Palladium-catalyzed C-H functionalization of heteroarenes with aryl bromides and chlorides

Article abstract of DOI:10.1021/jo101433g

Palladium-catalyzed C-H arylation of electron-enriched heteroarenes with aryl bromides and aryl chlorides proceeds in the presence of LiO-t-Bu as a base. The reaction allows one-pot synthesis of differently substituted 2,5-diarylthiazole with the same catalyst system by switching the solvent and the amount of base.

Full text of DOI:10.1021/jo101433g

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TABLE 1. Solvent Effect of the Palladium(II)-Catalyzed C-H
Coupling of Benzothiophene (1) with 2aa
Palladium-Catalyzed C-H Functionalization
of Heteroarenes with Aryl Bromides and Chlorides
Shunsuke Tamba, Youhei Okubo, Shota Tanaka,
Daiki Monguchi, and Atsunori Mori*
Department of Chemical Science and Engineering,
Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
entry
base (equiv)
solvent
NMP
TMU
DMF
DMF
toluene
1,4-dioxane
DMF
yieldb (%)
1
2
3
4
5
6
7
8
LiO-t-Bu (2)
LiO-t-Bu (2)
LiO-t-Bu (2)
LiO-t-Bu (3)
LiO-t-Bu (3)
LiO-t-Bu (3)
KO-t-Bu (2)
NaO-t-Bu (2)
0
48c
43
55c
0
amori@kobe-u.ac.jp
Received July 28, 2010
0
trace
0
DMF
aThe reaction was performed with 1 (0.5 mmol) and 2a (0.6 mmol) in
2 mL of solvent at 100 °C for 15 h. bUnless specified, the yield was
estimated by 1H NMR. cIsolated yield.
has been paid to investigate novel C-H coupling reactions of
heteroaromatic compounds so far.5
Palladium-catalyzed C-H arylation of electron-enriched
heteroarenes with aryl bromides and aryl chlorides pro-
ceeds in the presence of LiO-t-Bu as a base. The reac-
tion allows one-pot synthesis of differently substituted
2,5-diarylthiazole with the same catalyst system by
switching the solvent and the amount of base.
We have shown that functionalization of an electron-
deficient C-H bond such as that of azoles takes place in
the presence of a weak base or fluoride ion by the catalysis
of palladium/copper catalyst system,6 while the reaction of
an electron-enriched C-H bond such as the 2-position of
thiophene or the 5-position of thiazole is induced by electro-
philic substitution with a palladium catalyst.6,7 An alterna-
tive strategy for the functionalization of the above C-H
bond is the use of a stronger base to abstract the less acidic
hydrogen atom. Dougulis and Miura recently showed that
the use of a lithium salt of tertiary alcohols effectively
induced the copper(I)-catalyzed arylation reaction of several
heteroaromatic compounds.8 However, the majority of the
substrates employed for the coupling reaction are highly
reactive aryl iodides. Accordingly, it is intriguing to explore a
novel catalytic reaction that proceeds with higher perfor-
mance for the C-H functionalization of heteroaromatic
compounds. Herein, we describe the palladium-catalyzed
The transition-metal-catalyzed C-H functionalization
reaction has recently attracted much attention compared
with the related cross coupling of organometallic com-
pounds with organic halides due to its operational simplicity
avoiding the preparation of corresponding organometallic
reagents.1,2 The C-H coupling reaction of heteroaromatic
compounds involves a particular advantage since it is rela-
tively easy to specify the C-H bond to be subjected to the
