Efficient and facile catalyst-free one-pot synthesis and characterization of some novel bis(2-benzothiazole) derivatives

Article abstract of DOI:10.1002/jhet.1956

A general method for preparation of benzothiazole derivatives including oxidative cyclization of the corresponding Schiff bases was reported. Herein, we have been synthesized a series of new acyclic-substituted bis(2- arylbenzothiazoles). Synthesis of analogs substituted in the benzothiazole ring was achieved via the direct condensation reaction of o-aminothiophenol with some of dialdehyde compounds under catalyst free in high yields. The structure of these products has been fully characterized by physical and spectroscopic data such as IR, ¹H-NMR, ¹³C-NMR, UV-Vis, MS, and CHN analysis.

Full text of DOI:10.1002/jhet.1956

566
Efficient and Facile Catalyst-free One-Pot Synthesis and Characterization
Vol 51
of Some Novel Bis(2-benzothiazole) Derivatives
a
a
*
Hossein Naeimi and Reza Tarazian
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, 87317, I.R. Iran
*
E-mail: naeimi@kashanu.ac.ir
Received July 18, 2012
DOI 10.1002/jhet.1956
Published online 22 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
X
O
O
O
O
O
O
NH2
SH
EtOH (Abs)
reflux
X
2
N
N
S
S
A general method for preparation of benzothiazole derivatives including oxidative cyclization of the cor-
responding Schiff bases was reported. Herein, we have been synthesized a series of new acyclic-substituted
bis(2-arylbenzothiazoles). Synthesis of analogs substituted in the benzothiazole ring was achieved via the
direct condensation reaction of o-aminothiophenol with some of dialdehyde compounds under catalyst free
in high yields. The structure of these products has been fully characterized by physical and spectroscopic
1
data such as IR, H-NMR, 13C-NMR, UV-Vis, MS, and CHN analysis.
J Heterocyclic Chem., 51, 566 (2014).
INTRODUCTION
H2O [51], PCC [52], and CAN [53] have been used
in the cyclocondensation of 2-aminothiophenol with
aldehydes. Many of these methods have disadvantages
such as drastic reaction conditions, tedious workup, and
possibility of side reactions and generation of acidic or
toxic metallic wastes.
In this article, we reported direct synthesis of a some
new acyclic bis(2-arylbenzothiazole) derivatives from
cyclocondensation reaction of 2-aminothiophenol and a
series of dialdehyde compounds. This reaction carried
out via oxidative cyclization of imine intermediates in
absolute ethanol refluxing, under oxygen or air atmo-
sphere in high to excellent yields without further oxida-
tive reagent.
Benzothiazole is a privileged bicyclic ring system [1]
because it possesses potent antitumor properties [2–5] and
other extensive pharmaceutical utilities [6–8]. In particular,
2-arylbenzothiazoles have been know as useful compounds
for their utilities as imaging agents for b-amyloid [9],
antitumor [10–14], antituberculotics [15], antiparasitics [16],
calcium channel antagonists [17], chemiluminescent
agents [18], photosensitizers [19], and also as Alzheimer’s
disease agents [20–22].
Therefore, in recent years, the synthesis of these com-
pounds is of considerable interests. Extensive research has
been carried out for the structural modifications on ben-
zothiazol moiety to improve their biological properties, espe-
cially for their activities as anticancer compounds [23–26].
For example, some of the 2-phenylbenzothiazole derivatives
such as (PMX 610) [27], (DF 203), and (5F 203) [28] (Fig. 1)
have been reported to possess potent and selective antitumor
activity in human cancer cell lines. Numerous methods have
been reported for the synthesis of benzothiazoles [29–40].
One of the routs is based on Jacobson’s cyclization of
thiobenzanilides [41]. This rout requires to a multistep reac-
tion sequence. Recently, the various N-bis-benzothiazoles
were synthesized via oxidative cyclization of benzothiazollyl
thiocarbamides using Jacobson’s method that reported as
novel anticancer agents [25].
RESULTS AND DISCUSSION
Bis(2-arylbenzothiazoles) have been prepared from
the cyclocondensation reaction of 2-aminothiophenol
with dialdehydes in absolute ethanol reflux conditions,
without using any catalyst (Scheme 1). As shown in this
scheme, when 1 mol of dialdehyde (1a–f) and 2 mols of
2-aminothiophenol (2) were reacted together, bis(2-aryl-
benzothiazole) derivatives (3a–f) were obtained under
reflux conditions. The identity of products was comple-
tely demonstrated by physical and spectroscopic data.
