Synthesis and Spectral Characterization of Novel 2, 3-Disubstituted Quinazolin-4(3H) one Derivatives

New series of 2,3-disubstituted quinazolin-4(3H)one were synthesized via the reaction of the readily obtainable 2-thioxo-3-phenyl-quinazolin-4(3H)one 1 with ethyl chloroacetate followed by hydrazinolysis to afford the hydrazide 3 which allowed to react with different electrophilic reagents such as carbon disulphide, phenyl isothiocyanate, β-diketones, anhydrides, acrylonitrile, ethyl cinnamate, dimethyl acetylene dicarboxylate, aldehydes, arylidene malononitrile and lauroyl chloride. Some of the newly synthesized compounds showed promising anti-inflammatory activity.


Results and Discussion
In this investigation, Ethyl-2-(4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl thio)acetate 2 was obtained in fairly good yield upon treatment of quinazolin-2-thione derivative 1 with ethyl chloroacetate , in the presence of fused so dium acetate in refluxing ethanol. (Scheme 1) The structure of compound 2 was confirmed from the study of its spectral data (c.f. Exp.). The highest recorded peak at m/z = 340 (34.21%) represent the molecular ion peak.
In previous work [22], the reaction of ethyl S-(heteryl) thioglycollate with hydrazine in refluxing ethanol involves the elimination of this group and substituted by the hydrazine group. Mass fragmentation pattern of S-Alkylation product 2 3-Disubstituted Quinazolin-4(3H) One Derivatives When compound 2 was allowed to react with hydrazine hydrate afforded the 2-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-ylthio) acetohydrazide 3 which obtained via the nucleophilic nitrogen attack of the hydrazine moiety to the carbonyl group of the ester group through tetrahedral mechanism.
The structure of 3 was established through spectroscopic (IR, 1 HNMR and MS) beside the correct elemental analysis.
methyl thio]quinazolin-4(3H)one 4 was obtained in fairly good yield upon refluxing the hydrazide 3 with carbon disulphide in pyridine on water bath for 8hrs.The structure 4 was deduced from the correct analytical and spectroscopic data (IR, 1 HNMR). Full analysis for the mass spectrum of 4 shows the correct molecular ion peak at m/z = 368 (13.2%).The reaction is smoothly proceeded through tetrahedral pathway followed by 1,5-exo-trig cyclization to give 4. (Scheme 2)  In contrast, when the hydrazide 3 was treated with carbon disulphide in ethanolic potassium hydroxide, no combination was detected between the hydrazide 3 and the carbon disulphide and the solid separated was identified as the sulfur free compound which assigned as 3-phenyl-quinazolin-2,4(1H,3H)-dione5. This is may be due to the nucleophilic substitution reaction by the nucleophilic hydroxyl group at the C 2 position of the quinazolinone and the thiomethyl hydrazide group was knocked out via S N 2 aromatic mechanism. (Scheme 3) The structure 5 was confirmed from the study of the IR and mass spectrum together with chemical evidence and rigidly confirmed by m.p. comparison with that reported [23].
The EI fragmentation of the mass spectrum of compound 5 shows the radical cation peak at m/z = 238 (100%) which represent the molecular ion and the base peak. (c.f. Exp.) Furthermore, compelling evidence for the structure 5 is forthcoming from the preparation of authentic sample by the reaction of anthranilic acid with phenyl isocyanate in refluxing pyridine (Scheme 4). CO  Phenylisothiocyanate was added to the hydrazide 3 in boiling ethanol and yielded 1-[2-(4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl thio)acetyl]-4-phenyl thiosemicarbazide 6.
When the hydrazide 3 was allowed to react with phthalic anhydride in refluxing dioxane yielded N-

