pubs.acs.org/joc
reaction of 20-aminophenyl ketones and aldehydes has been
Synthesis of 2,3-Dihydroquinolin-4(1H)-ones through
Catalytic Metathesis of o-Alkynylanilines and
Aldehydes
reported as a relatively facile method for the direct prepara-
tion of 2,3-dihydroquinolin-4(1H)-ones, the procedure is
limited to the formation of 2-substituted products.5,6
Metal-catalyzed metathesis of alkyne and carbonyl com-
pounds has received attention as a straightforward and
atom economical approach to the formation of conjugated
enones via a formal [2 + 2] cycloaddition and cycloreversion
(eq 1).7,8 We recently developed a one-pot procedure for the
SbF5-alcohol complex-catalyzed synthesis of indanones
through alkyne-carbonyl metathesis and the subsequent
Nazarov cyclization.9 Au-catalyzed synthesis of cyclopenta-
nones by the similar approach was reported by Yamamoto
et al.10 These findings encouraged us to examine the forma-
tion of 2,3-dihydroquinolin-4(1H)-ones by means of the
catalytic alkyne-carbonyl metathesis of o-alkynylaniline
derivatives and aldehydes (eq 2). The metal-catalyzed cycli-
zation of o-alkynylanilines to indoles has been established as
an efficient synthetic method (eq 3).11,12 Even in the pre-
sence of an aldehyde, Pd- or Cu-catalyzed reaction of
o-alkynylaniline has been reported to afford the indole
product.12a,13 We herein describe the one-pot synthesis of
Akio Saito,*,† Jun Kasai,† Yu Odaira,† Haruhiko Fukaya,‡
and Yuji Hanzawa*,†
†Laboratory of Organic Reaction Chemistry, Showa
Pharmaceutical University, 3-3165 Higashi-
Tamagawagakuen, Machida, Tokyo 194-8543, Japan, and
‡School of Pharmacy, Tokyo University of Pharmacy and Life
Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392,
Japan
akio-sai@ac.shoyaku.ac.jp; hanzaway@ac.shoyaku.ac.jp
Received April 25, 2009
(5) (a) Chandrasekhar, S.; Vijeender, K.; Sridhar, C. Tetrahedron Lett.
2007, 48, 4935. (b) See also Draper, R. W.; Hu, B.; Iyer, R. V.; Li, X.; Lu, Y.;
Rahman, M.; Vater, E. Tetrahedron 2000, 56, 1811-1817.
(6) The other direct procedures: (a) Grigg, R.; Liu, A.; Shaw, D.;
Suganthan, S.; Woodall, D. E.; Yoganathan, G. Tetrahedron Lett. 2000,
41, 7125. (b) Ye, F.; Alper, H. J. Org. Chem. 2007, 72, 3218. (c) Nemoto, T.;
Fukuda, T.; Hamada, Y. Tetrahedron Lett. 2006, 47, 4365. (d) Baraznenok, I.
L.; Nenajdenko, V. G.; Churakov, A. V.; Nesterenko, P. N.; Balenkova, E. S.
Synlett 2000, 514. (e) See also Cheng, D.; Zhou, J.; Saiah, E.; Beaton, G. Org.
Lett. 2002, 4, 4411.
(7) Catalytic procedures for the alkyne-carbonyl metathesis: (a) Curini,
M.; Epifano, F.; Maltese, F.; Rosati, O. Synlett 2003, 552. (b) Rhee, J. U.;
Krische, M. J. Org. Lett. 2005, 7, 2493. (c) Jin, T.; Yamamoto, Y. Org. Lett.
2007, 9, 5259.
SbF5-MeOH catalytic system efficiently promotes the
alkyne-carbonyl metathesis of o-alkynylaniline deriva-
tives and aldehydes to afford 2,3-disubstituted dihydro-
quinolinones in moderate to high yields with high trans-
selectivity.
(8) Examples of stoichiometric procedures for the alkyne-carbonyl
metathesis: (a) Harding, C. E.; Hanack, M. J. Org. Chem. 1989, 54, 3054.
(b) Sisko, J.; Balog, A.; Curran, D. P. J. Org. Chem. 1992, 57, 4341. (c)
Wempe, M. F.; Grunwell, J. R. Tetrahedron Lett. 2000, 41, 6709. (d) Hayashi,
A.; Yamaguchi, M.; Hirama, M. Synlett 1995, 195. (e) Viswanathan, G. S.;
Li, C.-J. Tetrahedron Lett. 2002, 43, 1613.
(9) Saito, A.; Umakoshi, M.; Yagyu, M.; Hanzawa, Y. Org. Lett. 2008,
10, 1783.
(10) Jin, T.; Yamamoto, Y. Org. Lett. 2008, 10, 3137.
(11) (a) Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.; McKillop, A.
