One-pot synthesis of 2-aryl-and 2-alkylbenzo-thiazoles under microwave irradiation

Article abstract of DOI:10.3987/COM-05-10466

Eco-friendly direct solvent-free reactions of o-aminothiophenol and aromatic or aliphatic β-keto esters with microwave irradiation produced 2-substituted benzothiazoles in excellent yield. Experiments that compared microwave irradiation to conventional heating methods showed that the former gives the 2-substituted benzothiazoles faster and in higher yields. The formation of the titled compounds probably involves the nucleophilic addition of the thiol group to the keto group of the β-keto ester with subsequent elimination of ethyl acetate from the resulting adduct. The adduct then undergoes an intramolecular addition of the o-amino group to the carbonyl group to give an adduct from which water is eliminated to afford the 2- substituted benzothiazoles.

Full text of DOI:10.3987/COM-05-10466

HETEROCYCLES, Vol. 65, No. 9, 2005
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HETEROCYCLES, Vol. 65, No. 9, 2005, pp. 2119 - 2126
Received, 31st May, 2005, Accepted, 20th July, 2005, Published online, 22nd July, 2005
ONE-POT SYNTHESIS OF 2-ARYL- AND 2-ALKYLBENZO-
THIAZOLES UNDER MICROWAVE IRRADIATION
Sukanta Kamila, Hongming Zhang, and Edward R. Biehl*
Department of Chemistry, Southern Methodist University, Dallas, Texas 75275, USA,
Email-ebiehl@smu.edu
Abstract - Eco-friendly direct solvent-free reactions of o-aminothiophenol and
aromatic or aliphatic β-keto esters with microwave irradiation produced
2-substituted benzothiazoles in excellent yield. Experiments that compared
microwave irradiation to conventional heating methods showed that the former
gives the 2-substituted benzothiazoles faster and in higher yields. The formation
of the titled compounds probably involves the nucleophilic addition of the thiol
group to the keto group of the β-keto ester with subsequent elimination of ethyl
acetate from the resulting adduct. The adduct then undergoes an intramolecular
addition of the o-amino group to the carbonyl group to give an adduct from
which water is eliminated to afford the 2- substituted benzothiazoles.
INTRODUCTION
Recently, we have developed synthetic strategies for the preparation of a variety of structurally modified
heterocyclic compounds of medicinal interest.1-4 Here we report on a new method for preparing
2-substituted benzothiazoles. Our interest in these heterocycles comes from several sources. For example,
2-substituted benzothiazoles are active against Nematospiroideas dubius,5 Ascaris suu 6 and Hymemolepis
nana.7 In addition, benzothiazoles possessing 3-pyridinyl derivatives have greater anthelmintic7
activities than unsubstituted benzimidazoles.8a Also, certain benzothiazoles behave as potential
anti-inflammatory agents,8b and many 1,3-benzothiazoles have good fluorescent properties.9
There are several methods 7,8,10 for preparing arylbenzothiazoles. Most of them involve tedious routes or

