Efficient pyrimidone-promoted palladium-catalyzed Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1055/s-0031-1290885

An efficient Pd(OAc)₂/orotic acid catalytic system has been developed for Suzuki-Miyaura cross-coupling reaction of halides with aryl- and vinylboronic acids. The use of pyrimidone as ligand makes this method useful and attractive for the synthesis of stilbenes and derivative compounds. An attractive feature of this method is the tolerance of functional groups in both substrates. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290885

LETTER
▌1221
lEettferficient Pyrimidone-Promoted Palladium-Catalyzed Suzuki–Miyaura Cross-
Coupling Reaction
2
Efficient Pd(OAc) /Orotic Acid Catalytic System
Hong-Ping Zhang,* You-Zhi Dai, Xi Zhou, Huang Yu
Department of Biology and Chemistry Engineering, Shaoyang University, Shaoyang 422000, P. R. of China
Fax +86(739)5363951; E-mail: zhp4901@sina.com
Received: 05.02.2012; Accepted after revision: 27.02.2012
catalyzed Suzuki–Miyaura reaction. In the absence of li-
gands, only a 42% yield of the cross-coupling product was
isolated in the presence of 1.5 mol% of Pd(OAc) and two
Abstract: An efficient Pd(OAc) /orotic acid catalytic system has
been developed for Suzuki–Miyaura cross-coupling reaction of ha-
lides with aryl- and vinylboronic acids. The use of pyrimidone as li-
2
2
gand makes this method useful and attractive for the synthesis of equivalents of Cs CO in acetone at 80 °C (entry 1). The
2 3
stilbenes and derivative compounds. An attractive feature of this yield of the product increased sharply upon addition of
method is the tolerance of functional groups in both substrates.
pyrimidone ligand (entries 2–5). Among the pyrimidone
Keywords: Suzuki–Miyaura cross-coupling reaction, pyrimidones, ligands investigated, orotic acid (L1; Figure 1) was found
vinylboronic acids, halides, stilbenes
to be the best one, which gave the coupling product in
high yield (entry 2). The other ligands (L2–L4; Figure 1)
showed moderate efficiency, which gave the coupling
The palladium-catalyzed Suzuki–Miyaura cross-coupling product in 34–85% yield (entries 3–5). The results were
1
0
reaction represents one of the most important transforma- similar to the reported conclusions.
tions in constructing the carbon–carbon bonds in organic
1
synthesis. Phosphine-based ligands are generally air-sen-
sitive and expensive, which places significant limits on
their synthetic applications. Therefore, new types of li-
Pd(OAc)2, L1
Cs CO , acetone, 80 °C
1
2
1
2
R X
+
R B(OH)2
R –R
2
3
X = I, Br, Cl
1
2
2
gands, such as heterocyclic carbenes, imine and amine
R , R = aryl, vinyl
3
4
5
palladacycles, oxime palladacycles, diazabutadienes,
Scheme 1 Suzuki–Miyaura cross-coupling reaction with pyrimi-
6
7
2
-aryl-2-oxazolines and simple amines, as well as li-
done as ligand
8
gandless systems, have emerged for use in the Suzuki–
Miyaura cross-coupling reaction. Weakly bound ligands
tend to give high catalytic activity, but are unstable and
decompose into inactive palladium black, while catalytic
cycle is blocked by strongly bound ligands in complexes
O
O
O
O
Br
Me
NH
NH
NH
NH
9
HOOC
N
H
O
N
H
O
N
H
O
to give low catalytic activity. Thus, proper choice/design
N
H
S
of ligands will play a crucial role to generate efficient cat-
alysts in such reaction. Orotic acid is a key compound of
L1
L2
L3
L4
pyrimidine bases of nucleic acids in living organisms, and Figure 1 Ligands tested in this work
is also an interesting ligand in pyrimidine ring. Although,
the coordination sites with most potential are the proton-
ated carboxyl group and its adjacent nitrogen, when they
coordinate to metal ion, the complexation ability of the
exocyclic carbonyl oxygen is greatly enhanced. Herein
we wish to report pyrimidone as novel and efficient ligand
for palladium-catalyzed Suzuki–Miyaura cross-couplings
of halides with aryl- and vinylboronic acids (Scheme 1).
