Enolates with methyllithium

Treatment of silyl enolates with methyllithium followed by an addition of gallium trichloride affords the corresponding gallium enolates. The reaction of the resulting gallium enolates with a-halo carbonyl compounds in the presence of triethylborane provides 1,4-dicarbonyl compounds in good yields (Scheme 142).433... 

It was predicted, a priori, that isocomene could be formed simply by treating 4 with methyllithium, followed by exposure of the resultant tertiary carbinol to acid.2b However, many attempts to effect the addition of a variety of nucleophilic methyl derivatives to ketone 4 were unsuccessful. It was revealed by deuterium quenching experiments that ketone 4 undergoes ready enolization in the presence of nucleophilic methyl derivatives. Despite its hindered nature, however, the ketone carbonyl in 4 reacts with methylenetri-... 

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. 

A route involving trapping the enolate as a silyl enol ether, subsequent transme-tallation to the corresponding lithium enolate and alkylation turned out to be more efficient (Scheme 18.41) [123]. Thus, treatment of 120 with the cuprate 124 and chlorotrimethylsilane furnished the silyl enol ether 125, which was then converted into the desired enprostil derivative 127 with 68% yield over both steps by reaction with methyllithium and the allenic triflate 126. 

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. 

In this study, benzaldehyde and benzaldehyde-methyllithium adduct were fully optimized at HF/6-31G and their vibrational frequencies were calculated. The authors used MeLi instead of lithium pinacolone enolate, since it was assumed that the equilibrium IBs are not much different for the MeLi addition and lithium enolate addition. Dehalogena-tion and enone-isomerization probe experiments detected no evidence of a single electron transfer to occur during the course of the reaction. The primary carbonyl carbon kinetic isotope effects and chemical probe experiments led them to conclude that the reaction of lithium pinacolone enolate with benzaldehyde proceeds via a polar mechanism. 

Ss2 reaction with a,fi-epoxy ketones.6 The enolate 1 of 2,3-epoxycyclohexanone reacts with methyllithium to give, after acidic work-up, 2-methy -2-cyclohexenone (3), the product of SN2 addition. Reaction of 1 with lithium dimethyl cuprate on the other hand results in 6-methyl-2-cyclohexcnonc (2), the product of Sv2 addition. 

Disilylation of enones.1 In the presence of Pd[P(C6H5),]4, this disilane undergoes 1,4-addition to a,p-enones to give -y-(phenyldichlorosilyl) silyl enol ethers, which can be converted into lithium enolates by exchange with methyllithium. The reaction can provide 3-hydroxy ketones. The Michael addition is enantioselective when catalyzed by Cl2Pd[( + )-BINAP] (12, 53-57). 

Occasionally, it can be useful to run this reaction in reverse, generating the lithium enolate from the silyl enol ether. This can be done with methyllithium, which takes part in nucleophilic substitution at silicon to generate the lithium enolate plus tetramethylsilane. The reason why you might want to carry out this seemingly rather pointless transformation will become clear in Chapters 26 and 27. 

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... 

Note that the intermediate enol silyl ethers, for example (4), can be alkylated by treat ment with methyllithium in 1,2-dimethoxyethane followed by addition of an alky halide. An alkyl group can be introduced in this way at the bridgehead positior exclu.sivcly. 

The structure of catalyst 428 was proposed as a result of the several experiments shown in Sch. 60 and discussed below [89]. Firstly, it was observed that treatment of ALB catalyst 394 (Sch. 51) with methyllithium produced a solution from which the hexacoordinate aluminum species 434 (M = Li) could be crystallized in 43 % yield. The same compound could also be obtained from solutions prepared from 394 and nBuLi, and the sodium enolate of 425. Solid-state X-ray analysis of this compound revealed that it has the same structiu-e as the species 417 (Sch. 56) isolated by Feringa and coworkers during the preparation of ALB with excess BINOL (Sch. 55) [86]. The tris-BINOL(tris-lithium) alimunum complex 434 is not the active catalyst in the Michael addition of phosphonate 425 to cyclohexenone because the use of this material as catalyst gave the Michael adduct 426 in 28 % yield and 57 % ee which is dramatically lower than obtained by use of catalyst 428 (Sch. 59). In addition, the use of catalyst 434 (M = Li) gave the alkene product 429 in 13 % yield, a product that was not seen with catalyst 428. Additional evidence comes from the reaction between 425 and cyclopentenone with catalyst 434 (M = Li) which gives the adduct 427 in 78 % yield and 12 % ee. 

When a silyl enol ether is the trimethylsilyl derivative (Me3Si-0-C=C), treatment with methyllithium will regenerate the hthium enolate anion and the volatile trimethylsilane (Me3SiH). The enolate anion can be used in the usual reactions. In a similar reaction, a trimethylsilyl enol ether was treated with Cp2Zr (from Cp2ZrCl2/2 BuLiArHE/-78°C), and subsequent quenching with D2O led to incorporation of deuterium at the vinyl carbon (C=C-D). ... 

Treatment of amide 21 with methyllithium at -78 °C provides the corresponding methyl ketone in 92 % yield. The latter is converted regioselectively to the kinetic enolate at -78 and treated with PhNTf2 to afford enol triflate 23. 

Regioselectively generated silyl enol ethers react with methyllithium to afford regio-chemically pure lithium enolates. Treatment of these enolates with reactive electrophiles leads to regiospecifically alkylated ketones. 

Scheme 2 shows the results of two studies on the methylation of the lithium enolate of cyclopentanone (10), which was prepared by deprotonation of the ketone with trityllithium in DME or by cleavage of the 1-trimethylsiloxycyclopentene with methyllithium in THF. A signiEcant quantity of over-alkylation occurred when the enolate was treated with methyl iodide, particularly when DME was employed as the solvent at room temperature. Also, as indicated in Scheme 2, Noyori and coworkers showed that by adding 3 equiv. of HMPA to the enolate (10) and reducing the temperature at which the reaction was conducted, the yield of 2-methylcyclopentanone was greatly improved.

Enol silyi ethers are also synthetically important as precursors of lithium enolates. The treatment of enol silyi ethers with methyllithium affords the corresponding lithium enolates regiospecifically (eq (28)) [25]. 

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. 

---