such as a base,7 expensive and/or harmful metals,8 the oxidants
for the aromatization,9 and other additives.10 Thus, the develop-
ment of more simple and practical methods is strongly desired.11
Herein, we report a novel and most practical reaction course to
the synthesis of multifunctionalized quinolines using imines and
carbonyl compounds on a large scale.
Practical and Simple Synthesis of Substituted
Quinolines by an HCl-DMSO System on a Large
Scale: Remarkable Effect of the Chloride Ion
Shin-ya Tanaka, Makoto Yasuda, and Akio Baba*
Initially, we found the synthesis of quinoline 3aa12 using
heptanal 1a and benzylideneaniline 2a catalyzed by HCl (4 M
in dioxane) under an N2 atmosphere. The reaction was com-
pleted within 6 h and provided quinoline 3aa in 43% yield
accompanied by a considerable amount of 1,2-dihydroquinoline
4 and amine 5 (Table 1, entry 1).13 Using 2 equiv of imine 2a
increased the yield of 3aa to 81% without the formation of 4,
Department of Applied Chemistry and Handai Frontier
Research Center, Graduate School of Engineering, Osaka
UniVersity, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
ReceiVed September 24, 2005
(6) More than three step reaction sequences were taken for quinoline
synthesis. See: (a) Ishikawa, T.; Manabe, S.; Aikawa, T.; Kudo, T.; Saito,
S. Org. Lett. 2004, 6, 2361-2364. (b) Theeraladanon, C.; Arisawa, M.;
Nishida, A.; Nakagawa, M. Tetrahedron 2004, 60, 3017-3035. (c) Ichikawa,
J.; Wada, Y.; Miyazaki, H.; Mori, T.; Kuroki, H. Org. Lett. 2003, 5. 1455-
1458. (d) Suginome, M.; Fukuda, T.; Ito, Y. Org. Lett. 1999, 1, 1977-
1979. (e) Kobayashi, K.; Takagoshi, K.; Kondo, S.; Morikawa, O.; Konishi,
H. Bull. Chem. Soc. Jpn. 2004, 77, 553-559. (f) Abbiati, G.; Beccalli, E.
M.; Broggini, G.; Zoni, C. Tetrahedron 2003, 59, 9887-9893. (g) Wiebe,
J. M.; Caille´, A. S.; Lau, C. K. Tetrahedron 1996, 52, 11705-11724. (h)
Kobayashi, K.; Yoneda, K.; Miyamoto, K.; Morikawa, O.; Hisatoshi, K.
Tetrahedron 2004, 60, 11639-11645. (i) Kobayashi, K.; Yoneda, K.;
Mizumoto, T.; Umakoshi, H.; Morikawa, O.; Konishi, H. Tetrahedron Lett.
2003, 44, 4733-4736.
(7) (a) Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109-
1112. (b) Larock, R. C.; Kuo, M.-Y. Tetrahedron Lett. 1991, 32, 569-
572. (c) Strekowski, L.; Janda, L.; Patterson, S. E.; Nguyen, J. Tetrahedron
1996, 52, 3273. (d) Arcadi, A.; Marinelli, F.; Rossi, E. Tetrahedron 1999,
55, 13233-13250. (e) Kim, J. N.; Lee, H. J.; Lee, K. Y.; Kim, H. S.
Tetrahedron Lett. 2001, 42, 3737-3740. (f) Zhao, F.; yang, X.; Liu, J.
Tetrahedron 2004, 60, 9945-9951. (g) Cho, C. S.; Kim, B. T.; Kim, T.-J.;
Shim, S. C. Chem. Commun. 2001, 2576-2577. (k) Takashi, M.; Ichikawa,
J.; Chem. Lett. 2004, 33, 590-591.
(8) (a) Jiang, B.; Si, Y.-G. J. Org. Chem. 2002, 67, 9449-9451. (b)
Cho, C. S.; Kim, T. K.; Kim, B. T.; Kim, T.-J.; Shim, S. C. J. Organomet.
Chem. 2002, 650, 65-68. (c) McNaughton, B. R.; Miller, B. L. Org. Lett.
2003, 5, 4257-4259. (d) Du, W.; Curran, D. P. Org. Lett. 2003, 5, 1765-
1768.
(9) (a) Akiyama, T.; Nakashima, S.; Yokota, K.; Fuchibe, K. Chem. Lett.
2004, 33, 922-923. (b) Cho, C. S.; Oh, B. H.; Kim, J. S.; Kim, T.-J.; Shim,
S. C. Chem. Commun. 2000, 1885-1886. (c) Sangu, K.; Fuchibe, K.;
Akiyama, T. Org. Lett. 2004, 6, 353-355. (d) Cho, C. S.; Kim, B. T.;
Choi, H.-J.; Kim, T.-J.; Shim, S. C. Tetrahedron 2003, 59, 7997-8002.
(e) Kimpe, N. D.; Keppens, M. Tetrahedron 1996, 52, 3705-3718.
(10) Mahata, P. K.; Venkatesh, C.; Kumar, U. K. S.; Ila, H.; Junjappa,
H. J. Org. Chem. 2003, 68, 3966-3975. Most other quinoline syntheses
using Vilsmeier-type reactions referenced therein also need more than an
equimolar amount of POCl3.
