Efficient synthesis of diarylmethane derivatives by PdCl2 catalyzed cross-coupling reactions of benzyl chlorides with aryl boronic acids in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2015.10.053

The research provides a simple and efficient method for preparing diarylmethane derivatives using the cross-coupling reaction of benzyl chlorides and aryl boronic acids catalyzed by palladium chloride in DMF aqueous solution without additional ligand.

Full text of DOI:10.1016/j.tetlet.2015.10.053

Accepted Manuscript
Efficient synthesis of diarylmethane derivatives by PdCl2 catalyzed cross-cou-
pling reactions of benzyl chlorides with aryl boronic acids in aqueous medium
Guangkuan Zhao, Kena Zhang, Liang Wang, Jingya Li, Dapeng Zou, Yangjie
Wu, Yusheng Wu
PII:
S0040-4039(15)30250-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.10.053
TETL 46882
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 July 2015
13 October 2015
15 October 2015
Please cite this article as: Zhao, G., Zhang, K., Wang, L., Li, J., Zou, D., Wu, Y., Wu, Y., Efficient synthesis of
diarylmethane derivatives by PdCl2 catalyzed cross-coupling reactions of benzyl chlorides with aryl boronic acids
in aqueous medium, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.10.053
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PdCl2 catalyzed cross-coupling reactions of benzyl
chlorides with aryl boronic acids in aqueous medium
Guangkuan Zhao, Kena Zhang, Liang Wang, Jingya Li, Dapeng Zou*, Yangjie Wu, Yusheng Wu*

1
Tetrahedron Letters
Efficient synthesis of diarylmethane derivatives by PdCl2 catalyzed cross-coupling reactions of benzyl
chlorides with aryl boronic acids in aqueous medium
Guangkuan Zhaoa, Kena Zhanga, Liang Wanga, Jingya Lib,c, Dapeng Zoua,c, Yangjie Wua, and Yusheng
Wub,d
a The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, P. R. China.
b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province
c Tetranov Biopharm, LLC., No.75 Daxue Road, Zhengzhou, 450052, P. R. China.
d Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The research provides a simple and efficient method for preparing diarylmethane derivatives
using the cross-coupling reaction of benzyl chlorides and aryl boronic acids catalyzed by
palladium chloride in DMF aqueous solution without additional ligand.
2015 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Diarylmethane derivatives
Suzuki reaction
Simple catalytic system
———
 Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327; e-mail: yusheng.wu@tetranovglobal.com, zdp@zzu.edu.cn