Tetrahedron Lett. 1985, 26, 5963. (b) Iritani, K.; Matsubara, S.; Uchimoto,
K. Tetrahedron Lett. 1988, 29, 1799. (c) Arcadi, A.; Cacchi, S.; Marinelli,
F. Tetrahedron Lett. 1992, 33, 3915. (d) Kondo, Y.; Shiga, N.; Murata,
N.; Sakamoto, T.; Yamanaka, H. Tetrahedron Lett. 1994, 50, 11803.
(e) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671.
(f) Shen, Z.; Lu, X. Tetrahedron 2006, 62, 10896.
(12) (a) An example of Cu(I)-catalyzed reaction: Kamijo, S.; Sasaki, Y.;
Yamamoto, Y. Tetrahedron Lett. 2004, 45, 35. (b) An example of Cu(II)-
catalyzed reaction: Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem.
2004, 69, 1126. (c) An example of Pt(II)-catalyzed reaction: Shimada, T.;
Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 10546. (d) An
example of Au(III)-catalyzed reaction: Alfonsi, M.; Arcadi, A.; Aschi, M.;
Bianchi, G.; Marinelli, F. J. Org. Chem. 2005, 70, 2265. (e) An example of Ag-
catalyzed reaction: Van Esseveldt, B. C. J.; van Delft, F. L.; Smits, J. M. M.;
de Gelder, R.; Schoemaker, H. E.; Rutjes, F. P. J. T. Adv. Synth. Catal. 2004,
346, 823. (f) An example of In-catalyzed reaction: Sakai, N.; Annaka, K.;
Konakahara, T. Org. Lett. 2004, 6, 1527. (g) An example of Ir-catalyzed
reaction: Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005,
7, 5437. (h) An example of Rh(I)-catalyzed reaction: Trost, B. M.; McClory,
A. Angew. Chem., Int. Ed. 2007, 46, 1.
2,3-Dihydroquinolin-4(1H)-ones possess attractive phar-
macological properties1 and also serve as important syn-
thetic intermediates for the preparation of biologically active
compounds.2 The cyclization of 20-aminochalcones3 or 3-
anilinopropionic acid derivatives,4 which often suffer from
low yields, harsh conditions, or cumbersome synthesis of the
substrates, has been widely used for the preparation of 2,3-di-
hydroquinolin-4(1H)-ones. Although the proline-catalyzed
(1) (a) Beifuss, U.; Feder, G.; Bes, T.; Uson, I. Synlett 1998, 649. (b)
Chen, W.; Egar, A. L.; Hursthouse, M. B.; Malik, K. M. A.; Mathews, J. E.;
Roberts, S. M. Tetrahedron Lett. 1998, 39, 8495. (c) Xia, Y.; Yang, Z.-Y.;
Xia, P.; Bastow, K. F.; Tachibana, Y.; Kuo, S.-C.; Hamel, E.; Hackl, T.; Lee,
K.-H. J. Med. Chem. 1998, 41, 1155. (d) Zhang, S.-X.; Kuo, S.-C.; Brossi, A.;
Hamel, E.; Tropsha, A.; Lee, K.-H. J. Med. Chem. 2000, 43, 167.
(2) (a) Nishijima, K.; Shinkawa, T.; Yamashita, Y.; Sato, N.; Nishida,
H.; Kato, K.; Onuki, Y.; Mizota, M.; Ohtomo, K.; Miyano, S. Eur. J. Med.
Chem. 1998, 33, 267. (b) Nieman, J. A.; Ennis, M. D. Org. Lett. 2000, 2, 1395.
(3) (a) Donnelly, J. A.; Farrell, D. F. J. Org. Chem. 1990, 55, 1757. (b)
Kundu, N. G.; Mahanty, J. S.; Das, P.; Das, B. Tetrahedron Lett. 1993, 34,
1625. (c) Varma, R. S.; Saini, R. K. Synlett 1997, 857. (d) Kumar, K. H.;
Muralidharan, D.; Perumal, P. T. Synthesis 2004, 63. (e) Naseem Ahmed, N.;
van Lier, J. E. Tetrahedron Lett. 2006, 47, 2725. (f) Lee, J. I.; Jung, H. J. J.
Korean Chem. Soc. 2007, 51, 106.
(4) Recent examples of synthesis applications: (a) Lin, Z.; Tegley, C. M.;
Marschke, K. B.; Jones, T. K. Bioorg. Med. Chem. Lett. 1999, 9, 1009. (b)
Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang, W. J. Org. Chem. 2003, 68, 442. (c)
Kasiotis, K. M.; Fokialakis, N.; Haroutounian, S. A. Synthesis 2006, 1791.
(d) Larghi, E. L.; Obrist, B. V.; Kaufman, T. S. Tetrahedron 2008, 64, 5236.
(13) (a) Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000,
122, 5662. (b) Terrason, V.; Michaux, J.; Gaucher, A.; Wehbe, J.; Marque, S.;
Prim, D.; Campagne, J.-M. Eur. J. Org. Chem. 2007, 5332.
5644 J. Org. Chem. 2009, 74, 5644–5647
Published on Web 06/04/2009
DOI: 10.1021/jo900857c
r
2009 American Chemical Society