Monoarylation of dibromoarenes by simple palladium catalyst systems: Efficient synthesis of bromobiaryls from dibromoarenes and arylboronic acids

Article abstract of DOI:10.1055/s-0028-1088110

The Pd/C/Ph₃P- and Pd(PPh₃)₄/Ph ₃P-catalyzed cross-couplings of dibromoarenes with arylboronic acids to form bromobiaryls in good to excellent yields are described. Our study showed that readily available Pd/C/P

Full text of DOI:10.1055/s-0028-1088110

LETTER
1081
Monoarylation of Dibromoarenes by Simple Palladium Catalyst Systems:
Efficient Synthesis of Bromobiaryls from Dibromoarenes and Arylboronic
Acids
S
ynthesis of Brom
h
obiaryls eng-Guo Dong, Tao-Ping Liu, Qiao-Sheng Hu*
Department of Chemistry, College of Staten Island and the Graduate Center, City University of New York,
Staten Island, NY 10314, USA
Fax +1(781)9823910; E-mail: qiaohu@mail.csi.cuny.edu
Received 16 January 2009
Pd(0) cat.
Abstract: The Pd/C/Ph3P- and Pd(PPh3)4/Ph3P-catalyzed cross-
couplings of dibromoarenes with arylboronic acids to form bromo-
biaryls in good to excellent yields are described. Our study showed
that readily available Pd/C/Ph3P and Pd(PPh3)4/Ph3P were practical-
ly useful catalysts for the synthesis of bromobiaryls from dibromo-
arenes.
ArB(OH)2
(1 equiv)
+
+
Ar
Br
Br
Ar
I
Ar
Scheme
1
Palladium(0)-catalyzed cross-coupling reactions of
bromoiodobenzenes with arylboronic acids (1 equiv)
Key words: palladium, cross-coupling, dibromoarenes, mono-
arylation, arylboronic acids
We have recently documented the Pd(0)/t-Bu3P-catalyzed
cross-coupling of dihalobenzenes with arylboronic acids
(1 equiv) to form teraryls via ‘preferential oxidative addi-
tion’ process.12 As shown in Scheme 2, we reasoned that
the Pd(0) catalyst regenerated from the first reductive
elimination could (a) undergo oxidative addition with
1-aryl-n-halobenzene (AHB, n = 2, 3, or 4, Scheme 2,
path A), or diffuse out of the vicinity of the AHB to under-
go oxidative addition with more reactive dihalobenzene
(Scheme 2, path B). Therefore, factors that can influence
the oxidative addition rates or the diffusion process would
influence the outcome of the reaction. Increasing the oxi-
dative addition rates of the Pd(0) catalyst, for example, us-
ing more electron-rich phosphines as ligands, would thus
lead to the formation of diarylbenzenes as the major prod-
ucts. This analysis led to the discovery of Pd(0)/t-Bu3P
catalyst system, which contains very electron-rich t-Bu3P,
that can achieve the ‘preferential oxidative addition’ phe-
nomenon.12 Our study also demonstrated that the bulky
group either in the substrate or ligand destabilized the in-
teraction of the Pd(0) with the phenyl ring, leading to
higher diffusion rate. We thus envisioned that by varying
Bromobiaryls are important synthetic intermediates for
the synthesis of unsymmetrically substituted teraryls,
highly efficient ligands, and functionalized biaryls.1–3 As
Pd-catalyzed Suzuki cross-coupling reaction of aryl-
boronic acids with aryl halides represents one of the most
attractive methods to form biaryls,4,5 the cross-coupling of
arylboronic acids with bromohalobenzenes in principle
should also be an efficient method to access bromobiaryls.
However, because bromobiaryls could further react with
arylboronic acids to form teraryls, such Pd-catalyzed
bromobiaryl-forming process is often complicated by the
formation of significant amount of teraryls. Separation of
bromobiaryls and teraryls often proved to be difficult.
Such complication could be overcome by using
bromoiodobenzenes, which possess two halo groups with
significantly different reactivity, as the substrates
(Scheme 1).6,7 Nevertheless, dibromobenzenes are more
attractive substrates than bromoiodobenzenes because
they are more readily available and less expensive than
bromoiodobenzenes. Over the past years, scattered proto-
cols about the synthesis of bromobiaryls from dibro-
mobenzenes have been reported.8–11 Most of reported
methods required the use of excess of dibromobenzenes to
achieve good yields. Recently, Uozumi and Kikuchi re-
ported a very promising protocol with the use of poly-
styrene-supported palladium-catalyst system.9 However,
the use of less accessible polystyrene-supported palladi-
um catalysts coupled with no reported isolated yields sig-
nificantly limited the practical use of Uozumi and
Kikuchi’s method. It is thus still of great synthetic value
to develop simple, practically useful catalyst systems to
access monobromobiaryls from dibromoarenes.
ArB(OH)2 (1 equiv)
and/or
Br
Ar
Br
Pd(0)
Br
Ar
Ar
ArB(OH)2
ArB(OH)2
Pd(0)
+
Br
Pd
Br
Br
Br
Ar
X
Pd
Ar
Br
BrPd
path B
Br
first reductive
elimination
Br
SYNLETT 2009, No. 7, pp 1081–1086
Advanced online publication: 26.03.2009
DOI: 10.1055/s-0028-1088110; Art ID: S00709ST
x
x.
x
x.
2
0
0
9
Br
Ar Pd
Ar
Pd(0)
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Two possible pathways for Pd(0)-catalyzed cross-cou-
plings of dibromobenzenes with arylboronic acids (1 equiv)

