Synthesis of some derivatives containing both benzothiazole and benzoxazin-3-one

Abstract. Reaction of ethyl monochloro acetate and o-aminophenol derivatives gave two new benzo[b][1,4]oxazin-3(4H)-one containing benzo[d]thiazole ring with 2 methods in high yield. Structures of two benzo[b][1,4]oxazin-3(4H)-one based derivatives were elucidated with IR, 1D NMR, 2D NMR and MS spectra.

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11 HNUE JOURNAL OF SCIENCE DOI: 10.18173/2354-1059.2017-0049 Chemical and Biological Science 2017, Vol. 62, Issue 10, pp. 11-17 This paper is available online at SYNTHESIS OF SOME DERIVATIVES CONTAINING BOTH BENZOTHIAZOLE AND BENZOXAZIN-3-ONE Duong Quoc Hoan 1 , Le Ngoc Quan 1 and Vu Thi Thanh Thuy 2 1 Faculty of Chemistry, Hanoi National University of Education 2 Xuan Truong High School, Hanh Thien, Xuan Hong, Xuan Truong, Nam Dinh Abstract. Reaction of ethyl monochloro acetate and o-aminophenol derivatives gave two new benzo[b][1,4]oxazin-3(4H)-one containing benzo[d]thiazole ring with 2 methods in high yield. Structures of two benzo[b][1,4]oxazin-3(4H)-one based derivatives were elucidated with IR, 1D NMR, 2D NMR and MS spectra. Keywords: Oxazin, vanillin, o-aminophenol, benzo[d]thiazole, benzo[b][1,4]oxazin- 3(4H)-one. 1. Introduction Benzoxazine based compounds play an important in various agrochemicals [2]. In addition, 2H-1,4-benzoxazin-3-(4H)-one derivatives are known to possess useful biological and medicinal properties (Figure 1). The compound 2 is one of potential antibacterial agents and also is known as an inhibitor of bacterial histidine protein kinase [3]. Figure 1. Some examples of important benzo[b][1,4]oxazin-3(4H)-one scaffolds Similarly, Kikelj et al. found that the 2-methyl-3-oxo-3,4-dihydro-2H-1,4- benzoxazine-2- carboxylic acid 1 is a potent immunostimulant [4]. The compound 3 possesses D2 receptor antagonistic activity and is a potential antipsychotic agent [5]. Received September 25, 2017. Revised November 22, 2017. Accepted November 29, 2017. Contact Duong Quoc Hoan, e-mail address: Duong Quoc Hoan, Le Ngoc Quan and Vu Thi Thanh Thuy 12 Compound 4 exhibits microbiostatic properties having MFC values higher than the corresponding MICs. Moreover, the molecules containing benzoxazin-3(4H)-one moieties exhibited other activities, such as anti-inflammatory [7] antiulcer [8] antipyretic [9] antihypertensive [10] antifungal [11] potassium channel modulators [12] antirheumatic agents [13] and plant resistance factors against microbial diseases and insects [14]. Some of the other important benzoxazin-3(4H)-one derivatives have been described in the recent review [15, 16]. In addition, benzo[d]thiazole derivatives also give many useful bioactivities. They worked as fluorogenic substrates for the detection of nitroreductase and aminopeptidase activity in clinically important bacteria [17]; anticancer, antimicrobial, anticonvulsant, antidiabetic, antitubercular, antiviral, anti-inflammatory, antileishmanial, antioxidant activities [18]. The combination of benzo[d]thiazole and benzo[b][1,4]oxazin- 3(4H)-one has not been researched yet. Therefore, in this paper, synthesis of two benzo[b][1,4]oxazin-3(4H)-one derivatives containing benzo[d]thiazole ring 5a and 5b was reported. 