Monoalkylation carbanions

Reflecting its electronegative character, C q readily undergoes nucleophilic additions with various nucleophiles [7]. Apparently the most fundamental C-C bond forming reaction is the reaction with alkyllithium or Grignard reagents, giving the monoalkylated derivative of l,2-dihydro-C6o after protonation of the initially formed alkyl-Cso carbanion [48]. 

A significant feature in the synthesis of 2,2-disubstituted tetrahydropyrans from diethyl malonate is the selective chlorination by trifluoromethanesulfonyl chloride of carbanions which can be formed using triethylamine or DBU as the base (79TL3645). Monoalkylation of the diester with l-bromo-4-tetrahydropyranyloxybutane leads to the alcohol (237 R = H)... 

Carbanionic metal alkyls and hydridic metal hydrides will react with alcohols or phenols to give alkoxides and phenoxides, typically in excellent yields. The reaction is also important as it forms the basis for the calorimetric measurement of a large number of metal-alkyl bond dissociation energies.93,94 This synthetic method tends to be very convenient due to the volatility of the generated alkane or hydrogen side products. Monoalkyl alkoxides of Be,95 Mg96 and Zn97 can be obtained in this way (equation 26). 

It is widely held that protic ( acidic ) solvents favour monoalkylation of diethyl malonate carbanion, whereas aprotic ( inert ) solvents favour dialkylation. Exactly opposite results have now been obtained in the reactions of die alkali metal salts of diethyl malonate with 1,2-bis-, 1,2,4,5-tetrakis-, and 1,2,3,4,5,6-hexakis-(bromo-methyl)benzenes in ethanol and in DMSO, the former solvent preferring dialkylation (cyclization) and the latter monoalkylation.106 Other interesting related observations were made. 

A study of the mono- vs di-alkylation reactions of dibromide (9) with carbanions (lOc-g), covering a range of >15 pK units in DMSO, has revealed that the carbanions (lOd-g) derived from the less acidic carbon acids give exclusively the bis(monoalkylated) product (ii) however, carbanions (lOa-c) give the cyclic product (12) of dialkylation.21 This dichotomy is apparently a consequence of the relative rates of formation (by proton transfer, /id) and cyclization (kc) of die conjugate base of the monoalkylated intermediate. 

The reaction of selenoacetals with butyllithiums allows the synthesis of a large variety of a-seleno-alkyllithiums whose carbanionic centers are unsubstituted, monoalkyl substituted or dialkyl substituted. 

In general, the Se-Li exchange is easier (i) when carried out in THF rather than in ether, (ii) when s-or r-butyllithium is used instead of n-butylli um. Methyllithium is almost unreactive in most cases and (iii) if a better stabilization of the carbt onic center can be achieved. Thus phenyl selenoacetals react more rapidly than their methyl analogs (see Section 2.6.2.1.2), and a-selenoalkyllithiums where the carbanionic center is part of a three-membered cycle or is substituted by an aryl group are more readily obtained than those which are monoalkyl or dialkyl substituted. 

In the laboratory of D.R. Williams, a carbanion methodology for the alkylations and acylations of substituted oxazoles was investigated. The study showed that the monoalkylation of the dianion generated from 2-(5-oxazolyl)-1,3-dithiane exclusively led to the substitution of the carbon adjacent to sulfur. However, acylation reactions of the dianion afforded 4,5-disubstituted oxazoles. These new products presumably arose from carbonyinitrile ylide intermediates, which were generated by the selective C-acylation of a ring-opened dianion tautomer. This is the first example of a base-induced, low-temperature Cornforth rearrangement. 

Monoalkylation of the carbanion generated from methyl thiomethyl sulfoxide and 1,3-dithiane I-oxide - has been reported (Scheme 74, entry b) but reexamination of both reactions - proved unsatisfactory under conditions similar to those previously described or slightly modified. Neither the stepwise- nor the one-pot dialkylation was successful at 20 C, but the latter reaction was apparently achieved by Schill- by performing it at 50 °C with a slight excess (2.2 equiv.) of n-alkyl bromides in... 

The metals Hg, Sn, Pd, Pt, Au, and T, and the metalloids As, Se, Te, and S accept methyl carbanions from methylcobalamin (CH3B]2) in biological systems. The metals Pb, Cd, and Zn are not methylated owing to the extreme instability of their monoalkyl derivatives in aqueous systems, and CH3B,2 does not transfer methyl groups to these elements. Specific mechanisms of methylation will be discussed later. 

The behaviour of bisphosphoryl compounds such as 310 towards strong bases is reminiscent of that of analogous carbonyl compounds. Initial carbanion formation occurs at the more acidic site, but treatment of the initial anion with a stronger base generates a dianion, which may then be selectively monoalkylated at the more reactive site ". ... 

The use of esters of a (substituted-methyl)phosphonic acid to provide the carbanion site next to phosphoryl phosphorus was a natural step forward. The most successful development has been the use of the carbanion 346 derived from esters of methylenebisphospho-nic acid (or its monoalkylated derivatives). The anion 346 reacts with an aldehyde to afford the alkenylphosphonic diester 347 (R = Et, Ph, PhCH—CH, 2-thienyl, 2-pyridinyl, etc,) ". Use of the protected 3-pyridinylcarboxaldehyde 348 allowed the preparation of the ester 349, which, after reduction of the C=C bond and hydrolysis, afforded the phosphonic acid 350 Such reactions have also been carried out under phase-transfer condi-tions. Reactions between the lithium salt of the ester 351 and benzaldehyde or but-2-enal give the (alk-1 -enyl)phosphonic esters 352 and 353 in the ratio 1 4 the lithium salts 354 and 355 are formed concomitantly in the ratio 4 1. ... 

Monoalkylation of tosylacetonitrile. Alkylation of TSCH2CN ordinarily yields mainly dialkyl, derivatives selective monoalkylation of fairly stable carbanions is generally difficult. Japanese chemists found that monoalkylation with primary alkyl halides can be effected in 90-957, yield if DBU is used as base with benzene as solvent. Considerable dialkylation is observed under phase-transfer conditions. Yields from secondary halides are somewhat lower. The same conditions can be used for monoalkylation of methyl cyanoacetate and acetylacetone. ... 

In the most common case of R = alkyl the alkylated products are weaker CH acids so equilibrium 35c is shifted to the left thus, the concentration of the me-thinic carbanions is low. However, these carbanions are more nucleophilic than methylenic ones and react faster with R-X thus the dialkylation proceeds to some extent. Under the PTC conditions, concentration of carbanions in the organic phase is low (cannot exceed that of the catalyst) so they are always in the presence of a great excess of the carbanion precursors. For this reason, the concentration of carbanions produced from less acidic precursors is negligible and the alkylation process is reasonably selective in the sense of monoalkylation (eq. 36). 

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