Oxidation of 3,4-diaryl-2,5-dihydrothiophenes to 3,4-diarylthiophenes using CuBr2: Simple and efficient preparation of 3,4-diarylthiophenes

Article abstract of DOI:10.1002/ejoc.200700779

A class of 3,4-diarylthiophenes was prepared in excellent yield (80-91%) by oxidation of 3,4-diaryl-2,5-dihydrothiophenes with CuBr₂. The approach is also available for the synthesis of 3,4-diarylpyrroles and 3,4-diarylfuran. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700779

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700779
Oxidation of 3,4-Diaryl-2,5-dihydrothiophenes to 3,4-Diarylthiophenes Using
CuBr2: Simple and Efficient Preparation of 3,4-Diarylthiophenes
Yizhe Dang[a] and Yi Chen*[a]
Keywords: Sulfur heterocycles / Copper / Oxidation
A class of 3,4-diarylthiophenes was prepared in excellent
yield (80–91%) by oxidation of 3,4-diaryl-2,5-dihydrothio-
phenes with CuBr2. The approach is also available for the
synthesis of 3,4-diarylpyrroles and 3,4-diarylfuran.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
of 3,4-disubstituted thiophene derivatives including
Hinsburg condensation,[4] modification of 3,4-dibromothio-
phene,[5] and others,[6] are available, but most syntheses re-
quire expensive reagents or strict reaction conditions.
Dehydrogenation of 2,5-dihydrothiophenes to thiophenes
was reported with a variety of reagents such as hydrogen
peroxide,[7] perbenzoic acid,[8] phosphorus pentachloride,[9]
Introduction
3,4-Disubstituted thiophenes are one of the most impor-
tant class of heterocyclic compounds, not only as building
blocks in the synthesis of natural products or as key struc-
tural units[1] of compounds with interesting biological ac-
tivities but also in the field of materials chemistry.[2] In par-
ticular, 3,4-diarylthiophenes and analogs (Figure 1) have
interesting pharmacologic properties and are used as anti-
inflammatory agents.[3]
chloranil,[10]
2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ),[11] and sulfuryl chloride,[12] but many problems
were encountered with these reagents: difficult isolation,
low yield, long reaction time, expensive reagents, and pol-
luted gas as a byproduct. Recently, we found[13] that 3,4-
diaryl-2,5-dihydrothiophenes could be oxidized and bromi-
nated to 3,4-diaryl-2,5-dibromothiophenes by a one-pot re-
action with the use of Br2 in excellent yields, but the reac-
tion could not be stopped at the oxidation step and we
could not obtain 3,4-diarylthiophenes. Therefore, the devel-
opment of an efficient and convenient synthesis of 3,4-di-
arylthiophenes continues to be an active research area.[14]
In this paper, we found CuBr2 to be a highly efficient rea-
gent for the dehydrogenation of 3,4-diaryl-2,5-dihydrothio-
phenes to 3,4-diarylthiophenes. Using CuBr2 as the dehy-
drogenation reagent has some advantages: it is an inexpen-
sive reagent, it is easy to handle, and it provides excellent
yields of the products. The reaction is complete within 3–
4 h, and the product is isolated by normal work up pro-
cedures.
Figure 1. 3,4-Diarylthiophenes and analogs with interesting phar-
macologic properties.
Synthesis of 3,4-disubstituted heterocyclic compounds is
challenging due to the fact that selective substitution at one
or more of the β positions is not easy because of the ten-
dency of these systems to undergo aromatic substitution re- Results and Discussion
actions at the more electronically favorable α positions of
the heterocyclic ring. Several approaches to the preparation
The starting 3,4-diaryl-2,5-dihydrothiophenes (Scheme 1)
were prepared according to the literature[15] starting from
acetophenone and its derivatives, which were brominated
at the 2-position with Br2 in CHCl3. After sulfuration of
bromoacetophenone and its derivatives with Na2S in EtOH,
the sulfides were coupled through a McMurry coupling re-
action to afford 1a–7a in good yields (70–83%).