EI-MS of compound 7
The structure of 8 was confirmed from the correct analytical and spectroscopic data. No evidence for the formation of the phthalazine derivative 9 was detected, since, the IR spectrum of the product shows the carbonyl vibrational coupling bands at 1793 and 1738cm -1 together with υ C=O (quinazolinone) at 1684 cm -1 which agree well with the structure 8.(c.f.Exp.) The mass spectrum of 8 show the correct molecular ion peak at m/z = 456 (4.04 %) which upon loss of N-aminophthalimide radical afforded the base peak at m/z = 295 (100%).
Refluxing compound 3 with acrylonitrile in dioxane afforded 2-[2-(5-iminopyrazolidin-1-yl)-2-oxoethyl thio]-3phenylquinazolin-4(3H) one 10. The IR spectrum of 10 revealed the absence of the stretching absorption band for the nitrile group which indicates that the nitrile group involved in the cyclization process. The EI-MS is completely in accord with the assigned structure. (c.f. Exp.) Fusion of 3 with methylcinnamate on oil bath at 180 ᵒC yielded a crude solid product which triturated with ethanol to give 2-[2-oxo-2-(5-oxo-3-phenyl-Δ 3 pyrazolin-1-yl)ethyl thio]-3-phenylquinazolin-4(3H)one 11.The structure 11 was established by the spectroscopic and analytical data. 1 H-NMR spectrum of compound 11 (CDCl 3 ) lacked the signals attributable for ABX system -CH-CH 2 -which indicate the dehydrogenation during the reaction conditions. Ample evidence for the structure 11 is forthcoming from the analysis of the mass spectrum in which the highest recorded peak at m/z = 455 (64.9%) attributable for the M+1 radical cation.

Scheme 6
The reaction is smoothly proceeded through Michael addition followed by cyclization.

Scheme 7
The hydrazide 3 easily condensed with aromatic aldehydes such as salicylaldehyde, 2,6-dichlorobenzaldehyde and/or P-anisaldehyde in refluxing dioxane for 24hrs to give N'-Arylidene-2-(4-oxo-3-phenyl-3,4-dihydro-quinazolin-2yl thio) acetohydrazide 14a-c. The structure 14 was established from analytical and spectroscopic data. Furthermore, the mass spectra of 14a-c show the correct molecular ion peaks and The EI-MS fragmentation pattern in all cases were very close as the base peak at m/z = 295 (100%). (c.f. Exp.) Moreover, the 1 H-NMR spectra of compounds 14a and 14b showed two singlets for NH amide proton and two singlets for =CH olefinic proton, as well as, two singlets for -OH in case of 14a. This showed that compounds 14a and 14b were formed as a mixture of two geometrical (E-and Z-) isomers in which the E-isomers predominate.
The reaction of the hydrazide 3 with 3,4-dimethoxy α-cyano cinnamonitrile in refluxing pyridine for 8 hrs followed by acidification with ice cold hydrochloric acid yielded the anil derivative 14d as a mixture of E-and Zisomer and the pyrazolidine derivative 15 was not isolated. The IR spectrum of the product show the stretching absorption bands for υ NH at 3180cm -1 , υ CO at 1681 cm -1 and lack the absorption band for υ NH2 and υ C≡N which eliminate the assigned structure 15 and in accord with the proposed structure 14d. 1 H-NMR spectrum is another clue for the structure 14d.

Experimental
Melting points are measured on an electrothermal melting point apparatus. Elemental analyses were carried out at the microanalytical unit, Cairo Univeristy. The IR spectra were measured on a Unicam SP-1200 spectrometer using KBr Wafer technique. The 1 H-NMR spectra were measured in DMSO-d 6 on a Varian plus instrument (300MHz). Mass spectra were recorded on a shimadzu GC-MS QP-1000EX instrument operating at 70 ev.

General Procedure for the Reaction of Hydrazide 3
with Acetyl Acetone or Benzoyl Acetone; Formation of Pyrazol Derivative 13 A mixture of hydrazide 3 (0.65g, 0.002mol), acetyl acetone (0.2ml, 0.002mol) or benzoyl acetone (0.3g, 0.002mol) was refluxed in ethanol (50ml) for 7hrs. The reaction mixture was left overnight for slow evaporation. The solid product was collected, filtered off, dried and recrystallized from light petroleum and chloroform to give 13a and 13b respectively.