Efficient synthesis of 2-arylbenzothiazole derivatives with the aid of a low-valent titanium reagent

Article abstract of DOI:10.1080/00397910903227230

A novel and facile synthesis of 2-arylbenzothiazole derivatives was accomplished in good yields via the novel reductive cyclization of bis-(2-benzalaminophenyl)disulfide promoted by the TiCl4/Sm system. The advantages of this new method are the easily accessible starting materials, short reaction time, and moderate to good yields. Copyrigh

Full text of DOI:10.1080/00397910903227230

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Efficient Synthesis of 2-
Arylbenzothiazole Derivatives with the
Aid of a Low-Valent Titanium Reagent
Da-Qing Shi a , Shao-Feng Rong b & Guo-Lan Dou a
a Key Laboratory of Organic Synthesis of Jiangsu Province, College
of Chemistry, Chemical Engineering and Materials Science, Soochow
University, Suzhou, China
b College of Chemistry and Chemical Engineering, Xuzhou Normal
University, Xuzhou, China
Published online: 07 Jul 2010.
To cite this article: Da-Qing Shi , Shao-Feng Rong & Guo-Lan Dou (2010): Efficient Synthesis
of 2-Arylbenzothiazole Derivatives with the Aid of a Low-Valent Titanium Reagent, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:15, 2302-2310
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Synthetic Communications1, 40: 2302–2310, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903227230
EFFICIENT SYNTHESIS OF 2-ARYLBENZOTHIAZOLE
DERIVATIVES WITH THE AID OF A LOW-VALENT
TITANIUM REAGENT
Da-Qing Shi,1 Shao-Feng Rong,2 and Guo-Lan Dou1
1Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou, China
2College of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou, China
A novel and facile synthesis of 2-arylbenzothiazole derivatives was accomplished in good
yields via the novel reductive cyclization of bis-(2-benzalaminophenyl)disulfide promoted
by the TiCl4/Sm system. The advantages of this new method are the easily accessible
starting materials, short reaction time, and moderate to good yields.
Keywords: 2-Arylbenzothiazole; low-valent titanium reagent; reductive cyclization
INTRODUCTION
Benzothioazole derivatives are an important class of compounds that can be
utilized as not only a wide variety of biologically active and medicinally significant
compounds including Gram-positive antibacterial, antimicrobial, anti-HIV, anti-
biotic, anticancer, and antiparasitic agents[1] but also as advanced materials includ-
ing liquid crystals, nonlinear optics (NLO), organic light-emitting diodes (OLED),
heat-resistant fibers, whitening agents, and constituents of cyanine dyes.[2]
A number of methods have been reported for the synthesis of 2-arylbenzothia-
zole, which include condensation of thiobenzoic acid,[3] benzaldehyde,[4] 2-dibenzyl-
disulfane,[5] benzoyl chloride,[6] 3-oxo-3-phenylpropionic acid ethyl ester,[7]
benzonitrile,[8] and trichloromethylbenzene[9] with 2-aminobenzenethiol; radical
cyclization of phenylthioformamides promoted by potassium ferricyanide;[10]
palladium (Pd)–catalyzed cyclization of 2-bromophenylthioformamides;[11] flash
vacuum pyrolyses and photolyses of 2-methylthio-N-(arenylidene)anilines;[12] the
reaction of 2-chlorobenzothiazole and phenylmagnesium chloride with mangane-
se(II) chloride;[13] and oxidation of 2-phenyl-2,3-dihydrobenzothiazole.[14] Although
these methods have successfully led to
a
large library synthesis of
Received April 16, 2009.
Address correspondence to Da-Qing Shi, Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University,
Suzhou 215123, China. E-mail: dqshi@suda.edu.cn
2302

