Pd(II)/Bipyridine-Catalyzed Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Carboxylic Acids. Synthesis of β-Quaternary Carbons Substituted Carboxylic Acids

Article abstract of DOI:10.1021/acs.joc.7b01248

Pd(II)/bipyridine-catalyzed conjugate addition of arylboronic acids to α,β-unsaturated carboxylic acids (including β,β-disubstituted acrylic acids) was developed and optimized, which provided a mild and convenient method for the highly challenging synthesis of β-quaternary carbons substituted carboxylic acids.

Full text of DOI:10.1021/acs.joc.7b01248

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Article
Pd(II)/Bipyridine-Catalyzed Conjugate Addition of Arylboronic
Acids to #,#-Unsaturated Carboxylic Acids. Synthesis
of #-Quaternary Carbons Substituted Carboxylic Acids.
Rui Liu, Zhenyu Yang, Yuxin Ni, Kaixuan Song, Kai Shen, SHAOHUI LIN, and Qinmin Pan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01248 • Publication Date (Web): 12 Jul 2017
Downloaded from http://pubs.acs.org on July 12, 2017
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ABSTRACT: Pd(II)/bipyridine catalyzed conjugate addition of arylboronic acids to a,b-
unsaturated carboxylic acids (including b,b-disubstituted acrylic acids) was developed and
optimized, which provided a mild and convenient method for the highly challenging synthesis of
b-quaternary carbons substituted carboxylic acids.
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Introduction
Transition metals catalyzed conjugate addition of organometallic reagents to a,b-unsaturated
compounds are very powerful strategies to prepare b-substituted carbonyl molecules.1,2 Feringa
developed Cu(I)-catalyzed conjugate addition of alkylmetallic reagents to realize b-alkylation,3
and Hayashi built an elegant Rh(I)-catalyzed conjugate addition system with organoboron
compounds to different a,b-unsaturated electrophiles,1a,2c,4 in which perfect asymmetric
inductions were achieved. Compared with the well-documented Rh(I)-catalysis, Pd(II)-catalyzed
conjugate addition was relatively rare,5-8 and more economic. Uemura6e and Miyaura6d reported
the Pd(II)-catalyzed conjugate addition of organoboron reagents to enones and enals, which
started the Pd(II)-version in conjugate addition research.
In the previous decade, we published a series of Pd(II)/2,2‘-bipyridine(bpy)-catalyzed
conjugate addition of arylboronic acids to a,b-unsaturated carbonyl compounds,7,8d and the
electrophiles were expanded from enones and enals to inert a,b-unsaturated esters and amides.
This Pd(II)/bpy catalysis was oxygen and moisture stable, and high addition yields were usually
achieved under mild conditions. In 2010, we reported the first cationic Pd(II)/bpy-catalyzed
conjugate addition of arylboronic acids to b,b-disubstituted enones,8d and quaternary carbon
centers were successfully constructed with this highly efficient method. Stoltz finished the
asymmetric version of this reaction with chiral pyridinooxazoline ligands,8a,8c and highly
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enantioselective quaternary stereocenters were constructed. Also the mechanism of this reaction
was investigated with computational methods.8a, 9
7
8
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In our systematic investigation of Pd(II)-catalyzed conjugate addition, it‘s found that in
literature most substrates were focused on the a,b-unsaturated carboxylic derivatives, and a,b-
unsaturated carboxylic acids were rarely studied. It might be the acidity of carboxylic acids
which prevented its application. Actually, the only report we found about conjugate addition of
arylboronic acids to a,b-unsaturated carboxylic acids was a Rh(I)-catalytic reaction by Breit,10
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and acrylic acid was the only reactive substrate. a- and b-substituted a,b-unsaturated carboxylic
acids were inert to the above Rh(I)-catalytic reaction. There were some other reports about
conjugate addition of organolithium reagents to a,b-unsaturated carboxylic acid,11 in which
excess and highly flammable organolithium reagents were used and an acidification process
could not be avoided to get the b,b-disubstituted carboxylic acid products. In a Pd(0)-catalyzed
one pot synthesis of 3-arylpropanoic acid,12 aryl iodide and acrylic acid were used as the starting
materials, in which a hydrogenation was followed. Also the Rh(I)-catalyzed hydrogenation of
b,b-disubstituted acrylic acids could be used to synthesize b,b-disubstituted carboxylic acids.13
Since our Pd(II)-bipyridine catalysis could be well performed in acetic acid,7c we thought it‘s
highly consequential to expand the application of this methodology to a,b-unsaturated
carboxylic acid and even b,b-disubstituted acrylic acids. Hopefully b-arylpropionic acids can be
synthesized directly, which avoided the hydrolysis step of carboxylic derivatives. Meanwhile, b-
arylpropionic acids have been studied and reported as potent agonists and antagonists in
medicinal chemistry. 14
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Results and discussion
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Cinnamic acid was selected as the substrate to probe the reaction in air with HOAc/THF/H2O
as the solvent, which was the optimal solvent in our previous research7c, and the conjugate
addition was not observed at room temperature (Table 1, entry 1). With 3.0 equiv of
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phenylboronic acid loading at 40 C, 30% yield of the conjugate addition product was isolated
after 24 h (Table 1, entry 2). Inspired by this initial result, the temperature tests showed that 80
oC was optimal which gave a 98% yield after 24 h (Table 1, entries 3 and 4). At higher
temperature (100 oC), palladium precipitate was observed in the reaction (Table 1, entry 5). Also
we tried to decrease the loading of arylboronic acids to 2.0 equiv, and the isolation yield was still
up to 97% (Table 1, entry 6). The b-diphenylpropionic acid (3aa) product can be precipitated in
water, and then extracted by dichloromethane to remove inorganic byproducts. Thus column
chromatography was unnecessary in its purification process, and NMR-pure product was
obtained with an almost quantitative yield. Neutral solvents (THF, toluene, methanol and acetone)
were also surveyed, and only 40~58% yields were given (Table 1, entries 7-10), which means the
acidic solvent was crucial to the complete conversion of a,b-unsaturated carboxylic acid.
Table 1. Pd(OAc)2/Bipyridine-Catalyzed Conjugate Addition of Phenylboronic Acid to
Cinnamic Acida
O
Ph
O
Cat. Pd(OAc)2/bpy
HOAc/THF/H2O
OH
PhB(OH)2 +
Ph
Ph
OH
2a
3aa
1a
entry
solvent
temp (oC)
yield (%)b
1
2
HOAc/THF/H2O
HOAc/THF/H2O
rt
0c
40
30c
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HOAc/THF/H2O
60
80
100
80
80
80
80
80
81c
98c
82c
97
HOAc/THF/H2O
HOAc/THF/H2O
HOAc/THF/H2O
THF/H2Od
5
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6
7
40
8
Toluene/H2Od
MeOH/H2Od
58
9
53
10
Acetone/H2Oe
57
aReaction conditions: Pd(OAc)2 (0.05 mmol, 5 mol%), bpy (0.10 mmol, 10 mol%),
phenylboronic acid (2.00 mmol), cinnamic acid (1.00 mmol), HOAc/THF/H2O = 1.0 mL/2.0 mL/
0.6 mL, 24 h. bIsolated yield. cphenylboronic acid (3.00 mmol). dSolvent/H2O = 2.0 mL/0.6 mL.
eSolvent/H2O = 0.5 mL/2.5 mL.
