Synthesis of bicyclic pyridones via cyclocondensation of heterocyclic ketene aminals with β-Ketoester enol tosylates

Article abstract of DOI:10.1055/s-0029-1217984

A series of novel bicyclic pyridones were easily prepared by cyclic condensation of heterocyclic ketene aminals with -keto ester enol tosylates in the presence of a base to give products in excellent yields (80-95%).

Full text of DOI:10.1055/s-0029-1217984

LETTER
2821
Synthesis of Bicyclic Pyridones via Cyclocondensation of Heterocyclic Ketene
Aminals with b-Ketoester Enol Tosylates
Synthesis of
B
h
icyclic Pyrid
e
ones ng-Jiao Yan, Yan-Fei Niu, Rong Huang, Jun Lin*
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education,
School of Chemical Science and Technology, Yunnan University, Kunming 650091, P. R. of China
Fax +86(871)5033215; E-mail: linjun@ynu.edu.cn
Received 8 July 2009
places limitations on the flexibility and subsequent appli-
cations of this chemistry.
Abstract: A series of novel bicyclic pyridones were easily prepared
by cyclic condensation of heterocyclic ketene aminals with b-keto
ester enol tosylates in the presence of a base to give products in ex-
cellent yields (80–95%).
In order to develop an efficient method for the rapid gen-
eration of libraries of bicyclic pyridones (Figure 1), we
Key words: pyridones, cyclocondensation, heterocyclic ketene are focusing on the reaction of HKA 1 with b-keto ester
aminals, b-keto ester enol tosylates
enol tosylates 2. They are recognized as useful cross-
coupling reagents which have been widely employed in
C–C bond formation in organic synthesis.18 In addition, b-
keto ester enol tosylates are considerably less expensive
and more readily accessible than other reagents, such as
triflating agents.18a However, they are only useful as sin-
gle-site nucleophiles, and do not function as bisnucleo-
philes when forming cyclic compounds. In this
communication, we report herein an efficient method for
the rapid generation of libraries of the 5,6- and 6,6-ring bi-
cyclic pyridones 4a–l, 5a–i, and 6a–d based upon the re-
sults of cyclocondensation of HKA 1 with b-ketoester
enol tosylates 2 under basic conditions.
Heterocyclic ketene aminals (HKA) are versatile interme-
diates for the synthesis of a wide variety of fused hetero-
cyclic compounds.1 Reactions of HKA with 1,2- and 1,3-
bifunctional substrates leading to five- and six-membered
fused heterocycles have been reported. Five-membered-
ring systems belonging to aminopyrrolone derivatives2
have been synthesized. Six-membered-ring systems such
as 2-aminotetrahydropyridines,3 6-aminodihydropyridin-
ones,4
dihydropyridine-2-amines,5
6-aminopyridin-
ones,4a–c,6 6-iminodihydropyridine-2-amines7, and 2-
aminodihydropyridine8 have also been obtained. Further-
more, seven-membered 3-amino-2H-benzo[c]azepin-
1(5H)-one could also be obtained with ethyl 2-bromobenz-
oate.9
EWG
EWG
H
N
R
R
Z
n
n
N
N
These fused heterocyclic structures are frequently found
in pharmacophores and play important roles in the drug
industry and have found uses as herbicides, pesticides,10
anti-anxious agents,11 antileishmanial agents,12 antibacte-
rial and antitherapeutic drugs.13 Of these compounds, bi-
cyclic pyridones 3 are of general interest within medicinal
chemistry, and a series of substituted variants of 3 (n = 1,
2) have been reported as a basis for analgesics and anti-
inflammatory agents (Figure 1).14 Published methods for
the synthesis of bicyclic pyridones 3 (n = 1, 2) are based
on the following approaches: cyclocondensation of keten-
aminals,4a–c,6 addition of diamines to cyanobutenoic
esters,14a,b addition of diamines to halo-14 or thiometh-
ylpyridones,15 nucleophilic substitution and intramolecu-
lar condensation of 2,6-dihalopyridine,16 and other
methods.17 The first method is the most used procedure.
However, only propiolic ester4a,b,6a–f or diethyl but-2-
ynedioate6g can be used as the starting materials to under-
go cyclocondensation with ketene aminals. This, in turn,
O
3: n = 1, 2
O
4a–l: n = 1, Z = NH
5a–i: n = 2, Z = NH
6a–d: n = 1, Z = O
Figure 1 Bicyclic pyridones derived from HKA
Firstly, an easily available starting material 2-(nitrometh-
ylene)imidazolidine 1a was reacted with b-keto ester enol
tosylates 2a in 1,4-dioxane in the presence of Et3N under
refluxing temperature for 14 hours. The bicyclic pyridone
4a was successfully obtained in 80% yield (Scheme 1,
Table 1, entry 1). All new compounds 4–6 were fully
characterized on the basis of their H NMR, 13C NMR
1
spectra and high resolution mass spectra.19 The structure
EWG
TsO
R
R
dioxane
Et3N
Z
EWG
H
Z
n
n
+
N
OEt
(E)
reflux
N
H
O
O
EWG = NO2, COMe
COOEt, COAr
4a–l: n = 1, Z = NH
5a–i: n = 2, Z = NH
6a–d: n = 1, Z = O
2a: R = CF3
2b: R = Me
1: n = 1, 2; Z = NH, O
SYNLETT 2009, No. 17, pp 2821–2824
x
x
.x
x
.2
0
0
9
Advanced online publication: 25.09.2009
DOI: 10.1055/s-0029-1217984; Art ID: W10909ST
Scheme 1 Synthesis of bicyclic pyridones
© Georg Thieme Verlag Stuttgart · New York

