Palladium-catalyzed homocoupling of arenediazonium salts: an operationally simple synthesis of symmetrical biaryls

Article abstract of DOI:10.1016/j.tetlet.2007.08.083

A simple procedure for the intermolecular homocoupling of arenediazonium salts in air using a catalytic amount of palladium acetate is described. The optimum conditions were found to be 15 mol % palladium acetate in refluxing methanol, with no additional terminal reducing agent required. These optimized conditions were used to prepare biaryls from several arenediazonium tetrafluoroborate salts, and most examples proceeded in moderate to high yields.

Full text of DOI:10.1016/j.tetlet.2007.08.083

Tetrahedron Letters 48 (2007) 7687–7690
Palladium-catalyzed homocoupling of arenediazonium salts:
an operationally simple synthesis of symmetrical biaryls
Monique K. Robinson, Vasilina S. Kochurina and James M. Hanna, Jr.*
Department of Chemistry, Physics, and Geology, Winthrop University, Rock Hill, SC 29733, United States
Received 7 August 2007; revised 21 August 2007; accepted 22 August 2007
Available online 29 August 2007
Abstract—A simple procedure for the intermolecular homocoupling of arenediazonium salts in air using a catalytic amount of
palladium acetate is described. The optimum conditions were found to be 15 mol % palladium acetate in refluxing methanol, with
no additional terminal reducing agent required. These optimized conditions were used to prepare biaryls from several arenediazo-
nium tetrafluoroborate salts, and most examples proceeded in moderate to high yields.
Ó 2007 Elsevier Ltd. All rights reserved.
The preparation of biaryls is an important objective in
organic synthesis, since the biaryl unit is found in a
number of natural products, pharmaceuticals, conduct-
ing polymers, and optically active ligands for asymmet-
copper-mediated methods are known.10 Since arene-
diazonium tetrafluoroborates are easily prepared from
1
1
the corresponding arylamines, which are often more
readily available than the corresponding aryl halides
or phenols, we became interested in developing a transi-
tion-metal-catalyzed homocoupling protocol for the
synthesis of symmetrical biaryls from these compounds.
Very recently, Cepanec and coworkers reported the
copper(I) triflate catalyzed homocoupling of arenedi-
azonium salts using stoichiometric copper bronze as the
1
ric synthesis. Symmetrical biaryls have traditionally
2
been synthesized by the Ullmann reaction, but the high
temperatures which are typically required have spawned
3
,4a
the development of a number of milder palladium
-
4
and nickel -mediated protocols for the synthesis of these
compounds from both aryl halides and aryl sulfonates.
These methods usually also require the addition of a
stoichiometric amount a terminal reducing agent such
as zinc powder. Copper - and rhodium -based methods
for the homocoupling of aryl halides have been devel-
oped, and it has been shown that a system of zinc and
trimethylammonium formate will mediate the homo-
coupling of aryl halides without the need for a nickel
1
2
terminal reducing agent. Their protocol was carried
out in acetonitrile and required the exclusion of oxygen
and water. Electron-rich substrates were homocoupled
in good yield under these conditions, although elec-
tron-poor substrates were more efficiently homocoupled
using stoichiometric amounts of copper(I) triflate. Since
similar palladium-catalyzed methods have not been
studied, we embarked on an attempt to develop a viable
palladium-catalyzed route to symmetrical biaryls from
arenediazonium salts.
5
6
7
or palladium co-catalyst. Symmetrical biaryls are also
accessible through the copper-catalyzed homocoupling
8
of organosilicon halides, as well as the homocoupling
of arylboronic acids catalyzed by metals such as palla-
9
dium and gold.
When we considered the generally accepted mechanism
for the Pd-catalyzed homocoupling of aromatic electro-
3
a
In contrast, transition-metal-catalyzed routes to sym-
metrical biaryls from arenediazonium salts have not
received as much attention although stoichiometric
philes (Scheme 1), it became clear to us that a palla-
dium-catalyzed approach to the homocoupling of
arenediazonium salts had ample literature precedent.
The palladium-catalyzed cross-coupling of arenediazo-
1
3
nium tetrafluoroborates with arylboronic acids, potas-
1
4
15
sium organotrifluoroborates,
and aryl silanes
Keywords: Arenediazonium salts; Symmetrical biaryls; Palladium-
indicated that oxidative addition of an arenediazonium
salt to low-valent palladium (step ii) readily occurs.
Furthermore, the observation of products derived from
catalyzed homocoupling.
*
Corresponding author. Tel.: +1 803 323 4933; fax: +1 803 323
246; e-mail: hannaj@winthrop.edu
2
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.083