The reaction regarding to the preparation of benzothia-
zoles, is typically a nucleophilic addition reaction that
was involving three intermediates. Certainly, choice of
an appropriate solvent was important. Therefore, to study
the effect of the solvents on the reaction of dialdehyde,
The most commonly used method is of the condensation
of 2-aminothiophenol with substituted nitriles [42], car-
boxylic acids [43], acid chlorides [44], amides [45], esters
[46], and aldehydes [47]. A number of catalysts, namely;
(pmlm)Br [31], I2 [48], ZrOCl2.8H2O [49], TMSCl [50],
© 2013 HeteroCorporation

May 2014
One-Pot Synthesis of Bis(2-benzothiazole)
567
Table 2
Optimization of 2-aminothiophenol in the reaction with dialdehyde (1a).
Entry
ATPa (mmol)
Time (h)
Yield (%)b
1
2
3
4
2.0
2.2
2.5
2.8
15
15
15
15
70
80
90
90
Figure 1. Chemical structure of anticancer 2-arylbenzothiazole derivatives.
a2-aminothiophenol.
bIsolated yields.
Scheme 1
in the first step, from the intermolecular nucleophilic
attack of the nitrogen of 2-aminothiophenol on the carbonyl
group of dialdehyde, without using any base, was formed
unstable intermediate of hydroxyl amine (steps I and II). In
continuation, with elimination of two water molecules to
form the Schiff base intermediate (step III). Also, the imine
product was not stable and, as an unstable intermediate
undergo intramolecular nucleophilic attack of the thio
group, was converted to the 2,3-dihydrobenzothiazoline
intermediate (step IV). Finally, the thiazoline ring was
easily converted to stable aromatic thiazole ring under
oxygen atmosphere and without any catalyst and oxidant
(step V).
The obtained Schiff bases from step III are unstable
because they have the rigid and bulky structure with
steric hindrance. Thus, the formation of Schiff bases
was occurred in lower yields and long reaction times
in comparison with the reaction of salicylaldehyde (4)
with o-aminothiophenol (Table 3, entry 7). In this
recent reaction, the highly stable Schiff base (5) was
afforded in 97% yield and reaction time about 10 min
under mild condition (Scheme 3). However, the result-
ing products from cyclization of imine bands with —
SH groups and long reaction times can be related to
the instability because of rigid and bulky structures of
dialdehydes.
The structure of the products is fully assigned by spec-
troscopic data. In the IR spectra, the characteristic band
C═N stretching frequency relative to thiazole ring was
formed in the region between n = 1572–1586 cmꢀ1 as a
signal strong peak. The C—S—C stretching frequency
of thiazole ring is found at around n = 753 cmꢀ1. In the
1H-NMR spectra, the signals around d = 8.55 ppm and
d = 8.1 ppm are assigned to the protons of the ortho-S
and ortho-N of the benzene ring fused with thiazole ring.
The intramolecular cyclization of thiophenolic Schiff
base was characterized by the absence of CH═N proton
signal at d = 8.3–8.8 ppm and 2250 cmꢀ1 (S—H stretch)
peak. In the 13C-NMR spectra, the signal about d = 163
ppm is assigned to the phenolic carbon. The signal about
d = 156 ppm is assigned to the carbon of the thiazole
ring. The signals at around d = 152 ppm and d = 132 ppm
1a with 2-aminothiophenol was carried out in the various
solvents. The results are indicated in Table 1. As can be
seen in this table, it was remarkably enhanced in yield of
the reaction in absolute ethanol.
In continuation of this study, to application of the
optimum amount of the 2-aminothiophenol for all the
reactions and to obtain the product with higher yield,
the reaction of dialdehyde (1a) with various amounts
of 2-aminothiophenol have been investigated. The
corresponding results are summarized in Table 2. As
shown in this table, the optimum amount of the used
2-aminothiophenol was 2.5 mmols for 1 mmol of dialde-
hyde (1a). The obtained results regarding to the synthesis
of the bis(2-arylbenzothiazole) derivatives from the reac-
tion of 2-aminothiophenol with various dialdehydes are
shown in Table 3.
A proposed reasonable mechanism for these conversions
is shown in Scheme 2. By consideration of this mechanism,
Table 1
Results of the reaction of dialdehyde (1a) with 2-aminothiophenol in
different solvents.
