Synthesis, characterization, and antitumor activity of some novel S-functionalized benzo[d]thiazole-2-Thiol derivatives; Regioselective coupling to the-SH group

Article abstract of DOI:10.1515/znb-2018-0078

Several 2-substituted sulfanyl benzo[d]thiazoles were regioselectively synthesized by the reaction of benzo[d]thiazole-2-Thiol (1a) with a variety of reagents under different basic conditions. Some 2-(2,3-disubstituted propyl sulfanyl)benzo[d]thiazoles were obtained from 2-(allylthio)benzo[d]thiazole, which was prepared by the allylation of 1a with allyl bromide in the presence of sodium hydride in dry N,N-dimethylformamide. Reaction of 1a with various pyrazolyl-quinoxaline derivatives was also investigated. Better yields and shorter reaction time were achieved for the synthesis of some derivatives by using ultrasound irradiation. The structural elucidation of all compounds was based on both analytical and spectroscopic data. The newly synthesized compounds were tested in vitro for their antitumor activity against Ehrlich ascites carcinoma (EAC) cells grown in albino mice. Doxorubicin was used as a standard antitumor antibiotic, and some compounds showed half maximal inhibitory concentration (IC₅₀) in the range 40-68 μg mL^-1.

Full text of DOI:10.1515/znb-2018-0078

Z. Naturforsch. 2018; aop
ESlySnaytehdeRsamisa,dacnh*a, HraamcitdearMiz. aAbtdioelnH,aamnidd, SaawnstaintuAm. NoourreadcdtinivaintdyKohafdsijoamO.eBadahdah
novel S-functionalized benzo[d]thiazole-2-thiol derivatives;
regioselective coupling to the –SH group
https://doi.org/10.1515/znb-2018-0078
molecule known as an important vulcanization accelera-
tor in the rubber industry [1]. It was also used as a corro-
sion inhibitor for copper [2, 3], and AA 2024-T3 aluminum
alloys [4]. Recently, its role in promoting the performance
of electroless nickel plating baths was investigated, and
it was found to improve some physical properties such as
corrosion resistance and mechanical strength [5]. Some
benzo[d]thiazole-2-thiol derivatives are being widely
used in leather-processing operations for controlling the
growth of fungi and sulfate-reducing bacteria [6, 7] and
also as intermediates in the synthesis of cyanine dyes
modified by folic acid for use as breast cancer cell labels
[8]. Also benzo[d]thiazole-2-thiol is an important scaffold
known to be associated with several biological activities
[9–12]. Moreover, its 2-substituted sulfanyl derivatives have
shown many pharmacological and medicinal applications
such as antimicrobial, anti-inflammatory, antinociceptive,
antimycobacterial, anticonvulsant, antitumor, antituber-
cular, and analgesic acivity and as human cyclooxygenase
inhibitors [13–21].
Received April 20, 2018; accepted July 4, 2018
Abstract: Several 2-substituted sulfanyl benzo[d]thia-
zoles were regioselectively synthesized by the reaction
of benzo[d]thiazole-2-thiol (1a) with a variety of reagents
under different basic conditions. Some 2-(2,3-disubsti-
tuted propyl sulfanyl)benzo[d]thiazoles were obtained
from 2-(allylthio)benzo[d]thiazole, which was prepared by
the allylation of 1a with allyl bromide in the presence of
sodium hydride in dry N,N-dimethylformamide. Reaction
of 1a with various pyrazolyl-quinoxaline derivatives was
also investigated. Better yields and shorter reaction time
were achieved for the synthesis of some derivatives by
using ultrasound irradiation. The structural elucidation
of all compounds was based on both analytical and spec-
troscopic data. The newly synthesized compounds were
tested in vitro for their antitumor activity against Ehrlich
ascites carcinoma (EAC) cells grown in albino mice. Doxo-
rubicin was used as a standard antitumor antibiotic, and
some compounds showed half maximal inhibitory con-
centration (IC50) in the range 40–68 μg mL−1.
Ultrasound irradiation has been established as
an important technique in organic synthesis [22–24].
Keywords: antitumor activity; benzo[d]thiazole-2-thiol; In comparison with conventional energy sources, this
pyrazolyl-quinoxaline; ultrasound irradiation.
method is more convenient for many organic reactions
to improve the reaction rates, reaction times, product
yields, and selectivity. However, a limited number of syn-
thetic procedures has been reported for the S-alkylation
of benzo[d]thiazole-2-thiol under ultrasound irradia-
tion [25]. In continuation of our work on the synthesis
of thiazole derivatives [26–28], we report here a highly
regioselective synthesis of some novel biologically active
2-substituted sulfanyl benzo[d]thiazole derivatives under
very mild basic conditions (Fig. 1). Some reactions were
carried out under both conventional and ultrasound irra-
diation. Also, the antitumor activity of all compounds
against EAC cells was investigated.
