Synthesis of New 3-Substituted Quinazolin-4(3H)-one Compounds Via Linking of Some Five-Membered Ring Heterocyclic Moieties with Quinazolin-4(3H)-one Nucleus

In this research new compounds containing quinazolin-4(3H)-one nucleus linked to heterocyclic moieties were synthesized using ethyl (4'-oxoquinazolin-3'-yl) acetate (2) as a synthon. This compound was synthesized via 4-quinazolinone's (1) reaction with ethyl chloroacetate in the existence of K2CO3 as a base and acetone as a solvent. The ethyl α-(4'-oxoquinazolin-3'-yl) acetate (2) was converted to the corresponding hydrazide through its reaction with hydrazine hydrate (85 %). Compound (3) was reacted with two of acyl chlorides to synthesize the diacyl hydrazine compounds (4,5). The compound (5) was cyclized to the corresponding 1,3,4-oxadiazole (6) in presence of phosphorous oxychloride. The formyl derivative (7) of the hydrazide (3) was synthesized via its reaction with formic acid and consequently cyclized by phosphorous oxychloride to the corresponding 1,3,4-oxadiazole (8). The hydrazide (3) was also converted to the thiosemicarbazide derivative (9) by its reaction with ammonium thiocyanate under acidic conditions. Whereas other substituted thiosemicarbazide derivatives (10-12) were synthesized by the reaction of hydrazide (3) with organic isothiocyanate compounds. The resultant compounds (11, 12) were cyclized under basic conditions (4% sodium hydroxide solution) to give 1,3,4-triazole-2-thiole derivatives (13,14), whereas the cyclization of compounds (10-12) was performed under the acidic medium (conc. H2SO4) to give 2substituted amino-1,3,4-thiadiazoles (15-17). On the other side, the hydrazide's (3) reaction with isocyanate compounds affords the semicarbazide compounds (18,19). These compounds were cyclized under the basic condition to afford 1,3,4-triazol-2-ol compounds (20,21). The structures of the synthesized compounds were corroborated depending on the physical and spectral data. keywords: quinazolinone; oxadiazole; thiadiazole; triazole; carbohydrazide. تابكرم ريضحت 3 نيلوزانيوك ضوعم -(3H)4طبر ربع ةديدج نوا ريغ ةقلحلا ةيسامخ عيماجملا ضعب نيلوزانيوكلا ةاون عم ةسناجتملا -(3H)4نوا 1 * و يقا رعلا دمحا دمحم 2 نيدلادعس دشرا دنر 1 * قا رعلا ,لصوملا ,لصوملا ةعماج ,مولعلا ةيلك ,ءايميكلا مسق 2 ا رعلا ,لصوملا ,لصوملا ةعماج ,تانبلل ةيبرتلا ةيلك ,ءايميكلا مسق ق Journal of Education and Science (ISSN 1812-125X), Vol: 30, No: 1, 2021 (158-172) Downloaded from https://edusj.mosuljournals.com/ 159 ةصلاخلا ي ت نيلوزانيوكلا ةاون ىلع يوتحت ةديدج تابكرم ريضحت ثحبلا نمض -(3H)4مادختساب ةسناجتم ريغ ةيقلح عيماجمب ةطبترم نوأ α ( -'4 نيلوزانيوكوسكوا -3'ةيلوا ةًدام ليثلأا تلاخ)لي ًً (2) نيلوزانيوكلا لعافت ربع بكرملا اذه رضح . -(3H)4نوأ (1) عم ةًدعاق مويساتوبلا تانوبراك دوجوب ليثلأا تلاخ ورولك و .اًبيذم نوتيسلاا ـلا بكرم لِّ وحُ α ( -'4 نيلوزانيوكوسكوا -3'ليثلأا تلاخ)لي لباقملا ديزا رديهلا ىلا (3) يئاملا نيزا رديهلا عم هلعافت للاخ نم (85%) . ديزا رديهلا مدختسا (3) ةديدج ةعومجم ريضحتل ةيلوا ةًدام نم ةاون ةنمضتملا تابكرملا نيلوزانيوكلا -(3H)4نوأ ديزا رديهلا ل ِّ خداُ .