Cationic Pd(II)/bipyridine-catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carboxylic acids in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2018.02.013

An in-situ generated cationic Pd(II)/bipyridine-catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carboxylic acids in water was developed and optimized. For most substrates, nearly quantitative yields were given, and the products can be purified by simple washing without column chromatography. The reaction can be scaled up to 1.0 g easily with excellent yields. Also the loading of catalyst can be lowered to 1.0 mol% with modest yields, and the reaction provided a mild and easy way to synthesize β-disubstituted carboxylic acids.

Full text of DOI:10.1016/j.tetlet.2018.02.013

Accepted Manuscript
Cationic Pd(II)/Bipyridine-Catalyzed Conjugate Addition of Arylboronic Acids
to α,β-Unsaturated Carboxylic Acids in Aqueous Media
Yuxin Ni, Kaixuan Song, Kai Shen, Zhenyu Yang, Rui Liu, Shaohui Lin,
Qinmin Pan
PII:
S0040-4039(18)30170-9
https://doi.org/10.1016/j.tetlet.2018.02.013
TETL 49698
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
14 December 2017
5 February 2018
6 February 2018
Please cite this article as: Ni, Y., Song, K., Shen, K., Yang, Z., Liu, R., Lin, S., Pan, Q., Cationic Pd(II)/Bipyridine-
Catalyzed Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Carboxylic Acids in Aqueous Media,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.013
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Cationic Pd(II)/Bipyridine-Catalyzed Conjugate Addition of
Arylboronic Acids to α,β-Unsaturated Carboxylic Acids in Aqueous
Media
Yuxin Ni, Kaixuan Song, Kai Shen, Zhenyu Yang, Rui Liu, Shaohui Lin*, Qinmin
Pan*
State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Design and
Application, Key Laboratory of Organic Synthesis of Jiangsu Province, Green Polymer and Catalysis Technology Laboratory (GAPCT), College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, 199 Ren’ai Road, Suzhou 215123, P. R. China
Email: linshaohui@suda.edu.cn; qpan@suda.edu.cn
Abstract
An in-situ generated cationic Pd(II)/bipyridine-catalyzed conjugate addition of arylboronic acids to ,-unsaturated carboxylic acids in water was
developed and optimized. For most substrates, nearly quantitative yields were given, and the products can be purified by simple washing without
column chromatography. The reaction can be scaled up to 1.0 g easily with excellent yields. Also the loading of catalyst can be lowered to 1.0 mol%
with modest yields, and the reaction provided a mild and easy way to synthesize -disubstituted carboxylic acids.
Keywords:
Cationic Pd(II)/Bipyridine
Aqueous Media
Arylboronic acid
Unsaturated carboxylic acid
Conjugate addition
The conjugate addition of organometallic reagents to ,-unsaturated comounds in the presence of transition metal catalysts is a useful
strategy to construct carbon-carbon bonds.1 Organocopper reagents have been used in conjugate addition2, for which Corey’s group gave the
first report.3 Meanwhile, Hayashi developed the highly efficient Rh(I)-catalyzed asymmetric conjugate addition of arylboronic acids to a variety
of ,-unsaturated compounds.1b, 1e, 4 However, Cu(I)-catalyzed conjugate addition is limited to only alkylation, and Rh(I)-catalysts are very
expensive. Relatively, Pd(II)-catalyzed conjugate addition is more economic and practical but rarely surveyed.5-10 In Uemura6 and Miyaura’s7
pioneering research, they developed Pd(II)-catalyzed conjugate addition of organoboron reagents to enones and enals, which sparked scientist’s
inspiration of conjugate addition with Pd(II)-catalysis. In the previous decade, our group has been concentrating on Pd(II)-catalysis with
bidentate nitrogen compounds as ligands8. We have developed a series of Pd(II)/bipyridine(bpy)-catalyzed conjugate additions of arylboronic
acids to ,-unsaturated ketones, aldehydes, esters8a-8c and amides,8e under mild and efficient ambient conditions. With this methodology,
quaternary carbon centers were built firstly by conjugate addition of arylboronic acids to ,-disubstituted enones via cationic Pd(II)/bpy-
catalysis.8d At the same time, Minnaard finished Pd(II)-catalyzed asymmetric conjugate addition of arylboronic acids to enones.9 And Stoltz’s
group used chiral pyridinooxazoline ligands to construct highly enantioselective quaternary stereocenters.10 Also the mechanism of this reaction
has been explored.11 In our recent research, the Pd(OAc)2/bpy-catalyzed conjugate addition of arylboronic acids to ,-unsaturated carboxylic
acids and -disubstituted unsaturated carboxylic acids has been realized.8f Actually, no report of conjugate addition of arylboronic acids to ,-
unsaturated carboxylic acids was found in Pd(II)-catalysis before our research, and the only publication found in Rh(I)-catalysis was by Breit12,
in which acrylic acid was the only reactive substrate. In our reaction, good yields were obtained with Pd(OAc)2/bpy in HOAc. As arylboronic
acids and ,-unsaturated carboxylic acids are all water soluble, and the reaction is insensitive to air and moisture, it’s highly promising to
perform this reaction in water. Compared with organic solvents, water has many advantages such as natural abundance, low cost, simple
operation, synthetic efficiency.13 In fact, we have reported Pd(II)/bpy-catalyzed conjugate addition of arylboronic acids to ,-unsaturated
carbonyl compounds in aqueous media8b in 2006, in which the presence of surfactants was key to improve the yields. In this case, the direct
conjugate addition to ,-unsaturated carboxylic acids is rare and highly efficient, which would avoid the use of excess reactive organometallic
reagents and the neutralizatoin step during work-up.14 Performing the reaction in water efficiently could simplify the conditions as far as
possible.
Then we tried this reaction in pure water, with phenylboronic acid 1a and trans-cinnamic acid 2a as starting materials, Pd(OAc)2/bpy as the
o
catalysts (Scheme 1). The reaction was running for 2 days at 60 C, and about 80% of conjugate addition product was isolated (Table 1, entry
1). We thought it might be the poor solubility of Pd(OAc)2 in water that caused incomplete starting materials conversion.
Scheme
1.

