Anion stabilization

The TT-allylpalladium complexes 241 formed from the ally carbonates 240 bearing an anion-stabilizing EWG are converted into the Pd complexes of TMM (trimethylenemethane) as reactive, dipolar intermediates 242 by intramolecular deprotonation with the alkoxide anion, and undergo [3 + 2] cycloaddition to give five-membered ring compounds 244 by Michael addition to an electron-deficient double bond and subsequent intramolecular allylation of the generated carbanion 243. This cycloaddition proceeds under neutral conditions, yielding the functionalized methylenecyclopentanes 244[148], The syn-... 

The pA of 1,3-dithiane is 36.5 (Cs" ion pair in THF). The value for 2-phenyl-1,3-dithiane is 30.5. There are several factors which can contribute to the anion-stabilizing effect of sulfur substituents. Bond dipole effects contribute but carmot be the dominant factor because oxygen substituents do not have a comparable stabilizing effect. Polarizability of sulfur can also stabilize the carbanion. Delocalization can be described as involving 3d orbitals on sulfur or hyperconjugation with the a orbital of the C—S bond. MO calculations favor the latter interpretation. An experimental study of the rates of deprotonation of phenylthionitromethane indicates that sulfur polarizability is a major factor. Whatever the structural basis is, there is no question that thio substituents enhance... 

This reaction can also be applied to tertiary nitroalkanes lacking any additional functional group. The reactions with nitro compounds lacking additional anion-stabilizing groups are carried out in DMSO solution ... 

In general sulfur ylide-mediated epoxidation cannot be used to form an epoxide with an adjacent anion-stabilizing group such as an ester, as the requisite ylide is too stable and does not react with aldehydes [23], With the less strongly electron-withdrawing amide group, however, the sulfur ylide possesses sufficient reactivity for epoxidation. The first example of an asymmetric version of this reaction was by... 

Table 5.4 Electrophile trapping of lithiated epoxides containing anion-stabilizing groups.

Commonly employed anion-stabilizing groups are those containing silicon (Table 5.4, Entries 1-5). Magnus et al. reported that epoxysilane 147 could be deproto-nated with t-BuLi, and that the lithiated epoxide 148 thus generated could be trapped with allyl bromide to give epoxysilane 149 in a synthetically useful yield (Scheme 5.34) [55], Iodomethane (88%) and chlorotrimethylsilane (60%) could also be trapped. 

Since Eisch and Galle first introduced organyl substituents as anion-stabilizing groups for lithiated epoxides (Table 5.4, Entries 8-9) they have examined them extensively (Table 5.5) [54, 65]. 

The use of an ester as an anion-stabilizing group for a lithiated epoxide was demonstrated by Eisch and Galle (Table 5.5, Entry 11). This strategy has been extended to a,P-epoxy-y-butyrolactone 191, which could be deprotonated with LDA and trapped in situ with chlorotrimethylsilane to give 192, which was used in a total synthesis of epolactaene (Scheme 5.45) [69], The use of a lactone rather than a... 

Both benzothiazolyl and berizolriazoly] units have been employed as heteroaromatic anion-stabilizing groups for metalated epoxides (Scheme 5.47) [71]. The successful use of a simple alkyl bromide as electrophile with 200 is notable. 

Florio and coworkers have also reported the use of oxazolinyl groups as anion-stabilizing substituents. Lithiation/electrophile trapping of oxazolinylepoxide 202 provided access to acyloxiranes 205 [72], while deprotonation/electrophile trapping of oxazolinylepoxide 206 with nitrones gave access to enantiopure a-epoxy- 3-amino acids 208 (Scheme 5.48) [73],... 

Electrophile trapping of simple metalated epoxides (i. e., those not possessing an anion-stabilizing group) is possible. Treatment of epoxystannane 217 with n-BuLi (1 equiv.) in the presence of TMEDA gave epoxy alcohol 218 in 77% yield after trapping with acetone (Scheme 5.51) [76], In the absence of TMEDA, the non-stabilized epoxides underwent dimerization to give mixtures of enediols. 

