New approach to 2-quinolinones

Article abstract of DOI:10.1021/ol7030312

An efficient approach to 2-quinolinone derivatives 1 via Diels-Alder cyclization of exo-diene lactams 5 and dienophiles is reported.

Full text of DOI:10.1021/ol7030312

ORGANIC
LETTERS
2008
Vol. 10, No. 4
673-676
New Approach to 2-Quinolinones
Cheng-Chieh Huang and Nein-Chen Chang*
Department of Chemistry, National Sun Yat-Sen UniVersity, Kaohsiung 804, Taiwan
ncchang@mail.nsysu.edu.tw
Received December 17, 2007
ABSTRACT
An efficient approach to 2-quinolinone derivatives 1 via Diels−Alder cyclization of exo-diene lactams 5 and dienophiles is reported.
Polysubstituted quinolinones, dihydroquinolines, tetrahyd-
roquinolines, and quinolines are common motifs found in
Scheme 2
Scheme 1
natural products and pharmaceutical agents.1 Furthermore,
2-quinolinone derivatives have been paid considerable at-
tention in organic chemistry due to their use as anti-
inflammatories, antihypertensives, and analgesics2 and in the
preparation of antipsychotic agents.3 As such, a common
(1) For examples, see the following. Quinolin-2-ones: (a) Carling, R.
W.; Leeson, P. D.; Moore, K. W.; Smith, J. D.; Moyes, C. R.; Mawer, I.
M.; Thomas, S.; Chan, T.; Baker, R.; Foster, A. C.; Grimwood, S.; Kemp,
I. M.; Marshall, G. R.; Tricklebank, M. D.; Saywell, K. L. J. Med. Chem.
1993, 36, 3397. (b) Rowley, M.; Kulagowski, J. J.; Watt, A. P.; Rathbone,
D.; Stevenson, G. I.; Carling, R. W.; Baker, R.; Marshell, G. R.; Kemp, J.
A.; Foster, A. C.; Grimwood, S.; Hargreaves, R.; Hurley, C.; Saywell, K.
L.; Tricklebank, M. D.; Leeson, P. D. J. Med. Chem. 1997, 40, 4053. (c)
Foucaud, B.; Laube, B.; Schemm, R.; Kreimeyer, A.; Goeldner, M.; Betz,
H. J. Biol. Chem. 2003, 278, 24011. Tetrahydroquinolines: (d) Katritzky,
A.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031. Dihydroquino-
lines: (e) Michne, W. F.; Guiles, J. W.; Treasurywala, A. D.; Castonguay,
L. A.; Weigelt, C. A.; Oconnor, B.; Volberg, W. A.; Grant, A. M.;
Chadwick, C. C.; Krafte, D. S.; Hill, R. J. J. Med. Chem. 1995, 38, 1877.
(f) Gaillard, S.; Papamicael, C.; Marsais, F.; Dupas, G.; Levacher, V. Synlett
2005, 441. (g) van Straten, N. C. R.; van Berkel, T. H. J.; Demont, D. R.;
Karstens, W.-J. F.; Merkx, R.; Oosterom, J.; Schulz, J.; van Someren, R.
G.; Timmers, C. M.; van Zandvoort, P. M. J. Med. Chem. 2005, 48, 1697.
Quinolines: (h) Michael, J. P. Nat. Prod. Rep. 2003, 20, 476.
Scheme 3
cascade route to each class of compounds would be of
significant synthetic value.
(2) Setoguchi, N.; Takano, Y. Ch. Kitami. Jpn. Kokai Tokkyo Koho:
JP 01006269A2, Jan 1989.
(3) Howard, H. R. Eur. Pat. Appl. EP 409,435 (Cl. C07D403 14).
10.1021/ol7030312 CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/19/2008

the development of novel synthetic approaches remains an
active research area.5 2-Quinolinones, reasonable precursors
Scheme 4
Table 2. Aromatization of the Resulting Cycloadducts
Although many methods have been developed for the
synthesis of quinolines and their derivatives, most are not
Table 1. Diels-Alder Reaction of Diene 8 with Various
Dienophiles
of quinoline, are useful intermediates in organic synthesis.6
In general, the synthesis of quinolinone starts with benzene
and then builds up to the second ring. Following this strategy,
the presence of deactivated electron-withdrawing substituents
at benzene ring normally will give low yields of quinolinone.
(4) (a) Cho, C. S.; Oh, B. H.; Shim, S. C. Tetrahedron Lett. 1999, 40,
1499. (b) Zhou, L.; Zhang, Y. J. Chem. Soc., Perkin Trans. 1 1998, 2899.
(c) Larock, R. C.; Kero, M.-Y. Tetrahedron Lett. 1991, 32, 569. (d) Zhou,
L.; Tu, S.; Shi, D.; Dai, G.; Chen, W. Synthesis 1988, 851. (e) Larock, R.
C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291. (f) Ozawa, F.; Yanagihara,
H.; Yamamoto, A. J. Org. Chem. 1986, 51, 415.
(5) Wang, G. W.; Jia, C. S.; Dong, Y. W. Tetrahedron Lett. 2006, 47,
1059.
(6) (a) Holzapfel, C. W.; Dwyer, C. Heterocycles 1998, 48, 215. (b)
Cortese, N. A.; Ziegler, C. B.; Hrnjez, B. J.; Heck, R. F. J. Org. Chem.
1978, 43, 2952. (c) Chorbadjiev, S. Synth. Commun. 1990, 20, 3497. (d)
Kobayashi, K.; Kitamura, T.; Yoneda, K.; Morikawa, O.; Konishi, H. Chem.
Lett. 2000, 798. (e) Hino, K.; Furukawa, K.; Nagai, Y.; Uno, H. Chem.
Pharm. Bull. 1980, 28, 2618. (f) Hino, K.; Kawashima, K.; Oka, M.; Nagai,
Y.; Uno, H.; Matsumoto, J. Chem. Pharm. Bull. 1989, 37, 110. (g) Ferrer,
P.; Avendano, C.; Soellhuber, M. Liebigs Ann. Chem. 1995, 1895. (h)
Terpko, M. O.; Heck, R. F. J. Am. Chem. Soc. 1979, 101, 5281. (i) Kaupp,
G.; Gru¨ndken, E.; Matthies, D. Chem. Ber. 1986, 119, 3109. (j) Kano, S.;
Ozaki, T.; Hibino, S. Heterocycles 1979, 12, 489.
fully satisfactory either with regard to yield or reaction
conditions, generality, or operational simplicity.4 Therefore,
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Org. Lett., Vol. 10, No. 4, 2008

