Enol ethers, silyl with methyllithium

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. 

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). 

The enol ester or silyl enol ether route to enolates has advantages over direct deprotonation in certain cases. If direct deprotonation provides a mixture of regio- or stereo-isomers, it is often possible to trap the enolate mixture by esterification or silylation, separate the desired enol ester or silyl enol ether and regenerate the enolate by reaction with methyllithium. It is also useful for preparation of enolates from substances that are so electrophilic that direct deprotonation is complicated by self-aldolization. For example, aldehyde enolates have been prepared in this manner (equation 14). ... 

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... 

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. 

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. 

According to results published by Fer6zou and coworkers, the iV,iV-diisopropylcarba-moyl group of homoaldol adducts can be directly attacked by slim nucleophiles such as lithium ethynylide or excess methyllithium (equation 98) . The TIPS ether 359 was treated with three equivalents of methyllithium to yield [via the (Z)-enolate 360] the aldehyde 361. Trapping of 360 by TBSCl gives rise to the synthetically valuable (Z)-silyl enol ether 362. 

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. 

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. 

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). ... 

Finally like methyllithium (ref. 121) ammonium fluoride (ref. 122), tris-(dialkylamino)sulfonium salts (ref. 123) or alkali alkoxides (ref. 124), alkali amides in liquid ammonia are able to cleave the silicium-oxygen bond of silyl enol ethers (refs. 125, 126) leading to enolates. The sodium enolate obtained (Fig. 27) by treatment of a silyl enol ether with NaNH2 can be equilibrated in the medium, leading to two alkylated products, nevertheless no polyalkylated species is detected. With the use of LiNH2 only the expected reaction product is prepared but the use of KNH2 leads to a mixture of C-mono and dialkylated and O-alkylted products (ref. 125). 

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... 

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... 

One of the drawbacks of this procedure is that methyllithium is incompatible with a variety of functional groups. In addition, the lithium enolate may not be sufficiently reactive for alkylation. A solution to these problems has been found in the use of benzyltrimethylammonium fluoride to generate the enolate anion. The fluoride ion serves well to cleave silyl enol ethers and the ammonium enolates produced are more reactive than the lithium analogues. Even relatively unreactive alkylating agents such as 1-iodobutane give reasonable yields of specifically alkylated products. ... 

Related Mannich reactions have been reported by Holy and Wang. These chemists generated the silyl enol ethers under either thermodynamic or kinetic control, but cleaved the ether with methyllithium to the same lithium enolate and then added the Mannich salt. Product distributions demonstrated that the addition reaction is regiospecific. They also found that the reaction can be conducted by the trapping technique of conjugate addition of dimethylcopper-lithium to cyclohexenone followed by addition of the immonium salt (equation I.)... 

At first, we considered the transformation of the carbamate moiety into more reactive functions. It was shown that Z-O-enecarbamate can be transformed into Z-silyl enol ether 10 by treatment of 8 with methyllithium and quenching of this intermediate lithium enolate 9 by electrophilic silicon reagents. Assuming this lithium enolate intermediate 9 would be able to react with other electrophile reagents, the preparation of more reactive functions including Z-vinyl phosphate and Z-vinyl triflate was considered. The remaining and important question was whether the Z-stereochemistry of this double bond would be preserved. 

The use of a-silylated vinyl ketone is another approach to overcome drawbacks of the standard Robinson annulation conditions such as polymerization of the vinyl ketone. The a-silylated vinyl ketones are stable and can undergo Michael addition in standard aprotic conditions (conditions that induces polymerization for vinyl ketones), as well as protic conditions. Synthesis of the octalone 21 can be used as an example of this variation. The silylated ketone 20 reacts with lithium enolate 13 (generated by methyllithium from its corresponding enol silyl ether in THE) in /-butyl... 

The reaction of enolates, prepared from silyl enol ethers and methyllithium, with Tf20 affords vinyl triflates (eq 40). ... 

PhMe2SiLi cleaves silyl enol ethers to give the lithium eno-late more rapidly than does methyllithium, allowing f-butyldi-methylsilyl enol ethers to be purifed, and then converted into the lithium enolate at low temperature. It reacts with the N-sulfonamides of pyrroles, indoles, and secondary amines, but not primary amines, to remove the sulfonyl group (eq 25), but it opens A -sulfonylaziridines by attack on carbon. It adds to iron-coordinated cyclohexadiene (eq 26) and to chromium-coordinated benzene rings (eq 27). ... 

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