S. Tanaka et al. / Tetrahedron Letters 53 (2012) 1173–1176
1175
tion with NiCl2(dppf) at 60 °C also gave 3aa in a reasonable yield
Br
R1
(68%), whereas the reaction with other nickel catalyst NiCl2(PPh3)2
and NiCl2(dppp) proceeded in poor yields. The reaction with palla-
dium catalysts with phosphine ligands, PdCl2(PPh3)2, and PdCl2
(dppf)ÁCH2Cl2, proceeded in moderate yields. Higher catalytic activ-
ity was achieved with 2.0 mol % of palladium catalyst bearing a
N-heterocyclic carbene (NHC) ligand PEPPSI–SIPr,10 to afford 3aa
in an excellent yield at room temperature.
EtMgCl
Cy2NH 10 mol%
PEPPSI-SIPr
THF, rt
R1
S
THF, 60 °C, 24 h
Br
S
3da (R1=Me): 95%
3db (R1=OMe): 75%
R2
EtMgCl
Cy2NH 10 mol%
PEPPSI-SIPr
THF, rt, 24 h
R2
R1
S
THF, 60 °C, 24 h
The reaction of several thiophene derivatives was examined
with a variety of aryl bromides. The results are shown in Table 3.
Various aryl bromides bearing an electron-withdrawing or donat-
ing substituent reacted with 2-methylthiophene (1a) to afford
the coupling products in good to excellent yields. Although the
reaction with 4-bromo-N,N-dimethylaniline proceeded, the yield
was slightly lower (38%, entry 7). In addition, the reaction with
other thiophene derivatives benzo[b]thiophene (1b) and 2-alky-
nylthiophene 1c took place similarly to afford the corresponding
C–H arylation products with PEPPSI–SIPr.10 Thiophene (1d) reacted
with aryl bromides to afford 2-arylated thiophene (3da, 3db, 3dg)
in good to excellent yields (entries 17–19). The reaction of ben-
zo[b]furan was carried out with 4-bromobenzene to afford 3ec in
a 58% yield (entry 20).
It is also remarkable that the reaction with aryl chlorides 4 pro-
ceeded under similar conditions. The reaction of 2-methylthioph-
ene with 4-chlorotoluene (4a) was found to take place at 60 °C
for 24 h with PEPPSI–SIPr to afford 3aa in a quantitative yield,
whereas the use of NiCl2(dppe), which showed excellent perfor-
mance in the reaction with aryl bromide, resulted in a lower yield.
As shown in Table 4, several unactivated and activated aryl chlo-
rides such as 4a–e reacted smoothly with thiophene derivatives
1a and 1b to afford the corresponding coupling products in good
to excellent yields.
5a (R1 = Me, R2 = OMe): 51%
5b (R1 = OMe, R2 = CF3): 56%
Scheme 1. Synthesis of differently substituted 2,5-diarylthiophene by C–H
arylation.
pared in a manner shown in Table 3, at the 5-position was carried
out with EtMgCl and 10 mol % of Cy2NH for metalation to afford
the corresponding 2,5-diarylated thiophenes 5a–5b in good
yields.11
In conclusion, we have shown that metalation with a combina-
tion of an alkyl Grignard reagent and a catalytic amount of second-
ary amine is widely effective for heteroaromatic compounds such
as thiophenes and furans and thus metalated species are shown
to be employed not only for halothiophenes but a variety of aryl
bromides and chlorides. Accordingly, the protocol involving meta-
lation and the following cross coupling are effective for general
arylation of thiophene derivatives. Differently substituted 2,5-
diarylthiophene was also obtained in a facile manner with iterative
arylation reactions.
Acknowledgment
This work was supported by KAKENHI by MEXT, Japan for finan-
cial support.
Our further concern is focused on the synthesis of differently-
substituted 2,5-diarylthiophenes. As we have previously reported
that 2,5-diarylthiophene derivatives showed relatively stronger
photoluminescence than those of thiazoles,2i it is intriguing to
investigate a facile preparation method of the thiophene deriva-
tive. Synthesis of 2,5-diarylthiophene was performed as shown in
Scheme 1. The reaction of 2-arylated thiophene, which was pre-
References and notes
1. Diederich, F., Stang, P. J., Eds.Metal-Catalyzed Cross-Coupling Reaction; Wiley-
VCH: Weinheim, 1998.
