Palladium Charcoal-Catalyzed Suzuki-Miyaura Coupling to Obtain Arylpyridines and Arylquinolines

Article abstract of DOI:10.1021/jo034970r

A phosphine ligand, such as PPh₃ or 2-(dicyclohexylphosphino)biphenyl, is essential for the Pd/C-catalyzed Suzuki-Miyaura coupling of halopyridines and haloquinolines, although it has been reported that the reaction of phenyl chlorides can be catalyzed by nonprereduced Pd/C without any additives. In the reactions of bromopyridines, bromoquinolines, 2-chloropyridines, and 2-chloroquinolines, PPh₃ was effective enough to provide coupling products in good yields. However, in the reactions of 3-chloropyridine, 4-chloropyridine, and 6-chloroquinoline, sterically hindered 2-(dicyclohexylphosphino)biphenyl was indispensable as a ligand.

Full text of DOI:10.1021/jo034970r

P a lla d iu m Ch a r coa l-Ca ta lyzed Su zu k i-Miya u r a Cou p lin g To
Obta in Ar ylp yr id in es a n d Ar ylqu in olin es
Tsuyoshi Tagata and Mayumi Nishida*
Koei Chemical Company, Ltd., Kitasode, Sodegaura, Chiba 299-0266, J apan
m-nishida@koeichem.co.jp
Received J uly 6, 2003
A phosphine ligand, such as PPh3 or 2-(dicyclohexylphosphino)biphenyl, is essential for the Pd/C-
catalyzed Suzuki-Miyaura coupling of halopyridines and haloquinolines, although it has been
reported that the reaction of phenyl chlorides can be catalyzed by nonprereduced Pd/C without
any additives. In the reactions of bromopyridines, bromoquinolines, 2-chloropyridines, and 2-chloro-
quinolines, PPh3 was effective enough to provide coupling products in good yields. However, in the
reactions of 3-chloropyridine, 4-chloropyridine, and 6-chloroquinoline, sterically hindered 2-(dicy-
clohexylphosphino)biphenyl was indispensable as a ligand.
TABLE 1. Yield s of P d /C(0)-Ca ta lyzed Su zu k i-Miya u r a
Cou p lin g w ith TBAB
In tr od u ction
Suzuki-Miyaura coupling is a well-known synthetic
tool for C-C bond formation.1 This reaction has often
been used to obtain a wide variety of biaryl compounds,
which are used in pharmaceuticals, herbicides, and light-
emitting materials. In such cases, homogeneous pal-
ladium complexes are generally used as a catalyst.
However, the reaction with a heterogeneous catalyst such
as Pd/C has also recently been investigated.2 Compared
to air-sensitive and expensive homogeneous palladium
catalysts, palladium charcoal can be safely handled and
removed from the reaction mixture by simple filtration.
The recovered palladium charcoal can be purified and
reused as palladium metal. These features are great
advantages in an industrial process.
In 1994, the Roche group reported palladium charcoal-
catalyzed Suzuki-Miyaura coupling of phenyl bromides
and phenylboronic acids that proceeded without any
additives.2a They noted that there were two types of
Pd/C, which differed with regard to the degree of the
reduction of palladium. One, in which the degree of
palladium reduction is low [mainly Pd(II)], is shown as
[Pd(II)/C], and the other, in which the degree of pal-
ladium reduction is high [mainly Pd(0)], is shown as
[Pd(0)/C]. In 2001, Ko¨hler and co-workers successfully
coupled phenyl chlorides with an electron-withdrawing
TBAB
(equiv)
yield
(%)a
entry
1
1
3
1a : X ) 2-Br,
R ) H
0
0.1
0
0.1
0
0.3
1.5
0
0.1
0.3
0
1.5
0
3a : Y ) 2-Ph,
R ) H
21
67
54
85
55
67
95
49
67
87
34
69
24
38
79
2
3
1b: X ) 3-Br,
R ) H
3b Y ) 3-Ph,
R ) H
1c: X ) 4-Br,
3c: Y ) 4-Ph,
R ) H
R ) Hb
4
1d : X ) 2-Cl,
R ) 3-NO2
3d : Y ) 2-Ph,
R ) 3-NO2
5
6
1e: X ) 2-Cl,
R ) 5-CN
1f: X ) 2-Cl,
R ) 5-NO2
3e: Y ) 2-Ph,
R ) 5-CN
3f: Y ) 2-Ph,
R ) 5-NO2
0.3
1.5
a
b
Isolated yield. 4-Bromopyridinium hydrochloride was used
as a starting material.