To our surprise, there are no reports for Suzuki–Miyaura
cross-coupling reaction with pyrimidone as ligand.
Preliminary studies showed that L1 was the best ligand
for palladium-catalyzed Suzuki cross-coupling reaction.
Other reaction parameters, such as solvents, bases, and re-
action temperature, have also been tested. The cross-cou-
pling reaction of 4-bromoanisole with phenylboronic acid
was investigated under argon (Table 2). We first conduct-
ed the reaction in the presence of different loadings of
Pd(OAc) /L1, using Cs CO (2 equiv) as base, and ace-
1
0
2
2
3
tone as solvent (entries 1–3). It was observed that, using
, 3 mol% of L1, the desired 4-bro-
To examine the efficiency of Pd(OAc) /pyrimidone as a 1.5 mol% of Pd(OAc)
2
2
catalyst in the Suzuki–Miyaura cross-coupling reaction, a mobiphenyl (3) was obtained in 96% yield (entry 2). De-
model coupling reaction of 4-bromoanisole and phenyl- creasing the amounts of catalyst and ligand was found to
be detrimental to catalytic efficiency (entry 3). Subse-
quently, systems were tested using 1.5 mol% of different
palladium sources (entries 4–7), but the desired product
was formed in lower yields. The efficiency of
boronic acid was initially tested. The results are summa-
rized in Table 1. The results showed that these
pyrimidones were effective ligands for the palladium-
Pd(OAc) /L1 was also evaluated in the presence of differ-
2
SYNLETT 2012, 23, 1221–1224
Advanced online publication: 26.04.2012
ent inorganic bases and Et N, as well as in a different sol-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
3
DOI: 10.1055/s-0031-1290885; Art ID: ST-2012-W0111-L
Georg Thieme Verlag Stuttgart · New York
©

1222
H.-P. Zhang et al.
LETTER
Table 1 Screening of the Ligands for the Suzuki Reaction of 4-Bro-
Table 2 Optimization of the Cross-Coupling Reaction Promoted by
moanisole and Arylboronic Acida
Orotic Acida
OMe
OMe
+
[
Pd], L1
Pd(OAc)2, ligand
+
80 °C, acetone
Br
B(OH)2
Br
B(OH)2
MeO
MeO
1a
2a
3
Yield (%)b
Entry
Ligand
Entry Pd
Base
Solvent
Time Yield
b
1
2
3
4
none
L1
42
96
85
65
34
(1.5 mol%)
(h)
(%)
1
Pd(OAc)2
Cs CO
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
10
12
12
12
12
24
24
12
24
24
10
10
10
10
96
81
80
75
42
58
42
57
49
30
20
64
67
48
2
3
3
3
3
3
3
3
L2
2c
3d
4
Pd(OAc)
Pd(OAc)
PdCl2
Cs
Cs
CO
CO
2
2
2
L3
2
5
L4
Cs CO
2
a
Reaction conditions: Pd(OAc) (1.5 mol%), ligand (3 mol%), 4-bro-
2
5
Pd (dba)
Cs CO
2
moanisole (0.5 mmol), phenylboronic acid (0.6 mmol), Cs CO (1.0
2
3
2
3
mmol), acetone (5.0 mL), 80 °C, 11 h under argon.
b
6
PdCl
2
(PPh
3
)
2
Cs CO
2
Isolated yield.
7
Pd/C
Cs CO
2
vent. However, in all cases, no improvement could be
observed (entries 8–14).
