Efficient benzocyclohexane-ketoamine ligands for palladium-catalyzed Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1246/cl.160653

In the presence of 0.02 mol% Pd(OAc)₂, a series of benzocyclohexane-ketoamine ligands were demonstrated to form a highly efficient catalyst for the Suzuki-Miyaura cross-coupling of various aryl halides with arylboronic acids in ethanol/aqueous media under ambient atmosphere.

Full text of DOI:10.1246/cl.160653

Advance Publication Cover Page
Efficient Benzocyclohexan-Ketoamine Ligands for
Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction
Wanyun Liu,* Dayan Xiong, Ping Huo,* Xiaohui He, and Guangquan Mei
Advance Publication on the web August 17, 2016
doi:10.1246/cl.160653
© 2016 The Chemical Society of Japan
Advance Publication is a service for online publication of manuscripts prior to releasing fully edited, printed versions. Entire
manuscripts and a portion of the graphical abstract can be released on the web as soon as the submission is accepted. Note that the
Chemical Society of Japan bears no responsibility for issues resulting from the use of information taken from unedited, Advance
Publication manuscripts.

1
Efficient Benzocyclohexan-Ketoamine Ligands for
Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction
Wanyun Liu*1, Dayan Xiong1, Ping Huo*1, Xiaohui He2, and Guangquan Mei1,3
1Key Laboratory of Jiangxi University for Applied Chemistry and Chemical Biology, Yichun University, Yichun 336000, China;
2School of Materials Science and Engineering, Nanchang University, Nanchang 330031, China;
3State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, China
E-mail: liuwanyun@ycu.jx.cn (W. Liu); pinghuo@ycu.jx.cn (P. Huo).
In the presence of 0.02 mol% Pd(OAc)2, a series of
The combination of these β-ketoamine ligands and Pd(OAc)2
was found to form a highly efficient catalyst for the Suzuki-
Miyaura cross-coupling of various aryl bromides and
activated aryl chlorides with arylboronic acids. The desired
products could be obtained in high yields under aerobic
conditions, with a great tolerance of raw material for a broad
range of functional groups on the aryl halides.
benzocyclohexan-ketoamine ligands were demonstrated to
form a highly efficient catalyst for the Suzuki-Miyaura cross-
coupling of various aryl halides with arylboronic acids in
ethanol/aqueous media under ambient atmosphere.
Palladium-catalyzed Suzuki-Miyaura cross-coupling
reaction of aryl halides with arylboronic acids has become one
of the most powerful carbon-carbon bond forming methods
with the advantages of high yields, mild reaction conditions,
wide functional groups tolerance and commercial availability
of the diverse arylboronic acids.1 It has widely applied in the
synthesis of natural products, pharmaceuticals and functional
polymer materials.2 Generally speaking, the catalytic features
of Suzuki-Miyaura cross-coupling reaction rely on the
electronic or steric influence of the ligands used.3 Therefore,
the design and synthesis of ligands are very important. It is
well known that the palladium catalyzed Suzuki-Miyaura
cross-coupling reaction can be efficiently proceeded using
bulky, electron-rich phosphine ligands. Though these ligands
own superior donor capability and stabilization effects, most
phosphines suffer the serious drawbacks in highly toxic and
air- and moisture-sensitive.4 To overcome these disadvantages
and get efficient and air- and moisture-stable ligands, the
simple and efficient synthesis of phosphine-free ligands
remains a scientific challenge.
As shown in Scheme 1, the target β-ketoamine ligands
with various substituted aniline moieties, such as phenyl, 2,6-
dimethylphenyl, naphthyl and fluoryl, were prepared
according to the previously reported method,9 with some
modifications.