Metalated epoxides are a special class of a-alkoxy organometallic reagent. Unstabilized oxiranyl anions, however, tend to undergo a-elimination. On the other hand, attempts to metalate simple unfunctionalized epoxides may lead to nucleophilic ring opening. The anion-stabilizing capability of a trimethylsilyl substituent overcomes these problems. Epoxysilanes 22 were... 

Several reviews cover hetero-substituted allyllic anion reagents48-56. For the preparation of allylic anions, stabilized by M-substituents, potassium tm-butoxide57 in THF is recommended, since the liberated alcohol does not interfere with many metal exchange reagents. For the preparation of allylic anions from functionalized olefins of medium acidity (pKa 20-35) lithium diisopropylamide, dicyclohexylamide or bis(trimethylsilyl)amide applied in THF or diethyl ether are the standard bases with which to begin. Butyllithium may be applied advantageously after addition of one mole equivalent of TMEDA or 1,2-dimethoxyethane for activation when the functional groups permit it, and when the presence of secondary amines should be avoided. 

A carbanion can be a good leaving group in SNl-type solvolyses when the anion is highly stabilized by strong electron-withdrawing substituents. Mitsuhashi reported some examples of such reactions for substrates which eject an anion stabilized by cyano (and nitro) groups [81] (Mitsuhashi, 1986), [82] (Mitsuhashi and Hirota, 1990) and [83] (Hirota and Mitsuhashi,... 

Then, substitution of the sulfur atom of Cys with an oxygen would greatly decrease the rate of reaction, because nucleophilicity, anion-stabilizing effect and proton-donating ability of OH group are far smaller than that of an SH group. 

These last examples illustrate the effecte of heavy cations on anionic stability. The opposite case of an anionic effect is also possible. Thus diazonium salts are hardly stable but not dangerous when the anion is a chloride ion, whereas they become dangerous when the anion is a sulphide or carboxylate. 

Alkylation of dianions occurs at the more basic carbon. This technique permits alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. Since, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and nature of the base. A few examples of the formation and alkylation of dianions are collected in Scheme 1.7. In each case, alkylation occurs at the less stabilized anionic carbon. In Entry 3, the a-formyl substituent, which is removed after the alkylation, serves to direct the alkylation to the methyl-substituted carbon. Entry 6 is a step in the synthesis of artemisinin, an antimalarial component of a Chinese herbal medicine. The sulfoxide serves as an anion-stabilizing group and the dianion is alkylated at the less acidic a-position. Note that this reaction is also stereoselective for the trans isomer. The phenylsulfinyl group is removed reductively by aluminum. (See Section 5.6.2 for a discussion of this reaction.)... 

The reaction pattern can be used for the synthesis of 1,3-dicarbonyl compounds and other systems in which an acyl group is (3 to an anion-stabilizing group. 

These reactions accomplish the same overall synthetic transformation as the acylation of ester enolates, but use desulfurization rather than decarboxylation to remove the anion-stabilizing group. Dimethyl sulfone can be subjected to similar reaction sequences.232... 

Scheme 2.18 gives some representative olefination reactions of phosphonate anions. Entry 1 represents a typical preparative procedure. Entry 2 involves formation of a 2,4-dienoate ester using an a, 3-unsaturated aldehyde. Diethyl benzylphosphonate can be used in the Wadsworth-Emmons reaction, as illustrated by Entry 3. Entries 4 to 6 show other anion-stabilizing groups. Intramolecular reactions can be used to prepare cycloalkenes.264... 

The sulfoximine group provides anion-stabilizing capacity in a chiral environment and a number of synthetic applications have been developed based on these properties. 

More generally, many combinations of EWG substituents can serve as the anion-stabilizing and alkene-activating groups. Conjugate addition has the potential to form a bond a to one group and (3 to the other to form a a,y-disubstituted system. 

Retrosynthetically, there are inherently two possible approaches to the products of conjugate addition as represented below, where Y and Z represent two different anion-stabilizing groups. 

Among Michael acceptors that have been shown to react with ketone and ester enolates under kinetic conditions are methyl a-trimethylsilylvinyl ketone,295 methyl a-methylthioacrylate,296 methyl methylthiovinyl sulfoxide,297 and ethyl a-cyanoacrylate.298 Each of these acceptors benefits from a second anion-stabilizing substituent. The latter class of acceptors has been found to be capable of generating contiguous quaternary carbon centers. 

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