ةسناجتم ريغ ةيقلح عيماجمب ةطبترملا (3) يبكرم عم لًاعافت نيزا رديه ليسأ يئانثلا يبكرم ريضحتل ليسلأا ديرولك (4,5) بكرملا ةقلوح مت مث نمو ، (5) بكرم ىلا روفسفلا ديرولك يسكوأ دوجوب ـلا -4,3,1 داسكوا لوزايا .(6) ديزا رديهلا مدختسا امك (3) ديزا رديه ليمروفلا قتشم ريضحتل (7) ديرولك يسكوأ دوجوب قلوحتي يذلا ـلا ىلا روفسفلا -4,3,1 لوزاياداسكوأ (8) ديزا ريهلا ل وح كلذك . (3) ديزابراكيمسوياثلا بكرم ىلا (9) موينوملأا تانايسوياث عم هلعافتب رضح امنيب .ةيضماح فورظ تحت ديزابراكيمسوياثلا تاقتشم ت (10-12) ديزا رديهلا لعافتب (3) ةقلوح مت .ةيوضعلا تانايسوياثلا عم نيبكرملا (11,12) ( ةيدعاق فورظ تحت 4 نم % ـلا يبكرم نايطعيل )مويدوصلا ديسكورديه لولحم -4,3,1 لوزايا رت -2لوياث (13,14) تابكرملا قلوحتت امنيب (10-12) تابكرم يطعتل )زكرملا كيتيربكلا ضماح( ةيضماحلا فورظلا تحت -2 ضوعم ونيما -4,3,1ث لوزايادايا (15-17) ديزا رديهلا لعافتي ,ىرخا ةيحان نم . (3) ديزابراك يمسلا تابكرم يطعيل ةيوضعلا تانايسوزيلآا عم (18-19) ـلا تابكرم ىلا ةيدعاقلا فورظلا تحت قلوحتت يتلا -4,3,1 لوزايا رت -2لوا (20,21) اًدامتعا ةرضحملا تابكرملا بيكا رت تصخش . .ةيفيطلاو ةيئايزيفلا تانايبلا ىلع ةيحاتفملا تاملكلا : نونيلوزانيوكلا ؛لوزاياداسكوا ؛ ؛لوزاياداياث لوزايا رت ؛ ديزا رديهوبراك . INTRODUCTION There is a huge number of biologically active compounds that contains a heterocyclic core possessing various heteroatoms such as nitrogen, oxygen and sulfur. The biological importance of these compounds has drawn the attention of the chemists to synthesize interesting new derivatives containing heterocyclic moieties in order to improve their biological activity. Among these heterocyclic compounds is 4-quinazolinones which are of great heed owing to their discrete and wide biological activity and their importance in the pharmacological and medicinal fields, in addition to their diverse chemical applications. It has been found that the 4-quinazolinones own a broad spectrum of activity exemplified as anticancer [1-3], antifungal [4,5], antitumor [6-8], antipsychotic [9], antimicrobial [10], antioxidant [11,12], anti-HIV [14,15], anti-inflammatory and analgesic [16], antihypertensive [17] and anticonvulsant [18]. Furthermore, they were considered a fundamental part of many natural alkaloids [19,20]. On the other hand, it was found that many heterocyclic nuclei other than quinazoline-4(3H)-ones such as 1,3,4-oxadizole, 1,3,4-thiadiazole, and 1,3,4-triazole showed biological importance [21-23]. Because of the increase of the biological importance of the quinazoline-4(3H)-one derivatives, new quinazoline-4(3H)-one compounds were synthesized via linking of quinazoline-4(3H)-one nucleus with heterocyclic moieties at position 3 through a series of intermediates using ethyl α-(4'-oxoquinazolin-3-yl)acetate as a synthon.


EXPERIMENTAL
Open capillary tubes were used to measure the melting points by Stuard-SMP30 melting point device. Microwave irradiation was performed by microwave oven with power output 900 W. Infrared spectra were recorded as neat on Alfa Bruker ATR-FT.IR Co. Germany, 2003. Bruker Bio Spin 400 MHz spectrometer was used to record the 1 H and 13 C NMR spectra, using the deuterated DMSO as a solvent and TMS as an internal reference.