Scheme 1 The benzocyclohexan-ketoamine ligands
In order to investigate the effect of aryl ring substituents
on β-ketoamine ligands (L1-L4) toward Suzuki-Miyaura
cross-coupling
reaction,
4-bromoacetophenone
and
To our knowledge, phosphine-free ligands, such as
heterocyclic carbenes,5 α-diimine,6 phenolic Schiff base7 and
β-ketoamine8 have also emerged for use in the Suzuki-
Miyaura cross-coupling reaction. In particular, β-ketoamine
ligands and their palladium complexes have shown excellent
catalytic activity because of their strong σ-donating abilities.8a
phenylboronic acid were selected as coupling partners in the
presence of 0.02 mol% ligand and 0.02 mol% Pd(OAc)2. The
experiments were carried out under aerobic conditions at
room temperature for 2 h utilizing K2CO3 as a base in
EtOH/H2O (v/v, 1:1).
As illustrated in Table 1, the data revealed that these β-
ketoamine ligands were effective ligands for palladium-
catalyzed Suzuki-Miyaura cross-coupling. For a comparison,
in the absence of ligands, only 28 % yield of product was
produced in the presence of 0.02 mol% of Pd(OAc)2 (entry 1,
Table 1). However, when adding the ligands, the yield of
product increased dramatically, to a range of 81-99% (entries
2-5, Table 1), indicating that the catalysts were formed in situ.
From the Table 1, it could be found that the steric and
electronic substituents of the ligand played an important role
in catalytic ability. Among the ligands investigated, L1, with
no substituent on aryl ring, showed the lowest efficiency and
provided the coupling product in 81% yield (entry 2, Table 1).
L2 with methyl group on aryl ring was found to be more
efficient ligand and afforded the coupling product in 89%
yield (entry 3, Table 1). The results suggested that the
increase the electron-donating properties and the steric effect
of the ligand would lead to an improvement in the rate of
The
Pd(OAc)2/β-ketoamine
ligands
derived
from
acetylacetone system had been successfully developed by
Hong and coworkers,8b which showed moderate catalytic
activity for cross-coupling of aryl halides with arylboronic
acids. Recently, a series of β-ketoamine ligands with different
steric and electronic substituents on the backbone and aniline
moieties were used to catalyze Suzuki-Miyaura cross-
coupling reaction.8c Among these ligands, it could be found
that the ligand with sterically-demanding and electron-
donating phenyloxyl group on the ortho aniline moiety
exhibited the highest activity.
Inspired by the above results, we herein report a simple
and efficient preparation of
benzocyclohexan-ketoamine ligands
a
series of novel
which contains
benzocyclohexan ring on 2-acetyl-1-tetralone and phenyl ring
on aniline, which show a big steric effect and strong
electronic effect, the conjugation effect of phenyl and
benzocyclohexan rings also enhances the electronic effect.

2
a Reaction conditions: 1.0 mmol of 4-bromoacetophenone, 1.2 mmol of
phenylboronic acid, 2.0 mmol of base, n(Pd(OAc)2)=n(ligand), 4 ml
EtOH/H2O (v/v, 1:1). b Isolated yields.
oxidative addition and stablitization of the palladium species.
Comparatively, the activities of L3 and L4 with bulky
substituent on the aryl ring were higher than that of L1 and L2.
Particularly, the L4 with fluoryl on aryl ring exhibited the
highest activity up to 99% yield under the same conditions
(entry 5, Table 1). The reason was ascribed to the steric and
electron-donating properties.6
Based on the above results, L4 was chosen as the most
effective ligand in the following Suzuki-Miyaura cross-
coupling reactions of different aryl halides with arylboronic
acids. With the optimal reaction conditions in hand, we
checked the scope of the aryl bromides by conducting a series
of experiments (Table 3). Overall, aryl bromides bearing
either electron-rich or electron-deficient substituents all led to
biaryl compounds in moderate to high yields. Many important
functional groups, such as the methyl, methoxy, acetyl,
aldehyde, ester, amino, chloro and nitryl, were quite well-
tolerated (entries 1-8, Table 3). Most remarkably, aryl
bromides bearing a naphthalene ring underwent reaction
smoothly with yield as high as 96% within 3 hours (entry 9,
Table 3). Generally speaking, due to retarding both the
oxidative addition and transmetalation processes, the aryl
halides with ortho-substituent had less active. But in this
study, the sterically hindered ortho-substituent aryl bromides
were also a competent coupling partner leading to high
product yield (entries 10-13, Table 3). Furthermore, the effect
of various para-substituents on the aryl boronic acids toward
the cross coupling were investigated (entries 14-16, Table 3).
