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H2SO4 (0.75 equiv.),
MeOH, reflux, 17 hr
TMS
OMe
+
ArCHO
NH2
N
Ar
5. For reviews on quinoline synthesis, see: (a) Claret, P. A.. In Comprehensive
Organic Chemistry; Barton, D., Ollis, W. D., Eds.; Pergamon Press: Oxford,
1979; Vol. 4, pp 1479–1489; (b) Jones, G.. In Comprehensive Heterocyclic
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In Science of Synthesis; Black, D. S., Ed.; Thieme: Stuttgart, 2005; Vol. 15,
pp 389–549; (d) Larsen, R. D.. In Science of Synthesis; Black, D. S., Ed.;
Thieme: Stuttgart, 2005; Vol. 15, pp 551–660; (e) Kouznetsov, V. V.;
2
1
3
air
H2SO4
-MeOTMS
MeOH
´
´
´
Vargas Mendez, L. Y.; Melendez Gomez, C. M. Curr. Org. Chem. 2005, 9,
141–161; (f) Madapa, S.; Tusi, Z.; Batra, S. Curr. Org. Chem. 2008, 12,
1116–1183; (g) Arisawa, M.; Terada, Y.; Theeraladanon, C.; Takahashi, K.;
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701–718.
TMS
Ar
OMe
TMS
TMS
MeOH
-H+
N
H
Ar
N
H
N
H
Ar
HSO4
C
B
A
6. (a) Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. Chem. Commun. 2001, 2576–2577;
(b) Cho, C. S.; Kim, B. T.; Choi, H.-J.; Kim, T.-J.; Shim, S. C. Tetrahedron 2003, 59,
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9001; (d) Vander, H. M.; Ledoux, N.; Allaert, B.; Voort, P. V. D.; Drozdzak, R.;
Vos, D. D.; Verpoort, F. New J. Chem. 2007, 31, 1572–1574; (e) Martinez, R.;
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7451–7456; (b) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52,
15031–15070; (c) Yadav, J. S.; Reddy, B. V. S.; Rao, R. S.; Naveenkumar, V.;
Nagaiah, K. Synthesis 2003, 1610–1614; (d) Zhao, Y.-L.; Zhang, W.; Wang, S.;
Liu, Q. J. Org. Chem. 2007, 72, 4985–4988.
Scheme 4. Proposed mechanism for the acid promoted cyclization of
2-(2-(trimethylsilyl)ethynyl)aniline 1a with arylaldehydes 2 in methanol.
1a as substrate. This result suggests that the mechanism in Scheme
4 is more reasonable, which involves: (1) imine formation under
acid catalysis; (2) intramolecular attack of the alkyne to iminium
A; (3) the resulting vinyl cation B quenched by methanol; and fi-
nally (4) desilylation and air oxidation of 1,2-dihydroquinoline C
to give the final product.
8. (a) Zhang, X.; Campo, M. A.; Larock, R. C. Org. Lett. 2005, 7, 763–766; (b) Luo, Y.;
Li, Z.; Li, C.-J. Org. Lett. 2005, 7, 2675–2678; (c) Gabriele, B.; Mancuso, R.;
Salerno, G.; Ruffolo, G.; Plastina, P. J. Org. Chem. 2007, 72, 6873–6877; (d) Amii,
H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109–1112; (e) Li, L.; Jones, W.
D. J. Am. Chem. Soc. 2007, 129, 10707–10713; (f) Cho, C. S.; Kim, J. U. Tetrahedron
Lett. 2007, 48, 3775–3778; (g) Zhang, Z.; Tan, J.; Wang, Z. Org. Lett. 2008, 10,
173–175. and references cited therein.
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Suginome, M.; Fukuda, T.; Ito, Y. Org. Lett. 1999, 1, 1977–1979; (c) Fayol, A.;
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Wang, Y.-G. Tetrahedron Lett. 2006, 47, 3127–3130.
In summary, we have demonstrated a convenient method for
the construction of 4-alkoxy-2-arylquinolines from 2-(2-(trimeth-
ylsilyl)ethynyl)anilines 1 and arylaldehydes 2 in alcoholic solvents
catalyzed by sulfuric acid. This novel three-component, one-pot
reaction provides an efficient way for the synthesis of diversified
4-alkoxy-2-arylquinolines.
Acknowledgment
10. (a) Goodwin, S.; Smith, A. F.; Valsquez, A. A.; Horning, E. C. J. Am. Chem. Soc.
1959, 81, 6209–6213; (b) Fournet, A.; Vagneur, B.; Rilchomme, P.; Bruneton, J.
Can. J. Chem. 1989, 67, 2116.
11. Ko, T.-C.; Hour, M.-J.; Lien, J.-C.; Teng, C.-M.; Lee, K.-H.; Kuo, S.-C.; Huang, L.-J.
Bioorg. Med. Chem. Lett. 2001, 11, 279–282.
This work was financially supported by Start-up Foundation for
New Investigators from Guangzhou Institutes of Biomedicine and
Health (GIBH).