With this optimal conditions, we started to explore the scope of different arylboronic acids and
a,b-unsaturated carboxylic acids. Firstly, a series of arylboronic acids were subjected to the
optimal conditions with cinnamic acid as the substrate. It‘s found that most arylboronic acids
with electron-donating groups (p-tolyl) and electron-withdrawing groups gave excellent yields
(Table 2, entries 1-2, 4-7). In the case of p-methoxyphenylboronic acid (Table 2, entry 3), the
yields were decreased to 55% due to the fast hydrolysis of arylboronic acid with electron-
donating groups in the presence of Pd(II)-bpy, which was very similar to our previous results.7c
In the solvent of acetone/H2O, the yield was improved to 76% (Table 2, entry 3). When the
chloro group was substituted on p-, o- or m-positions of arylboronic acid (Table 2, entries 4-6),
good to excellent yields were achieved. p-Fluorophenylboronic acid gave 95% yield of product
(Table 2, entry 7), and the isolated yield of 2-naphthylboronic acid reaction was nearly
quantitative (Table 2, entry 8). In the presence of (E)-2-phenylvinylboronic acid, the reaction
gave a disordered mixture with Pd metal precipitate (Table 2, entry 9). And for 2-furylboronic
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acid, no expected reaction was observed with only fast hydrolysis of 2-furylboronic acid (Table 2,
entry 10). It revealed that this catalytic conjugate addition is insensitive to most arylboronic acids.
Then, phenylboronic acid was set as the invariable, and more a,b-unsaturated carboxylic acids
were investigated. Different substitutes were introduced into the phenyl ring of cinnamic acid,
and the reactions kept very high isolated yields (Table 2, entries 11-16). Even for 3-(p-
nitrophenyl)propenoic acid, the reaction was proceeded smoothly with a 94% yield (Table 2,
entry 15). For 3-(o-nitrophenyl)propenoic acid (Table 2, entry 16), the yield decreased to 70%.
More importantly, all the conjugate addition products of cinnamic acid series can be purified by
simple water washing and solvent extractions without column chromatography. This strategy
will be highly simple and efficient for the synthesis of b-diarylpropionic acids. In the case of
crotonic acid (Table 2, entry 17), an 82% yield of conjugate addition was obtained. For acrylic
acid, 3,3-diphenylpropanoic acid (3aa) was isolated as the main product (Table 2, entry 18),
which was also similar to our previously reported conjugate addition result of ethyl acrylate.7c
It‘s a diarylation product of acrylic acid with a high yield. For a-methylcinnamic acid, no
reaction was observed after 24 h (Table 2, entry 19). The substrates screening demonstrated this
Pd(II)/bipyridine-catalyzed conjugate addition is mild and highly functional groups-tolerable,
and most examples produced nearly quantitative yields of conjugate addition products.
Table 2. Pd(OAc)2/Bipyridine-Catalyzed Conjugate Addition of Arylboronic Acids to
a,b-Unsaturated Carboxylic Acids a
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O
Ar
O
Cat. Pd(OAc)2/bpy
ArB(OH)2
+
HOAc/THF/H2O
80 oC
R
OH
R
OH
a,b-unsaturated
carboxylic acid
entry
ArB(OH)2
product
yield (%)b
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B(OH)2
O
Ph
O
5
1
2
97
97
Ph
Ph
OH
OH
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Ph
OH
3aa
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B(OH)2
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O
O
O
O
O
O
1b
Ph
OH
OH
OH
3ba
OMe
B(OH)2
55c
76d
3
4
Ph
Ph
OH
OH
2a
2a
1c
Ph
Ph
OMe
3ca
Cl
B(OH)2
96
1d
Cl
3da
B(OH)2
Cl
O
O
Cl
O
5
6
85
95
Ph
Ph
OH
OH
2a
2a
Ph
OH
1e
3ea
Cl
B(OH)2
O
Ph
OH
Cl
1f
3fa
F
B(OH)2
O
7
95
Ph
OH
O
2a
1g
Ph
OH
F
3ga
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B(OH)2
5
6
7
8
NO2
O
O2N
Ph
O
16
70
OH
OH
3ag
2g
2h
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1a
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B(OH)2
O
Ph
O
17
18
19
82
95
OH
OH
OH
3ah
1a
B(OH)2
O
Ph
O
Ph
OH
O
3aa
2i
1a
B(OH)2
Ph
OH
---
NR
2j
1a
aReaction conditions: Pd(OAc)2 (0.05 mmol, 5 mol%), bpy (0.10 mmol, 10 mol%), arylboronic
acid (2.00 mmol), a,b-unsaturated acid (1.00 mmol), HOAc/THF/H2O = 1.0 mL/2.0 mL/ 0.6 mL,
o
b
c
d
80 C, 24 h. Isolated yield. 4.0 equiv of arylboronic acid. 2.0 equiv of arylboronic acid,
Acetone/H2O = 0.5 mL/2.5 mL as solvent. Disordered reaction with Pd precipitate. fNo reaction
e
with fast hydrolysis of 2-furylboronic acid.
With these results in hand, we started to survey the reactions of b,b-disubstituted acrylic acids.
Up to now, all the b,b-disubstituted electrophiles used in Pd(II)-catalyzed conjugate addition of
arylboronic acids were limited to enones, and b,b-disubstituted acrylate has been proved to be
unreactive to cationic Pd(II) catalysis in our previous report.8d There were only very few
examples to achieve the Rh(I)-catalyzed conjugate addition to b,b-disubstituted substrates.15 The
conjugate addition to b,b-disubstituted acrylic acids is highly challenging, and would provide a
highly efficient one-step preparation method for b-quaternary carbons substituted carboxylic
acids.
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Scheme 1. Pd(OAc)2/bpy-Catalyzed Conjugate Addition of Phenylboronic Acid to 3,3-
Dimethylacrylic Acid
7
8
9
5 mol% Pd(OAc)2
O
O
10 mol% bpy
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60
PhB(OH)2 +
Ph
OH
45%
OH
HOAc/THF/H2O
60 oC, 48 h
1a
5aa
4a
Firstly, 3,3-dimethylacrylic acid (4a) was chosen as the substrate for its smaller steric
hindrance to probe the conjugate addition (Scheme 1). The reaction was firstly performed in
o
acetic acid at 60 C, with Pd(OAc)2/bpy as catalysts. Surprisingly, 45% yield of 3-methyl-3-
phenylbutanoic acid (5aa) was isolated as the conjugate addition product after 48 h, which was
1
13
confirmed by H, C NMR and Mass spectra. Inspired by this initial result, (E)-3-phenylbut-2-
enoic acid (4b) as a typical b,b-disubstituted acrylic acid was prepared and subjected to different
conditions to optimize the reaction.
