Preparation of some benzo[d]thiazole derivatives from vanillin

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Some new derivatives of vanillin containing benzo[d]thiazole ring have been synthesized successfully. A home microware was used to complete the reaction of vanillin and o-aminothiophenol without any solvents to generate benzo[d]thiazole[d]thiazole 3 for 4 min. in high yield.

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Nội dung Text: Preparation of some benzo[d]thiazole derivatives from vanillin

JOURNAL OF SCIENCE OF HNUE DOI: 10.18173/2354-1059.2016-0054 Natural Sci. 2016, Vol. 61, No. 9, pp. 42-47 This paper is available online at http://stdb.hnue.edu.vn PREPARATION OF SOME BENZO[d]THIAZOLE DERIVATIVES FROM VANILLIN Duong Quoc Hoan and Pham Thi Thuy Dinh Faculty of Chemistry, Hanoi National University of Education Abstract. Some new derivatives of vanillin containing benzo[d]thiazole ring have been synthesized successfully. A home microware was used to complete the reaction of vanillin and o-aminothiophenol without any solvents to generate benzo[d]thiazole[d]thiazole 3 for 4 min. in high yield. The Williamson ether synthesis gave an ester 4 followed by a hydrolysis to form a substituted acetic acid 5 containing a benzo[d]thiazole ring. All new compounds were screened on IR, NMR and MS spectra to analyze their structures. Keywords: Benzo[d]thiazole, microware, substituted acetic acid. 1. Introduction Benzo[d]thiazole ring was first synthesized from formic acid and o-aminothiphenol by Hofmann, A. W [1], in 1880. However, recently, the applications of the derivatives containing this ring have been studied extensively for anti-cancer activity. For example, amazingly, 2-(4-aminophenyl) benzothiazoles and their corresponding N-acetylated derivatives (Figures 1A and B) [2] have showed a remarkable anti-cancer activity against certain cancer cell lines particularly against: breast, colon and ovarian ones in vitro anti-cancer screening program of the National Cancer Institute (NCI). The anti-cancer activity of these molecules is assumed to be due to the formation of reactive intermediates that can bind covalently to DNA. Surprisingly, among an extended library of very close structural analogues, only a compound possessing a 2-(3,4-dimethoxyphenyl) group and a fluoro substituent in the benzo[d]thiazole ring, especially at the 5-position exhibited potent anti-cancer activity (Figure 1C). However, compounds with no substituent in the benzo[d]thiazole moiety retained sub-micromolar activity against certain cancer cell lines [3, 4]. OMe OMe OMe S S S NH2 NHCOCH3 OMe N N F N A B C N Cl S Y O H H X n N N R N MeO N NH Cl O S D O E O Figure 1. Some examples of benzo[d]thiazole derivatives Received October 4, 2016. Accepted November 3, 2016. Contact Duong Quoc Hoan, e-mail address: hoandq@hnue.edu.vn 42
Preparation of some benzo[d]thiazole derivatives from vanillin Studying bigger derivatives containing benzo[d]thiazole, Ahmed Kamal et al. reported a series of compounds like D, then tested their anti-cancer activity. The results showed that they were highly potent compounds for anti-cancer drug [5]. Masao Yoshida et al. showed that compound E had good selective cytotoxicity against a tumorigenic cell line, WI-38 VA-13, but no cytotoxicity against the normal parental cell line, WI-38 [3]. In this work, the target compound 5 has