7688
M. K. Robinson et al. / Tetrahedron Letters 48 (2007) 7687–7690
arenediazonium salts, this result demonstrates the pref-
erence for homocoupling of the diazonium group in
the presence of a bromo substituent, which could be
elaborated further by, for example, a Suzuki coupling.
Encouraged by this result, we began to optimize the con-
ditions of the homocoupling reaction, using the reaction
of 1a as the model system. First, we investigated the
effect of concentration on the yield and product distribu-
tion. According to the assumed mechanism, the forma-
tion of biaryl 2a requires the formation of the diaryl
Pd complex, which arises from the (bimolecular) dispro-
portionation step (step iii, Scheme 1). Therefore, we
thought we could increase the rate of diaryl Pd complex
formation and improve the yield of 2a by increasing the
concentration of the reaction mass. We did indeed find
that higher concentrations favor a higher yield of 2a
and these results are shown in Table 1. The best yields
of 2a were produced within 1 h at 1a concentrations of
0
.5–1.0 M (entries 4 and 5). Because the reaction mass
was more fluid at a concentration of 0.5 M, we used this
concentration for further optimization studies.
Scheme 1. Pd-catalyzed homocoupling of aryl electrophiles.
We then turned our attention to the optimization of cat-
alyst precursor loading, and the results are shown in Ta-
ble 2. As indicated, the best yields of 2a were seen using
the homocoupling of arenediazonium salts as by-prod-
ucts in palladium-catalyzed cross-coupling reactions
1
4
showed the feasibility of the disproportionation (step
iii) and reductive elimination (step iv) steps. Additional
precedent was provided by one early literature report of
the homocoupling of an arenediazocyanide mediated by
1
2
0–15 mol % of Pd(OAc) . Increasing the amount to
0 mol % did not improve the yield or the product distri-
2
bution. The reaction was usually complete within 1 h in
refluxing methanol, although it could be carried out at
room temperature for a longer time period (entry 2).
1
6
PdCl2. The fact that palladium(II) is known to cata-
1
7
lyze the oxidation of alcohols also suggested to us that
an alcohol solvent might function as both the initial
reducing agent (step i) and the terminal reducing agent
Also, the reaction in the absence of Pd(OAc) (entry 8)
2
produced very little biaryl 2a, confirming that the homo-
coupling pathway is catalyzed by the palladium salt. In-
stead this reaction led primarily to reduced product 3a
along with 4-bromoanisole (4a, derived from reaction
of 1a with methanol) and 4-fluorobromobenzene (5, de-
rived from the Schiemann reaction of 1a).
(
step v) and allow the homocoupling to be carried out
in an operationally simple manner without the addition
1
8
of a zero-valent metal or other terminal reductant. We
have indeed found that several arenediazonium tetra-
fluoroborates can be successfully converted to symmetri-
cal biaryls in good yield using an operationally simple
system of palladium acetate in refluxing methanol with-
out the need for an additional terminal reductant and
without any special oxygen- or water-exclusion tech-
niques. Herein we report the results of our study.
We chose to begin by looking at the homocoupling of
4
1
0
-bromobenzenediazonium tetrafluoroborate (Scheme 2,
a) in methanol. We were pleased to find that when a
Our supposition that methanol is the terminal reductant
is supported by the fact that the formation of palladium
black is observed during the reaction. Furthermore,
.1 M methanolic solution of 1a was refluxed in the pres-
0
ence of palladium acetate (10 mol %), 4,4 -dibromo-
biphenyl (2a) was produced in 45% yield. In addition
to the homocoupled product, the reduced product,
bromobenzene (3a) was also formed in 35% yield. Along
with proving the viability of a palladium-catalyzed
homocoupling protocol for the synthesis of biaryls from
a
Table 1. Concentration effect on the homocoupling of 1a (Scheme 2)
b
Entry
[1a] (M)
Yield (%)
2
a
3a
1
2
3
4
0.05
0.1
0.25
0.5
40
45
54
59
59
45
35
19
12
3
c
5
1.0
a
All reactions were performed in refluxing methanol in the presence of
Pd(OAc) (10 mol %).
Determined by GC analysis using an internal standard.
Pd(OAc) of 15 mol %. 4-Bromoanisole (4a, 1%) was also detected in
this reaction.
2
b
c
2
Scheme 2. Pd-catalyzed homocoupling of 1a.