2. Reviews on C–H functionalization of heteroaromatic compounds: (a) Campeau,
L.-C.; Fagnou, K. Chem. Commun. 2006, 1253; (b) Ackermann, L.; Vicente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792; (c) McGlacken, G. P.; Bateman,
L. M. Chem. Soc. Rev. 2009, 38, 2447; (d) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 174; (e) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007,
36, 1173; (f) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40,
5068; (g) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074;
(h) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200; (i) Sugie, A.; Mori, A. Bull.
Chem. Soc. Jpn. 2008, 81, 548; (j) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39,
1118.
Table 4
C–H coupling of several thiophene derivatives with aryl chloridea
Entry Substrate Aryl–Cl
Catalyst
Temp.
(°C),
time (h)
Yieldb
(%)
3. For reviews: (a) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40,
1885; (b) Nicolaou, K. C.; Chen, J. S.; Edmonds, D. J.; Estrada, A. A. Angew. Chem.,
Int. Ed. 2009, 48, 660; (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4442.
4. For reviews: (a) Osaka, I.; McCullough, R. D. Acc. Chem. Res. 2008, 41, 1202; (b)
Takimiya, K.; Shinamura, S.; Osaka, I.; Miyazaki, E. Adv. Mater. 2011, 23, 4347;
(c) Pron, A.; Gawrys, P.; Zagorska, M.; Djurado, D.; Demadrille, R. Chem. Soc. Rev.
2010, 39, 2577.
5. (a) Tanaka, S.; Tamba, S.; Tanaka, D.; Sugie, A.; Mori, A. J. Am. Chem. Soc. 2011,
133, 16734; (b) Tamba, S.; Shono, K.; Sugie, A.; Mori, A. J. Am. Chem. Soc. 2011,
133, 9700; (c) Mori, A. J. Synth. Org. Chem. Jpn. 2011, 69, 1202; (d) Tamba, S.;
Tanaka, S.; Okubo, Y.; Okamoto, S.; Meguro, H.; Mori, A. Chem. Lett. 2011, 40,
398.
PEPPSI–
SIPr
>99
(3aa)
Cl
Me
1
2
1a
1a
60, 24
4a
4a
NiCl2(dppe) Rt, 24
32
(3aa)
PEPPSI–
Rt, 24
SIPr
82
(3ab)
Cl
Cl
OMe
3
4
1a
1a
4b
83
(3ac)
Rt, 24
4c
CF3
52
(3ae)
Cl
5
6
1a
1b
Rt, 24
60, 21
4e
6. See also: Asselin, S. M.; Bio, M. M.; Langille, N. F.; Ngai, K. Y. Org. Process Res.
Dev. 2010, 14, 1427.
4a
4b
4c
4e
74
(3ba)
63
(3bb)
77
(3bc)
82
(3be)
7. (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45,
2958; (b) Lin, W.; Baron, O.; Knochel, P. Org. Lett. 2006, 8, 5673; (c) Mosrin, M.;
Knochel, P. Org. Lett. 2008, 10, 2497; (d) Clososki, G. C.; Rohbogner, C. J.;
Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 7681; (e) Rohbogner, C. J.; Clososki,
G. C.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 1503; (f) Piller, F. M.; Knochel,
P. Org. Lett. 2009, 11, 445; (g) Hauser, C. R.; Walker, H. G. J. Am. Chem. Soc. 1947,
69, 295; (h) Hauser, C. R.; Frostick, F. C. J. Am. Chem. Soc. 1949, 71, 1350.
8. General procedure: To a solution of 0.99 M EtMgCl (0.61 mL, 0.6 mmol) in THF
were added dicyclohexylamine (0.01 mL, 0.05 mmol), and 2-methylthiophene
(1a, 0.048 mL, 0.50 mmol) dropwise under an nitrogen atmosphere. After
stirring at 60 °C for 24 h, 1.4 mL of THF and N,N-dimethylformamide (0.5 mL,
7
8
9
1b
1b
1b
Rt, 19
Rt, 24
Rt, 19
a
Unless noted, the reaction was performed with substrate (0.5 mmol), EtMgCl
(0.5 mmol), amine (0.05 mmol), aryl chloride (0.60 mmol) and catalyst (2.0 mol %)
in 2.0 mL of THF.
b
Isolated yield.