been designed combining the benzo[d]thiazole core that exhibited potent and selective cytotoxicity against a tumorigenic cell line, an aromatic hydrocarbon moiety binding to alphilatic moiety of DNA, and pharmacophore part for increasing hydrogen bonding ability (Figure 2). Hence, the designed compound 5 gives a hope for the chemistry. Aromatic hydrocarbon S O N O Pharmacophore O H benzothiazole core 5 Figure 2. Design of the target compound 2. Content 2.1. Experiment Solvents and other chemicals were purchased from Sigma-Aldrich, Merck were used as received, unless indicated. The 1H NMR and 13C NMR spectra were recorded on the Bruker Avance 500 NMR spectrometer in DMSO-d6. Chemical-shift data for each signal was reported in ppm units. IR spectra were recorded on the Mattson 4020 GALAXY Series FT-IR. Mass spectra were obtained on LC-MSD-Trap-SL spectrometer, from Mass Spectrometry Facility of the Vietnam Academy of Science and Technology. The 800W Sanyo, Thailand, home microware was used. 4-(benzo[d]thiazol-2-yl)-2-methoxyphenol (3)[6] Vanillin (0.5 g, 3.3 mmol) and 2-aminothiophenol (3.5 mL, 3.3 mmol) were mixed thoroughly in a 100 mL beaker. The mixture was radiated with microwave oven in medium mode (Sanyo, 800 watt) for 4 min. The progress of the reaction was monitored with the TLC. The crude product was removed from the oven and directly recrystallized from ethyl acetate/hexane to yield the pure 4-(benzo[d]thiazol-2-yl)-2-methoxyphenol (3) in  100 % yield. 1 H NMR (DMSO-d6, 500 MHz):  (ppm): 9.82 (s, 1H), 8.07 (d, J 7.5 Hz, 1H), 8.00 (d, J 8.5 Hz, 1H), 7.63 (d, J 2Hz, 1H), 7.50 (t, J 6.0 Hz, 2H), 7.40 (t, J 7.5 Hz, 1H), 6.94 (d, J 8.0 Hz, 1H), 3.90 (s, 3H). Ethyl 2-(4-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy) acetate (4) [7] Anhydrous K2CO3 (414 mg, 3 mmol) was added to a stirred solution of compound 3 (257 mg, 1 mmol) in acetone (10 mL) and stirred at ambient temperature for 30 min. Ethyl chloroacetate (2 mL, 2 mmol, 1.145 g/mL) was added. The reaction mixture was heated at 60 - 70 C. The progress of the reaction was monitored with the TLC. Then cooled to room temperature and filtered. The 43
Duong Quoc Hoan and Pham Thi Thuy Dinh insoluble residue was extracted with acetone (3 x 3 mL). The combined organic extracts were evaporated in vacuo and the crude was dissolved in sodium hydroxide and extracted with ethyl acetate. The organic layers were dried and evaporated to give ester 4 in 30 % yield. The aqueous layer was acidified to recover the starting material 3. IR (cm-1): 3100, 2973, 2818, 1742, 1581, 1476, 1272, 1143, 1001. 1H NMR (DMSO-d6, 500 MHz):  (ppm): 8.10 (d, J 8.0 Hz, 1H), 8.03 (d, J 8.0 Hz, 1H), 7.68 (s, 1H), 7.57 (d, J 8.0 Hz, 1H), 7.52 (t, J 7.5 Hz, 1H), 7.43 (t, J 7.5 Hz, 1H), 7.08 (d, J 8.5Hz, 1H), 4.79 (s, 2H), 4.16 (q, J 7 Hz, 2H), 3.92 (s, 3H), 1.20 (t, J 7 Hz, 3H). 13C NMR (DMSO-d6, 125 MHz)  (ppm): 168.15, 167.30, 153.53, 149.56, 149.24, 134.33, 126.62, 126.51, 125.19, 122.53, 122.15, 120.45, 113.54, 110.00, 64.87, 61.06, 55.75, 13.92. 2-(4-(Benzo[d]thiazol-2-yl)-2-methoxyphenoxy) acetic acid (5) To a solution of compound 4 (170 mg, 0.05 mmol) in MeOH/water (4/1, 10 mL) was added lithium hydroxide (6 mg, 0.25 mmol, 5 equivalent). The reaction mixture was stirred at reflux temperature. Work-up of the reaction involved acidifying to pH 4-5 with 5% HCl. The residue provided a title compound as a white-colored solid in nearly quantitative yield of (150 mg), mp. 168 C. IR (cm-1): 3500-3200 (br), 3100, 2924, 2849, 1723, 1596, 1519, 1260, 1140, 1004. 