2
Tetrahedron Letters
To avoid the use of surfactants to improve the materials solubility as in our previous publication,8b we tried highly water-soluble cationic
-
palladium catalyst [Pd(bpy)(μ-OH)]22+2NO3 in this reaction (Table 1, entry 2). With weaker coordinating counter anions, cationic Pd(II) is
easier to achieve transmetallation and alkenes insertion than neutral Pd(II) species,15 which was also extensively used in copolymerization of
alkenes,15a,16 C-H activations17 and other C-C bond formations.18 Surprisingly, the reaction gave a complete conversion in only 10 h which was
much faster than with Pd(OAc)2/bpy in H2O (Table 1, entry 1) or HOAc8f, and a 98% yield was given. At the same time, it was found that the
product was precipitated in cold water, so the pure product could be isolated simply by filtration and washing, and column chromatography
could be avoided. At this point, the conjugate addition of arylboronic acids to ,-unsaturated carboxylic acids in pure water has been realized.
Since the preparation of this cationic palladium is a multi-step synthesis and the yield is very low, we tried to prepare the cationic palladium in-
situ in this reaction, and actually this methodology has been used successfully in our previous work of nucleophilic addition to imines.8f Then
o
PdCl2-bpy and AgNO3 were directly mixed in reaction at 60 C, and this method afforded a 96% isolation yield (Table 1, entry 4). So in our
optimized conditions, the aforehand preparation of cationic palladium is unnecessary and the purification is very simple. All the reaction
components were air-stable and mixed in water, and the products could be isolated by filtration. In the control experiment, no reaction
happened in the absence of AgNO3 (Table 1, entry 6). For the temperature effect, no product was observed at 40 oC (Table 1, entry 3). At 80 oC,
palladium black was observed (Table 1, entry 5) although an excellent yield could be also obtained. Then, we tried to scale up the cinnamic
acid to 1.0 g with only 2.5 mol% catalyst loading, and the reaction gave a 95% yield after 2 days (Table 1, entry 7). When the catalyst loading
was decreased to 1.0 mol%, a 70% yield was still given after 3 days (Table 1, entry 8). Compared with the conjugate addition in organic
solvents, the reaction carried in water is much faster, and the reaction temperature is lower.8f
With this optimal conditions, we started to explore the scope of different arylboronic acids and ,-unsaturated carboxylic acids (Table 2).
Firstly, arylboronic acids with electron donating group were investigated. The best yield was obtained with p-tolyboronic acid (Table 2, entry
2). The yield decreased sharply when p-methoxyphenylboronic acid was used (Table 2, entry 3), it is because the electron donating groups on
phenyl ring accelerate the Pd(II)-catalyzed hydrolyzation of arylboronic acid in water. And the o-methoxyphenylboronic acid also gave a very
low yield (Table 2, entry 4). Meanwhile, m-methoxyphenylboronic acid could gave a modest yield (Table 2, entry 5) in which m-
methoxyphenyl group is less electron donating. In the case of p-fluorophenylboronic and p- chlorophenylboronic acid with electron
withdrawing groups, the yields were nearly quantitative (Table 2, entries 6 and 7). And m-chlorophenylboronic acid and o-chlorophenylboronic
acid also tend to proceed completely to give excellent yields (Table 2, entries 8 and 9). But for the less reactive 2-fluoro-5-pyridylboronic acid,
the reaction was very slow and yield was also low, and the reactants still could be observed after two days (Table 2, entry 10). 1-
naphthylboronic acid (Table 2, entry 11) gave a low yield (44%) after 48 h for its steric hinderance. For 2-naphthyboronic acid (Table 2, entry
12), the reaction gave a 92% yield due to smaller steric hindrance. For the highly sterically hindered phenanthrylboronic acid, no reaction could
be observed (Table 2, entry 13). Also the alkenylboronic acid ((E)-1-pentenylboronic acid) was tested, and no expected product was detected
with only palladium black formation (Table 2, entry 14). Then, we screened a series of ,-unsaturated carboxylic acids with different
substitutes on -aryl groups, and whether for the carboxylic acids with electron donating groups (Table 2, entries 15 and 16) or electron
withdrawing groups (Table 2, entries 17 and 18), excellent to quantitative yields were given in all examples. In the case of -alkyl-substituted
unsaturated carboxylic acids (Table 2, entry 19), 55% of the conjugate addition product was isolated; and for acroleic acid (Table 2, entry 20),
50% yield can be obtained, meanwhile some 3,3-diphenylpropanoic acid 3aa can also be detected in this reaction, which was supposed to be
formed by the subsequent conjugate addition to the Heck-type side product (cinnamic acid).8a
In summary, we have developed a convenient and economic Pd(II)/bpy catalyzed conjugate addition of arylboronic acid to α, β-unsaturated
carboxylic acid in aqueous media. Compared with the reaction in organic solvents, water accelerates the conjugate addition and gave a green
and safe option. This reaction can be scaled up to 1.0 g easily, and for most substrates, excellent to quantitative yields were given, and the
products can be purified by simple filtration and washing.
Table 1. Pd(II)/bpy catalyzed conjugate addition of phenylboronic acid to cinnamic acida
Temperature (oC)
Entry
Catalyst
Yield (%)b
Time（h）
1
2
3
4
5
6
7
8
Pd(OAc)2/bpy
60
60
48
10
48
10
10
48
48
72
80
98
[Pd(bpy)(μ-OH)]22+2NO3
PdCl2-bpy/AgNO3
PdCl2-bpy/AgNO3
PdCl2-bpy/AgNO3
PdCl2-bpy
-
，
40
60
80
60
60
60
trace
96
96
trace
95c
70d
PdCl2-bpy/AgNO3
PdCl2-bpy/AgNO3
aReaction condition: cinnamic acid (1.0 mmol), phenylboronic acid (2.0 mmol), Pd(II) (0.05 mmol, 5.0 mol%), AgNO3 (0.1 mmol) in water (2
mL).
bIsolated yield.
ccinnamic acid (1.0 g, 6.75 mmol), phenylboronic acid (13.5 mmol), Pd(II) (0.17 mmol, 2.5 mol%), AgNO3 (0.34 mmol) in water (8 mL).
dcinnamic acid (5.0 mmol), phenylboronic acid (10.0 mmol), Pd(II) (0.05 mmol, 1.0 mol%), AgNO3 (0.1 mmol) in water (5 mL).