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require the use of expensive chemicals. The microwave-assisted synthesis11(a) offers considerable
advantages over conventional heating because of rapid heating and substantial rate enhancements of a
wide range of organic reactions. Cleaner reactions are also commonly achieved with marked
improvement in yield and in selectivity.11(b)
Recently, the use of microwave irradiation for one-step syntheses of 2-substituted benzothiazoles by a
two-component system have been reported.12,13 In those studies, a carboxylic acid or aldehyde and
o-aminothiophenol were first supported on silica gel, and then subjected to microwave irradiation to give
the corresponding 2-substitued benzothiazoles in modest yields (61–81%). We report an improved, more
eco-friendly synthesis of 2-substituted benzothiazoles with significantly higher yields (93-99%) by the
reaction of aromatic and aliphatic β-keto esters and o-aminothiophenols under microwave irradiation
without solvent or the use of solid support.
RESULTS AND DISCUSSION
The synthesis of benzothiazoles involves (Scheme1) the microwave (MW) irradiation of a 1:1 equivalent
mixture of o-aminothiophenol and the appropriate alkyl or aryl β-keto ester. The results are shown in
Table 1. Most products obtained were solids and thus were recrystallized from ethyl acetate-hexane
mixtures. The liquid products were purified by column chromatography using a 1:4 solution of ethyl
acetate-hexane as eluent.
S
MW
SH
O
O
R2
R1
R1
N
150 W, 250 psi
240 oC, 4 min
OEt
R2
NH2
1
2
3
Scheme 1
1
13
The structures of 3a-j were assigned on the basis of H NMR and C NMR spectroscopy and in case of
3b by X-Ray crystallographic analysis. An ORTEP drawing of 3b is shown in Figure 1.
The experimental procedure is quite easy; one mixes the o-aminothiophenol and the β-keto ester in a
tightly capped test tube that is then subjected to microwave irradiation (150 W output, 250 psi) without
solvent or solid support. The reactions were performed either under wattage control or temperature
control (240 °C) with no significant differences in reaction times or yields. We also were able to scale up
these reactions to give multi-gram quantities of 3 in similar yields. For example 3 g (98% yield) of
2-phenyl benzothiazole (3a) was obtained from the reaction of o-aminothiophenol (2a) and ethyl benzoyl
acetate (1a) in a one batch reaction.
Marx14 reported that treatment of o-aminothiophenol (2a) with the β-keto ester (1f) in boiling xylene
solution for 30 min gave the seven-membered compound, 2-methyl-6,7-benzo-1-thia-5-azacyclohepta-

HETEROCYCLES, Vol. 65, No. 9, 2005
2121
Table 1 Preparation of Benzothiazoles
β−Keto ester
O
Entry
1
Aminothiophenol
Product
S
Yield, %
98
O
SH
OEt
N
NH2
3a
2a
1a
S
SH
O
O
O
2
N
97
98
OEt
NH2
3b
2a
O
1b
O
O
SH
S
S
3
4
OEt
N
NH2
S
3c
1c
2a
SH
S
O
O
95
93
OEt
NH2
N
2a
1d
3d
S
SH
O
O
N
5
6
OEt
NH2
3e
2a
1e
SH
NH2
2a
S
O
O
Me
N
3f
S
96
OEt
1f
OEt
7
8
N
Cl
NH2
Cl
97
96
3g
2b
1a
O
O
SH
S
O
OEt
N
Cl
Cl
NH2
O
3h
2b
2a
1b
SH
O
O
OMe
S
OEt
NH2
97
99
9
MeO
N
1g
3i
SH
OMe
OMe
OMe
MeO
MeO
S
OEt
10
NH2
N
OMe
2a
1h
3j

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HETEROCYCLES, Vol. 65, No. 9, 2005
Figure 1 ORTEP structure of compound (3b).
benzothiazapine (4) was obtained in only 28% yield (see Scheme 2); none of the expected benzothiazoles
were observed. However, when we repeated the same reaction in xylene with microwave irradiation,
2-methylbenzothiazole (3f), rather than 4, was obtained, but again in a poor yield of 20%.
Me
S
Xylene
O
SH
O
Reflux, 30 min
OEt
Me
N
NH2
H
O
2a
1f
4
Scheme 2
Evidence of the microwave effect in this solvent-free reaction, where the possible specific effects are not
moderated or impeded by solvents, was obtained by comparing yields of 3a from the reactions of 1a and
2a run for 4 min at various temperatures using microwave irradiation and conventional heating. We
started these experiments by running the reactions at room temperature. As these 4-min reactions were
subsequently carried out at increasingly higher temperatures, the relative yields of 3a gradually increased
reaching a maximum at 240 °C where the yield of 3a was ~4 times greater under microwave irradiation
(98%) as compared to that (24%) under conventional heating.
A possible mechanism shown in Scheme 3 involves nucleophilic attack by the sulfur atom of 2 to the
carbonyl carbon rather than the ester carbonyl of 1 with the subsequent elimination of ethyl acetate
affording adduct (5). Ethyl acetate was detected by GC/MS spectral analysis of the reaction mixtures.
Adduct (5) then undergoes intramolecular nucleophilic addition of the amino group to the carbonyl group
to give the 2-hydroxybenzothiazole (6). Elimination of water from 6 affords the product (3).
O
O
S
O
S
SH
S
N
-CH COOEt
OH
3
R
O
R
R
R
R
2
R
2
1
R
2
1
R
1
1
N
H
NH2
NH2
2
1
5
6
3
Scheme 3 Possible Mechanism for the Synthesis of Benzothiazoles (3)