[a] Laboratory of Organic Optoelectronic Functional Materials
and Molecular Engineering, Technical Institute of Physics and
Chemistry, Chinese Academy of Science,
Beijing 100080, China
Fax: +86-10-6254-4049
E-mail: yichencas@yahoo.com.cn
Eur. J. Org. Chem. 2007, 5661–5664
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Y. Dang, Y. Chen
SHORT COMMUNICATION
Scheme 1. The synthetic route of 3,4-diaryl-2,5-dihydrothiophenes and 3,4-diarylthiophenes.
3,4-Diarylthiophenes 1b–7b were obtained by treatment Table 1. The effects of CuBr2 and the solvent on the preparation
of 1b.
of 3,4-diaryl-2,5-dihydrothiophenes 1a–7a with CuBr2 in a
solution of ethyl acetate/chloroform (Scheme 1). The reac-
tion was simple and quick: the mixture was heated at reflux
until no further starting material was detected by TLC (2–
4 h). After the reaction mixture was cooled down to room
temperature, the grey powder was filtered off, and the solu-
tion was then washed with water, NaHCO3 (10%), and a
saturated solution of NaCl and extracted with dichloro-
methane. The combined organic layer was dried with
MgSO4. After evaporation of the solvent, target com-
pounds 1b–7b were obtained without further purification in
excellent yields (80–91%).
Entry CuBr2
[equiv.]
Solvent
Time Yield of 1b Recovery of 1a
[h]
[%]
[%]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
3
3
3
3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCM
THF
CH3CN
Cyclohexane
4
4
4
4
4
4
4
4
4
0
100
60
35
Ͻ5
Ͻ5
Ͻ5
Ͻ5
Ͻ5
Ͻ5
25
50
85
82
85
80
84
78
The effect of CuBr2 and solvent was examined in an ef-
fort to improve the yields of the 3,4-diarylthiophenes. As
presented in Table 1, without the CuBr2 reagent, no conver-
sion of 1a into 1b was detected in the reaction and starting
material 1a was recovered quantitatively. The yield of 1b,
however, greatly improved from 25 to 85% when the
number of equivalents of CuBr2 was increased from one to
three, but no increase in the yield of 1b was obtained when
the number of equivalents of CuBr2 was greater than three.
It is worth noting that the conversion of 1a into 1b did not
occur when other copper reagents such as CuCl2, CuI, or
Cu(OOCCH3)2 were used to replace CuBr2, although the
mechanism is not clear. Additionally, it was found that sol-
vents have little influence on both the yield and the conver-
sion of 1b, and no significant changes were detected when
different solvents were employed in the reaction. Similar
results were obtained when 3,4-diaryl-2,5-dihydrothio-
phenes 2a–7a were converted into corresponding 3,4-diaryl-
thiophenes 2b–7b with the use of the CuBr2 reagent.
To extend the scope of the oxidation reaction with
CuBr2, 1,3,4-triaryl-2,5-dihydropyrrole 8a[15e] and 3,4-di-
aryl-2,5-dihydrofuran 9a[15d] were employed as templates. It
was found that both 8a and 9a could also be oxidized into
1,3,4-triarylpyrrole 8b and 3,4-diarylfuran 9b in reasonable
yields of 66 and 58%, respectively (Scheme 2). This suggests
that CuBr2 may also be efficient for the preparation of
1,3,4-triarylpyrroles and 3,4-diarylfurans, and a more de-
tailed study on the conversion of 1,3,4-triaryl-2,5-dihy-
dropyrroles and 3,4-diaryl-2,5-dihydrofuran to 1,3,4-triaryl-
pyrroles and 3,4-diarylfurans, respectively, is currently un-
der investigation.
Scheme 2. The oxidation of 3,4-diaryl-2,5-dihydropryyole 8a and
3,4-diaryl-2,5-dihydrofuran 9a into 3,4-diarylpyrrole 8b and 3,4-di-
arylfuran 9b.
Conclusions
A new synthetic approach for the preparation of 3,4-di-
arylthiophenes by oxidation of 3,4-diaryl-2,5-dihydrothio-
phenes with the use of CuBr2 was developed. This reaction
sequence is advantageous, as the procedure is simple and
offers excellent yields of the products with the use of cheap
reagents.