Entry
Solvent
CH2Cl2
Time (h)
Yield (%)a
1
2
3
4
5
30
24
20
20
15
20
40
50
60
90
THF
CH3CN
CH3OH
C2H5OH
aIsolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

568
H. Naeimi and R. Tarazian
Vol 51
Table 3
Results related to the reaction of different dialdehydes with 2-aminothiophenol.
Entry
Substrate (1a–f)
Time (h)
15
mp (ꢁC)
Product (3a–f)
Yield (%) a
1
142–144
3a
90
2
15
152–154
3b
90
3
15
158–160
3c
90
4
20
208–210
3d
75
5
20
20
124–126
104–106
110
3e
3f
75
75
97
6
7b
1/6
aIsolated yields.
bThe reaction carried out at RT.
are assigned to the carbon atoms of ortho-N and ortho-S.
The carbon atoms of the linked to thiazole ring are
assigned around d = 136 ppm. In UV spectrum, a moder-
ately intensive band observed in the range of l = 235–
268 nm is attributable to the p!p* transitions of
aromatic rings, and the strong band observed in the
range of l = 318–325 nm is due to the n!p* transitions
C═N of the thiazole rings. Finally, the elemental
analysis (CHN) was confirmed the formation of corre-
sponding products.
Journal of Heterocyclic Chemistry
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One-Pot Synthesis of Bis(2-benzothiazole)
569
Scheme 2
Apparatus.
IR spectra were recorded as KBr pellet on a
Perkin-Elmer 781 spectrophotometer and an Impact 550 Nicolet
1
FT–IR spectrophotometer. H-NMR and 13C-NMR spectra were
recorded in CDCl3 solvent on a Bruker DRX-400 spectrometer
(400 MHz) using TMS as an internal reference. UV-Vis spectra
were recorded in CDCl3 solvent on a Perkin-Elmer model
550 spectrophotometer in wavelength 200–800 nm. In addition,
the MS spectra were recorded on a Shimadzu QP 1100 EX
mass spectrometer operating at an ionization potential of 70 eV.
Elemental analysis for CHN was performed using a Vario EL
analyzer. Melting points were obtained with a Yanagimoto
micromelting point apparatus are uncorrected. The purity
determination of the substrates and reactions monitoring were
accomplished by TLC on silica gel polygram SILG/UV 254
plates.
General procedure for synthesis of bis(2-arylbenzothiazole)
derivatives (3a–f).
In a standard procedure, in a round-
bottomed flask equipped with a reflux condenser (50 mL),
dialdehyde (1 mmol) in absolute ethanol (20 mL) was heated
until all of the dialdehyde dissolved completely (in the case of
1d, 4 drops of DMF further dissolving was added ). Then, 2-
aminothiophenol (0.3 g, 2.5 mmol) in dry ethanol (10 mL) was
added dropwise to the stirred solution of dialdehyde. The
solution was refluxed for 15–20 h. After cooling, the solvent
was removed in vacuum. A pale yellow product was obtained in
yields 75–90% without require to the further purification. The
products were fully identified by physical and spectroscopic data.
2,20-[1,3-Propanediylbis(2-phenoxy)]bis(benzothiazole)
(3a). Pale yellow solid; mp 142–144ꢁC; IR (KBr)/υ (cmꢀ1): 1582
(s, C═N), 1497 (s, C═C), 753 (s, C—S), 1242 (s, C—O, Ar),
1290 (s, C—O, Al), 1452 (s, CH2), 3061 (w, C—H, Ar), 2925
(w, C—H, Al); 1H-NMR (CDCl3, 400 MHz)/d ppm: 2.75 (q, 2H),
4.62 (t, 4H), 7.1 (d, 2H), 7.14 (t, 2H), 7.38 (q, 4H), 7.51 (t, 2H),
7.90 (d, 2H), 8.10 (d, 2H), 8.55 (d, 2H); 13C-NMR (CDCl3,
100 MHz)/d ppm: 29.32, 65.97, 112.49, 121.29, 121.36, 122.34,
122.87, 124.66, 126.05, 129.77, 131.90, 135.94, 152.15, 156.41,
162.96; UV (CDCl3)/lmax (nm): 234, 324; MS (EI): m/z: 494
(M+, 8), 374 (10), 284 (2), 267 (100), 252 (50), 240 (46),227 (81),
211 (41), 198 (25), 183 (10), 171 (7), 154 (12); Anal. Calcd for
C29H22O2N2S2: C, 70.45; N, 5.67; O, 6.48; S, 96; H, 4.45. Found:
C, 70.3; N, 5.77; O, 6.81; S, 12.1; H, 5.02.
