Ether, dimethyl deprotonation

Asymmetric deprotonation of monocyclic cycloalkanones is not restricted to cyclohexanones. Thus, deprotonation of 3-phenylcyclobutanone with lithium bis[(S)-l-phenylethyl]amide in THF at — 100 °C in the presence of chlorotriethylsilane affords (—)-(/ )-3-pheny 1-1 -(triethylsi-lyloxy)-l-cyclobutene with 92% ee in 70% yield59d. Interestingly, with lithium (/ )-2,2-dimethyl-A-[( / )-2-(4-methyl-l-piperazinyl)-l-phenylethyl]propylamidc in THF/HMPA an ee value of only 47 % for the enol ether is recorded. 

Cyclic cyanohydrin ethers, 6-alkyl-2,2-dimethyl-l,3-dioxane-4-carbonitriles 1, are easily available from silylated aldols. Deprotonation of 1 and subsequent alkylation gives, v+ -4,6-disubsti-tuted 2,2-dimethyl-l,3-dioxane-4-carbonitriles 2 in good yields in a highly diastereoselective reaction48. Primary bromoalkanes and oxiranes have been used as alkylating reagents. Reduction of the alkylation products 2 afforded the protected, vj. -l,3-diols 3 with complete retention of configuration (see Section D.2.I.). 

The enantiomerically pure l-[(benzyl(dimethyl)silyl)methyl]pyrrolidine, obtained from ben-zyl(chloro)(dimethyl)silane and (5,)-2-(methoxymethyl)pyrrolidine , afforded after deprotonation and subsequent alkylation the diastereomerically pure (by NMR spectroscopy) (a-alkylben-zyl)silanes2. To obtain this high degree of diastereoselectivity, the alkylation had to be performed in the weakly complexing solvent diethyl ether. In THF a diastereomeric ratio of only 3 1 was found with iodomethane as alkylating agent. 

However, the methyl cation (in itself a very energetic, unprobable species in the condensed state) is not expected to attack a carbon-hydrogen bond in dimethyl ether (or methanol) in preference to the oxygen atom. The more probable attack on oxygen would lead to the trimethyloxonium ion, which was observed experimentally447,463 On the action of a basic site the trimethyloxonium ion can then be deprotonated to form dimethyloxonium methylide ... 

Butylpotassium and butylcesium deprotonate furan at the 2-position (75BSF1302), but butyllithium is the reagent of choice. When furan is treated with butyllithium the reactions in Scheme 114 occur (77JCS(P1)887>. The conditions, however, may be controlled to yield predominantly the mono- or the di-lithio derivative. By carbonation and esterification of the reaction mixture obtained by treatment of furan with butyllithium and TMEDA (1 1 1) in ether at 25 °C for 30 min, a 98% yield of methyl furan-2-carboxylate is obtained. Similarly, a butyllithium TMEDA furan ratio of 2.5 2.5 1 in boiling hexane for 30 min results in 91% of dimethyl furan-2,5-dicarboxylate and 9% of the monoester. Competition experiments indicate that furan reacts with butyllithium faster than thiophene under non-ionizing conditions but that the order is reversed in ether or in the presence of TMEDA. 

Dimethylated cumulenyllithium 783 has been prepared by deprotonation of the corresponding cumulenyl methyl ether with n-BuLi in ether or THF at — 30 °C. These anions reacted with aldehydes and ketones to produce the corresponding adducts (55-90% yield)1097. However, due to the instability of these types of compounds, they have not been used in organic synthesis as acyllithium equivalents. 

The 4-hydroxyl of 8,9-0-isopropylidene derivative 4b has been protected as its 4-t-butyl-dimethyl-silyl ether 4e. Then, the 7-hydroxyl has been converted to its xantate ester 4f, by deprotonation with butyl litium, treatment with carbon disulfide and alkylation with methyl iodide. Deoxygenatiobn of the 7-position has been accomplished by heating with tributyl-tin hydride in xylenes. Then, the cleavage of acetonide and of silyl ether, by heating in 80% acetic acid, followed by hydrogenolysis to remove the benzyl ester, afford 7-deoxy-Neu%Ac-ctMe Im. 

The synthesis of the coupling partner (enone 124) began in the manner reported by Noda [70] (Scheme 30). Thus, starting with commercially available acetylacetaldehyde dimethylacetal (125), the dithiane protection of both the ketone and the dimethyl acetal units under acidic conditions afforded compound 131 in 86% yield as a white crystalline solid. Deprotonation with n-BuLi, followed by the addition of / -benzyl glycidyl ether (132) provided an 80% yield of the hydroxyl ether 133. Deprotection of the dithiane moiety with HgCb in acetonitrile and water revealed the two carbonyl units, which underwent spontaneous cyclization to the enone 124. Spectroscopic data for this compound were in complete agreement with the published data [70]. 

Recently Yoshida et al. have employed silyl-stabilized a-alkoxy organolithium reagents for the synthesis of a variety of carbonyl compounds. Methoxy(trimethylsilyl)methane and methoxybis(trimethyl-silyl)methane, when deprotonated with Bu Li and Bu"Li respectively, give anions which can be alkylated with a variety of electrophiles. Electrolysis of a solution of the alkylated product in methanol yields, by virtue of the reduced oxidation potential of ethers a-substituted with silicon, either the dimethyl acetal or in the latter case the orthoester. The mildness of the electrolytic process recommends the method for the preparation of a variety of carbonyl compounds. 

Interligand asymmetric induction. Group-selective reactions are ones in which heterotopic ligands (as opposed to heterotopic faces) are distinguished. Recall from the discussion at the beginning of this chapter that secondary amines form complexes with lithium enolates (pp 76-77) and that lithium amides form complexes with carbonyl compounds (Section 3.1.1). So if the ligands on a carbonyl are enantiotopic, they become diastereotopic on complexation with chiral lithium amides. Thus, deprotonation of certain ketones can be rendered enantioselective by using a chiral lithium amide base [122], as shown in Scheme 3.23 for the deprotonation of cyclohexanones [123-128]. 2,6-Dimethyl cyclohexanone (Scheme 3.23a) is meso, whereas 4-tertbutylcyclohexanone (Scheme 3.23b) has no stereocenters. Nevertheless, the enolates of these ketones are chiral. Alkylation of the enolates affords nonracemic products and O-silylation affords a chiral enol ether which can... 

Determination of the acidity of hydrocarbons is more difficult. As most are very weak acids, very strong bases are required to cause deprotonation. Water and alcohols are far more acidic than most hydrocarbons and are unsuitable solvents for generation of hydrocarbon anions. A strong base deprotonates the solvent rather than the hydrocarbon. For synthetic purposes, aprotic solvents such as ether, THF, and dimethoxyethane are used, but for equilibrium measurements solvents that promote dissociation of ion pairs and ion clusters are preferred. Weakly acidic solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and cyclohexylamine are used in the preparation of moderately basic carbanions. The high polarity and cation-solvating ability of DMSO and DMF facilitate dissociation of ion pairs so that the equilibrium data obtained refer to the free ions, rather than to ion aggregates. 

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