group.2c In their paper, the reactive catalyst for Suzuki-
Miyaura coupling was characterized by high Pd disper-
sion (e.g. >50%), a low degree of Pd reduction (no
prereduction before use), and high water content (>50%).
However, there has been no previous report on the
Suzuki-Miyaura coupling of heteroaromatic halides with
Pd/C. We report here the Suzuki-Miyaura coupling of
halopyridines and haloquinolines using Pd/C.
(1) (a) Suzuki, A. Acc. Chem. Res. 1982, 15, 178. (b) Suzuki, A. Pure
Appl. Chem. 1985, 57, 1749. (c) Suzuki, A. Pure Appl. Chem. 1991,
63, 419. (d) Suzuki, A. Pure Appl. Chem. 1994, 66, 213. (e) Miyaura,
N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (f) Snieckus, V. Chem. Rev.
1990, 90, 879. (g) Matteson, D. S. Tetrahedron 1989, 45, 1859. (h)
Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 3437. (i)
Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
(j) Saito, S.; Sakai, M.; Miyaura, N. Tetrahedron Lett. 1996, 37, 2993.
(2) (a) Marck, G.; Villiger, A.; Buchecker, R. Tetrahedron Lett. 1994,
35, 3277. (b) LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J . R., J r.
Org. Lett. 2001, 3, 1555. (c) Heidenreich, R. G.; Ko¨hler, K.; Krauter, J .
G. E.; Pietsch, J . Synlett 2002, 7, 1118. (d) Mori, Y.; Seki, M. J . Org.
Chem. 2003, 68, 1571. (e) Sakurai, H.; Tsukuda, T.; Hirao, T. J . Org.
Chem. 2002, 67, 2721. (f) Gala, A.; Stanford, J .; J enkins, J .; Kugelman,
M. Org. Process Res. Dev. 1997, 1, 163. (g) Ennis, D. S.; McManus, J .;
Wood-Kaczmar, W.; Richardson, J .; Smith, G. E.; Carstairs, A. Org.
Process Res. Dev. 1999, 3, 248.
Resu lts a n d Discu ssion
First, we examined reactions using Pd(0)/C in the
absence of an additive. According to the Roche method,
halopyridine 1 was treated with phenylboronic acid (2)
(1.9 equiv) in the presence of Pd(0)/C (4.5 mol %), using
10.1021/jo034970r CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/06/2003
9412
J . Org. Chem. 2003, 68, 9412-9415

Arylpyridines and Arylquinolines
TABLE 2. Yield s of P d /C(0)-Ca ta lyzed Su zu k i-Miya u r a Cou p lin g w ith P P h 3
entry
substrate
ligand
product
yield (%)a
85
90
60
1
2
3
4
5
6
7
1a : X ) 2-Br, R ) H
1b: X ) 3-Br, R ) H
1c: X ) 4-Br, R ) Hb
1d : X ) 2-Cl, R ) 3-NO2
1e: X ) 2-Cl, R ) 5-CN
1f: X ) 2-Cl, R ) 5-NO2
1g: X ) 2-Cl, R ) H
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
none
PPh3
none
PPh3
none
PPh3
None
PPh3
none
PPh3
none
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
3a : Y ) 2-Ph, R ) H
3b: Y ) 3-Ph, R ) H
3c: Y ) 4- Ph, R ) H
3d : Y ) 2-Ph, R ) 3-NO2
3e: Y ) 2-Ph, R ) 5-CN
3f: Y ) 2-Ph, R ) 5-NO2
3a : Y ) 2-Ph, R ) H
94
90
85
no reactiond
82
16
quant
30
8
9
1h : X ) 2-Cl, R ) 3-CN
1i: X ) 2-Cl, R ) 5-CF3
4a : X ) 2-Cl
3g: Y ) 2-Ph, R ) 3-CN
3h : Y ) 2-Ph, R ) 3-CF3
6a : Y ) 2-Ph
85
10
11
12
no reactiond
91
4b: X ) 3-Br
6b: Y ) 3-Ph
no reactiond
82
36
72
25
19
2
9
5
7
13
14
15
16
17
1j: X ) 2-Cl, R ) 6-OMe
1k : X ) 2-Cl, R ) 3-NH2