Scheme 3
2,20-[1,2-Bismethyldiylbis(2-phenoxy)]bis(benzothiazole)
(3b). Pale yellow solid; mp 152–154ꢁC; IR (KBr)/υ (cmꢀ1):
1583 (s, C═N), 1496 (s, C═C), 753 (s, C—S), 1232 (s, C—O,
Ar), 1290 (s, C—O, Al), 1450 (s, CH2), 3061 (w, C—H, Ar),
1
CONCLUSION
2924 (w, C—H, Bn); H-NMR (CDCl3, 400MHz)/d ppm: 5.51
(s, 4H), 7.05(d, 2H), 7.1 (t, 2H), 7.31 (q, 4H), 7.48 (t, 2H), 7.49
(d, 2H), 7.67 (t, 2H), 7.78 (d, 2H), 8.08 (d, 2H), 8.50 (d, 2H);
13C-NMR (CDCl3, 100 MHz)/d ppm: 69.25, 112.91, 121.31,
121.57, 122.58, 122.85, 124.65, 125.98, 128.94, 129.82,
129.87, 131.77, 134.69, 136.02, 152.19, 156.19, 162.95; UV
(CDCl3)/lmax (nm): 237, 318; MS (EI): m/z: 556 (M+, 10), 329
(100), 314 (18), 227 (40), 211 (20), 198 (23), 104 (50), 78 (23);
Anal. Calcd for C34H24O2N2S2: C, 73.38; N, 5.04; O, 5.75; S,
11.51; H, 4.32. Found: C, 72.90; N, 5.23; O, 6.20; S, 11.1; H, 4.57.
2,20-[1,3-Bismethyldiylbis(2-phenoxy)]bis(benzothiazole)
(3c). Pale yellow solid; mp 158–160ꢁC; IR (KBr)/υ (cmꢀ1): 1583
(s, C═N), 1495 (s, C═C), 753 (s, C—S), 1237 (s, C—O, Ar), 1291
(s, C—O, Al), 1450 (s, CH2), 3060 (w, C—H, Ar), 2923 (w, C—H,
Bn); 1H-NMR (CDCl3, 400 MHz)/d ppm: 5.38 (s, 4H), 7.04(d, 2H),
7.1 (t, 2H), 7.31 (t, 2H), 7.41 (t, 2H), 7.46 (q, 4H), 7.56 (d, 2H),
7.76 (t, 2H), 8.07 (d, 2H), 8.53 (d, 2H); 13C-NMR
In this study, we reported direct synthesis of a
some new acyclic bis(2-arylbenzothiazole) derivatives.
These heterocyclic compounds were formed via oxidative
cyclization of the corresponding Schiff bases, in high
to excellent yields under catalyst free with advantages
such as clean workup, facile separation, and simple
purification.
EXPERIMENTAL
Materials.
All of the chemicals and solvents were
purchased from Merck and Fluka Chemical Company. The
dialdehydes have been prepared and characterized as mentioned
in accordance to the procedure previously reported [54].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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H. Naeimi and R. Tarazian
Vol 51
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(CDCl3, 100MHz)/d ppm: 70.82, 113.14, 120.9, 121.26, 122.79,
124.61, 125.92, 127.16, 127.73, 128.97, 129.86, 131.71, 136.11,
13671, 152.14, 156.15, 163.03; UV (CDCl3)/lmax (nm): 236, 325;
MS (EI): m/z: 556 (M+, 10), 329 (100), 314 (18), 227 (40), 211
(20), 198 (23), 104 (50), 78 (23); Anal. Calcd for C34H24O2N2S2:
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2,20-[1,4-Bismethyldiylbis(2-phenoxy)]bis(benzothiazole)
(3d). Pale yellow solid; mp 208–210ꢁC; IR (KBr)/υ (cmꢀ1):
1572 (s, C═N), 1486 (s, C═C), 752 (s, C—S), 1244 (s, C—O,
Ar), 1290 (s, C—O, Al), 1452 (s, CH2), 3055 (w, C—H, Ar),
2922 (w, C—H, Bn); 1H-NMR (CDCl3, 400MHz)/d ppm: 5.38
(s, 4H), 7.12(d, 2H), 7.16 (t, 2H), 7.32 (t, 2H), 7.46 (q, 4H), 7.61
(d, 4H), 7.83 (d, 2H), 8.10 (d, 2H), 8.58 (d, 2H); 13C-NMR
(CDCl3, 100MHz)/d ppm: 70.75, 112.98, 121.34, 121.54, 122.75,
122.81, 124.65, 125.97, 128.20, 129.87, 131.76, 136.14, 136.19,
152.16, 156.23, 163.07; UV (CDCl3)/lmax (nm): 268, 323; MS
(EI): m/z: 556 (M+, 10), 329 (100), 314 (18), 227 (40), 211 (20),
198 (23), 104 (50), 78 (23); Anal. Calcd for C34H24O2N2S2:
C, 73.38; N, 5.04; O, 5.75; S, 11.51; H, 4.32. Found: C, 72.95;
N, 5.15; O, 6.22; S, 11.33; H, 4.34.