1082
C.-G. Dong et al.
LETTER
factors that could lead to slower oxidative addition, for ex- terphenyl) ratio (89:11) was observed with toluene as sol-
ample, the use of less electron-rich ligand such as Ph3P vent and K2CO3 (2 M in H2O) as base (Table 1, entries 1–
and larger amount of the ligands, and/or faster diffusion 4). We also examined the catalyst system of Pd/C with ad-
rates, for example, bulkier Pd catalysts, higher reaction ditional phosphines. We found Ph3P was the most effec-
temperature, etc., it could be possible to develop catalyst tive ligand for the formation of monocoupling product
systems that would favor the diffusion pathway and the while more electron-rich PCy3 and t-Bu3P yielded more
formation of monohalobiarenes as the major products. dicoupling terphenyl products (Table 1, entries 5–9), con-
Herein, we report our effort to substantiate such a possi- sistent with our previous observation.12 Among the sol-
bility.
vents and bases we screened, THF and toluene were the
best solvents and aqueous K2CO3 was the most effective
base (Table 1, entries 5, 8, 10–13). By using 12% Ph3P
relative to Pd/C and with toluene or THF as solvent, a 97:3
ratio of monocoupling product to dicoupling product was
obtained. We have also tested to add more Ph3P to catalyst
system. We found that the ratio of monocoupling product
to dicoupling product did not change much but the con-
version slightly increased (Table 1, entries 15–18).
Our study began with the use of palladium on charcoal
(10%, Pd/C) as catalyst as we reasoned that this palladium
species has relatively large size and slow oxidative addi-
tion rate, which both features would favor the diffusion
process. Our results are listed in Table 1. We found with
no additional ligands, although the conversion was mod-
erate, respectable monocoupling product (2-bromo-4¢-bi-
phenyl) to dicoupling product (4,4¢¢-dimethyl-1,1¢,2¢,1¢¢-
Table 1 Pd/C Catalyst Screeninga
Br
Br
Pd cat.
(HO)2B
+
+
solvent,
base, 100 °C
Br
M
D
Entry
1
Pd Catalyst
3% Pd/C
3% Pd/C
3% Pd/C
3% Pd/C
Solvent
THF
Base
Conversion (%)b M/Dc
K3PO4 (S)
51
45
30
62
14
12
20
74
65
62
52
80
15
30
83
90
90
80
46:54
73:27
89:11
70:30
85:15
27:73
52:48
96:4
2
toluene
toluene
toluene
THF
K3PO4 (S)
3
K2CO3 (2 M)
K2CO3(S)
4
5
3% Pd/C + 6% Ph3P
3% Pd/C + 6% PCy3
3% Pd/C + 6% t-Bu3P
3% Pd/C + 6% Ph3P
3% Pd/C + 6% t-Bu3P
3% Pd/C + 12% Ph3P
2% Pd/C + 8% Ph3P
3% Pd/C +12% Ph3P
3% Pd/C + 12% Ph3P
3% Pd/C + 12% Ph3P
3% Pd/C + 15% Ph3P
3% Pd/C + 18% Ph3P
5% Pd/C + 20% Ph3P
5% Pd/C + 25% Ph3P
K3PO4 (S)
6
THF
K3PO4 (S)
7
THF
K3PO4 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
K2CO3 (2 M)
8
toluene
toluene
THF
9
15:85
97:3
10
11
12
13
14
15
16
17
18
toluene
toluene
–
97:3
95:5
48:52
53:47
95:5
DMF
THF
THF
94:6
THF
96:4
THF
96:4
a Reaction conditions: 1,2-dibromobenzene (1.0 equiv), p-tolylboronic acid (1.0 equiv), base (s: solid, 3 equiv; 2 M: 2 M in H2O, 2 mL), solvent
(0.5 mL), 100 °C.
b Conversion based on 1,2-dibromobenzene by 1H NMR.
c Ratio based on 1H NMR.
Synlett 2009, No. 7, 1081–1086 © Thieme Stuttgart · New York

