Solvent-free synthesis of 2-aryl and 2-alkylbenzothiazoles on silica gel under microwave irradiation

Article abstract of DOI:10.1081/SCC-200026663

2-Substituted benzothiazoles have been synthesized by the condensation of o-aminothiophenol and aromatic or aliphatic aldehydes in the presence of silica gel under microwave irradiation (MW) and solvent-free conditions. The silica gel can be easily recovered and reused for subsequent reactions without loss of the activity.

Full text of DOI:10.1081/SCC-200026663

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Solvent‐Free Synthesis
of 2‐Aryl and
2‐Alkylbenzothiazoles on
Silica Gel Under Microwave
Irradiation
Mitsuo Kodomari a , Yoshimi Tamaru a & Tadashi
Aoyama b
a Department of Applied Chemistry, Shibaura
Institute of Technology, Shibaura, Minato‐ku,
Tokyo, 108‐8548, Japan
b Department of Materials and Applied Chemistry,
Faculty of Science and Engineering, Nihon
University, Chiyoda‐ku, Tokyo, Japan
Published online: 06 Jan 2011.
To cite this article: Mitsuo Kodomari , Yoshimi Tamaru & Tadashi Aoyama (2004)
Solvent‐Free Synthesis of 2‐Aryl and 2‐Alkylbenzothiazoles on Silica Gel Under
Microwave Irradiation, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 34:16, 3029-3036, DOI:
10.1081/SCC-200026663
To link to this article: http://dx.doi.org/10.1081/SCC-200026663
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 16, pp. 3029–3036, 2004
Solvent-Free Synthesis of 2-Aryl and
2-Alkylbenzothiazoles on Silica Gel
Under Microwave Irradiation
1
2
Mitsuo Kodomari,1, Yoshimi Tamaru, and Tadashi Aoyama
*
1Department of Applied Chemistry, Shibaura Institute of Technology,
Shibaura, Minato-ku, Tokyo, Japan
2Department of Materials and Applied Chemistry, Faculty of Science and
Engineering, Nihon University, Chiyoda-ku, Tokyo, Japan
ABSTRACT
2-Substituted benzothiazoles have been synthesized by the condensation
of o-aminothiophenol and aromatic or aliphatic aldehydes in the presence
of silica gel under microwave irradiation (MW) and solvent-free con-
ditions. The silica gel can be easily recovered and reused for subsequent
reactions without loss of the activity.
Key Words: 2-Arylbenzothiazole; 2-Alkylbenzothiazole; Silica gel;
Microwave irradiation.
*
Correspondence: Mitsuo Kodomari, Department of Applied Chemistry, Shibaura
Institute of Technology, Shibaura, Minato-ku, Tokyo 108-8548, Japan; E-mail:
kodomari@sic.shibaura-it.ac.jp.
3029
DOI: 10.1081/SCC-200026663
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3030
Kodomari, Tamaru, and Aoyama
INTRODUCTION
2-Substituted benzothiazoles are an important class of compounds in
medicinal and organic chemistry. The benzothiazoyl-moiety is a structure
element of compounds with potent and selective antitumor activity. For
example, 2-(4-aminophenyl)benzothiazoles exhibit nanomolar inhibitory
activity against a range of human breast, ovarian, colon, and renal cell lines
in vitro.[1] The benzothiazole nucleus is a key element in some thermally
stable rigid-rod polymer possessing high tensile strength and modulus.[2]
There are many methods for the synthesis of 2-arylbenzothiazoles. The
most common direct method is the condensation of an ortho-aminothiophenol
with the substituted aromatic aldeydes[3] and carboxylic acids or its derivatives
in polyphosphoric acid (PPA),[4] polyphosphate ester,[5] or a mixture of methane-
sulfonic acid and phosphorous pentoxide.[6] Other methods include potassium
ferricyanide cyclization of thiobenzanilides (Jacobson’s method),[7] reaction
of a,a,a-trihalomethyl aromatic compounds with o-aminothiophenol in
PPA,[8] palladium-catalyzed reaction of aryl halides with o-aminothiophenol
in the presence of carbon monoxide,[9] reaction of 2,20-dinitrodiphenyl disul-
fide with acid chlorides or acid anhydrides in the presence of TiCl4/Sm,[10]
and ceric ammonium nitrate mediated reaction of thiophenols and aromatic
nitriles.[11] Some methods have been used successfully for the preparation of
2-arylbenzothiazoles. However, most of these methods suffer from drawbacks,
namely high thermal conditions, long reaction time and the use of acid or base
catalysts and toxic metallic compounds that result in waste streams. In recent
years, the use of microwave irradiation (MW) to simplify and improve classi-
cal organic reactions has become a very popular method,[12] because it often
leads to high yields, clean reactions, and shorter reaction times. Solvent-free
organic synthesis using MW and inorganic supports have attracted immense
interest as environmentally benign methodologies.[13]
The methods for the synthesis of benzothiazoles using MW under solvent-
free conditions have been reported as follows; a condensation of orthoesters
with o-aminothiophenol using KFS clay,[14] benzaldoximes or aromatic alde-
hydes with o-aminothiophenol using Ca(OCl)2/Al2O3 or MnO2/SiO2,[15]
b-chlorocinnamaldehydes with o-aminothiophenol using p-toluenesulfonic
acid,[16] and aromatic aldehydes with o-aminothiophenol in an ionic liquid.[17]
We have carried out the reaction of aromatic or aliphatic aldehydes with
o-aminothiophenol in the presence of silica gel under MW and solvent-free
conditions (Sch. 1).
It has been found that the 2-arylbenzothiazoles and 2-alkylbenzothiazoles
were obtained in good yield, respectively. In order to determine the optimum
conditions for synthesis of 2-arylbenzothiazoles in faster and more efficient
way, molar ratios of reagents and the irradiation time and power level of