2
Tetrahedron
Introduction
product in higher yield (Table 1, entries 4 vs 20-27). No product
was detected without base (Table 1, entry 19).
Palladium catalyzed Suzuki-Miyaura cross-coupling reaction
Table 1. Screening of solvent, base for the cross-coupling
reaction of 4-(chloromethyl)benzonitrile with phenyl boronic
acid.a
has become an important method for the construction of carbon-
carbon bond.[1] In recent years, several simple Suzuki-Miyaura
catalytic systems without traditional ligand were applied to
synthesize biaryl derivatives. For examples, LeBlond and
coworkers first reported Pd/C as effective catalyst for the cross
coupling reaction using aryl chlorides as substrates.[2] They
indicated that solvent effected on the pathway of homo- and
cross-coupling of aryl chlorides, and found the solvent system
DMA/H2O (20/1) favored the cross-coupling pathway of aryl
chlorides to obtain the Suzuki cross-coupling product selectively.
Liu and coworkers developed the palladium acetate-catalyzed
ligand-free Suzuki reaction in aqueous.[3] They discovered that
Pd(OAc)2-H2O-acetone catalytic system is highly active for the
mono-Suzuki coupling reaction, and Pd(OAc)2-H2O-DMF system
more suitable for the synthesis of polyaryls. Deng and coworkers
found that the combination of Pd(OAc)2, MeONa, alcohols was
also effective to catalyze the cross coupling reaction of aryl
halides and aryl boronic acids.[4] The group of Liu Chun reported
a kind of N,O-bidentate ligand formed from EtOH and DMA via
the hydrogen bond which was effective for Suzuki reaction of
aryl chlorides.[5] And in the next year, their group developed a
catalytic system of PdCl2 in DMF-H2O solvent in presence of
K2CO3 for the cross coupling of aryl bromides and aryl boronic
acids.[6] These previous studies indicated that both solvent and
base had a fundamental influence on Suzuki-Miyaura reaction,
and suitable combination of different solvents and bases could
promote the Suzuki-Miyaura reaction.
Entry
1
Base
Solvent
Yield%b
72
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
--
DMF
2
DMF/H2O(6:1)
DMF/H2O(5:1)
DMF/H2O(4:1)
DMF/H2O(3:2)
DMF/H2O(1:1)
DMF/H2O(2:3)
DMF/H2O(1:4)
H2O
93
3
94
4
96
5
70
6
53
7
26
8
9
9
7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
DMA/H2O(4:1)
NMP/H2O(4:1)
Ethanol/H2O(4:1)
Methanol/H2O(4:1)
Dioxane/H2O(4:1)
THF/H2O(4:1)
MeCN/H2O(4:1)
Toluene/H2O(4:1)
Acetone/H2O(4:1)
DMF/H2O(4:1)
DMF/H2O(4:1)
DMF/H2O(4:1)
DMF/H2O(4:1)
DMF/H2O(4:1)
DMF/H2O(4:1)
DMF/H2O(4:1)
DMF/H2O(4:1)
DMF/H2O(4:1)
89
51
8
9
Trace
N. R.
5
Diarylmethanes are one of privileged structural components
ubiquitously found in pharmaceuticals and biologically active
compounds[7], and they are also subunits in supramolecular host
structures[8]. Most recently, the palladium catalyzed cross-
coupling reactions of benzyl halides with aryl boronic acids have
proved to be very powerful for construction of these
compounds[9]. But few aforementioned simple Suzuki-Miyaura
catalytic systems without traditional ligand were applied to
prepare diarylmethane derivatives.
Bandger and coworkers[10] had described that ligand-free
palladium catalyzed cross-coupling reactions of aryl boronic
acids with benzyl halides using acetone:water (3:1) as the solvent
at room temperature. However, their conditions were effective on
the coupling reaction between benzyl bromides and aryl boronic
acids, but had no effect on more available benzyl chloride.
Herein, we report that PdCl2 could catalyze the cross-coupling
reaction of benzyl chlorides and aryl boronic acids in DMF
aqueous solution under air to prepare diarylmethanes derivatives.
N. R.
Trace
N. R.
85
Na2CO3
Et3N
57
CH3COONa
NaOH
Cs2CO3
NaHCO3
t-BuOK
K3PO4
66
44
80
84
19
27
59
a
Reaction conditions: 4-(chloromethyl)benzonitrile (0.5 mmol), phenyl
boronic acid (0.6 mmol), PdCl2 (3 mol%), base (1.0 mmol), solvent (5 ml), 90
°C, 1 h, under air. b Yields were determined by GC-MS using n-dodecane as
an internal standard.
Results and Discussion
Secondly, the impact of catalyst loading, reaction temperature,
reaction time was also studied. As shown in Table 2, 1 mol% of
PdCl2 could satisfy the reaction and gave excellent yield of
product after 1 h (Table 2, entries 3-6), and the reaction couldn’t
proceed without catalyst (Table 2, entry 1). When the reaction
was scaled up to 10 mmol scale, even 0.2 mol% PdCl2 could
efficiently catalyze the model reaction with a 93% yield of the
product by prolonged the reaction time to 3 h (Table 2, entry 2).
In
preliminary
studies,
the
reaction
of
4-
(chloromethyl)benzonitrile with phenyl boronic acid was chosen
as a model reaction for optimization. Firstly, the impact of
different solvents and bases was investigated and are summarized
in Table 1. When the reaction was carried out in DMF, a 72%
yield of target product was obtained (Table 1, entry 1). It is well
known that a suitable amount of water may improve Suzuki-
Miyaura reactions due to the increase of dissolved base and gave
the best result with 96% cross coupling product yield (Table 1,
entry 4). Decreasing or increasing the ratio of DMF/H2O led to
declined yields (Table 1, entries 1-9). Several different solvents
were also tested under similar conditions but all gave inferior
results compared to DMF (Table 1, entries 4 vs 10-18). The study
of different bases showed that K2CO3 delivered the desired
o
o
Decreasing the reaction temperature from 90 C to 25 C the
yields were decreased (Table 2, entries 3 vs 7-8). Moreover, the
yield was not further improved evidently by increasing the
o
temperature from 90 oC to 110 C (Table 2, entry 3 vs 9). So the
o
subsequent experiments were carried out at 90 C. Additionally,
time optimization revealed that the reaction gave excellent yield
after 1 h. When the reaction time was prolonged to 2 hours, the
yield did not increase (Table 2, entries 3, 10, 11). Finally, the

