Synthesis of Enaminone-Pd(II) Complexes and Their Application in Catalysing Aqueous Suzuki-Miyaura Cross Coupling Reaction

Article abstract of DOI:10.1002/cjoc.201900417

A series of Pd(II)-enaminone complexes, termed Pd(eao)₂, have been synthesized and characterized. The investigation on the catalytic activities of these new Pd(II)-reagents has proved that the Pd(eao)₂-1 possesses excellent catalytic activity for the Suzuki- Miyaura cross coupling reactions of aryl bromides/chlorides with aryl/vinyl boronic acids in the environmentally benign media of aqueous PEG400 at low loading (5 mol‰). The superiority of this Pd(II)-reagent to those commercial Pd(II) and Pd(0) catalysts in catalyzing the reactions has been confirmed by parallel experiments. What's more, Pd(eao)₂-2 has been found as a practical catalyst for the homo-coupling reactions of aryl boronic acids.

Full text of DOI:10.1002/cjoc.201900417

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of Chemistry
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中 国 化 学 - An International Journal
Accepted Article
Title: Synthesis of Enaminone-Pd(II) Complexes and Their Application in Catalysing
Aqueous Suzuki-Miyaura Cross Coupling reaction
Authors: Leiqing Fu, Xiaoji Cao, Jie-Ping Wan* and Yunyun Liu*
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Chinese Journal
of Chemistry
Pd(II)-enaminone complexes, Synthesis, Catalytic application,
Suzuki-Miyaura coupling, Homo-coupling
Report
CJC
中
国 化 学 - An International Journal
Synthesis of Enaminone-Pd(II) Complexes and Their Application in
Catalysing Aqueous Suzuki-Miyaura Cross Coupling reaction
Leiqing Fu,a,b Xiaoji Cao,c Jie-Ping Wan*,a and Yunyun Liu*,a
a College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P. R. China
b College of Chemistry and Bio-Engineering, Yichun University, Yichun 336000, P. R. China
c Research Centre for Measurement and Analysis, Zhejiang University of Technology, Hangzhou, 310014, P. R. China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
A series of Pd(II)-enaminone complexes, termed Pd(eao)2 have been synthesized and characterized. The investigation on the catalytic activities of these
new Pd(II)-reagents proved that the Pd(eao)2-1 possesses excellent catalytic activity to the Suzuki-Miyaura cross coupling reactions of aryl
bromides/chlorides with aryl/vinyl boronic acids in the environmentally benign media of aqueous PEG400 at low loading (5 mol‰). The superiority of this
Pd(II)-reagent to those commercial Pd(II) and Pd(0) catalysts in catalyzing the reactions has been confirmed by parallel experiments. What is more,
Pd(eao)2-2 has been found as practical catalyst for the homo-coupling reactions of aryl boronic acids.
effective catalytic methods enabling the practical coupling of aryl
bromides and chlorides consists of one major trend in current
Background and Originality Content
Enaminones are valuable and building blocks with easy
research of Suzuki-Miyaura reaction.
availability[1] and possess enriched reaction sites for the
In addition to realizing reactions using less reactive aryl
designation of numerous new organic reactions.[2] Notably,
halides, the identification of sustainable medium such water or
employment of enaminones as ligands of transition metal catalyst
nontoxic aqueous medium constitutes another important issue in
has recently won important advances in a variety of different
coupling reactions such as Ullmann-type C-N, C-O and C-S
coupling reactions.[3] Specifically, as the efforts in preparing stable
metal-enaminone compounds, Shi et al[4] have reported the
synthesis and crystallographic characterization of tetradentate
enaminone-copper complexes. Pilet and co-workers[5] have
prepared and characterized a Ni(Ⅱ) tetranuclear cubane-like
complex and a mixed Cu(Ⅱ)-Dy(Ⅲ) nonanuclear complex by
using a ethanolamine-derived trifluoromethyl enaminone ligand.
