Table 1. Optimization of the Reaction Conditions
Scheme 1. General Strategies for Construction of Quinoline
Rings
entry
catalyst
SeCl4
condition
yielda
25%
1
0.3 equiv, DCM, rt, 12 h
2
BF3OEt2 0.3 equiv, DCM, rt, 12 h
28%
3
TiCl4
0.3 equiv, DCM, rt, 12 h
0.3 equiv, DCM, rt, 12 h
0.5 equiv, DCM, rt, 12 h
9%
4
Sc(OTf)3
SnCl4
15%
5
65%
6
BF3OEt2 0.5 equiv, DCM, rt, 12 h
BF3OEt2 0.5 equiv, DCE, rt, 12 h
BF3OEt2 0.5 equiv, THF, rt, 12 h
BF3OEt2 0.5 equiv, MeCN, rt, 12 h
BF3OEt2 0.1 equiv, DCM, rt, 12 h
BF3OEt2 1.0 equiv, MeOH, rt, 12 h
BF3OEt2 1.0 equiv, EtOH, rt, 12 h
BF3OEt2 1.0 equiv, EtOAc, rt, 12 h
74% (50%b)
33%
Owing to the important applications of quinolines,
their synthesis had been extensively studied for more than
100 years since the discovery of quinoline.6,7 By far the
7
8
26%
9
20%
10
11
18
19
14
15%
most prevalent strategies for constructing quinoline rings
8
39%b
29%b
49%
€
are the classic annulation reactions such as Friedlander,
Combes,9 Povarov,10 DoebnerꢀMiller,11 and Skraup12
syntheses, etc. (Scheme 1a,b). However, these methods
usually suffer from one or more limitations which include
poor regioselectivity, low yield, high temperature, long
reaction time, harsh reaction conditions, and tedious
reaction procedures. Therefore, the development of mild,
simple, and complementary approaches to quinoline deri-
vatives is still highly desired because of their extreme
significance.
BF3OEt2 1.0 equiv, 1,4-dioxane, rt, 12 h 59%
a Conversion ratio. b Isolated yield.
compounds such as bicyclobutanes, silyloxy dienes, and
six-membered cyclic compounds.13 In those studies,
3-ethoxycyclobutanones were involved as a formal 1,
4-dipole.14 Recently our group reported the synthesis of
pyrazoles through a ‘3 þ 2’ annulation reaction between
3-ethoxycyclobutanones and substituted hydrazines.15
Our studies demonstrated, for the first time, 3-ethoxycy-
clobutanones can beemployed asa 1,3-dicarbonyl synthon
for useful chemical transformations. Based on these find-
ings, we therefore envisioned that if aromatic amines were
adopted as substrates instead of substituted hydrazines in
the reaction, theoretically a ‘3 þ 3’ annulation between
3-ethoxycyclobutanones and aromatic amines would be
possible. In contrast to forming pyrazoles with substituted
hydrazines, a formal cycloaddition between 3-ethoxycy-
clobutanones and substituted aromatic amines could
furnish corresponding 2-alkylquinoline derivatives as pro-
ducts (Scheme 1c). Herein we report the development of a
new efficient one-step approach toward regioselective
synthesis of quinolines through Lewis acid promoted
annulation reactions between 3-ethoxycyclobutanones
and substituted aromatic amines.
Serving as a versatile intermediate, 3-ethoxycyclobuta-
nones have been used to prepare various types of
(7) For recent examples: (a) Venkatesan, H.; Hocutt, F.; Jones, T.;
Rabinowitz, M. J. Org. Chem. 2010, 75, 3488–3491. (b) Huo, Z.; Ilya D.
Gridnev, I.; Yoshinori Yamamoto, Y. J. Org. Chem. 2010, 75, 1266–
1270. (c) Gao, G.; Niu, Y.; Yan, Z.; Wang, H.; Wang, G.; Shaukat, A.;
Liang, Y. J. Org. Chem. 2010, 75, 1305–1308. (d) Gøgsig, T. M.;
Lindhardt, A. T.; Skrydstrup, T. Org. Lett. 2009, 11, 4886–4888. (e)
Zhang, Z.; Tan, J.; Wang, Z. Org. Lett. 2008, 10, 173–175. (f) Li, L.;
Jones, W. D. J. Am. Chem. Soc. 2007, 129, 10707–10713. (g) Austin, M.;
Egan, O. J.; Tully, R.; Pratt, A. C. Org. Biomol. Chem. 2007, 5, 3778–
3786. (h) Atechian, S.; Nock, R.; Norcross, R. D.; Ratni, H.; Thomas,
A. W.; Verron, J.; Masciadri, R. Tetrahedron 2007, 63, 2811–2823.
(8) (a) Friedlander, P. Chem. Ber. 1882, 15, 2572. (b) Marco-
ꢁ
Contelles, J.; Perez-Mayoral, E.; Samadi, A.; Carreiras, M. C.; Soriano,
E. Chem. Rev. 2009, 109, 2652. (c) Sridharan, V.; Ribelles, P.; Ramos,
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M. T.; Menendez, J. C. J. Org. Chem. 2009, 74, 5715. (d) Miller, B. L.;
Mcnaughton, B. R. Org. Lett. 2003, 5, 4257. (e) Hu, Y.-Z.; Zhang, G.;
Thummel, R. P. Org. Lett. 2003, 5, 2251.
(9) (a) Combes, A. Bull. Soc. Chim. Fr. 1888, 49, 89. (b) Jerry L. Born,
J. J. Org. Chem. 1972, 37, 3952–3953.
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(10) (a) Vicente-Garcıa, E.; Catti, F.; Ramon, R.; Lavilla, R. Org.
Lett. 2010, 12, 860–863. (b) Shindoh, N.; Tokuyama, H.; Takemoto, Y.;
Takasu, K. J. Org. Chem. 2008, 73, 7451–7456. (c) Zhao, Y.; Zhang, W.;
Wang, S.; Qun Liu, Q. J. Org. Chem. 2007, 72, 4985–4988.
To test our hypothesis, a model study was initiated with
2,2-dimethyl 3-ethoxycyclobutanone and 4-nitroaniline
(Table 1). As a Lewis acid promoter, 0.3 equiv of SnCl4
was added to the reaction mixture. Delightfully the reac-
tion afforded the desired product 3 (entry 1) with complete
regioselectivity after overnight stirring at room tempera-
ture. Encouraged by this preliminary result, we started to
(11) (a) Mackenzie, A. R.; Moody, C. J.; Rees, C. W. Tetrahedron
1986, 42, 3259. (b) Boger, D. L.; Chen, J. H. J. Org. Chem. 1995, 60, 7369.
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Org. Lett., Vol. 13, No. 21, 2011
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