SYNTHESIS OF 2-ARYLBENZOTHIAZOLE DERIVATIVES
2303
2-arylbenzothiazoles, many still suffer from drawbacks such as unsatisfactory yields,
long reaction times, side reactions, expensive catalyst, high temperature, and inac-
cessible starting materials. Therefore, the development of more efficient methods
for the preparation of this kind of compound is still an active ongoing research area,
and there is scope for further improvement toward milder reaction conditions and
improved yields. In this article, we describe a new route to 2-arylbenzothiazole.
Low-valent titanium reagents have an exceedingly good ability to promote
reductive coupling of carbonyl compounds and are attracting increasing interest in
organic synthesis.[15] Many other functional groups can also be coupled.[16] Recently,
we have reported some intermolecular reductive coupling reaction induced by
low-valent titanium reagents (TiCl4=Sm system).[17]
RESULTS AND DISCUSSION
When bis-(2-benzalaminophenyl)disulfide 1 was treated with low-valent
titanium prepared from titanium tetrachloride and samarium powder in anhydrous
tetrahydrofuran (THF), the cyclization product 2-arylbenzothiazole 2 was obtained
(Scheme 1).
In a preliminary study, bis-(2-(4-methylbenzalamino)phenyl)disulfide (1b),
which was readily prepared by a literature procedure,[4b] was used to define the
reaction conditions for the reductive cyclization (Scheme 2). Different low-valent
titanium reagent systems were examined. The results of these comparative experi-
ments are summarized in Table 1. From the results, it is obvious that the TiCl4=
Sm system (entry 2) demonstrates superior activity and is the best reductive reagent
among those examined. Further optimization of the reaction conditions revealed
that a 1:2 ratio of TiCl4 and Sm at 40 ꢀC gave better results than those under the
other reaction conditions (entry 5–9, Table 1).
To apply this reaction to a library synthesis, various kinds of bis-(2-benzalami-
nophenyl)disulfides were reacted to give the corresponding 2-aryl-benzothiazole, and
representative examples are shown in Table 2. Most of the bis-(2-benzalaminophe-
nyl)disulfides gave the expected products in moderate to good yields, either bearing
Scheme 1. The synthesis of 2-arylbenzothiazole.
Scheme 2. Model reaction for the optimization of reaction conditions.

2304
D.-Q. SHI, S.-F. RONG, AND G.-L. DOU
Table 1. Optimization of low-valent titanium system (TiCl4=Sm ratio) and tempera-
ture in the synthesis of 2-arybenzothiazole (2b)
Entry
M
Ratioa
Temperature (ꢀC)
Yield (%)
1
2
3
4
5
6
7
8
9
Zn
Sm
Al
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
1:3
rt
rt
65
75
45
60
91
78
0
rt
Fe
rt
40
Sm
Sm
Sm
Sm
Sm
60
Reflux
40
40
60
0
aRatio of TiCl4 and M.
electron-withdrawing groups (such as halide) or electron-donating groups (such as
alkyl and alkoxyl groups) under the same reaction conditions. Therefore, we con-
cluded that the electronic nature of the substituents has no significant effects on this
reaction. However, when the aromatic group were 2-chlorophenyl and 2,4-dichloro-
phenyl, the desired products were not obtained. We think that the steric hindrance
effect plays a critical role in this reaction. All the products were characterized by
1
infrared (IR) and H NMR.
We propose the following possible mechanism to account for the reaction.
Compound 1 is reduced by Ti(0) to free radical 3 and negative ion 4. Negative ion
h
=
4 cyclizes by the nucleophilic attrack of S on C N group to give the intermediate
5. Finally, the expected product 2 is obtained by aromatization (Scheme 3).
In summary, a series of 2-arylbenzothiazoles were synthesized via reductive
cyclization of bis-(2-benzalaminophenyl)disulfides promoted by the TiCl4=Sm sys-
tem. The advantages of this new method are the easily accessible starting materials,
short reaction time, and moderate to excellent yields.
EXPERIMENTAL
All reagents were used as received. THF was distilled from sodium–
benzophenone immediately prior to use. All the reactions were conducted under
an N2 atmosphere. Melting points were determined in open capillaries and are
uncorrected. IR spectra were recorded on a Varian 1000 Fourier transform (FT)–
1
IR spectrometer in KBr with absorptions in centimetersꢁ1. H NMR (400 MHz)
spectra were recorded on a Varian Invoa 400-MHz spectrometer in dimethylsulfox-
ide (DMSO-d6). J values are in hertz. Chemical shifts are expressed in parts per mil-
lion downfield from internal standard TMS.
General Procedure for the Synthesis of 2-Arylbenzothiazole (2)
TiCl4 (0.4 mL, 3 mmol) was added dropwise using a syringe to a stirred suspen-
sion of samarium powder (0.9 g, 6 mmol) in freshly distilled anhydrous THF (10 mL)
at rt under a dry N2 atmosphere. After completion of the addition, the mixture was
refluxed for 2 h. The suspension of low-valent titanium reagent formed was cooled to