3
9
3-CH3
2-CH3
H
H
90
83
92c
84
81
74
69
50
36
46
51
83
87
90
75
73
optimum reaction condition is 1.0 mol% of PdCl2 in presence of
K2CO3 in DMF/H2O (4:1) for 1 h at 90 °C under air.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
H
Table 2. Screening of catalyst loading, reaction temperature,
reaction time for the cross-coupling reaction of 4-
(chloromethyl)benzonitrile with phenyl boronic acid.a
H
H
4-OCH3
4-F
H
4-CN
4-CN
4-CN
4-CN
4-CN
4-CN
4-CN
4-CN
4-CN
4-Cl
2-Cl
4-COCH3
4-F
Entry
PdCl2 (mol%)
Temp. (°C)
Time (h)
Yield%b
N. R.
93c
96
3-F
1
--
90
90
90
90
90
90
25
60
110
90
90
1
4-Br
2
0.2
1.0
2.0
3.0
4.0
1.0
1.0
1.0
1.0
1.0
3
4-CN
3-CF3
2-CH3
4-CH3
4-OCH3
3-COCH3
3-COCH3
3
1
4
1
95
5
1
96
6
1
97
7
1
52
8
1
88
24
9
1
97
a
10
0.5
2
86
Reaction conditions: substituted benzyl chloride (0.5 mmol), substituted
phenyl boronic acid (0.6 mmol), PdCl2 (1.0 mol%), K2CO3 (1.0 mmol),
DMF/H2O (4:1, 5 ml), 1 h , 90 oC, under air. b Isolated yields. c GC-MS yield.
11
96
a
Reaction conditions: 4-(chloromethyl)benzonitrile (0.5 mmol), phenyl
boronic acid (0.6 mmol), PdCl2, K2CO3 (1.0 mmol), DMF/H2O (4:1, 5 ml),
This research showed the present catalytic system was
effective on the coupling reaction between benzyl chloride and
aryl boronic acid. To gain insight into the interaction among our
catalytic system, the catalytic system was reinvestigated in the
absence of reaction substrates (Table 4 and Figure 1). As can be
seen from Figure 1, the direct phenomenon of vessel 4 and 6
were much different from others. Lots of Pd black deposited onto
the wall of vessel 6, obtaining colorless and transparent solution,
which in accordance with our former experimental results that in
the presence of suitable amount of H2O the model reaction could
be accomplished in an hour due to the improved solubility of
K2CO3 as well as the rapid generation of Pd(0). Whereas, the
phenomenon of vessel 4 was a little out of our expectation that
almost all PdCl2 combined with K2CO3 generating light yellow
solid and separating with upper layer colorless and transparent
solution. In order to satisfy our curiosity, the solid complex was
separated out and used to catalyze the model reaction in pure
DMF without additional PdCl2 and K2CO3, and it works well
after prolonged the reaction time to 2 hours. It could also be
reused two times with 96% yields of corresponding product
respectively. Further 1H NMR and IR analysis revealed that DMF
was also included in the solid complex (see the Supporting
b
under air. Yields were determined by GC-MS using n-dodecane as an
internal standard. Reaction conditions: 4-(chloromethyl)benzonitrile (10
c
mmol), phenyl boronic acid (12 mmol), PdCl2 (0.2 mol%), K2CO3 (20 mmol),
DMF/H2O (4:1, 50 ml), under air.
After establishing the optimized reaction conditions, the
reaction of benzyl chlorides and aryl boronic acids bearing
electron-donating and electron-withdrawing substituents at the
aromatic ring were investigated. Four general trends could be
seen from Table 3: 1). Most reactions proceed smoothly to give
the corresponding products in moderate to good yields. 2) The