Table 2. Cationic Pd(II)/bpy catalyzed conjugate addition of arylboronic acids to α, β-unsaturated carboxylic acidsa
Yield（%
）
Yield（%
）
Time
(h)
Time
(h)
Entry
1
Substrate
Product
Entry
11
Substrate
Product
b
b
10
96
96
48
44
92
2
3
12
12
13
12
48
48
36
40
--
--
48
48
--
--
4
5
14
15
12
70
12
96
6
7
12
12
96
95
16
17
12
12
90
95
8
9
12
12
48
97
95
30
18
19
20
12
48
48
90
55
10
50c
aReaction conditions: arylboronic acid (2.0 mmol), α, β-unsaturated carboxylic acid (1.0 mmol), PdCl2-bpy (0.05 mmol), AgNO3 (0.1 mmol) in
water (2 mL) at 60 oC; Cinnamic acid as the α, β-unsaturated carboxylic acid substrate for entries 1-14; Phenylboronic acid as the arylboronic
acid substrate for entries 15-20.
bIsolated yield.
cSome 3,3-diphenylpropanoic acid can also be found in this reaction.

2
Tetrahedron
Acknowledgments
We gratefully acknowledge the National Natural Science Foundation of China, Specialized Research Fund for the Doctoral
Program (SRFDP) of Higher Education (No. 20113201120006), the Priority Academic Program Development (PAPD) of Jiangsu
Higher Education Institutions, Soochow University Funds (Nos. 14109001, Q410900510) and Suzhou Industrial Park Fund for
financial support.
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4
Tetrahedron
Highlights
1. Highly efficient Pd(II)-catalyzed conjugate addition in pure water.
2. Easily scaled up 1.0 g. Products easily purified by filtration without columns.
3. Catalyst loading could be lowered to 1.0 mol% with modest yields.
4. Reaction is air and moisture insensitive.
5. 11 of 20 examples yielded >90% with high functional groups tolerance.

5
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Cationic Pd(II)/Bipyridine-Catalyzed Conjugate Addition
of Arylboronic Acids to α,β-Unsaturated Carboxylic
Acids in Aqueous Media
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Yuxin Ni, Kaixuan Song, Kai Shen, Zhenyu Yang, Rui Liu, Shaohui Lin*, Qinmin Pan*