Pd(II)/bipyridine catalyzed conjugate addition of arylboronic acids to α,β-unsaturated amides

Article abstract of DOI:10.1016/j.tetlet.2016.05.022

The Pd(II)/bipyridine-catalyzed conjugate addition of arylboronic acid to α,β-unsaturated amides was developed and optimized, and the reaction was proceeded smoothly in air. A series of arylboronic acid and α,β-unsaturated amide substrates were surveyed, and modest to excellent yields were given.

Full text of DOI:10.1016/j.tetlet.2016.05.022

Tetrahedron Letters 57 (2016) 2723–2726
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd(II)/bipyridine catalyzed conjugate addition of arylboronic acids
to a,b-unsaturated amides
⇑
⇑
Jiamin Ji, Zhenyu Yang, Rui Liu, Yuxin Ni, 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, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The Pd(II)/bipyridine-catalyzed conjugate addition of arylboronic acid to
developed and optimized, and the reaction was proceeded smoothly in air. A series of arylboronic acid
a,b-unsaturated amides was
Received 30 January 2016
Revised 28 April 2016
Accepted 3 May 2016
Available online 7 May 2016
and
a
,b-unsaturated amide substrates were surveyed, and modest to excellent yields were given.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Palladium(II)
Bipyridine
Arylboronic acid
Unsaturated amide
Conjugate addition
Transition metal catalysis is vital to modern synthesis,1 and
transition-metal-catalyzed conjugate addition has been an effi-
cient approach to C–C bonds formation.2 In Hayashi’s pioneering
work,3 rhodium(I)-catalyzed conjugate addition of arylboronic
acids to b-substituted cyclic enones which was catalyzed by Pd
(TFA)2-pyridinooxazoline, and highly enantioselective all carbon
quaternary carbon centers were generated.8 In the following
research by Stoltz, the mechanism of this conjugate addition was
studied and explained thoroughly.8d,9 Also this Pd(II)-catalyzed
conjugate addition was used in some synthesis applications.8e
We reviewed the reports of Pd(II)-catalyzed conjugate additions
of arylboronic acids and found that most Michael acceptors were
acids to
a,b-unsaturated carbonyl compounds was developed as
a powerful strategy, in which air and moisture benign arylboronic
acids were performed as excellent nucleophiles. Compared with
the high cost of rhodium catalysts, Miyaura provided a more eco-
nomical option of palladium(II) catalysis, and Pd(II)-catalyzed con-
focused
on
a
,b-unsaturated
ketones4,6,8
esters,6a
and
jugate addition of arylboronic acids to
a,b-unsaturated ketones
nitroalkenes.10 For
a,b-unsaturated amides, Hayashi reported
was reported.4
excellent results in his Rh(I)-catalyzed reactions11, but it’s rarely
surveyed in Pd(II)-catalyzed conjugate addition, which might be
the weak electron withdrawing ability of amide groups. Only a
few conjugate addition examples of acrylamide can be found in
previous publication of Pd(II) catalysis,6a,7b and the Pd(II)-
As a part of our research of divalent palladium catalysis, we
started the survey of Pd(II)-bipyridine(bpy) catalyzed conjugate
addition of arylboronic acids to
a,b-unsaturated carbonyl com-
pounds, in which bipyridine played a magnificent role to stabilize
Pd(II) species and to inhibit b-H elimination.5 We published a ser-
ies of highly efficient Pd(II)-bpy catalyzed conjugate additions of
catalyzed oxidative Heck reaction of arylboronic acids with
unsaturated amides was surveyed.12 Herein, we reported the Pd
(II)/bpy-catalyzed conjugate addition to ,b-unsaturated amides.
a,b-
arylboronic acids to
a
,b-unsaturated ketones, aldehydes, esters,
a
etc.6 Especially for the b,b-disubstituted enones, cationic Pd(II)-
bpy complex catalyzed the construction of quaternary carbons.6c
After that, nitrogen ligand-based Pd(II) catalysis attracted more
chemists’ interest compared with Pd(II)-phosphine catalysis.7
Stoltz reported the asymmetric conjugate addition of arylboronic
To probe the reaction conditions, phenylboronic acid and N-
methylmaleimide were chosen as model reactants to optimize
the reaction. Firstly, the optimal conditions for conjugate addition
to a,b-unsaturated ketones and esters were applied. At 40 °C, only
20% of the expected product was found after 2 days, and most of
the starting material N-methylmaleimide remained (Table 1, entry
1). In consideration of the fluoride improving the nucleophilicity of
organoboronic acids,13 KFꢀ2H2O was added to the reaction, which
⇑
Corresponding authors. Tel.: +86 512 67060327; fax: +86 512 65880089 (S.L.);
tel.: +86 512 65882062; fax: +86 512 65880089 (Q.P.).
E-mail addresses: linshaohui@suda.edu.cn (S. Lin), qpan@suda.edu.cn (Q. Pan).
http://dx.doi.org/10.1016/j.tetlet.2016.05.022
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

