ORGANIC
LETTERS
2009
Vol. 11, No. 5
1043-1045
Novel Approach to
3,4-Dihydro-2(1H)-quinolinone Derivatives
via Cyclopropane Ring Expansion
Takayuki Tsuritani,* Yuhei Yamamoto, Masashi Kawasaki, and Toshiaki Mase
Process Research, PreClinical Department, Banyu Pharmaceutical Co. Ltd., 3 Okubo,
Tsukuba, Ibaraki 300-2611, Japan
Received November 19, 2008
ABSTRACT
N-(1′-Alkoxy)cyclopropyl-2-haloanilines are transformed to 3,4-dihydro-2(1H)-quinolinones via palladium-catalyzed cyclopropane ring expansion.
The reaction tolerates a variety of functional groups such as ester, nitrile, ether, and ketone groups.
The benzo-fused lactam skeleton is an important element in
a number of pharmacologically and biologically active
compounds. The 3,4-dihydro-2(1H)-quinolinone scaffold is
one important member of this class, and its derivatives are
found in many natural products and drug candidates.1 3,4-
Dihydro-2(1H)-quinolinones are classically synthesized via
electrophilic aromatic substitution reactions, such as the
Friedel-Crafts reaction,2a Beckmann rearrangement of in-
danone oxime,2b and cyclization of nitrenium ion;2c,d how-
ever, these methods require a stoichiometric amount of metal
salt. Moreover, the reactions with electron deficient substrates
in general give unsatisfactory results. Recently, various
reports of efficient catalytic systems for the preparation of
3,4-dihydro-2(1H)-quinolinones have been published.3
During the course of our study we found that 2-methoxy-
3,4-dihydroquinoline (2a) was formed as a byproduct when
N-(1′-methoxy)cyclopropyl-2-iodoaniline (1a) was subjected
to Larock indole synthesis conditions (Scheme 1).4,5 This
Scheme 1. Larock Indole Synthesis against
N-(1′-Methoxy)cyclopropyl-2-iodoaniline
(1) (a) Chen, M.-H.; Fitzgerald, P.; Singh, S. B.; O’Neill, E. A.;
Schwartz, C. D.; Thompson, C. M.; O’Keefe, S. J.; Zaller, D. M.; Doherty,
J. B. Bioorg. Med. Chem. Lett. 2008, 18, 2222. (b) Singer, J. M.; Barr,
B. M.; Coughenour, L. L.; Gregory, T. F.; Walters, M. A. Bioorg. Med.
Chem. Lett. 2005, 15, 4560. (c) Oshiro, Y.; Sakurai, Y.; Sato, S.; Kurahashi,
N.; Tanaka, T.; Kikuchi, T.; Tottori, K.; Uwahodo, Y.; Miwa, T.; Nishi, T.
J. Med. Chem. 2000, 43, 177. (d) Zhao, H.; Thurkauf, A.; Braun, J.;
Brodbeck, R.; Kieltyka, A. Bioorg. Med. Chem. Lett. 2000, 10, 2119. (e)
Tamura, Y. S.; Goldman, A. E.; Bergum, W. P.; Semple, E. J. Bioorg.
Med. Chem. Let. 1999, 9, 2573.
result prompted us to examine this palladium-catalyzed
cyclopropane ring expansion reaction. The 3,4-dihydroquino-
(2) (a) Beck, J. R.; Kwok, R.; Booher, R. N.; Brown, A. C.; Patterson,
L. E.; Pranc, P.; Rockey, B.; Pohland, A. J. Am. Chem. Soc. 1968, 90,
4706. (b) Torisawa, Y.; Nishi, T.; Minamikawa, J. Bioorg. Med. Chem.
Lett. 2007, 17, 448. (c) Kikugawa, Y.; Nagashima, A.; Sakamoto, T.;
Miyazawa, E.; Shiiya, M. J. Org. Chem. 2003, 68, 6739. (d) Cherest, M.;
Lusinchi, X. Tetrahedron Lett. 1989, 30, 715.
(3) (a) Fujita, K.; Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi,
R. Org. Lett. 2004, 6, 2785. (b) Yang, B. H.; Buchwald, S. L. Org. Lett.
1999, 1, 35. (c) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron
1996, 52, 7525. (d) Ali, B. E.; Okuro, K.; Vasapollo, G.; Alper, H. J. Am.
Chem. Soc. 1996, 118, 4264. (e) Jones, K.; Wilkinson, J.; Ewin, R.
Tetrahedron Lett. 1994, 35, 7673
.
10.1021/ol802669r CCC: $40.75
Published on Web 02/04/2009
2009 American Chemical Society