A novel synthesis of benzo[b]thiophene

Article abstract of DOI:10.1007/s11164-012-0918-x

We report a convenient method of preparation of benzo[b]thiophene, using 2-chlorobenzaldehyde and 2-mercaptoacetonitrile as starting materials. The process comprises two steps, neither of which has been reported previously. The reactions in this work are

Full text of DOI:10.1007/s11164-012-0918-x

Res Chem Intermed
DOI 10.1007/s11164-012-0918-x
A novel synthesis of benzo[b]thiophene
•
Zutai Liao Xuehao Lv Ming Tao
•
Received: 11 September 2012 / Accepted: 8 November 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract We report a convenient method of preparation of benzo[b]thiophene,
using 2-chlorobenzaldehyde and 2-mercaptoacetonitrile as starting materials. The
process comprises two steps, neither of which has been reported previously. The
reactions in this work are clean and efficient.
Keywords Benzo[b]thiophene Á Coupling Á Decyanation
Introduction
Benzo[b]thiophene and its derivatives are important, because they are widely used in
the preparation of, for example, medicines [1–5], pesticides [6, 7], and semicon-
ductors [8, 9]. Benzo[b]thiophene can be synthesized by benzene ring closure or
thiophene ring closure. Kitamura et al. [10] reported the synthesis of benzo[b]thi-
ophene by cyclization of (2-(2-bromovinyl)phenyl)(methyl)sulfane; Rudzki et al.
[11] synthesized benzo[b]thiophene from ((2-bromophenyl)ethynyl)trimethylsilane
via cyclization with sodium sulfide; Voronkov et al. [12] reported the synthesis of
benzo[b]thiophene by cyclization of (1,2-dichloroethyl)benzene and hydrogen
sulfide; Denyagina et al. [13] reported cyclization of bromobenzene, ethyne, and
hydrogen sulfide to give benzo[b]thiophene; Reinecke et al. [14] reported two-step
benzene ring closure using thiophene-2,3-dicarboxylic acid as the starting material.
There are also many other methods of preparation of benzo[b]thiophene [15–19]; for
these, however, yields are much lower.
We recently found a new method of preparation of benzo[b]thiophene using
2-chlorobenzaldehyde and 2-mercaptoacetonitrile as starting materials.
Z. Liao (&) Á X. Lv Á M. Tao
Jiangxi Renming Pharmaceutical Chemicals Ltd., Jiangxi 332700, China
e-mail: vicethym@gmail.com
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Z. Liao et al.
Result and discussion
The whole process can be illustrated by the following scheme:
l
C
S
S
a
N
3O
H
C
Cat.
+
N
C
N
C
HS
H
O
The first step is coupling between 2-chlorobenzaldehyde and methanethiol
substituted with an electron-withdrawing group; similar coupling has been reported
elsewhere. Brouwer [20] reported the coupling between 2-chlorobenzaldehyde and
2-mercaptoacetic acid, which gives benzo[b]thiophene-2-carboxylic acid. The
process is efficient (benzo[b]thiophene-2-carboxylic acid can be obtained with
87.6 % yield) but consumes much alkali and produces too much waste water. In this
work we replaced the carboxyl group with cyano, and were surprised when the result of
coupling was 2-cyanobenzo[b]thiophene in comparable yield at lower temperature.
The second step is a decyanation reaction, which has also been reported before.
Weigert et al. [21] reported hydrodecyanation using Pd as catalyst, but this reaction
is limited because hydrogen cyanide is produced. Yuzawa et al. [22] reported
decyanation with Pt/TiO2 as catalyst and ammonia as reagent, so the hydrogen
cyanide was bound as soon as it was produced. In this work we used a combination
of hydrogen and ammonia as the reagent, and Pd/TiO2 and Cu as catalyst, and the
reaction was complete in a shorter time.