Synthesis of 2-Substituted Benzothiazoles
3031
Scheme 1.
microwave set-up were investigated. After some experimentation, we have
found a set of conditions that generally provides 2-arylbenzothiazoles in
good yields. The optimum conditions employed are that a molar ratio of alde-
hyde and o-aminothiophenol is 1 : 2 and irradiation time and power level of
microwave set-up are 5 min and 600 W. Although 2,20-diaminodiphenyl
disulfide was formed along with the 2-arylbenzothiazoles that could be
easily isolated by passing through a column of silica gel. Substituted aromatic
aldehydes react with o-aminothiophenol in the presence of silica gel under
MW to afford the corresponding 2-arylbenzothiazoles in good yield. The
silica gel is easily recovered from the reaction mixture and reused for sub-
sequent reactions.
The results are summarized in Table 1. As shown in the table, the 2-
arylbenzothiazoles were obtained in good yield independent of substituents
on the aryl rings, with the exception of nitro and hydroxy groups. The reaction
proceeded efficiently in the presence of silica gel and are completed within
5 min under solvent-free and MW conditions. The same reactions took 3–
4 hr under oil-bath heating to afford comparable yields with those obtained
by MW. The yield of 2-arylbenzothiazoles bearing hydroxyl or nitro group
at para position on the aryl ring is lower than that of the 2-arylbenzothiazoles
bearing hydroxyl or nitro group at ortho position on the aryl ring. It seems that
the low reactivity of benzaldehydes bearing nitro and hydroxy groups at para
position is due to these groups being absorbed more strongly on the surface of
silica gel than that of a carbonyl group on the same aryl ring. Therefore the
carbonyl group in the benzaldehydes bearing nitro and hydroxy group at
para position is less activated than that in benzaldeydes bearing the other sub-
stituents. Reaction of aromatic heterocyclic compounds with o-aminothiophe-
nol afforded the corresponding 2-heteroarylbenzothiazoles in good to high
yield. For instance, a mixture of 3-pyridinecarboxaldehyde and o-aminothio-
phenol supported on silica gel was irradiated in a microwave oven at 600 W
for 5 min to give 2-(3-pyridinyl)-benzothiazole in 95% yield. Aliphatic alde-
hydes also reacted with o-aminothiophenol under similar conditions to give
the corresponding 2-alkylbenzothiazoles (Sch. 2). However, the yields were
lower than that of the aromatic aldehydes (Table 2).
A mixture of aldehyde and o-aminothiophenol supported on silica gel was
subjected to MW intermittently. Thus, MW was carried out for 5 min followed