Experimental Section
1
General Methods: H and 13C NMR spectra were recorded at 400
and 100 MHz, respectively, with TMS as an internal reference and
CDCl3 as the solvent. HRMS spectra were recorded with a GCT-
5662
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Eur. J. Org. Chem. 2007, 5661–5664

Simple and Efficient Preparation of 3,4-Diarylthiophenes
MS spectrometer. All chemicals for synthesis were purchased from
commercial suppliers, and the solvents were used without further
purification. Reactions were monitored by TLC silica gel plates
(60F-254). Column chromatography was performed on silica gel
(Merck, 70–230 mesh).
7.87 (d, J = 4.3 Hz, 1 H), 7.83 (d, J = 2.0 Hz, 1 H), 7.62 (dd, J =
8.8, 2.2 Hz, 1 H), 7.59 (t, J = 6.7, 7.3 Hz, 1 H), 7.51 (t, J = 7.2,
6.5 Hz, 1 H), 7.20 (s, 2 H), 6.62 (s, 2 H), 2.20 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 137.6, 133.9, 132.9, 131.7, 131.5,
130.0, 128.5, 128.0, 127.8, 127.3, 126.0, 125.1, 120.4, 119.8, 118.7,
117.4, 14.1 ppm. HRMS: calcd. for C24H17Cl2NS2 453.0179; found
453.0177. C24H17Cl2NS2 (454.44): calcd. C 63.63, H 3.78; found C
63.55, H 3.71.
9b: Yield: 167 mg (58%). M.p. 98–100 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.43 (s, 2 H), 6.34 (s, 2 H), 2.35 (s, 6 H), 2.15 (s, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 140.5, 135.3, 133.1, 128.5,
127.4, 121.5, 15.3, 13.9 ppm. HRMS: calcd. for C16H16OS2
288.0643; found 288.0645. C16H16OS2 (288.43): calcd. C 66.71, H
5.60; found C 66.66, H 5.54.
General Procedure for the Conversion of 1a–9a into 1b–9b: To a
mixture of CuBr2 (0.67 g, 3.0 mmol) in ethyl acetate (30 mL) heated
at reflux was added compound 1a–9a (1.0 mmol) in CHCl3
(30 mL), and the mixture was heated at reflux until the starting
material disappeared (TLC detection). The mixture was cooled
down to ambient temperature, and the grey powder was filtered.
The solution was washed with water (50 mL), NaHCO3 (10%,
50 mL), and a saturated solution of NaCl (50 mL) and then ex-
tracted with CH2Cl2. The combined organic layer was dried with
MgSO4. After evaporation of the solvent, target compounds 1b–9b
were obtained without further purification.
Acknowledgments
1b: Yield: 201 mg (85%). M.p. 115–116 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.30 (s, 2 H), 7.29–7.27 (m, 6 H), 7.22–7.20 (m, 4 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 141.9, 136.7, 129.2, 128.3,
127.0, 124.2 ppm. HRMS: calcd. for C16H12S 236.0660; found
236.0663. C16H12S (236.34): calcd. C 81.41, H 5.12; found C 81.48,
H 5.06.
This work was supported by the National Natural Science Founda-
tion of China (No. 60337020).
[1] a) W. G. Gribble in Comprehensive Heterocyclic Chemistry
(Eds: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon,
Oxford, 1996; b) J. B. Press in The Chemistry of Heterocyclic
Compounds: Thiophene and Its Derivatives (Ed.: S. Gronowitz),
John Wiley & Sons, Inc., New York, 1991; c) J. B. Press, R. K.
Russell in Progress in Heterocyclic Chemistry (Eds: H. Susch-
itzky, E. F. V. Scriven), Pergamon, Oxford, 1992.
[2] a) J. Roncali, Chem. Rev. 1992, 92, 711–738; b) D. Fichou (Ed.),
Handbook of Oligo- and Polythiophenes, Wiley-VCH,
Weinheim, 1999; c) H. E. Katz, Z. Bao, S. L. Gilat, Acc. Chem.
