Palladium-catalyzed alkenation of thiophenes and furans by regioselective C-H bond functionalization

Article abstract of DOI:10.1016/j.tetlet.2009.03.124

A palladium-catalyzed direct alkenation of thiophenes and furans has been developed in the presence of AgOAc and pyridine. A variety of olefinic substrates such as acrylates, acrylamides, and acrylonitrile can perform the direct oxidative coupling reactio

Full text of DOI:10.1016/j.tetlet.2009.03.124

Tetrahedron Letters 50 (2009) 2758–2761
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Palladium-catalyzed alkenation of thiophenes and furans
by regioselective C–H bond functionalization
*
Jinlong Zhao, Lehao Huang, Kai Cheng, Yuhong Zhang
Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed direct alkenation of thiophenes and furans has been developed in the presence of
AgOAc and pyridine. A variety of olefinic substrates such as acrylates, acrylamides, and acrylonitrile can
perform the direct oxidative coupling reactions with various thiophenes and furans to give the mono-alk-
enylated products in good yields. In most cases, the (E)-isomers were isolated as the major products.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 14 January 2009
Revised 16 March 2009
Accepted 17 March 2009
Available online 21 March 2009
Keywords:
Palladium
Heterocycles
Thiophene
Alkenation
C–H activation
Thiophenes and furans are important aromatic heterocycles
that serve as key components of a variety of biologically active
molecules and functional materials.1 The traditional alkenation of
these heterocycles often involves the formylation and subsequent
Wittig reactions.2 Recently, the development of transition metal-
catalyzed cross-coupling reactions between the functionalized
heterocycles and olefins has provided the versatile tools for the
synthesis of alkenylated heteroaromatic rings in the presence of
phosphine ligands.3 Although these reactions are very useful, they
often suffered from disadvantages of prefunctionalization of het-
erocycles and formation of undesired waste salts. Therefore, the
exploration of catalytic reactions involving Csp2–Csp2 bond forma-
tion via C–H bond activation rather than C–X or C–M bond cleav-
age aroused much attention currently.4 Fujiwara and co-workers
pioneered the palladium-assisted oxidative coupling of arenes
and aromatic heterocycles with olefins.5 They found that both aro-
matic and olefinic C–H bonds in acetic acid could be activated by
stoichiometric or catalytic amount of palladium to give the alkeny-
lated aromatic compounds.6 Ishii and co-workers reported the di-
rect oxidative coupling reactions of arenes with olefins catalyzed
by Pd(OAc)2 in acetic acid combined with heteropolyoxometalate
under dioxygen.7 Under their reaction conditions, furan and substi-
tuted thiophenes could be converted to the heterocycle-substi-
tuted olefins.8 Quite recently, the lithium salts were found to
have special effect on the reactions of Pd(OAc)2–Cu(OAc)2 cata-
lyzed direct alkenation of thiophenes and furans with olefins.9 In
addition, the palladium-catalyzed decarbonylative olefination has
also been utilized in the olefination of aromatic compounds.10
Herein, we report the development of palladium-catalyzed direct
oxidative reactions of thiophenes and furans with olefins in the
presence of AgOAc and pyridine. The reactions are regio- and ster-
eoselective, giving the products substituted at 2-position with (E)-
isomers as major products in one step.
We initially studied the effects of catalysts, solvents, and bases
on the alkenation reaction of thiophene and n-butyl acrylate at
120 °C in DMF for 12 h. It was found that the reaction was sluggish
when 10 mol % Pd(OAc)2 was used as the catalyst (Table 1, entry 1).
However, the addition of silver(I) compounds such as Ag2O, AgNO3,
Ag2CO3, and AgOAc, improved the efficiency of the coupling reac-
tion significantly (Table 1, entries 2–5), and an 83% isolated yield
was obtained by using 1 equiv of AgOAc (Table 1, entry 5). Silver
compounds presumably functioned as stoichiometric oxidants.