8
Pd(OAc)2
K CO
2
3
9
Pd(OAc)2
Et N
The effectiveness of L1 as the ligand was further con-
firmed using various aryl chlorides and aryl boronic acids
under the optimum reaction conditions in acetone with
Cs CO (Table 3). The electron-rich and electron-poor 11
aryl chlorides were smoothly converted into the corre-
sponding biphenyl compounds in high yields (entries 2, 4,
3
1
0
Pd(OAc)2
K PO
3
4
1
1
Pd(OAc)
Pd(OAc)
Cs
Cs
CO
CO
H O
2
2
3
2
2
2
3
3
3
3
1
2e
4
2
acetone–H
O
2
6
and 9). In the more sterically demanding coupling reac- 13
Pd(OAc)2
Pd(OAc)2
Cs CO
EtOH
2
tion of 2-chloro-1,4-dimethylbenzene with phenylboronic
acid, the product was obtained in a moderate yield (entry
1
Cs CO
1,4-dioxane
2
9
). The reactions of various arylboronic acids with aryl
a
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), [Pd] (1.5
chlorides were also examined (entries 1, 3, 5, 10 and 11). mol%), ligand (3 mol%), base (1.0 mmol) and solvent (5.0 mL) at 80
As can be seen from the data contained in Table 3, the re- °C under argon.
b
Isolated yield.
action appeared to be sensitive to the substituents on the
boronic acid. Results suggested that the reaction with both
electron-deficient and electron-rich arylboronic acids pro-
ceeded with difficulty to afford the respective biaryls with
a moderate yield, and both the rate and the yield of the re-
c
Pd(OAc) (1 mol%) and L1 (2 mol%).
2
d
Pd(OAc) (0.1 mol%) and L1 (0.2 mol%) at 100 °C.
2
e
Acetone–H O (1:1; 2 mL).
2
action for electron-deficient boronic acids were higher in 90% and 82% yield (entries 1 and 2); even an ortho-
than those for the electron-rich boronic acids. For exam- substituted aryl iodide afforded the corresponding stil-
ple, 4-methoxyphenylboronic acid afforded the product in bene compound in high yield (entry 4). However no reac-
5
8% yield after 18 hours; however, 4-acetylphenylboron- tion occurred when (Z)-vinylboronic acid was utilized
ic acid gave a 72% yield and needed 10 hours (entries 3 (entry 3). In addition, aryl-substituted (E)-vinylboronic
and 10).
acid coupled with inactive aryl bromides showed higher
reactivity, while that substituted with alkyl gave poor
yields (entries 5 and 6). Vinyl bromides were also tested
as the coupling partners (entries 9–11). (E)-(2-Bromovi-
nyl)benzene (1l) coupled with boronic acids 2a and 2g af-
forded successfully the corresponding products in
excellent yields, after a significantly increased reaction
As the next step of this work, we synthesized (E)-stilbenes
from Pd(OAc) /L1-catalyzed Suzuki–Miyaura cross-cou-
2
pling reaction between aryl halides 1 and aryl- and vinyl-
boronic acids 2. As shown in Table 4, a variety of aryl
iodides and aryl bromides were subjected to the optimized
palladium-catalyzed cross-coupling reaction conditions
with vinylboronic acids to provide the stilbenes in moder-
ate to high yields (entries 1–8). Noteworthy was that the
configuration of vinylboronic acids had tremendous influ-
ence on the reaction activity; (E)-vinylboronic acids were
found to favor the reaction. When using 4-iodoanisole and
temperature and the loadings of Pd(OAc) /L1 (entries 10
2
and 11). A blank reaction was studied to further confirm
the role of ligand L1 in the reaction of aryl halides and vi-
nylboronic acids (entry 12). As mentioned in Table 1, the
reaction yield decreased considerably in the absence of
L1.
