One-pot Three-component Synthesis of Novel Quinazoline-4-carboxylic Acid and Derivatives

D. Gök / Hacettepe J. Biol. & Chem., 2020, 48 (3), 283-290 Research Article Hacettepe Journal of Biology and Chemistry journal homepage: www.hjbc.hacettepe.edu.tr One-pot Three-component Synthesis of Novel Quinazoline-4-carboxylic Acid and Derivatives Aynı Ortamda Üç Bileşenli Yeni Kinazolin-4-karboksilik Asit ve Türevlerinin Sentezi Derviş Gök Depart. of Chemistry and Chemical Processing Technologies, Kutahya Technical Sciences Vocational School, Dumlupinar University, Kutahya, Turkey. ABSTRACT 2 -Phenyl-quinazoline-4-carboxylic acid (2) was synthesized from the one-pot three-component reaction of (2-aminophenyl)-oxo-acetic acid sodium salt obtained from the hydrolysis of isatin with ammonium acetate and benzaldehyde. Some novel quinazoline-ester derivatives (3a-d) were then obtained by the reaction between 2 and various alcohols. Finally, quinazoline-amide derivatives (5a-e) were synthesized from the reaction of various amines and 2-phenyl-quinazoline-4carbonyl chloride (4), obtained by the reaction of compound 2 with SOCl2. The structures of synthesized compounds were clarified by 1H NMR, 13C NMR, IR, mass spectrometry analysis methods. Key Words Quinazoline-4-carboxylic acid, isatin, ester, amide. ÖZ A monyum asetat ve benzaldehit ile isatinin hidrolizinden elde edilen (2-amino-fenil)-okso-asetik asit sodyum tuzunun aynı ortamda üç bileşenli reaksiyonundan 2-fenil-kinazolin-4-karboksilik asit (2) sentezlendi. Daha sonra 2 ve çeşitli alkoller arasındaki reaksiyonlarından bazı yeni kinazolin-ester türevleri (3a-d) elde edildi. Son olarak 2 bileşiği ile SOCl2’nin reaksiyonundan elde edilen 2-fenil-kinazolin-4-karbonil klorür ve çeşitli aminlerin reaksiyonundan kinazolin-amit türevleri (5a-e) sentezlendi. Sentezlenen bileşiklerin yapıları 1H NMR, 13C NMR, IR, kütle spektrometri analiz metotları tarafından doğrulandı. Anahtar Kelimeler Kinazolin-4-karboksilik asit, isatin, ester, amit. Article History: Nov 18, 2018; Revised Dec, 23 2019; Accepted: Jan 29, 2020; Available Online: May 3, 2020. DOI: https://doi.org/10.15671/hjbc.736847 Correspondence to: D. Gök, Department of Chemistry and Chemical Processing Technologies, Kutahya Technical Sciences Vocational School, Dumlupinar University, Kutahya, Turkey. E-Mail: 284 D. Gök / Hacettepe J. Biol. & Chem., 2020, 48 (3), 283-290 INTRODUCTION Q uinazoline and its derivatives are among the most important N-heterocyclic structures. The compounds containing the quinazoline ring both form the core structure of many natural products and exhibit useful biological activities such as anticancer [1], antimicrobial [2], anti-oxidant [3], antimalarial [4], anti-inflammatory [5], antiplasmodial [6], antiviral [7], anti-HIV [8], anticonvulsant [9], and anti-diabetic [10]. Bicyclic quinazoline ring constitutes the core structure of some drug molecules such as icotinib [11], lapatinib [12], and prazosin [13]. In addition, some compounds based on quinazoline are used as anticancer drugs such as erlotinib [14] and gefitinib [15]. Studies have shown that some quinazoline derivatives are a novel chiral fluorescent tubulin binding agent with highly potent antiproliferative properties against human cancer cells [16]. Furthermore, quinazoline derivatives are known to exhibit aurora a kinase inhibitor effect [17] and cytotoxic activity against human cancer cell [18]. Some of them also exhibit the inhibitory effect of epidermal growth factor receptor tyrosine kinase [19] and act as anti-cancer DNA binding alkaloids [20]. In the study of Seo et al., 3,4-dihydroquinazoline derivatives have been found to perform excellent T-type calcium channel blocking activity [21]. The above studies clearly demonstrate the importance of quinazoline derivatives. Their increasing importance has led to the development of different methods for their synthesis. Some reactions for their synthesis are aerobic oxidative coupling reactions of N-arylamidines with benzyl alcohol or aromatic aldehydes in air [22], cyclization and aromatization reactions of amidine hydrochlorides with methyl 2-halobenzoate, 2-halophenylketone, or 2-halobenzaldehyde derivatives [23], and cyclization reactions benzamidines and 2-bromobenzylbromides [24]. Different procedures have been developed for the synthesis of quinazolines such as photochemical methods [25], copper-catalyzed syntheses [26], reactions of urea maltose and ammonium chloride mixture [27], the use of microwave irradiation [28], and tandem reactions from benzylic amines and 2-aminobenzophenones [29]. The isatin compound was used as the starting compound in many reactions. It was also the starting compound of our reactions. It was hydrolyzed in alkaline medium to form (2-amino-phenyl)-oxo-acetic acid sodium salt. Quinazoline-4-carboxylic acid derivative was synthesized from one-pot three-component reaction of (2-amino-phenyl)-oxo-acetic acid sodium salt with ammonium acetate and benzaldehyde compounds. The literature review showed that the carboxyl group bound to the quinazoline ring was absent and that it was synthesized for the first time in our study. This paper reports the synthesis and characterization of some new quinazoline-4-carboxylic acid derivatives. Firstly, quinazoline-4-carboxylic acid sodium salt was synthesized via reactions between readily available benzaldehyde (2-amino-phenyl)-oxo-acetic acid sodium salt and ammonium acetate in ethanol under mild conditions without catalyst. Two mechanisms are proposed for this reaction where the quinazoline ring is formed [30]. The proposed mechanisms are shown in scheme 1. In the first reaction mechanism (path a), the condensation reaction of the aldehyde and 2-aminobenzophenone gives aldimine compound. The condensation reaction of ammonium acetate with this intermediate then gives diimine compound. The diimine compound is converted to the quinazoline compound by the cyclization reaction followed by aromatization reactions. In the other mechanism (path b), the condensation reaction of the aldehyde and ammonium acetate gives aldimine compound. Subsequent cyclization and aromatization reactions of 2-aminobenzophenone with this intermediate aldimine are converted to the quinazoline compound. The quinazoline compound formed in these two reaction mechanisms is obtained by air oxidation of the 1,2-dihydroquinazoline compound. As seen from the reaction mechanism, one of the two nitrogen atoms found in the quinazoline ring comes from the amine group of the hydrolysis isatin compound and the other is the reactant ammonium acetate. Since we used the sodium salt of the hydrolysis isatin compound in the quinazoline reaction, we obtained the quinazoline compound as the carboxylic acid salt (1). Then, when we acidified this carboxylic acid salt with HCl(aq), we converted to 2-phenyl-quinazoline-4carboxylic acid (2). The presence of the carboxyl group bound to the quinazoline ring then allowed the synthe- D. Gök / Hacettepe J. Biol. & Chem., 2020, 48 (3), 283-290 Schem (...truncated)