3032
Kodomari, Tamaru, and Aoyama
Table 1. Solvent-free synthesis of 2-arylbenzothiazoles.a
Yield
(%)b
Compound
Ar
M.p./8C (lit.)
3a
3b
3c
3d
3e
3f
C6H5
93
92
97
70
88
53
87
84
82
61
75
94
113–114 (113[16]
)
4-CH3C6H4
2-CH3C6H4
4-CH3OC6H4
2-CH3OC6H4
4-HOC6H4
2-HOC6H4
4-ClC6H4
85 (85[3]
53–54
)
121–122 (119–121[16]
101–102
)
)
227 (227–228[3]
)
3g
3h
3i
131–132 (127–128[3]
117–118 (119–121[16]
)
2-ClC6H4
4-NO2C6H4
2-NO2C6H4
81–82 (84–85[15]
)
3j
230–231 (229–230[16]
127–128 (135–136[15]
)
)
3k
3l
134–135 (135–136[3]
)
3m
73
159–160 (158–160[17]
)
3n
3o
84
78
99 (98–100[17]
)
103–104 (103[3]
)
aAll reactions were carried out using aldehyde (1 mmol), o-aminothiophenol (2 mmol),
and silica gel (2 g) under microwave irradiation at 600 W for 5 min.
bBy GLC.
by mixing for 2 min outside the oven. This intermittent irradiation-mixing
cycle was repeated two times. The reaction of propionaldehyde with
o-aminothiophenol was carried out under MW for 5 min to afford 2-ethylbenzo-
thiazole in 37% yield. In contrast, the same reaction under intermittent
irradiation for 10min afforded 76% yield of it. The yield was not increased
when total irradiation time was prolonged more than 10min. The yield of
2-alkylbenzothiazoles did not depend on the length of alkyl chain of aliphatic
aldehydes and was moderate.
Scheme 2.

Synthesis of 2-Substituted Benzothiazoles
Table 2. Solvent-free synthesis of 2-alkylbenzothiazoles.a
3033
Yield
(%)b
Compound
R
5a
5b
5c
5d
5e
5f
CH2CH3
CH2CH2CH3
CH(CH3)2
76
67
61
66
83
71
68
CH2CH2CH2CH3
CH2CH(CH3)2
CH(CH2CH3)2
CH2CH2CH2CH2CH2CH3
5g
aAll reactions were carried out using aldehyde (1 mmol), o-ami-
nothiophenol (2 mmol) and silica gel (2 g) under intermittent
irradiation (2 ꢀ 5 min).
bBy GLC.
In summary, we have developed a simple, convenient, and rapid method
for the synthesis of 2-substituted benzothiazoles from aldehydes and
o-aminothiophenol in the presence of silica gel without solvent under MW.
The present method avoids the use of hazardous solvent, toxic catalysts,
and extended reaction times.
EXPERIMENTAL
Silica gel for column chromatography was used as a solid support without
any treatment. The MW was carried out using an unmodified domestic oven
operated at 2450MHz. Melting points were uncorrected. IR spectra were
recorded on a Horiba FT-710 spectrometer in KBr with absorptions in cm21
.
1H NMR spectra were recorded on JEOL JNM-LA 300 and TMS was used
as internal standard. Mass spectra were recorded on JEOL-600H at 70eV. Pro-
ducts were characterized by comparison of their spectroscopic data (1H NMR,
IR and Mass) and Melting points with those reported in the literature.
General Procedure for the Synthesis of 2-Arylbenzothiazoles 3
To a solution of aromatic aldehyde (3 mmol) and o-aminothiophenol
(6 mmol) in diethyl ether (10 mL) was added silica gel (3 g). The slurry was
mixed thoroughly and the solvent was removed by rotary evaporation. The
solid obtained was subjected to MW using a domestic microwave oven oper-
ated at 600 W for 5 min. After cooling, the product was extracted with ethyl