Synthesis of diacyl hydrazine compounds (4,5) [27]:
An acyl chloride (0.005 mole) was added slowly to a previously cooled and stirred solution of the hydrazide (3) (0.005 mole, 1.09 g) in dry pyridine (20 ml). After the completion of the addition, refluxing the mixture with stirring for (4 h) was carried out then the mixture was poured on ice-cooled water (50 ml), followed by neutralization with NaHCO3 (10%). The resultant mixture was filtrated and the remaining solid material was washed thoroughly with water, then ethanol was used to recrystallize the products. The physical data of compounds 4,5 are listed in Table 1.

Journal of Education and Science
The essential intermediate for the preparation of diverse heterocyclic compounds is the carbohydrazide derivative (3) of the quinazolin-4-(3H)-one (1). The carbohydrazide compound (3) was synthesized from the corresponding ester (2). The first synthetic step is the synthesis of quinazolin-4-(3H)-one (1) as starting material according to our previous paper [24] from the reaction of anthranilic acid (0.1 mole) with formamide (0.5 mole), either by irradiation of the reaction mixture with microwave irradiation (green method) or by the conventional method. The quinazolin-4-(3H)-one (1) was converted to the corresponding ester (2) via alkylation process using ethyl chloroacetate in dried acetone in the existence of K2CO3 as an alkali material. The alkylation occurred at the nitrogen-3 rather than oxygen as identified from the spectral data. The appearance of characteristic spectral bands in the infrared spectrum at 1718 and 1679 cm -1 for the esteric and amido carbonyl (C=O) bond stretching respectively, supported the alkylation at N-3 position, and not at the oxygen of the quinazolinone moiety. Moreover, the infrared spectrum [34,35] of the ester (2) (Fig. 1) exhibited further bands at 1606 cm -1 for the aromatic C=C bond stretching and at 1160 and 1234 cm -1 related to the symmetrical and asymmetrical C-O bond stretching.   The 13 CNMR spectrum (Fig. 3) [35,36] showed the following chemical shifts, δ(ppm) at: 14 The ester (2) was used to synthesize the hydrazide compound (3) and the later compound was considered as a precursor to synthesize the new heterocyclic compounds. The hydrazide (3) was synthesized from the reaction of the ester (2) with hydrazine hydrate (85%). The (IR, 1 HMNR, 13 CNMR) [35][36][37] spectral information was used to confirm the structure of hydrazide compound (3). The infrared spectrum (Fig. 4) exhibited two bands at (1675 and 1652) cm -1 related to C=O bond stretching for the amido and hydrazido carbonyl groups respectively. It is worth noting that the appearance of bands at 3287 and 3147 cm -1 related to the amino & amido N-H bond stretching and the disappearance of the band at 1718 cm -1 for the esteric carbonyl bond stretching indicate the complete conversion of the ester (2) to the hydrazide (3).   The hydrazide (3) was used as a precursor to prepare a series of some new 4-quinazolinones through several synthetic routes. The first one involves the reaction of hydrazide )3( with benzoyl and p-toluoyl chloride to afford N,N'-diacyl hydrazine compounds (4&5) respectively. The compound (5) was treated with phosphorus oxychloride to produce 1,3,4-oxadiazole compound (6). The IR spectra of compounds (4&5) showed merging bands at 1664 & 1662 cm -1 for the carbonyl bond stretching and at 3230, 3232 cm -1 related to N-H bond stretching. The 1 H nuclear magnetic resonance spectrum (Fig.  7) of compound (4) showed the following chemical shifts, δ(ppm) at  The infrared spectrum of the derivative (6) exposed the lack of hydrazido carbonyl bond stretching and appearance of the absorption band at 1605 cm -1 for the combination of C=C and C=N bonds stretching and at 1073 and 1220 cm -1 related to the symmetrical and asymmetrical C-O bond stretching of the oxadiazole moiety in addition to the band at 1655 cm -1 for the carbonyl bond of quinazolinone moiety.
The second route involves the reaction of the hydrazide (3) with formic acid to form the formyl derivatives (7) of the hydrazide. The resultant compound (7) was cyclized in the presence of phosphoryl oxychloride to form the mono-substituted 1,3,4-oxadiazole compound (8). The infrared spectrum of (7) exposed merging bands at 1676 cm -1 for C=O bonds, in addition to aromatic bond stretching at 1606 cm -1 and absorption band and 1585 cm -1 related to combination C=N and C=C bonds stretching. The 1 H nuclear magnetic resonance spectrum (Fig. 8) of (7) exhibited the following chemical shifts δ(ppm), at  The structure of 1,3,4-oxadiazole compound (8) was confirmed from its IR spectrum which exposed a disappearance of absorption bands of the hydrazido carbonyl bond stretching and presence of absorption bands: at 1672 cm -1 related to the stretching of the quinazolinone C=O bond; at 1605 cm -1 for the stretching of the combination of C=C and C=N bonds and at 1036 cm -1 for stretching of the symmetrical C-O bond for the oxadiazole moiety.
