M in diethyl ether, 4.0 mL) was added to a suspension of CuCN (2.0 mmol, 0.18 g) in THF (10 mL) at -75°C. The reaction mixture was then stirred until a clear solution was obtained and allowed to warm to room temperature. The appropriate (Z)-vinylic telluride A (2.0 mmol) or B (1.0 mmol) was added and stirred for 45 min. The solution was cooled back to -75°C and the corresponding enone (2.2 mmol) was added. After 20 min, chlorotrimethylsilane (2.6 mmol, 0.60 g) diluted in THF (5 mL) was added. The reaction mixture was stirred for 1 h, allowed to warm to room temperature and then treated with 1 1 solution of saturated aqueous NH4CI and NH4OH (20 mL), extracted with ethyl acetate (3x20 mL), dried, evaporated and the residue was purified by Kiigelrohr distillation affording the silyl enol ethers. 

House and Trost prepared an approximately IM solution of this reagent in 1,2-dimethoxyethane for use in an extensive study of compositions of enolate anions from ketones and enol acetates as follows. The solvent was removed from 15 ml. of a 1 Af ethereal solution of methyllithium under reduced pressure, and the residual solid was dissolved in 15 ml. of 1,2-dimethoxyethane. Triphenylmethane (18.3 mmoles) was added, and the mixture stirred under nitrogen until a test for methyl-lithium was negative. Reaction of an enol acetate with trityllithium can then be carried out as a titration and stopped when the solution is pale pink. 

Enolate anions [1, 688, before references]. House and Trost12 developed a method for the preparation of a specific enolate anion by treatment of an enol acetate with methyllithium. 

Enol acetates and silyl enol ethers may be prepared from enolates. This is sometimes advantageous because they are stable enolate equivalents. Enol acetates can be cleaved with 2 equiv. of methyllithium... 

In addition to the methods described for controlling the ratio of thermodynamic and kinetic products, other techniques have been developed to trap the enolate, based on reactions with reagents that prefer O-alkylation. Reaction of a ketone with acetic anhydride, usually in the presence of a catalytic amount of perchloric acid, generates the thermodynamic enol acetate When this is treated with methyllithium, the... 

Some solutions to the problem of the formation of a specific enolate from an unsymmetrical ketone were discussed above. Another solution makes use of the structurally specific enol acetates or enol silanes (silyl enol ethers). Treatment of a trimethylsilyl enol ether with one equivalent of methyllithium affords the corresponding lithium enolate (along with inert tetramethylsilane). Equilibration of the... 

Cleavage of enol trimethylsilyl ethers or enol acetates by methyllithium (entries 1 and 2, Scheme 1.3) as a route to specific enolate formation is limited by the availability of these materials. Preparation of the enol trimethylsilyl ethers and enol acetates from the corresponding ketones usually affords a mixture of the two possible derivatives, which must be then separated. It is sometimes possible to find conditions that favor the formation of one isomer for example, reaction of 2-methyl-cyclohexanone with lithium diisopropylamide and trimethylchlorosilane affords the less highly substituted enol ether preferentially by 99 1 over the more highly substituted one (kinetically controlled conditions). ... 

Enolates can also be prepared by reaction of enol esters - - or silyl enol ethers with alkyllithium reagents. House has worked out a protocol wherein these enolates are allowed to react with aldehydes to give the corresponding aldols. Higher yields of aldol products are obtained when the lithium enolate is generated in ether or 1,2-dimethoxyethane (DME) by reaction of an enol acetate with methyllithium. Lower yields are obtained if the enolate is produced by reaction of a silyl enol ether with methyllithium. For the aldol reaction, ether or mixtures of ether and DME are superior to THF. Acceptable yields of aldol adducts are obtained in ether at low temperatures (-20 to -50 C). In the more polar solvents DME or THF, the addition of anhydrous ZnCh or MgBra results in higher yields. An example is seen in equation (13). The stereochemistry of this process is discussed in Section 1.6.5. 

Treatment of the acetylenic ketones 186 with lithium dialkylcuprates and trapping the resultant enolates with acetic anhydride produced the enyne-allene 187 (Scheme 20.39) [72], Regeneration of the oxyanion-substituted enyne-allene system using methyllithium at -20 °C led to the formation of either the indanones 188 or the ben-zofluorenones 189 through a Schmittel cyclization reaction. 

The quaternary center was constructed stereospecifically by Claisen rearrangement (Scheme 46). The necessary enol ether was obtained by reaction of the secondary alcohol of 399 with ethyl vinyl ether and mercuric acetate. To change the polarity of the endocyclic double bond, the unsaturated ketone was reduced with lithium aluminum hydride to the allylic alcohol, 400, at low temperature. Then, prolonged heating with xylene led to the aldehyde, 401. Protection of the secondary alcohol was achieved by bromoether formation with W-bromosuccinimide in acetonitrile before the aldehyde of 402 was reacted with methyllithium. The epimeric mixture of secondary alcohols was protected as acetates 403. Then, the cyclic ketone... 

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