Investigation on the one-step preparation of 2-substituted benzo[B]thiophenes

Article abstract of DOI:10.1080/10426507.2012.717140

A convenient and efficient synthesis of 2-substituted benzo[b]thiophenes is described. This one-step reaction of alkylthiobenzaldehyde and activated electrophiles proceeded smoothly in toluene at 120 °C with magnesium oxide as a catalyst. The target 2-sub

Full text of DOI:10.1080/10426507.2012.717140

This article was downloaded by: [Open University]
On: 09 July 2013, At: 06:26
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
Investigation on the One-Step
Preparation of 2-Substituted
Benzo[B]Thiophenes
a
a
a
Qian Zhao , Chao Qian & Xin-Zhi Chen
a
Department of Chemical and Biological Engineering, Key
Laboratory of Biomass Chemical Engineering of Ministry of
Education , Zhejiang University , Hangzhou , China
Accepted author version posted online: 09 Aug 2012.Published
online: 05 Jul 2013.
To cite this article: Qian Zhao , Chao Qian & Xin-Zhi Chen (2013) Investigation on the One-Step
Preparation of 2-Substituted Benzo[B]Thiophenes, Phosphorus, Sulfur, and Silicon and the Related
Elements, 188:7, 873-878, DOI: 10.1080/10426507.2012.717140
To link to this article: http://dx.doi.org/10.1080/10426507.2012.717140
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“
Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Phosphorus, Sulfur, and Silicon, 188:873–878, 2013
Copyright ꢀ
Taylor & Francis Group, LLC
C
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.717140
INVESTIGATION ON THE ONE-STEP PREPARATION OF
-SUBSTITUTED BENZO[B]THIOPHENES
2
Qian Zhao, Chao Qian, and Xin-Zhi Chen
Department of Chemical and Biological Engineering, Key Laboratory of Biomass
Chemical Engineering of Ministry of Education, Zhejiang University,
Hangzhou, China
GRAPHICAL ABSTRACT
O
CHO
S
+
O
catalyst
S
2 3
ClCH COCH
Cl
SCH
3
O
O
2
a
3a
1a
4a
Abstract A convenient and efficient synthesis of 2-substituted benzo[b]thiophenes is de-
scribed. This one-step reaction of alkylthiobenzaldehyde and activated electrophiles proceeded
◦
smoothly in toluene at 120 C with magnesium oxide as a catalyst. The target 2-substituted
benzo[b]thiophenes are obtained in moderate yields and the side reaction is inhibited via
azeotropic distillation. According to the experiments, a plausible mechanism is presented.
Keywords 2-Substituted benzo[b]thiophenes; aldol condensation; mechanism
INTRODUCTION
-Acetylbenzo[b]thiophene (1a) (Figure 1) and its derivatives are valuable com-
2
pounds as chemical intermediate products which include drugs, herbicides, lubricant ad-
ditives, and functional polymers.1 The synthesis of 1a and its analogs is attracting much
attention in both academia and industry.
,2
Much effort has been focused on green and highly effective methods, and good
progress has been made.1 Farrar reported the preparation of 1a by the acetylation
of benzo[b]thiophene with acetic anhydride in the presence of Lewis acid catalyst. This
method has few steps but requires expensive materials.
–15
3
4
Hsaio developed a method which gave benzo[b]thiophenes from 2-mercaptobenzoic
acids via reduction, in situ S-alkylation, re-oxidation, and cyclization (Scheme 1). How-
ever, structurally different substituted 2-mercaptobenzoic acids are not always available and
sometimes not easy to prepare. Moreover, the use of lithium aluminum hydride restricted its
Received 3 June 2012; accepted 14 July 2012.
This work was supported by the Natural Science Foundation of Zhejiang Province (Y4100147, R4090358).
Address correspondence to Xin-zhi Chen, Ph.D., Department of Chemical and Biological Engineering, Key
Laboratory of Biomass Chemical Engineering of Ministry of Education, Zhejiang University, Hangzhou 310027,
China. E-mail: chemtec@163.com
8
73

