Recyclable and reusable Pd(OAc)2/PPh3/PEG-2000 system for homocoupling reaction of arylboronic acids under air without base

Article abstract of DOI:10.1002/aoc.3254

A stable and efficient Pd(OAc)₂/PPh₃/PEG-2000 catalytic system for homocoupling of arylboronic acids has been developed. In the presence of Pd(OAc)₂ and PPh₃, the homocoupling reaction of arylboronic acids was carried out smoothly in PEG-2000 at 70°C under air without base to afford a variety of symmetric biaryls in good to excellent yields. The isolation of the products was readily performed by extractionwith diethyl ether, and the Pd(OAc)₂/PPh₃/PEG-2000 systemcould be easily recycled and reused six times without significant loss of catalytic activity.

Full text of DOI:10.1002/aoc.3254

Full Paper
Received: 21 September 2014
Revised: 22 October 2014
Accepted: 24 October 2014
Published online in Wiley Online Library: 1 December 2014
(wileyonlinelibrary.com) DOI 10.1002/aoc.3254
Recyclable and reusable Pd(OAc)2/PPh3/PEG-
2000 system for homocoupling reaction of
arylboronic acids under air without base
Jianhui Xia, Mingzhu Cheng, Qiurong Chen and Mingzhong Cai*
A stable and efficient Pd(OAc)2/PPh3/PEG-2000 catalytic system for homocoupling of arylboronic acids has been developed. In the
presence of Pd(OAc)2 and PPh3, the homocoupling reaction of arylboronic acids was carried out smoothly in PEG-2000 at 70°C un-
der air without base to afford a variety of symmetric biaryls in good to excellent yields. The isolation of the products was readily
performed by extraction with diethyl ether, and the Pd(OAc)2/PPh3/PEG-2000 system could be easily recycled and reused six times
without significant loss of catalytic activity. Copyright © 2014 John Wiley & Sons, Ltd.
Keywords: palladium; PEG-2000; symmetric biaryl; arylboronic acid; green chemistry
chemical reactions.[10] So far, PEGs have been successfully used as
reaction media for palladium-catalyzed carbon–carbon coupling re-
Introduction
Biaryls are widely used as chiral phosphine ligands,[1] as monomers
of functional polymers[2] and as important intermediates in the syn-
thesis of natural products and pharmaceutics.[3] Among numerous
methods for accessing biaryl structures,[4] the Suzuki–Miyaura cou-
pling reaction is one of the most reliable tools for the preparation of
unsymmetric biaryls.[5] As for the synthesis of symmetric biaryls, the
main method is the classic Ullmann reaction, which, however, is car-
ried out at high temperatures (>200°C) and cannot tolerate many
functional groups for a long period of time.[6] Recently, the synthe-
sis of symmetric biaryls by the palladium-catalyzed homocoupling
of arylboronic acids has received much attention[7] since
arylboronic acids are easily accessible, are air- and moisture-stable
and are of relatively low toxicity. The homocoupling reaction of
arylboronic acids generally proceeds in the presence of a homoge-
neous palladium catalyst such as Pd(OAc)2, Pd2(dba)3 or PdCl2.
However, industrial applications of these homogeneous palladium
catalysts remain a challenge because they are expensive and can-
not be recycled. Therefore, from the standpoint of green chemistry,
the development of a recyclable and reusable catalyst system that
allows for highly efficient homocoupling of a wide range of
arylboronic acids is worthwhile.
