Efficient Pd(OAc)2/pyrimidine catalytic system for Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1055/s-2005-869875

A combination of Pd(OAc)₂ and 2-aminopyrimidine-4,6-diol was found to be a stable and efficient catalytic system for the Suzuki-Miyaura cross-coupling of aryl halides with arylboronic acids. In the presence of Pd(OAc)₂ and 2-aminopyrimidine-4,6-diol, various ArX (X = I, Br, and Cl) were coupled with arylboronic acids efficiently to afford the corresponding cross-coupled products in moderate to excellent yields. Furthermore, high turnover numbers (up to 1000000 for the reaction of iodobenzene with phenylboronic acid) for the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction were observed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869875

LETTER
1897
Efficient Pd(OAc)2/Pyrimidine Catalytic System for Suzuki–Miyaura
Cross-Coupling Reaction
Efficient
P
id(O 2
A
c
n
)
/Pyrimidin
-
e
C
ataly
H
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research, College of Chemistry and Chemical Engineering,
Hunan Normal University, Changsha 410081, P. R. China
Fax +86(731)8872531; E-mail: jhli@hunnu.edu.cn
Received 27 April 2005
Table 1 Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reac-
tion of 1-(4-Bromophenyl)ethanone (1a) and Phenylboronic Acid (2a)a
Abstract: A combination of Pd(OAc)2 and 2-aminopyrimidine-
4,6-diol was found to be a stable and efficient catalytic system for
the Suzuki–Miyaura cross-coupling of aryl halides with arylboronic
acids. In the presence of Pd(OAc)2 and 2-aminopyrimidine-4,6-
diol, various ArX (X = I, Br, and Cl) were coupled with arylboronic
acids efficiently to afford the corresponding cross-coupled products
in moderate to excellent yields. Furthermore, high turnover num-
bers (up to 1000000 for the reaction of iodobenzene with phenyl-
boronic acid) for the palladium-catalyzed Suzuki–Miyaura cross-
coupling reaction were observed.
O
O
Pd(OAc)2/L
Br
+
PhB(OH)2
MeCN, 80 °C
2a
1a
3
Entry
1
Ligand
–
Time (h)
Yield (%)b
24
5
50
89
2c
HO
N
Key words: Pd(OAc)2, pyrimidine, aryl halide, Suzuki–Miyaura
NH2
NH2
NH2
cross-coupling reaction, arylboronic acid
N
HO
(L1)
HO
3
5
5
100
100
81
The Suzuki–Miyaura cross-coupling reaction has been
proven as a powerful tool for C-C bond formation in the
construction of the biaryl skeleton in organic synthesis.1–8
Since its invention, the development of an efficient and
selective catalytic systems for the Suzuki–Miyaura cross-
coupling reaction has attracted much attention.1–8 Gener-
ally, phosphine ligands are required to improve the
palladium-catalyzed Suzuki–Miyaura cross-coupling re-
action.1–3 However, many of the phosphine ligands are
sensitive to air and are subject to P–C bond degradation at
elevated temperature resulting in significant limititations
on their synthetic applications.9 Thus, development of
phosphine-free palladium catalytic systems is still a prom-
ising area for organic chemists.4–8 Here, we report that the
combination of Pd(OAc)2 and 2-aminopyrimidine-4,6-
diol (L1) as a stable and highly efficient catalytic system
has been developed for the Suzuki–Miyaura reaction of
aryl halides and arylboronic acids (Equation 1).
N
N
HO
(L1)
HO
4d
N
N
HO
(L1)
MeO
5
24
N
NH2
N
MeO
(L2)
N
6
7
24
24
88
80
NH2
N
(L3)
Me
N
NH2
N
Me
(L4)
Cl
Pd(OAc)2
2-aminopyrimidine-4,6-diol
(1)
+
R'B(OH)2
X
8
9
24
24
74
40
R'
Cs2CO3, MeCN
R
N
R
NH2
X = I, Br, Cl
N
Cl
Equation 1
(L5)
HO
N
The efficiency of pyrimidines as ligands for the palladi-
um-catalyzed Suzuki–Miyaura cross-coupling reaction of
1-(4-bromophenyl)ethanone (1a) and phenylboronic acid
(2a) was first evaluated, and the results are summarized in
Table 1. The results showed that 2-aminopyrimidine-4,6-
N
HO
(L6)
a Reaction conditions: 1a (0.4 mmol), 2a (0.5 mmol), Pd(OAc)2
(3 mol%), ligand (6 mol%), Cs2CO3 (2 equiv), and MeCN (5 mL) at
80 °C.
b Isolated yield.
c L1 (3 mol%).
d L1 (12 mol%).
SYNLETT 2005, No. 12, pp 1897–1900
Advanced online publication: 04.07.2005
DOI: 10.1055/s-2005-869875; Art ID: U12405ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.0
8
.2
0
0
5