Furthermore, the complex of Cu(II), Ni(II), Co(II) and Pd(II) with
different enaminone ligands have also been prepared and clearly
identified by Svete and co-workers.[6] Amazingly, unlike the works
on their preparation and characterization, the application of these
reported metal-enaminone complexes as potential catalysts has
rarely been investigated. In this context, preparation of new
enaminone-metal complexes such as Pd-complexes with
distinctive catalytic applications is a promising and important
issue for both enaminone chemistry and transition metal
catalysis.[7] Actually, enaminones have been reported to
undertake vinyl C-H arylation reaction via Pd(II) catalysis.[8]
Suzuki-Miyaura reaction.[13] To design practical Pd-catalyst for
Suzuki-Miyaura coupling reactions employing water or aqueous
medium, the hydrophilicity of the catalyst itself is thus crucial for
the expected catalytic effect. While enaminone structure has
been known as featured hydrophilic candidate as illustrated in
recent works,[14] it is theoretically feasible to prepare
Pd-enaminone complexes as catalysts for efficient Suzuki-Miyaura
coupling reactions in water-based medium. Herein, we present
our work on the preparation, characterization of new Pd(eao)2
catalysts and their attractive application in the Suzuk-Miyaura
biaryl synthesis using aryl bromides/chlorides with excellent
substrate tolerance by utilizing mixed water and PEG400 as well
recognized environmentally benign medium.[15] Additionally, such
Pd(II) catalyst has also been identified to catalyse boronic acid
homo-coupling reactions of aryl boronic acids by simply modifying
the organic backbone of the complex and reaction conditions.[16]
Results and Discussion
At the beginning, the attempts in preparing the
enaminone-Pd(II) complexes led to the observation that
Pd(II)-complexes Pd(eao)2-1~Pd(eao)2-4 could be practically
synthesized by simply stirring enaminones 1 with Pd(OAc)2
(Scheme 1, and see the experimental section for detail). The
structure of these complexes were full characterized with
spectroscopic analysis, and the typical compound Pd(eao)2-1 was
unambiguously assigned by X-ray single crystal diffraction.[17]
Following the assignment on the structure of these Pd(eao)2
compounds, we then turned to investigate their application in
Suzuki-Miyaura coupling reaction is one of the most reliable
tactics in forging C-C bonds for a large number of diversity- and
target-oriented syntheses, including the synthesis of natural
[9]
products, pharmaceuticals, materials and agrochemicals etc.
Among the numerous reports on Suzuki-Miyaura coupling
reactions, the common sense is that aryl iodide is the most
reactive aryl source.[10] Equivalent aryl bromide[11] and chloride,[12]
although more easily available and much cheaper, are less
reactive and not adequately practical. Therefore, developing
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catalyzing organic reactions. Thus, the Suzuki-Miyaura coupling
reaction of p-methoxylphenyl bromide 2a and phenyl boronic acid
3a was selected as model reaction to optimize the parameters.
Delightfully, these Pd(eao)2 species displayed excellent catalytic
activity to this cross coupling reaction providing biaryl 4a in
aqueous PEG400 medium (entries 1-4, Table 1). More notably,
parallel experiments proved that the most practical Pd(eao)2-1
was also a significantly better catalyst than the commercial Pd-
5
6
Pd(OAc)2
Pd(PPh3 )2Cl2
Pd(PPh3 )4
Pd(eao)2-1
Pd(eao)2-1
Pd(eao)2-1
Pd(eao)2-1
Pd(eao)2-1
Pd(eao)2-1
Pd(eao)2-1
Pd(eao)2-1
Pd(eao)2-1
Pd(eao)2-1
PEG400/H2O
PEG400/H2O
PEG400/H2O
H2O
NaHCO3
51
62
NaHCO3
NaHCO3
NaHCO3
NaHCO3
-
7
60
8
59
9
PEG400
74
10
11
12
13
14c
15d
16c,e
17c,f
PEG400/H2O
PEG400/H2O
PEG400/H2O
PEG400/H2O
PEG400/H2O
PEG400/H2O
PEG400/H2O
PEG400/H2O
trace
76
KOH
NaOAc
Et3N
63
R1
R2
O
NH2
R2
31
HN
O
O
NaOBu-t
equiv)
(1
MeCN, 40 o
NaHCO3
NaHCO3
NaHCO3
NaHCO3
83
R1
Pd
Pd(OAc)2
C
NH
78
1
R2
R1
87
Pd(eao)2
85
aReaction conditions: 2a (1 mmol), 3a (1.2 mmol), Pd-catalyst (1 mol%)
and base additive (2 mmol) in 4 mL medium (3mL PEG400 and 1 mL water
in entries with mixed media), stirred at 70 oC for 6 h under air. bIsolated
yield based on 2a. cWith 0.5 mol% Pd(eao)2-1. dWith 0.25 mol% Pd(eao)2-1.
