Synthesis of Novel 3H-Quinazolin-4-ones Containing Pyrazolinone, Pyrazole and Pyrimidinone Moieties

The diazonium salt of 3-(4-aminophenyl)-2-methyl-3H-quinazolin-4-one (2a) and its 6-bromo derivative 2b reacted with some active methylene compounds, namely ethyl acetoacetate (3), ethyl cyanoacetate (4) and acetylacetone (5), to afford the corresponding hydrazono quinazolinone derivatives 6-8. Treatment of 6a,b with hydrazine hydrate or phenyl hydrazine in refluxing ethanol afforded the corresponding pyrazolin-5-one derivatives of 3H-quinazolin-4-one 9a-d. Cyclization of 7a,b with hydrazine hydrate yielded the corresponding products 10a,b. Reaction of 8a,b with phenyl hydrazine or with urea afforded the corresponding derivatives 11a,b and 12a,b, respectively. Compounds 6-12 were identified by C,H,N analysis, IR, 1H-NMR, 13C-NMR and mass spectroscopy.

Compounds 6-8 were characterized by their elemental analysis, IR, 1 H-NMR, 13 C-NMR and MS data (see Experimental). For example, the IR spectrum of 6a shows an absorption band at 3431 cm -1 , corresponding to the vibration of the NH group, a band at 1773 cm -1 , characteristic of the carboxylic ester moiety, while bands at 1713 cm -1 1649 cm -1 correspond to the characteristic acetyl and for quinazolinone C=O groups, respectively.
Proton assignments in 1 H-NMR spectra for compounds 6-8, which are listed in the Experimental section, were made by 1   Hydrazono derivatives 6a,b were cyclized with hydrazine or phenyl hydrazine in boiling ethanol was expected to lead to the formation of the corresponding pyrazolin-5-one derivatives of 3Hquinazolin-4-one 9a-d (Scheme 2). The structures of the new compounds 9a-d were confirmed by analytical data, IR, 1 H-NMR, 13 C-NMR and mass spectra (see Experimental). Their IR spectra showed the disappearance of the characteristic bands of the acetyl carbonyl group and carboxylic acid ester and the appearance of strong bands in the 3325-3458 cm -1 region, attributed to NH group stretching and the bands of the quinazolinone and pyrazolinone ring C=O groups appearing at 1674 and 1680 cm -1 , respectively. The 1 H-NMR spectra of 9a-d showed the absence of the signals for the ethyl group, while the pyrazolinone CH 3 signal appeared at δ 2.52 -2.75 ppm. The 13 C-NMR of 9a, for example, confirmed the absence of the acetyl C=O and carboxylic acid ester groups and the appearance of two methyl group signal in the high field region. The other carbon atoms of quinazolinone, pyrazolinone and phenyl moieties all appeared at the expected chemical shifts (see Experimental). The structure of 9b was also confirmed by its mass spectrum, that shows molecular ion peaks (M + ) at m/z 439 (34.84 %, 79 Br) and m/z 441 (35.00 %, 81 Br).  Assignment of the structures of compounds 10a,b was obtained by elemental analysis and IR, 1 H-NMR and mass spectra. The IR spectra of 10a,b were characterized by the disappearance of the υ CN band and the appearance of a band at 3312 -3318 cm -1 attributed to the stretching vibration of the NH 2 group (see Experimental). Diagnostically important signals in the 1 H-NMR spectrum of 10a were two singlet signals at 9.72 and at 12.10 attributed to the two NH groups and a singlet at 5.05 -5.18 attributable to the NH 2 protons. As expected for the proposed structure, in the presence of deuterium oxide, the signals of the NH and NH 2 groups disappeared and the other signals not change.

General
Melting points were determined on an Electrothermal MEL-TEMP II melting point apparatus and are reported uncorrected. IR spectra were recorded on a Unicam SP 1200 spectrophotometer using KBr discs. 1 H-and 13 C-NMR spectra were recorded for DMSO-d6 solutions with a Bruker AC 250 FT spectrometer operating at 250 MHz for 1 H-and 62.9 MHz for 13 C-measurements. Chemical shifts are reported in ppm relative to tetramethylsilane. The mass spectral data were obtained with a Micro Spectrometer model 7070 at 70 eV and a 90 o C inlet temperature. All analytical samples were homogeneous by thin layer chromatography, which was performed on EM Silica gel 60 F 254 sheets (0.2 mm) using 5: 2 (v: v) chloroform -acetone or 3: 1 (v: v) petroleum ether -ethyl acetate as eluents. The spots were detected with a model UVGL-58 UV lamp. Elemental analyses were obtained from the Central Microanalysis Laboratory Service of Cairo University, Cairo, Egypt.
General procedure for the preparation of hydrazono derivatives 6-8 To an ice-cold mixture of the appropriate active methylene compound (ethyl acetoacetate, ethyl cyanoacetate or acetylacetone) (0.01 mole) and sodium acetate (4.10 g; 0.05 mole) in ethanol (50 mL), was added dropwise with stirring a solution of diazonium salt compound 2a or 2b (0.01 mole) over 15 minutes. The stirring was continued for 30 minutes and the reaction mixture then left for 2 hours at room temperature. The solid product was collected and recrystallized from ethanol to give the corresponding hydrazono derivatives 6-8. The following hydrazones were prepared in this manner:

General Procedures for the Cyclization Reactions Method A: With Hydrazine Hydrate
A mixture of the appropriate 6a,b or 7a,b (0.005 mole) and hydrazine hydrate (0.32 mL, 0.01 mole) in ethanol (30 mL) was heated under reflux for 4-6 hours. The solvent was concentrated and the reaction product was allowed to cool. The separated product was filtered off, washed with water, dried and recrystallized from ethanol. The following title compounds were prepared as just described:

Method B: With Phenyl Hydrazine
To a solution of the appropriate 6a,b or 8a,b (0.01 mole) in glacial acetic acid (30 mL) was added phenyl hydrazine (1.30 g, 0.012 mole) and anhydrous sodium acetate (0.82 g, 0.01 mole). The reaction mixture was heated under reflux for 4 hours. The mixture was poured into ice-cold water and stored in a refrigerator. The crude product, which separated, was washed with water, dried and recrystallized from methanol. The following title compounds were prepared as just described:

Method C: With Urea
A mixture of hydrazono derivatives 8a,b (0.005 mole) and urea (0.6 g, 0.01 mole) in ethanol (40 mL) was heated under reflux for 5 hours. After cooling to room temperature, crushed ice was added and the mixture was stirred for 1 hour. The separated product was collected by filtration and recrystallized from aqueous ethanol. The following title compounds were prepared as just described: