Copper-catalyzed tandem S-alkylation and S-alkenylation of sodium sulfide: Synthesis of 2,3-dihydrothiophenes and thiophenes

Article abstract of DOI:10.1016/j.tetlet.2013.01.019

An efficient synthetic approach to variously substituted 2,3-dihydrothiophenes has been developed. The reaction proceeded by copper-catalyzed tandem S-alkylation and S-alkenylation of sodium sulfide with 1,4-diiodobut-1-enes to afford the corresponding 2,

Full text of DOI:10.1016/j.tetlet.2013.01.019

Tetrahedron Letters 54 (2013) 1475–1477
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed tandem S-alkylation and S-alkenylation of sodium sulfide:
synthesis of 2,3-dihydrothiophenes and thiophenes
Qian Liao a, Wei You a, Zhen-Bang Lou b, Li-Rong Wen b, Chanjuan Xi a,
⇑
a Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084, China
b College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, 53 Zhengzhou Road, Qingdao 266042, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic approach to variously substituted 2,3-dihydrothiophenes has been developed. The
reaction proceeded by copper-catalyzed tandem S-alkylation and S-alkenylation of sodium sulfide with
1,4-diiodobut-1-enes to afford the corresponding 2,3-dihydrothiophene derivatives in high yields. The
2,3-dihydrothiophenes could bear alkyl, aryl as well as heteroaryl substituents. The resulted 2,3-dihydro-
thiophenes could be further transferred into the corresponding thiophenes by oxidation.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 3 December 2012
Revised 2 January 2013
Accepted 8 January 2013
Available online 12 January 2013
Keywords:
Tandem reaction
Dihydrothiophene
Thiophene
Sodium sulfide
Copper
Thiophenes and dihydrothiophenes have emerged as a class of
important heterocycles, which not only exhibit a variety of biolog-
ical and medical properties,1,2 but are also widely used in material
science3 and organic synthesis as versatile intermediates.4 Many
efforts have been dedicated to the synthesis of this class of hetero-
cycles.5–7 Recently, great advances have been made in the transi-
tion-metal-catalyzed C–S bond formations,8 which is the key step
in the access to these sulfur containing heterocycles. Among them,
the copper-catalyzed aryl C–S bond formation9 has provided an
excellent complement to the palladium-catalyzed reactions.8b,10
Furthermore, this methodology was successfully extended to the
formation of vinyl C–S bond.11 Accordingly, a straightforward
method for the synthesis of thiophenens, especially highly substi-
tuted thiophenes, via copper-catalyzed double S-alkenylation of
inorganic sulfides with 1,4-dihalo-1,3-dienes has been devel-
oped.12 As part of an ongoing program in our laboratory on the
copper-catalyzed C–S bond formation, we envisioned that dihydro-
thiophene derivatives could be accessed by the combination of
S-alkylation and S-alkenylation from inorganic sulfides and
1,4-dihalobut-1-ene derivatives. Herein we would like to report a
copper-catalyzed one-pot tandem S-alkylation and S-alkenylation
of Na2S with 1,4-diiodobut-1-ene to afford dihydrothiophenes,
which can also be further transferred into di- or trisubstituted
thiophenes.
zirconacyclopentenes.13 At the beginning, (E)-1,2-diphenyl-1,4-dii-
odobut-1-ene 1a and sodium sulfide were selected as the model
substrates for the optimization of the reaction conditions. The re-
sults are summarized in Table 1. Inspired by our previous work,12a
our initial test was carried out in acetonitrile at 140 °C. The ex-
pected product was isolated in 50% yield and fully characterized
by NMR and GC–MS (entry 1). When some commonly used ligands
such as N,N-dimethylenediamine (DMEDA), 1,10-phenanthroline
(1,10-phen), or ethylene glycol were added, the reaction tempera-
ture could be lowered to 110 °C and product 2a was observed in ca.
60% yield (entries 2–4). When the reaction was carried out at 80 °C,
the desired product was afforded less than 10% yield, along with
bis((E)-4-iodo-3,4-diphenylbut-3-en-1-yl)thioether 2a0 as the main
product (entry 5). When we switched the solvent to 1,4-dioxane, 2a
was obtained in 34% yield, along with ca. 60% of 2a0 (entry 6).
When N,N-Dimethylformamide (DMF) was used as the solvent,
the yield of the product could be improved to 80% (entry 7). When
the reaction temperature was lowered to 50 °C, the expected prod-
uct was observed in 67% yield (entry 8). To our surprise, when the
reaction was carried out in N-methyl-2-pyrrolidone (NMP), the
yield of desired product was improved to 88% (entry 9). If the reac-
tion was treated without copper catalyst, the product was formed
in 35% yield, along with ca. 20% of 2a0 (entry 10). On the basis of
these results, the optimal condition involved the following param-
eters: 10 mol % of CuI as a precatalyst, ethylene glycol as a ligand,
NMP as a solvent, and reaction temperature at 80 °C. It is notewor-
thy that the reaction did not seem to be affected by the crystal
water in sodium sulfide. Utilization of potassium sulfide instead
of sodium sulfide afforded a mixture of products under the optimal
The requested 1,4-diiodobut-1-enes were conveniently pre-
pared in high yields through iodination of the corresponding
⇑
Corresponding author. Tel.: +86 10 62782695; fax: +86 10 62771149.
E-mail address: cjxi@tsinghua.edu.cn (C. Xi).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.019

1476
Q. Liao et al. / Tetrahedron Letters 54 (2013) 1475–1477
Table 1
Table 2 (continued)
Optimization between 1,4-diiodobut-1-ene 1a and Na2Sa
Entry
1,4-Diiodobut-1-ene
Time (h)
15
Temp (°C)
Yieldb (%)
45 (40)
Ph
Ph
S
CuI (10 mol%)
Ph
Et
Et
Ph
Ligand (20 mol%)
Et
2i
I
I
Et
1i
Na2S•9H2O
+
I
I
S
Solvent, Temp., 24 h
9
2a
1a
Ph
Ph
Ph
Entry
Ligand
Solvent
Temp (°C)
Yieldb (%)
Ph
S
Et
2j
Et
1
2
3
4
5
6
7
8
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Dioxane
DMF
DMF
NMP
NMP
140
110
110
110
80
80
80
50
80
— (50)
56
58
I
I
DMEDA
1,10-Phen
10
23
75 (70)
1j
p-tolyl
Unless otherwise noted, the reactions were performed in a sealed tube with 1
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
—
60
p-tolyl
<10c
34d
80
a
(1.0 mmol), Na2Sꢀ9H2O (3.0 mmol), CuI (10 mol %), ligand (20 mol %) in NMP (5 mL)
67
88
35
at 80 °C.
9
1H NMR yield, using Cl2C@CHCl as internal standard; isolated yield is given in
b
10e
80
parenthesis.
a
Unless otherwise noted, the reactions were performed in a sealed tube with 1a
(1.0 mmol), Na2Sꢀ9H2O (3.0 mmol), CuI (10 mol %), ligand (20 mol %) in solvent
(5 mL) for 24 h.
b
Table 3
1H NMR yield, using Cl2C@CHCl as internal standard; isolated yield is given in
Oxidation of 2,3-dihydrothiophenes to thiophenesa
parenthesis.
c
90% Bis((E)-4-iodo-3,4-diphenylbut-3-en-1-yl)thioether 2a0 was observed.
R1
R1
S
d
BQ (1.5 eq.)
60% Bis((E)-4-iodo-3,4-diphenylbut-3-en-1-yl)thioether 2a0 was observed.
R2
R3
R2
R3
tert-butyl peroxide (15 eq.)
e
Without CuI.
S
EtOAc, 100 oC
R4
R4
2
3
Table 2
CuI-catalyzed S-alkylation and S-alkenylation of Na2Sa
Entry
1
Thiophene (Yield)
Entry
3
Thiophene (Yield)
Entry
1
1,4-Diiodobut-1-ene
Time (h)
Temp (°C)
Yieldb (%)
90 (81)
Ph
Ph
S
Ph
Ph
S
Ph
S
(55%)
Ph
24
I
I
S
3a
(72%)
S
2a
1a
3e
Ph
Ph
S
Ph
Et
2b
Ph
Et
Et
2
24
85 (70)
I
I
S
S
2
4
1b
3h (69%)
p-tolyl
Ph
Bu
Ph
S
3j (57%)
Bu
2c
Bu
2d
Bu
a
3
4
23
24
80 (65)
50 (43)
I
I
Isolated yields.
1c
Bu
S
Bu
conditions, which included 4,5-diphenyl-2,3-dihydrothiophene 2a,
2,3-diphenylthiophene 3a, and 5,6-diphenyl-3,4-dihydro-1,2-
dithiine in the ratio of 8:6:1.
I
I
1d
S
Having the efficient catalytic system for the coupling reaction in
hand, we next explored the scope of the tandem S-alkylation and
S-alkenylation under the optimized conditions. The results are
summarized in Table 2. Besides (E)-1,2-diphenyl-1,4-diiodobut-1-
ene 1a, 1-phenyl-2-ethyl-1,4-diiodobut-1-ene 1b, and 1-phenyl-
2-butyl-1,4-diiodobut-1-enes 1c were also suitable substrates for
the formation of the corresponding products 2b and 2c in good
yields (entries 2 and 3), respectively. 1,2-Dibutyl substituted
diiodide 1d reacted smoothly with Na2S under the condition to
produce 2,3-dihydrothiophene 2d in moderate yield (entry 4).
When 1,2-di(thiophen-2-yl) substituted diiodide 1e generated
from 1,2-di(thiophen-2-yl)ethyne13 was employed, 40,50-dihydro-
2,20:30,200-terthiophene 2e was obtained in high yield (entry 5).
When diiodide fused with a five-membered ring was used, the
reaction occurred smoothly to afford the desired bicyclic dihydro-
thiophene 2f in 62% yield (entry 6). Similarly, 2,3-dihydrobenzothi-
ophenes 2g and 2h could also be synthesized in good yields
(entries 7 and 8). Tri-substituted 2,3-dihydrothiophenes 2i and 2j
were also obtained in moderate to good yields (entries 9 and 10).
S
5
20
72 (60)
S
S
1e
I
I
S
2e
Ph
Ph
S
I
I
6
7
20
20
—(62)
2f
1f
2g
Bu
I
I
1g
76 (63)
S
Bu
I
I
S
8
20
68 (63)
2h
1h
Ph
Ph

Q. Liao et al. / Tetrahedron Letters 54 (2013) 1475–1477
1477
Mater. 2005, 17, 4892; (d) Koumura, N.; Wang, Z.-S.; Mori, S.; Miyashita, M.;
Suzuki, E.; Hara, K. J. Am. Chem. Soc. 2006, 128, 14256; (e) Yasuda, S.; Yoshida,
S.; Sasaki, J.; Okutsu, Y.; Nakamura, T.; Taninaka, A.; Takeuchi, O.; Shigekawa, H.
J. Am. Chem. Soc. 2006, 128, 7746.
As the precursors of thiophenes, dihydrothiophenes undergo a
dehydrogenative aromatization process to give the corresponding
thiophenes.7e,14 In this text, the typical examples are described in
Table 3. The resulted dihydrothiophene 2a was treated with p-
benzoquinone and tert-butyl peroxide at 100 °C for 36 h. 2,3-
Diphenylthiophene 3a was obtained in 72% yield. Under the same
condition, a branched terthiophene 3e was also obtained in 55%
yield. When the crude product 2h was treated under the oxidative
condition, 2-phenylbenzothiophene 3h was isolated in 69% yield.
Thiophenes with three different substituents such as 3j could be
also synthesized in 57% yield by oxidizing dihydrothiophene 2j.
In conclusion, we have developed an efficient synthetic ap-
proach to variously substituted 2,3-dihydrothiophenes based on
copper-catalyzed tandem S-alkylation and S-alkenylation of Na2S
with 1,4-diiodobut-1-enes. Under oxidative conditions, 2,3-dihy-
drothiophenes can be further transformed to di- or trisubstituted
thiophenes.
4. (a) Lipshutz, B. H. Chem. Rev. 1986, 86, 795; (b) Rassu, G.; Zanardi, F.; Battistini,
L.; Casiraghi, G. Chem. Soc. Rev. 2000, 29, 109.
5. Hartough, H. D., Hochgesang, F. P., Blicke, F. F., Eds.Chemistry of Heterocyclic
Compounds: Thiophene and its Derivatives; John Wiley & Sons: Hoboken,
2008; Vol. 3,. p 47.
6. (a) Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367; (b) Barton, T. J.; Zika, R. G. J. Org.
Chem. 1970, 35, 1729; (c) Stephensen, H.; Zaragoza, F. J. Org. Chem. 1997, 62,
6096; (d) Ong, C. W.; Chen, C. M.; Wang, L. F. Tetrahedron Lett. 1998, 39, 9191;
(e) McKibben, B. P.; Cartwright, C. H.; Castelhano, A. L. Tetrahedron Lett. 1999,
40, 5471; (f) Fazio, A.; Gabriele, B.; Salerno, G.; Destri, S. Tetrahedron 1999, 55,
485; (g) Castanedo, G. M.; Sutherlin, D. P. Tetrahedron Lett. 2001, 42, 7181; (h)
Frutos Hoener, A. P.; Henkel, B.; Gauvin, J.-C. Synlett 2003, 63; Matloubi
Moghaddam, F.; Zali Boinee, H. Tetrahedron 2004, 60, 6085; (j) Zhang, H.; Yang,
G.; Chen, J.; Chen, Z. Synthesis 2004, 3055; (k) Minetto, G.; Raveglia, L. F.; Sega,
A.; Taddei, M. Eur. J. Org. Chem. 2005, 5277; (l) Kaleta, Z.; Makowski, B. T.; Soós,
T.; Dembinski, R. Org. Lett. 2006, 8, 1625; (m) Wang, Y.; Dong, D.; Yang, Y.;
Huang, J.; Ouyang, Y.; Liu, Q. Tetrahedron 2007, 63, 2724.
7. (a) Birch, S. F.; McAllan, D. T. Nature 1950, 165, 899; (b) Sauer, N. N.; Angelici, R.
J.; Huang, Y. C. J.; Trahanovsky, W. S. J. Org. Chem. 1986, 51, 113; (c) Rahim, M.
A.; Fujiwara, T.; Takeda, T. Synlett 1999, 1029; (d) McDonald, F. E.; Burova, S. A.;
Huffman, L. G., Jr. Synthesis 2000, 970; (e) Hatayama, A.; Kawakami, H.;
Ohkubo, K.; Kumamoto, T. Proc. Sch. Sci. Tokai Univ. 2000, 35, 65; (f) Sasaki, S.;
Adachi, K.; Yoshifuji, M. Org. Lett. 2007, 9, 1729; (g) Sun, J.; Xia, E.-Y.; Zhang, L.-
L.; Yan, C.-G. Eur. J. Org. Chem. 2009, 5247.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (20972085 and 21032004) and National Basic
Research Program of China (2012CB933402).
8. (a) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205; (b) Beletskaya, I. P.;
Ananikov, V. P. Chem. Rev. 2011, 111, 1596.
9. (a) Xu, H.-J.; Zhao, X.-Y.; Deng, J.; Fu, Y.; Feng, Y.-S. Tetrahedron Lett. 2009, 50,
434; (b) Sperotto, E.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G. J. Org.
Chem. 2008, 73, 5625; (c) Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Eur. J.
Org. Chem. 2008, 640; (d) Rout, L.; Sen, T. K.; Punniyamurthy, T. Angew. Chem.,
Int. Ed. 2007, 46, 5583; (e) Carril, M.; SanMartin, R.; Domínguez, E.; Tellitu, I.
Chem. Eur. J. 2007, 13, 5100; (f) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863; (g)
Verma, A. K.; Singh, J.; Chaudhary, R. Tetrahedron Lett. 2007, 48, 7199; (h) Chen,
Y.-J.; Chen, H.-H. Org. Lett. 2006, 8, 5609; (i) Deng, W.; Zou, Y.; Wang, Y.-F.; Liu,
L.; Guo, Q.-X. Synlett 2004, 1254; (j) Bates, C. G.; Gujadhur, R. K.; Venkataraman,
D. Org. Lett. 2002, 4, 2803; (k) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4,
3517; (l) Pinchart, A.; Dallaire, C.; Gingras, M. Tetrahedron Lett. 1998, 39, 543.
10. (a) Kuhn, M.; Falk, F. C.; Paradies, J. Org. Lett. 2011, 13, 4100; (b) Alvaro, E.;
Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 7858; (c) Fernandez-Rodriguez, M. A.;
Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180.
Supplementary data
Supplementary data (experimental procedures and full charac-
terization including 1H NMR, and 13C NMR data, and NMR spectra
for compounds 2a–2j, 3a, 3e, 3h and 3j) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.01.019.
References and notes
11. (a) Kabir, M. S.; Van Linn, M. L.; Monte, A.; Cook, J. M. Org. Lett. 2008, 10, 3363;
(b) Wang, Z.; Mo, H.; Bao, W. Synlett 2007, 91; (c) Zheng, Y.; Du, X.; Bao, W.
Tetrahedron Lett. 2006, 47, 1217; (d) Bates, C. G.; Saejueng, P.; Doherty, M. Q.;
Venkataraman, D. Org. Lett. 2004, 6, 5005; (e) Kabir, M. S.; Lorenz, M.; Van Linn,
M. L.; Namjoshi, O. A.; Ara, S.; Cook, J. M. J. Org. Chem. 2010, 75, 3626.
12. (a) You, W.; Yan, X.; Liao, Q.; Xi, C. Org. Lett. 2010, 12, 3930; (b) Li, C.-L.; Zhang,
X.-G.; Tang, R.-Y.; Zhong, P.; Li, J.-H. J. Org. Chem. 2010, 75, 7037.