These results are better than that using Pd(OAc)2 (5 mol %)–
Cu(OAc)2 (2 equiv) system in acetic acid,6c in which a 3% yield
was obtained for the reaction of thiophene and methyl acrylate
at 100 °C for 8 h. The combined catalytic system of Pd(OAc)2 with
Cu(OAc)2 was less effective under the reaction conditions (Table 1,
entry 8), and Pd(OAc)2 was superior to PdCl2 and Pd(PPh3)4 (Table
1, entries 5–7). A number of solvents that are routinely used in the
palladium-catalyzed C–H bond activation reactions were tested,
including 1,4-dioxane, toluene, acetic acid, NMP, DMF, and DMSO
(Table 1, entries 14–18). The best result was obtained by DMF that
was used in all subsequent reactions. Poor yield was observed in
acetic acid (Table 1, entry 16). The bases influenced the reaction
markedly (Table 1, entries 5, and 9–13). Pyridine turned out to
* Corresponding author. Tel.: +86 571 87952723; fax: +86 571 87953244.
E-mail address: yhzhang@zju.edu.cn (Y. Zhang).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.124

J. Zhao et al. / Tetrahedron Letters 50 (2009) 2758–2761
2759
Table 1
be better than DBACO or DMAP, but the inorganic bases such as
K2CO3 and KOH were ineffective.
Effect of catalysts, solvents, and basesa
Dialkenation was observed when 0.5 mmol thiophene was trea-
ted with 0.5 mmol n-butyl acrylate under the reaction conditions,
but the excessive thiophene could retard the dialkenation effi-
ciently. When 2 mmol thiophene was used, only monoalkenylated
(E)-isomer was obtained, leading to good regio- and stereoselectiv-
ity. The dialkenation product could be produced further by using
the monoalkenylated products as substrates (Scheme 1).
With the optimized conditions in hand (10 mol % Pd(OAc)2,
2 equiv of AgOAc, 2 equiv of pyridine, 120 °C in DMF), we then
examined the scope and limitation of the method. The results are
summarized in Table 2. A variety of thiophenes were examined.
The reaction of thiophene and n-butyl acrylate furnished the direct
coupling product in 83% yield (Table 2, entry 1). Thiophenes bear-
ing electron-donating substituents such as 2-methyl and 2-meth-
oxyl derivatives gave the products in good yields (Table 2, entries
2 and 3). A mixture of (E)-butyl 3-(4-methylthiophen-2-yl)acrylate
and (E)-butyl 3-(3-methylthiophen-2-yl)acrylate was obtained
with 3-methylthiophene and the ratio of two regio-isomers was
approximately 4:5 (Table 2, entry 4). The aryl-substituted thio-
phenes showed relatively lower reactivity, and the high yields
were obtained after the treatment of excessive olefins (Table 2, en-
tries 5–9, and 12). The substituents in the aryl ring showed little
catalyst, additive
solvent, base
+
CO2Bu-
n
CO2Bu-
n
S
S
Entry
Catalyst (mol %)/oxidant
Solvent
Base
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Pd(OAc)2 (10%)
DMF
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
TEA
23
76.
41
82
83
67
42
Trace
44
77
61
38
32
59
77
29
66
57
Pd(OAc)2 (10%)/Ag2O
Pd(OAc)2 (10%)/AgNO3
Pd(OAc)2 (10%)/Ag2CO3
Pd(OAc)2 (10%)/AgOAc
PdCl2 (10 %)/AgOAc
DMF
DMF
DMF
DMF
DMF
Pd(PPh3)4 (10%)/AgOAc
Pd(OAc)2(10%)/Cu(OAc)2
Pd(OAc)2 (10%)/AgOAc
Pd(OAc)2 (10%)/AgOAc
Pd(OAc)2 (10%)/AgOAc
Pd(OAc)2 (10%)/AgOAc
Pd(OAc)2 (10%)/AgOAc
Pd(OAc)2 (10%)/AgOAc
Pd(OAc)2 (10%)/AgOAc
Pd(OAc)2 (10%)/AgOAc
Pd(OAc)2 (10%)/AgOAc
Pd(OAc)2 (10%)/AgOAc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Dioxane
Toluene
AcOH
NMP
DMSO
DABCO
DMAP
K2CO3
KOH
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
a
Reaction conditions: thiophene (2.0 mmol), n-butyl acrylate (0.5 mmol,
1 equiv), 2 equiv of oxidant, additive (2.0 mmol), Pd(OAc)2 (10 mol %), 120 °C, 12 h.
b
Isolated yields based on n-butyl acrylate.
