Hydrolysis of 2-Aminobenzoate Esters

The hydrolysis of 2-aminobenzoate esters in the range of pH 4 to 8.5 oeeurs by in-tramoleeular general base catalysis of the 2-amino group. The amine enhances the reactivity of the water by partially removing a proton as the water attacks the carbonyl group. 

Successful polymer supported stereoselective Diels-Alder reaction was performed using immobilized enantiopure 4-(3-hydroxy-4,4-dimethyl-2-oxopyrro-lidin-l-yl)benzoic acid 12 as a chiral auxiliary [15]. The corresponding resin-bound acrylate derivate has been applied as the dienophile 13. Preparation of the precursor started with the combination of pantolactone 10 and the sodium salt of 4-aminobenzoic acid. Conversion into the corresponding benzyl ester followed. The obtained racemate was esterified with (lS)-camphanic acid chloride to a dia-stereomeric mixture to gain the enantiopure compounds by chromatographic separation. After subsequent saponification of the camphanic acid moiety and hydrolysis of the benzyl ester the (R)-enantiomer 11 was coupled to Rink amide resin (Scheme 12.6). 

For the synthesis of the AMT ester (VIII.151), bromide (VIII. 156)-HBr was condensed in situ with 4-aminobenzoic acid and the product, 4-amino-4-deoxypteroic acid (APA), was treated directly with a mixture of formic and acetic acid to obtain the W °-formyl derivative (FmAPA, 65% yield) [292]. Condensation of FmAPA with y-r-butyl a-methyl L-glutamate to form the diester (VIII. 155) was accomplished in 82% yield by a modified mixed anhydride procedure involving four cycles of in situ carboxyl group reactivation. Hydrolysis of the methyl ester and W -formyl group at the same time with NaOH proved impossible as a result of an unforeseen loss of the y-t-butyl ester. When the a-methyl ester was first removed under mild conditions with Ba(0H)2, however, the relatively stable V -formyl derivative (VIII.154) was isolated satisfactorily in 79% yield. Subsequent cleavage of the W -formyl group was then accomplished by carefully controlled hydrolysis in 0.25 M NaOH (1.75 h at 25 °C). In an alternative synthesis, FmAPA was activated by reaction with bis(4-nitrophenyl) carbonate to obtain the corresponding... 

The dissociative mechanism of acyl transfer ElcB), which prevails for the alkaline hydrolysis of 2,4-dinitrophenyl 4-hydroxybenzoate, could not be detected in a series of extended analogues. Thus, kinetic studies of the alkaline hydrolysis of the 2,4-dinitrophenyl esters of 4-(4 -hydroxyphenyl)benzoic acid (24), 4-(4 -hydroxyphenyl) azobenzoate (26 Z = Y = N), Al-(4 -hydroxybenzylidene)-4-aminobenzoate (26 Z = CH, Y = N) and 4 -hydroxy-fran5-stilbene-4-carboxylate (26 Z = Y = CH) showed that these compounds did not form the corresponding ElcB intermediates (25) and (27), but instead reacted through the usual Bac2 mechanism. ... 

Fife et al. have reported intramolecular GB-assisted ester hydrolysis. The pseudo-first-order rate constants (k bj.) are pH-independent from pH 8 to pH 4. The triflnoroethyl, phenyl, and p-nitrophenyl esters of 2-aminobenzoic acid hydrolyze with similar rate constants in the pH-independent reactions, and the rates of these water reactions are twofold slower in D2O than in HjO. The most likely mechanism involves the intramolecular GB assistance by the neighboring amino group. The rate enhanc ents in the pH-independent reaction in comparison with the pH-indepen-dent hydrolysis of the corresponding para-substituted esters are 50- to 100-fold. 

To determine the meehanism of the reaetion in the pH-independent region, the hydrolysis of phenyl, /7-nitrophenyl and trifluoroethyl 2-aminobenzoates 1-3 has been studied (Seheme 23.1). The three esters hydrolyze with similar rate eonstants... 

The importance of the free amino group in the process also comes across when comparing the rate constants of hydrolysis of phenyl benzoate and phenyl 2-aminobenzoate 1 in the same pH 4-8.5 range. As depicted in Fig. 23.2, the hydrolysis of phenyl benzoate is considerably slower than that of 1. As both esters only differ by the presence of the amino group in the aromatic ring, the differences in reaction rates again point to the involvement of the amino group in the reaction. 

Many more aminobenzoate amino esters were synthesized, and some were developed as local anesthetics. The only ones still of importance are tetracaine, No. 3, and chloropro-caine, No. 1. An examination of the data on the three aminoalkyl p-aminobenzoates (Nos. 1, 2, and 3, Table 13-6) illustrates some classic. SARs within that series. For example, the o-chloro atom of chloroprocaine would predictably enhance the ester groups instability as exemplified by a four-fold faster rate of hydrolysis—and therefore inactivation (15-fold when compared with tetracaine). The partition coefficients indicate a 570 times greater... 

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