12. (a) Singh, O. V.; Kapil, R. S. Synlett 1992, 751; (b) Verma, R. S.; Kumar, D.
Tetrahedron Lett. 1998, 39, 9113–9116; (c) Mphahlele, M. J.; Mogamisi, F. K.;
Tsanwani, M.; Hlatshwayo, M. S.; Mampa, M. R. J. Chem. Res., Synop. 1999, 706–
707; (d) Arcadi, A.; Marinelli, F.; Rossi, E. Tetrahedron 1999, 55, 13233–13250;
(e) Kumar, K. H.; Perumal, P. T. Tetrahedron 2007, 63, 9531–9535.
13. (a) Domling, A. Chem. Rev. 2006, 106, 17–89; (b) Kobayashi, K.; Takagoshi, K.;
Kondo, S.; Morikawa, O.; Konishi, H. Bull. Chem. Soc. Jpn. 2004, 77, 553.
References and notes
1. (a) Bilker, O.; Lindo, V.; Panico, M.; Etiene, A. E.; Paxton, T.; Dell, A.; Rogers, M.;
Sinden, R. E.; Morris, H. R. Nature 1998, 392, 289; (b) Roma, G.; Braccio, M. D.;
Grossi, G.; Mattioli, F.; Ghia, H. Eur. J. Med. Chem. 2000, 35, 1021; (c) Chen, Y.-L.;
Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C. J. Med. Chem. 2000, 44, 2374; (d)
Winstanley, P. A. Parasitol. Today 2000, 16, 146.
2. (a) Fang, K.-C.; Chen, Y.-L.; Sheu, J.-Y.; Wang, T.-C.; Tzeng, C.-C. J. Med. Chem.
2000, 43, 3809; (b) Chevalier, J.; Atifi, S.; Eyraud, A.; Mahamoud, A.; Barbe, J.;
Pages, J.-M. J. Med. Chem. 2001, 44, 4023; (c) Phan, L. T.; Jian, T.; Chen, Z.; Qiu,
Y.-L.; Wang, Z.; Beach, T.; Polemeropoulos, A.; Or, Y. S. J. Med. Chem. 2004, 47,
2965; (d) Benkovic, S. J.; Baker, S. J.; Alley, M. R. K.; Woo, Y.-H.; Zhang, Y.-K.;
Akama, T.; Mao, W.; Baboval, J.; Rajagopalan, P. T. R.; Wall, M.; Kahng, L. S.;
Tavassoli, A.; Shapiro, L. J. Med. Chem. 2005, 48, 7468.
3. (a) Majerz-Maniecka, K.; Oleksyn, B.; Musiol, R.; Podeszwa, B.; Polanski, J.
Abstracts of Papers, Joint Meeting on Medicinal Chemistry, Vienna, Austria, June
20–23, 2005; In Sci. Pharm., 2005, 73, 194; (b) Vargas, L. Y.; Castelli, M. V.;
Kouznetsov, V. V.; Urbina, J. M.; Lopez, S. N.; Sortino, M.; Enriz, R. D.; Ribas, J. C.;
Zacchino, S. Bioorg. Med. Chem. 2003, 11, 1531; (c) Singh, M.; Singh, M. P.;
Ablordeppey, S. Y. Drug Dev. Ind. Pharm. 1996, 22, 377.
14. General procedure: To
a
solution of 2-(2-(trimethylsilyl)ethynyl)anilines
1
(0.5 mmol) and aldehydes
2
(1.5 mmol) in 10 mL of dry alcohols was
added sulfuric acid (37 mg, 0.375 mmol). The reaction mixture was stirred
at 65 °C for 17 h under air. After removal of most solvent under vacuum,
50 mL of EtOAc was added. The solution was washed successively with
saturated NaHCO3 twice and brine and then dried over Na2SO4.
The residue was purified by column chromatography on silica gel after
evaporation
of
solvent.
Compound
3c
4-methoxy-2-(4-methoxy-
phenyl)quinoline: 1H NMR (400 MHz, CDCl3) d: 8.17 (d, J = 8.4 Hz, 1H),
8.09 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.46
(t, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.04 (d, J = 8.8 Hz, 2H), 4.11 (s, 3H), 3.89 (s,
3H). 13C NMR (100 MHz, CDCl3) 162.7, 160.8, 158.4, 149.2, 132.9, 129.9,
129.0, 128.9, 125.1, 121.6, 120.2, 114.1, 97.5, 55.6, 55.4. MS (EI) 266
[M+H]+. HRMS calcd for C17H15O2N: 265.1103, found: 265.1097.
15. Hintermann, L.; Labonne, A. Synthesis 2007, 1121–1150.
4. (a) Dassonneville, L.; Lansiaux, A.; Wattelet, A.; Wattez, N.; Mahieu, C.; Van
Miert, S.; Pieters, L.; Bailly, C. Eur. J. Pharmacol. 2000, 409, 9; (b) Dassonneville,