Electron-donating ester substituent

Salbutamol is made from aspirin, itself simply the acetate ester of the natural product salicylic acid, by a series of substitution reactions. The first is a Friedel-Crafts acylation (an electrophilic substitution) in which aspirin itself is the acylating agent it is an isomerization in which the acetyl group gets transferred from O to C. Acylation occurs para to the electron-donating alkoxy substituent, and gives this ketone. 

Oishi and his co-workers have reported that aromatic thiono-esters (408), in the presence of boron trifluoride ethyl-etherate, rearrange to the corresponding thiolo-esters (409). The disappearance of the thiono-ester took place in accordance with first-order kinetics, and electron-donating para-substituents were found to accelerate the conversion, which was characterized by the Hammett p value of -1.38. The mechanism of the rearrangement was considered to involve the intermediate (410), in agreement with the results of cross-over experiments. The thermal rearrangement of thioaroyl thiocyanates (411) to thioaroyl isothiocyanates (412) was also found to be influenced by substituents. Thiono-ester-thiolo-ester... 

Outcomes from the reactions of radicals with substituted acrylate esters depend on the attacking radical (refer Table 1.3 and Scheme 1.4). The results may be summarized as follows (the methyl substituent is usually considered to be electron donating - Section 1.2.2) ... 

Carboxylic acids with an electron donating substituent in the a-position decarboxylate in a two-electron oxidation to carbocations (see chap. 7). These can react with the solvent (alcohol, acetic acid, water) or the unreacted carboxylate to ethers, esters, or alcohols (Eq, 14). In some cases the carbon skeleton rearranges, which is a clear indication of the cationic pathway. 

This homoenolate methodology has been extended to the use of nitrones 170 as electrophiles [72]. Scheldt and co-workers have shown that enantiomerically enriched y-amino esters 172 can be prepared with excellent levels of stereocontrol from an enal 27 and a nitrone 170 using the NHC derived from triazolium salt 164 (Scheme 12.37). The oxazinone product 171, formally a result of a [3-1-3] cycloaddition, is cleaved to afford the y-amino ester product 172. The reaction shows broad substrate scope, as a range of substituted aryl nitrones containing electron donating and withdrawing substituents are tolerated, while the enal component is tolerant of both alkyl and aryl substituents. 

These reactions are found to be promoted by electron-donating substituents in the diene, and by electron-withdrawing substituents in the alkene, the dienophile. Reactions are normally poor with simple, unsubstituted alkenes thus butadiene (63) reacts with ethene only at 200° under pressure, and even then to the extent of but 18 %, compared with 100% yield with maleic anhydride (79) in benzene at 15°. Other common dienophiles include cyclohexadiene-l,4-dione (p-benzoquinone, 83), propenal (acrolein, 84), tetracyanoethene (85), benzyne (86, cf. p. 175), and also suitably substituted alkynes, e.g. diethyl butyne-l,4-dioate ( acetylenedicarboxylic ester , 87) ... 

In HO -catalyzed hydrolysis (specific base catalyzed hydrolysis), the tetrahedral intermediate is formed by the addition of a nucleophilic HO ion (Fig. 3.1, Pathway b). This reaction is irreversible for both esters and amides, since the carboxylate ion formed is deprotonated in basic solution and, hence, is not receptive to attack by the nucleophilic alcohol, phenol, or amine. The reactivity of the carboxylic acid derivative toward a particular nucleophile depends on a) the relative electron-donating or -withdrawing power of the substituents on the carbonyl group, and b) the relative ability of the -OR or -NR R" moiety to act as a leaving group. Thus, electronegative substituents accelerate hydrolysis, and esters are more readily hydrolyzed than amides. 

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