The effect of reaction conditions on yield was investigated. For the cyclization step,
several bases were used and compared. The effects of temperature and reagent ratio on
yield of 2-cyanobenzo[b]thiophene were also examined. The results are listed in
Table 1. Use of other bases, for example NaOH, Na2CO3, and KOH, resulted in much
poorer performance than CH3ONa. The cyclization process includes dehydration, and
reaction between hydroxide and 2-mercaptoacetonitrile also produces water, which
prevents progress of the cyclization. Also, NaOH, Na2CO3, and KOH are weak bases
compared with CH3ONa, so condensation proceeds slowly. Comparison of entries 2,
5, 6, and 7 shows that the optimum temperature for the reaction is 85 °C; at this
temperature the rate of cyclization is favored and byproducts are diminished. The
molar ratio of 2-chlorobenzaldehyde to CH3ONa has a substantial effect on the
reaction, probably because less CH3ONa cannot keep the reaction environment
sufficiently basic to favor the condensation reaction, whereas too much CH3ONa
results in conversion of the cyano group to carbonyl via alcoholysis.
In the decyanation step, two other catalysts, Pd and Pt/TiO2, were selected for
comparison, and the effect of reaction temperature on the yield of benzo[b]thiophene was
also investigated. The results are listed in Table 2, from which it is apparent that the
catalyst used in this work is more efficient than those used in previous work. The probable
reason is that both Pd and Pt are of high catalytic activity in hydrogenation, whereas Cu is
more active in catalysis of rupture of the C–CN bond, because the cyano group has
chemical properties similar to those of halogen atoms. The reaction temperature also
substantially affects the yield of benzo[b]thiophene. Low temperature reduces the rate of
the reaction whereas if the temperature is too high the yield of byproducts is increased.
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A novel synthesis of benzo[b]thiophene
Table 1 Effect of reaction conditions on the yield of 2-cyanobenzo[b]thiophene
Entry
Base used
Temperature (°C)
n(2-chlorobenzaldehyde):n(CH3ONa)
Yielda (%)
1
2
3
4
5
6
7
8
9
NaOH
85
85
85
85
55
75
95
85
85
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.0
1:1.5
20.3
85.4
21.7
21.5
45.8
79.5
84.1
67.9
75.5
CH3ONa
Na2CO3
KOH
CH3ONa
CH3ONa
CH3ONa
CH3ONa
CH3ONa
Reaction conditions: 3 h
a
Isolated yield
Table 2 Effect of reaction conditions on the yield of benzo[b]thiophene
Entry
Catalyst
Temperature ( °C)
Yielda (%)
1
2
3
4
5
Pd
250
250
250
200
300
80.3
79.5
90.2
78.8
80.4
Pt/TiO2
Pd/TiO2-Cu
Pd/TiO2-Cu
Pd/TiO2-Cu
Reaction conditions: in autoclave, 0.5 MPa hydrogen, 4 h
a
Isolated yield
Conclusion
We report a convenient method for preparation of benzo[b]thiophene, using
2-chlorobenzaldehyde and 2-mercaptoacetonitrile as the starting materials. The
process comprises two steps, coupling and decyanation, neither of which has been
reported previously. The reactions in this procedure are clean and efficient.
Experimental
The reactions were carried out in a batch reactor. The reaction mixtures were
analyzed by HPLC.
2-Cyanobenzo[b]thiophene
To 20 mL toluene, add 7 g 2-chlorobenzaldehyde, 3.3 g sodium methoxide, and
3.7 g 2-mercaptoacetonitrile. Increase the temperature to 85 °C and maintain for
3 h. When the reaction is complete, filter, then remove the solvent under vacuum.
A solid mixture which contains mainly 2-cyanobenzo[b]thiophene is obtained. Pure
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Z. Liao et al.
2-cyanobenzo[b]thiophene can be separated by use of column chromatography.
1H NMR (400 MHz, CDCl3): d = 7.40–7.51 (m, 2H), 7.79–7.86 (m, 3H);
13C NMR (100 MHz, CDCl3) d = 141.0, 137.1, 133.2, 127.2, 124.7, 124.4,
121.5, 114.3, 108.8 [23].
Benzo[b]thiophene
In an autoclave, mix the solid mixture obtained in the last step, 0.5 g Pd/TiO2 (5 %),
1 g Cu powder, 20 mL toluene, and 20 mL aqueous ammonia solution (20 %).
Replace the air in the autoclave with hydrogen and increase the pressure to 0.5 MPa.
Increase the temperature to 250 °C and maintain for 4 h. When the reaction is
complete, cool, separate the organic layer, and wash it with dilute hydrochloric acid.