HN
O
O
Pd
NH
f
eThe reaction temperature was 80 oC. The reaction temperature was 90
CCDC 1943349
-1, 56%
Pd(eao)2
oC.
Cl
Cl
OMe
With the optimized reaction parameters, the scope of the present
catalytic system using different aryl bromides and chlorides with
aryl boronic acids were conducted. The results from these
experiments indicated that the present protocol was a generally
applicable approach in the synthesis of biaryls by efficiently
forging new C-C bond (Table 2). When phenyl boronic acid 3a was
fixed to react with bromobenzenes, a variety of functional
structures, including alkyl, alkoxyl, halogen, ketone, formyl,
hydroxyl, carboxyl as well as naphthyl were generally tolerated to
the biaryl synthesis by providing products with excellent yields
(4a-4q, Table 2). On the other hand, for the aryl boronic acid
component, identically satisfactory tolerance to available aryl
boronic acids, such as those alkyl, aryl, hydroxyl, nitro and cyano
substituted phenyl boronic acids (4a, 4c, 4r-4z, 4aa, Table 2) as
well as naphthyl boronic acids (4p and 4q, Table 2) reacted with
bromobenzene to give corresponding biaryl products with
generally good to excellent yields, without suffering from evident
impact from the substituents. Interestingly, even vinyl boronic
acid could take part in the cross coupling to provide diaryl alkene,
albeit with relatively lower yield (4ab, Table 2). Besides the
general tolerance to bromobenzenes and boronic acids, a more
noteworthy point of the present method was that some aryl
chlorides could also be used for the coupling reaction by cleaving
the inert aromatic C-Cl bond at elevated temperature, and
corresponding products could be obtained with fair to excellent
yields (4j, 4m, 4i and 4ac, Table 2). Furthermore, the scale-up
synthesis of 4a using 10 mmol 2a gave a high yield of 62%
product, proving the valuable applicability of the catalyst in large
amount biaryl synthesis.
Ph
HN
O
O
HN
O
O
HN
O
O
Pd
Pd
Pd
NH
Ph
NH
NH
Cl
Cl
MeO
2-4, 49%
Pd(eao)
-3, 71%
Pd(eao)2
-2, 52%
Pd(eao)2
Scheme 1 Preparation and structures of Pd(eao)2 complexes
catalysts such as Pd(OAc)2, Pd(PPh3 )2Cl2 and Pd(PPh3 )2 (entries
5-7, Table 1). In order to further improve the yield of 4a, other
reaction parameters were then screened. Representatively, using
solely water or PEG400 as medium gave lower product yield
individually (entries 8-9, Table 1). Only trace product was
observed in the absence of base (entry 10, Table 1). Alternative
the base additive, including KOH, NaOAc and Et3N provided 4a
with evidently lower yield than the entry with NaHCO3 (entries
11-13, Table 1). It was notable that lowering the loading of
Pd(eao)2-1 to 0.5 mol% gave identically excellent result,
confirming the high catalytic activity of this catalyst at very low
loading (entries 14-15, Table 1). Finally, further improvement on
the product yield was achieved by heightening the reaction
temperature to 80 oC (entries 16-17, Table 1).