(E)-vinylboronic acids, the desired product was obtained
Synlett 2012, 23, 1221–1224
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Pd(OAc) /Orotic Acid Catalytic System
1223
2
Table 3 Cross-Coupling of Aryl Chlorides with Boronic Acidsa
Table 4 Synthesis of (E)-Stilbenes from Pd(OAc) /L1-Catalyzed
2
Suzuki–Miyaura Cross-Coupling Reactiona
R2
Cl
Pd(OAc)2, L1, Cs2CO3
Pd(OAc)2, L1
1
2
1
2
R X
+
R B(OH)2
R –R
R1
+
R2
Cs2CO3, acetone, 80 °C
80 °C, acetone, Ar
1
2
B(OH)2
R1
1
2
1
2
Entry R X
R B(OH)
Time Yield
2
b
(
h)
(%)
Entry Aryl chloride
ArB(OH)2
Time Yield
b
(h)
(%)
B(OH)2
MeO
I
1
10
90 (10)
Cl
B(OH)2
1
20
61 (4)
1h
2
g
1
b
2b
MeO
Cl
B(OH)2
B(OH)2
B(OH)2
2c
3c
1h
14
24
82 (11)
2
3
4
5
16
16
10
12
74 (3)
58 (3)
85 (5)
68 (6)
2
2
h
i
1
c
2a
MeO
B(OH)2
1h
trace (12)
1b
2
a
I
O2N
Cl
4
2g
20
82 (13)
2a
1i
1
d
5
6
1a
2g
2h
30
48
78 (10)
28 (11)
F
B(OH)2
1b
1a
2
d
O2N
O
7
8
2g
2h
14
14
92 (14)
90 (15)
Cl
Br
6
2a
10
87 (7)
1
j
1
e
1j
7
8
1c
2a
2a
17
18
68 (8)
71 (4)
Br
Cl
9d
2a
2a
36
30
42 (16)
84 (17)
1
f
1k
Br
Cl
9
2a
18
44 (9)
0c,d
1
1
1l
1
g
1c,d 1l
2g
2g
30
24
90 (18)
34 (10)
B(OH)2
B(OH)2
12e
1
0
1
1b
1b
O
10
10
72(7)
1h
2
e
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Pd(OAc) (1.5
mol%), L1 (3 mol%) and Cs CO (1 mmol) in acetone at 80–85 °C
under Ar.
Isolated yield.
The reaction was carried out at 100 °C.
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Pd(OAc) (3
mol%), L1 (6 mol%) and Cs CO (1 mmol) in acetone under Ar.
The reaction was carried out in the absence of L1.
2
2
3
O2N
1
70 (5)
b
c
2
f
d
a
2
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Pd(OAc) (1.5
mol%), L1 (3 mol%), Cs CO (1 mmol), and acetone (5.0 mL) at 80–
5 °C under argon.
Isolated yield.
2
2
3
2
3
e
8
b
gand makes this method useful and attractive for the syn-
In summary, we have developed a general method for thesis of stilbenes and derivative compounds. An
Suzuki–Miyaura cross-coupling reaction of halides with attractive feature of this method is the tolerance of func-
aryl- and vinylboronic acids. The use of pyrimidone as li- tional groups in both substrates.
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1221–1224

1
224
H.-P. Zhang et al.
LETTER
(7) (a) Schneider, S. K.; Herrmann, W. A.; Herdtweck, E.
Acknowledgment
J. Mol. Catal. A: Chem. 2006, 245, 248. (b) Liao, C.-Y.;
Chan, K.-T.; Zeng, J.-Y.; Hu, C.-H.; Tu, C.-Y.; Lee, H. M.
Organometallics 2007, 26, 692. (c) Li, J.-H.; Hu, X.-C.; Xie,
Y.-X. Tetrahedron Lett. 2006, 47, 9239.
We gratefully acknowledge the Excellent Youths in Institutions of
Higher Education of Hunan Province (No. 10B097), and the Scien-
tific and Technological Plan of Hunan Province (No. 2011FJ4130)
for financial support.
(8) (a) Cano, R.; Ramon, D. J.; Yus, M. Tetrahedron 2011, 67,
5
2
432. (b) Li, C.; Li, X.-Q.; Zhang, C. J. Chem. Res., Synop.
008, 9, 525. (c) Du, Z.; Zhou, W.; Wang, F.; Wang, J.-X.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmorinftIangoimnuSpinorttfoIangiStupor
Tetrahedron 2011, 67, 4914. (d) Zarei, A.; Khazdooz, L.;
Hajipour, A. R.; Rafiee, F.; Azizi, G.; Abrishami, F.
Tetrahedron Lett. 2012, 53, 406.
(
9) Aizawa, S.; Majumder, A.; Yokoyama, Y.; Tamai, M.;
Maeda, D.; Kitamura, A. Organometallics 2009, 28, 6067.