SYNTHESIS OF 2-ARYLBENZOTHIAZOLE DERIVATIVES
2305
Table 2. Synthesis of 2-arybenzothiazole via the TiCl4=Sm–mediated reductive cyclization of bis-
(2-benzalaminophenyl)disulfide
Entry
Substratea
Product
Yield (%)b
2a
70
2b
2c
2d
91
81
88
2e
2f
82
89
2g
2h
2i
79
69
92
(Continued )

2306
D.-Q. SHI, S.-F. RONG, AND G.-L. DOU
Table 2. Continued
Entry
Substratea
Product
Yield (%)b
2j
65
2k
52
aAll substrates were prepared according to the literature procedure.[4b]
bIsolated yields by recrystallization from acetone.
Scheme 3. A proposed mechanism for the synthesis of 2-arylbenzothiazole.
rt, and a solution of bis-(2-benzalaminophenyl)disulfide (1 mmol) in THF (10 mL)
was added dropwise. The reaction mixture was stirred at 40 ꢀC for 10 min under
an N2 atmosphere. After this period, the TLC analysis of the mixture showed the
reaction to be completed. The reaction mixture was quenched with 5% HCl
(30 mL) and extracted with ClCH2CH2Cl (3 ꢂ 30 mL). The combined extracts were
washed with water (2 ꢂ 50 mL) and dried over anhydrous Na2SO4. After evaporation
of the solvent under reduced pressure, the crude products were purified by recrystal-
lization from acetone.
2-Phenylbenzothiazole (2a)
Yellow solid. Mp 115–116 ꢀC (lit.[4a] mp 113–114 ꢀC). IR (KBr) cmꢁ1: 3064,
1554, 1479, 1433, 1314, 1283, 1253, 1225, 1159, 1070, 963, 766, 729, 686. 1H
NMR (400 MHz, DMSO-d6) (d, ppm): 7.45–7.61 (m, 5H, ArH), 8.07–8.12 (m, 3H,
ArH), 8.16 (d, J ¼ 8.0 Hz, 1H, ArH).
2-(4-Methylphenyl)benzothiazole (2b)
Yellow solid. Mp 85–86 ꢀC (lit.[4a] mp 85 ꢀC). IR (KBr) cmꢁ1: 3058, 3023, 2915,
2856, 2731, 1609, 1482, 1433, 1407, 1312, 1378, 1252, 1228, 1121, 1181, 961, 818, 758,