R=CO2Bu-n
n-BuO2C
CO2Bu-n
S
45%
+
R
n-BuO2C
S
R= CO2N(CH )
3 2 n-BuO2C
CONMe2
40%
S
Scheme 1. Reaction conditions: thiophenes (0.5 mmol), acrylates or acrylamide (2 mmol), pyridine (2.0 mmol), AgOAc (200 mol %), Pd(OAc)2 (10 mol %), 120 °C, 12 h.
Table 2
Palladium-catalyzed direct alkenylationa
10 mol % Pd(OAc)2, DMF, 120 o
2 equiv AgOAc, 2 equiv pyridine
C
+
R
X
X
R
A
Entry
1
A
R
Product
Yieldb (%)
83
CO2Bu-n
CO2Bu-n
CO2Bu-n
S
S
2
3
4
5
87
Me
Me
CO2Bu-n
S
S
CO2Bu-n
CO2Bu-n
CO2Bu-n
62
89 (4:5)
MeO
Me
MeO
Me
CO2Bu-n
S
S
CO2Bu-n
S
S
80c
CO2Bu-n
S
S
(continued on next page)

2760
J. Zhao et al. / Tetrahedron Letters 50 (2009) 2758–2761
Table 2 (continued)
Entry
A
R
Product
Yieldb (%)
87c
CO2Bu-n
6
CO2Bu-n
S
S
MeO
OHC
MeO
OHC
7
8
CO2Bu-n
CO2Bu-n
75c
76c
CO2Bu-n
CO2Bu-n
S
S
S
S
F3C
F3C
9
CO2Bu-n
80c
CO2Bu-n
S
S
10
11
12
13
14
15
16
17
18
19
20
CO2Bu-n
CO2Bu-t
CO2Bu-t
CONMe2
CONMe2
CONMe2
CN
84
CO2Bu-n
S
S
90
CO2Bu-t
S
S
S
78c
CO2Bu-t
S
MeO
S
MeO
S
85
CONMe2
90
Me
Me
CONMe2
S
S
70
MeO
Me
MeO
Me
CONMe2
S
S
S
38 (1:2)d,e
CN
S
S
CN
46 (1:2)e
MeO
MeO
CN
S
CO2Bu-n
CO2Bu-n
CONMe2
CONMe2
76
90
64
76
CO2Bu-n
O
O
Me
CO2Bu-n
Me
O
O
O
O
CONMe2
O
O
21
Me
CONMe2
Me
a
Reaction conditions: thiophene (2.0 mmol), n-butyl acrylate (0.5 mmol, 1 equiv), 2 equiv of AgOAc, pyridine (2.0 mmol), Pd(OAc)2 (10 mol %), 120 °C, 12 h.
Isolated yields.
Thiophenes (0.5 mmol), acrylates, or acrylamide (2.0 mmol).
Thiophenes (2.0 mmol), acrylnitrile (2.0 mmol).
The ratio of Z- to E-isomers in parentheses.
b
c
d
e

J. Zhao et al. / Tetrahedron Letters 50 (2009) 2758–2761
2761
Ag
Acknowledgments
AgOAc
Pd(0)
Pd(OAc)2
Funding from Zhejiang Provincial Natural Science Foundation of
China (R407106) and Natural Science Foundation of China (No.
205710631) is acknowledged.
X
HOAc
References and notes
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Bacskai, B. J.; Swager, T. M. Angew. Chem., Int. Ed. 2005, 44, 5452–5456.