Table 3. Formation of 2-Quinolinone Derivatives
Table 3. Formation of 2-Quinolinone Derivatives
Here, we wish to report a new approach to 2-quinolinones 1
in which the construction of benzene ring was at the last
stage.
Recently, we developed a one-pot procedure which
converted readily available glutarimide 2 to the correspond-
ing ene lactams 3 (Scheme 1).7 We envisioned that these
results can be applied to the synthesis of exo-diene lactams
5. Diels-Alder cyclization of 5 with dienophiles and then
aromatization of the resulting products 6 will give 2-quino-
linones 1 (Scheme 2).
We first studied the synthesis of diene lactam 8. Sequential
reaction of readily available 78 with sodium hydride, meth-
ylmagnesium bromide, and then acetic anhydride furnished
diene lactam 8 in 55% yield. Diene 8 is very stable and can
be stored at room temperature for several months.
With diene 8 in hand, we then focused our attention on
the Diels-Alder reaction of 8 with various dienophiles
(Table 1). The reactions of diene 8 with alkene dienophiles
provide regioselectively the corresponding bicyclic ene
lactams in reasonable yield (entries 1-3).9 Dienophiles with
triple bonds similarly undergo Diels-Alder reaction (entries
4 and 5) (Table 1). In the case of ethyl propiolate, a mixture
of 13a and 13b in a 2:1 ratio was observed. Presumably,
part of 13a was air oxidized to 13b during the reaction. Aza-
polycyclic aromatic compounds have been shown in recent
(7) Tsai, M. R.; Chen, B. F.; Cheng, C. C.; Chang, N. C. J. Org. Chem.
2005, 70, 1780.
(8) Chen, C. Y.; Chang, M. Y.; Hsu, R. T.; Chen, S. T.; Chang, N. C.
Tetrahedron Lett. 2003, 44, 8627.
(9) Govaerts, T. C.; Vogels, I. A.; Compernolle, F.; Hoornaert, G. J.
Tetrahedron 2004, 60, 429.
Org. Lett., Vol. 10, No. 4, 2008
675

applications to have useful optical properties.10 Thus, we
turned our attention to the Diels-Alder reactions of 8 with
quinone derivatives (entries 6-8). The reactions only
produced dihydroquinones 14-16. Air oxidation of the
Diels-Alder reaction adducts to the corresponding dihyd-
roquinones might account for the results.
yield. The reaction of diene 24 with 1,4-naphthoquinone gave
a mixture of 30a and 30b in a 1:4 ratio (entry 3).
Nevertheless, diene lactam 24 afforded 2-quinolinone 33 as
the sole product (entry 6). We have no clear reason for the
results.
Attempts to extend this approach to alkylidene substrates
40a and 40b failed, presumably due to the unstability of this
type of diene lactams during Diels-Alder reaction (Scheme
4).
In conclusion, we provided a new approach to 2-quino-
linone derivatives which contain an aryl and electron-
withdrawing groups at the benzene ring. The application of
these results to the synthesis of tetracene and pentacene
analogues is currently underway in our laboratory. Their
optical properties will also be examined.
We next focused our attention on the aromatization of the
Diels-Alder reaction products. Treatment of bicyclic ene
lactam 12 with NBS and sodium methoxide successfully
afforded 2-quinolinone derivative 17a in 70% yield. Fol-
lowing a similar procedure, the mixture of 13a and 13b was
converted to 17b. Ene lactams 15 and 16 produced the
corresponding 3-tosyl-2-quinolinones 17c and 17d, respec-
tively (Table 2). Alternatively, treatment of 15 with sodium
hydride and methyl iodide produced 18 (Scheme 3).
Having successfully obtained 2-quinolinones 17a-d and
18, we then examined the scope of the new approach.
Following the procedures in Table 1, a series of diene lactams
24-27 were prepared and subjected to the Diels-Alder
reaction and aromatization process. The results are shown
in Table 3. Attempts to prepare imide 23 were unsuccessful.
The diene lactams which contained aromatic backbones
furnished the corresponding 2-quinolinones in reasonable
Acknowledgment. Financial support from the National
Science Council of the Republic of China is gratefully
acknowledged.
Supporting Information Available: 1H and 13C NMR
data for all new compounds and experimental details. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Li, A.; Kindelin, P. J.; Klumpp, D. A. Org. Lett. 2006, 8, 1233.
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