SYNTHESIS OF 2-ARYLBENZOTHIAZOLE DERIVATIVES
2307
1
729, 692. H NMR (400 MHz, DMSO-d6) (d, ppm): 2.40 (s, 3H, CH3), 7.39 (d,
J ¼ 10.4 Hz, 2H, ArH), 7.45 (t, J ¼ 10.0 Hz, 1H, ArH), 7.55 (t, J ¼ 10.0 Hz, 1H,
ArH), 7.99 (d, J ¼ 10.4 Hz, 2H, ArH), 8.05 (d, J ¼ 10.8 Hz, 1H, ArH), 8.14 (d,
J ¼ 10.4 Hz, 1H, ArH).
2-(4-Methoxyphenyl)benzothiazole (2c)
Yellow solid. Mp 134–135 ꢀC (lit.[4a] mp 133–135 ꢀC). IR (KBr) cmꢁ1: 2835,
1605, 1521, 1485, 1434, 1412, 1310, 1260, 1226, 1172, 1114, 1027, 969, 833, 758,
1
730, 692. H NMR (400 MHz, DMSO-d6) (d, ppm): 3.85 (s, 3H, OCH3), 7.10–7.14
(m, 2H, ArH), 7.40–7.44 (m, 1H, ArH), 7.50–7.54 (m, 1H, ArH), 8.00–8.06 (m,
3H, ArH), 8.10 (d, J ¼ 8.0 Hz, 1H, ArH).
2-(3,4-Methylenedioxyphenyl)benzothiazole (2d)
Yellow solid. Mp 125–126 ꢀC (lit.[18] mp 126–127 ꢀC). IR (KBr) cmꢁ1: 2907,
1497, 1475, 1435, 1353, 1311, 1257, 1239, 1096, 1038, 979, 936, 883, 850, 761, 729.
1H NMR (400 MHz, DMSO-d6) (d, ppm): 6.16 (s, 2H, OCH2O), 7.08–7.10 (m,
1H, ArH), 7.41–7.45 (m, 1H, ArH), 7.50–7.54 (m, 1H, ArH), 7.60–7.63 (m, 2H,
ArH), 8.01 (d, J ¼ 7.6 Hz, 1H, ArH), 8.10 (d, J ¼ 8.0 Hz, 1H, ArH).
2-(3,4-Dimethoxyphenyl)benzothiazole (2e)
Yellow solid. Mp 129–131 ꢀC (lit.[3] mp 132–134 ꢀC). IR (KBr) cmꢁ1: 2965,
2939, 2841, 1599, 1522, 1482, 1431, 1337, 1262, 1167, 1074, 1018, 943, 875, 808,
1
764, 733, 696. H NMR (400 MHz, DMSO-d6) (d, ppm): 3.85 (s, 3H, OCH3), 3.89
(s, 3H, OCH3), 7.13 (d, J ¼ 8.0 Hz, 1H, ArH), 7.41–7.45 (m, 1H, ArH), 7.50–7.54
(m, 1H, ArH), 7.61–7.65 (m, 2H, ArH), 8.03 (d, J ¼ 7.6 Hz, 1H, ArH), 8.10 (d,
J ¼ 8.0 Hz, 1H, ArH).
2-(3,4,5-Trimethoxyphenyl)benzothiazole (2f)
White solid. Mp 145–146 ꢀC (lit.[19] mp 141–144 ꢀC). IR (KBr) cmꢁ1: 2836,
1583, 1518, 1487, 1463, 1430, 1413, 1333, 1281, 1251, 1228, 1162, 990, 888, 844,
1
809, 763, 733. H NMR (400 MHz, DMSO-d6) (d, ppm): 3.76 (s, 3H, OCH3), 3.92
(s, 6H, 2 ꢂ OCH3), 7.35 (s, 2H, ArH), 7.44–7. 48 (m, 1H, ArH), 7.53–7.57 (m, 1H,
ArH), 8.07 (d, J ¼ 7.6 Hz, 1H, ArH), 8.14 (d, J ¼ 8.0 Hz, 1H, ArH).
2-(4-Chlorophenyl)benzothiazole (2g)
Yellow solid. Mp 119–120 ꢀC (lit.[4a] mp 117–119 ꢀC). IR (KBr) cmꢁ1: 3055,
2990, 1646, 1569, 1506, 1589, 1474, 1434, 1399, 1315, 1251, 1227, 1174, 1089,
1
1012, 971, 828, 756, 730, 691. H NMR (400 MHz, DMSO-d6) (d, ppm): 7.46–7.50
(m, 1H, ArH), 7.54–7.58 (m, 1H, ArH), 7.62–7.65 (m, 2H, ArH), 8.06–8.11 (m,
3H, ArH), 8.16 (d, J ¼ 8.0 Hz, 1H, ArH).