Table 3. Pd(II)/bpy-Catalyzed Conjugate Addition of Phenylboronic Acid to (E)-3-
Phenylbut-2-enoic Acida
Me
O
Cat. Pd(II)/bpy
O
Ph Me
Ph
PhB(OH)2
+
Ph
OH
OH
4b
1a
5ab
temp
(oC)
60
Time
(h)
72
yield
(%)b
34c,d
entry
1
catalyst
solvent
Pd(OAc)2/bpy
HOAc/THF/H2O
2+
2
3
4
[Pd(bpy)(m-OH)]2 2OTf-
CH3OH
60
80
60
72
72
72
tracee
0e
2+
[Pd(bpy)(m-OH)]2 2OTf-
CH3OH
2+
[Pd(bpy)(m-OH)]2 2OTf-
CH3NO2
0e
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2+
5
[Pd(bpy)(m-OH)]2 2OTf-
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
CH3NO2
HOAc/THF/H2O
HOAc/THF/H2O
CH3OH
80
40
80
60
60
60
60
60
60
60
60
60
60
60
60
60
72
72
72
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72
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72
72
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72
48
48
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48
48
48
0e
tracec,d
22c,d
24c
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8
9
t-BuOH
20c
10
11
12
13
14
15
16
17
18
19
20
CH3NO2
31c
CH3NO2
40c,f
58c,d,f
90d,f,g
91 f,g
86c
HOAc/THF/H2O
HOAc/THF/H2O
CH3NO2
H2O
2+
[Pd(bpy)(m-OH)]2 2OTf-
H2O
70e
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
Pd(OAc)2/bpy
H2O/Acetone
H2O/CH3OH
H2O/THF
96c,h
89c,h
90c,h
20c
Acetone
aReaction conditions: phenylboronic acid (1.00 mmol), (E)-3-phenylbut-2-enoic acid (0.50
b
c
mmol). Isolated yield. Pd(OAc)2 (0.025 mmol, 5 mol%), bpy (0.05 mmol, 10 mol%).
dHOAc/THF/H2O = 1.0 mL/2.0 mL/0.6 mL. [Pd(bpy)(m-OH)]2 2OTf- (0.0125 mmol, 5 mol%
Pd(II)). f Phenylboronic acid (1.50 mmol). gPd(OAc)2 (0.050 mmol, 10 mol%), bpy (0.10 mmol,
20 mol%). hH2O/solvent = 2.5 mL/0.5 mL.
e
2+
Compared with 3,3-dimethylacrylic acid (4a), (E)-3-phenylbut-2-enoic acid (4b) was much
less reactive, and the reaction in HOAc/THF/H2O (Table 3, entry 1) only gave a 34% yield after
3 days, with most starting material 4b remained. It means the conjugate addition of arylboronic
acids to b,b-disubstituted acrylic acids was highly challenging for the steric hindrance at b
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position and low reactivity of substituted acrylic acids. As cationic Pd(II) with bpy ligand has
been proved to be a highly reactive catalyst for the conjugate addition to b,b-disubstituted
enones in MeOH,8d 4b was tested under cationic Pd(II) conditions in MeOH (Table 3, entries 2,
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o
3). Unfortunately, only trace of the target product was detected at 60 C after 3 days, and
o
completely no conjugate addition product was observed at 80 C. CH3NO2 was a very good
solvent for cationic Pd(II)-catalyzed nucleophilic addition of arylboronic acids to unsaturated
electrophiles,16 so we ran this reaction in CH3NO2, and no expected product could be detected
(Table 3, entries 4, 5). In all these entries with cationic Pd(II) catalysts (Table 3, entries 2-5),
very serious palladium black precipitate was observed with biphenyl formation, and the biphenyl
was supposed to be formed by reductive elimination of diarylpalladium(II) species, which were
generated by the double transmetallation between cationic Pd(II) and arylboronic acids. It‘s
speculated that the high Lewis acidity of cationic Pd(II) would accelerate the transmetallation,17
and it might not be good for the conversion of low reactive b,b-disubstituted acrylic acid
substrates. It‘s hypothesized that the slower transmetallation of neutral Pd(OAc)2/bpy with
phenylboronic acid would help the conjugate addition.
Then we turned back to the neutral Pd(OAc)2/bpy catalyst and examined the temperature
o
effects. In HOAc/THF/H2O, the reaction was hardly to go at 40 C (Table 3, entry 6), and the
reaction at 80 oC gave a lower yield (22%) than at 60 oC (34%) (Table 3, entries 1,7). Palladium
black was also observed at 80 oC, so 60 C was set as the optimal temperature. MeOH, t-BuOH
o
and CH3NO2 as solvents (Table 3, entries 8-10) were tried with neutral Pd(OAc)2/bpy catalyst,
and the reactions gave pretty low yields, but better than the results of cationic Pd(II).
Considering the long reaction time would cause extra arylboronic acid consumption due to its
protonolysis, 3 equiv of phenylboronic acid was loaded in CH3NO2 and HOAc/THF/H2O (Table
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3, entries 11, 12), the yields were improved to a modest 58% yield. Furthermore, we increased
the Pd(II) loading to 10 mol%, and conjugate addition yields in CH3NO2 and HOAc/THF/H2O
were improved to 90% and 91%. Although the complete conversion of b,b-disubstituted acrylic
acid could be achieved by high catalyst loading and excess arylboronic acid, but 10 mol% of
Pd(II) was unacceptable because it increased the cost and would restrict the application of this
method.
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In our research of Pd(II)/bpy-catalyzed conjugate addition of arylboronic acid to different
electrophiles, water has been used as solvent in the conjugate addition of arylboronic acids to
a,b-unsaturated carbonyl compounds,7b and reactions in aqueous solution have attracted so many
chemists‘ interest for the cost and environmental friendly concern.18 So we tried this reaction in
pure water with 5 mol% Pd(OAc)2 and 2 equiv of phenylboronic acid. Surprisingly, 86% yield of
conjugate addition product was isolated after 48 h (Table 3, entry 15), and for comparison,
cationic Pd(II) gave a 70% yield in water (Table 3, entry 16). It means the solvent effect played
an important role in this conjugate addition to b,b-disubstituted acrylic acids. Also some water-
miscible solvents were tried in the reaction, and it‘s found that acetone helped the complete
conversion of acid substrates to give a 96% yield (Table 3, entry 17). Also MeOH and THF
contributed to a little yield increase in water (Table 3, entries 18, 19). Meanwhile, the reaction in
pure acetone gave a very low yield (Table 3, entry 20). Thus we finished the optimization of this
challenging reaction with Pd(OAc)2/bpy catalysts and aqueous solvents, but these reaction
conditions was not suitable for the conjugate addition to b-monosubstituted acrylic acids (Table
1, entry 10).