bond formation compared with that of, for example, mono-
substituted benzene. In addition, a number of heteroaro-
matic components are found in biologically active mole-
cules3 as well as advanced organic materials;4 therefore,
development of a practical synthetic strategy for such mole-
cules is an important issue in organic synthesis. Much effort
(5) Selected examples of Pd-catalyzed C-H bond arylation, see:
(a) Durbin, M. J.; Willis, M. C. Org. Lett. 2008, 10, 1413. (b) Yanagisawa,
S.; Ueda, K.; Sekizawa, H.; Itami, K. J. Am. Chem. Soc. 2009, 131, 14622.
(c) Dong, J. J.; Doucet, H. Eur. J. Org. Chem. 2010, 611. (d) Miyasaka, M.;
Fukushima, A.; Satoh, T.; Hirano, K.; Miura, M. Chem.;Eur. J. 2009, 15,
3674. (e) Ohnmacht, S. A.; Culshaw, A. J.; Greaney, M. F. Org. Lett. 2010,
12, 224. (f) Gryko, D. T.; Vakuliuk, O.; Gryko, D.; Koszarna, B. J. Org.
Chem. 2009, 74, 9517. (g) Pschierer, J; Plenio, H. Angew. Chem., Int. Ed.
10.1002/anie.201002045.
(6) (a) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.;
Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125,
1700. (b) Miyaoku, T.; Mori, A. Heterocycles 2009, 77, 151.
(7) (a) Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui, K.; Mori, A.
Org. Lett. 2005, 7, 5083. (b) Takahashi, M.; Masui, K.; Sekiguchi, H.;
Kobayashi, N.; Mori, A.; Funahashi, M.; Tamaoki, N. J. Am. Chem. Soc.
2006, 128, 10930. (c) Masuda, N.; Tanba, S.; Sugie, A.; Monguchi, D.;
Koumura, N.; Hara, K.; Mori, A. Org. Lett. 2009, 11, 2297. (d) Matsuda, S.;
Takahashi, M.; Monguchi, D.; Mori, A. Synlett 2009, 1941.
(1) Metal-Catalyzed Cross-Coupling Reaction; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: Weinheim, 1998.
(2) Reviews on C-H bond arylation: (a) Campeau, L.-C.; Fagnou, K.
Chem. Commun. 2006, 1253. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.;
Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382. (c) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174. (d) Seregin, I. V.; Gevorgyan, V.
Chem. Soc. Rev. 2007, 36, 1173. (e) Satoh, T.; Miura, M. Chem. Lett. 2007,
36, 200. (f) Ackermann, L. Synlett 2007, 507. (g) Li, B.-J.; Yang, S.-D.; Shi,
Z.-J. Synlett 2008, 949. (h) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269.
(i) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48,
9792. (j) Mori, A.; Sugie, A. Bull. Chem. Soc. Jpn. 2008, 81, 548.
(3) For reviews: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem., Int. Ed. 2005, 44, 4442. (b) Ligault, B.; Petrov, I.; Gorelsky, S. I.;
Fagnou, K. J. Org. Chem. 2010, 75, 1047.
(8) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
(b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128.
(c) Matsuyama, N.; Kitahara, M.; Hirano, K.; Satoh, T.; Miura, M. Org.
Lett. 2010, 12, 2358. (d) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.;
Vicente, R. Org. Lett. 2008, 10, 3081. (e) Do, H.-Q.; Kashif Khan, R. M.;
Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185. (f) Phipps, R. J.; Grimster,
N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172.
(4) For reviews, see: (a) Osaka, I.; McCullough, R. D. Acc. Chem. Res.
2008, 41, 1202. (b) Cheng, Y.-J.; Yang, S.-H.; Hsu, C.-S. Chem. Rev. 2009,
109, 5868.
6998 J. Org. Chem. 2010, 75, 6998–7001
Published on Web 09/21/2010
DOI: 10.1021/jo101433g
r
2010 American Chemical Society