2308
D.-Q. SHI, S.-F. RONG, AND G.-L. DOU
2-(4-Bromophenyl)benzothiazole (2h)
White solid. Mp 131–132 ꢀC (lit.[20] mp 132–133 ꢀC). IR (KBr) cmꢁ1: 3057,
1507, 1476, 1433, 1396, 1314, 1068, 1012, 971, 827, 753, 721, 684. 1H NMR
(400 MHz, DMSO-d6) (d, ppm): 7.47–7.51 (m, 1H, ArH), 7.55–7.59 (m, 1H, ArH),
7.77–7.79 (m, 2H, ArH), 8.04 (d, J ¼ 8.4 Hz, 2H, ArH), 8.08 (d, J ¼ 8.0 Hz, 1H,
ArH), 8.17 (d, J ¼ 8.0 Hz, 1H, ArH).
2-(3,4-Bichlorophenyl)benzothiazole (2i)
Yellow solid. Mp 118–120 ꢀC (lit.[21] mp 115–116 ꢀC). IR (KBr) cmꢁ1: 1557,
1
1501, 1456, 1432, 1374, 1310, 1231, 1136, 1027, 985, 865, 824, 757, 725, 690. H
NMR (400 MHz, DMSO-d6) (d, ppm): 7.48–7.52 (m, 1H, ArH), 7.56–7.59 (m, 1H,
ArH), 7.81–7.84 (m, 1H, ArH), 8.03–8.05 (m, 1H, ArH), 8.08 (d, J ¼ 8.0 Hz, 1H,
ArH), 8.18 (d, J ¼ 8.0 Hz, 1H, ArH), 8.27–8.28 (m, 1H, ArH).
2-(4-N,N-Dimethylaminophenyl)benzothiazole (2j)
Yellow solid. Mp 170–172 ꢀC (lit.[19] mp 174–175 ꢀC). IR (KBr) cmꢁ1: 3053,
2900, 2815, 1609, 1486, 1430, 1369, 1314, 1227, 1188, 1012, 963, 943, 817, 752,
1
721, 688. H NMR (400 MHz, DMSO-d6) (d, ppm): 3.02 [s, 6H, N(CH3)2], 6.82
(d, J ¼ 8.8 Hz, 2H, ArH), 7.36 (t, J ¼ 7.4 Hz, 1H, ArH), 7.47 (t, J ¼ 7.6 Hz, 1H,
ArH), 7.88–7.94 (m, 3H, ArH), 8.03 (d, J ¼ 8.0 Hz, 1H, ArH).
2-(2-Thiophenyl)benzothiazole (2k)
Brown solid. Mp 94–96 ꢀC (lit.[3] mp 98–100 ꢀC). IR (KBr) cmꢁ1: 3094, 3056,
1591, 1541, 1475, 1435, 1416, 1314, 1223, 1125, 1078, 1053, 1009, 941, 912, 852,
1
826, 761, 713. H NMR (400 MHz, DMSO-d6) (d, ppm): 7.24–7.26 (m, 1H, ArH),
7.42–7.46 (m, 1H, ArH), 7.50–7.54(m, 1H, ArH), 7.84–7.85 (m, 1H, ArH), 7.88 (d,
J ¼ 4.8 Hz, 1H, ArH) 8.00 (d, J ¼ 8.0 Hz, 1H, ArH), 8.10 (d, J ¼ 8.0 Hz, 1H, ArH).
ACKNOWLEDGMENT
We are grateful to the Foundation of Key Laboratory of Organic Synthesis of
Jiangsu Province for financial support.
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