1l: X ) 3-Cl, R ) H
1m : X ) 4-Cl, R ) Hc
4c: X ) 6-Cl
3i: Y ) 2-Ph, R ) 6-OMe
3j: Y ) 2-Ph, R ) 3-NH2
3b: Y ) 3-Ph, R ) H
3c: Y ) 4-Ph, R ) Hb
6c: Y ) 6-Ph
no reaction
a
b
Isolated yield. 4-Bromopyridinium hydrochloride was used as a starting material. c 4-Chloropyridinium hydrochloride was used as
d
a starting material. In the reactions without PPh3, 1.9 equiv of PhB(OH)2 was used.
Na2CO3 (3.7 equiv) as a base in DME-H2O at 80 °C
overnight. The coupling product 33 was obtained in
21-54% yield {Table 1, entries 1-6 (TBAB 0 equiv)}. To
improve the yields of the products, TBAB was added to
the reaction, since TBAB has been reported to work
effectively.4 Although the yields were improved {Table
1, entries 1, 2, and 4 (TBAB 0.1 equiv)}, larger amounts
of TBAB were needed depending on the substrate struc-
ture {Table 1, entries 3, 5, and-6 (TBAB 1.5 equiv)}.
ridines with an electron-withdrawing group 1d -f, 1h ,
and 1i, and haloquinoline 4a ,b, proceeded smoothly and
gave the products in good yields (Table 2, entries 1-12).
However, the reactions of 2-chloropyridines with an
electron-donating group 1j,k gave unsuccessful results
(Table 2, entries 13 and 14). In the case of 3-chloropyri-
dine (1l) and 4-chloropyridine (1m ), the yields of the
products were extremely low (Table 2, entries 15 and 16).6
Furthermore, the reaction did not take place with 6-chlo-
roquinoline (4c). The reactivity of the substrate showed
the same tendency as was seen in the reaction with a
homogeneous catalyst; i.e., chloropyridines with an elec-
tron-withdrawing group were more reactive than those
with an electron-donating group. Unlike the reported
reaction of phenyl chlorides,2c a phosphine ligand was
essential for the reaction of halopyridines. It has been
reported that the Pd/C-catalyzed Heck reaction is ac-
companied by a Pd leaching process,7 in which Pd leaches
into a solution, catalyzes the reaction, and reprecipi-
tates on the charcoal at the end of the reaction. Thus, in
Pd/C-catalyzed Suzuki-Miyaura coupling, Pd may also
leach into solution and become an active species by
interacting with phosphine ligands.8
Second, following the Roche method, 18 mol % of PPh3
was added to the mixture5 of halopyridine 1, phenylbo-
ronic acid (2) (1.2 equiv), Pd(0)/C (4.5 mol %), and
Na2CO3 (3.7 equiv) in DME-H2O. The reaction mixture
was then heated at 80 °C overnight. The reactions of
bromopyridines 1a -c, 2-chloropyridine (1g), 2-chloropy-
(3) Compounds 3a -c are commercially available from Tokyo Kasei
Kogyo Co., Ltd. Compounds 3d , 3e, and 3f are described in the
following citations a, b, and c, respectively. (a) Ali, N. M.; McKillop,
A.; Mitchell, M. B.; Rebelo, R. A.; Wallbank, P. J . Tetrahedron 1992,
48, 8117. (b) Shiano, M.-J .; Liu, K.-H.; Lin, P.-Y. Heterocycles 1993,
38, 507. (c) Tohda, Y.; Eiraku, M.; Nakagawa, T.; Usami, Y.; Ariga,
M.; Kawashima, T.; Tani, K.; Watanabe, H.; Mori, Y. Bull. Chem. Soc.