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Table 4. Pd(OAc)2/bpy-Catalyzed Conjugate Addition of Arylboronic Acids to b,b-
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7
Disubstituted Acrylic Acidsa
8
9
R2
O
R1 R2
O
Cat. Pd(OAc)2/bpy
ArB(OH)2 +
R1
OH
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H2O/Acetone
60 oC
Ar
OH
a,b-unsaturated
entry
1
ArB(OH)2
product
yield (%)b
96
carboxylic acid
B(OH)2
O
Me
O
Ph Me
Ph
Ph
Ph
OH
OH
OH
1a
4b
Me
5ab
B(OH)2
O
5bb
2
3
4
5
91
26
98
98
1b
O
Me
4b
Ph
MeO
OH
Me
B(OH)2
Me
O
O
O
5cb
1c
Ph
Ph
Ph
OH
OH
OH
O
Me
4b
OMe
B(OH)2
Ph
OH
Cl
Me
5db
1d
O
Me
4b
Cl
B(OH)2
Ph
OH
F
Me
5gb
1g
O
Me
4b
F
Ph
OH
B(OH)2
Me
O
5hb
1h
6
7
90
98
Ph
OH
O
Me
4b
Ph
Ph
OH
Me
O
B(OH)2
5bb
OH
O
Me
1a
4c
Me
OH
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MeO
Me
O
B(OH)2
5cb
OH
8
9
97
95
O
4d
Me
1a
MeO
Ph
OH
F
Me
O
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B(OH)2
5gb
OH
O
Me
1a
4e
Me
F
Ph
O2N
OH
O
B(OH)2
OH
5af
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11
93
97
O
4f
Me
1a
O2N
Ph
OH
B(OH)2
O
O
O
Ph
Ph
OH
OH
OH
1a
4g
4h
5ag
B(OH)2
12
---
NR
1a
B(OH)2
O
O
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92
Ph
OH
OH
1a
4a
5aa
O
B(OH)2
Ph
OH
---
NR
1a
2j
aReaction conditions: Pd(OAc)2 (0.025 mmol, 5 mol%), bpy (0.05 mmol, 10 mol%),
phenylboronic acid (1.00 mmol), b,b-disubstituted acrylic acid (0.50 mmol), H2O/acetone = 2.5
mL/ 0.5 mL, in air, 60 oC, 48 h. bIsolated yield.
With the optimized conditions in hand, a series of arylboronic acids and b,b-disubstituted
acrylic acids were investigated to probe the scope of substrates. Firstly, p-tolylboronic acid gave
pretty good 91% yield (Table 4, entry 2). The yield of p-methoxyphenylboronic acid entry (Table
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4, entry 3) dropped to 26% due to the fast protonolysis of arylboronic acids with strong electron
donating groups. For the arylboronic acids with electron withdrawing groups (p-chloro and p-
fluoro), nearly quantitative yields of conjugate addition products were obtained (Table 4, entries
4, 5). For the sterically hindered 2-naphthylboronic acid (Table 4, entry 6), the reaction in
H2O/acetone still gave 90% yield of addition product, which demonstrated this strategy is a
powerful tool to construct the quaternary carbons for low reactive b,b-disubstituted acrylic acids.
Then the effect of substitutes on acrylic acids was investigated, and it revealed that the reaction
was highly tolerable to the functional groups on acrylic acids. For all the b-electron donating
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groups (p-tolyl and p-methoxyphenyl) substituted acids (Table 4, entries 7, 8), and b-electron
withdrawing groups (p-fluoro and p-nitrophenyl) substituted acids (Table 4, entries 9, 10), the
reaction gave very high yield, and especially the (E)-3-(4-Nitrophenyl)but-2-enoic acid (4f)
(Table 4, entry 10) still afforded a 93% yield. When the b-alkyl substitute was changed to ethyl
group, excellent (97%) yield was maintained (Table 4, entry 11). In the case of b-diphenyl
acrylic acid (4h), no reaction was observed with 4h unreacted. It could be explained that the high
stability and steric hindrance blocked the conjugate addition. For the relatively reactive 3,3-
dimethylacrylic acid (4a), the reaction in H2O/acetone gave a 92% yield. For a-methylcinnamic
acid, no reaction was observed in H2O/acetone either (Table 4, entry 14), which was the same as
in HOAc/THF/H2O (Table 2, entry 19).
In general, most arylboronic acids and b,b-disubstituted acrylic acids provided excellent
conjugate addition yields, and the H2O/acetone solvent was crucial to the complete substrates
conversion. A series of b-quaternary carbons substituted carboxylic acids were synthesized very
easily, and this reaction has very high potential in organic synthesis because the transformation
of carboxyl group to other functional groups can be realized conveniently.
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In conclusion, a highly efficient and air-stable Pd(OAc)2/ bpy-catalyzed conjugate addition of
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arylboronic acids to a,b-unsaturated carboxylic acids (including b,b-disubstituted acrylic acids)
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was developed, and a highly challenging one-step synthesis of b-quaternary carbons substituted
carboxylic acids was achieved in aqueous solution.
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EXPERIMENTAL SECTION
General information. All reagents and solvents were used without further purification, and all
the reactions were performed under air atmosphere. Commercially available arylboronic acids
were purchased from InnoChem Company (China), which were used as received. b,b-
Disubstituted acrylic acids19 and cationic Pd(II) [Pd(bpy)( m -OH)]2 2OTf- 16 were prepared
2+
according to literature. NMR spectra were recorded on an Agilent 400 MHz spectrometer,
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chemical shifts were calibrated by TMS (0.0 ppm for H NMR) or CDCl3 (77.0 ppm for C
NMR) as internal references. Infrared spectra were obtained on a Nicolet iS 10 machine. Mass
spectra were provided on Agilent 5973 machines. HRMS were performed on the Bruker
microTOF-Q III instrument (ESI).
General Procedure for the Conjugate addition of Arylboronic acid to cinnamic acid: To a
Schlenk tube with a cooling finger, phenylboronic acid (1a) (244.0 mg, 2.00 mmol), cinnamic
acid (2a) (148.0 mg, 1.00 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), bpy (15.6 mg, 0.10 mmol),
HOAc (1.0 mL), THF (2.0 mL) and H2O (0.6 mL) were added under air atmosphere. The
mixture was stirred and heated at 80 oC for 24 h until the substrate disappeared as monitored by
TLC. The solution was transferred into a flask, and the solvent was removed under vacuum. 5
o
mL water was added to the crude product and heated to 60 C for 5 min with stirring, and then
water was removed by filtration. This process was repeated, and the product was dissolved in 10
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mL CHCl3, dried by Na2SO4, filtered and concentrated under vacuum. 218.5 mg of 3,3-
diphenylpropionic acid (3aa) was isolated, with a 97% yield.