LETTER
Synthesis of Bromobiaryls
1083
Our Pd/C/Ph3P study suggested that Pd(0)/Ph3P complex- reaction result as that of Pd(PPh3)4/Ph3P (Table 2, entry
es might also be good catalysts for the selective monoary- 12), and PdCl2/Ph3P gave a slightly less satisfactory result
lation of dibromobenzenes. We have thus tested the use of (Table 2, entry 13).
readily available Pd(PPh3)4 as catalyst for the reaction
With Pd/C/Ph3P and Pd(PPh3)4/Ph3P as catalyst systems,
(Table 2). With only Pd(PPh3)4 as catalyst, we found a ra-
we have examined several 1,2-dibromoarenes and arylbo-
tio of 85:15 (monocoupling product to dicoupling prod-
ronic acids (1 equiv) for the cross-coupling reactions, and
uct) was observed with excellent conversion (Table 2,
our results are listed in Table 3. We found in general high
entry 1). As the use of larger amount of ligand would sta-
ratios of monobromobiaryl to terphenyls were observed,
bilize the Pd(0) catalyst and lead to faster diffusion, we
and good to excellent yields of monobromobiaryls were
expected that the use of larger amounts of ligands would
obtained. We also observed that 1,2-dibromobenzenes
favor the formation of more monocoupling products. We
gave higher ratio of monobromobiphenyls than that of
thus tested to add more Ph3P into the catalyst system. We
1,3- and 1,4-dibromobenzenes, likely because more hin-
found the addition of 2–4 equivalents of Ph3P relative to
dered 2-bromobiphenyls underwent oxidative addition
Pd(PPh3)4 gave the best results, with the ratio of mono-
slower than 3- and 4-bromobiphenyls. In addition, we ob-
coupling product to dicoupling product as high as 95:5
served that unsymmetrical 4-methyl-1,2-dibromobenzene
(Table 2, entries 2–7). While a similar result was observed
gave the two monoarylated compounds in the ratio of
for Pd2(dba)3/Ph3P to that of Pd(PPh3)4/Ph3P, the combi-
57:43 (Table 3, entry 8), suggesting the initial oxidative
nations of Pd2(dba)3 with other ligands gave inferior re-
addition rates for the two C–Br bonds with palladium(0)
sults than that of Pd(PPh3)4/Ph3P (Table 2, entries 3–5, 8–
were not much different from each other.
11). We have also tested Pd(OAc)2/Ph3P and PdCl2/Ph3P
as catalysts, we found that Pd(OAc)2/Ph3P gave similar
Table 2 Pd(0)-Catalyzed Cross-Coupling Reactions of 1,2-Dibromobenzene with p-Tolylboronic Acida
Br
Br
Br
Pd cat.
(HO)2B
+
+
solvent, 2 M K2CO3
80 or 100 °C, 20 h
M
D
Entry
Pd Catalyst
3% Pd(PPh3)4
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
THF
Conversion (%)b M/Dc
1
2
3
4
5
6
7
8
9
96
96
98
93
95
96
94
74
81
85:15
88:12
93:7
3% Pd(PPh3)4 + 3% Ph3P
3% Pd(PPh3)4 + 6% Ph3P
3% Pd(PPh3)4 + 9% Ph3P
3% Pd(PPh3)4 +12% Ph3P
3% Pd(PPh3)4 + 15% Ph3P
3% Pd(PPh3)4 + 6% Ph3P
1.5% Pd2(dba)3 + 12% P(o-tolyl)3
1.5% Pd2(dba)3 + 12% P(OPh)3
93:7
95:5
94:6
94:6
toluene
toluene
61:39
75:25
O
10
1.5% Pd2(dba)3 + 12%
toluene
73
69:31
P
3
11
12
13
1.5% Pd2(dba)3 +24% Ph3P
3% Pd(OAc)2 +18% Ph3P
3% PdCl2 +18% Ph3P
toluene
toluene
toluene
90
94
86
96:4
93:7
87:13
a Reaction conditions: 1,2-dibromobenzene (1.0 equiv), p-tolylboronic acid (1.0 equiv), K2CO3 (2 M in H2O, 2 mL), toluene or THF (0.5 mL),
80 °C (THF as solvent), 100 °C (toluene as solvent).
b Conversion based on 1,2-dibromobenzene by 1H NMR.
c Ratio based on 1H NMR.
Synlett 2009, No. 7, 1081–1086 © Thieme Stuttgart · New York