J pn. 1990, 63, 2820.
(4) (a) Ishikura, M.; Kamada, M.; Terashima M. Heterocycles 1984,
22, 265. (b) Bedford, R. B.; Blake, M. E.; Butts, C. P.; Holder, D. Chem.
Commun. 2003, 4, 466. (c) Castant, A.-S.; Colobert, F.; Desmurs, J .-
R.; Schlama, T. J . Mol. Catal. A: Chem. 2002, 182-183, 481-487. (d)
Botella, L.; Najera, C. Angew. Chem., Int. Ed. 2002, 41, 179. (e) Zapf,
A.; Beller, M. Chem. Eur. J . 2000, 6, 1830. (f) Zim, D.; Monterio, A. L.;
Dopont, J . Tetrahedron Lett. 2000, 41, 8199. (g) Badone, D.; Baroni,
M.; Cardamone, R.; Ielmini, A.; Guzzi, U. J . Org. Chem. 1997, 62, 7170.
(5) The effects of the molar ratio of Pd and PPh3 were examined. In
the Roche method, the molar ratio of Pd and PPh3 was 1:4. When the
reaction of 2-chloropyridine was carried out in the presence of Pd and
PPh3 at molar ratios of 1:2 and 1:6, the respective yields were 80%
and 77%.
(6) Compound 6a is commercially available from Sigma-Aldrich Co.
Compounds 3g, 3h , 3i, 3j, 6b, 6c, and 7 are described in the following
reports a, b, c, d, e, f, and g, respectively. (a) Court, J .; Vidal, S.;
Bonnier, J .-M. Bull. Soc. Chem. Fr. 1972, 3107. (b) WO 02/02714 A2.
(c) Dufournet, R.; Court, J .; Bonnier, J .-M. Bull. Soc. Chem. Fr. 1974,
1112. (d) J pn. Kokai Tokkyo Koho. J P-H08-310972-A2. (e) Sakamoto,
T.; Kondo, Y.; Murata, N.; Yamanaka, H. Tetrahedron 1993, 49, 9713.
(f) Kaslow, C. E.; Hayer, M. J . Am. Chem. Soc. 1951, 73, 4986. (g)
Miller, R. B.; Svoboda, J . J . Synth. Commun. 1994, 24, 1187.
(7) Heidenreich, R.-G.; Krauter, J . G. E.; Pietsch, J .; Ko¨heler, K. J .
Mol. Catal. A: Chem. 2002, 182-183, 499-509.
J . Org. Chem, Vol. 68, No. 24, 2003 9413

Tagata and Nishida
TABLE 3. Yield s of P d /C(II)-Ca ta lyzed Su zu k i-Miya u r a Cou p lin g w ith P P h 3
entry
substrate
product
yield (%)
1
2
3
4
5
6
1j: X ) 2-Cl, R ) 6-OMe
1k : X ) 2-Cl, R ) 3-NH2
1l: X ) 3-Cl, R ) H
1m : X ) 4-Cl, R ) Ha
4c: X ) 6-Cl
3i: X ) 2-Ph, R ) 6-OMe
3j: X ) 2-Ph, R ) 3-NH2
3b: X ) 3-Ph, R ) H
3c: X ) 4-Ph, R ) H
6c: X ) 6- Ph
90
97
2
9
NRc
97b
8
9
a
b
4-Chloropyridinium hydrochloride was used as a starting material. When Pd(0)/C was used, the yield was 20%. c NR ) no reaction.