HETEROCYCLES, Vol. 65, No. 9, 2005
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A referee has suggested another possible mechanism which, as shown in Scheme 4, involves the initial
addition of the amino group of 2 rather than the thiol group onto the carbonyl group. There is some
R
SH
SH
O
SH
N
+
HO
R
NH2
R
N
H
CO2Et
CO2Et
2
1
CO2Et
-MeCOOEt
SH
S
R
O
R
N
H
N
H
CO2Et
-MeCOOEt
-HOH
S
OH
3
R
N
H
Scheme 4
literature precedent for this in that Itoh et al.15 have postulated a similar addition between
2 and an aldehyde. At this time, there is not sufficient data to decide upon the two above
mechanism.
CONCLUSIONS
In summary, we have developed a high yield, efficient, solvent free method using microwave irradiation
for the synthesis of 2-alkyl- and 2-arylbenzothiazoles. The yields are for the most part significantly lower
than those obtained in this investigation. The successful use of microwave irradiation in this study
provides yet another example of the participation of specific effects in some microwave-assisted organic
syntheses.
EXPERIMENTAL
General Data: Melting points were taken on a Mel-Temp capillary apparatus and are uncorrected with
respect to stem correction. 1H and 13C NMR spectra were recorded on a 400 MHz Bruker ADVANCE
DRX-400 Multinuclear NMR spectrometer. Chemical shifts are reported in reference to TMS as internal
standard. The microwave irradiation reactions were carried out in a CEM-Driver instrument at 240 °C
and 150 W voltage with 250 PSI pressure. Elemental analyses were obtained from the SMU Analytical

