Green synthesis of biphenyl carboxylic acids via Suzuki–Miyaura cross-coupling catalyzed by a water-soluble fullerene-supported PdCl2 nanocatalyst

Article abstract of DOI:10.1177/1747519819836505

A green synthesis of variously substituted biphenyl carboxylic acids was achieved through Suzuki–Miyaura cross-coupling of a bromobenzoic acid with an aryl boronic acid using a water-soluble fullerene-supported PdCl₂ nanocatalyst (C₆₀-TEGs/ PdCl₂). Yields of more than 90% were obtained at room temperature in 4 h using 0.05 mol% catalyst and 2 equiv. K₂CO₃.

Full text of DOI:10.1177/1747519819836505

836505CHL0010.1177/1747519819836505Journal of Chemical ResearchLiu et al.
research-article2019
Research Paper
Journal of Chemical Research
2019, Vol. 43(1-2) 50–52
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Green synthesis of biphenyl carboxylic
acids via Suzuki–Miyaura cross-coupling
catalyzed by a water-soluble
https://doi.org/10.1177/1747519819836505
DOI: 10.1177/1747519819836505
journals.sagepub.com/home/chl
fullerene-supported PdCl2 nanocatalyst
Wanyun Liu, Xiuming Zhou, Ping Huo,
Jingbo Li and Guangquan Mei
Abstract
A green synthesis of variously substituted biphenyl carboxylic acids was achieved through Suzuki–Miyaura cross-coupling
of a bromobenzoic acid with an aryl boronic acid using a water-soluble fullerene-supported PdCl2 nanocatalyst (C60-TEGs/
PdCl2). Yields of more than 90% were obtained at room temperature in 4 h using 0.05 mol% catalyst and 2 equiv. K2CO3.
Keywords
Supported palladium nanocatalyst, biphenyl carboxylic acid, green synthesis, Suzuki–Miyaura cross-coupling reaction
Introduction
Biphenyl carboxylic acid compounds play an important
role in organic synthesis, in the pharmaceutical and petro-
chemical industries and in materials chemistry.1–4 The
pharmaceutical compounds Fenbufen and Flurbiprofen,
which are excellent nonsteroidal anti-inflammatory drugs,
are good examples. Biphenyl compounds are usually syn-
thesized through a series of sometimes lengthy reactions.
However, the defects of these traditional synthetic meth-
Figure 1. Water-soluble fullerene supported PdCl2
nanocatalyst [C60-TEGS/PdCl2].
ods cannot be neglected, such as complicated steps, harsh
reaction conditions, side reactions, difficult separation
Results and discussion
Optimization of the coupling reaction
conditions
and purification, low yield and serious environmental pol-
lution. This is obviously contrary to the theme of green
environmental protection, energy saving and emission
reduction, and is not in line with the concept of green
chemistry. Fortunately, the construction of C–C bonds by
The Suzuki–Miyaura cross-coupling reaction between
4-bromobenzoic acid (1; R1 = CO2H) and phenyl boronic
acid (2; R2 = H) catalyzed by C60-TEGS/PdCl2 (Scheme 1)
was selected as a model reaction in order to optimize the
reaction conditions (amount of catalyst, base used and reac-
tion time) and the results are shown in Table 1. When the
a
Suzuki–Miyaura cross-coupling reaction can be
achieved in only one step and the unnecessary derivatiza-
tion steps can be reduced.5–8 Recently we synthesized a
fullerene-supported PdCl2 nanocatalyst (Figure 1) and
successfully used it to synthesize biphenyl compounds via
a Suzuki–Miyaura cross-coupling of aryl bromides and
chlorides with aryl boronic acids.9 We now report its suc-
cessful use in synthesizing biphenyl carboxylic com-
pounds via a Suzuki–Miyaura cross-coupling of aryl
bromides containing a carboxyl group with aryl boronic
acids.
Key Laboratory of Jiangxi University for Applied Chemistry and
Chemical Biology, Yichun University, Yichun, P.R. China
Corresponding author:
Wanyun Liu, Key Laboratory of Jiangxi University for Applied Chemistry
and Chemical Biology, Yichun University, Yichun 336000, P.R. China.
Email: liuwanyun2006@163.com

