Steric and electronic substituent effects in hydrolysis and aminolysis of 4‐alkyl‐4‐methyl‐2‐aryl‐4,5‐dihydro‐1,3‐oxazol‐5‐ones

Abstract

The kinetics and mechanism of the acid-catalysed hydrolysis of substituted 4-alkyl-4-methyl-2-aryl-4,5-dihydro-1,3-oxazol-5-ones to the corresponding 2-alkyl-2-benzoylaminopropanoic acids were studied. The Taft correlation of rate constants of the acid-catalysed hydrolysis with alkyl substitution at the 4-position of the 1,3-oxazol-5-one ring is non-linear. In the Hammett correlation, the value of decreases with increasing steric demand of the alkyl substituent. With the 4-isopropyl and tert-butyl derivatives, ¼ À0.63 and À0.32, respectively. The protonated 4-isopropyl and tert-butyl derivatives undergo nucleophilic attack by water at the carbonyl carbon atom at the 5position of the 1,3-oxazol-5-one ring to the extents of ca 70% and 60%, respectively. Another reaction path consists in nucleophilic attack by water at the 2-position of the 1,3-oxazol-5-one ring. The reaction kinetics of aminolyses of substituted 4-isopropyl-4-methyl-2-phenyl-1,3-oxazol-5(4H)-ones (1a, 1b, 1f) giving substituted N-{1,2-dimethyl-1-[(propylamino)carbonyl]-propyl}benzamides (3a, 3b, 3f, 4a) was studied in aqueous propylamine buffers. In the case of the aminolysis of 1a and 1b with propylamine, the rate-limiting step consists in the decomposition of the intermediate In AE catalysed by both the acidic and the basic buffer components. The base-catalysed route is four times faster in both cases. In the case of the aminolysis of 1f with propylamine and that of 1a with ethylenediamine, the ratelimiting step is the formation of the intermediate In AE , the subsequent reaction step being accelerated by substitution and/or intramolecular catalysis. EXPERIMENTAL MaterialsThe new dialkyl-2-aryl-4,5-dihydro-1,3-oxazol-5-ones were prepared by a known method 11 of ring closure and

2-Amino-2-alkyl(aryl)propanenitriles as key building blocks for the synthesis of five-membered heterocycles

“…The paper 60 was focused on study of kinetics and mechanism of acid-and base-catalysed hydrolysis of substituted 4-alkyl-2-aryl-4-methyl-4,5-dihydro-1,3-oxazol-5-ones to the corresponding 2-alkyl-2-benzoylaminopropanoic acids. The Taft correlation for acid-catalysed hydrolysis of 1,3-oxazol-5-one ring carrying various 4-alkyl substituents was not linear.…”

“…The results of the above-mentioned study 60 provided a source of inspiration for an elegant synthesis of variously sterically hindered poly(ethylene glycol)carboxylic acids. These acids were prepared by the following reaction sequence (Scheme 13).…”

“…[58][59][60][61] The first synthesis of azlactone was described as cyclo-condensation reaction of hippuric acid with benzaldehyde in the presence of acetic acid anhydride. 58 Generally, oxazol-5-ones are prepared by cyclization dehydration of corresponding α-N-acylamino acids, mostly by treatment with acetic acid anhydride or polyphosphoric acid.…”

New and Simple Synthetic Method for Carboxylic Acid Functionalized Poly(ethylene glycol)

“…The subsequent transformation of terminal nitrile groups into carboxylic functional groups was carried out by using our earlier described synthesis and kinetic study of hydrolysis of substituted 4-alkyl-4-methyl-2-aryl-4,5-dihydro-1,3-oxazol-5-ones (azlactones). 13 In this case the hydrolysis of nitrile group proceeds with the assistance of neighboring amidic group as a sequence of a ring-closure reaction and hydrolysis. The ring closure producing the azlactone was performed in polyphosphoric acid.…”

“…14 This method was adopted for preparation of 2-{4-[amethoxypoly(ethylene glycol)]oxybenzoylamino}-2,3-dimethylbutyric acid 15 (3a, 82%) and 2-(4-{a-[4-(1-carboxy-1-methylethylcarbamoyl)phenoxy]poly(ethylene glycol)-w-yloxy}benzoylamino)-2-methylpropionic acid 16 (3b, 89%). The course of transformation of nitrile group into carboxylic functional group was monitored by 13 C NMR spectroscopy, 17 which in the case of polymers 3a,b showed a signal at d = 174.7 ppm typical of the CO 2 H group, while the signal at d = 124.8 ppm typical of CN group (2a,b) completely disappeared. 15,16 Using GPC,18 it was demonstrated that the treatment with polyphosphoric acid did not cause any degradation of the poly(ethylene glycol) chain.…”