1 Introduction
In recent years, there have been interesting developments
in the chemistry of benzo[d]thiazole derivatives because
of their variable biological activities and wide spectrum of
practical qualities. Benzo[d]thiazole-2-thiol (2-mercapto-
benzothiazole, MBT) is a privileged bicyclic heteroatomic
*Corresponding author: El Sayed Ramadan, Department of
Chemistry, Faculty of Science, Alexandria University, Alexandria
21524, Egypt, e-mail: elsayedramadan2008@yahoo.com
Hamida M. Abdel Hamid: Department of Chemistry, Faculty of
Science, Alexandria University, Alexandria 21524, Egypt; and
Department of Chemistry, Faculty of Science, King Abdul Aziz
University, Jeddah, Saudi Arabia
Sawsan A. Noureddin and Khadija O. Badahdah: Department of
Chemistry, Faculty of Science, King Abdul Aziz University, Jeddah,
Saudi Arabia
2 Results and discussion
The readily available benzo[d]thiazole-2-thiol (1a) [29]
was used as a precursor for the synthesis of our target
compounds. It has been reported that MBT could exist in
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ꢀꢀꢀꢁ
2ꢀ ꢀE.S. Ramadan et al.: Synthesis of some 2-sulfanyl benzo[d]thiazoles
H
medium afforded regioselectively the 2-substituted sulfa-
nyl derivatives 2a rather than the N-3 analogs 2b (Fig. 1).
2-(Benzo[d]thiazol-2-ylthio)acetamide (3) was obtained
in 78% yield by heating 1a with 2-chloroacetamide in the
presence of triethylamine as the base (Scheme 1). The reac-
tion was completed in 8 h. When the reaction was con-
ducted under ultrasound irradiation in the presence of a
catalytic amount of anhydrous potassium carbonate, it
required 25 min and the yield of 3 improved to 89%. The
1H NMR spectrum of 3 showed a singlet peak and a broad
singlet peak at δꢀ=ꢀ4.14 and 7.78 ppm, characteristic for the
protonsofS–CH2 andNH2 groups, respectively. Thefouraro-
matic protons appeared in two sets; the first was observed
as two triplets at δꢀ=ꢀ7.38 and 7.47 ppm due to H-5 and H-6,
while the second set consisted of two doublets in a lower
N
S
N
SH
S
S
1b:BTT
1a:MBT
1. Base
2. R
X
R
N
N
S
S
S
S
R
2a
2b
Fig. 1:ꢀRegioselective S-alkylation of 2-mercaptobenzothiazole.
different solvents as an equilibrium mixture of two tau- field at δꢀ=ꢀ7.83 and 8.01 ppm, which were assigned to H-4
tomeric forms: 2-mercaptobenzothiazole (1a) (MBT, thio– and H-7 as a consequence of their proximity to the nitro-
enol tautomer), and benzothiazoline-2-thione (1b) (BTT, gen and sulfur atoms of the benzothiazole ring. Reaction
thione tautomer) [30]. However, the thio–enol tautomer of compound 1a with 2-chloroacetyl chloride was carried
1a is easily converted into its salt by means of a base, out in the presence of a 5% aqueous solution of potassium
thus coupling reactions of the SH group in 1a are favored hydroxide to yield S-benzo[d]thiazol-2-yl 2-chloroethane
in a fairly basic medium. In this work, we found that the thioate (4) in good yield. S-Benzo[d]thiazol-2-yl 2-(1H-imi-
reaction of MBT with various coupling reagents in basic dazol-1-yl)ethanethioate (6) was obtained in 83% yield by
H
N
N
S
N
S
N
S
O
S
N
S
S
NH2
O
3
1b
6
O
Cl
H
N
NH2
N
O
5
O
Cl
N
N
N
S
Cl
Cl
S
SH
S
KOH
S
Et
N, ))
)
S
3
O
O
Cl
1a
Br
4
7
NaH / DMF
N
S
N
S
N
Br2
KMnO4
Na2CO3
S
Br
S
S
OH
H2O
S
OH
Br
10
Ac2O / Py
8
9
N
S
OCOCH3
S
OCOCH3
11
Scheme 1:ꢀRegioselective coupling to the –SH group of benzo[d]thiazole-2-thiol (1a).
