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)

Synthesis, antiproliferative activity, and mechanism of action of a series of 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides

“…They showed signals attributable to the β-olefinic protons at 6.66–6.97 δ with coupling constants of 16.6–14.7 Hz, as required for E -structures [12], while the α-olefinic hydrogens were found along with aromatic multiplets. Moreover, their 1 H NMR spectra showed both the NH and NH 2 amidic signals; the cinnamamido NH proton appeared as a singlet at 11.77–11.92 δ , while, according to the literature [13], the presence of an intramolecular hydrogen bond renders the benzamido NH 2 protons diastereotopic. H a is easily exchangeable with D 2 O and appeared as a singlet at 8.24–8.44 δ .…”

“…Colchicine 18 , whose antileukemic activity is well known, and the 2-cinnamamidobenzamide 4 [13] (Fig. 1), were used as reference compounds.…”

Synthesis, antiproliferative activity, and mechanism of action of a series of 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides

“…They showed signals attributable to the β-olefinic protons at 6.66–6.97 δ with coupling constants of 16.6–14.7 Hz, as required for E -structures [12], while the α-olefinic hydrogens were found along with aromatic multiplets. Moreover, their 1 H NMR spectra showed both the NH and NH 2 amidic signals; the cinnamamido NH proton appeared as a singlet at 11.77–11.92 δ , while, according to the literature [13], the presence of an intramolecular hydrogen bond renders the benzamido NH 2 protons diastereotopic. H a is easily exchangeable with D 2 O and appeared as a singlet at 8.24–8.44 δ .…”

“…Colchicine 18 , whose antileukemic activity is well known, and the 2-cinnamamidobenzamide 4 [13] (Fig. 1), were used as reference compounds.…”

Synthesis and Biological Evaluation of Quinazoline-4-thiones

“…Efficient methods for synthesis of quinazolin-4-ones are e.g. acylation of 2-aminobenzamides with an appropriate acyl chloride followed by cyclization in basic medium [ 39 ], or one-pot synthesis under solvent-free conditions [ 40 ]. Derivatives of 2,2-dimethyl-1,2-dihydroquinazoline-4(3 H )-thione can be prepared by condensation of 2-aminothiobenzamides with acetone under mild conditions [ 41 ].…”

One‐Pot Copper(I)‐Catalyzed Synthesis of 2‐Aryl‐quinazolin‐4(3 H )‐ones via N‐ benzylation / C sp3 – H Oxidation/ CN Hydrolysis/Cyclization

“…Literature illustrates that formation of required quinazolin‐4(3 H )‐ones is accompanied by the occurrence of aminal intermediate or dihydrogenated quinazolinones as side products, and sometimes dihydrogenated quinazolinone have been isolated as the main product . Among the diverse protocols used for the synthesis of these heterocyclic scaffolds, intramolecular cyclization of amides is rarely utilized due to the intricacy in preparation of starting amides via traditional methods, poor reactivity of amides, and unproductive cyclizations with an array of nucloephiles.…”

Synthesis, antiproliferative activity, and mechanism of action of a series of 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides

“…They showed signals attributable to the β-olefinic protons at 6.66–6.97 δ with coupling constants of 16.6–14.7 Hz, as required for E -structures [12], while the α-olefinic hydrogens were found along with aromatic multiplets. Moreover, their 1 H NMR spectra showed both the NH and NH 2 amidic signals; the cinnamamido NH proton appeared as a singlet at 11.77–11.92 δ , while, according to the literature [13], the presence of an intramolecular hydrogen bond renders the benzamido NH 2 protons diastereotopic. H a is easily exchangeable with D 2 O and appeared as a singlet at 8.24–8.44 δ .…”

“…Colchicine 18 , whose antileukemic activity is well known, and the 2-cinnamamidobenzamide 4 [13] (Fig. 1), were used as reference compounds.…”

Synthesis and Biological Evaluation of Quinazoline-4-thiones

“…Efficient methods for synthesis of quinazolin-4-ones are e.g. acylation of 2-aminobenzamides with an appropriate acyl chloride followed by cyclization in basic medium [ 39 ], or one-pot synthesis under solvent-free conditions [ 40 ]. Derivatives of 2,2-dimethyl-1,2-dihydroquinazoline-4(3 H )-thione can be prepared by condensation of 2-aminothiobenzamides with acetone under mild conditions [ 41 ].…”

One‐Pot Copper(I)‐Catalyzed Synthesis of 2‐Aryl‐quinazolin‐4(3 H )‐ones via N‐ benzylation / C sp3 – H Oxidation/ CN Hydrolysis/Cyclization

“…Literature illustrates that formation of required quinazolin‐4(3 H )‐ones is accompanied by the occurrence of aminal intermediate or dihydrogenated quinazolinones as side products, and sometimes dihydrogenated quinazolinone have been isolated as the main product . Among the diverse protocols used for the synthesis of these heterocyclic scaffolds, intramolecular cyclization of amides is rarely utilized due to the intricacy in preparation of starting amides via traditional methods, poor reactivity of amides, and unproductive cyclizations with an array of nucloephiles.…”

Synthesis, antiproliferative activity, and mechanism of action of a series of 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides

“…They showed signals attributable to the β-olefinic protons at 6.66–6.97 δ with coupling constants of 16.6–14.7 Hz, as required for E -structures [12], while the α-olefinic hydrogens were found along with aromatic multiplets. Moreover, their 1 H NMR spectra showed both the NH and NH 2 amidic signals; the cinnamamido NH proton appeared as a singlet at 11.77–11.92 δ , while, according to the literature [13], the presence of an intramolecular hydrogen bond renders the benzamido NH 2 protons diastereotopic. H a is easily exchangeable with D 2 O and appeared as a singlet at 8.24–8.44 δ .…”

“…Colchicine 18 , whose antileukemic activity is well known, and the 2-cinnamamidobenzamide 4 [13] (Fig. 1), were used as reference compounds.…”

Synthesis and Biological Evaluation of Quinazoline-4-thiones

“…Efficient methods for synthesis of quinazolin-4-ones are e.g. acylation of 2-aminobenzamides with an appropriate acyl chloride followed by cyclization in basic medium [ 39 ], or one-pot synthesis under solvent-free conditions [ 40 ]. Derivatives of 2,2-dimethyl-1,2-dihydroquinazoline-4(3 H )-thione can be prepared by condensation of 2-aminothiobenzamides with acetone under mild conditions [ 41 ].…”

One‐Pot Copper(I)‐Catalyzed Synthesis of 2‐Aryl‐quinazolin‐4(3 H )‐ones via N‐ benzylation / C sp3 – H Oxidation/ CN Hydrolysis/Cyclization

“…Literature illustrates that formation of required quinazolin‐4(3 H )‐ones is accompanied by the occurrence of aminal intermediate or dihydrogenated quinazolinones as side products, and sometimes dihydrogenated quinazolinone have been isolated as the main product . Among the diverse protocols used for the synthesis of these heterocyclic scaffolds, intramolecular cyclization of amides is rarely utilized due to the intricacy in preparation of starting amides via traditional methods, poor reactivity of amides, and unproductive cyclizations with an array of nucloephiles.…”