position of substituents have little effect on the reaction yields
(Table 3, entries 1, 2; 8, 9, 10; 15, 16; 20, 21; 23, 24), and they
all gave the desired products in good isolated yields. 3) Benzyl
chlorides with electron-withdrawing substituents or aryl boronic
acids with electron-donating substituents tend to give better
yields (Table 3, entries 1, 6, 18, 22). 4) The process tolerates a
variety of functional groups that are available for further
functionalization. In addition, halogen substituents such as
fluoro, chloro could survive the mild reaction conditions (Table
3, entries 3, 13, 15, 16, 23, 24), but substrates with aryl bromide
unit gave the byproduct of biaryl derivatives which is an
explanation of their low corresponding yields (Table 3, entries 7,
17).
Information)
to
form
a
possible
complex
of
(PdCl2)x(K2CO3)y(DMF)z. On the basis of the literature report,
DMF may function as the following three kinds of roles in
organometallic chemistry. 1) Aprotic solvent. 2) Weak ligand[11]
.
Table 3. The cross-coupling of various benzyl chlorides and
aryl boronic acids under optimized reaction conditions.a
3) Reducing agent. More recently, DMF was also applied into
preparing metal nanoparticles, with respect to its temperature-
dependent reducing ability as well as possible weakly interaction
with metal through the carbonyl oxygen.[12] So in the optimum
reaction condition, DMF possibly played as a crucial role for the
success of the coupling. It is not only an aprotic solvent but also
weak ligand for the catalytic cycle. By combination of suitable
ratio of DMF and H2O, it is also played as a reducing agent to
generate highly active Pd(0). And the Pd(0) may works in soluble
palladium clusters form surrounded by DMF according to the
literature reports.[13]
Entry
R1
R2
H
H
H
H
H
H
H
H
Yield%b
90
1
2
3
4
5
6
7
8
4-CN
2-CN
88
4-Cl
85
4-NO2
4-COOCH3
4-OCH3
4-Br
77
58
30
Table 4. The reinvestigation of our catalytic system without
reaction substrates. a
36
Entry
PdCl2
DMF
H2O
K2CO3
4-CH3
87

4
Tetrahedron
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1
2
3
4
5
6
3 mg
3 mg
3 mg
3 mg
3 mg
3 mg
5 ml
--
--
--
5 ml
1 ml
--
--
4 ml
5 ml
--
--
8.
138 mg
138 mg
138 mg
5 ml
1 ml
4 ml
9.
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a All above studies were carried out at 90 oC, 1h, under air.
Figure 1 the corresponding phenomenon of Table 4
Conclusion
To sum up, we have developed a simple and efficient method
to prepare diarylmethane derivatives in good yields under mild
experimental conditions. Various functional groups that are
available for further functionalization could survive in our
catalytic system. DMF functions as solvent and weak ligand in
our catalytic system. Further study about the scope, mechanism
and synthetic applications of our catalytic system is ongoing.
Acknowledgments
We are grateful to the Natural Science Foundation of China
(20772114, 21172200), Research Program of Fundamental and
Advanced Technology of Henan Province (122300413203), and
Technology Research and Development Funds of Zhengzhou
(141PRCYY516) for financial support.
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