References and Notes
(
1) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(10) Yesilel, O. Z.; Ölmez, H. J. Therm. Anal. Calorim. 2007, 89,
555.
(b) Stanforth, S. P. Tetrahedron 1998, 54, 263.
(
c) Kirshhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem. Int. Ed.
(11) Typical Experimental Procedure for the Palladium-
Catalyzed Suzuki–Miyaura Cross-Coupling Reaction:
A mixture of aryl halide 1 (0.5 mmol), arylboronic acid 2
2
002, 41, 1945. (d) Barder, T. E.; Walker, S. D.; Martinelli,
J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
e) Godoy, F.; Segarra, C.; Poyatos, M.; Peris, E.
(
(0.6 mmol), PdCl (0.0075 mmol), orotic acid (0.015 mmol),
2
Organometallics 2011, 30, 684. (f) Kotha, S.; Chavan, A. S.;
Shaikh, M. J. Org. Chem. 2012, 77, 482.
2) (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
and acetone (5 mL) was stirred in a Schlenk tube at 80 °C
under Ar for 10 h. Complete consumption of the starting
material was monitored by TLC and GC–MS analysis. After
the reaction was complete, the mixture was poured into
EtOAc, washed with brine (3 × 10 mL), and extracted with
EtOAc. The combined organic layers were dried over anhyd
Na SO and evaporated under vacuum. The residue was
(
1
22, 4020. (b) Altenhoff, G.; Goddard, R.; Lehmann, C. W.;
Glorius, F. J. Am. Chem. Soc. 2004, 126, 15195. (c) Diebolt,
O.; Costa, R. C.; Braunstein, P.; Cavallo, L.; Nolan, S. P.;
Slawin, A. M. Z.; Cazin, C. S. J. Organometallics 2010, 29,
2
4
1
1
443. (d) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41,
440.
purified by flash column chromatography (hexane or
hexane–EtOAc) providing the desired coupled product 3 in
96% yield.
(
3) (a) Jo, T. S.; Kim, S. H.; Shin, J.; Bae, C. J. Am. Chem. Soc.
009, 131, 1656. (b) Magnus, P.; Sane, N.; Fauber, B. P.
12
2
4-Methoxybiphenyl (3): white solid; mp 86.5–87.2 °C (lit.
1
J. Am. Chem. Soc. 2009, 131, 16045. (c) Baratta, W.;
Benedetti, F.; Fanfoni, L.; Felluga, F.; Magnolia, S.;
Putignano, E.; Rigo, P. Organometallics 2010, 29, 3563.
4) Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2001, 17,
mp 86 °C). H NMR (400 MHz, CDCl ): δ = 7.54 (t, J = 9.4
3
Hz, 4 H), 7.41 (t, J = 9.4 Hz, 2 H), 7.31 (t, J = 9.6 Hz, 1 H),
1
3
6.98 (d, J = 8.9 Hz, 2 H), 3.85 (s, 3 H). C NMR (100 MHz,
(
CDCl ): δ = 159.1, 140.7, 133.7, 128.7, 128.1, 126.7, 126.6,
3
+
1
540.
114.2, 55.3. LRMS (EI, 70 eV): m/z (%) = 186 (16) [M + 2],
184 (100) [M ], 153 (45), 119 (25).
+
(
(
5) Botella, L.; Najera, C. Angew. Chem. Int. Ed. 2002, 41, 179.
6) (a) Grasa, G. A.; Hillier, A. C.; Nolan, S. P. Org. Lett. 2001,
(12) (a) Beadle, J. B.; Korzeniowski, S. H.; Rosenberg, D. E.;
Garcia-Slanga, B. J.; Gokel, G. W. J. Org. Chem. 1984, 49,
1594. (b) Li, J.-H.; Liu, W.-J. Org. Lett. 2004, 6, 2809.
(c) Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem. Soc. 2004, 126,
3
, 1077. (b) Eisenstecken, B. E.; Kopacka, D.; Wurst, K.;
Moller, T.; Pevny, F.; Winter, R. F.; Bildstein, B.
Organometallics 2010, 29, 3169.
3
058.
Synlett 2012, 23, 1221–1224
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.