Tamba et al.
JOCNote
TABLE 2. Arylation of Benzothiophene (1) with 4-Bromotoluene (2a)
TABLE 3. Pd-Catalyzed C-H Arylation of Heteroarenes with
with Various Palladium Catalystsa
Aryl Bromidesa
entry
Pd cat. (mol %)
yieldb (%)
1
2
3
4
5
6
PdCl2(PPh3)2 (2)
PdCl2dppf (2)
55
42
68
97
62
70
PdCl2dt-bpf (2)c
Pd(Pt-Bu3)2 (2)
Pd(OAc)2 (2)/JohnPhos (4)d
Pd(OAc)2 (2)/t-Butyl XPhos (4)e
aThe reaction was performed with 1 (0.5 mmol) and 2a (0.6 mmol) in
2 mL of DMF at 100 °C for 15 h. bThe yield was estimated by 1H NMR
c
yield. d-t-bpf =1,10-bis(di-tert-butylphosphino)ferrocene. dJohnPhos =
2-(di-tert-butylphosphino)biphenyl. etert-Butyl Xphos =2-di-tert-butyl-
phosphino-20,40,60-triisopropylbiphenyl.
C-H arylation reactions with aryl bromides and chlorides,
which occurs efficiently with LiO-t-Bu as an additive.9
We first studied the reaction of benzothiophene (1) with
4-bromotoluene (2a) in the presence of an additive and a
catalytic amount of palladium(II) complex under various
reaction conditions. Table 1 summarizes the results. Several
bases were examined as an additive to undergo the reac-
tion. Among those, the reaction with lithium tert-butoxide10
resulted in giving 2-(4-methylphenyl)benzothiophene (3a) in
a reasonable yield. The use of 3 equiv of LiO-t-Bu was found
to give the coupling product 3 in a superior yield. DMF or
N,N,N0,N0-tetramethylurea (TMU) was a choice of the sol-
vent, while other polar aprotic solvents as well as less polar
ones were totally ineffective. Potassium and sodium tert-
butoxides were ineffective in undergoing the reaction.
Although the reaction of several heteroaromatic compounds
involving thiophene derivatives with aryl halides was shown
to take place in the presence of catalytic CuI in the presence
of LiO-t-Bu,8 the reaction with a palladium catalyst pro-
ceeded under mild conditions with a reduced amount of aryl
bromide (1.2 equiv) at 100 °C for 15 h. The reaction was
foundtoproceedina superior yieldtothatwithPdCl2(PPh3)2.
Although the use of Pd(OAc)2 with several other bulky
phosphines also underwent the coupling reaction, the yield
was slightly decreased.
The reaction conditions found in Table 2 were applied to
the reaction of several heteroaromatic compounds and aryl
bromides as summarized in Table 3. Various aryl bromides
bearing an electron-withdrawing or -donating substituent
reacted with benzothiophene (1) to afford the coupling
products 3a-g in good to excellent yields. In addition, the
reaction with other thiophene derivatives proceeded simi-
larly to afford the corresponding C-H arylation products.
Furthermore, other heteroaromatic compounds such as
(9) Selected examples of Pd-catalyzed C-H bond arylation with aryl
chlorides: (a) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K.
J. Am. Chem. Soc. 2006, 128, 581. (b) Chiong, H. A.; Pham, Q.-N.; Daugulis,
O. J. Am. Chem. Soc. 2007, 129, 9879. (c) Chiong, H. A.; Daugulis, O. Org.
Lett. 2007, 9, 1449. (d) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K.
J. Am. Chem. Soc. 2006, 128, 8754. (e) Lafrance, M.; Shore, D.; Fagnou, K.
Org. Lett. 2006, 8, 5097.
(10) For recent examples using tert-butoxides in C-H coupling reactions,
see: (a) Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008,
130, 3266. (b) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett.
2008, 10, 4673. (c) Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett.
2009, 11, 1733. (d) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2009, 11, 1737. (e) Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. Org.
Lett. 2009, 11, 4156. (f) Kim, S. H.; Chang, H. Org. Lett. 2010, 12, 1868.
(g) Kawano, T.; Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2010, 75, 1764. (h) Vechorkin, O.; Proust, V.; Hu, X. Angew. Chem.,
Int. Ed. 2010, 49, 3061.
aUnless noted, the reaction was performed with 1 (0.5 mmol) and 2a
(0.6 mmol) in 2 mL of DMF at 100 °C for 15 h. bIsolated yield. cReaction
temperature: 60 °C.
furan and thiazole (at the 5-position) also underwent the
reaction.
It is also remarkable that the reaction with aryl chlorides
(4) proceeded under similar conditions. As shown in Table 4,
several unactivated and activated aryl chlorides such as 4a-d
J. Org. Chem. Vol. 75, No. 20, 2010 6999

