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Organic & Biomolecular Chemistry
Page 4 of 6
ARTICLE
Journal Name
intramolecular attack to the ester carbonyl group and subsequent
ethanol elimination reaction (Scheme 3, Path II, b). For the 4-
pyridone 6i, the path is similar to a Path II (a) (Scheme 3).
There are no conflicts to declare.
DOI: 10.1039/C9OB02456E
OEt
Path I
Acknowledgements
OEt
OEt
O
O
O
EtO2
C
OEt
3a
-EtOH
CO2Et
1a 2a
O
CO2Et
This work was supported by the National Natural Science
Foundation of China (Nos. 21662046 and 21202142), the
program for the application fundamental research of Yunnan
Province (No. 2018FB019), and the Program for Innovative
Research Team (in science and technology) at the University of
Yunnan Province.
Michael addition
Base
CO2Et
HN
Ph
Int-I
OEt
EtO2
OEt
N
C
N
EtO2
C
Ph
Ph
B
A
OEt
OEt
OEt
O
O
O
O
O
OEt
EtO2
C
CO2Et
CO2Et
CO2Et
O -EtOH
EtO
O-
OEt
4a
OEt
EtO2
OEt
EtO2
Imine-enamine
tautomerism
O
H
N
H
N
Cyclization
EtO2
Base
C
N
N
C
C
EtO2
C
Ph
F
Ph
Ph
Ph
E
D
C
Path II
Notes and reference
(a) Control of reagent addition order/ Step by step feeding
O
EtO2
C
CO2Et
EtO2
C
CO2Et
EtO
N
1
For selected recent reports, see: (a) J. Diesel, A. M.
Finogenova and N. Cramer, J. Am. Chem. Soc., 2018, 140,
4489; (b) V. Nagaraju, D. Purnachander, N. S. V. M. R.
Mangina, S. Suresh, B. Sridhar and G. V. Karunakar, Org.
Biomol. Chem., 2015, 13, 3011; (c) H. J. Jessen and K.
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Maldonado, S. A. Fuhrman, L. S. Zalman, T. Tuntland, C. A.
Lee, A. K. Patick, D. A. Matthews, T. F. Hendrickson, M. B.
Kosa, B. Liu, M. R. Batugo, J. P. Gleeson, S. K. Sakata, L. Chen,
M. C. Guzman, J. W. Meador, R. A. Ferre and S. T. Worland, J.
Med. Chem., 2002, 45, 1607; (g) E. Lo Presti, R. Boggia, A.
Feltrin, G. Menozzi, P. Dorigo and L. Mosti, Farmaco, 1999,
54, 465; (h) A. G. E. Amr and M. M. Abdulla, Bioorg. Med.
Chem., 2006, 14, 4341; (i) M. T. Cocco, C. Congiu and V.
Onnis, Eur. J. Med. Chem., 2000, 35, 545; (j) J. J. Kaminski, A.
M. Doweyko, J. Med. Chem., 1997, 40, 427.
O
EtO2
C
C
CO2Et
CO2Et
HN
2a
N
OEt
1ee
3a
EtO2
Br
Br
aza-Michael addition
Base
Br
H
G
Int-II
O
O
OEt
OEt
-O
EtO
N
EtO2
C
C
EtO2
C
O
-EtOH
-EtOH
zation
OEt
6a
EtO2
EtO2
C
N
Cycli
Br
Br
Base
I
J
(b)
One-pot
O
EtO
CO2Et
EtO2
C
OEt
CO2Et
N
O
O
O
HN
CO2Et
Br
3a
EtO2
C
EtO
OEt
1ee
2a
EtO
EtO2
C
N
Br
OEt
Br
K
L
Int-III
O
O
EtO
N
O
OEt
OEt
EtO2
C
OEt
-O
EtO
O
EtO2
C
C
EtO2
C
O
EtO2
C
-EtOH
-EtOH
OEt
6a
EtO2
N
Br
EtO2
C
N
zation
Cycli
Base
Br
Br
the vinylic anion species
2
(a) J. Kim, H. Kim and S. B. Park, J. Am. Chem. Soc., 2014, 136,
14629; (b) M. Torres, S. Gil and M. Parra, Curr. Org. Chem.,
McGlacken, Eur. J. Org. Chem., 2018, 44, 6068.
