LETTER
Synthesis of Bicyclic Pyridones
2823
Z
EWG
H
Z
N
O
EWG
EWG
H
Z
EWG
H
trans–cis
isomerization
n
Z
n
n
Michael
addition
condensation
Z
EWG
TsO
n
n
– TsOH
R
OTs
N
R
R
O
N
R
N
EtO
N
R
OEt
O
H
OEt
OEt
1
2
7
8
9
4–6
O
O
Scheme 2 Proposed mechanism for the formation of bicyclic pyridones
Huang, Z.-T. Synthesis 2000, 1439. (e) Yu, C.-Y.; Wang,
L.-B.; Li, W.-Y.; Huang, Z.-T. Synthesis 1996, 959.
(3) Jones, R. C. F.; Patel, P.; Hirst, S. C.; Turner, I. Tetrahedron
1997, 53, 11781.
(4) (a) Huang, Z.-T.; Liu, Z.-R. Heterocycles 1986, 24, 2247.
(b) Jones, R. C. F.; Patel, P.; Hirst, S. C.; Smallridge, M. J.
Tetrahedron 1998, 54, 6191. (c) Jones, R. C. F.; Smallridge,
M. J. Tetrahedron Lett. 1988, 29, 5005. (d) Yaqub, M.; Yu,
C.-Y.; Jia, Y.-M.; Huang, Z.-T. Synlett 2008, 1357. (e) Yu,
C.-Y.; Yang, P.-H.; Zhao, M.-X.; Huang, Z.-T. Synlett 2006,
1835. (f) Yu, C.-Y.; Yan, S.-J.; Huang, Z.-T. Acta
Crystallogr., Sect. E: Struct. Rep. Online 2006, 62, o2731.
(5) Zhang, J.-H.; Wang, M.-X.; Huang, Z.-T. J. Chem. Soc.,
Perkin Trans. 1 1999, 2087.
(6) (a) Huang, Z.-T.; Tzai, L. H. Chem. Ber. 1986, 119, 2208.
(b) Huang, Z.-T.; Liu, Z.-R. Synth. Commun. 1989, 19,
1801. (c) Huang, Z.-T.; Wang, M.-X. J. Chem. Soc., Perkin
Trans. 1 1993, 1085. (d) Zhao, M.-X.; Wang, M.-X.;
Huang, Z.-T. Tetrahedron 2002, 58, 1309. (e) Wang, L.-B.;
Huang, Z.-T. Synth. Commun. 1997, 27, 409. (f) Huang,
Z.-T.; Wang, X.-J. Chem. Ber. 1987, 120, 1803. (g) Takao,
T.; Satomi, N. Bull. Chem. Soc. Jpn. 1993, 66, 2118.
(7) Liao, J.-P.; Zhang, T.; Yu, C.-Y.; Huang, Z.-T. Synlett 2007,
761.
1e > 1c > 1b >1a. The reactivity order of six-membered
HKA also showed the same tendency, i.e., 1l > 1k > 1i >
1j.
In order to expand the scope of the cyclocondensation
reaction, HKA were replaced by N,O-acetal (Table 1, en-
tries 22–25). The reaction proceeded smoothly under the
same conditions, and the reactivity of N,O-acetal 1m–o
was found to be similar to that of the HKA.
The mechanism of the cyclocondensation reaction is de-
picted in Scheme 2. HKA 1 reacted via Michael addition
with compound 2 to give the adduct 7 followed by elimi-
nation of tosylate to form compound 8. The trans–cis
isomerization then provided 9, subsequent imine–enam-
ine tautomerization and condensation afforded the target
product 4–6.
In conclusion, we have developed a procedure for the fac-
ile synthesis of the bicyclic pyridones by simply refluxing
a reaction mixture of HKA and b-ketoe ster enol tosylates
catalyzed by Et3N. As a result, a library of novel bicyclic
pyridones was rapidly constructed in good yields. Prelim-
inary biological activity screening using 3-(4,5-dimeth-
ylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
colorimetric assay showed some of the title compounds 4–
6 possessed moderate anticancer activities against the
K562, HL60, A431, HepG2, and Skov-3 cell lines (see
Supporting Information for details).
(8) Yu, C.-Y.; Yan, S.-J.; Zhang, T.; Huang, Z.-T.
CN101041660, 2006.
(9) Xu, Z.-H.; Jie, Y.-F.; Wang, M.-X.; Huang, Z.-T. Synthesis
2002, 523.
(10) (a) Tieman, C. H.; Kollmeyer, W. D.; Roman, S. A.
DE 2,445,421, 1976. (b) Tieman, C. H.; Kollmeyer, W. D.
US 3,948,934, 1976. (c) Porter, P. E.; Kollmeyer, W. D.
US 4,053,623, 1977.
Consequently, this simple process presented herein has
great potentials for application to parallel synthesis in
drug discovery.
(11) (a) Jordan, A. D.; Vaidya, A. H.; Rosenthal, D. I.; Dubinsky,
B.; Kordik, C. P.; Sanfilippo, P. J.; Wub, W. N.; Reitza,
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Dubinsky, B.; Taylor, R. J. Jr.; Gardocki, J. F. J. Med. Chem.
1995, 38, 16.
Supporting Information for this article is available online at
Acknowledgment
The authors wish to greatly acknowledge the financial support from
the National Natural Science Foundation of China (grant Nos
30860342, 20762013).
(12) Suryawanshi, S. N.; Pandey, S.; Rashmirathi; Bhatt, B. A.;
Gupta, S. Eur. J. Med. Chem. 2007, 511.
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ElmegeedaG, A. Steroids 2007, 72, 459.
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References and Notes
(1) For reviews, see: (a) Huang, Z.-T.; Wang, M.-X.
Heterocycles 1994, 37, 1233. (b) Huang, Z.-T.; Wang,
M.-X. Prog. Nat. Sci. 1999, 11, 971.
(2) (a) Gupta, A. K.; Ila, H.; Junjappa, H. Synthesis 1988, 284.
(b) Huang, Z.-T.; Liu, Z.-R. Chem. Ber. 1989, 122, 95.
(c) Zhang, J.-H.; Wang, M.-X.; Huang, Z.-T. J. Chem. Soc.,
Perkin Trans. 1 1999, 321. (d) Nie, X.-P.; Wang, M.-X.;
(15) Hehemann, D. G.; Winnik, W. J. Heterocycl. Chem. 1994,
31, 393.
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