It could be found that no significant difference was obeserved
in yield or in the reaction time. When the phenylboronic acid
with ortho-substituents reacted with the aryl halides, the
catalytic system could also show good activity through
prolonged reaction time (entry 17, Table 3). However, rather
low activity was observed at 6 h toward the reaction of aryl
bromide with ortho-substituents and phenylboronic with
ortho-substituents (entry 18, Table 3).
Table 1 Influence of β-ketoamine ligands on the palladium-catalyzed
Suzuki-Miyaura cross-coupling reaction of 4-bromoacetophenone
with phenylboronic acida
Entry
Ligand
No L
L1
L2
L3
Yield(%)b
1
2
3
4
5
28
81
89
92
99
L4
a
Reaction conditions: 1.0 mmol of 4-bromoacetophenone, 1.2 mmol of
phenylboronic acid, 2.0 mmol of K2CO3, 0.02 mol% Pd(OAc)2, 0.02
mol% ligand, 4 ml EtOH/H2O (v/v, 1:1), room temperature, 2 h.
b Isolated yields.
In order to determine the most suitable palladium-
catalyzed Suzuki-Miyaura cross-coupling reaction condition,
initial investigations of 4-bromoacetophenone with
phenylboronic acid catalyzed by L4/Pd(OAc)2 were conducted
with various conditions, such as the amount of the ligand and
Pd(OAc)2, reaction time, and different base. As shown in
Table 2, the effect of the amount of the ligand and Pd(OAc)2
on the coupling reaction was studied. We could found that
lowering the amount of ligand and Pd(OAc)2 from 0.2 mol%
to 0.02 mol% did not affect the reaction performance in 0.5 h
(entries 1-4, Table 2). The amount of ligand decreased to 0.01
mol%, the reaction yield had shown a sharp decline (entry 5,
Table 2). Then the reaction time was also investigated and
found that played an important role on the coupling reaction.
Increasing the reaction time from 0.5 h to 2.0 h (entries 4, 6-8,
Table 2), the yield improved remarkable. The reaction time
was prolonged to 2.5 h, the yield hardly went on increasing
(entry 9, Table 2). The reason was that the substrate was
completely converted to the product over 2 h. Furtherly, an
investigation of the influence of the base suggested that the
common and inexpensive inorganic bases, such as K2CO3 are
more effective, while other bases such as Na2CO3, KOH,
Ca(OH)2, NaOEt, K3PO4, gave slightly lower yields (entries
10-14, Table 2).Therefore, the 0.02 mol % of the ligand, 2 h
of reaction time and 2.0 mmol of K2CO3 as base would be the
most effective condition.
To demonstrate the generality of this catalytic system,
the reaction of unactivated aryl chlorides with phenylboronic
acid was explored. To our delight, by increasing the amount
of ligand and Pd(OAc)2 to 0.2 mol% in conjuction with
reaction time (12 hours) and temperature (80 °C), good yields
were still obtained (entries 19-20, Table 3). In contrast to the
aryl bromides, the elecronic effect of substituents on aryl
chlorides was significant differnence in yield. The aryl
chlorides bearing electron-deficient substituents led to biaryl
compounds in higher yields.