2. Content 2.1. Experiments * Tools and chemicals Solvents and other chemicals were purchased from Sigma-Aldrich, Merck were used as received, unless indicated. The 1 H NMR and 13 C NMR spectra were recorded on the Bruker Avance 500 NMR spectrometer in DMSO. Chemical-shift data for each signal was reported in ppm units. Mass spectra were obtained from Mass Spectrometry Facility of The Vietnam Academy of Science and Technology on LC-MSD-Trap-SL spectrometer. IR spectra were recorded on the Mattson 4020 GALAXY Series FT-IR. * Synthetic procedure Synthesis of 5-nitrovanillin (2a) [19] Concentrated HNO3 (2 mL) was carefully added to a cooled (5 °C) solution of vanillin (5 g, 33 mmol) and acetic acid (50 mL) over a period of 30 min. The gold colored precipitate that formed was filtered, washed with water, and allowed to dry (5.21 g, 80%), mp. = 171 °C. Synthesis of 4-hydroxy-3-nitrobenzaldehyde (2b) Following the procedure of 2a, using 4-hydroxybenzaldehyde (4.0 g, 33 mmol), HNO3 (2 mL) and acetic acid (50 mL) gave 2b as a pale gold powder (4.4 g, 80%), mp. 194 °C. Synthesis of 4-(benzo[d]thiazol-2-yl)-2-methoxy-6-nitrophenol (3a) [19] 4-Hydroxy-3-methoxy-5-nitrobenzaldehyde (2a, 0.55 g, 3.3 mmol) and 2- aminothiophenol (0.35 mL, 3.3 mmol) were mixed well in an 100 mL beaker. The resulting mixture was irradiated with a domestic microwave oven for 4 minutes at 400 W power level. The mixture was stood for cooling down at room temperature and solidifying. The by re-crystallization from hot ethyl acetate/n-hexane (1:1) yielded the title compound 3a as a pale pink solid (0.98 g, 98%, 302.3 g/mol), mp. = 163 °C. Synthesis of some derivatives containing both benzothiazole and benzoxazin-3-one 13 Synthesis of 4-(benzo[d]thiazol-2-yl)-2-nitrophenol (3b) Following the procedure of 3a, using 4-hydroxy-3-nitrobenzaldehyde (2b, 0.44 g, 3.3 mmol) and 2-aminothiophenol (0.35 mL, 3.3 mmol) yielded the title compound 3b as a pale yellow solid (0.85 g, 95%, 272 g/mol). Synthesis of 2-amino-4-(benzo[d]thiazol-2-yl)-6-methoxyphenol hydrochloride (4a)[19] Iron powder (8.0 g, 0.14 mol) was added portion wise with stirring to a hot mixture of 4-(benzo[d]thiazol-2-yl)-2-methoxy-6-nitrophenol (3a) (6.4 g, 20 mmol) in ethanol (20 mL) and concentrated hydrochloric acid (30 mL) at reflux temperature. After completion of the addition, the refluxing was continued for 6 hours. Upon cooling a yellow precipitate formed, which was filtered off, washed with absolute ethanol, dried to yield the title product 4a as a yellow powder (5.6 g, 95%, 308.8 g/mol) mp: decomposed at 280 °C. Synthesis of 2-amino-4-(benzo[d]thiazol-2-yl)phenol hydrochloride (4b) Following the procedure of 4a, iron powder (8 g, 0.14mol), 4-(benzo[d]thiazol-2-yl)- yl)-2-nitrophenol (3b) (5.44 g, 20mmol) in ethanol (40 mL) and