1H NMR (DMSO-d6, 500 MHz):  (ppm): 13,00 (br. 1H), 8.10 (d, J 7.5 Hz, 1H), 8.02 (d, J 8.0 Hz, 1H), 7.67 (s, 1H), 7.58 (d, J 8.0 Hz, 1H), 7.52 (t, J 7.5 Hz, 1H), 7.43 (t, J 7.5 Hz), 7.02 (d, J 8.5 Hz, 1H), 4.79 (s, 2H), 3.91 (s, 3H).13C-NMR (DMSO-d6, 125 MHz)  (ppm): 169.74, 167.04, 153.54, 149.96, 149.15, 134.29, 126.49, 126.15, 125.13, 122.48, 122.14, 120.61, 113.13, 109.91, 64.89, 55.70. MS: calcd. for [C16H13NO4S] 315.34, found –MS: 314.5; + MS = 316.6. 2.2. Results and discussion 2.2.1. Synthesis Synthesis of benzo[d]thiazole core 3 was carried out from o-aminothiophenol (1) and vanillin (2) using microware without any solvents. The mixture of these starting materials was heated every minute in the microware in a fume hood. The progress of the reaction was checked with TLC every minute. Surprisingly, it took four minutes to complete and helped quantitative yield become a good start for a long sequence of synthesis without further purification. OMe OHC OH OMe SH S ClCH2COOEt 2 OH NH2 microware N NaI, axeton 1 3,  100% K2CO3 OMe OMe S S LiOH OCH2COOH OCH2COOEt N MeOH N 5, 100% 4,  30% Scheme 1. Synthesis of benzo[d]thiazole derivatives from vanillin 44
Preparation of some benzo[d]thiazole derivatives from vanillin The nucleophile substitution of compound 3 and ethyl monochloro acetate was run (as procedure shown in ref. 7) to make compound 4 known as the Williamson ether synthesis. Unfortunately, the yield of the reaction was low and the starting material 3 was recovered to increase the product yield. A modification was made. The hydrolysis of compound 4 in basic condition gave good yield of the pure target product 5. 2.2.2. Structural determination Since these derivatives contained a nitrogen atom, the molecular weight must be an odd number, respectively [8]. Compound 5 was selected for MS method analysis by electro-spray ionization (ESI-FTICR- MS). It was C16H13NO4S. Compound 3 was first synthesized by Hofmann, A. W in 1880, however, recorded 1H NMR in this work to confirm its structure. Compound 3 had seven aromatic protons in the range of  8.07 ppm  6.94 ppm, and three others of methoxy group at  3.90 ppm. Especially, its 1H NMR showed a proton of phenolic group at  9.82 ppm. The result was compared with reported data by Mukhopadhyay, C [9]. The formation of compounds 4 and 5 did not affect much the benzo[d]thiazole core, therefore, the 1H NMR and 13C NMR spectral analysis was considered only during the change. The 1H NMR of compound 4 identified the appearance of five protons of the ethyl group at  4.17 ppm for methylene group as a quartet due to the splitting of methyl group, and another peak at  1.29 ppm as a triplet due to the splitting of methylene group. One of the most important peaks that belonged to protons of O-CH2-CO was at  4.79 ppm. Accordingly, the C NMR spectrum showed a peak of carbon O-CH2-CO at  64.87 ppm, moreover, the peak at  13 61.06 ppm belonged to O-CH2 carbon, and at  13.92 ppm for the CH3 group (see the experimental section). Since Acid 5 was a product of the hydrolysis reaction, the disappearance of ethoxy group was a good agreement to explain the formation of the target product. On the 1H NMR of compound 5, the peak at 13.00 ppm as a broad one agreed with