As environmentally benign organic synthesis is becoming more
and more important, it is desirable to avoid the use of any easily vol-
atile and toxic organic solvents. There are also significant economic
and environmental reasons for developing recyclable catalytic reac-
tions from both academic and industrial perspectives. To satisfy
both recyclability and environmental concerns, a more facile
method is to immobilize a catalyst in a liquid phase by dissolving
it into a nonvolatile and nonmixing liquid, such as an ionic liquid[8]
or poly(ethylene glycol) (PEG).[9] Although ionic liquids offer some
advantages, the tedious preparation of ionic liquids and their envi-
ronmental safety are still debated since the toxicity and environ-
mental burden data are for the most part unknown. However,
PEGs, possessing negligible vapor pressure, are known to be inex-
pensive, thermally stable, recoverable, nontoxic compounds which
serve as suitable media for environmentally friendly and safe
actions such as Heck reaction,[9a] Suzuki reaction,[9b–9d] the
homocoupling and cross-coupling of aryl halides,[9e] the direct
arylation of 1,2,3-triazoles with aryl bromides,[9f] Hiyama reaction,[9g]
carbonylative Suzuki reaction[9h] and carbonylative Sonogashira
reaction[9i] with easy recyclability of the solvent and palladium cat-
alysts. Recently, Wang and co-workers reported a Pd(PPh3)4/PEG-
400-catalyzed protocol for the atom-efficient Stille cross-coupling
reactions of organotins with aryl bromides.[11] However, to the best
of our knowledge, no palladium-catalyzed homocoupling of
arylboronic acids in PEGs has been reported to date. We herein
report the application of a Pd(OAc)2/PPh3/PEG-2000 system as
an extremely effective and reusable catalytic medium for
homocoupling reaction of arylboronic acids under air without
base. The developed methodology has important practical ad-
vantages deserving special note.
Results and Discussion
In our initial screening experiments, the homocoupling of
phenylboronic acid was selected as model reaction to optimize
the reaction conditions. The influences of palladium catalysts, sol-
vents, bases and reaction temperatures on the reaction were inves-
tigated and the results are summarized in Table 1. At first, the
palladium catalyst effect was examined in PEG-2000 in the absence
of base, and a significant palladium catalyst effect is observed. It is
evident that the reaction does not occur in the absence of a phos-
phine ligand (Table 1, entries 1, 3 and 5), moderate to high yields
are obtained when PdCl2(PPh3)2, Pd(OAc)2/2PPh3, Pd(OAc)2/2P(1-
*
Correspondence to: Mingzhong Cai, Key Laboratory of Functional Small Organic
Molecules, Ministry of Education and Department of Chemistry, Jiangxi Normal
University, Nanchang 330022, PR China. E-mail: caimzhong@163.com
Key Laboratory of Functional Small Organic Molecules, Ministry of Education and
Department of Chemistry, Jiangxi Normal University, Nanchang 330022, PR China
Appl. Organometal. Chem. 2015, 29, 113–116
Copyright © 2014 John Wiley & Sons, Ltd.

J. Xia et al.
Table 1. Reaction condition screening for the homocoupling of
Table 2. Homocoupling of various arylboronic acids in PEG-2000 under
phenylboronic acida
aira
Entry
Pd source
Solvent
Base Temp. (°C) Yieldb (%)
Entry
Ar
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
PdCl2
PEG-2000
PEG-2000
PEG-2000
PEG-2000
PEG-2000
PEG-2000
—
—
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
60
80
100
Trace
59
1
Ph
Ph
Ph
2a[7i]
2a
89
91
69
90
87
89
93
90
94
86
82
71
88
86
85
89
87
92
57
63
88
NRf
36
PdCl2(PPh3)2
Pd(OAc)2
2c
3d
4
—
Trace
89
2a
Pd(OAc)2/2PPh3
Pd(dba)2
—
4-MeC6H4
2b[7i]
2c[7f]
2d[7f]
2e[7g]
2f[7g]
2 g[7i]
2 h[7i]
2i[9e]
2j[9e]
2 k[7h]
2 l[9e]
2 m[9e]
2n[7g]
2o[7f]
2p[7g]
2q[7i]
2r[7g]
2 s[7i]
2 t
—
Trace
24
5
4-MeOC6H4
4-Me2NC6H4
3-MeC6H4
PdCl2/2P(1-Nap)3
—
6
Pd(OAc)2/2P(1-Nap)3 PEG-2000
—
53
7
Pd(PPh3)4
PEG-2000
PEG-2000
—
22
8
3-MeOC6H4
4-ClC6H4
Pd(dba)2/2PPh3
—
34
9
10 Pd(OAc)2/2P(o-tol)3 PEG-2000
—
61
10
11
12
13
14
15
16
17
18
19
20
21e
22
23
4-FC6H4
11 Pd(OAc)2/2PPh3
12 Pd(OAc)2/2PPh3
13 Pd(OAc)2/2PPh3
14 Pd(OAc)2/2PPh3
15 Pd(OAc)2/2PPh3
16 Pd(OAc)2/2PPh3
17 Pd(OAc)2/2PPh3
18 Pd(OAc)2/2PPh3
19 Pd(OAc)2/2PPh3
20 Pd(OAc)2/2PPh3
21 Pd(OAc)2/2PPh3
22 Pd(OAc)2/2PPh3
H2O
—
0
4-NCC6H4
[bmim][PF6]
[bmim][BF4]
PEG-1000
PEG-600
—
Trace
Trace
85
4-O2NC6H4
4-CF3C6H4
4-OHCC6H4
4-MeOCOC6H4
4-MeCOC6H4
3,4-CH2O2C6H3
3,5-Me2C6H3
2-MeC6H4
—
—
—
82
PEG-400
—
81
PEG-2000
PEG-2000
PEG-2000
PEG-2000
PEG-2000
PEG-2000
Cs2CO3
K2CO3
Et3N
—
86
85
83
61
2-MeOC6H4
1-Naphthyl
3-Pyridyl
—
88
—
87
3-Thienyl
2u[7i]
aReaction conditions: phenylboronic acid (0.5 mmol), palladium catalyst
(3 mol%), base (2.5 equiv.), solvent (5.0 ml or 5 g) under air for 8 h.