2822
S.-J. Yan et al.
LETTER
of product 4d was further confirmed by X-ray crystallo-
graphic analysis (Figure 2).20
Encouraged by this result, we explored the scope and lim-
itations of the cyclocondensation reactions involving var-
ious HKA 1a–l with two b-keto ester enol tosylates 2a,b
(Table 1, entries 1–21). The results demonstrated that
HKA, with various substituents and different ring sizes,
were all good substrates for the cyclocondensation reac-
tion. The reactions usually took 3–14 hours at refluxing
temperature in 1,4-dioxane under basic conditions for
completion, and the yields were generally good.
Figure 2 X-ray crystal structure of 4d
The structures of the HKA 1 have an obvious influence on
the reactivity and product yield. For example, the reactiv-
ity of 1 was increased by the electron-rich properties of
the group on the aromatic ring (Table 1, entries 1–7, 8–12,
13–17, 18–21). Under the experimental conditions, the
reactivity order of five-membered HKA is 1g > 1f > 1d >
Table 1 Synthesis of Bicyclic Pyridones
Entry
1
HKA
1a
1b
1c
1d
1e
1f
Enol tosylates Product
n
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
1
1
1
1
Z
EWG
R
Yield (%)a
80
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2a
2a
2a
2a
2a
2b
2b
2b
2b
2a
2a
2a
2b
4a
4b
4c
4d
4e
4f
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
NO2
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Me
Me
Me
Me
Me
CF3
CF3
CF3
CF3
CF3
Me
Me
Me
Me
CF3
CF3
CF3
Me
2
COMe
82
3
COOEt
83
4
4-ClC6H3CO
C6H4CO
95
5
90
6
4-MeC6H3CO
4-MeOC6H3CO
COMe
94
7
1g
1b
1d
1e
1f
4g
4h
4i
95
8
82
9
4-ClC6H3CO
C6H4CO
88
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4j
90
4k
4l
4-MeC6H3CO
4-MeOC6H3CO
4-FC6H3CO
4-ClC6H3CO
C6H4CO
78
1g
1h
1i
84
5a
5b
5c
5d
5e
5f
83
89
1j
85
1k
1l
4-MeC6H3CO
4-MeOC6H3CO
4-ClC6H3CO
C6H4CO
90
91
1i
94
1j
5g
5h
5i
90
1k
1l
4-MeC6H3CO
4-MeOC6H3CO
C6H4CO
92
93
1m
1n
1o
1m
6a
6b
6c
6d
85
O
4-MeC6H3CO
4-MeOC6H3CO
C6H4CO
87
O
89
O
83
a Isolated yields.
Synlett 2009, No. 17, 2821–2824 © Thieme Stuttgart · New York

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.
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1997, 53, 11781.
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(b) Jones, R. C. F.; Patel, P.; Hirst, S. C.; Smallridge, M. J.
Tetrahedron 1998, 54, 6191. (c) Jones, R. C. F.; Smallridge,
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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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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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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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.
Synlett 2009, No. 17, 2821–2824 © Thieme Stuttgart · New York

2824
S.-J. Yan et al.
LETTER
for 3–14 h until the b-keto ester enol toslates 2 were
completely consumed. The mixture was quenched by the
addition of H2O (50 mL). The reaction mixture was filtered
off, and the residue was washed with H2O to give a crude
product that was recrystallized by EtOH or acetone to form
the final products 4–6.
Compound 4d: yellow solid; mp 184–187.5 °C. IR (KBr):
3366 (NH), 3079 (C=CH), 1679 (C=O), 1602 (C=O), 1558
(C=C), 1324 (CN), 1165 (CF) cm–1. 1H NMR (500 MHz,
DMSO-d6): d = 3.68 (t, J = 9.2 Hz, 2 H, CH2), 4.11 (t,
J = 9.1 Hz, 2 H, CH2), 6.00 (s, 1 H, CH=), 7.56–7.79 (m, 5
H, ArH, NH). 13C NMR (125 MHz, DMSO-d6): d = 42.6
(NCH2), 43.7 (NCH2), 91.8 (CCOAr), 104.3 (CHCO), 122.5
(q, J = 211.3 Hz, CF3), 128.5 (2 × CHar), 131.1 (2 × CHar),
137.0 (Car), 137.8 (Car), 140.0 (q, J = 30 Hz, CCF3), 154.4
(C=CCOAr), 159.0 (C=O), 190.2 (COAr). HRMS (TOF
ES–): m/z calcd for C15H9ClF3N2O2 [M – H+]: 341.0310;
found: 341.0308.
(16) (a) Cheng, D.-C.; Croft, L.; Abdi, M.; Lightfoot, A.;
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(d) Podhorez, D. E. J. Heterocycl. Chem. 1991, 28, 971.
(e) Sylvia, S.; Daniel, S.; Simon, S.; Zhang, X.; Volkhard, A.
Synthesis 2005, 3107.
(17) (a) Tilak, B. D.; Ayyangar, N. R.; Rao, U. S. Indian J.
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(19) General Procedure for the Cyclocondensation Reaction
A 50 mL round-bottom flask was charged with b-keto ester
enol tosylates 2 (1 mmol), 1,4-dioxane (10 mL), and Et3N (3
mL), then the solution was added to HKA 1 (1 mmol), and
the solution was refluxed. The resulting solution was stirred
(20) CCDC 738457 contains the supplementary crystallographic
data for compound 4d. These data can be obtained free of
charge from The Cambridge Crystallographic Data Center
via www.ccdc.cam.ac.uk/data_request/cif.
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