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E.S. Ramadan et al.: Synthesis of some 2-sulfanyl benzo[d]thiazolesꢂ
the nucleophilic substitution reaction of compound 4 with methanol (14). Its IR spectrum indicated the absence of
imidazole (5) in dry N,N-dimethylformamide. The signal the OAc group found in its precursor, and instead showed
due to the N–CH2 protons in its 1H NMR spectrum appeared a band at 3420.42 cm−1 for the O–H stretching vibration.
as a singlet at δꢀ=ꢀ3.89 ppm, while one singlet and two When compound 14 was subjected to the reaction with
doublet peaks at δꢀ=ꢀ7.01, 7.39, and 7.42 ppm were attributed phosphoryl chloride, the chloro derivative 15 was obtained
to the imidazolyl protons. When compound 1a was reacted in 80% yield. Unequivocal synthesis of 15 was achieved
with 2-(chloromethyl)oxirane in dry acetone and a cata- by treating the dichloro pyrazolyl-quinoxaline derivative
lytic amount of triethylamine under ultrasound irradiation 16 with 1a in the presence of NaH in DMF. The reaction
for 5 min, it gave 2-((oxiran-2-ylmethyl)thio)benzo[d]thia- is highly regioselective, as the coupling of compound 16
zole (7) in 71% yield. Conventional synthesis of 7 required with two equivalents of 1a under a similar reaction condi-
longer reaction time and gave only 49% yield. The 1H NMR tions afforded exclusively the monosulfanyl derivative 15
spectrum of compound 7 confirmed its structure, where (Scheme 2).
the H-3′ and H-3ʺ of the oxirane ring appeared as a doublet
of doublet at δꢀ=ꢀ3.68 and 3.71 ppm, while H-2′ was observed
as a multiplet at δꢀ=ꢀ4.71–4.74 ppm, in addition to the S–CH2 3 Antitumor activity
protons which resonated as a doublet at δꢀ=ꢀ4.43 ppm.
The allyl group is considered an excellent The antitumor efficacy of the synthesized compounds
precursor for various chemical modifications, and thus against Ehrlich ascites carcinoma (EAC) cell line was dem-
2-(allylthio)benzo[d]thiazole (8) was prepared by the reac- onstrated and compared with doxorubicin as control. The
tion of 1a with allyl bromide in the presence of sodium effective dose was calculated as the half maximal inhibi-
hydride in dry N,N-dimethylformamide. Reaction of 8 tory concentration (IC50 in μg mL−1), which corresponds
with bromine in water gave 2-((2,3-dibromopropyl)thio) to the concentration of the compound resulting in 50%
1
benzo[d]thiazole (9). Its H NMR spectrum showed two mortality in the total cell count (Table 1). The obtained
doublet of doublets at δꢀ=ꢀ3.88 and 4.11 ppm, another two results revealed that compounds 8, 9, and 15 displayed
doublet of doublets at δꢀ=ꢀ4.99, 5.06 ppm, and a multi- the highest activity against EAC cells with IC50 values
plet at δꢀ=ꢀ5.35–5.38 ppm due to CH2-S, CH2-Br, and CH-Br 42, 41, and 40 μg mL−1, respectively. On the other hand,
groups, respectively. This indicated that the addition of compounds 3, 6, and 7 displayed moderate activity with
bromine to the double bond had taken place. Hydroxyla- IC50 values 68, 70, and 51 μg mL−1, while 4, 11, 13, and 14
tion of compound 8 with potassium permanganate in the showed no activity at all. It is clear that pyrazolyl-quinox-
presence of sodium carbonate gave the corresponding diol aline derivative 15 showed the lowest IC50 value, indicat-
10. Subsequent acetylation of 10 with acetic anhydride in ing the highest potency against the EAC cell line.
dry pyridine afforded 3-(benzo[d]thiazol-2-ylthio)propane-
1,2-diyl diacetate (11) as a syrupy product. Its 1H NMR spec-
trum showed two singlet peaks at δꢀ=ꢀ1.95 and 2.10 ppm for
4 Experimental section
the two acetyl groups in addition to other signals, which
confirmed its structure (Section 4).
The introduction of benzo[d]thiazole-2-thiol nucleus 4.1 Materials and measurements
into pyrazolyl-quinoxalines 12 and 16 [31] is of interest from
a biological point of view. Thus, a facile route to the con- Commercially available solvents and reagents were puri-
jugated pyrazolyl-quinoxaline linked to the benzo[d]thia- fied according to standard procedures. Melting points
zole ring was developed by a nucleophilic displacement of were measured on a Mel-Temp apparatus (Dubuque,
the chlorine atom in compound 12 by the sodium salt of 1a IA, USA) and are uncorrected. Thin-layer chromatogra-
under both conventional and ultrasound irradiation to give phy (TLC) was performed on aluminum silica gel 60 F254
(3-(3-(benzo[d]thiazol-2-ylthio)quinoxalin-2-yl)-1-phenyl- (E-Merk). The spots were detected by iodine and UV light
1H-pyrazol-5-yl)methyl acetate (13). In comparison with the absorption. Fourier transform infrared (FT-IR) spectra
conventionalheatingmethod,thereactiontimewasreduced were recorded on a Perkin Elmer SP 100 spectrometer.
from 11 h to 30 min and the yield of the product increased 1H NMR and 13C NMR spectra were recorded on Bruker
from 49% to 63% when the reaction was achieved under WM 400 and 600 MHz spectrometers. Chemical shifts (δ)
ultrasound irradiation. Deacetylation of compound 13 are given in ppm relative to the signal for TMS as an internal
with aqueous sodium hydroxide produced (3-(3-(benzo[d] standard, and coupling constants (J) are reported in hertz
thiazol-2-ylthio)quinoxalin-2-yl)-1-phenyl-1H-pyrazol-5-yl) (Hz). The reactions that were carried out by ultrasound
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ꢀꢀꢀꢁ
4ꢀ ꢀE.S. Ramadan et al.: Synthesis of some 2-sulfanyl benzo[d]thiazoles
S
N
N
N
S
N
N
Cl
1a
NaH / DMF
C.M. or )))
1. NaOH
2. AcOH
N
N
OCOCH3
OCOCH3
N
N
Ph
Ph
12
13
S
N
S
N
1a
NaH /
N
N
Cl
N
N
N
S
N
N
S
POCl3
DMF
N
N
Cl
Cl
OH
Ph
N
Ph
N
N
Ph
14
16
15
Scheme 2:ꢀSynthesis of pyrazolyl-quinoxaline derivatives containing compound 1a.
Table 1:ꢀIn vitro antitumor activity of the synthesized compounds
The reaction mixture was heated under reflux for 8 h.
The separated product was filtered off, dried, and recrys-
tallized from ethanol to give compound 3 as colorless
crystals. Yield: 78% (2.08 g), Rfꢀ=ꢀ0.88 (EtAc/MeOH,
1:1), m.p. 139–140°C. IR (KBr): νꢀ=ꢀ3353.29, 3211.44 (NH2),
1677.87 (C=O), 1615.75 (C=C, C=N) cm−1. 1H NMR (600 MHz,
[D6]DMSO): δꢀ=ꢀ4.14 (s, 2 H, S–CH2), 7.38 (t, Jꢀ=ꢀ7.2 Hz, 1
H, Ar-H), 7.47 (t, Jꢀ=ꢀ7.2 Hz, 1 H, Ar-H), 7.78 (bs, 2 H, D2O-
exchangeable, NH2), 7.83 (d, Jꢀ=ꢀ7.8 Hz, 1 H, Ar-H), 8.01
against Ehrlich ascites carcinoma (EAC) cells.
−1
−1
Compound
IC50 (μg mL )
Compound
IC50 (μg mL )
3
4
6
7
8
9
68
–
70
51
42
41
11
–
–
–
40
38
13
14
15
Doxorubicin
13
(d, Jꢀ=ꢀ7.8 Hz, 1 H, Ar-H). C NMR (150 MHz, [D6]DMSO):
δꢀ=ꢀ36.75 (S–CH2), 120.92, 121.73, 124.34, 126.27, 134.57,
152.47 (Ar-C), 166.31 (C-2 of benzo[d]thiazole ring), 168.05
(C=O). C9H8N2OS2 (224.30): calcd. C 48.19, H 3.59, N 12.49;
found C 48.27, H 3.88, N 12.32.
irradiation was done using a Daihan (WiseClean, D-400H)
ultrasonic bath. Microanalyses were performed on a Perkin
Elmer elemental analyzer at the Faculty of Science, King
Abdul Aziz University. Antitumor activity was performed in
the Operations Development Section, Egyptian Petroleum
Research Institute (EPRI), Cairo, Egypt.
4.2.2 Method B
4.2 2-(Benzo[d]thiazol-2-ylthio)acetamide (3) A solution of compound 1a (2.0 g, 11.96 mmol) in dry
acetone (50 mL) was treated with a solution of 2-chloro-
acetamide (1.12 g, 11.97 mmol) in a mixture of ethanol/
acetone (1:10, 100 mL) and anhydrous potassium carbon-
4.2.1 Method A
A solution of compound 1a (2.0 g, 11.96 mmol) in dry ate (1.98 g, 14.32 mmol). The reaction mixture was soni-
acetone (50 mL) was treated with a solution of 2-chloro- cated at a frequency of 40 kHz for 25 min at 40°C, cooled to
acetamide (1.12 g, 11.97 mmol) in a mixture of ethanol/ room temperature, and poured into crushed ice (20 g). The
acetone (1:10, 100 mL) and triethylamine (2.0 mL). separated solid was filtered, dried, and recrystallized from
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E.S. Ramadan et al.: Synthesis of some 2-sulfanyl benzo[d]thiazolesꢂ
ethanol to give a product (89% yield, 2.40 g) identical to 3:1). IR (KBr): νꢀ=ꢀ1625.0, 1580.0 (C=C, C=N), 1245.0 (C–O)
1
that obtained from method A.
cm−1. H NMR (400 MHz, [D6]DMSO): δꢀ=ꢀ3.68, 3.71 (dd,
Jꢀ=ꢀ7.8, 7.8 Hz, 2 H, H-3′ and H-3ʺ of oxirane ring), 4.43 (d,
Jꢀ=ꢀ14.0 Hz, 2 H, S–CH2), 4.71–4.74 (m, 1 H, H-2′ of oxirane
ring), 7.73 (t, Jꢀ=ꢀ6.9 Hz, 1 H, Ar-H), 7.80 (t, Jꢀ=ꢀ6.9 Hz, 1 H,
Ar-H), 8.13 (d, Jꢀ=ꢀ8.3 Hz, 1 H, Ar-H), 8.32 (d, Jꢀ=ꢀ8.1 Hz, 1 H,
Ar-H). C10H9NOS2 (223.31): calcd. C 53.78, H 4.06, N 6.27;
4.3 S-Benzo[d]thiazol-2-yl
2-chloroethanethioate (4)
A solution of compound 1a (2.0 g, 11.96 mmol) in 5% found C 53.30, H 3.59, N 6.27.
aqueous solution of potassium hydroxide (45 mL) was
treated with 2-chloroacetyl chloride (2.0 mL, 25.09 mmol).
The reaction mixture was heated under reflux for 3 h. The 4.5.2 Method B
product that separated out on cooling was filtered, dried,
and recrystallized from ethanol to give colorless crystals. A solution of compound 1a (2.0 g, 11.96 mmol) in dry acetone
Yield: 69% (1.99 g), Rfꢀ=ꢀ0.74 (EtAc/MeOH, 1:1), m.p. 101– (60 mL) was treated with 2-(chloromethyl)oxirane (1.0 mL,
103°C (lit. [32] m.p. 97–98°C).
12.75 mmol) and triethylamine (2.0 mL). The reaction
mixture was subjected to ultrasound irradiation at 40 kHz
for 5 min, and the reaction mixture was processed as before
to give a colorless syrup of compound 7 (71% yield, 1.89 g).
4.4 S-Benzo[d]thiazol-2-yl 2-(1H-imidazol-
1-yl)ethanethioate (6)
A solution of compound 4 (0.53 g, 2.17 mmol) and imida- 4.6 2-(Allylthio)benzo[d]thiazole (8)
zole (5) (0.15 g, 2.20 mmol) in dry N,N-dimethylformamide
(10 mL) was stirred at room temperature for 10 h. Then, it A solution of compound 1a (1.0 g, 5.98 mmol) in dry N,N-
was poured into cold water (10 mL) and the product was dimethylformamide (5.0 mL) was treated with sodium
extracted with ethyl acetate (3ꢀ×ꢀ10 mL). The extract was hydride (0.20 g, 8.33 mmol), and then it was heated
dried over anhydrous sodium sulfate and then evapo- under reflux for 1 h. The resulting mixture was cooled,
rated in vacuo. The isolated product was recrystallized allyl bromide (0.98 mL, 11.32 mmol) was added, and the
from ethanol to give colorless crystals. Yield: 83% (0.50 g), mixture was stirred overnight at room temperature. It was
Rfꢀ=ꢀ0.66 (EtAc/MeOH, 1:1), m.p. 290–292°C. IR (KBr): poured into 20 mL of cold water, and the product was
νꢀ=ꢀ1652.0 (C=O), 1580.0 (C=C, C=N) cm−1. 1H NMR (600 MHz, extracted with methylene chloride (3ꢀ×ꢀ15 mL). The methy-
[D6]DMSO): δꢀ=ꢀ3.89 (s, 2 H, N–CH2), 7.01 (s, 1 H, CH of imi- lene chloride extract was dried with anhydrous magne-
dazole ring), 7.30 (t, Jꢀ=ꢀ7.2 Hz, 1 H, Ar-H), 7.39 (d, Jꢀ=ꢀ7.8 Hz, sium sulfate and concentrated under reduced pressure.
1 H, CH of imidazole ring), 7.41 (t, Jꢀ=ꢀ7.2 Hz, 1 H, Ar-H), 7.42 The crude material obtained was distilled to give a color-
(d, Jꢀ=ꢀ7.8 Hz, 1 H, CH of imidazole ring), 7.77 (d, Jꢀ=ꢀ7.2 Hz, 1 less oil (0.73 g, 59% yield) [33].
H, Ar-H), 7.94 (d, Jꢀ=ꢀ7.2 Hz, 1 H, Ar-H). C12H9N3OS2 (275.35):
calcd. C 52.34, H 3.29, N 15.26; found C 52.16, H 3.59, N 15.72.
4.7 2-((2,3-Dibromopropyl)thio)benzo[d]
thiazole (9)
4.5 2-((Oxiran-2-ylmethyl)thio)benzo[d]
To a suspension of compound 8 (0.70 g, 3.38 mmol) in
water (6.0 mL), bromine (1.0 mL) was added dropwise
during 1 h with gentle stirring. The mixture was stirred for
a further 3 h, and kept overnight at room temperature. The
thiazole (7)
4.5.1 Method A
A solution of compound 1a (2.0 g, 11.96 mmol) in dry mixture was then diluted with 50 mL of boiling ethanol,
acetone (60 mL) was treated with anhydrous potassium and the separated product was filtered off, washed with
carbonate (1.98 g, 14.3 mmol). The mixture was stirred at water, dried, and recrystallized from ethanol to give pale
room temperature for 3 h, then 2-(chloromethyl)oxirane yellow crystals. Yield: 76% (0.94 g), Rfꢀ=ꢀ0.56 (EtAc/MeOH,
(1.0 mL, 12.75 mmol) was added, and the mixture was kept 1:1), m.p. 225–227°C. IR (KBr): νꢀ=ꢀ1645.08 (C=C, C=N) cm−1.
overnight with vigorous stirring. The solvent was evapo- 1H NMR (600 MHz, [D6]DMSO): δꢀ=ꢀ3.88 (dd, Jꢀ=ꢀ7.2, 7.8 Hz,
rated in vacuo and the product was separated out as color- 1 H, S–CH2), 4.11 (dd, Jꢀ=ꢀ2.0, 2.4 Hz, 1 H, S–CH2), 4.99 (dd,
less syrup. Yield: 49% (1.30 g), Rfꢀ=ꢀ0.83 (n-hexane/EtAc, Jꢀ=ꢀ6.0, 6.6 Hz, 1 H, CH2–Br), 5.06 (dd, Jꢀ=ꢀ3.6, 3.6 Hz, 1 H,
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6ꢀ ꢀE.S. Ramadan et al.: Synthesis of some 2-sulfanyl benzo[d]thiazoles
CH2–Br), 5.35–5.38 (m, 1 H, CH–Br), 7.72 (t, Jꢀ=ꢀ7.8 Hz, 1 H, mixture, a white solid separated out. It was filtered off
Ar-H), 7.79 (t, Jꢀ=ꢀ7.8 Hz, 1 H, Ar-H), 8.16 (d, Jꢀ=ꢀ8.4 Hz, 1 H, and recrystallized from EtOH to give colorless crystals.
13
Ar-H), 8.38 (d, Jꢀ=ꢀ7.8 Hz, 1 H, Ar-H). C NMR (150 MHz, Yield: 49% (1.47 g), Rfꢀ=ꢀ0.89 (EtAc/MeOH, 1:1), m.p. 208–
1
[D6]DMSO): δꢀ=ꢀ34.70 (CH2–Br), 36.98 (CH2–S), 52.77 (CH– 211°C. IR (KBr): νꢀ=ꢀ1730.63 (C=O) cm−1. H NMR (600 MHz,
Br), 114.95, 124.11, 127.39, 127.94, 128.87, 141.24 (Ar-C), 174.36 [D6]DMSO): δꢀ=ꢀ2.06 (s, 3 H, CH3CO), 5.24 (s, 2 H, CH2OC-
(C-2 of benzo[d]thiazole ring). C10H9Br2NS2 (367.12): calcd. C OCH3), 7.31–8.19 (m, 14 H, Ar-Hꢀ+ꢀpyrazole-H). 13C NMR
32.72, H 2.47, N 3.82; found C 32.30, H 2.80, N 3.73.
(150 MHz, [D6]DMSO): δꢀ=ꢀ20.38 (OCOCH3), 56.10 (CH2O-
COCH3), 109.63, 110.95, 112.34, 115.11, 123.42–147.76, 154.0
(Ar-C), 169.80 (OCOCH3). C27H19N5O2S2 (509.60): calcd. C
63.64, H 3.76, N 13.74; found C 64.06, H 3.68, N 14.24.
4.8 3-(Benzo[d]thiazol-2-ylthio)propane-
1,2-diyl diacetate (11)
A suspension of compound 8 (1.10 g, 5.31 mmol) in a solu- 4.9.2 Method B
tion of sodium carbonate (2.0 g, 18.86 mmol) in water
(10 mL) was stirred at room temperature for 10 min. An To a solution of compound 1a (1.0 g, 5.98 mmol) in dry
alkaline solution of potassium permanganate was then DMF (10 mL), NaH (0.30 g, 12.5 mmol) was added. Then,
added dropwise until the color of KMnO4 persisted. The a solution of 12 (2.27 g, 5.99 mmol) in a mixture of EtOH
mixture was stirred for a further 3 h, then kept overnight and DMF (2:1, 90 mL) was added. The reaction mixture
at room temperature, and the product was extracted with was sonicated at 40 kHz for 30 min at 45°C. The reaction
CH2Cl2 (4ꢀ×ꢀ10 mL). The extract was evaporated in vacuo mixture was processed as before to give a product identi-
till dryness, and the separated residue of diol 10 (0.55 g, cal to that obtained from method A (63% yield, 1.9 g).
2.28 mmol) was dissolved in dry pyridine (10 mL), followed
by adding 10 mL of acetic anhydride with occasional stir-
ring. The mixture was kept at 18–20°C overnight and then 4.10 (3-(3-(Benzo[d]thiazol-2-ylthio)qui-
poured into crushed ice (20 g). The product was extracted
noxalin-2-yl)-1-phenyl-1H-pyrazol-5-yl)
with CH2Cl2 (4ꢀ×ꢀ10 mL) and the solvent was evaporated
methanol (14)
under reduced pressure to give a colorless oil. Yield: 69%
1
(0.51 g), Rfꢀ=ꢀ0.75 (EtAc/MeOH, 1:1). H NMR (400 MHz, A solution of compound 13 (0.60 g, 1.18 mmol) in absolute
CDCl3): δꢀ=ꢀ1.94, 2.10 (2s, 6 H, 2 COCH3), 3.97 (d, Jꢀ=ꢀ6.76 Hz, EtOH (25 mL) was treated with an aqueous solution of NaOH
2 H, S–CH2), 5.17–5.39 (m, 2 H, CH2OCOCH3), 5.96–6.06 (0.50 M, 30 mL) and the mixture was heated under reflux for
(m, 1 H, CHOCOCH3), 7.27 (t, Jꢀ=ꢀ7.2 Hz, 1 H, Ar-H), 7.38 (t, 9 h. The resulting solution was cooled and neutralized with
Jꢀ=ꢀ7.2 Hz, 1 H, Ar-H), 7.74 (d, Jꢀ=ꢀ7.5 Hz, 1 H, Ar-H), 7.85 (d, glacial acetic acid. The product was filtered off, washed
Jꢀ=ꢀ8.1 Hz, 1 H, Ar-H). C14H15NO4S2 (325.40): calcd. C 51.67, with water, and recrystallized from EtOH to give colorless
H 4.65, N 4.30; found C 51.50, H 4.92, N 3.88.
crystals. Yield: 58% (0.32 g), Rfꢀ=ꢀ0.35 (n-hexane/EtAc, 3:1),
1
m.p. 244–246°C. IR (KBr): νꢀ=ꢀ3420.42 (O–H) cm−1. H NMR
(600 MHz, [D6]DMSO): δꢀ=ꢀ4.55 (s, 1 H, D2O-exchangeable,
4.9 (3-(3-(Benzo[d]thiazol-2-ylthio)quinoxa- O–H), 5.60 (s, 2 H, CH2OH), 7.31–7.84 (m, 14 H, Ar-Hꢀ+ꢀpyra-
13
zole-H). C NMR (150 MHz, [D6]DMSO): δꢀ=ꢀ56.08 (CH2OH),
lin-2-yl)-1-phenyl-1H-pyrazol-5-yl)methyl
111.31, 115.24–131.96, 132.02, 139.39, 143.88, 146.69, 149.01,
acetate (13)
154.13 (Ar-C). C25H17N5OS2 (467.57): calcd. C 64.22, H 3.66, N
4.9.1 Method A
14.98; found C 64.32, H 3.95, N 15.09.