1898
J.-H. Li et al.
LETTER
diol (L1) was the most effective ligand for the reaction, (L2–L6) as the ligands were less effective than L1, and the
and the amount of L1 affected the reactions. Without any results suggested that both the OH and NH2 groups on the
ligand, only a 50% yield of the corresponding cross-cou- pyrimidine skeleton play crucial roles in the reaction
pled product 3 was isolated after 24 hours in the presence (Table 1, entries 3, 5–9). Only moderate yields of 3 were
of 3 mol% of Pd(OAc)2 and two equivalents of Cs2CO3 obtained, after a reaction time of 24 hours, when pyrim-
(Table 1, entry 1), whereas the yield of 3 increased to 89% idines L2–L5 bearing no OH group were used as the
when 3 mol% of L1 was added (Table 1, entry 2). A quan- ligands. Furthermore, pyrimidine-4,6-diol (L6) having no
titative yield was obtained when the amount of L1 was in- NH2 group disfavored the reaction (Table 1, entry 9).
creased to 6 mol% (Table 1, entry 3). Identical results
were observed even when the amount of L1 was further in-
creased to 12 mol% (Table 1, entry 4). Other pyrimidines
a
Table 2 The Suzuki–Miyaura Cross-Coupling Reaction of ArX (1) with ArB(OH)2 (2) in the Presence of Pd(OAc)2/L1
Pd(OAc)2/L1
X
+
R'
R'B(OH)2
R
R
Cs2CO3, MeCN
2
1
3–13
R¢B(OH)2
Entry
1
ArX
Pd (mol%)
0.5
Time (h)
19
Yield (%)b
O
98 (3)
B(OH)2
Br
(2a)
(1a)
(1a)
2
3
4
(2a)
(2a)
0.01
0.0001
0.5
36
48
19
89 (3)
68 (3)
93 (4)
(1a)
(1a)
F
B(OH)2
(2b)
(2a)
5
6
0.0001
0.0001
25
25
93 (5)
91 (6)
O2N
I
(1b)
(2a)
(2a)
I
I
I
NO2
(1c)
7
8
0.0001
0.0001
25
25
89 (7)
NO2
(1d)
(2a)
(2b)
100 (8)
(1e)
(1e)
9
0.0001
0.0001
25
25
87 (9)
10
(1e)
90 (10)
Cl
B(OH)2
(2c)
MeO
11
12
(1e)
0.0001
0.0001
28
28
85 (11)
91 (11)
B(OH)2
(2d)
(2a)
MeO
I
(1f)
13
(2a)
0.5
17
98 (5)
O2N
Br
(1g)
Synlett 2005, No. 12, 1897–1900 © Thieme Stuttgart · New York