8
74
Q. ZHAO ET AL.
S
O
1
a
Figure 1 2-acetylbenzo[b]thiophene (1a).
5
industrial application. Gallagher developed an alternative, general and rapid one-pot syn-
thesis of 2-substituted benzo[b]thiophenes from available benzaldehydes via S-alkylation
and in situ aldol condensation. Compared to Hsaio’s route, the use of lithium aluminum
hydride was avoided. However, the overall yield of 2-substituted benzo[b] thiophenes was
poor.
COOH
SH
LiAlH
4
S
Y
ClCH
Y
2
Py-SO3
Y=CO
2
Et, CN, COPh, COMe.
Scheme 1
In order to synthesize 2-acetylbenzo[b]thiophene, we focused on the reaction between
2-methylthiobenzaldehyde (2a) with chloroacetone (3a) in the presence of a catalyst, which
was characterized by higher yields (Scheme 2). This process involved fewer steps, compared
to Hsaio’s route, potentially easing cost and expediting future screening studies. Moreover,
it was considered to be an industrial way to synthesize 1a and its analogs. However, many
factors of the process have not been discussed in detail. A systematic study on the catalyst
which would be a significant influence on the yield of reaction has not been reported. To the
best of our knowledge, there are no examples studying the byproduct of this reaction. The
inhibition of side reactions remain a problem. So, in view of the mentioned shortcomings,
we attempt to consider the factors leading to completion of the reaction.
O
CHO
catalyst
S
ClCH2COCH3
O
+
S
Cl
SCH3
O
3
a
1
a
O
2
a
mainproduct
4
a
byproduct
Scheme 2
In this paper, we report a convenient method for the synthesis of 1a and its analogs
in toluene. The experimental parameters are optimized for yield of the final product.

PREPARATION OF 2-SUBSTITUTED BENZO[B]THIOPHENES
875
Table 1 Effect of different catalysts on the synthesis of 1aCatalyst
Yield/%
2
a:3a molar
ratio
Temperature/
◦
4aa
1ab
Entry
Catalyst
C
Time/h
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
CaCl2
AlCl3
NaCO3
K2CO3
NaOH
KOH
CaO
MgO
MgO
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1
1:1.2
1:1.5
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
120
120
120
120
120
120
120
120
120
120
120
120
80
10
10
10
10
4
4
3
4
4
4
2
3
5
5
5
—
—
—
—
—
—
41.2c
42.4c
46.5c
48.9c
31.7c
c
27.9
c
d
d
c
d
23.3 (7.8)
70.4 (88.3)
d
d
0.7
83.1
c
c
d
17.7 (0.8)
75.3 (95.0)
d
d
1
1
1
1
1
1
MgO
1.6
93.6
Ca(OH)2
Mg(OH)2
triethylamine
TMAOH
Ba(OH)2
29.1c
22.5c
—
66.8c
71.0c
38.9c
c
80
120
—
—
47.2
52.8c
1
0 wt%, based on 2a.
a
Determined by GC.
b
Isolated yield.
c
Solvent-free.
d
Toluene was employed as the entrainer.
RESULTS AND DISCUSSION
Chloroacetone (3a) was employed as an activated electrophile, which reacted with 2-
methylthiobenzaldehyde (2a) in the presence of catalyst. The influence of different catalysts
was studied, as shown in Table 1.
A possible mechanism for the formation of product 1a is shown in Scheme 3. Upon
reaction of 2-methylthiobenzaldehyde 2a with chloroacetone 3a compound A is formed.
Then, the catalyst attacks the α-H of A via in situ aldol condensation to give the intermediate
B. Dehydroxylation of B affords 2-acetylbenzo[b]thiophene 1a. 1a Reacted with 3a further
to form the byproduct 4a under the basic conditions.
According to the plausible mechanism, in situ aldol condensation is the key step. As
2
is well known, either Lewis acid or base can be used as catalyst in this process. We tested
the Lewis acid initially. All the Lewis acids led to unsatisfactory results (Table 1, entries 1
and 2), as the yields did not exceed 50%. During the long reaction time, 2a did not react
completely. When the relatively weak base such as K2CO3 or NaCO3 was used (Table 1,
entries 3 and 4), yields of less than 50% with part conversion were achieved. Thus, we
wondered whether strong base favors the reaction. In an attempt to improve the yield, we
executed the reaction in the presence of a known strong base such as NaOH and KOH.
However, it was found that neither of them was effective (Table 1, entries 5 and 6).
In order to obtain a suitable catalyst, alkali metal oxides such as CaO and MgO
were examined. When the alkali metal oxide was adopted, product 1a was obtained in
moderate yields (Table 1, entries 7–10). Since water is produced during the reaction, and
the alkali metal oxide could react with the water to give the corresponding hydroxide, we
tried Ca(OH)2 and Mg(OH)2. Interestingly, a slightly lower yield was obtained in a shorter