2. (a) Jiang, B.; Dou, Y.; Xu, X. Y.; Xu, M. Org. Lett. 2008, 10, 593–596; (b) Molander,
G. A.; Oliveira, R. A. Tetrahedron Lett. 2008, 49, 1266–1268; (c) El-Batta, A.;
Jiang, C. C.; Zhao, W.; Anness, R.; Cooksy, A. L.; Bergdahl, M. J. Org. Chem. 2007,
72, 5244–5259; (d) Thiemann, T.; Watanabe, M.; Tanaka, Y.; Mataka, S. New J.
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3. (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945–2963; (b)
Ehrentraut, A.; Zapf, A.; Beller, M. Synlett 2000, 1589–1592; (c) Morales-
Morales, D.; Redon, R.; Yung, C.; Jensen, C. M. Chem. Commun. 2000, 1619–
1620; (d) Ostermeier, M.; Prieb, J.; Helmchen, G. Angew. Chem., Int. Ed. 2002, 41,
612–614; (e) Schnyder, A.; Aemmer, T.; Indolese, A. F.; Pittelkow, U.; Studer, M.
Adv. Synth. Catal. 2002, 344, 495–498; (f) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc.
2001, 123, 6989–7000.
PdOAc
X
1
HPdOAc
R
X
PdOAc
R
X
R
2
Scheme 2.
4. (a) Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666–7673;
(b) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de
Vries, J. G.; van Leeuwen, P. W. N. M. J. Am.Chem. Soc. 2002, 124, 1586–1587; (c)
Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156–4157; (d) Dams,
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3515.
effect on the reactions and good yields were obtained with both
electron-withdrawing and electron-donating groups under the
reaction conditions (Table 2, entries 5–8). 2-(Naphthalen-1-yl)thi-
ophene gave the corresponding coupling product in 80% yield (Ta-
ble 2, entry 9). It should be noted that benzo[b]thiophene reacted
equally efficiently to yield the expected product in very good yield
(Table 2, entry 10). The coupling reaction worked smoothly with
the diverse acrylate such as t-butyl acrylate (Table 2, entries 11
5. Fujiwara, Y.; Maruyama, O.; Yoshidomi, M.; Taniguchi, H. J. Org. Chem. 1981, 46,
851–855.
6. (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633–639; (b)
Fujiwara, Y.; Asano, R.; Moritani, I.; Teranishi, S. J. Org. Chem. 1976, 41, 1681–
1683; (c) Akiyama, F.; Miyazaki, H.; Kaneda, K.; Teranishi, S.; Fujiwara, Y.; Abe,
M.; Taniguchi, H. J. Org. Chem. 1980, 45, 2359–2361; (d) Fujiwara, Y.; Noritani,
I.; Danno, S.; Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166–7169; (e)
Kitamura, T.; Yamane, M.; Inoue, K.; Todaka, M.; Fukatsu, N.; Meng, Z.;
Fujiwara, Y. J. Am. Chem. Soc. 1999, 121, 11674–11679.
7. (a) Hatamoto, Y.; Sakaguchi, S.; Ishii, Y. Org. Lett. 2004, 6, 4623–4625; (b)
Yamada, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2005, 70, 5471–5474; (c) Yokota,
T.; Tani, M.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2003, 125, 1476–1477.
8. Tani, M.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004, 69, 1221–1226.
9. Maehara, A.; Satoh, T.; Miura, M. Tetrahedron 2008, 64, 5982–5986.
10. (a) GooBen, L. J.; Paetzold, J. Angew. Chem., Int. Ed. 2002, 41, 1237–1241; (b)
Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10, 1159–1162; (c)
Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250–
11251.
11. (a) Beletskay, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–3066; (b)
Moreno-Manas, M.; Perea, M.; Pleixats, R. Tetrahedron Lett. 1996, 37, 7449–
7452; (c) Guertler, C.; Buchwald, S. L. Chem. Eur. J. 1999, 5, 3107–3112.
12. (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem.