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3,3-Diphenylpropanoic acid (3aa).13 White solid (218.5 mg, 97%). mp = 152-153 oC. 1H NMR
(400 MHz, CDCl3) / 7.34 œ 6.95 (m, 10H), 4.45 (t, J = 8.0 Hz, 1H), 3.01 (d, J = 8.0 Hz, 2H). 13C
NMR (100 MHz, CDCl3) / 177.6, 143.2, 128.6, 127.6, 126.6, 46.6, 40.4. IR (KBr): ꢀ = 1697,
3026 cm-1; MS (ESI) m/z: 225 (M - H+).
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3-Phenyl-3-p-tolylpropanoic acid (3ba).13 White solid (233.0 mg, 97%). mp = 129-131 C. H
NMR (400 MHz, CDCl3) / 7.50 œ 6.91 (m, 9H), 4.48 (t, J = 8.0 Hz, 1H), 3.06 (d, J = 8.0 Hz, 2H),
13
2.29 (s, 3H). C NMR (100 MHz, CDCl3) / 177.7, 143.5, 140.3, 136.1, 129.3, 128.5, 127.5,
127.4, 126.5, 46.2, 40.5, 21.0. IR (KBr): ꢀ = 1708, 3026 cm-1; MS (ESI) m/z: 239 (M - H+).
3-(4-Methoxyphenyl)-3-phenylpropanoic acid (3ca).13 White solid (141.0 mg, 55%). mp = 118-
119 oC. 1H NMR (400 MHz, CDCl3) / 7.45 œ 7.06 (m, 7H), 6.97 œ 6.69 (m, 2H), 4.48 (t, J = 8.0
Hz, 1H), 3.76 (s, 3H), 3.05 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) / 177.8, 158.2,
143.6, 135.4, 128.6, 128.5, 127.5, 126.5, 114.0, 55.2, 45.8, 40.6. IR (KBr): ꢀ = 1707, 3028 cm-1;
MS (ESI) m/z: 255 (M - H+).
3-(4-Chlorophenyl)-3-phenylpropanoic acid (3da).13 White solid (250.1 mg, 96%). mp = 112-
113 oC. 1H NMR (400 MHz, CDCl3) / 7.46 œ 7.08 (m, 9H), 4.49 (t, J = 8.0 Hz, 1H), 3.05 (d, J =
13
8.0 Hz, 2H). C NMR (100 MHz, CDCl3) / 177.1, 142.7, 141.7, 132.4, 129.0, 128.8, 128.7,
127.5, 126.8, 46.0, 40.2. IR (KBr): ꢀ = 1709, 3028 cm-1; MS (ESI) m/z: 259 (M - H+).
3-(2-Chlorophenyl)-3-phenylpropanoic acid (3ea).13 White solid (221.3 mg, 85%). mp = 138-
139 oC. 1H NMR (400 MHz, CDCl3): / = 7.46 - 7.05 (m, 9H), 5.03 (t, J = 8.0 Hz, 1H), 3.06 (d, J
13
= 8.0 Hz, 2H); C NMR (100 MHz, CDCl3): / 176.9, 141.6, 140.5, 134.0, 130.0, 128.6, 128.2,
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127.9, 127.6, 127.0, 126.8, 42.8, 39.6 ; IR (KBr) ꢀ = 1701, 3028 cm-1; MS (ESI) m/z: 259 (M-
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-
H+); HRMS Calcd for C15H12ClO2 : 259.0531. Found: 259.0535.
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3-(3-Chlorophenyl)-3-phenylpropanoic acid (3fa). White solid (246.1 mg, 95%). mp = 101-
102 oC. 1H NMR (400 MHz, CDCl3): / = 7.34-7.07 (m, 9H), 4.49 (t, J = 8.0 Hz, 1H), 3.06 (d, J =
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8.0 Hz, 2H); C NMR (100 MHz, CDCl3): / 177.0, 145.3, 142.4, 134.4, 129.9, 128.8, 127.8,
127.5, 126.92, 126.89, 125.8, 46.3, 40.1 ; IR (KBr) ] = 1709, 3028 cm-1; MS (ESI) m/z: 259 (M-
H+); HRMS Calcd for C15H12ClO2 : 259.0531. Found: 259.0534.
-
3-(4-Fluorophenyl)-3-phenylpropanoic acid (3ga).13 White solid (231.6 mg, 95%). mp = 110-
112 oC. 1H NMR (400 MHz, CDCl3) / 7.47 œ 7.09 (m, 7H), 7.05 œ 6.84 (m, 2H), 4.50 (t, J = 8.0
Hz, 1H), 3.05 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) / 177.4, 161.5 (d, J = 162.0 Hz),
143.0, 138.9 (d, J = 2.0 Hz), 129.1 (d, J = 6.0 Hz), 128.7, 127.5, 126.8, 115.4 (t, J = 14.0 Hz),
45.9, 40.5. 19F NMR (375 MHz, CDCl3) / -116.3. IR (KBr): ꢀ = 1709, 3029 cm-1; MS (ESI) m/z:
243 (M - H+).
3-(2-Naphthyl)-3-phenylpropanoic acid (3ha).13 White solid (270.1 mg, 98%). mp = 120-121
oC. 1H NMR (400 MHz, CDCl3) / 7.89 œ 7.61 (m, 4H), 7.60 œ 7.06 (m, 8H), 4.68 (t, J = 8.0 Hz,
1H), 3.21 (dd, J = 16.0, 8.0 Hz, 1H), 3.15 (dd, J = 16.0, 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3)
/ 177.8, 143.1, 140.6, 133.4, 132.2, 128.6, 128.3, 127.8, 127.7, 127.5, 126.7, 126.4, 126.1, 125.7,
125.6, 46.6, 40.3. IR (KBr): ꢀ = 1707, 3055 cm-1; MS (ESI) m/z: 275 (M - H+).
3-(4-Nitrophenyl)-3-phenylpropanoic acid (3af). White solid (255.0 mg, 94%). mp = 123-124
oC. 1H NMR (400 MHz, CDCl3) / 8.24 œ 8.05 (m, 2H), 7.51 œ 7.09 (m, 7H), 4.63 (t, J = 8.0 Hz,
1H), 3.13 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) / 176.1, 150.7, 146.8, 141.5, 129.0,
128.6, 127.5, 127.3, 123.9, 46.4, 39.7. IR (KBr): ꢀ = 1709, 3028 cm-1; MS (ESI) m/z: 270 (M -
H+). HRMS Calcd for C15H12NO4 : 270.0763. Found: 270.0772.