Table 1 The optimization on the Pd-catalyzed Suzuki-Miyaura reactiona
B(OH)2
Pd-cat./base
MeO
Br
MeO
T
solvent,
4a
2a
3a
Table 2 Scope of the Suzuki-Miyaura cross coupling with Pd(eao)2-1
Entry
Catalyst
Solvent
Base
Yield (％)b
catalysisa
1
2
3
4
Pd(eao)2-1
Pd(eao)2-2
Pd(eao)2-3
Pd(eao)2-4
PEG400/H2O
PEG400/H2O
PEG400/H2O
PEG400/H2O
NaHCO3
NaHCO3
NaHCO3
NaHCO3
82
79
65
57
-1
mol%)
equiv
PEG400/water, 80 oC
Pd(eao)2 (0.5
Ar/R
X
R/Ar
B(OH)2
NaHCO3
2
,
R
R
3
2
4
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Enaminone-Pd(II) Complexes Synthesis and Catalytic Suzuki-Miyaura Coupling
Chin. J. Chem.
to excellent yield regardless the site of the C-Br bond in the
heteroaryl ring. On the other hand, brominated electron deficient
heteroaryl systems such as pyridine (6e-6g, Scheme 2), pyrazine
(6h-6l, Scheme 2) and benzothiazole (6s, Scheme 2) were also
smoothly employed to react with boronic acids under the present
catalytic conditions to give biaryl products with satisfactory results.
The synthesis of diverse heteroayryl functionalized products 6
further confirmed the general applicability of the Pd(eao)2 catalyst
in the Suzuki-Miyaura coupling reactions.
R
Ar
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
X
product
4a
yield (％)b
87(62c)
82
4-MeO
3-MeO
2-MeO
4-Me
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
4b
4c
78
4d
4e
4f
96
2-Me
83
2,6-Me2
4-CH2CO2H
4-CH2OH
H
58
4g
96
-1
mol%)
equiv
PEG400/water, 80 o
Pd(eao)2 (0.5
HetAr Ar
HetAr Br
Ar
4h
4i
99
B(OH)2
3
NaHCO3
2
,
6
5
C
99
4-COMe
3-COMe
2-COMe
4-CHO
4-Cl
4j
99
F
O
4k
95
N
H
OMe
NO2
4l
87
N
H
N
88%c
H
6a
,
6b
6c
,
93%
89%
94%
,
6d
,
4m
4n
94
84
N
N
N
N
3-COMe-4-OH
Ph
Br
4o
91
N
N
N
70%d
66%d
6g
81%
6i
,
,
74%
S
naphth-1-yl
Ph
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
4p
4q
4a
4c
92
88
90
83
86
80
84
88
75
86
87
74
78
82
88
81
44
65d
41d
34d
83d
6f
6h 74%
,
,
6e
,
naphth-2-yl
Ph
N
N
N
N
N
H
4-MeOC6H4
2-MeOC6H4
4-HOC6H4
2-HOC6H4
3-MeC6H4
4-NCC6H4
3-OHCC6H4
3-NO2C6H4
4-FC6H4
2-ClC6H4
4-PhC6H4
3-PhC6H4
naphth-1-yl
naphth-2-yl
PhCH=CH
Ph
OMe
N
H
6m
, 68%
H
4r
6k 77%
,
6l
6j 69%
,
,
83%
H
4s
NO2
S
S
S
S
H
4t
OMe
H
4u
4v
4w
4x
6p
6q
83%
94%
,
,
6n
6o 75%
89%
,
,
H
H
S
S
F
OMe
c
H
N
H
4y
4z
6s
, 76%
6r
91%
,
H
Scheme 2a,b Suzuki-Miyaura coupling of heteroaryl bromides. aStandard
conditions as employed in Table 2. bIsolated yield based on 5. cThe
reaction temperature was 120 ℃. dThe reaction temperature was 100 oC.