3034
Kodomari, Tamaru, and Aoyama
acetate. The extract was filtered and the filtrate was evaporated under reduced
pressure to leave the crude product. The product was purified by column
chromatography on silica gel (hexane : ethyl acetate ¼ 10 : 1) or recrystalliza-
tion in methanol.
2-(2-Methylphenyl)-benzothiazole (3c). White crystals, mp 53–548C
(methanol); 1H NMR (CDCl3, 300 MHz) d: 2.65 (s, 3H), 7.26–7.41 (m, 4H),
7.50 (t, 1H, J ¼ 7.6 Hz), 7.75 (d, 1H, J ¼ 7.5 Hz), 7.90 (d, 1H, J ¼ 7.9 Hz), 8.1
(d, 1H, J ¼ 8.0 Hz); MS m/z (%): 225 (Mþ, 100), 113 (48), 108 (19), 91 (25),
82 (11), 69 (23).
2-(2-Methoxyphenyl)-benzothiazole (3e). White crystals, mp 101–
1
1028C (methanol); H NMR (CDCl3, 300 MHz) d: 4.02 (s, 3H), 7.02–7.15
(m, 2H), 7.33–7.50 (m, 3H), 7.91 (d, 1H, J ¼ 7.9 Hz), 8.09 (d, 1H,
J ¼ 8.0 Hz), 8.53 (d, 1H, J ¼ 7.7 Hz); MS m/z (%): 241 (Mþ, 100), 211
(63), 208 (34), 136 (67), 108 (44), 82 (20), 69 (41).
General Procedure for the Synthesis of 2-Alkylbenzothiazoles 5
To a mixture of aliphatic aldehyde (3 mmol) and o-aminothiophenol
(6 mmol) in diethylether (10 mL) silica gel (3 g) was added. The slurry was
mixed thoroughly and the solvent was removed by rotary evaporation. The
solid obtained was subjected to MW at 600 W for 5 min. The reaction
mixture was then mixed outside the oven for 2 min and again irradiated for
another 5 min. After cooling, the product was extracted with ethyl acetate.
The extract was filtered and the filtrate was evaporated under reduced pressure
to leave the crude product. The crude product was purified by Kugelrohr
distillation under vacuum or chromatography on silica gel.
2-Ethylbenzothiazole (5a). Colorless liquid; 1H NMR (CDCl3,
300 MHz) d: 1.43 (t, 3H, J ¼ 7.6 Hz), 3.10 (q, 2H, J ¼ 7.6 Hz), 7.28 (t, 1H,
J ¼ 7.6 Hz), 7.40 (t, 1H, J ¼ 7.6 Hz), 7.78 (d, 1H, J ¼ 8.0Hz), 7.96 (d, 1H,
J ¼ 8.0Hz); MS m/z (%): 163 (Mþ, 56), 162 (100), 148 (15), 136 (11), 109
(17), 82 (6), 69 (15).
2-iso-Propylbenzothiazole (5c). Colorless liquid; 1H NMR (CDCl3,
300 MHz) d: 1.48 (d, 6H, J ¼ 7.0 Hz), 3.35–3.49 (m, 1H), 7.33 (t, 1H,
J ¼ 7.6 Hz), 7.44 (t, 1H, 7.6 Hz), 7.84 (d, 1H, J ¼ 8.3 Hz), 7.98 (d, 1H,
J ¼ 8.3 Hz); MS m/z (%): 177 (Mþ, 97), 162 (100), 149 (77), 135 (80), 109
(87), 82 (26), 69 (53).
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Received in Japan February 23, 2004