Soc. Jpn. 1998, 71, 467–473; (b) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt,
M. J. J. Am. Chem. Soc. 2006, 128, 2528–2529; (c) Garg, N. K.; Caspi, D. D.; Stoltz,
B. M. J. Am. Chem. Soc. 2004, 126, 9552–9553; (d) Zhang, H. M.; Ferreira, E. M.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43, 6144–6148.
and 12). N,N-Dimethylacrylamide was also found to be compatible
with the coupling reaction, and gave the desired products in good
yields (Table 2, entries 13–15). In the case of acrylnitrile, the yields
decreased (Table 2, entries 16 and 17). In addition, Z and E isomers
were produced at a ratio of 1:2, which is possibly because CN group
is relatively small and makes the energy of Z- and E-isomer transi-
tion state of b-hydro elimination closer.5,11 However, the reactions
of thiophene bearing electron-withdrawing substitutes such as
acyl and ester groups were sluggish, indicating that the reaction
might undergo an electrophilic metalation processes.12
The coupling reaction works well with furans (Table 2, entries
18–21). Furan and 2-methyl furan reacted with n-butyl acrylate
efficiently and afforded the expected coupling products in high
yields. N,N-Dimethylacrylamide was also a good coupling partner
and good yields were delivered.
Because the thiophenes bearing electron-withdrawing groups
are inactive under the reaction conditions, we suppose that an
electrophilic metalation mechanism is favored as shown in Scheme
2.5,9,13 Initially, the electronic attack of Pd(II) into thiophene forms
the intermediate 1, which inserts into olefins to afford the interme-
diate 2. The subsequent b–hydro elimination results in the product
and liberates Pd(0) as well as acetic acid. The Pd(II) is regenerated
from the oxidation of Pd(0) by silver(I) compounds.
In conclusion, we have developed an efficient and new method
for the coupling of thiophenes and furans with various olefins
through palladium-mediated direct alkenation in conjunction with
AgOAc and pyridine.14 The method provides the desired products
in good yields, and in most cases, high regio- and stereoselectivi-
ties are presented. Studies to expand the substrate scope of the
method are currently in progress in our laboratory.
13. (a) Grimster, N. P.; Godfrey, C. D.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44,
3125–3129; (b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127,
8050–8057.
14. General procedure: A mixture of acrylates or acrylamide (0.5 mmol), Pd(OAc)2
(11 mg, 10 mol%), thiophenes or furans (2 mmol), AgOAc (1 mmol), pyridine
(2 mmol), DMF (1 mL) was sealed with lined cap and stirred at 120 °C for 12 h.
Afterward, CH2Cl2 (45 mL) was added to the reaction mixture, and then
washed with deionized water (3 Â 15 mL), dried with Na2SO4 and
concentrated. The residue was purified by flash column chromatography to
afford the corresponding products (E)-butyl 3-(5-methoxythiophen-2-
yl)acrylate. The product was obtained as brown oil (Rf = 0.33 in 91%
petroleum ether/9% EtOAc). 1H NMR (400 MHz, CDCl3, TMS) d 7.62 (d, 1H,
J = 15.6 Hz), 6.92 (d, 1H, J = 4.0 Hz), 6.15 (d, 1H, J = 4.0 Hz), 5.93 (d, 1 H,
J = 15.6 Hz), 4.16 (t, 2H, J = 6.6 Hz), 3.92 (s, 3H), 1.62–1.70 (m, 2H), 1.37–1.47
(m, 2H), 0.95 (t, 3H, J = 7.0 Hz). 13C NMR (CDCl3, 100 MHz): d 169.0, 167.2,
138.1, 130.9, 126.2, 113.1, 104.8, 64.1, 60.1, 30.8, 19.1, 13.7. MS (EI): m/z (%):
242 (7) [M++2], 241 (15) [M++1], 240 (100) [M+], 184 (69), 167 (82), 140 (61).
HRMS (EI): Calcd for C12H16O3S: [M+] 240.0816. Found: 240.0820.