Res. 2001, 34, 359–369; d) T. Otsubo, Y. Aso, K. Takimiya, J.
Mater. Chem. 2002, 12, 2565–2575; e) C. R. Newman, C. D.
Frisbie, D. A. de Silva Filho, J.-L. Bredas, P. C. Ewbank, K. R.
Mann, Chem. Mater. 2004, 16, 4436–4451; f) A. Facchetti, M.-
H. Yoon, T. J. Marks, Adv. Mater. 2005, 17, 1705–1725; g) H.
Rath, V. Prabhuraja, T. K. Chandrashekar, N. Nag, D. Gos-
wami, B. S. Joshi, Org. Lett. 2006, 8, 2325–2328.
[3] a) K. Brown, J. F. Cavalla, U. S. Patent 3,644,399, 1972; b) K.
Brown, J. F. Cavalla, U. S. Patent 3,743,656, 1973; c) J. J. Talley,
S. R. Bertenshaw, P. W. Collins, T. D. Penning, D. B. Reitz,
R. S. Rogers, U. S. Patent 7,030,153 B2, 2006.
[4] a) P. J. Garratt, K. P. C. Vollhardt, J. Am. Chem. Soc. 1972, 94,
7087–7092; b) Y. Miyahara, J. Heterocycl. Chem. 1979, 16,
1147–1151.
[5] a) P. Spagnolo, P. Zanirato, S. Gronowitz, J. Org. Chem. 1982,
47, 3177–3180; b) S. Gronowitz, M. Temciuc, A.-B. Hornfeldt,
J. Heterocycl. Chem. 1993, 30, 1111–1116; c) J. L. Reddinger,
J. R. Reynolds, J. Org. Chem. 1996, 61, 4833–4834; d) X.-S. Ye,
H. N. C. Wong, J. Org. Chem. 1997, 62, 1940–1954.
[6] a) Y. Sakamoto, S. Komatsu, T. Suzuki, J. Am. Chem. Soc.
2001, 123, 4643–4644; b) T. M. Pappenfus, M. W. Burand,
D. E. Janzen, K. R. Mann, Org. Lett. 2003, 5, 1535–1538; c) J.
Casado, T. M. Pappenfus, L. L. Miller, K. R. Mann, E. Orti,
P. M. Viruela, R. Pou-Amerigo, V. Hernandez, J. T. L. Navar-
rete, J. Am. Chem. Soc. 2003, 125, 2524–2534; d) A. Facchetti,
M.-H. Yoon, C. L. Stern, H. E. Katz, T. J. Marks, Angew.
Chem. Int. Ed. 2003, 42, 3900–3903.
[7] A. Stoll, R. Suess, Helv. Chim. Acta 1974, 57, 2487–2492.
[8] T. Takaya, S. Kosaka, Y. Otsuji, E. Imoto, Bull. Chem. Soc.
Jpn. 1968, 41, 2086–2095.
[9] O. Hromatka, D. Binder, Chem. Abstr. 1976, 85, 5612.
[10] H. Ruschig, W. Meixner, H. G. Alpermann, U. S. Patent
3,445,473, 1969.
2b: Yield: 268 mg (88%). M.p. 136–137 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.31 (s, 2 H), 7.25 (d, J = 8.6 Hz, 4 H), 7.11 (d, J =
8.4 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.5, 134.8,
133.2, 130.4, 128.7, 124.7 ppm. HRMS: calcd. for C16H10Cl2S
303.9880, found 303.9882 (100%). C16H10Cl2S (305.23): calcd. C
63.22, H 3.31; found C 63.31, H 3.28.
3b: Yield: 240 mg (91%). M.p. 70–72 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.29 (s, 2 H), 7.13–7.08 (m, 8 H), 2.36 (s, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 141.8, 136.6, 133.9, 129.0, 123.7,
21.3 ppm. HRMS: calcd. for C18H16S 264.0973; found 264.0974.
C18H16S (264.39): calcd. C 81.86, H 6.11; found C 81.78, H 6.05.