bIsolated yield.
aReaction conditions: arylboronic acid (0.5 mmol), Pd(OAc)2 (0.015 mmol),
PPh3 (0.03 mmol), PEG-2000 (5 g) at 70 °C under air for 8 h.
bIsolated yield.
cThe reaction was run under oxygen atmosphere.
dThe reaction was carried out under Ar.
eFor 24 h.
Nap)3 and Pd(OAc)2/2P(o-tol)3 are used as the catalyst (Table 1, en-
tries 2, 4, 7 and 10), whereas PdCl2/2P(1-Nap)3, Pd(PPh3)4 and Pd
(dba)2/2PPh3 afford low yields (Table 1, entries 6, 8 and 9), so Pd
(OAc)2/2PPh3 was finally selected as the catalyst for the reaction.
Our next studies focused on the effect of solvent on the model re-
action. The reaction fails when other green solvents such as H2O or
ionic liquids are used (Table 1, entries 11–13). In addition, the effi-
ciency of PEGs of various chain lengths on the reaction was also ex-
amined under the same reaction conditions (Table 1, entries 14–
16). PEG-2000 is superior to PEG-600, PEG-1000 and PEG-400. It is
well known that a base can activate phenylboronic acid in cross-
coupling reactions.[12] Subsequently, we tested various bases,
namely Cs2CO3, K2CO3 and Et3N (Table 1, entries 17–19). The results
indicate that addition of a base does not enhance the result. Finally,
the reaction temperature was also screened, 70 °C being found to
be optimal, a lower yield being observed when the reaction tem-
perature is reduced to 60 °C (Table 1, entry 20). Therefore, the opti-
mal catalytic system involves the use of Pd(OAc)2/2PPh3 (3mol%) in
PEG-2000 at 70 °C under air for 8 h (Table 1, entry 4).
Having obtained satisfactory results in the homocoupling of
phenylboronic acid, a variety of arylboronic acids were then exam-
ined to explore the scope of substrates under the optimized reac-
tion conditions. The results are listed in Table 2. The
homocoupling reaction of arylboronic acids 1b–1d and 1 g–1n
bearing both electron-donating groups and electron-withdrawing
groups at the para position proceeds smoothly under the opti-
mized conditions to afford the corresponding 4,4′-disubstituted
biaryls 2b–2d and 2 g–2n in 71–94% yields (Table 2, entries 4–6
fNo reaction.
