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.
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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
42
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].
NH2
S
N
OMe
NHCOCH3
S
N
OMe
OMe
S
N
OMe
F
X
S
NR
Y O
MeO
n
N
N
O
H
A B C
D
H
N
O S
N
NH
O
Cl
Cl
E
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
Preparation of some benzo[d]thiazole derivatives from vanillin
43
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.
O
S
N O
HO
benzothiazole core
Aromatic hydrocarbon
Pharmacophore
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
1
H NMR and
13
C 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
Duong Quoc Hoan and Pham Thi Thuy Dinh
44
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.
1
H 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).
13
C
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).
13
C-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.
OH
S
N
OMe
SH
NH2
OH
OMe
OHC
OCH2COOEt
S
N
OMe
ClCH2COOEt
NaI, axeton
K2CO3
LiOH
MeOH
OCH2COOH
S
N
OMe
1
2
microware
3, 100%
4, 30%
5, 100%
Scheme 1. Synthesis of benzo[d]thiazole derivatives from vanillin
Preparation of some benzo[d]thiazole derivatives from vanillin
45
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
1
H 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
1
H NMR and
13
C NMR spectral analysis was considered only
during the change. The
1
H 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
13
C NMR spectrum showed a peak of carbon O-CH2-CO at 64.87 ppm, moreover, the peak at
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
1
H
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.
Duong Quoc Hoan and Pham Thi Thuy Dinh
46
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.
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