Table 3 Suzuki-Miyaura cross-coupling reaction of aryl halides with
phenylboronic acid under aerobic conditionsa
Table 2 Optimization of reaction conditions at room temperaturea
Catalyst
(mol%)
0.2
Time
(h)
0.5
0.5
0.5
0.5
0.5
1
1.5
2
2.5
2
Entry
Base
Yield(%) b
Time
(h)
Yield
(%)b
Entry
1
Aryl halide
Aryl boronic
1
2
3
4
5
6
7
8
9
10
11
12
13
14
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
KOH
91
89
88
87
65
91
95
99
98
95
93
72
93
94
0.1
Br
B(OH)2
Me
2
2
96
97
0.05
0.02
0.01
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.02
Br
2
3
4
5
MeO
O
C
H3C
B(OH)2
B(OH)2
B(OH)2
B(OH)2
Br
2
2
2
99
98
98
Br
Br
OHC
O
2
2
2
2
Ca(OH)2
NaOEt
K3PO4
C
HCO
3

3
Foundation of Jiangxi Provincial Education Department
(GJJ151020 and GJJ151031).
Supporting Information is also available electronically
on the CSJ-Journal Web site, http://www.csj.jp/journals/
chem-lett/index.html.
B(OH)2
B(OH)2
B(OH)2
6
7
8
Br
Br
2
2
2
97
99
99
HN
2
Cl
Br
O2N
Br
B(OH)2
B(OH)2
9
3
4
96
91
References and Notes
1
a) A. Suzuki, Y. Yamamoto, Chem. Lett. 2011, 40, 894. b) N.
Miyaura, A. Suzuki, Chem. Rev.1995, 95, 2457. c) A. Suzuki, J.
Organomet. Chem. 2002, 653, 83. d) F. R. Fortea-Perez, I. Schlegel,
M. Julve, D. Armentano, G. D. Munno, S. Stiriba, J. Organomet.
Chem. 2013, 743, 102. e) X. J. Jiang, S. Sakthivel, K. Kulbitski, G.
Nisnevich, M. Gandelman, J. Am. Chem. Soc. 2014, 136, 9548. f)
Y. Liu, X. F. Bai, Chem. Lett. 2016, 45, 705.
CH3
10
Br
NH
2
11
12
B(OH)2
B(OH)2
4
4
93
96
Br
2
3
a) L. F. Liu, Y. Dong, B. Pang, J. H. Ma, J. Org. Chem. 2014, 79,
7193. b) D. Zhang, Q. R. Wang, Coord. Chem. Rev. 2015, 286, 1.
c) S. P. Stanforth, Tetrahedron 1998, 54, 263. d) V. F. Slagt, A. H.
M. De Vries, J. G. De Vries, R. M. Kellogg, Org. Process. Res.
Dev. 2010, 14, 30. e) V. Polshettiwar, A. Decottignies, C. Len, A.
Fihri, ChemSusChem 2010, 3, 502.
a) V. Leigh, W. Ghattas, H. Mueller-Bunz, M. Albrecht, J.
Organomet. Chem. 2014, 771, 33. b) P. Gu, Q. Xu, M. Shi,
Tetrahedron 2014, 70, 7886. c) S. Yaşar, C. Şahin, M. Arslan, I.
Özdemir, J. Organomet. Chem. 2015, 776, 107. d) J. Xue, Z. G.
Zhou,Y. L. Liu, L. Huang, H. W. Yu,Y. R. Xie, C. Lai, Transition
Met. Chem. 2012, 37, 331. e) C. Tan, F. S. Liu, D. S. Shen, T.
Cheng, Z. Z. Zhou, Catal. Lett. 2011, 141, 1332.
NO2
Br
CH3
Br
CH3
Br
H3C
B(OH)2
13
6
77
O
C
H3C
B(OH)2
H3C
14
15
16
2
2
2
98
97
99
4
a) S. Jindabot, K.Teerachanan, P. Thongkam, S. Kiatisevi, T. Kham-
naen, P. Phiriyawirut, S. Charoenchaidt, T. Sooksimuang, P.
Kongsaeree, P. Sangtrirutnugul, J. Organomet. Chem. 2014, 750,
35. b) N. Nakagawa, T. Hatakeyama, M. Nakamura, Chem. Lett.