Liu et al.
51
[C60-TEGs/PdCl2]
Base, H2O, r.t.
Br
B(OH)2
+
R2
R1
R2
R1
3a-u
1
2
Scheme 1. Biphenyl carboxylic acids via Suzuki – Miyaura cross-coupling catalyzed by water-soluble fullerene-supported PdCl2
nanocatalyst.
Table 1. Optimization of the conditions (amount of catalyst,
base used and reaction time) for the preparation of biphenyl-
4-carboxylic acid (3a; R1 = 4-CO2H, R2 = H) by treatment of
4-bromobenzoic acid (1; R1 = 4-CO2H) with phenyl boronic
acid (2; R2 = H) in the presence of a water-soluble fullerene-
supported PdCl2 nanocatalyst (C60-TEGs/PdCl2) (Scheme 1)a.
boronic acids were carried out under the optimized condi-
tions and the results are shown in Table 2. When 4-bro-
mobenzoic acid was coupled with an aryl boronic acid with
electron-donating or electron-withdrawing groups at the
para-position, the corresponding products were obtained in
excellent yields (Table 2, entries 1–3). However, the yield of
3,5-difluoroaryl boronic acid coupling with 4-bromoben-
zoic acid decreased to 76% (Table 2, entry 4a), which dem-
onstrated that reactivity of the coupling reaction decreased
when the aryl boronic acid contained strongly electron-
withdrawing groups. When we increased the amount of the
catalyst to 0.10% mol, the yield recovered to 93% (Table 2,
entry 4c). When 3-bromobenzoic acid, 4-bromophenylacetic
acid and 5-bromosalicylic acid replaced 4-bromobenzoic
acid, it was found that the coupling yields with the various
aryl boronic acids were high and followed the above rules
(Table 2, entries 5–19). There were no clear differences in
yield among 3-bromobenzoic acid, 4-bromobenzoic acid,
4-bromophenylacetic acid and 5-bromosalicylic acid.
However, under the same conditions, the coupling reaction
of 2,4-difluorophenyl boronic acid with its more hindered
ortho-position led to a significantly lower yield of 73%
(Table 2, entry 20c). In order to obtain a higher yield, it
needed a longer reaction time (6 h) and a greater amount of
catalyst (0.25% mol). It is probable that a steric effect is
being observed. Because they are more atom economical
and cheaper than aryl bromides, aryl chlorides were also
used as substrates in the coupling reaction. 4-Chlorobenzoic
acid was coupled with phenyl boronic acid with 0.50 mol%
of water-soluble fullerene supported PdCl2 nanocatalyst to
give a 75% yield at a higher temperature in 12 h (Table 2,
entry 21), whereas for the more challenging reaction of
4-chlorobenzoic and 4-fluoroaryl boronic acid a slightly
lower yield was obtained (Table 2, entry 22). Thus, aryl
chlorides containing a carboxyl group are much more diffi-
cult to couple with aryl boronic acids requiring stronger
conditions of heating and a prolonged reaction time.
Entry C60-TEGs/PdCl2 (mol%) Base
Time (h) Yield (%)b
1
2
3
4
5
6
7
8
0.15
0.10
0.05
0.025
0.01
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
NaHCO3
KF
4
4
4
4
4
1
2
3
6
4
4
4
4
4
98
98
97
89
50
41
73
91
97
91
86
77
93
98
9
10
11
12
13
14
K3PO4
Cs2CO3
aReaction conditions: a mixture of 4-bromobenzoic acid (1; R1 = 4-CO2H)
(1.0 mmol), phenyl boronic acid (2; R2 = H) (1.2 mmol) and a base
(2.0 mmol) in H2O (5.0 mL) was stirred for various times at room
temperature in the presence of various amounts of C60-TEGs/PdCl2.
bIsolated yields.
amount of catalyst was increased from 0.01 to 0.05 mol%,
the yield was significantly enhanced, but the yield did not
increase after increasing the amount of catalyst to 0.15
mol% (Table 1, entries 1–5). Thus 0.05 mol% of catalyst is
the optimal dose for this reaction. On prolonging the reac-
tion time from 1 to 4 h (Table 1, entries 3 and 6–8), the yield
increased markedly. In 6 h (Table 1, entry 9), the yield
remained at 97%. On varying the base (Table 1, entries 2
and 10–14), we found that Cs2CO3 was superior, leading to
a high yield of 98% within 4 h. The yield with K2CO3 was
similar but other bases such as Na2CO3, NaHCO3, KF and
K3PO4 gave lower yields. However, considering that
Cs2CO3 is more expensive than K2CO3, K2CO3 was chosen
Experimental
as the best base. In summary, 0.05 mol% C60-TEGs/PdCl2, C60 fullerene, tetraethylene glycol (TEG), palladium chlo-
4 h of reaction time and 2.0 mmol of K2CO3 as base were ride, phenyl boronic acid, aryl halides and lithium hydroxide
the optimal conditions.
were purchased from Energy Chemical and were used with-
out further purification. Other commercially available rea-
gents were purchased from Aladdin and were used without
Substrate expansion
1
further purification. H NMR spectra (400 MHz) were
To investigate further the scope and generality of this obtained on a BrukerARX 400 NMR spectrometer in CDCl3.
methodology, the cross-couplings of various aryl bromides Chemical shifts (δ) are given in ppm and coupling constants
containing a carboxyl or a phenol group with various aryl (J) are given in hertz (Hz). The XT4A melting point measur-