1084
C.-G. Dong et al.
LETTER
Table 3 Pd/C/Ph3P- and Pd(PPh3)4/Ph3P-Catalyzed Cross-Coupling Reactions of Dibromobenzenes with Arylboronic Acidsa
Br
+
Ar
Ar
Br
Pd cat. (3%)
ArB(OH)2
R
+
R
R
THF, K2CO3,
80 °C or toluene,
K2CO3, 100 °C
Br
Ar
D
M
Br
Entry
ArB(OH)2
Method
M/Db
Yield (%)c
R
Br
Br
1
2
3
A
B
A
99:1
99:1
94:6
82
75
56
B(OH)2
Br
Br
B(OH)2
OMe
Br
Br
B(OH)2
Br
Br
MeO
MeO
4
5
6
7
A
B
B
A
94:6
97:3
96:4
99:1
71
69
62
95
B(OH)2
B(OH)2
Br
Br
Br
Br
B(OH)2
Br
Br
B(OH)2
Br
Br
F
8
9
A
A
97:3
96:4
86d
82
B(OH)2
Br
Br
B(OH)2
Br
B(OH)2
10
11
A
B
81:19
86:14
60
67
Br
Br
B(OH)2
Br
Br
Br
Br
B(OH)2
B(OH)2
12
13
A
B
85:15
93:7
51
61
Br
Br
a Reaction conditions: dibromobenzene (1.0 equiv), arylboronic acid (1.0 equiv), K2CO3 (2 M, 1.5 mL), THF or toluene (0.5 mL). Method A:
3% Pd(PPh3)4 + 6% Ph3P, THF, 80 °C; method B: 3% Pd/C + 12% Ph3P, toulene, 100 °C.
b Ratio based on 1H NMR.
c Isolated yields of bromobiphenyls.
d Two isomers (57:43) were obtained.
Synlett 2009, No. 7, 1081–1086 © Thieme Stuttgart · New York