TABLE 4. Liga n d Effects on P d /C(0)-Ca ta lyzed Su zu k i-Miya u r a Cou p lin g
entry
substrate
ligand
product
yield (%)
1
2
3
4
5
6
1l: X ) 3-Cl, R ) H
1l: X ) 3-Cl, R ) H
1l: X ) 3-Cl, R ) H
1m : X ) 4-Cl, R ) H
4c: X ) 6-Cl
dppp
dppb
12
12
12
3b: X ) 3-Ph, R ) H
3b: X ) 3-Ph, R ) H
3b: X ) 3-Ph, R ) H
3c: X ) 4-Ph, R ) H
6c: X ) 6-Cl
NRb
NRb
88
92
77
10
12
11
80a
a
b
Pd(II)/C was used. When Pd(0)/C was used, the yield was 8%. NR ) no reaction.
Third, the combination of Pd(II)/C and PPh3 was used
in the reaction of 2-chloropyridines with an electron-
donating group 1j,k , 3-chloropyridine (1l), 4-chloropyri-
dine (1m ), 6-chloroquinoline (4c), and 3-bromoaniline (8).
As described above, Pd(II)/C has been shown to be more
reactive than Pd(0)/C.2c Therefore, it was expected that
the combination of Pd(II)/C and PPh3 would be effective
for the reaction of less-reactive substrates. In fact, the
reactions of 2-chloropyridines with an electron-donating
group and 3-bromoaniline (8) gave high yields (Table 3,
entries 1, 2, and 6).9 However, the products were not
obtained in good yields (Table 3, entries 3-5) in the
reactions of 3-chloropyridine (1l), 4-chloropyridine (1m ),
and 6-chloroquinoline (4c).
effects were studied by using 3-chloropyridine (1l) with
Pd(0)/C. Although the reactions in the presence of
dppb (9 mol %) or dppp (9 mol %) instead of PPh3 (18
mol %) resulted in unsatisfactory conversion (Table 4,
entries 1 and 2), the sterically hindered ligand 2-(dicy-
clohexylphosphino)biphenyl (9 mol %)10,11 dramatically
improved the yield (Table 4, entries 1 and 3). It has
been reported that bulky and electron-rich ligands in-
crease the yields of homogeneous Suzuki-Miyaura coup-
ling reactions.10c Electron-rich phosphine ligands facili-
tate oxidative addition, and the steric bulk around the
metal promotes reductive elimination. Thus, during the
Pd/C-catalyzed reaction, 2-(dicyclohexylphosphino)biphe-
nyl (12) would interact with the leaching Pd and show
the same effects. The combination of Pd(0)/C and 2-(di-
cyclohexylphosphino)biphenyl was also effective for the
reactions of 4-chloropyridine and 6-chloroquinoline (Table
4, entries 4 and 5).12 Although this combination was not
effective enough for the reaction of 4-methoxyphenyl
chloride, the combination of Pd(II)/C and 2-(dicyclohexyl-
Finally, to improve the yields in the reactions of
less-reactive pyridines such as 3-chloropyridine (1l),
4-chloropyridine (1m ), and 6-chloroquinoline (4c), ligand
(8) The Pd content in the recovered Pd/C and crude product was
measured in the Pd/C-catalyzed coupling of 2-chloroquinoline (4a ) and
phenylboronic acid (2). To a solution of 2-chloroquinoline (3.60 g, 22.0
mmol) and phenylboronic acid (3.23 g, 26.4 mmol) in DME (25 mL)
were added 2 M K2CO3 (30 mL) and NE Chemcat STD 5% Pd/C (water
content 55.4%) (2.62 g, 0.12 mmol; Pd content is 61 mg), and the
reaction mixture was stirred at 80 °C for 9 h. After the reaction was
completed, Pd/C was filtered, washed twice with 30 mL of AcOEt,
and dried under reduced pressure to give 2.22 g of Pd/C. The com-
bined organic layers were washed with brine and dried over Na2SO4.