2015, 44, 486.
O
C
H3C
B(OH)2
H3CO
Br
5
a) W. A. Herrmann, M. Elison, J. Fischer, C. Köcher, G. R. J. Artus,
Angew Chem. Int. Ed. 1995, 34, 2371. b) V. P. W. Böhm, C. W. K.
Gstöttmayr, T. Weskamp, W. A. Herrmann, J. Organomet. Chem.
2000, 595, 186. c) H. Min, H. Miyamura, S. Kobayashi, Chem. Lett.
2016, 45, 837. d) X. F. Chen, H. H. Ke, Y. Chen, C. W. Guan, G.
Zou, J. Org. Chem. 2012, 77, 7572.
O
C
H3C
Br
B(OH)2
F
CH3
B(OH)2
CH3
B(OH)2
O
C
H3C
Br
Cl
17
18
4
6
86
68
6
a) P. Huo, J. B. Li, W. Y. Liu, X. H. He, G. Q. Mei, Chem. Lett.
2016, 45, 454. b) G. A. Grasa, A. C. Hillier, S. P. Nolan, Org. Lett.
2001, 3, 1077. c) R. Martin, S. L. Buchwald, Acc Chem. Res. 2008,
41, 1461.
CH3
Br
7
8
Z. G. Zhou, Z. Y. Zhou, A. C. Chen, X. H. Zhou, Q. Qi, Y. R. Xie,
Transition Met. Chem. 2013, 38, 401.
O
C
H3C
19c
20c
12
12
63
31
B(OH)2
B(OH)2
a) J. Cui, M. J. Zhang, Y. W. Zhang, Inorg. Chem. Commun. 2010,
13, 81. b) Y. C. Lai, H. Y. Chen, W. C. Hung, C. C. Lin, F. E.
Hong, Tetrahedron 2005, 61, 9484. c) Z. Z. Zhou, F. S. Liu, D. S.
Shen, C. Tan, L. Y. Luo, Inorg. Chem. Commun. 2011, 14, 659.
a) K. T. Wang, Y. W. Chen, X. H. He, Y. M. Liu, W. H. Zhou, J.
Polym. Sci. Part A: Polym. Chem. 2011, 49, 3304. b) X. H. He, Y.
M. Liu, L. Chen, Y. W. Chen, D. F. Chen, J. Polym. Sci. Part A:
Polym. Chem. 2012, 50, 4695. c) L. Chen, Z. C. Zhong, C. Chen, X.
H. He, Y. W. Chen, J. Organomet. Chem. 2014, 752, 100.
Cl
Me
a
9
Reaction conditions: 1.0 mmol of aryl bromide, 1.2 mmol of aryl
boronic acid, 2.0 mmol of K2CO3, 0.02 mol % Pd(OAc)2, 0.02 mol %
ligand, 4 ml EtOH/H2O (v/v, 1:1), room temperature.
b Isolated yields.
c Reaction conditions: 1.0 mmol of aryl chloride, 1.2 mmol of aryl boronic
acid, 2.0 mmol of K2CO3, 0.2 mol % Pd(OAc)2, 0.2 mol % ligand, 4 ml
EtOH/H2O (v/v, 1:1), reaction temperature: 80 °C.
A series of benzocyclohexan-ketoamine ligands were
successfully employed in the palladium-catalyzed Suzuki-
Miyaura cross-coupling reaction. It was shown that the ligand
with bulky steric and electron-donating substituent was
facilitated for the Suzuki-Miyaura cross-coupling reaction. A
significant advance in the efficiency of Suzuki-Miyaura cross-
coupling of aryl bromides or aryl chlorides with arylboronic
acids to give desired biaryls was demonstrated in
ethanol/aqueous media under ambient atmosphere.
This work was supported by the National Natural
Science Foundation of China (21261024), the Natural Science
Foundation of Jiangxi Province (20151BAB206021) and the