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J. Ji et al. / Tetrahedron Letters 57 (2016) 2723–2726
Table 1
gave a little higher yield but b-H elimination product N-methyl-2-
phenylmaleimide (3aa0) was also observed (Table 1, entry 2).
Then the reaction temperature was increased to 60 °C, and a
56% yield was obtained after 24 h (Table 1, entry 3). When the
reaction was heated up to 80 °C, complete starting material con-
version was observed and the conjugate addition yield was
improved to 93% (Table 1, entry 4). Also the reaction in neutral sol-
vent (THF/H2O) was tested, and only half of the starting has been
converted to the product after 24 h (Table 1, entry 5). Some other
solvents (CH3OH and toluene) were also tested in this reaction
(Table 1, entries 6 and 7), only modest yields of conjugate addition
were given. It’s revealed that acidic conditions were necessary for
complete conversion of starting materials. After the reaction in
acidic solvent, TLC showed that phenylboronic acid still could be
observed. Then the loading of phenylboronic acid was reduced to
2 equiv, and reaction yield was nearly the same (Table 1, entry
8). So far the reaction conditions have been optimized, and no inert
gas protection was necessary.
Pd(II)-bipyridine catalyzed conjugate addition of phenylboronic acid to N-
methylmaleimidea
Entry Solvent
Ratio
1a:2a
Temperature
(°C)
Time
(h)
Yieldb
(%)
1
2
3
4
HOAc/THF/H2O = 1 mL/
2 mL/0.6 mL
HOAc/THF/H2O = 1 mL/
2 mL/0.6 mL
HOAc/THF/H2O = 1 mL/
2 mL/0.6 mL
HOAc/THF/H2O = 1 mL/
2 mL/0.6 mL
THF/H2O = 2 mL/0.6 mL
CH3OH
Toluene
HOAc/THF/H2O = 1 mL/2
mL/0.6 mL
3
3
3
3
40
40
60
80
48
48
24
24
20
27c
56
93
5
6
7
8
3
3
3
2
80
80
80
80
24
24
24
24
51
53
62
92
To investigate the substrates scope, different arylboronic acids
and
a,b-unsaturated amides were tested in the optimized condi-
tions. The reaction of p-tolylboronic acid with N-methylmaleimide
gave excellent conjugate addition yield (Table 2, entry 2). For p-
methoxyphenyl-, p-chlorophenyl- and p-fluorophenylboronic
acids, high yields were also obtained (Table 2, entries 3–5). But
for 1-naphthylboronic acid, the reaction was very slow and only
42% yield of product was isolated after 60 h (Table 2, entry 6). It
a
Reaction conditions: N-methylmaleimide (1.0 mmol), Pd(OAc)2 (0.05 mmol),
and bpy (0.20 mmol). The optimized conditions highlighted in bold.
b
Isolated yield.
c
KFꢀ2H2O (3.0 mmol) as additives, 5% of N-methyl-2-phenylmaleimide (3aa0)
isolated.
Table 2
Pd(II)-bipyridine catalyzed conjugate addition of arylboronic acid to
a
,b-unsaturated amidesa
Entry
1
ArB(OH)2
a
,b-Unsaturated amide
Product
Time (h)
24
Yieldb (%)
92
O
O
B(OH)2
1a
N
Me
2a
N
3aa
Me
Ph
O
O
O
O
2
3
4
Me
MeO
Cl
B(OH)2
1b
N
Me
2a
N Me
22
20
24
90
83
74
O
O
O
3ba
Me
MeO
Cl
O
B(OH)2
1c
N
Me
2a
N Me
O
O
O
3ca
O
B(OH)2
1d
N
Me
2a
N Me
O
O
O
3da
O
5
6
F
B(OH)2
1e
N
Me
2a
N Me
24
60
87
42
O
O
O
3ea
F
B(OH)2
O
N
Me
2a
N
Me
1f
O
O
3fa