13. (a) Takahashi, T.; Kageyama, M.; Denisov, V.; Hara, R.; Negishi, E. Tetrahedron
Lett. 1993, 34, 687; (b) Aoyagi, K.; Kasai, K.; Kondakov, D. Y.; Hara, R.; Suzuki,
N.; Takahashi, T. Inorg. Chim. Acta 1994, 220, 319; (c) Takahashi, T.; Aoyagi, K.;
Kondakov, D. Y. J. Chem. Soc., Chem. Commun. 1994, 747; (d) Xi, C.; Huo, S.; Afifi,
T. H.; Hara, R.; Takashashi, T. Tetrahedron Lett. 1997, 38, 4099; (e) Xi, Z.; Liu, X.;
Lu, J.; Bao, F.; Fan, H.; Li, Z.; Takahashi, T. J. Org. Chem. 2004, 69, 8547; (f) Xi, Z.;
Song, Z.; Liu, G.; Liu, X.; Takahashi, T. J. Org. Chem. 2006, 71, 3154.
1. Blicke, F. F. In Chemistry of Heterocyclic Compounds: Thiophene and its
Derivatives; Hartough, H. D., Hochgesang, F. P., Blicke, F. F., Eds.; John Wiley &
Sons: Hoboken, 2008; Vol. 3, p 29.
2. (a) Mishra, R.; Tomar, I.; Singhal, S.; Jha, K. K. Pharm. Chem. 2011, 3, 38; (b) Wu,
C.; Decker, E. R.; Blok, N.; Bui, H.; You, T. J.; Wang, J.; Bourgoyne, A. R.; Knowles,
V.; Berens, K. L.; Holland, G. W.; Brock, T. A.; Dixon, R. A. F. J. Med. Chem. 2004,
47, 1969; (c) Doré, K.; Dubus, S.; Ho, H.-A.; Lévesque, I.; Brunette, M.; Corbeil,
G.; Boissinot, M.; Boivin, G.; Bergeron, M. G.; Boudreau, D.; Leclerc, M. J. Am.
Chem. Soc. 2004, 126, 4240; (d) Lisowski, V.; Enguehard, C.; Lancelot, J.-C.;
Caignard, D.-H.; Lambel, S.; Leonce, S.; Pierre, A.; Atassi, G.; Renard, P.; Rault, S.
Bioorg. Med. Chem. Lett. 2001, 11, 2205; (e) Ramos, A. C.; Peláez, R.; Luis López,
J.; Caballero, E.; Medarde, M.; San Feliciano, A. Tetrahedron 2001, 57, 3963; (f)
Modica, M.; Santagati, M.; Guccione, S.; Russo, F.; Cagnotto, A.; Goegan, M.;
Mennini, T. Eur. J. Med. Chem. 2000, 35, 1065; (g) Koike, K.; Jia, Z.; Nikaido, T.;
Liu, Y.; Zhao, Y.; Guo, D. Org. Lett. 1999, 1, 197.
14. (a) Belo, D.; Alves, H.; Lopes, E. B.; Duarte, M. T.; Gama, V.; Henriques, R. T.;
Almeida, M.; Pérez-Benítez, A.; Rovira, C.; Veciana, J. Chem.-Eur. J. 2001, 7, 511;
(b) Rossy, P. A.; Hoffmann, W.; Müller, N. J. Org. Chem. 1980, 45, 617; (c)
Rungtaweevoranit, B.; Butsuri, A.; Wongma, K.; Sadorn, K.; Neranon, K.;
Nerungsi, C.; Thongpanchang, T. Tetrahedron Lett. 2012, 53, 1816.
3. (a) Funahashi, M.; Zhang, F.; Tamaoki, N. Adv. Mater. 2007, 19, 353; (b) Ma, C.-
Q.; Mena-Osteritz, E.; Debaerdemaeker, T.; Wienk, M. M.; Janssen, R. A. J.;
Bäuerle, P. Angew. Chem., Int. Ed. 2007, 46, 1679; (c) Murphy, A. R.; Liu, J.;
Luscombe, C.; Kavulak, D.; Fréchet, J. M. J.; Kline, R. J.; McGehee, M. D. Chem.