Esters from nucleophilic substitution reactions

Sulfonate esters are especially useful substrates in nucleophilic substitution reactions used in synthesis. They have a high level of reactivity, and, unlike alkyl halides, they can be prepared from alcohols by reactions that do not directly involve bonds to the carbon atom imdeigoing substitution. The latter aspect is particularly important in cases in which the stereochemical and structural integrity of the reactant must be maintained. Sulfonate esters are usually prepared by reaction of an alcohol with a sulfonyl halide in the presence of pyridine ... 

In a one-pot synthesis of thioethers, starting from potassium 0-alkyl dithiocarbonate [36], the base hydrolyses of the intermediate dialkyl ester, and subsequent nucleophilic substitution reaction by the released thiolate anion upon the unhydrolysed 0,5-dialkyl ester produces the symmetrical thioether. Yields from the O-methyl ester tend to be poor, but are improved if cyclohexane is used as the solvent in the hydrolysis step (Table 4.13). In the alternative route from the 5,5-dialkyl dithiocarbonates, hydrolysis of the ester in the presence of an alkylating agent leads to the unsymmetrical thioether [39] (Table 4.14). The slow release of the thiolate anions in both reactions makes the procedure socially more acceptable and obviates losses by oxidation. 

Historically, the thermal transesterification of (-)-ethyl p-toluene-sulfinate 224 with n-butanol affording (+)-n-butyl p-toluenesulfinate 225 described by Phillips in 1925 (100) is the first nucleophilic substitution reaction at chiral sulfur involving a Walden-type inversion. The evidence for inversion of configuration in this reaction was based on the assumption that both (-)-esters 224 and 225 obtained from the kinetic resolution have the same configuration. 

Polymeric phosphonium salt-bound carboxylate, benzenesulphinate and phenoxide anions have been used in nucleophilic substitution reactions for the synthesis of carboxylic acid esters, sulphones and C/O alkylation of phenols from alkyl halides. The polymeric reagent seems to increase the nucleophilicity of the anions376 and the yields are higher than those for corresponding polymer phase-transfer catalysis (reaction 273). 

Enolate ions can be formed from aldehydes and ketones containing protons on an a-carbon (Following fig.). Enolate ions can also be formed from esters if they have protons on an a-carbon. Such protons are slightly acidic and can be removed on treatment with a powerful base like lithium diisopropylamide (LDA). LDA acts as a base rather than as a nucleophile since it is a bulky molecule and this prevents it attacking the carbonyl group in a nucleophilic substitution reaction. 

These reactions are used to make anhydrides, carboxylic acids, esters, and amides, but not acid chlorides, from other acyl compounds. Acid chlorides are the most reactive acyl compounds (they have the best leaving group), so they are not easily formed as a product of nucleophilic substitution reactions. They can only be prepared from carboxylic acids using special reagents, as discussed in Section 22.10A. 

The formation of the sultone (160) probably involves addition of the complex across the alkene double bond, a 1,2-hydride shift and an intramolecular nucleophilic substitution reaction. The sultone (161) is formed by addition of sulfur trioxide to give the unstable p-sultone which rearranges to the more stable y-isomer (161). Another useful route to sultones is by metallation of alkanesulfonate esters for example, butane-1,3-dimethylsulfonate (162), prepared from butanel,3-diol, yields the 8-sultone, namely 6-methyl-l,2-oxathiin-2,2-dioxide (163) (Scheme 67). 

Perimidinones are available from 1,8-naphthalenediamines in cyclization reactions with potassium cyanate, carbonate, and chlorocarbonate esters, phosgene, and urea all methods give satisfactory results. 2-Alkoxy- and aryloxyperimidines are readily available by nucleophilic substitution reactions in the 2-position <81RCR8I6>. 

Scheme 20.8 Nucleophilic substitution reactions ofsulfonate esters in [bmim][X] (X=Cl,Br, I, OAc, and SCN) media. Reproduced from Liu et al. [203] with permission from the Georg Thieme Verlag.

Other interesting syntheses of mPEG butyric acid have also been published in the patent literature [80]. For example, ortho-ester 23 can be obtained by a two-step procedure from 4-bromobutanoyl chloride and 3-methyl-3-oxetanemethanol 22 (Equation 3.8). A nucleophilic substitution reaction of 23 with mPEG-alkoxide, followed by hydrolysis, gives the required acid 19b (Equation 3.8). The decrease in the acidity of the proton a- to the now protected carbonyl, removes the possibility of elimination reactions observed with 3-bromopropionate and related halo-esters. 

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