The solvent was removed under reduced pressure to give crude prod-
uct (5.35 g). The Pd contents of the recovered Pd/C and crude product
were measured by a flame atomizer, and found to be 2.11% (47 mg)
and 0.24% (13 mg), respectively. Thus, 80% of the Pd in the original
Pd/C was recovered in the filtered Pd/C, and 20% contaminated the
crude product. Coordination between Pd and nitrogen made the
amount of Pd in the crude product greater in heteroaromatic com-
pounds.
(9) Compound 9 is commercially available from Tokyo Kasei Kogyo
Co., Ltd.
(10) (a) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999,
38, 2413. (b) Tomori, H.; Fox, J . M.; Buchwald, S. L. J . Org. Chem.
2000, 65, 5334. (c) Wolfe, J . P.; Singer, R. A.; Yang, B. H.; Buchwald,
S. L. J . Am. Chem. Soc. 1999, 121, 9550.
(11) In the reaction of 3-chloropyridine in the presence of Pd and
2-(dicyclohexylphosphino)biphenyl in a molar ratio of 1:4 and 1:1, the
product was obtained in respective yields of 75% and 82%.
(12) The reactions of 1j and 1k were carried out with the Pd(0)/C-
phosphine 12 system, and gave the products in respective yields of
87% yield and 79%. It is assumed that more-reactive halopyridines
and haloquinolines, such as 1a -i, 4a ,b, and 5, would also give the
products in good yields.
9414 J . Org. Chem., Vol. 68, No. 24, 2003

Arylpyridines and Arylquinolines
Su p p or tin g In for m a tion Ava ila ble: Experimental data
for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
phosphino)biphenyl was effective in this case (Table 4,
entry 6).13
Con clu sion
J O034970R
In conclusion, we studied Suzuki-Miyaura coupling
catalyzed by palladium charcoal and found that a phos-
phine ligand was indispensable for the reaction of ha-
lopyridines and haloquinolines. The sterically hindered
ligand 2-(dicyclohexylphosphino)biphenyl was extremely
effective in this reaction. Industrial-scale manipulation
of this process is now under investigation.14
(14) The coupling reaction of 3-amino-2-chloropyridine and triphen-
ylboroxine was carried out at a 100-g scale in the presence of 0.45 mol
% of Pd in n-butanol, which was more suitable than DME for an
industrial process. A flask was charged with triphenylphosphine (8.28
g, 32 mmol), 3-amino-2-chloropyridine (232 g, 1.8 mol), triphenylborox-
ine (225 g, 0.72 mol), KHCO3 (216 g, 2.16 mol), Degussa E 106 NE/W
10% Pd /C (water content 50.8%) (17.6 g, 8.1 mmol), n-butanol (684
mL), and H2O (1080 mL). After the reaction mixture was stirred at
reflux for 9 h under nitrogen, Pd/C was filtered off and rinsed with
n-butanol (300 mL). The organic layer was separated, washed with
water, and evaporated to give a brown oil, which was purified by
distillation to give 3-amino-2-phenylpyridine (243 g, yield 79%) as a
white solid (bp 138-140 °C/1.0 mmHg, mp; 61-63 °C). Contamination
of the product by Pd was not detected by a flame atomizer.
Ack n ow led gm en t. The authors are grateful for the
assistance of Mr. Masaki Shimada.
(13) Compound 11 is commercially available from Tokyo Kasei
Kogyo Co., Ltd.
J . Org. Chem, Vol. 68, No. 24, 2003 9415