H
4aa
4p
4q
4ab
4j
H
H
As another useful coupling model, the homo-coupling of two
molecules of aryl boronic acid constitutes an important protocol
in the synthesis of symmetrical biaryls. Therefore, we also
examined the potential catalytic application of the Pd(eao)2
reagents to the boronic acid homo-coupling. Interestingly, the
brief optimization on reaction conditions proved that the
H
4-COMe
4-CHO
H
Ph
Cl
4m
4i
Ph
Cl
4-NO2
Ph
Cl
4ac
aGeneral conditions: aryl halide 2 (1 mmol), boric acid 3 (1.2 mmol),
Pd(eao)2-2 was
a
practical catalyst for the expected
Pd(eao)2-1 (0.5 mol%), NaHCO3 (2 mmol) in mixed PEG400/H2O (3 mL/1
homo-coupling reaction by refluxing in toluene in the presence of
Na2CO3 (see SI). Under the optimal conditions, the homo-coupling
reactions of aryl boronic acids were briefly examined and the
results were outlined in Scheme 3. Based on the acquired results,
the aryl boronic acids with distinct substructures, including
electron withdrawing and donating group functionalized phenyl
boronic acids (4ba-4be, 4i, Scheme 3), as well as the sensitive
group substituted boronic acid (4bf, Scheme 3) could be
practically coupled. What’s more, the boronic acids with biaryl
(4be, Scheme 3) and fused aryl (4bg-4bh, Scheme 3) backbones
also participated in the reaction by providing corresponding
products with good to excellent yields. These results further
disclosed the promise of these newly synthesized Pd(eao)2
mL), stirred at 80 ℃ for 6 h under air. bIsolated yield based on 2. Yield
c
from 10 mmol scale reaction. dThe reaction temperature was 120 oC.
In order to further demonstrate the application of the
Pd(eao)2 catalyst, the reactions of heteroaryl bromides were then
investigated. As expected, the aryl bromides featured with a
variety of heteroaryl backbones could efficiently react with 3 for
the synthesis of corresponding biaryls 6 bearing heteroaryl
structure (Schmeme 2). Specifically, the brominated electron
enriched aromatic substrates, including bromoindole (6a-6c,
Scheme 2), bromofuran (6d, Scheme 2), bromothiophene (6m-6p,
Scheme 2) and bromobenzothiophene (6q-6r, Scheme 2) reacted
with aryl boronic acids to give corresponding product with good
Chin. J. Chem. 2019, 37, XXX－XXX
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First author et al.
Report
reagents in catalyzing important organic reactions.
Pd(eao)2-1 (0.005 mmol), NaHCO3 (2 mmol) and mixed
PEG400/H2O (3 mL/1 mL)). Then the mixture was heated up to 80
oC (or 120 oC for the reactions of aryl chlorides), and stirred at the
-2 mol%)
Pd(eao)2 (2
B(OH)2
Na
2CO
equiv)
3 (2
toluene, reflux
R
R
R
same temperature for
6 h. After cooling down to room
3
4
temperature, 5 mL of water was added, and the resulting mixture
was extracted with ethyl acetate (3 × 10 mL). The organic phases
were combined and washed with small amount of water for three
times. After drying with anhydrous Na2SO4, the solid was filtered
and the solvent in the acquired solution was removed under
reduced pressure. The resulting residue was subjected to flash
silica gel column chromatography to provide pure products with
the elution of petroleum ether.
MeO
OMe
4ba
73%
,
4bb
78%
,
4i
74%
72%
,
Ph
Ph
F
F
4be
General procedure for the boronic acid homo-coupling
4bd
4bg
,
60%
4bc
,
87%
,
reactions. To a 25 mL round-bottom flask equipped with
OHC
CHO
condenser were charged with boronic acid 3 (1 mmol), Na2CO3 (1
mmol), Pd(eao)2-2 (0.01 mmol) and toluene (4 mL). Then the
mixture was stirred at reflux for 6 h. After cooling down to room
temperature, 5 mL of water was added, and the resulting mixture
was extracted with ethyl acetate (3 × 10 mL). The organic phases
were combined and washed with small amount of water for three
times. After drying with anhydrous Na2SO4, the solid was filtered
and the solvent in the acquired solution was removed under
reduced pressure. The resulting residue was subjected to flash
silica gel column chromatography to provide pure products with
the elution petroleum ether.