The third route involves the reaction of hydrazide (3) with ammonium thiocyanate to synthesize the thiosemicarbazide derivative (9). This compound showed the following absorption bands in its IR spectrum at 3408, 3198 cm -1 for the primary and secondary N-H bond stretching respectively, at 1670 and 1655 cm -1 for the cyclic and acyclic amido C=O bond stretching and at 1167 cm -1 for the stretching of the C=S bond. The 1 H nuclear magnetic resonance spectrum for the derivative (9) showed the following chemical shifts δ(ppm), (Fig. 9)   The fourth route involves the reaction of the hydrazide (3) with organic isothiocyanates (allyl, pchlorophenyl, n-butyl-isothiocyanate) to synthesize 1,4-disubstituted thiosemicarbazides (10)(11)(12). These compounds were used as precursors to synthesis new heterocyclic compounds via two synthetic pathways. The first one is the cyclization of compounds (10&11) under basic condition (4% sodium hydroxide solution) to form the 1,3,4-triazol-2-thiol derivatives (13&14), while the second one is the cyclization of compounds (10-12) under acidic condition (concentrated H 2 SO 4 ) to prepare 2-monosubstituted amino-1,3,4-thiadiazole derivatives (15)(16)(17). IR spectra of compounds (10)(11)(12) (Table 7) shows absorption peaks: at 1676-1677 cm -1 due to quinazolinone carbonyl bond stretching, at 1653-1655 cm -1 due to hydrazido carbonyl bond stretching, at 1602-1612 cm -1 for the stretching of the combination of C=C and C=N bonds and 1193-1216 cm -1 for the C=S bond stretching. An additional absorption band for compound (11) appeared at 767 cm -1 related to C-Cl bond stretching. Downloaded from https://edusj.mosuljournals.com/ 169 The proton nuclear magnetic resonance spectrum of (12) showed the following chemical shifts δ(ppm), (Fig. 10)   The infrared spectra are recognized by the absence of the hydrazido carbonyl bond stretching and emersion of the following peaks: at 1670 cm -1 related to quinazolinone carbonyl bond stretching, at 1589,1600 cm -1 for the stretching of the combination of C=C and C=N bond, and at 1285,1249 cm -1 assigned to the stretching of the thione bond respectively. The compound (13) displays an additional band at 814 cm -1 related to the stretching of the C-Cl bond. The IR spectra (Fig. 11) of 1,3,4thiadiazoles (15)(16)(17) (Table 8) are recognized by the absence of the thiosemicarbazide C=O and C=S bond stretching and emersion of bands at 1664-1657 cm -1 related to quinazolinone C=O bond stretching, 1602-1607 cm -1 for the combination C=N and C=C bond stretching in addition to peaks at 690-702 cm -1 related to the C-S bond stretching.

Fig 11: IR spectrum of compound 17
The last route involves the reaction of the hydrazide (3) with an organic isocyanate compound to synthesize 4-(cyclohexyl / p-toluene sulfonyl) semicarbazide compounds (18,19). These compounds were cyclized under basic condition (4% sodium hydroxide solution) to afford the 1,3,4-triazoles (20,21). The IR spectra of the semicarbazide compounds (18, 19) exposed merging bands: at 1667, 1677 cm -1 for the C=O bonds, at 1608, 1616 cm -1 for the combination C=N and C=C bond stretching. The compound (19) showed additional two peaks at 1167 & 1355 cm -1 for the symmetrical and asymmetrical SO2 bond stretching. The proton nuclear magnetic resonance spectrum of (18) (Fig. 12) displayed the following chemical shifts δ(ppm), at: 1.14-  The IR spectra of the triazoles (20&21) exposed the disappearance of the peaks of the semicarbazide carbonyl bond stretching and appearance of the quinazolinone C=O bond stretching at 1676 and 1684 cm -1 respectively, in addition to the stretching of C=N bond of the triazole moiety at 1624 & 1625 cm -