concentrated hydrochloric acid (40 mL) gave a greyish yellow precipitate 4b (5.56 g, 95%, 278.5 g/mol), mp: decomposed at 262 °C. Synthesis of 6-(benzo[d]thiazol-2-yl)-8-methoxy-2H-benzo[b][1,4]oxazin-3(4H)-one (5a) Method 1: To a mixture of potassium carbonate (303 mg, 2.2 mmol), ethyl monochloroacetate (0.14 mL, 1.25 mmol, d = 1.145 g/mL, 122 g/mol ), NaI (0.15 g, 1 mmol) was added into a round bottom flask containing 2-amino-4-(benzo[d]thiazol-2-yl)- 6-methoxyphenol hydrochloride (4a, 308 mg, 1.0 mmol, 308g/mol) in acetone (10 mL). The resulting solution was refluxed for 6 hour. The progress of reaction was monitored with TLC (eluent: ethyl acetate/n-hexane: 1/2, v/v). After filtration, the mother liquid was concentrated in vacuo. The residue was re-crystallized in 96% ethanol to give 5a (234 mg, 75 %, 312 g/mol) a white solid, mp. 162 °C. Method 2: To a mixture of ethyl monochloroacetate (0.14 mL, 1.25 mmol, d = 1.145 g/mL, 122 g/mol), 2-amino-4-(benzo[d]thiazol-2-yl)-6-methoxyphenol hydrochloride (4a, 308 mg, 1.0 mmol, 308g/mol) in DMF (3 mL) and triethylamine (0.35 mL, 2.5 mmol, 101 g/mol, d = 0.725 g/mL) was stirred and warmed up at 50 C for 4 h. The progress of reaction was monitored with TLC (eluent: ethyl acetate/ n-hexane:1/2, v/v). The mixture then was diluted with water (10 mL) and cooled down in an ice bath for 10 min. The solid was collected and re-crystallized 96% ethanol to give 5a (250 mg, 80 %, 312 g/mol) a white solid. IR (KBr, cm -1 ): 3320, 3090, 2879, 1703, 1600, 1540, 1416, 1021, 890; 1 H NMR (DMSO, 500 MHz)  (ppm): 8.03 (d, J = 8.0 Hz, 1H, H2), 7.44 (td, J = 0.5, 8.0, 1H, H3), 7.53 (td, J = 0.5, 7.5 Hz, 1H, H4), 8.11 (d, J = 8.0, 1H, H5), 7.29 (d, J = 1.5 Hz, 1H, H9), 7.34 (d, J = 1.5 Hz, 1H, H13), 3.90 (s, 3H, H16), 4.65 (s, 2H, H15), 10.84 (s, 1H, H(NH)); 13 C NMR (DMSO, 125 MHz)  (ppm): 134.3 (C1), 122.2 (C2), 125.3 (C3), 126.6 (C4), 122.6 (C5), 153.5 (C6), 166.6 (C7), 126.8 (C8), 105.4 (C9), 148.7 (C10), 134.9 (C11), 128.5 (C12), 107.4 (C13), 66.7(C15), 164.5 (C14), 56.0 (C16); MS (ESI): calcd. for [M+H] + , [C16H13N2O3S] + 313, found 313; calcd. for [M-H] - , [C16H11N2O3S] - , 311, found 311. Duong Quoc Hoan, Le Ngoc Quan and Vu Thi Thanh Thuy 14 Synthesis of 6-(benzo[d]thiazol-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (5b) Following the procedure of 5a (method 2), using ethyl monochloroacetate (0.14 mL, 1.25 mmol, d = 1.145 g/mL, 122 g/mol), 2-amino-4-(benzo[d]thiazol-2-yl)phenol hydrochloride (4b, 280 mg, 1 mmol, 278 g/mol) in DMF (3 mL) and triethylamine (0.35 mL, 2.5 mmol, 101 g/mol, d = 0.725 g/mL) gave 5b as a white powder (191 mg, 68%, 282 g/mol), mp. 210 °C; IR (KBr, cm -1 ): 3310, 3087, 2900, 1872, 1700, 1605, 1540, 1406, 1022, 887; 1 H NMR (DMSO, 500 MHz)  (ppm): 10.90 (s, 1H, H(NH)), 8.13 (d, J = 7.5 Hz, 1 H, H2), 8.02 (d, J = 8.5 Hz, 1H, H5), 7.70 (d, J = 1.5 Hz, 1H), 7.63 ( dd, J = 1.5, 8.5 Hz, 1H, H9), 7.53 (td, J = 1.5, 8.5 Hz, H4), 7.45 (td, J = 1.5, 8.5 Hz, 1 H, H9), 7.12 (d, J = 8.5Hz, 1H, H10), 4.69 (s, 2H, H15); 13 C NMR (DMSO, 125 MHz)  (ppm): 166.4, 164.2, 153.5, 145.7, 134.2, 127.8, 127.1, 126.5, 125.2, 122.5, 122.4, 122.1, 116.8, 114.0, 66.73; MS (ESI): calcd. for [M+H] + , [C15H11N2O2S] + 283, found 283; calcd. for [M-H] - , [C15H9N2O2S] - , 281, found 281. 