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3-(2-Nitrophenyl)-3-phenylpropanoic acid (3ag). White solid (190.0 mg, 70%). mp = 150-151
oC. 1H NMR (400 MHz, CDCl3): / 7.82 - 7.74 (m, 1H), 7.56 - 7.47 (m, 1H), 7.39 - 7.19 (m, 7H),
5.22 (t, J = 8.0 Hz, 1H), 3.13 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): / 175.9, 149.8,
141.1, 137.4, 132.7, 129.3, 128.8, 127.7, 127.5, 127.1, 124.6, 40.4, 39.9 ; IR (KBr) ꢀ = 1712,
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3029 cm-1; MS (ESI) m/z: 270 (M - H+); HRMS Calcd for C15H12NO4 : 270.0772. Found:
270.0765.
3-Phenylbutyric acid (3ah).13 White solid (134.3 mg, 82%). mp = 36-38 C. H NMR (400
MHz, CDCl3) / 7.41 œ 7.09 (m, 5H), 3.38 œ 3.15 (m, 1H), 2.67 (dd, J = 16.0, 8.0 Hz, 1H), 2.57
(dd, J = 16.0, 8.0 Hz, 1H), 1.32 (d, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) / 178.6, 145.4,
128.5, 126.7, 126.5, 42.6, 36.1, 21.8. IR (KBr): ꢀ = 1701, 3041 cm-1; MS (ESI) m/z: 163 (M -
H+).
o
1
General Procedure of the Preparation of (E)-3-Phenylbut-2-enoic Acid (4b)19: Sodium
hydride (1.7g, 41.7 mmol, 1.5 equiv, 60% in mineral oil) was dissolved in THF (130 mL), and
triethyl phosphonoacetate (9.3g, 41.7 mmol, 1.5 equiv) was added dropwise to the suspension at
0°C, and stirred until gas evolution had ceased. Then acetophenone (3.3g, 27.8 mmol, 1.0 equiv)
in THF (10 mL) was added by syringe. The reaction was stirred at room temperature and
monitored by TLC. The reaction mixture was quenched with saturated aqueous NH4Cl solution.
The organic phase was separated, and the aqueous layer was extracted with EtOAc. The
combined organic phases were washed with saturated aqueous NaCl solution, dried over
anhydrous Na2SO4, and concentrated under vacuum pressure. Purification by silica gel
chromatography (PE:EA = 40:1 to 10:1) gave ethyl 3-phenylbut-2-enoate as an oil (5.1g, yield
98%).
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In a 50 mL round-bottom flask, ethyl 3-phenylbut-2-enoate (500.0 mg, 2.51 mmol) was placed,
EtOH (5.4 mL) added, and the reaction solution was stirred at room temperature, aqueous NaOH
solution (10%, 10.8 mL) added. The reaction was stirred until no raw material was monitored by
TLC. Then the mixture was acidified with HCl (1 N), then extracted with diethyl ether. The
combined organic phase was washed with saturated aqueous NaCl solution, dried over Na2SO4,
and concentrated under vacuum pressure. Purification by recrystallization (CH2Cl2/PE) produced
(E)-3-phenylbut-2-enoic acid (4b) (386 mg, yield 95%).
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(E)-3-Phenylbut-2-enoic acid (4b).13 1H NMR (400 MHz, CDCl3) / = 7.55-7.46 (m, 2H), 7.44-
7.34 (m, 3H), 6.18 (s, 1H), 2.61 (s, 3H).
(E)-3-(4-Tolyl)but-2-enoic acid (4c).20 1H NMR (400 MHz, CDCl3) / = 7.47-7.36 (m, 2H),
7.23-7.14 (m, 2H), 6.17 (s, 1H), 2.59 (s, 3H), 2.38 (s, 3H).
(E)-3-(4-Methoxyphenyl)but-2-enoic acid (4d).21 1H NMR (400 MHz, CDCl3) / = 7.56-7.42 (m,
2H), 7.00-6.84 (m, 2H), 6.15 (s, 1H), 3.84 (s, 3H), 2.59 (s, 3H).
(E)-3-(4-Fluorophenyl)but-2-enoic acid (4e).22 1H NMR (400 MHz, CDCl3) / = 7.55-7.43 (m,
2H), 7.14-7.02 (m, 2H), 6.14 (s, 1H), 2.59 (s, 3H).
(E)-3-(4-Nitrophenyl)but-2-enoic acid (4f).23 1H NMR (400 MHz, CDCl3) / = 8.35-8.19 (m,
2H), 7.71-7.52 (m, 2H), 6.23 (s, 1H), 2.63 (s, 3H).
(E)-3-Phenylpent-2-enoic acid (4g).24 1H NMR (400 MHz, CDCl3) / = 7.53-7.43 (m, 2H),
7.42-7.32 (m, 3H), 6.06 (s, 1H), 3.13 (q, J = 7.6 Hz, 2H), 1.09 (t, J = 7.6 Hz, 3H).
3,3-Diphenylprop-2-enoic acid (4h).25 1H NMR (400 MHz, CDCl3) /= 7.46-7.24 (m, 8H), 7.23-
7.14 (m, 2H), 6.32 (s, 1H).
General Procedure for the Conjugate addition of Arylboronic acid to 3-Phenylbut-2-
enoic Acid (4b): To a Schlenk tube, phenylboronic acid (1a, 122 mg, 1.0 mmol), 3-Phenylbut-2-
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enoic Acid (4b, 81 mg, 0.5 mmol), Pd(OAc)2 (5.86 mg, 0.025 mmol), bpy (7.81 mg, 0.05 mmol),
H2O (2.5 mL) and acetone (0.5 mL) were added. The solution was stirred at 60ꢀ in air until no
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starting substrate was spotted as monitored by TLC. Water (8 mL) was added to the reaction,
extracted with CH2Cl2 (10 mLþ3), dried over Na2SO4 and concentrated by vacuum. The residue
was purified by column chromatography on silica gel (PE:EA = 5: 1 to 1: 1) to give 3,3-
diphenylbutanoic acid (5ab, 115 mg, yield 96%).
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3,3-Diphenylbutanoic acid (5ab).14 White solid (115 mg, 96%). mp = 100-101 C. H NMR
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(400 MHz, CDCl3): / = 7.31-7.25 (m, 4H), 7.23-7.14 (m, 6H), 3.16 (s, 2H), 1.88 (s, 3H); C
NMR (100 MHz, CDCl3): / 176.8, 148.0, 128.1, 127.0, 126.1, 46.1, 45.2, 27.9 ; IR (KBr) ꢀ =
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1708 cm-1; MS (ESI) m/z: 239 (M-H+); HRMS Calcd for C16H15O2 : 239.1078, Found: 239.1070.
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3-Phenyl-3-p-tolylbutanoic acid (5bb). White solid (116 mg, 91%). mp = 80-81 C. H NMR
(400 MHz, CDCl3): / = 7.31-7.22 (m, 2H), 7.21-7.14 (m, 3H), 7.10-7.00 (m, 4H), 3.13 (s, 2H),
2.31 (s, 3H), 1.85 (s, 3H).13C NMR (100 MHz, CDCl3) / 177.2, 148.1, 145.1, 135.6, 128.8, 128.1,
126.9, 126.8, 126.1, 46.2, 44.9, 28.0, 20.9 ; IR (KBr) ꢀ = 1709 cm-1; MS (ESI) m/z: 253 (M-H+);
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HRMS Calcd for C17H17O2 : 253.1234. Found: 253.1244.
