Flow nuclear magnetic resonance study of the addition, dehydration, and cyclization steps for reaction between hydrazine and ethyl acetoacetate

Abstract

The proton nuclear magnetic resonance spectra of a reaction mixture of hydrazine and ethyl acetoacetate (EAA) in aqueous solution under flowing and stopped-flow conditions provides kinetic information concerning the rapid addition step to form the carbinolamine (CA) intermediate and the slower dehydration and cyclization steps to form the anti hydrazone and 3-methylpyrazol-5-one, respectively. The addition step was studied while flowing at rates faster than the dehydration and cyclization rates so that no product signal was observed. Under these conditions, a broad signal resulting from the coalescence of the CH3 proton resonances of EAA and CA is observed. Analysis of the line shape of this broad signal yields the addition rate constant, which has a value that appears to be pH dependent and is of the order of 103 M−1 s−1. Stopped-flow spectra provide the time dependence for the reactant and product signals. Analysis of these time dependences provides information concerning the mechanism of product formation. In contrast with hydroxylamine, CA appears to undergo dehydration and cyclization at comparable rates in the pH range, 8.8–9.2 when hydrazine is the nucleophile. In addition, the anti hydrazone cyclizes at an appreciable rate. These intramolecular cyclization rates are compared with the intermolecular values.

A concise route to 4-aminomethylpyrazoles and 4-aminomethylisoxazoles from acetylacetone-derived hexahydropyrimidines under mild conditions

“…Accordingly, the following mechanism can be proposed for such systems (Fig. 4) (Cocivera et al, 1978;Katritzky et al, 1987).…”

“…For symmetrically substituted hydrazine, both routes ultimately produce the same pyrazolone product. However, Cocivera et al (1978) demonstrated that route a is the main pathway for HHP-ETAA conjugates.…”

Mechanisms of heterocycle ring formation. Part 5. A carbon-13 nuclear magnetic resonance study of pyrazolinone synthesis by the reaction of β-ketoesters with substituted hydrazines

“…Reactants were mixed in a 1 : 1 mole ratio in CD3CN solution, and the spectrum monitored for the disappearance of starting material peaks, for the initial formation, maximum concen- Pyrazolinone formation is also quite facile in the reaction between (3a) and (4c); after 15 min no starting materials remain. In addition to product (15c), however, the E-methylhydrazone (9c) is now present in lesser but comparable amount, and its consumption, by the path (9) to (13)-( 15), requires an additional 24 h. The essential isomerization, (E)-(9c) to (2)-(13c), is assumed to proceed via the enamine tautomer (33) and the adverse effect of a-methylation upon this process finds precedent in the much slower rate of deprotonation (aqueous NaOH) of the keto form of ethyl z-methylacetoacetate (I) compared with the unbranched parent ester (11), k(ii) = 200 k(,,,, as noted by Alcais and Br~uillard.~' We note that other workers28 report a 10% yield of 2,3,4-trimethyl-3-pyrazolin-5-one (16c) along with a 50% yield of (15c) after an equimolar aqueous solution of ethyl z-methylacetoacetate (4c) and methylhydrazine (3a) was heated for 15 h at 70 "C.…”