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HETEROCYCLES, Vol. 65, No. 9, 2005
Service Laboratories. All chemicals were purchased from Aldrich Chemicals.
General procedure: The appropriate o-aminothiophenol (1.6 mmol) and aromatic or aliphatic β-keto
ester (1.6 mmol) were mixed and the resulting mixture was heated under MW irradiation condition at
240 °C for 4 min. The resulting solid mixtures were recrystallized from ethyl acetate-hexane to obtain the
titled compounds. The liquid product mixtures were purified by column chromatography using ethyl
acetate-hexane (1:4) as eluent. The results are shown below.
2-Phenylbenzothiazole (3a): Isolated as a white crystalline solid (ethyl acetate-hexane), mp 112–114 °C.
1H NMR (CDCl3) δ 7.41 (dd, J = 2.5, 8.0 Hz, 1H, aromatic), 7.50–7.52 (m, 4H, aromatic), 7.93 (dd, J =
2.5, 7.8 Hz, 1H, aromatic), 8.09–8.10 (m, 3H, aromatic). 13C NMR (CDCl3) δ 122.0, 123.6, 125.6, 126.7,
127.9, 129.4, 131.3, 134.0, 135.5, 154.5, 168.5. Anal. Calcd for C13H9NS: C, 73.90; H, 4.29; N, 6.63.
Found: C, 73.99; H, 4.38; N, 6.70.
2-(Furan-3-yl)benzothiazole (3b): Isolated as a yellow solid (CH2Cl2-hexane), mp 83–84 °C. 1H NMR
(CDCl3) δ 6.99 (s, 1H, aromatic ), 7.39 (dd, J = 7.8, 8.0 Hz, 1H, aromatic), 7.50 (dd, J = 7.8, 8.0 Hz, 1H,
aromatic), 7.55 (s, 1H, aromatic), 7.88 (d, J = 8.0 Hz, 1H, aromatic), 8.04 (d, J = 8.0 Hz, 1H, aromatic),
8.13 (s, 1H, aromatic). 13C NMR (CDCl3) δ 109.6, 121.9, 122.2, 123.2, 125.5, 126.7, 134.7, 143.0, 144.6,
154.1, 160.0. Anal. Calcd for C11H7NOS: C, 65.65; H, 3.51; N, 6.96. Found: C, 65.43; H, 3.50; N, 7.01.
2-(3-Thienyl)benzothiazole (3c): Isolated as a yellow solid, mp 91–93°C (pentane). 1H NMR (CDCl3) δ
7.18 (s, 1H, aromatic), 7.29 (s, 1H, aromatic), 7.40 (dd, J = 7.8, 8.0 Hz, 1H, aromatic), 7.49 (dd, J = 7.8,
8.0 Hz, 1H, aromatic), 7.55 (s, 1H, aromatic), 7.79 (d, J = 7.8 Hz, 1H, aromatic), 8.10 (d, J = 7.8 Hz, 1H,
aromatic). 13C NMR (CDCl3) δ 121.9, 122.0, 123.0, 124.9, 125.1, 126.1, 127.3, 133.3, 141.9, 154.3,
166.1. Anal. Calcd for C11H7NS2: C, 60.80; H, 3.25; N, 6.45. Found: C, 60.84; H, 3.30; N, 6.44.
2-tert-Butylbenzothiazole (3d): Isolated as a yellow solid mp 65–68 °C (ethyl acetate-hexane). 1H NMR
(CDCl3) δ 1.26 (s, 9H, t-Bu), 7.46 (dd, J = 7.8, 8.0 Hz, 1H, aromatic), 7.74 (d, J = 7.8 Hz, 1H, aromatic),
7.87 (d, J = 7.8 Hz, 1H, aromatic), 8.00 ( d, J = 7.8 Hz, 1H, aromatic). 13C NMR (CDCl3) δ 31.3 (x3),
39.1, 122.3, 122.5, 125.1, 125.3, 133.4, 154.5, 167.1. Anal. Calcd for C11H13NS: C, 69.07; H, 6.85; N,
7.32. Found: C, 69.15; H, 6.88; N, 7.39.
2-Isopropylbenzothiazole (3e): Isolated as a brown viscous liquid. 1H NMR (CDCl3) δ 1.51 (d, J = 4.0
Hz, 6H, (CH3)2CH-), 3.41–3.45 [m, 1H, -CH(CH3)2], 7.36 (dd, J = 7.8, 8.0 Hz, 1H, aromatic), 7.47 (dd,
J = 7.8, 8.0 Hz, 1H, aromatic), 7.87 (d, J = 7.8 Hz, 1H, aromatic), 8.01 (d, J = 7.8 Hz, 1H, aromatic). 13C
NMR (CDCl3) δ 23.9 (x2), 39.1, 121.9, 122.1, 125.3, 125.8, 133.5, 153.1, 166.3. Anal. Calcd for
C10H11NS: C, 67.76; H, 6.25; N, 7.90. Found: C, 67.87; H, 6.33; N, 7.99.
2-Methylbenzothiazole (3f): Isolated as a viscous oil. 1H NMR (CDCl3) δ 2.80 (s, 3H, CH3), 7.31 (dd, J
= 7.8, 8.0 Hz, 1H, aromatic), 7.42 (dd, J = 7.8, 8.0 Hz, 1H, aromatic), 7.79 (d, J = 7.8 Hz, 1H, aromatic),