2.2. Results and discussion Compounds 1a,b  4a,b were prepared in high yield, Scheme 1 [19]. Compound 5a was prepared following 2 methods. These methods gave quite the same yield about 75  80 %; however, method 1 took longer time (6 h) and more chemicals such as sodium iodide, potassium carbonate meanwhile the second method using triethylamine instead and limit amount of N,N-dimethylformamide (DMF). The solvent change helped shorten time of reaction in the method 2. The observation might be a result of the solubility of organic base-triethylamine and starting materials in DMF. Take the advantages of the method 2, compound 5b was also prepared in good yield. Scheme 1. Synthesis of the target compounds Mechanism of the cyclization of the benzo[b][1,4]oxazin-3(4H)-ones was suggested by Sharifi et al. [21]. In our cases, arylamonium hydrochloride I was reacted with base to form o-amino phenolate II that was a good O-nucleophile to replace chloride following the mechanism of SN2 forming ester III. Intramolecular cyclization happened when the amino group as a nucleophile attacked the carbonyl group (>C=O) following AN(C=O) mechanism, then followed by ethanol elimination giving product (Scheme 2). Synthesis of some derivatives containing both benzothiazole and benzoxazin-3-one 15 Scheme 2. Suggested mechanism of benzo[b][1,4]oxazin-3(4H)-one Structures of compounds 5a and 5b were elucidated by IR, 1D NMR, 2D NMR and MS spectra [20]. Both IR spectra of 5a and 5b showed the stretching vibration of N-H bond at 3300 cm -1 and vibration of >C=O bond at 1700 cm -1 . They were first two signals indicating the oxazin cyclyzation happened. Mass spectrum of 5a showed a base peak at m/z 313 au which was accordant with pseudo molecular weight M+H that agreed with molecular formula C16H12N2O3S. Similarly, mass spectrum of compound 5b gave a base peak at m/z 283 au which was assigned for pseudo molecular weight of M+H. Hence, molecular formula of 5b is C15H10N2O2S. Figure 2. HMBC part of compound 5a 1 H NMR spectrum of compound 5a showed 12 protons and 9 peaks, respectively. It was easy to assign three singlet peaks at 10.84 ppm for proton of –NH- group; 4.65 ppm for H15 and 3.90 ppm for H16. The 13 C NMR spectrum of compound 5a included 16 carbons peaks. Similar to 1 H NMR spectrum, the peak at 56.0 ppm and 66.6 ppm were indicated C16 and C15. However, the rest of protons and carbons were only assigned Duong Quoc Hoan, Le Ngoc Quan and Vu Thi Thanh Thuy 16 based on HSQC and HMBC spectral analysis. The 2D NMR analysis was shown in Figure 2. The benzo[d]thiazole ring was referred results of our group [19], therefore H2, H3, H4, H5, C1C7 were assigned accurately after had a check (see the experimental section and picture a in the Figure 2). H9 and H13 was distinguished because of cross