Tamba et al.
JOCNote
TABLE 4. Pd-Catalyzed C-H Arylation of Heteroarenes with Aryl
SCHEME 2
Chloridesa
as a solvent. As suggested by the results of the entry 6 of
Table 1, the use of a less polar solvent is completely ineffec-
tive for the reaction of an electron-enriched C-H bond such
as the 2-position of thiophene. Indeed, the reaction at the
5-position of thiazole, which is a typical electron-enriched
carbon atom, hardly occurred in 1,4-dioxane.11
Thus, the regioselective C-H arylation reaction lead to
facile synthesis of 2,5-diarylthiazole derivatives6a,12 by one-
pot iterative 2-arylation and following 5-arylation with
thiazole. Unsubstituted thiazole 17 was first subjected to
the reaction of 4-bromotoluene (2a) in 1,4-dioxane with 1.2
equiv of LiO-t-Bu at 100 °C for 5 h to undergo the 2-arylation.
It is remarkable to observe 2-position selective arylation with-
out copper cocatalyst.13 Following addition of DMF, 3.0
equiv of LiO-t-Bu and 4-bromoanisole (2c) afforded 2,5-
diarylthiazole 12c in 56% overall yield (Scheme 2).
In summary, we have shown a facile palladium-catalyzed
C-H arylation reaction of heteroaromatic compounds
with aryl bromides and chlorides. The reaction proceeded
smoothly to afford the corresponding coupling products in
reasonable yields. It was also found that regioselective C-H
arylation of thiazole took place at the 2-position of thia-
zole by judicious choice of solvent. Differently substituted
2,5-diarylthiazole was thereby obtained in a facile manner.
aUnless noted, the reaction was performed with 1 (0.5 mmol) and 2a
(0.6 mmol) in 1 mL of DMF at 100 °C for 15 h. bIsolated yield. cA
mixture of DMF (1 mL) and 1,4-dioxane (1 mL) was employed as a
solvent system.
SCHEME 1
Experimental Section
reacted smoothly with thiophene derivatives 1, 5, and 13
to afford the corresponding coupling product in good to
excellent yields.
General Procedure for C-H Coupling of Thiophene Deriva-
tives with Aryl Halide Representative for the Preparation of
2-(4-Trifluoromethyl)benzo[b]thiophene (3d). To a 20 mL
Schlenk tube equipped with a magnetic stirring bar was added
a 2.2 M THF solution of LiO-t-Bu (1.5 mmol, 0.68 mL) under
nitrogen atmosphere. The solvent was removed under reduced
pressure. To the residue were successively added Pd(Pt-Bu3)2
(5.1 mg, 0.01 mmol), benzo[b]thiophene 1 (68 mg, 0.5 mmol),
4-bromobenzotrifluoride (2d) (135 mg, 0.6 mmol), and DMF
(2.0 mL). The mixture was stirred at 100 °C for 15 h. After being
cooled to room temperature, the reaction mixture was poured
into water, and the organic materials were extracted with diethyl
ether. The organic layer was washed with water twice and dried
over anhydrous sodium sulfate. The solvent was removed under
reduced pressure to leave a crude oil, which was purified by
The C-H functionalization reaction with LiO-t-Bu as a
base was found to proceed not only at the C-H bond of a
relatively electron-enriched carbon atom such as thiophene
but also at an electron-deficient C-H bond. The reaction of
benzothiazole (15) with 4-bromotoluene (2a) did not proceed
when DMF was employed as a solvent; however, it was
found to occur smoothly by switching the employed solvent
to less polar. The reaction in 1,4-dioxane at 100 °C afforded
the coupling product 16a in 96% yield. In contrast to our
previous case using NaOH or TBAF as an additive, where
Pd/Cu catalyst system was effective, the reaction was found
to proceed without copper cocatalyst.6a,b It is also remark-
able that the reaction of 15 was performed with a smaller
amount of base (Scheme 1).
(11) The reaction in DMF gave unidentified side products.
(12) (a) Shikuma, J.; Mori, A.; Masui, K.; Matsuura, R.; Sekiguchi, A.;
Ikegami, H.; Kawamoto, M.; Ikeda, T. Chem. Asian J. 2007, 2, 301. (b) Mori,
A.; Shikuma, J.; Kinoshita, M.; Ikeda, T.; Misaki, M.; Ueda, Y.; Komura,
M.; Asaoka, S.; Iyoda, T. Chem. Lett. 2008, 37, 272.
This solvent effect was successfully applied to the regiose-
lective C-H arylation reaction of thiazole (17). The reaction
of 4-bromotoluene (2a) and 17 took place at the 2-position
selectively when the reaction was carried out in 1,4-dioxane
(13) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467. Also see ref 6a.
7000 J. Org. Chem. Vol. 75, No. 20, 2010

Tamba et al.
JOCNote
column chromatography on silica gel using hexane as an eluent
to afford 96 mg of 3d as a colorless solid (69% yield): mp
195.2-196.6 °C; 1H NMR (500 MHz, CDCl3) δ 7.26-7.34 (2H,
m), 7.56 (1H, s), 7.60 (2H, d, J = 8.2 Hz), 7.72-7.76 (3H, m),
7.78 (1H, dd, J = 7.9, 0.6 Hz); 13C NMR (75 MHz, CDCl3)
δ121.03, 122.35, 123.95, 124.13 (q, JC-F = 279 Hz), 124.80,
124.98, 125.93 (q, JC-F = 4 Hz), 126.59, 130.00 (q, JC-F = 35
Hz), 137.72, 139.79, 140.40, 142.28; IR (neat) 824, 1070, 1111,
1168, 1330; HRMS (EIþ) calcd for C15H9F3S 278.0377, found
m/z 278.0377.
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research (B) by the Ministry of
Education, Culture, Sports, Science and Technology (MEXT),
Japan. We thank Nara Institute of Science and Technology,
Kyoto-Advanced Nanotechnology Network, supported by
MEXT, for measurements of high resolution mass spectra.
Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 20, 2010 7001