LETTER
Efficient Pd(OAc)2/Pyrimidine Catalytic System
1899
a
Table 2 The Suzuki–Miyaura Cross-Coupling Reaction of ArX (1) with ArB(OH)2 (2) in the Presence of Pd(OAc)2/L1 (continued)
Pd(OAc)2/L1
X
+
R'
R'B(OH)2
R
R
Cs2CO3, MeCN
2
1
3–13
Entry
14
ArX
R¢B(OH)2
(2a)
Pd (mol%)
0.01
Time (h)
38
Yield (%)b
83 (8)
Br
(1h)
15
(2a)
0.5
17
91 (11)
MeO
Br
(1i)
(1i)
16
17
18
(2a)
(2d)
0.01
0.5
36
19
21
86 (11)
81 (12)
80 (13)
(1i)
(1i)
0.5
B(OH)2
Me
(2e)
a Reaction conditions: 1 (0.4 mmol), 2 (0.5 mmol), Pd(OAc)2/L1 (1: 2), Cs2CO3 (2 equiv) and MeCN (5 mL) at 80 °C.
b Isolated yield.
Table 3 Cross-Coupling of ArCl (1) with ArB(OH)2 (2) in the
Presence of Pd(OAc)2/L1
As demonstrated in Table 2, the palladium-catalyzed
Suzuki–Miyaura reaction with 2-aminopyrimidine-4,6-
diol ancillary ligand (L1) proved to be exceptionally effi-
cient. Treatment of various aryl halides including iodides
(1b–f) and bromides (1a, 1g–i) with arylboronic acids
(2a–e), afforded moderate to excellent yields of the corre-
sponding coupled products in the presence of 0.5 to
0.0001 mol% Pd. For coupling of aryl iodides 1b–f with
arylboronic acids 2a–d the catalyst loadings could be
decreased to 0.0001 mol%, and good yields were still
obtained (Table 2, entries 5–12). For the coupling of aryl
bromides, the catalytic efficiency was decreased to some
extent. For example, when the catalyst loading was de-
creased to 0.5 mol%, aryl bromide 1a was also efficiently
coupled with phenylboronic acid (2a) in quantitative yield
after prolonged stirring. Further decreasing the catalyst
loading to 0.0001 mol% led to a 68% yield of 3 after a
reaction time of 48 hours (Table 2, entries 1–3). Other aryl
bromides 1g–i were suitable substrates at loadings of 0.5
to 0.01 mol% Pd (Table 2, entries 13–18).
a
Pd(OAc)2/L1
Cl
+
R'
R'B(OH)2
R
R
Cs2CO3, MeCN
2
1
Entry ArX
1c
R¢B(OH)2 Time (h) Yield (%)b
(2a)
26
10 (5)
O2N
Cl
(1j)
(1j)
2
3
(2a)
(2a)
24
24
80 (5)
79 (3)
O
Cl
(1k)
(1k)
4
5
(2b)
(2a)
25
23
74 (4)
78 (8)
Cl
(1l)
(1l)
The scope of the Pd(OAc)2/L1 catalytic system was fur-
ther extended to the reactions of aryl chloride 1j–n with
arylboronic acids, and the results are summarized in
Table 3. The results indicated that employing 2-amino-
pyrimidine-4,6-diol (L1) as the ligand was also effective
for the palladium-catalyzed Suzuki–Miyaura reaction of
aryl chlorides with arylboronic acids, and the suitable Pd
loading was 3 mol%. For example, treatment of 1j with 2a
afforded a 80% yield of 5 within 24 hours in the presence
6
7
(2d)
(2a)
23
19
60 (11)
68 (14)
Me
Cl
(1m)
8
(2a)
24
10 (11)
MeO
Cl
(1n)
of 3 mol% of Pd(OAc)2, 6 mol% of L1 and two equiva- a Reaction conditions: 1 (0.4 mmol), 2 (0.5 mmol), Pd(OAc)2 (3
mol%), L1 (6 mol%), Cs2CO3 (2 equiv), and MeCN (5 mL) at 110 °C.
lents of Cs2CO3 (Table 3, entry 1), whereas a rather lower
yield was observed when the Pd loadings were reduced
to 0.5 mol% (Table 3, entry 2). Coupling of other aryl
b Isolated yield.
c Pd(OAc)2 (0.5 mol%).
chlorides including 1-(4-chlorophenyl)ethanone (1k),
chlorobenzene (1l), and 1-chloro-4-methylbenzene (1m),
Synlett 2005, No. 12, 1897–1900 © Thieme Stuttgart · New York

1900
J.-H. Li et al.
LETTER
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were also carried out smoothly in moderate to good yields
(Table 3, entries 3–7). Unfortunately, the Pd(OAc)2/L1
catalytic system was less effective for coupling deactivat-
ed 1-chloro-4-methoxybenzene (1n), and only a 10%
yield of the desired product (11) was isolated after 24
hours (Table 3, entry 8).
In summary, a stable and highly efficient Pd(OAc)2/2-
aminopyrimidine-4,6-diol catalytic system has been de-
veloped for the Suzuki–Miyaura cross-coupling reaction
(the maximal TONs up to 1 000 000 for the reaction of io-
dobenzene with phenylboronic acid). To the best of our
knowledge, it is the first example on the use of 2-ami-
nopyrimidine-4,6-diol as an efficient ligand for the palla-
dium-catalyzed Suzuki–Miyaura cross-coupling reaction.
Currently, further efforts to extend the application of these
ligands in other transition metal-catalyzed transforma-
tions are underway in our laboratory.
Palladium-Catalyzed Suzuki–Miyaura Cross-Coupling Reac-
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First, Pd(OAc)2 (0.02 mmol) was dissolved in MeCN (200 mL), and
2-aminopyrimidine-4,6-diol (0.04 mmol) was dissolved in MeCN
(200 mL). Then identical amounts of Pd(OAc)2 (MeCN solution)
and aminopyrimidine-4,6-diol (MeCN solution) (1:2) were added to
a mixture of aryl halide 1 (0.4 mmol), ArB(OH)2 2 (0.50 mmol),
Cs2CO3 (2 equiv), and MeCN (5 mL) in a sealed tube (by syringe).
The mixture was stirred at the indicated reaction temperature for the
desired time (TLC). The mixture was filtered and evaporated; the
residue was purified by flash column chromatography (hexane or
hexane–EtOAc) to afford 3–14. All the products 3–14 are
known.3,5,7
Acknowledgment
We thank the National Natural Science Foundation of China (No.
20202002) for financial support.
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Synlett 2005, No. 12, 1897–1900 © Thieme Stuttgart · New York