To a stirred solution of compound 1a (1.0 g, 5.98 mmol)
in dry DMF (10 mL), NaH (0.30 g, 12.5 mmol) was added. 4.11 2-((3-(5-(Chloromethyl)-1-phenyl-
After the evolution of H2 gas was almost complete, the
1H-pyrazol-3-yl)quinoxalin-2-yl)thio)
mixture was heated under reflux for 1 h. A solution of
benzo[d]thiazole (15)
compound 12 (2.27 g, 5.99 mmol) in a mixture of EtOH and
DMF (2:1, 90 mL) was added, and the reaction mixture was 4.11.1 Method A
heated under reflux for an additional 10 h, until the reac-
tion was complete. The reaction progress was monitored A suspension of compound 14 (0.20 g, 0.43 mmol) in phos-
by TLC using EtAc/MeOH (1:1). Upon cooling the reaction phoryl chloride (7.0 mL) was heated on a boiling water
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ꢁꢀꢀꢀ
ꢂ7
E.S. Ramadan et al.: Synthesis of some 2-sulfanyl benzo[d]thiazolesꢂ
bath for 7 h, then cooled to 20°C, treated with ice-cold to contain 2.5ꢀ×ꢀ106 viable cells per mL. EAC cells, RPMI
water (50 mL), and basified with aqueous K2CO3 to pH 9. 1640 medium (Sigma Chemical Co.), and the tested com-
The product was collected by filtration and recrystallized pounds in DMSO were added in sterile test tubes. The
from EtOH as colorless crystals. Yield: 80% (0.16 g), Rfꢀ=ꢀ0.76 cells were incubated for 1 and 24 h at 37°C under a con-
(EtAc/MeOH, 1:1), m.p. 136–138°C. IR (KBr): νꢀ=ꢀ1635.03 stant overlay of 5% CO2. EAC viable cells were counted
1
(C=C, C=N) cm−1. H NMR (600 MHz, [D6]DMSO): δꢀ=ꢀ4.90 by trypan blue exclusion using a hemocytometer as
(s, 2 H, CH2–Cl), 7.29–8.31 (m, 14 H, Ar-Hꢀ+ꢀpyrazole-H). mentioned above. The fraction of surviving cells was
13C NMR (150 MHz, [D6]DMSO): δꢀ=ꢀ27.48 (CH2–Cl), 110.27, calculated as T/C, where T and C represent the number
134.85, 121.30–131.60, 138.78–140.25, 144.67, 147.76, 148.90, of viable cells in unit volume and the number of total
152.37, 164.85 (Ar-C). C25H16ClN5S2 (486.01): calcd. C 61.78, (viable dead) cells in the same unit volume, respectively.
H 3.32, N 14.41; found C 61.95, H 3.64, N 14.52.
4.11.2 Method B
5 Supporting information
A solution of compound 1a (0.17 g, 1.02 mmol) in dry DMF Copies of 1H NMR and 13C NMR spectra of the synthesized
(3.0 mL) was treated with NaH (0.05 g, 2.1 mmol) and compounds are given as Supporting Information available
heated under reflux for 1 h. Then, a solution of compound online (https://doi.org/10.1515/znb-2018-0078).
16 (0.18 g, 0.51 mmol) in absolute EtOH (25 mL) was added.
The reaction mixture was heated under reflux for an addi-
tional 7 h. The product that separated out on cooling was
filtered and recrystallized from EtOH to give colorless crys-
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Supplementary Material: The online version of this article offers
supplementary material (https://doi.org/10.1515/znb-2018-0078).
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Z. Naturforsch.ꢂ
ꢂ2018 | Volume x | Issue x(b)
Graphical synopsis
El Sayed Ramadan, Hamida M. Abdel
Hamid, Sawsan A. Noureddin
and Khadija O. Badahdah
Synthesis, characterization, and antitu-
mor activity of some novel S-functional-
ized benzo[d]thiazole-2-thiol derivatives;
regioselective coupling to the –SH group
https://doi.org/10.1515/znb-2018-0078
Z. Naturforsch. 2018; x(x)b: xxx–xxx
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