the proton of OH group in the carboxylic group. Besides, two protons at  4.79 ppm were for O-CH2-CO group. This signal was a good agreement with that of carbon on the 13 C NMR spectrums at  64.89 ppm, (See Figure 3). The functional groups of compounds 4 and 5 were further elucidated by infrared spectroscopy method. Firstly, as shown above, the differences between the structures of compound 4 and 5 were the vibration of carbonyl of the ester and of carboxylic group. The vibration of carbonyl group in ester (1742 cm-1) was bigger than that of carboxylic group (1723 cm-1) [7]. Secondly, the proton of carboxylic had a broad band in range 3500 - 3200 cm-1, while ester did not. Therefore, the data of IR method matched with NMR spectral one, and all reaction happened as directed. 45
Duong Quoc Hoan and Pham Thi Thuy Dinh Figure 3. NMR spectra of the target compound 5 in DMSO-d6 3. Conclusion In conclusion, ethyl 2-(4-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy) acetate (4) and 2-(4- (benzo[d]thiazol-2-yl)-2-methoxyphenoxy) acetic acid (5) are new derivatives containing benzo[d]thiazole synthesized from vanillin. These structures were determined on IR, NMR and MS spectra. Using home microware in the synthesis of compound 3 took short time, and gave pure compound 3. The Williamson ether synthesis is being modified to increase the yield of compound 4. Anti-cancer against KB cell of compound 5 has been screening. REFERENCES [1] Hofmann, A. W. 1880. Uebereine Reihe aromatischer, den Senfölen und Sulfocyanaten isomerer Basen. Chemische Berichte, 13, 8-22. [2] Chung Y., Shin Y.-K., Zhan, C.-G., Lee, S., Cho H. 2004. Synthesis and evaluation of antitumor activity of 2- and 6-[(1,3-benzothiazol-2-yl)aminomethyl]-5,8-dimethoxy-1,4- naphthoquinone derivatives. Arch. Pharmacol. Res., 27, 893. [3] Yoshida M., Hayakawa I., Hayashi N., Agatsuma T., Oda Y., Tanzawa F., Iwasaki S., Koyama K., Furukawa H., Kurakata S., 2005. Synthesis and biological evaluation of benzothiazole derivatives as potent antitumor agents. Bioorg. Med. Chem. Lett., 15, 3328. 46
Preparation of some benzo[d]thiazole derivatives from vanillin [4] Caleta I., Kralj M., Branimir Bertosa B., Sanja Tomic S., Pavlovic G., Pavelic K., Karminski-Zamola G., 2009. Novel Cyano- and Amidinobenzothiazole Derivatives: Synthesis, Antitumor Evaluation, and X-ray and Quantitative Structure - Activity Relationship (QSAR) Analysis. J. Med. Chem., 52, 1744. [5] Kamal A. et al., 2010. Synthesis, DNA-binding ability and anticancer activity of benzothiazole/benzoxazole-pyrrolo[2,1-c][1,4]benzodiazepine conjugates. Bioorg. Med. Chem., 18, 4747-4761. [6] Hroch K., Benek O., Guest P., Aitken L., Soukup O., Janockova J., Musil K., Dohnal V., Dolezal R., Kuca K., Smith T. K., Gunn-Moore F., Musilek K., 2016. Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer’s disease treatment. Bioorg. Med. Chem. Lett., 26 (15), 3675-3678. [7] Duong Quoc Hoan, Dam Thi Uyen, Pham Thi Yen, Nguyen Hien, 2015. Synthesis and structure of some phenoxyacetic acid derivatives from curcumin and monocarbonyl curcumin analogs. Vietnam J. Chem. 53(6e1,2), 348-353. [8] Silverstein R. M., Webster F. X., Kiemle D. J., 2005. Spectrometric identification of organic compounds. John Wiley  Sons, Inc. [9] Mukhopadhyay C., Arup Datta A., 2007. A green method for the synthesis of 2- arylbenzothiazoles. Heterocycles, 71 (8), 1837-1842. 47