M. K. Robinson et al. / Tetrahedron Letters 48 (2007) 7687–7690
7689
a
2
Table 2. Effect of Pd(OAc) loading on the homocoupling of 1a
b
Entry
Pd(OAc)
2
(mol %)
Yield (%)
2
a
3a
1
2
20
20
15
15
10
5
62
65
66
15
59
54
34
5
10
9
c
3
4
13
10
12
14
25
61
d
5
6
7
1
0
e
8
a
All reactions were performed at a 1a concentration of 0.5 M in
refluxing methanol.
Determined by GC analysis using an internal standard. Unless
otherwise noted, yields reported are an average of at least two
experiments.
Scheme 3. Scope and limitations of the homocoupling reaction.
b
the desired 2a. Occasionally, a small amount of the
Schiemann product 5 was also detected.
c
Reaction mass was stirred at room temperature for three days.
d
0
Reaction carried out in the presence of 2,2 -bipyridine (15 mol %).
Compounds 4a (42%) and 5 (10%) were also produced. Results are
based on one experiment only.
Compounds 4a (15%) and 5 (4%) were also detected.
With the optimized conditions in hand (0.5 M arene-
diazonium salt and 15 mol % Pd(OAc)2 in refluxing
methanol), we proceeded to study the scope and limita-
tions of the homocoupling reaction using this protocol
e
0
(
Scheme 3). The results are shown in Table 4. In most
when a molar equivalent of 2,2 -bipyridine (relative to
cases, moderate to high yields were obtained. A 2-meth-
oxy group exhibited some steric effect, leading to a lower
yield of homocoupled product from the reaction of 1d
the Pd(OAc) ) was added in an attempt to stabilize the
active catalyst species and prevent the formation of
2
palladium black, only a 15% yield of 2a was observed
0
(entry 4) when compared to 1f (entry 6).
(
entry 4). Since 2,2 -bipyridine is known to inhibit the
1
7
Pd(OAc) -catalyzed oxidation of alcohols, we believe
2
The reaction of the cyano-substituted compound 1i
produced no biaryl 2i, but gave primarily two products
derived from the reaction with the methanol solvent—4i
and methyl 4-methoxybenzoate (entry 9). We speculate
that this may be the result of coordination of the cyano
this result further supports our hypothesis that metha-
nol is functioning as the terminal reducing agent in this
reaction. Based on these results, additional optimization
studies were carried out in the presence of 15 mol %
Pd(OAc)2.
group to Pd(OAc) interfering with the reduction of the
2
catalyst precursor, similar to the result in the presence of
We next conducted a survey of potential catalyst precur-
0
2,2 -bipyridine (vide supra). Further evidence for this
sors and the results are shown in Table 3. Pd(OAc) and
2
type of effect was provided by an experiment in which
diazonium salt 1a was refluxed in 3:1 acetonitrile–meth-
Pd(O CCF ) were shown to be the most effective (en-
2
3 2
tries 1 and 4). PdCl was somewhat effective, giving a
2
anol with Pd(OAc) . This experiment gave only a 16%
3
6% yield of 2a and a favorable 2a:3a ratio (entry 2).
2
However a significant amount of 4a, derived from reac-
tion of 1a with methanol, was also formed. Pd(PPh3)
4
Table 4. Scope and limitations of the Pd-catalyzed homocoupling
reaction (Scheme 3)
a
gave a moderate overall yield, but produced 2a and 3a
in essentially equivalent amounts (entry 5). Other
palladium compounds led to much lower amounts of
b
Entry
R
Product
Yield (%)
2
3
4
1
2
3
4
4-Br
4-Cl
4-CH
2-CH
3-CH
4-CH
H
4-COCH
4-CN
4-NO
a
b
c
d
e
f
66
74
82
66
25
88
55
44
0
13
11
3
6
17
4
5
18
4
0
0
—
0
36
0
26
9
a
Table 3. Effect of catalyst precursor on the homocoupling of 1a
c
b
Entry
Catalyst precursor
Yield (%)
3
3
3
3
O
O
O
2
a
3a
4a
5
d
5
1
2
3
Pd(OAc)
PdCl
Pd (dba)
Pd(O
Pd(PPh
Pd/C (10%)
Pd(acac)
PdCl
2
66
36
7
60
24
5
13
9
1
12
25
35
5
0
21
1
1
0
1
24
40
0
3
0
0
0
0
3
0
6
7
8
2
g
h
i
c
2
3
3
e
4
5
6
7
2
CCF
3
)
2
9
16
0
3
)
4
10
2
j
67
30
a
All reactions were performed at an arenediazonium salt concentra-
tion of 0.5 M, with 15 mol % Pd(OAc) in refluxing methanol.
Determined by GC analysis using an internal standard. Yields
reported are an average of at least two experiments.
Compound 4c was detected by GC/MS, but was not quantified.
3-Fluoroanisole was detected by GC/MS, but was not quantified.
Methyl 4-methoxybenzoate, 4-fluorobenzonitrile, and methyl 4-flu-
orobenzoate were also identified in the reaction mixture by GC/MS.
Of these, methyl 4-methoxybenzoate had the largest GC area.
2
5
0
c
2
8
K
2
4
2
b
a
All reactions were performed at a 1a concentration of 0.5 M, with
5 mol % catalyst precursor in refluxing methanol.
Determined by GC analysis using an internal standard. Unless
otherwise noted, yields reported are an average of at least two
experiments.
c
d
e
1
b
c
Results are based on one experiment only.