peaks of H (>NH group) with C13 at 107.4 ppm then indicated H13 at 7.29 ppm, so the peak at 7.34 ppm was for H9 and the peak at 105.3 ppm on the 13 C NMR was for C9, respectively, picture b in Figure 2. The cross peak of proton of >NH group was used to identify C11 at 134.9 ppm. C10 was indicated by a cross peak of H16 with C10 at 148.7 ppm, picture b in the Figure 2. Similarly, structure of compound 5b was elucidated and showed in the experimental section. 3. Conclusion The cyclization forming benzo[b][1,4]oxazin-3(4H)-one was carried out with 2 methods. The method 2 using DMF and triethylamine was better in yield, time and workup. IR, MS, 1D and 2D NMR spectral analysis strongly agreed with the expected structures. REFERENCES [1] Xiao Tian, Li-Ying Wang, Shuai Xia, Zhu-Bo Li, Xing-Hui Liu, Yuan Yuan, Liang Fang, Hua Zuo, 2002. Synthesis of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as platelet aggregation inhibitors, Bioorganic & Medicinal Chemistry Letters., 22, pp. 204-206. [2] La, D. S.; Belzile, J.; Bready, J. V.; Coxon, A.; DeMelfi, T.; Doerr, N.; Estrada, J.; Flynn, J. C.; Flynn, S. R.; Graceffa, R. F.; Harriman, S. P.; Larrow, J. F.; Long, A. M.; Martin, M.W.; Morrison, M. J.; Patel, V. F.; Roveto, P. M.;Wang, L.;Weiss, M.W.; Whittington, D. A.; Teffera, Y.; Zhao, Z. Y.; Polverino, A. J.; Harmang, J. C., 2008. Novel 2,3-dihydro-1,4- benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis, J. Med. Chem., 51, pp. 1695-1705. [3] Frechette, R.; Weidner-Wells, M. A., 1997. WO Patent Appl. 9717333. [4] Kikelj, D.; Suhadolc, E.; Rutar, A.; Pecar, S.; Puncuh, A.; Urleb, U.; Leskovsek, V.; Marc, G.; Sollner Dolenc, M.; Krbavcic, A.; Sersa, G.; Novakovic, S.; Povsic, L.; Stalc, A., 1996. Eur. Pat. EP0695308. [5] Wise, L.D.; Wustrow, D.J.; Belliotti, T., 1997. WO Patent Appl. 9745419. [6] Tietze, L. F.; Beller, M.; Terfort, A.; Dolle, A., 1991. First Synthesis and Structural Determination of Blepharin and 1′-Epiblepharin, Synthesis, pp. 1118-1120. [7] Smid, P.; Coolen, H. K. A. C.; Keizer, H. G.; van Hes, R.; de Moes, J.-P.; den Hartog, A. P.; Stork, B.; Plekkenpol, R. H.; Niemann, L. C.; Stroomer, C. N. J.; Tulp, M. T. M.; van Stuivenberg, H. H.; McCreary, A. C.; Hesselink, M. B.; Herremans, A. H. J.; Kruse, C. G., 2005. Synthesis, Structure−Activity Relationships, and Biological Properties of 1- Heteroaryl-4-[ω-(1H-indol-3-yl)alkyl]piperazines, Novel Potential Antipsychotics Combining Potent Dopamine D2 Receptor Antagonism with Potent Serotonin Reuptake Inhibition, J. Med. Chem. 48, pp. 6855-6869. Synthesis of some derivatives containing both benzothiazole and benzoxazin-3-one 17 [8] Fringuelli, R.; Pietrella, D.; Schiaffella, F.; Guarraci, A.; Perito, S.; Bistoni, F.; Vecchiarelli, A., 2002. Anti-Candida albicans properties of novel benzoxazine analogues, Bioorg. Med. Chem., 10, pp.1681-1686. [9] Macchiarulo, A.; Costantino, G.; Fringuelli, D.; Vecchiarelli, A.; Schiaffella, F.; Fringuelli, R., 2002. 