2,20-[1,5-Pentane-3-oxadiylbis(2-phenoxy)]bis(benzothiazole)
(3e). Pale yellow solid; mp 124–126ꢁC; IR (KBr)/υ (cmꢀ1): 1586
(s, C═N), 1497 (s, C═C), 751 (s, C—S), 1251 (s, C—O, Ar),
1293 (s, C—O, Al), 1450 (s, CH2), 3055 (w, C—H, Ar), 2928
1
(w, C—H, Al); H-NMR (CDCl3, 400MHz)/d ppm: 4.23 (t, 4H),
4.43 (t, 4H), 7.05(d, 2H), 7.13 (t, 2H), 7.32 (t, 2H), 7.41 (t, 2H),
7.48 (t, 2H), 7.80 (d, 2H), 8.08 (d, 2H), 8.53 (d, 2H); 13C-NMR
(CDCl3, 100MHz)/d ppm: 68.62, 69.81, 112.60, 121.18, 121.49,
122.54, 122.77, 124.64, 125.92, 129.70, 131.78, 136.06,
152.08, 156.40, 163.07; UV (CDCl3)/lmax (nm): 236, 323; MS
(EI): m/z: 524 (M+, 8), 404 (10), 314 (4), 297 (100), 282 (50), 270
(46), 253 (45), 240 (40), 227 (81), 211 (41), 198 (25), 183 (10),
171 (7), 154 (12), 139 (9); Anal. Calcd for C30H24O3N2S2:
C, 68.7; N, 5.34; O, 9.16; S, 12.21; H, 4.58. Found: C, 69.21;
N, 5.34; O, 8.95; S, 12.11; H, 4.23.
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2,20-[1,8-Octane-3,6-dioxadiYLbis(2-phenoxy)]bis(benzothiazole)
(3f). Pale yellow solid; mp 104–106ꢁC; IR (KBr)/υ (cmꢀ1): 1582
(s, C═N), 1492 (s, C═C), 757 (s, C—S), 1250 (s, C—O, Ar),
1295 (s, C—O, Al), 1451 (s, CH2), 3056 (w, C—H, Ar), 2886
1
(w, C—H, Al); H-NMR (CDCl3, 400 MHz)/d ppm: 3.86 (s, 4H),
4.07 (t, 4H), 4.32 (t, 4H), 6.98 (d, 2H), 7.12 (t, 2H), 7.31 (t, 2H),
7.40 (td, 2H), 7.47 (t, 2H), 7.89 (d, 2H), 8.07 (d, 2H), 8.54
(d, 2H); 13C-NMR (CDCl3, 100MHz)/d ppm: 68.36, 69.62, 71.01,
112.52, 121.16, 121.33, 122.42, 122.78, 124.58, 125.88, 129.59,
131.74, 136.16, 152.09, 156.41, 163.15; UV (CDCl3)/lmax (nm):
237, 325; MS (EI): m/z: 568 (M+, 8), 448 (10), 358 (4), 341 (100),
326 (50), 314 (46), 297 (45), 282 (40), 270 (35), 253 (33), 240
(30), 227 (81), 211 (41), 198 (25), 183 (10), 171 (7), 154 (12),
139 (9); Anal. Calcd for C32H28O4N2S2: C,68.09; N, 4.96;
O, 11.35; S, 11.26; H, 4.96. Found: C, 68.09; N, 5.15; O, 11.20;
S, 10.85; H, 5.05.
Acknowledgment. The authors are grateful to University of
Kashan for supporting this work by grant no. 159148/6.
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