83%
4bf
,
4bh
71%
86%
,
,
Scheme 3a,b Pd(eao)2-catalyzed boronic acid homo-coupling reactions.
aGeneral conditions: 6 (1 mmol), Na2CO3 (2 mmol), Pd(eao)2-2 (2 mol%) in
toluene (4 mL), stirred at reflux for 6 h. bYields of isolated product.
Conclusions
In conclusion, we have synthesized
a series of new
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
mono-nuclear Pd(II)-enaminone complexes termed Pd(eao)2 and
characterized they structures. These new Pd(eao)2 reagents have
been found as excellent catalysts in catalyzing the Suzuki-Miyaura
cross coupling reactions as well as boronic acid homo-coupling
reactions with broad substrate tolerance and product yields at low
catalyst loading. Besides providing one more example on
sustainable and scalable Suzuki biaryl synthesis, the discovery on
these stable new Pd(eao)2 reagents provides valuable Pd(II)
catalyst candidates in the catalysis of more diverse and important
organic reactions. More diverse applications of such Pd(eao)2
catalyst in organic synthesis are yet in progress in the lab.
Acknowledgement
This work is financially supported by National Natural Science
Foundation of China (21861019) and the Education Department
of Jiangxi Province (GJJ170213). The authors also thank Prof. Dr.
Fangfang Pan in the College of Chemistry, Central China Normal
University for his kind help in analysing the crystallographic data.
Experimental
References
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mmol) and MeCN (4 mL). The mixture was heated up to 40 oC, and
stirred at the same temperature for 12 h. After cooling down to
room temperature, 5 mL of water was added, and the resulting
mixture was extracted with ethyl acetate (3 × 15 mL). The organic
phases were combined and washed with small amount of water
for three times. After drying with anhydrous Na2SO4, the solid was
filtered and the solvent in the acquired solution was removed
under reduced pressure. The resulting residue was subjected to
flash silica gel column chromatography to provide pure products
with the elution of mixed petroleum ether/ethyl acetate (v/v =
5:1).
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Chin. J. Chem. 2019, 37, XXX－XXX
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Enaminone-Pd(II) Complexes Synthesis and Catalytic Suzuki-Miyaura Coupling
Chin. J. Chem.
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This article is protected by copyright. All rights reserved.

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CCDC 1943349 contains full crystallographic data for the compound
Pd(eao)2-1.
(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
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www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Enaminone-Pd(II) Complexes Synthesis and Catalytic Suzuki-Miyaura Coupling
Chin. J. Chem.
Entry for the Table of Contents
Page No.
Synthesis of Enaminone-Pd(II) Complexes and
Their Application in Catalysing Aqueous
Suzuki-Miyaura Cross Coupling reaction
R
H
Ar
Br/Cl
Ar'
N
O
O
N
Ar
Ar'
=
Pd
H
R
B(OH)2
0.5 mol% Pd-cat.
Pd(eao)2
water/PEG 400
Ar
Ar
Pd(eao)2
Ar
2-1
CCDC 1943349)
(
Ar
B(OH)2
Pd(eao)
Ar
*
*
*
*
=
Ar'
heteroaryl
cross
Extraordinary low Pd-loading
Excellent substrate tolerance
aryl,
2 mol% Pd-cat.
coupling
Acqueous
A series of unprecedented Pd(II)-enaminone complexes, termed Pd(eao)2 have been synthesized
and characterized, these Pd(II)-catalysts have been identified as excellent catalysts for the
Suzuki-Miyaura reaction featuring broad application scope and sustainability in catalysis.
Leiqing Fu, Xiaoji Cao, Jie-Ping Wan,* Yunyun
Liu*
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.