4b: Yield: 327 mg (83%). M.p. 147–148 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.41 (d, J = 8.4 Hz, 4 H), 7.31 (s, 2 H), 7.05 (d, J =
8.4 Hz, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.4, 135.2,
131.6, 130.7, 124.7, 121.4 ppm. HRMS: calcd. for C16H10Br2S
393.8849; found 393.8847. C16H10Br2S (394.13): calcd. C 48.79, H
2.56; found C 48.68, H 2.51.
5b: Yield: 282 mg (84%). M.p. 146–147 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.86 (s, 2 H), 7.80–7.75 (m, 4 H), 7.66 (d, J = 8.5 Hz,
2 H), 7.49 (s, 2 H), 7.48–7.44 (m, 4 H), 7.26 (dd, J = 8.4, 8.5 Hz,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 141.9, 134.3, 134.3,
133.8, 132.5, 128.1, 127.8, 127.7, 127.6, 127.5, 126.2, 126.0,
124.7 ppm. HRMS: calcd. for C24H16S 336.0973; found 336.0975.
C24H16S (336.45): calcd. C 85.77, H 4.50; found C 85.68, H 4.53.
6b: Yield: 243 mg (80%). M.p. 88–90 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.34 (s, 2 H), 6.34 (s, 2 H), 2.36 (s, 6 H), 2.15 (s, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 140.7, 135.6, 133.2, 128.3,
127.1, 121.2, 15.1, 13.5 ppm. HRMS: calcd. for C16H16S3 304.0414;
found 304.0416. C16H16S3 (304.50): calcd. C 63.21, H 5.30; found
C 63.30, H 5.21.
7b: Yield: 283 mg (82%). M.p. 113–115 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.21 (s, 2 H), 6.49 (s, 2 H), 2.11 (s, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 135.9, 134.3, 132.6, 128.1, 125.4,
124.3, 13.9 ppm. HRMS: calcd. for C14H10Cl2S3 343.9322; found
343.9325. C14H10Cl2S3 (345.34): calcd. C 48.89, H 2.93; found C
48.88, H 2.84.
[11] O. Hromatka, D. Binder, U. S. Patent 4,028,373, 1977.
[12] P. A. Rossy, W. Hoffmann, N. Muller, J. Org. Chem. 1980, 45,
617–620.
8b: Yield: 300 mg (66%). M.p. 105–106 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.96 (d, J = 8.8 Hz, 1 H), 7.89 (d, J = 4.2 Hz, 1 H),
[13] Y. Dang, Y. Chen, J. Org. Chem. 2007, 72, 6901–6904.
Eur. J. Org. Chem. 2007, 5661–5664
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Y. Dang, Y. Chen
SHORT COMMUNICATION
[14] a) T. Izumi, S. Kobashi, K. Takimiya, Y. Aso, T. Otsubo, J.
Am. Chem. Soc. 2003, 125, 5286–5287; b) A. Facchetti, M.
Mushrush, M.-H. Yoon, C. L. Stern, G. R. Hutchison, M. A.
Ratner, T. J. Marks, J. Am. Chem. Soc. 2004, 126, 13480–13501;
c) K. Takimiya, N. Niihara, T. Otsubo, Synthesis 2005, 10,
1589–1592; d) S. Ando, J.-I. Nishida, H. Tada, Y. Inoue, S.
Tokito, Y. Yamashita, J. Am. Chem. Soc. 2005, 127, 5336–5337;
e) Y. Wang, M. D. Watson, J. Am. Chem. Soc. 2006, 128, 2536–
2537.
[15] a) J. E. McMurry, K. L. Kees, J. Org. Chem. 1977, 42, 2655–
2656; b) J. Nakayama, H. Machida, M. Hoshino, Tetrahedron
Lett. 1985, 26, 1981–1982; c) Y. Chen, D. X. Zeng, M. G. Fan,
Org. Lett. 2003, 5, 1435–1437; d) Z.-N. Huang, B.-A. Xu, S.
Jin, M.-G. Fan, Synthesis 1998, 1092–1094; e) N. Xie, Y. Chen,
J. Mater. Chem. 2006, 16, 982–985.
Received: August 23, 2007
Published Online: October 18, 2007
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Eur. J. Org. Chem. 2007, 5661–5664