A variety of substituted quinolines are synthesized from
imines and enolizable carbonyl compounds under aerobic
conditions, in which only water is a byproduct. In DMSO,
a catalytic amount of HCl activates carbonyl compounds
quite effectively to give the quinolines. A simple and
practical procedure is demonstrated on a large scale.
Substituted quinolines which are included in natural products
and drugs play important roles in medicinal chemistry. Their
biological activities1 are widely used as, e.g., antimalarial,
antiinflammatory, and antibacterial agents.2 Because of their
importance, the synthesis of substituted quinolines has been a
focus of organic chemistry since Skraup’s procedure was
reported over a century ago,3 and a large number of general
synthetic methods have been reported.4 However, most of the
synthetic routes still suffer from various problems: (1) harsh
conditions,5 (2) multisteps,6 and (3) a large amount of promoters
(1) (a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605. (b) Balasubramanian,
M.; Keay, J. G. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, New
York, 1996; Vol. 5, p 245.
(2) (a) Larsen, R. D.; Corley, E. G.; King, A. O.; Carrol, J. D.; Davis,
P.; Verhoeven, T. R.; Reider, P. J.; Labelle, M.; Gauthier, J. Y.; Xiang, Y.
B.; Zamboni, R. J. J. Org. Chem. 1996, 61, 3398-3405. (b) Chen, Y.-L.;
Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C. J. Med. Chem. 2001,
44, 2374-2377. (c) Roma, G.; Braccio, M. D.; Grossi, G.; Mattioli, F.;
Ghia, M. Eur. J. Med. Chem. 2000, 35, 1021-1035. (d) Dube´, D.; Blouin,
M.; Brideau, C.; Chan, C.-C.; Desmarais, S.; Ethier, D.; Falgueyret, J.-P.;
Friesen, R. W.; Girard, M.; Girard, Y.; Guay, J.; Riendeau, D.; Tagari, P.;
Young, R. N. Bioorg. Med. Chem. Lett. 1998, 8, 1255-1260. (e) Maguire,
M. P.; Sheets, K. R.; McVety, K.; Spada, A. P.; Zilberstein, A. J. Med.
Chem. 1994, 37, 2129-2137.
(11) Recently, some useful approaches assisted by microwave and/or
Lewis acid catalysts have been reported, although none of them were
performed on a large scale. (a) Makioka, Y.; Shindo, T.; Taniguchi, Y.;
Takai, K.; Fujiwara, Y. Synthesis 1995, 801-804. (b) Song, S. J.; Cho, S.
J.; Park, D. K.; Kwon, T. W.; Jenekhe, S. A. Tetrahedron Lett. 2003, 44,
255-257. (c) Arcadi, A.; Chiarini, M.; Giuseppe, S. D.; Marinelli, F. Synlett
2003, 203-206. (d) Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U. Tetrahedron
2003, 59, 813-819. (e) Yadav, J. S.; Reddy, B. V. S.; Rao, R. S.;
Naveenkumar, V.; Nagaiah, K. Synthesis 2003, 1610-1614. (f) Yadav, J.
S.; Reddy, B. V. S.; Premalatha, K. Synlett 2004, 963-966. (g) Yadav, J.
S.; Reddy, B. V. S.; Sreedhar, R.; Rao, S.; Nagaiah, K. Synthesis 2004, 14,
2381-2385. (h) De, S. K.; Gibbs, R. A. Tetrahedron Lett. 2005, 46, 1647-
1649.
(12) 2-Arylquinolines are biologically active and occur in structures of
antimalarial compounds and antitumor agents. See: (a) Craig, P. N. J. Med.
Chem. 1972, 15, 144-149. (b) Atwell, G. J.; Baguley, B. C.; Denny, W.
A. J. Med. Chem. 1989, 32, 396-401.
(13) Quinoline synthesis using imines and Cu-acetylides involving
dehydrogenative aromatization by imines was reported. See: Huma, H. Z.;
Halder, R.; Kalra, S. S.; Das, J.; Iqbal, J. Tetrahedron Lett. 2002, 43, 6485-
6488.
(3) Skraup, H. Chem. Ber. 1880, 13, 2086-2087.
(4) For recent reports on quinoline synthesis, see: (a) Zhang, X.; Campo,
M. A.; Yao, T.; Larock, R. C. Org. Lett. 2005, 7, 763-766. (b) Igarashi,
T.; Inada, T.; Sekioka, T.; Nakajima, T.; Shimizu, I. Chem. Lett. 2005, 34,
106-107 and references therein.
(5) (a) Matsugi, M.; Tabusa, F.; Minamikawa, J.-i. Tetrahedron Lett.
2000, 41, 8523-8525. (b) Linderman, R. J.; Kirollos, K. S. Tetrahedron
Lett. 1990, 31, 2689-2692. (c) Strekowski, L.; Czarny, A.; Lee, H. J.
Fluorine Chem. 2000, 104, 281-284. (d) Panda, K.; Siddiqui, I.; Mahata,
P. K.; Ila, H.; Junjappa, H. Synlett 2004, 449-452.
10.1021/jo052004y CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/02/2005
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