LETTER
Synthesis of Bromobiaryls
1085
As aryl-substituted pyridines have attracted great interest In summary, based on our understanding of the mecha-
in organic synthesis,13 we have further expanded the di- nism of Pd-catalyzed cross-coupling reactions and our
bromoarene scope to dibromopyridines. Our results are previous study on ‘preferential oxidative addition’, we
listed in Table 4. We found both Pd/C/Ph3P and identified, by varying factors that could influence the ox-
Pd(PPh3)4/Ph3P were highly efficient catalyst systems. idative addition rates and/or diffusion rates of the Pd(0)
High yields of 2-aryl-3-bromopyridines were obtained. intermediates, readily available Pd/C/Ph3P and Pd(PPh3)4/
The observed excellent ratio of monobromobiaryls and di- Ph3P complexes as highly efficient catalysts for the mono-
arylpyridines might likely be due to the different reactivi- cross-coupling reaction of dibromoarenes with arylboron-
ty of the two C–Br bonds in 2,3-dibromopyridine.14 Our ic acids. The easy availability of the catalyst systems, and
study provides a highly efficient method to access 2-aryl- the high yields of monobromobiaryl products make our
3-bromopyridines, which could further be converted to protocols potentially very useful in the preparation of
other aryl-substituted pyridines.
monobromobiaryls including 2-aryl-3-bromopyridines.15
Table
4
Pd/C/Ph3P- and Pd(PPh3)4/Ph3P-Catalyzed Cross-Cou-
pling Reactions of 2,3-Dibromopyridine with Arylboronic Acidsa
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Br
Br
Ar
Ar
Ar
Pd cat. (3%)
ArB(OH)2
+
+
THF, K2CO3, 80 °C or
toluene, K2CO3, 100 °C
Br
N
N
N
Acknowledgment
M
D
We gratefully thank the NSF (CHE0719311) for funding. Partial
support from the donors of the Petroleum Research Fund, admini-
stered by the American Chemical Society (44428-AC1), and the
PSC-CUNY Research Award Programs is also gratefully acknow-
ledged. We also thank Frontier Scientific, Inc. for its generous gifts
of arylboronic acids (other than 2,5-dimethylphenylboronic acid)
and Pd(PPh3)4, and Combi-Blocks, Inc. for its generous gift of 2,5-
dimethylphenylboronic acid.
Entry ArB(OH)2
Method M/Db
Yield (%)c
A
A
A
B
96:4d
98:2
99:1
95:5
92
B(OH)2
76
80
94
B(OH)2
References and Notes
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B(OH)2
B(OH)2
MeO
A
98:2
81
B(OH)2
A
B
95:5
99:1
81
97
B(OH)2
B(OH)2
OMe
A
99:1
80
B(OH)2
a Reaction conditions: dibromobenzene (1.0 equiv), arylboronic acid
(1.0 equiv), K2CO3 (2 M, 1.5 mL), THF or toluene (0.5 mL). Method
A: 3% Pd(PPh3)4 + 6% Ph3P, THF, 80 °C; method B: 3% Pd/C + 12%
Ph3P, toluene, 100 °C.
(3) For recent examples, see: (a) Ashburn, B. O.; Carter, R. G.
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b Ratio based on 1H NMR.
c Isolated yields of 2-bromobiaryls.
d A ratio of M/D = 87:13 was observed with 3% Pd(PPh3)4 as catalyst.
Synlett 2009, No. 7, 1081–1086 © Thieme Stuttgart · New York

1086
C.-G. Dong et al.
LETTER
(9) Polymer-supported substrates or ligands/catalysts:
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(b) Simkovsky, N. M.; Ermann, M.; Roberts, S. M.; Parry,
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(7) For an example of using organometallic reagents to
control the selectivity between Br group and OTf group for
the formation of 2-bromobiaryls, see: Espino, G.;
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(8) (a) Cheng, X.; Zhu, S.-F.; Qiao, X.-C.; Yan, P.-C.; Zhou,
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(15) We have also tested Pd/C/Ph3P- and Pd(PPh3)4/Ph3P-
catalyzed cross-coupling reactions of o-bromoiodobenzenes
with arylboronic acids and found bromobiaryls were formed
exclusively with excellent yields.
Synlett 2009, No. 7, 1081–1086 © Thieme Stuttgart · New York

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