3-(4-Methoxyphenyl)-3-phenylbutanoic acid (5cb). White solid (35 mg, 26%). mp = 99-100 oC.
1H NMR (400 MHz, CDCl3): / = 7.32-7.23 (m, 2H), 7.21-7.14 (m, 3H), 7.13-7.03 (m, 2H), 6.86-
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6.75 (m, 2H), 3.78 (s, 3H), 3.13 (s, 2H), 1.85 (s, 3H). C NMR (100 MHz, CDCl3): / 175.6,
157.7, 148.4, 140.0, 128.08, 128.06, 126.9, 126.1, 113.4, 55.2, 46.1, 44.6, 28.1 ; IR (KBr) ꢀ =
-
1707 cm-1; MS (ESI) m/z: 269 (M-H+); HRMS Calcd for C17H17O3 : 269.1183. Found: 269.1191.
3-(4-Chlorophenyl)-3-phenylbutanoic acid (5db). White solid (135 mg, 98%). mp = 100-101oC.
1H NMR (400 MHz, CDCl3): / = 7.32-7.19 (m, 5H), 7.19-7.00 (m, 4H), 3.12 (s, 2H), 1.84 (s,
13
3H); C NMR (100 MHz, CDCl3): / 176.3, 147.7, 146.4, 132.0, 128.5, 128.24, 128.20, 126.8,
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126.4, 45.9, 44.9, 28.0 ; IR (KBr) ꢀ = 1709 cm-1; MS (ESI) m/z: 273 (M-H+); HRMS Calcd for
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C16H14ClO2 : 273.0688. Found: 273.0696.
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3-(4-Fluorophenyl)-3-phenylbutanoic acid (5gb). White solid (127 mg, 98%). mp = 125-126
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oC. H NMR (400 MHz, CDCl3): / = 7.32-7.25(m, 2H), 7.22-7.08 (m, 5H), 6.99-6.89 (m, 2H),
3.12 (s, 2H), 1.85 (s, 3H); 13C NMR (100 MHz, CDCl3): / 176.3, 161.2 (d, J = 163.0 Hz), 148.0,
143.5, 128.7, 128.2, 126.8, 126.3, 114.8 (d, J = 14.0 Hz), 46.1, 44.8, 28.2 ; 19F NMR (375 MHz,
CDCl3) / -117.1; IR (KBr) ꢀ = 1707 cm-1; MS (ESI) m/z: 257 (M-H+); HRMS Calcd for
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C16H14FO2 : 257.0983. Found: 257.0994.
3-(2-Naphthyl)-3-phenylbutanoic acid (5hb). White solid (131 mg, 90%). mp = 159-160 oC. 1H
NMR (400 MHz, CDCl3): / = 7.86-7.73(m, 3H), 7.72-7.66 (m, 1H), 7.51-7.42 (m, 2H), 7.28-
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7.23 (m, 2H), 7.22-7.12 (m, 4H), 3.26 (s, 2H), 1.96 (s, 3H); C NMR (100 MHz, CDCl3): /
175.4, 147.8, 145.2, 133.0, 131.9, 128.2, 128.1, 127.8, 127.4, 127.0, 126.4, 126.2, 126.0, 125.8,
124.6, 45.7, 45.3, 27.8 ; IR (KBr) ꢀ = 1708 cm-1; MS (ESI) m/z: 289 (M-H+); HRMS Calcd for
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C20H17O2 : 289.1234. Found: 289.1235.
3-(4-Nitrophenyl)-3-phenylbutanoic acid (5af). Yellow oil (133 mg, 93%). 1H NMR (400 MHz,
CDCl3): / = 8.18-8.07 (m, 2H), 7.41-7.19 (m, 5H), 7.17-7.08 (m, 2H), 3.20 (s, 2H), 1.90 (s, 3H);
13C NMR (100 MHz, CDCl3): / 176.5, 155.3, 146.7, 146.2, 128.5, 128.1, 126.8, 126.7, 123.3,
45.7, 45.5, 27.8; IR (KBr) ꢀ = 1708 cm-1; MS (ESI) m/z: 284 (M-H+); HRMS Calcd for
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C16H14NO4 : 284.0928. Found: 284.0931.
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3,3-Diphenylpentanoic acid (5ag). White solid (123 mg, 97%). mp = 123-124 C. H NMR
(400 MHz, CDCl3): / = 7.30-7.22 (m,4H), 7.21-7.08 (m,6H), 3.12 (s, 2H), 2.36 (q, J = 7.2 Hz,
2H), 0.69 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): / 176.9, 147.0, 127.9, 127.7, 126.1,
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48.9, 41.8, 30.4, 8.7 ; IR (KBr) ꢀ = 1707 cm-1; MS (ESI) m/z: 253 (M-H+); HRMS Calcd for
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C17H17O2 : 253.1234. Found: 253.1239.
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3-Methyl-3-phenylbutanoic acid (5aa).26 White solid (82 mg, 92%). mp = 56-58 C. H NMR
(400 MHz, CDCl3): / = 7.40-7.34 (m, 2H), 7.34-7.27(m, 2H), 7.22-7.16 (m, 1H), 2.64 (s, 2H),
1.46 (s, 6H); 13C NMR (100 MHz, CDCl3): / 178.0, 147.9, 128.2, 126.0, 125.3, 48.0, 37.0, 28.8 ;
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IR (KBr) ꢀ = 1706cm-1; MS (ESI) m/z: 177 (M-H+); HRMS Calcd for C11H13O2 : 177.0921,
Found: 177.0929.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Characterization data of substrates and NMR spectra of product compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
*Email: linshaohui@suda.edu.cn; qpan@suda.edu.cn
ORCID
Shaohui Lin: 0000-0003-1825-0860
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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This paper is dedicated to Professor Xiyan Lu (Shanghai Institute of Organic Chemistry, CAS,
China) on the occasion of his 90th birthday. We gratefully acknowledge the National Natural
Science Foundation of China (Nos. 21104049, 21176163, 21576174), 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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REFERENCES
(1) (a) Berthon, G.; Hayashi, T. in Catalytic Asymmetric Conjugate Reactions; Córdova, A.,
Ed.; Wiley-VCH: Weinheim, 2010. (b) Alexakis, A. The conjugate addition reaction, in
Transition Metals for Organic Synthesis: Building Blocks and Fine Chemicals, 2nd ed.; Beller,
M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004. (c) Perlmutter, P. Conjugate Addition
Reactions in Organic Synthesis; Pergamon Press: Oxford, 1992.