and 9–16). A wide range of functional groups including chloro,
fluoro, cyano, ester, aldehyde, ketone, methoxy, methyl, amino,
trifluoromethyl and nitro groups on the benzene rings are well tol-
erated. But strongly electron-withdrawing substituents such as ni-
tro and cyano groups decrease reaction rates, resulting in slightly
lower conversions of the starting boronic acids (Table 2, entries
11 and 12). In addition to para-substituted phenylboronic acids,
meta-substituted 1e and 1f could be employed to give the desired
products 2e and 2f in excellent yields (Table 2, entries 7 and 8). Di-
substituted phenylboronic acids 1o and 1p also undergo
homocoupling effectively to furnish 2o and 2p in 87 and 92%
yields, respectively (Table 2, entries 17 and 18). We then turned
our focus to determining steric effects in the reaction. The reactions
of o-tolylboronic acid 1q and o-methoxyphenylboronic acid 1r give
the corresponding biphenyl products 2q and 2r in moderate yields
(Table 2, entries 19 and 20). However, bulky 1-naphthaleneboronic
acid 1 s undergoes homocoupling to afford the desired product 2 s
in 88% yield (Table 2, entry 21). Furthermore, we found that biaryl is
the only product, while no side products, such as phenol or arene
which are often byproducts of this reaction,[13] are observed. We
also investigated the reaction of heteroarylboronic acids, but the re-
sults are not satisfactory. As for 3-pyridineboronic acid 1 t, we ob-
tain almost none of the desired product 2 t (Table 2, entry 22).
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Appl. Organometal. Chem. 2015, 29, 113–116

Palladium-catalyzed homocoupling of arylboronic acids in PEG
Table 3. Recyclability of Pd(OAc)2/PPh3/PEG-2000 systema
using a PerkinElmer 683 instrument.1H NMR spectra were recorded
using a Bruker Avance 400 MHz spectrometer with tetramethylsilane
as an internal standard and CDCl3 as solvent.13C NMR spectra were
recorded using a Bruker Avance 400 MHz spectrometer with CDCl3
as solvent. Melting points were uncorrected.
Cycle
Yieldb (%)
Cycle
Yieldb (%)
General Procedure for Palladium-Catalyzed Homocoupling
Reaction of Arylboronic Acids in PEG-2000
1
3
5
90
89
89
2
4
6
91
90
88
A mixture of arylboronic acid (0.5 mmol), Pd(OAc)2 (0.015 mmol)
and PPh3 (0.03 mmol) in PEG-2000 (5g) was stirred at 70°C under
air for 8 h. After being cooled to room temperature, the resulting
suspension was extracted four times with diethyl ether (4× 10 ml).
The residue of the extraction was subjected to a second run of
the homocoupling reaction by charging with the same substrate
(arylboronic acid) under the same conditions without further addi-
tion of Pd(OAc)2 or PPh3. The combined ether phase was concen-
trated under reduced pressure. The residue was purified by flash
column chromatography on silica gel using petroleum ether or a
mixture of petroleum ether and EtOAc as eluent.
aReaction conditions: p-tolylboronic acid (0.5 mmol), Pd(OAc)2 (0.015 mmol),
PPh3 (0.03mmol), PEG-2000 (5g) at 70°C under air for 8h.
bIsolated yield.
Using thiophene-3-boronic acid 1u as substrate, only 36% yield of
2u is obtained even for longer reaction time (Table 2, entry 23).
In order to prove the mechanism, we performed a few reactions and
the results are listed in Table 2 (entries 1–3). When the reaction is car-
ried out under argon atmosphere, only 69% yield of 2a is obtained.
Much higher yields of 89–91% are achieved when the reaction is per-
formed under air or oxygen atmosphere. These results indicate that ox-
ygen is important in the homocoupling reaction of arylboronic acids.
To check the reusability of PEG-2000 and the catalyst, the
homocoupling reaction of p-tolylboronic acid was examined in
the presence of 3 mol% of Pd(OAc)2 and 6 mol% of PPh3 and the re-
sults are summarized in Table 3. After initial experimentation, the
reaction mixture was extracted with diethyl ether (4 × 10 ml), and
the solidified Pd(OAc)2/PPh3/PEG-2000 system was subjected to
the second run by charging with the same substrate (p-tolylboronic
acid) without addition of Pd(OAc)2 or PPh3. We were gratified to ob-
serve that the Pd(OAc)2/PPh3/PEG-2000 system can be recycled
and reused six times without significant loss of activity. The results
of six runs show that they are almost consistent in yields and rates.
In addition, the leaching of palladium in the product was also deter-
mined. Inductively coupled plasma analysis of the extract found
that palladium content is less than 0.55 ppm.
Compounds 2a–2u are known compounds and were character-
ized by comparing their 1H NMR, 13C NMR and IR spectra with those
found in the literature.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (no. 21462021) and Key Laboratory of Functional Small Or-
ganic Molecules, Ministry of Education (no. KLFS-KF-201213) for fi-
nancial support.
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