Kinetics and Mechanism of the Base-Catalysed Cyclisation of 2-(Substituted benzoylamino)benzamides Giving Quinazolin-4-one and Quinazolin-4-thione Derivatives

Abstract

Acylation of 2-aminobenzamide and 2-(methylamino)benzamide with substituted benzoyl chlorides in acetone has been used to prepare the respective 2-(substituted benzoylamino)benzamides 1a−i, which were then subjected to sodium methoxide catalysed ring closure to give the respective 2-(substituted phenyl)quinazolin-4-ones 2a−i. The kinetics of the cyclisation reactions were monitored by UV/Vis spectroscopy at 25 °C in methanolic solutions of sodium methoxide. In the case of 2-(substituted benzoylamino)benzamides 1a−i and 2-(substituted benzoylamino)thiobenzamides 3a−j, non-linear dependences of observed rate constants kobs on the sodium methoxide concentrations were obtained, the shape of them being typical of a reaction with rapid pre-equilibrium. All the cyclisation reactions satisfactorily obeyed the Hammett correlation. In the case of 2-[(benzoyl)(methyl)amino]benzamides 1e−i, increasing sodium methoxide concentration resulted in a progressive increase in kobs values which is probably due to formation of dianion. In the case of 2-(substituted benzoylamino)thiobenzamides 3b and 3h, which differ in the presence of a methyl group on the nitrogen atom the values of the activation Gibbs energy ΔG‡25 °C, activation enthalpy ΔH‡25 °C, and activation entropy ΔS‡25 °C for their respective cyclisations to 2-(substituted phenyl)quinazoline-4-thiones 4b and 4h were determined. Whereas the ΔG‡25 °C values were very close for the two substances, the ΔH‡25 °C and ΔS‡25 °C distinctly differed. This was interpreted by the enthalpy and entropy factors operating against each other in the cyclisation. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)