1,4-Benzothiazine and 1,4-benzoxazine imidazole derivatives with antifungal activity: a docking study, Bioorg. Med. Chem., 10, pp. 3415-3423. [10] Lanni, T. B., Jr.; Greene, K. L.; Kolz, C. N.; Para, K. S.; Visnick, M.; Mobley, J. L.; Dudley, D. T.; Baginski, T. J.; Liimatta, M. B., 2007. Design and synthesis of phenethyl benzo[1,4]oxazine-3-ones as potent inhibitors of PI3Kinaseγ, Bioorg. Med. Chem. Lett., 17, pp. 756-760. [11] Huang, M.-Z.; Huang, K.-L.; Ren, Y.-G.; Lei, M.-X.; Huang, L.; Hou, Z.-K.; Liu, A.-P.; Qu, X.-M. , 2005. Synthesis and Herbicidal Activity of 2-(7-Fluoro-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)isoindoline-1,3-diones, J. Agric. Food Chem., 53, pp. 7908-7914. [12] Anderluh, M.; Cesar, J.; Stefanic, P.; Kikelj, D.; Janes, D.; Murn, J.; Nadrah, K.; Tominc, M.; Addicks, E.; Giannis, A.; Stegnar, M.; Dolenc, M. S., 2005. Design and synthesis of novel platelet fibrinogen receptor antagonists with 2H-1,4-benzoxazine-3(4H)-one scaffold. A systematic study, Eur. J. Med. Chem., 40, pp. 25-49. [13] Scheunemann, M.; Sorger, D.; Kouznetsova, E.; Sabri, O.; Schliebs, R.; Wenzel, B.; Steinbach, J., 2007. Sequential ring-opening of trans-1,4-cyclohexadiene dioxide for an expedient modular approach to 6,7-disubstituted (±)-hexahydro-benzo[1,4]oxazin-3-ones, Tetrahedron Lett., 48, pp. 5497-5501. [14] Niemeyer, H. M., 2009. Hydroxamic acids derived from 2-hydroxy-2H-1,4-benzoxazin- 3(4H)-one: key defense chemicals of cereals, J. Agric. Food Chem., 57(5), pp. 1677-1696. [15] Ilas, J.; Anderluh, P. S.; Dolenc, M. S.; Kikelj, D., 2005. Recent advances in the synthesis of 2H-1,4-benzoxazin-3-(4H)-ones and 3,4-dihydro-2H-1,4-benzoxazines, Tetrahedron, 61, p. 7325. [16] Liang Fang, Hua Zuo, Zhu-Bo Li, Xiao-Yan He, Li-Ying Wang, Xiao Tian, Bao-Xiang Zhao, Jun-Ying Miao, Dong-Soo Shin, 2011. Synthesis of benzo[b][1,4]oxazin-3(4H)-ones via smiles rearrangement for antimicrobial activity, Med. Chem. Res. 20, pp. 670-677. [17] Marie Cellier, Olivier J. Fabrega, Elizabeth Fazackerley, Arthur L. James, Sylvain Orenga, John D. Perry, Vindhya L. Salwatura, Stephen P. Stanforth, 2011. 2-Arylbenzothiazole, benzoxazole and benzimidazole derivatives as fluorogenic substrates for the detection of nitroreductase and aminopeptidase activity in clinically important bacteria, Bioorganic & Medicinal Chemistry, 19, pp. 2903-2910. [18] Ruhi Ali and Nadeem Siddiqui, 2013. Biological Aspects of Emerging Benzothiazoles: A Short Review, Journal of Chemistry, pp. 1-12. [19] Duong Quoc Hoan, Vu Thi Anh Tuyet, Le Thanh Duong, Nguyen Hien, 2017. Preparation of some new benzo[d]thiazole derivatives, Vietnam Journal of Chemistry, International Edition, 55(4), pp. 433-437. [20] Silverstein, R. M.; Webster, F. X.; KiemLe, D. J., 2005. Spectrometric identification of organic compounds, John Wiley  Sons, Inc. [21] Ali Sharifi, Mehdi Barazandeh, M. Saeed Abaee, Mojtaba Mirzaei, 2010. [Omim][BF4], a green and recyclable ionic liquid medium for the one-pot chemoselective synthesis of benzoxazinones, Tetrahedron Lett. 51, pp. 1852-1855. 18
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