8
76
Q. ZHAO ET AL.
CHO
SCH
CHO
CH3
CHO
O
+
-CH Cl
3
Cl
3
S
Cl
S
H
B
O
2
a
3a
A
O
O
O
OH
CH
O
O
BH
-
OH
S
S
H
S
S
O
B
B
+
ClCH COCH
O
2
3
S
-HCl
O
O
1
a
4
a
Scheme 3
time when Ca(OH)2 and Mg(OH)2 were used as catalyst (Table 1, entries 11 and 12). It
provided us the clue that the compound 3a may react with the final product 1a further to
give the byproduct 4a under these conditions to decrease the yield. Meanwhile, the rate
of the reaction was accelerated in the presence of Ca(OH)2 and Mg(OH)2. Analysis of the
reaction mixture by gas chromatography–mass spectrum (GC–MS) showed the appearance
of 4a. Thus, it could be concluded that the alkaline catalyst was employed as neutralizing
reagent to accelerate the side reaction and the basicity of catalyst plays an important role
which affects the yield of the product 1a. Two solutions were tested respectively.
Toluene was chosen as an entrainer to remove water produced in the reaction. Notably,
the yield greatly improved to 95% using MgO as the catalyst (Table 1, entry 9). The dramatic
increase in reaction yield could be ascribed to its prevention of the side reaction and the
simultaneous intensive enhancement of both heat and mass transfer. At the same time, other
bases such as triethylamine, tetramethylammonium hydroxide (TMAOH), Ba(OH)2 were
employed. Finally, we found that none of them was effective (Table 1, entry 13–15).
Considering the side reaction of product 1a with 3a, the molar ratio of 2a and 3a
were studied and the optimal conditions were screened (Table 1, entries 8–10). 10 wt%
◦
MgO was optimized for the yield and the minimization of the byproduct, in 4 h at 120 C
using toluene as an entrainer. The best ratio of 2a and 3a was 1:1.2 for the purpose of lower
cost and higher yield.
Having identified the optimized conditions (Table 1, entry 9), we next evaluated
the process with various alkylthiobenzaldehydes (2) with the halo compound of general
formula (3). Further results are summarized in Table 2.
As listed in Table 2, this protocol could be extended to different alkylthiobenzalde-
hydes 2. The reactions went smoothly under the optimal conditions, tolerated various
substituent groups on the phenyl ring of 2 and afforded the desired product 1 in moderate
to good yields. The electrophilic ability of 3 and the substituent groups of 2 determined the
reaction. In addition, the formation of byproduct could be inhibited successfully.