J. Ji et al. / Tetrahedron Letters 57 (2016) 2723–2726
2725
Table 2 (continued)
Entry
ArB(OH)2
a
,b-Unsaturated amide
Product
Time (h)
12
Yieldb (%)
B(OH)2
1g
O
O
7
N
Me
2a
N Me
91
O
O
3ga
O
8
9
B(OH)2
1h
O
—
48
45
0c
N
Me
2a
O
O
O
B(OH)2
N
Ph
N
Ph
43
1a
2b
Ph
Ph
3ab
O
O
O
O
10
11
12
B(OH)2
24
40
60
51
81
0
NH2
2c
NH2
NH2
1a
3ac
O
O
Ph
Ph
B(OH)2
Ph
NH2
Ph
1a
2d
3ad
O
B(OH)2
Ph
—
Me
Me
N
H
1a
2e
O
O
13
14
B(OH)2
Ts
Ts
24
48
76
0c
N
H
Me
N
H
1a
2f
3af
O
B(OH)2
Ph
—
Me
N
1a
2g
Me
a
Reaction conditions:
a,b-unsaturated amide (1.0 mmol), arylboronic acid (2.0 mmol), Pd(OAc)2 (0.05 mmol) and bpy (0.20 mmol), HOAc/THF/H2O = 1 mL/2 mL/0.6 mL,
80 °C.
b
Isolated yield.
No conjugate addition products were observed.
c
might be its steric hindrance as a nucleophile retarded the conju-
gate addition. Meanwhile the less hindered 2-naphthylboronic acid
provided a 91% yield (Table 2, entry 7), which confirmed our spec-
ulation. For 2-furanylboronic acid (Table 2, entry 8), no expected
product was observed and all the 2-furanylboronic acid decom-
posed quickly. It might be the high electron density of furan ring
which led to the fast protonolysis of 2-furanylboronic acid in the
reaction.6a
Compared
with
N-methylmaleimide,
N-
phenylmaleimide showed low reactivity, and prolonged time
(45 h) gave 43% yield (Table 2, entry 9).
For acyclic amides, the conjugate addition proceeded smoothly
for cinnamide and gave 81% yield surprisingly (Table 2, entry 11).
For acrylamide, modest yield of product was isolated (Table 2,
entry 10), which was very similar to our previous results.6a In the
case of N-phenyl-2-butenamide, no expected product was
observed and the starting material remained unreacted (Table 2,
entry 12). It might be the electrodonating property of N-phenyl
group that makes
a,b-unsaturated double bond less
electrodeficient, which led to the low reactivity. Then N-(4-
toluenesulfonyl)-2-butenamide was synthesized and subjected to
the same reaction. The reaction gave 76% yield of conjugate
addition product (Table 2, entry 13), and it strongly supported
our hypothesis. For tertiary amide N-methyl-N-phenyl-2-
butenamide (Table 2, entry 14), no reaction occurred either. In
Scheme 1. Plausible mechanism of Pd(II)-catalyzed conjugate addition to
unsaturated amides.
a,b-
The plausible mechanism of this Pd(II)-catalyzed conjugate
addition was proposed (Scheme 1), and it’s very similar to the pre-
viously speculated one.6a The transmetallation of arylboronic acid
with Pd(II) species triggered the reaction, and C@C bond of the
amide inserted into the carbon-palladium bond. The protonolysis
this substrate screening, different arylboronic acids and
a,b-
unsaturated amides were surveyed, and most cases gave modest
to excellent yields.

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J. Ji et al. / Tetrahedron Letters 57 (2016) 2723–2726
Metals for Organic Synthesis: Building Blocks and Fine Chemicals; Wiley-VCH:
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catalyst. Compared with the conjugate addition to ,b-
unsaturated ketones, the weak electro withdrawing ability of
a
2. (a) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.; Feringa, B. L.
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amide groups might lower the electrophilicity of
amides and reduce the conjugate addition yields.
a,b-unsaturated
In conclusion, we optimized the Pd(II)/bpy-catalyzed conjugate
addition of arylboronic acid to ,b-unsaturated amides, which is
more difficult than ,b-unsaturated ketones and esters, and the
reaction was proceeded smoothly in air. Modest to excellent yields
3. (a) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829; (b) Hayashi, T. Pure
Appl. Chem. 2004, 76, 465. and the references therein.
a
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a
were given for different arylboronic acids and
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Acknowledgments
7. For Pd(II)-phosphine catalyzed conjugate additions of arylboronic acids, see
also (a) Gini, F.; Hessen, B.; Minnaard, A. J. Org. Lett. 2005, 7, 5309; (b)
Horiguchi, H.; Tsurugi, H.; Satoh, T.; Miura, M. J. Org. Chem. 2008, 73, 1590.
8. (a) Liu, Y.; Han, S. J.; Liu, W. B.; Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740; (b)
Kikushima, K.; Holder, J. C.; Gatti, M.; Stoltz, B. M. J. Am. Chem. Soc. 2011, 133,
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J. 2012, 19, 74; (d) Holder, J. C.; Zou, L.; Marziale, A. N.; Liu, P.; Lan, Y.; Gatti, M.;
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Shockley, S. E.; Holder, J. C.; Stoltz, B. M. Org. Lett. 2014, 16, 6362; (f) Shockley,
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We gratefully thank Professor Xiyan Lu (Shanghai Institute of
Organic Chemistry, CAS, China) for the helpful discussion. We also
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 Univer-
sity Funds (Nos. 14109001, Q410900510) and Suzhou Industrial
Park Fund for financial support.
9. Yu, L.; Houk, K. N. J. Org. Chem. 2011, 76, 4905.
10. He, Q.; Xie, F.; Fu, G.; Quan, M.; Shen, C.; Yang, G.; Gridnev, I. D.; Zhang, W. Org.
Lett. 2015, 17, 2250.
Supplementary data
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Lett. 2004, 6, 3425.
12. Inamoto, K.; Kawasaki, J.; Hiroya, K.; Kondo, Y.; Doi, T. Chem. Commun. 2012,
4332.
Supplementary data (preparation of substrates, typical experi-
mental procedures, characterization of all products, 1H and 13C
NMR spectra) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2016.05.022.
13. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b) Suzuki, A. J. Orgnomet.
Chem. 1999, 576, 147.
References and notes
1. (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd
ed.; Wiley-VCH: Weinheim, Germany, 2004; (b) Beller, M.; Bolm, C. Transition