7690
M. K. Robinson et al. / Tetrahedron Letters 48 (2007) 7687–7690
yield of biaryl 2a, along with a 21% yield of reduced
product 3a. The 3-methoxy diazonium salt 1e surpris-
ingly gave a very low yield (25%) of biaryl 2e. The rea-
son for this result is unclear at this time.
the Winthrop University Research Council for financial
support.
References and notes
In conclusion, we have developed a synthesis of symmet-
rical biaryls from arenediazonium tetrafluoroborates
using a catalytic amount of palladium acetate in reflux-
ing methanol. The reaction is operationally simple, can
be carried out with no special oxygen- or water-exclu-
sion techniques, proceeds in moderate to high yield in
most cases, and does not require addition of a zero-va-
lent metal or other terminal reductant. In addition, the
reaction can be carried out chemoselectively in the pres-
ence of bromine and chlorine substituents, allowing the
products to be further transformed using, for example, a
Suzuki coupling. We believe that this protocol is an
effective complement to existing methods for biaryl syn-
thesis. Further study of the scope and mechanism of this
reaction is continuing in our laboratory.
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shaped flask equipped with a spin vane and a reflux
condenser was charged with catalyst precursor and
methanol as indicated in Tables 1–3. 4-Bromo-
benzenediazonium tetrafluoroborate (1a, 0.5 mmol)
was added, and the mixture was stirred at reflux until
the reaction mass did not produce a reddish-purple color
upon treatment with an alkaline solution of H-acid
1
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2
1
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(
4-amino-5-hydroxy-2,7-naphthalenedisulfonic
acid),
indicating that the diazonium salt had been consumed.
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with 30 mL of methylene chloride, and filtered through
a Celite pad. An appropriate internal standard was
5
908–5910.
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5
1
added, and the resulting solution was analyzed by GC.
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0
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,4 -Dibromobiphenyl (2a), bromobenzene (3a), 4-
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shaped flask equipped with a spin vane and a reflux
condenser was charged with methanol (1 mL), Pd(OAc)2
(
0.075 mmol), and an appropriate internal standard.
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0.5 mmol) was then added. The mixture was stirred
1
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(
at reflux until the reaction mass did not produce a
reddish-purple color upon treatment with an alkaline
solution of H-acid (4-amino-5-hydroxy-2,7-naphthalen-
edisulfonic acid), indicating that the diazonium salt
had been consumed (usually within 1 h). The mixture
was cooled to room temperature, diluted with 30 mL
of methylene chloride, and filtered through a Celite
pad. The resulting solution was analyzed by GC. Prod-
ucts were identified by comparison of their retention
times with authentic samples and by GC/MS.
1
1
1
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Acknowledgments
We gratefully acknowledge the Winthrop University
Department of Chemistry, Physics, and Geology and