H
Int-
I
J
O
EtO2
C
CO2Et
EtO2
C
CO2Et
EtO
N
O
EtO2
C
C
CO2Et
CO2Et
HN
2a
N
OEt
1a 3a
EtO2
aza-Michael addition
Base
N
M
Int-7
3
4
H. Baron, F. G. P. Remfry and J. F. Thorpe, J. Chem. Soc.
Trans., 1904, 85, 1726.
(a) I. Hachiya, K. Ogura and M. Shimizu, Org. Lett., 2002, 4,
2755; (b) M. Fujii, T. Nishimura, T. Koshiba, S. Yokoshima and
T. Fukuyama, Org. Lett., 2013, 15, 232.
O
O
OEt
OEt
-O
EtO
N
EtO2
C
C
EtO2
C
O
-EtOH
-EtOH
OEt
6i
EtO2
EtO2
C
N
zation
Cycli
Base
O
P
5
6
7
8
Y. Yang, C. Fei, K. Wang, B. Liu, D. Jiang and B. Yin, Org. Lett.,
2018, 20, 2273.
H. R. Bai, R. R. Sun, S. T. Liu, L. J. Yang, X. B. Chen and C.
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Scheme 3. The proposed mechanism
Conclusions
In summary, we have successfully developed an efficient and
practical one-pot three-component cascade reaction catalyzed by
Cs2CO3 under solvent-free conditions. The transformation involved
(a) B. Li, B. Zhang, X. Zhang and X. Fan, J. Org. Chem., 2016,
81, 9530; (b) S. Rajkumar, K. Shankland, J. M. Goodman and J.
A. Cobb, Org. Lett., 2013, 15, 1386; (c) L. Fan, J. Liu, L. Bai, Y.
Wang and X. Luan, Angew. Chem. Int. Ed., 2017, 56, 14257;
(d) H. Jiang, R. Mai, H. Cao, Q. Zhu and X. Liu, Org. Biomol.
Chem., 2009, 7, 4943; (e) J. P. Wan, Y. Lin, Q. Huang and Y.
Liu, J. Org. Chem., 2014, 79, 7232; (f) X. Feng, Q. Wang, W.
Lin, G. L. Dou, Z. B. Huang and D. Q. Shi, Org. Lett., 2013, 15,
2542; (g) C. L. Ji, Y. Pan, F. Z. Geng, W. J. Hao, S. J. Tu and B.
Jiang, Org. Chem. Front., 2019, 6, 474.
(a) T. Liu, J. Liu, S. Xia, J. Meng, X. Shen, X. Zhu, W. Chen, C.
Sun and F. Cheng, ACS Omega, 2018, 3, 1409; (b) T. Liu, J. Liu,
X. Shen, J. Xu, B. Nian, N. He, S. Zeng and F. Cheng, Synthesis,
2019, 51, 1365; (c) T. Liu, Y. Zhang, R. Yu and F. Cheng,
Synthesis, 2020, 52, 253; (d) T. Liu, Y. Li, F. Cheng, X. Shen, J.
Liu and J. Lin, Green Chem., 2019, 21, 3536.
steps
intermolecular
including
Michael
addition/ethanol
elimination/
diethyl
cyclization
utilizing anilines,
acetylenedicarboxylate and diethyl ethoxymethylenemalonate. This
chemoselective, one-pot, three-component cascade reaction
process was controlled by substitution of anilines, providing the
multisubstituted 2-pyridones and 4-pyridones in good to excellent
yields. Further studies on the applicability of the multisubstituted
pyridones obtained through this process for the preparation of new
potent bioactive molecules are currently ongoing in our laboratory.
9
10 (a) H. R. Bai, F. J. Liu, X. J. Wang, P. Wang and C. Huang, ACS
Conflicts of interest
4 | J. Name., 2012, 00, 1-3
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