Remove the solvent from the organic layer under vacuum to give 2.6 g benzo[b]thi-
ophene, 77 % yield (98 % purity). 1H NMR (400 MHz, CDCl3): d = 7.90–7.87 (m,
1H),7.81–7.78 (m, 1H), 7.41 (d, J = 5.4 Hz, 1H), 7.38–7.32 (m, 3H); 13C NMR
(100 MHz, CDCl3) d = 138.9, 138.7, 126.1, 124.4, 124.2, 123.7, 123.4, 121.8 [24].
Acknowledgments We are grateful for generous financial support from the Innovation Fund for Small
Technology-based Firms (12C26213603831).
References
1. S. Dadiboyena, Eur. J. Med. Chem. 51, 17–34 (2012)
2. P.S. Shinde, S.S. Shinde, A.S. Renge, G.H. Patil, A.B. Rode, R.R. Pawar, Lett. Org. Chem. 6(1),
8–10 (2009)
3. S.M.N. Efange, D.C. Mash, A.B. Khare, Q.J. Ouyang, J. Med. Chem. 41(23), 4486–4491 (1998)
4. F. Burkamp, S.R. Fletcher, J. Heterocyclic Chem. 39(6), 1177–1187 (2002)
5. S. Galiano, O. Erviti, S. Perez, A. Moreno, L. Juanenea, I. Aldana, A. Monge, Bioorg. Med. Chem.
Lett. 14(3), 597–599 (2004)
6. D.P. Mcdonnell, D.L. Clemm, T. Hermann, M.E. Goldman, J.W. Pike, Mol. Endocrinol. 9(6),
659–669 (1995)
7. B.K. Moorthy, J. Indian Chem. Soc. 67(11), 909–911 (1990)
8. B. Wex, B.R. Kaafarani, A.G. Oliver, J.A.K. Bauer, D.C. Neckers, J. Org. Chem. 68(21), 8258–8260 (2003)
9. M.M. Payne, S.A. Odom, S.R. Parkin, J.E. Anthony, Org. Lett. 6(19), 3325–3328 (2004)
10. T. Kitamura, S. Kobayashi, H. Taniguchi, Chem. Lett. 10, 1637–1638 (1988)
11. T. Kashiki, S. Shinamura, M. Kohara, E. Miyazaki, K. Takimiya, M. Ikeda, H. Kuwabara, Org. Lett.
11(11), 2473–2475 (2009)
12. M.G. Voronkov, E.N. Deryagina, M.A. Kuznetsova, Zh. Org. Khim. 20(7), 1591–1592 (1984)
13. E.N. Deryagina, N.A. Korchevin, E.N. Sukhomazova, N.V. Russavskaya, M.G. Voronkov, Zh. Org.
Khim. 29(11), 2246–2250 (1993)
14. M.G. Reinecke, J.G. Newsom, L.J. Chen, J. Am. Chem. Soc. 103(10), 2760–2769 (1981)
15. C.L. Li, X.G. Zhang, R.Y. Fang, P. Zhong, J.H. Li, J. Org. Chem. 75(20), 7037–7040 (2010)
16. M. Prats, C. Galvez, L. Beltran, Heterocycles 34(5), 1039–1046 (1992)
17. M.G. Voronkov, E.N. Deryagina, E.N. Sukhomazova, N.K. Gusarova, G.G. Efremova, B.A. Trofi-
mov, Zh. Org. Khim. 19(6), 1221–1224 (1983)
18. M.G. Voronkov, E.N. Deryagina, E.N. Sukhomazova, Zh. Org. Khim. 18(8), 1736–1743 (1982)
19. M.G. Voronkov, E.N. Deryagina, M.A. Kuznetsova, Zh. Org. Khim. 18(8), 1743–1749 (1982)
20. W. G. Brouwer, Preparation of benzo[b]thiophene-2-carboxylic acids. WO9947510, (1999)
21. F.J. Weigert, M. Moguel, J. Mol. Catal. 75(2), 209–218 (1992)
22. H. Yuzawa, H. Yoshida, Chem. Commun. 46(46), 8854–8856 (2010)
23. S.L. Zhou, K. Junge, D. Addis, S. Das, M. Beller, Org. Lett. 11(11), 2461–2464 (2009)
24. N. Barbero, R. Martin, Org. Lett. 14(3), 796–799 (2012)
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