HETEROCYCLES, Vol. 65, No. 9, 2005
2125
7.95 (d, J = 8.0 Hz, 1H, aromatic). 13C NMR (CDCl3) δ 20.4, 121.7, 122.7, 125.0, 126.2, 136.0, 153.7,
167.2. Anal. Calcd for C8H7NS: C, 64.39; H, 4.73; N, 9.39. Found: C, 64.50; H, 4.80; N, 9.30.
5-Chloro-2-phenylbenzothiazole (3g): Isolated as a yellow solid mp 102–105 °C (CH2Cl2-hexane). 1H
NMR (CDCl3) δ 7.38 (dd, J = 7.8, 8.0 Hz, 2H, aromatic), 7.49–7.53 (m, 4H, aromatic), 7.83 (dd, J = 2.5,
7.8 Hz, 1H, aromatic), 8.10 (d, J = 7.8 Hz, 1H, aromatic). 13C NMR (CDCl3) δ 21.9, 124.5, 126.3, 127.0,
128.5, 129.3, 129.5, 130.1, 133.1, 136.9, 154.5, 169.5. Anal. Calcd for C13H8NClS: C, 63.54; H, 3.28; N,
5.70. Found: C, 63.58; H, 3.37; N, 5.78.
5-Chloro-2-(furan-3-yl)benzothiazole (3h): Isolated as a white solid, mp 89–92 °C (CH2Cl2-hexane), 1H
NMR (CDCl3) δ 6.98 (s, 1H, aromatic), 7.40 (s, 1H, aromatic), 7.51 (d, J =7.8 Hz, 1H, aromatic), 7.88 (d,
J =2.5 Hz, 1H, aromatic), 8.05 (d, J = 7.8 Hz, 1H, aromatic), 8.13 (s, 1H, aromatic). 13C NMR (CDCl3) δ
109.5, 121.3, 122.3, 123.2, 125.5, 126.8, 134.7, 143.5, 144.6, 154.1, 162.1. Anal. Calcd for C11H6NClS: C,
56.06; H, 2.57; N, 5.94. Found: C, 56.20; H, 2.68; N, 5.97.
2-(3’-Methoxyphenyl)benzothiazole (3i): Isolated as a yellow viscous liquid. 1H NMR (CDCl3) δ 3.93(s,
3H, OMe), 7.05(dd, J = 1.8, 8.0 Hz, 1H, aromatic), 7.41 (dd, J = 4.0, 8.0 Hz, 2H, aromatic), 7.51(dd, J =
7.8, 8.0 Hz, 1H, aromatic), 7.66 (d, J = 8.0 Hz, 1H, aromatic), 7.70 (s, 1H, aromatic), 7.91 (d, J = 8.0 Hz,
1H, aromatic), 8.10 (d, J = 8.0 Hz, 1H, aromatic). 13C NMR (CDCl3) δ 55.91, 112.4, 117.7, 120.6, 122.0,
123.6, 125.6, 126.7, 130.4, 135.2, 135.4, 154.4, 160.4, 168.4. Anal. Calcd for C14H11NOS: C, 69.68; H,
4.59; N, 5.80. Found: C, 69.81; H, 4.66; N, 5.85.
2-(3’,4’,5’-Trimethoxyphenyl)benzothiazole (3j): Isolated as a yellow solid mp 95–98 °C (ethyl
acetate-hexane).1H NMR (CDCl3) δ 3.92 (s, 3H, OMe), 3.98 (s, 3H, -OMe), 3.99 (s, 3H, OMe), 7.2 (s, 1H,
aromatic), 7.33–7.40 (m, 2H, aromatic), 7.48 (dd, J =7.8, 8.0 Hz, 1H, aromatic), 7.89 (dd, J = 2.5, 7.8 Hz,
1H, aromatic), 8.07 (dd, J = 2.5, 7.8 Hz, 1H, aromatic). 13C NMR (CDCl3) δ 56.69, 56.76, 61.3, 105.2,
106.2, 121.9, 123.4, 125.5, 126.7, 129.4, 135.4, 141.0, 153.4, 153.9, 154.4, 168.2. Anal. Calcd for
C16H15NO3S: C, 63.77; H, 5.02; N, 4.65. Found: C, 63.80; H, 5.11; N, 4.70.
ACKNOWLEDGEMENTS
We thank the Welch Foundation, Houston, TX for partial financial support of this work.
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