52
Journal of Chemical Research 43(1-2)
Table 2. Yields of a series of variously substituted biphenyls
(3a–u; R1, R2 = various) prepared by the reaction of
After the reaction was completed, distilled water (25 mL) was
added to the mixture and dilute 2 mol/L HCl was added drop-
wise to pH 3.0-4.0 with stirring, and the mixture was heated
to 100 °C for 10 min. The white solid that had formed was
filtered off and washed with hot water. After drying, it was
dissolved in ether (5 mL) and was rapidly separated using a
silica gel column. Elution with ether left behind small amounts
of impurities and traces of palladium black to give a crude
product. The ether solution was evaporated to 3–5 mL and
recrystallized to obtain a pure product. All the products 3a–u
are known compounds and were characterized by comparing
their melting points and 1H NMR spectra with those prepared
recently by using a water-soluble glycine-based Pd catalyst,
bromobenzoic acids (1; R1 = various) with an aryl boronic acid
(2; R2 = various) in the presence of a water-soluble fullerene-
supported PdCl2 nanocatalyst (C60-TEGs/PdCl2) (Scheme 1)a.
Entry (1, R1)
(2, R2)
Product Yield (%)b
1
2
3
4
4-CO2H
4-CO2H
4-CO2H
4-CO2H
4-CH3
4-F
4-OCH3
3b
3c
3d
97
97
98
76a
93c
96
3,5-Difluoro 3e
5
3-CO2H
H
3f
6
7
8
9
3-CO2H
3-CO2H
3-CO2H
3-CO2H
4-CH3
4-F
4-OCH3
3,5-Difluoro 3j
H
4-CH3
4-F
4-OCH3
3,5-Difluoro 3o
H
4-CH3
4-F
4-OCH3
3,5-Difluoro 3t
2,4-Difluoro 3u
3g
3h
3i
96
96
97
91c
97
96
96
97
92c
96
95
95
96
91c
73c 90d
75e
72e
1
PdCl2(NH2CH2CO2H)2.10 The melting points and H NMR
data of 3a–u are listed in the supplemental material.
10
11
12
13
14
15
16
17
18
19
20
21
22
4-CH2CO2H
4-CH2CO2H
4-CH2CO2H
4-CH2CO2H
4-CH2CO2H
3-CO2H-4-OH
3-CO2H-4-OH
3-CO2H-4-OH
3-CO2H-4-OH
3-CO2H-4-OH
3-CO2H-4-OH
3k
3l
3m
3n
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship and/or publication of this article.
Funding
3p
3q
3r
3s
The author(s) disclosed receipt of the following financial support for
the research, authorship and/or publication of this article: This work
was supported by the National Natural Science Foundation of China
(No. 21764016 and No. 21664014), the Natural Science Foundation
of Jiangxi Province (No. 20161BAB215197) and the Foundation of
Jiangxi Provincial Education Department (No. GJJ151031 and
GJJ170901).
4-Chlorobenzoic acid H
4-Chlorobenzoic acid F
3a
3c
aReaction conditions: a mixture of a bromobenzoic acid (1; R1 = various)
(1.0 mmol), an aryl boronic acid (2; R2 = various) (1.2 mmol) and K2CO3
(2.0 mmol) in H2O (5.0 mL) was stirred for 4 h at room temperature in
the presence of 0.05 mol% C60-TEGs/PdCl2.
Supplemental material
The supplemental material for this article is available online.
bIsolated yields.
c0.10 mol% catalyst was used
References
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(1.5 mmol) (2; R2 = H or F) was used for 12 h at 80°C in the presence
of 0.50 mol% catalyst.
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Suzuki-Miyaura cross-coupling reaction
catalyzed by C60-TEGs/PdCl2
A50 mL flask was charged with an aryl halide (1.0 mmol), an
aryl boronic acid (1.2 mmol), K2CO3 (2.0 mmol), nanocata-
lyst (0.05 mol% Pd) and deionized water (5 mL). The reac-
tion was stirred at room temperature for 4 h. The progress of
the reaction was monitored by thin-layer chromatography.