(2) For the reviews, see: (a) Hawner, C.; Alexakis, A. Chem. Commun. 2010, 46, 7295. (b)
Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008,
108, 2824. (c) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829. (d) Fagnou, K.; Lautens,
M. Chem. Rev. 2003, 103, 169. (e) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771. (f)
Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033; (g) Krause, N.; Hoffmann-Roder, A.
Synthesis 2001, 171.
(3) (a) Lopez, F.; Minnaard, A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179. (b) Feringa, B.
L. Acc. Chem. Res. 2000, 33, 346.
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(4) (a) Hayashi, T. Pure Appl. Chem. 2004, 76, 465. and the references therein. (b) Hayashi, T.;
Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716. (c) Hayashi, T.; Senda, T.;
7
8
9
Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591. (d) Takaya, Y.; Ogasawara, M.;
Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579. (e) Sakai, M.; Hayashi,
H.; Miyaura, N. Organometallics 1997, 16, 4229.
10
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16
17
18
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21
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23
24
25
26
27
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59
60
(5) For the reviews of Pd-catalyzed conjugate addition, see: (a) Liu, Y.; Han, S.-J.; Liu, W.-R.;
Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740. (b) Gutnov, A. Eur. J. Org. Chem. 2008, 4547.
(6) For Pd-catalyzed conjugate addition of organoboron reagents, see: (a) Holder, J. C.;
Marziale, A. N.; Gatti, M.; Mao, B.; Stoltz. B. M. Chem. –Eur. J. 2013, 19, 74. (b) Poláćková,
V.; Bariak, V.; Łebesta, R. Chem. Pap. 2011, 65, 338. (c) Xu, Q.; Zhang, R.; Zhang, T.; Shi, M.
J. Org. Chem. 2010, 75, 3935. (d) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew. Chem. Int.
Ed. 2003, 42, 2768. (e) Cho, C. S.; Motofusa, S.; Ohe, K.; Uemura, S. J. Org. Chem. 1995, 60,
883. and references cited therein.
(7) (a) Ji, J.; Yang, Z.; Liu, R.; Ni, Y.; Lin, S.; Pan, Q. Tetrahedron Lett. 2016, 57, 2723. (b)
Lin, S.; Lu, X. Tetrahedron Lett. 2006, 47, 7167. (c) Lu, X.; Lin, S. J. Org. Chem. 2005, 70,
9651.
(8) For Pd(II)-catalyzed conjugate addition of organoboronic acids to b,b-disubstituted enones,
see: (a) Holder, J. C.; Zou, L.; Marziale, A. N.; Liu, P.; Lan, Y.; Gatti, M.; Kikushima, K.; Houk,
K. N.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 14996. (b) Gottumukkala, A. L.; Matcha, K.;
Lutz, M.; deÓVries×, J. G.; Minnaard, A. J. Chem. –Eur. J. 2012, 18, 6907. (c) Kikushima, K.;
Holder, J. C.; Gatti, M.; Stoltz, B. M. J. Am. Chem. Soc. 2011, 133, 6902. (d) Lin, S.; Lu, X. Org.
Lett. 2010, 12, 2536. and references cited therein.
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(9) (a) Lan, Y.; Houk, K. N. J. Org. Chem. 2011, 76, 4905. (b) Peng, Q.; Yan, H.; Zhang, X.;
Wu, Y.-D. J. Org. Chem. 2012, 77, 7487.
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(10) Vautravers, N. R.; Breit, B. Synlett 2011, 17, 2517.
10
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57
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59
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(11) (a) Aurell, M. J.; Banuls, M. J.; Mestres, R.; Munoz, E. Tetrahedron 1999, 55, 831. (b)
Aurell, M. J.; Mestres, R.; Munoz, E. Tetrahedron Lett. 1998, 39, 6351. (c) Plunian, B.; Vaultier,
M.; Mortier, J. Chem. Commun. 1998, 81.
(12) Ohtaka, A.; Yamaguchi, T.; Nishikiori, R.; Shimomura, O.; Nomura, R. Asian J. Org.
Chem. 2013, 2, 399.
(13) Li, Y.; Dong, K.; Wang, Z.; Ding, K. Angew. Chem. Int. Ed. 2013, 52, 6748.
(14) Tucker, T. J.; Lumma, W. C.; Lewis, S. D.; Gardell, S. J.; Lucas, B. J.; Sisko, J. T.; Lynch,
J. J.; Lyle, E. A.; Baskin, E. P.; Woltmann, R. F.; Appleby, S. D.; Chen, I.-W.; Dancheck, K. B.;
Naylor-Olsen, A. M.; Krueger, J. A.; Cooper, C. M.; Vacca, J. P. J. Med. Chem. 1997, 40, 3687.
(15) (a) Shintani, R.; Hayashi, T. Org. Lett. 2011, 13, 350. (b) Shintani, R.; Tsutsumi, Y.;
Nagaosa, M.; Nishimura, T.; Hayashi, T. J. Am. Chem. Soc. 2009, 131, 13588. (c) Shintani, R.;
Duan, W.-L.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, 5628.
(16) (a) Lin, S.; Lu, X. J. Org. Chem. 2007, 72, 9757. (b) Zhao, B.; Lu, X. Org. Lett. 2006, 8,
5987.
(17) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 4978.
(18) (a) Herrerías, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007, 107, 2546. (b) Li, C.-J.
Chem. Rev. 2005, 105, 3095. (c) Li, C.-J. Chem. Rev. 1993, 93, 2023.
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(19) (a) Hu, X.-H.; Zhang, J.; Yang, X.-F.; Xu, Y.-H.; Loh, T.-P. J. Am.Chem. Soc. 2015, 137,
3169. (b) Abe, M.; Nishikawa, K.; Fukuda, H.; Nakanishi, K.; Tazawa, Y.; Taniguchi, T.; Park,
S.-Y.; Hiradate, S.; Fujii,Y.; Okuda, K.; Shindo, M. Phytochemistry 2012, 84, 56.
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(20) Jiménez, J.; López, M.; Carranza, V.; Mendoza, A. Tetrahedron Lett. 2017, 58, 235.
(21) Fukuyama, T.; Arai, M.; Matsubara, H. J. Org. Chem. 2004, 69, 8105.
(22) Wiley, R. H.; Van der Plas, H. C. J. Chem. Eng. Data. 1965, 10, 72.
(23) Gupta, M.; Wakhloo, B. P. Arkivoc. 2007, 94.
(24) Yan, Q.; Kong, D.; Zhao, Wei.; Zi, G.; Hou, G. J. Org. Chem. 2016, 81, 2070.
(25) Tanaka, S.; Watanabe, K.; Tanaka, Y.; Hattori, T. Org. Lett. 2016, 18, 2576.
(26) Nieman, James. A.; Coleman, J. E.; Wallace, D. J.; Piers, E.; Lim, L. Y.; Roberge, M.;
Andersen, R. J. J. Nat. Prod. 2003, 66, 183.
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