PREPARATION OF 2-SUBSTITUTED BENZO[B]THIOPHENES
Table 2 Scope and limitations of the protocola
877
CHO
SCH
S
catalyst
R1
+
ClCH R
R2
2
2
R1
3
2
3
1
b
Entry
R1
R2
Product 1
Yield /%
1
2
3
4
5
6
7
H
COMe
CN
1a
1b
1c
1d
1e
1f
95.0
87.4
82.3
83.2
88.9
95.7
97.1
H
H
H
CO2Me
COOH
COMe
COMe
COMe
6-Cl
6-Me
4-MeO
1g
a
All reactions were run with substrate 2 (0.2 mol), substrate 3 (0.24 mol), and MgO (10 wt%, based on 2) in
◦
the solution of toluene at 120 C for 4 h.
b
Isolated yield.
EXPERIMENTAL
Melting points were determined using WRR melting point apparatus. GC analyses
were performed on GC Agilent 1790F series using capillary column. NMR spectrums were
recorded in dimethyl sulfoxide (DMSO) or CDCl3 using Bruker, AV 400, 400 MHz. Starting
materials and reagents were commercially purchased and used without further purification.
General procedure for the synthesis of 2-acetylbenzo[b]thiophene. To a 250 mL three-
necked flask equipped with a mechanical stirrer, a thermometer and a water separator, add
2-methylthiobenzaldehyde (2a) (30.0 g, 0.20 mol), magnesium oxide (3.0 g), and toluene
(50.0 g). Then, chloroacetone (3a) (23.0 g, 0.24 mol) was added dropwise under vigorous
stirring after heating to reflux. The water produced in the reaction was separated. The
reaction was completed in 4 h. After completion of the reaction, the insoluble material was
removed by filtration while keeping the mixture hot, and then the toluene was removed
◦
under vacuum at 60 C. Thus, 2-Acetylbenzo[b]thiophene was obtained. (1a): light yellow
◦
4
◦
solid (33.5 g, 95.0% yield), mp: 86.7–88.3 C (lit. Mp: 87.0–88.0 C).
CONCLUSION
5
In conclusion, compared to Gallagher’s route, we have successfully developed an
efficient one-step synthesis of 2-substituted benzo[b]thiophenes via an MgO-promoted
reaction between alkylthiobenzaldehyde and an activated electrophile. The final target
product can be obtained with moderate yields of more than 82% and the formation of
byproduct can almost be avoided if the produced water is removed via azeotropic distillation.
REFERENCES
1
. Dickman, D. A.; Horrom, B. W.; Roden, B. A.; Chemburkar, S. R. U.S. Patent, 5, 169,961(A),
991.
1

8
78
Q. ZHAO ET AL.
2. Kagano Hirokazu; Goda Hiroshi; Yoshida Katsuhiko; Nakano Masahito. EP Patent, 0, 572,712
1992.
3
4
5
6
7
8
9
. Farrar, M. W. J. Am. Chem. Soc. 1950, 72, 4433-4436.
. Hsiao, C. N.; Bhagavatula, L.; Pariza, R. J. Synth. Commun. 1990, 20, 1687-1695.
. Gallagher, T.; Pardoe, D. A.; Porter, R. Tetrahedron Lett. 2000, 41, 5415-5418.
. Yazawa, N.; Saito, Y.; Hiyoshi, H. U.S. Patent, 5, 166,705 1993.
. Basha, A.; Brooks, D. W. J. Org. Chem. 1993, 58, 1293-1294.
. Chemburkar, S. R.; Anderson, D. G.; Reddy, R. E. Synth. Commun. 2010, 40(13), 1887-1894.
. Liu, Z. Y.; He, X. B.; Yang, Z. Y.; Shao, H. Y.; Li, X.; Guo, H. F.; Zhang, Y. Q.; Si, S. Y.; Li, Z.
R. Bioorg. Med. Chem. Lett. 2009, 19(5), 4167-4170.
1
1
1
1
0. Yoshida, Y.; Murata, M.; Hiyoshi, H. JP Patent, 6, 087,852 1994.
1. Sashida, H.; Sadamori, K.; Tsuchiya, T. Synth. Commun. 1998, 28, 713-727.
2. Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905-1909.
3. Kashiki, T.; Shinamura, S.; Kohara, M.; Miyazaki, E.; Takimiya, K.; Ikeda, M.; Kuwabara, H.;
Org. Lett. 2009, 11, 2473-2475.
1
4. Engel, E. O. G. Hetarenes: 5-Membered Rings with One Heteroatom. In: R. P. Kreher (Ed.),
Methoden der Organischen Chemie (Houben-Weyl), Vol. E6b; Georg Thieme Verlag: Stuttgart,
New York, 1994; pp. 217-274.
1
5. Zhang, T. Y.; O’Toole, J.; Proctor, C. S. J. Sulfur Chem. 1999, 22, 1-47.