a polysubstituted indole,9 the extensive annulation that
produces a quinoline skeleton through a combination of
the 2-ethynylaniline with a reaction substrate, such as an
aldehyde and a ketone, has not been studied extensively
(1,2- and 2,3-bond forming reaction: path c).10 In this
context, we previously reported that use of a 2-ethynyl-
aniline with a trimethylsilyl group or with no substituent
group on the terminal triple bond exclusively afforded
polysubstituted quinoline derivatives via indium-promoted
intermolecular dimerization of the ethynylaniline11 and
developed a Hf(OTf)4-doped Me3SiCl system-catalyzed
aminomethylation of heterocycles with several N,O-acetals
that led to the preparation of a variety of non-natural
aromatic amino acid derivatives.12
acid (TFA), promoted the [5 þ 1] annulation of 2-ethynyl-
aniline with ethyl glyoxylate in the presence of piperidine.
This method is the first example for the preparation of a
quinoline skeleton throughcopper-catalyzed[5þ 1] annula-
tion and the direct introduction of an ester substituent at the
2-position on the skeleton.
Table 1 shows the results of intermolecular annulation
of ethynylaniline (1a) with N,O-acetal 2, which was pre-
pared from methyl 2-bromo-2-methoxyacetate and piper-
idine in the presence of a base by the procedure previously
reported under several conditions.12c Initially, when the
reaction ran in chloroform without a catalyst, the adduct
4a was obtained in a 62% yield (entry 1). No trace of either
the indole or quinoline derivative was observed. To pro-
mote intramolecular cyclization of the adduct 4a, the addi-
tion of 10 mol % of InBr3 to the reaction system was then
examined under similar conditions. Interestingly, a slight
formation of quinoline derivative 3a was observed (entry 2).
Thus, the additive effect of several copper catalysts, which
may be able to undergo intramolecular cyclization,13 was
investigated. When the reaction was performed with CuCl,
the selective formation of the corresponding quinoline
derivative was observed in a 51% yield (entry 3). Also,
the use of CuBr and CuBr2 showed a similar annulation
effect (entries 4 and 5). When the reaction was conducted
Scheme 1. Approach to a Quinoline Skeleton Through an
Intramolecular Cyclization Mode of an Alkyne
Table 1. Examinations of Reaction Conditions
We report herein a novel copper-catalyzed [5 þ 1]
annulation of 2-ethynylanilines with an N,O-acetal, which
functions as a C1 unit, leading to the preparation of quino-
line derivatives. We also disclosed that the combination of
a Lewis acidic metal and a Brønsted acid, trifluoroacetic
(6) Selected recent papers for copper-catalyzed preparation of qui-
nolines, see: (a) Huang, H.; Jiang, H.; Chen, K.; Liu, H. J. Org. Chem.
2009, 74, 5476. (b) Patil, N. T.; Raut, V. S. J. Org. Chem. 2010, 75, 6961.
(7) (a) Pisaneschi, F.; Sejberg, J. J. P.; Blain, C.; Ng, W. H.; Aboagye,
E. O.; Spivey, A. C. Synlett 2011, 241. (b) Mahanty, J. S.; De, M.;
Das, P.; Kundu, N. G. Tetrahedron 1997, 53, 13397. (c) Torii, S.; Xu,
L. H.; Sadakane, M.; Okumoto, H. Synlett 1992, 513.
(8) (a) Zhao, J.; Peng, C.; Liu, L.; Wang, Y.; Zhu, Q. J. Org. Chem.
2010, 75, 7502. (b) Mitamura, T.; Nomoto, A.; Sonoda, M.; Ogawa, A.
Bull. Chem. Soc. Jpn. 2010, 83, 822. (c) Suginome, M.; Fukuda, T.;
Ito, Y. Org. Lett. 1999, 1, 1977.
(9) Selected reviews for intramolecular preparation of indoles, see:
(a) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. Biomol. Chem. 2011, 9,
641. (b) Barluenga, J.; Rodriguez, F.; Fananas, F. J. Chem. Asian J.
2009, 4, 1036. (c) Kruger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal.
2008, 350, 2153. (d) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
(10) (a) Okamoto, N.; Takeda, K.; Ishikura, M.; Yanada, R. J. Org.
Chem. 2011, 76, 9139. (b) Wang, Y.; Peng, C.; Liu, L.; Zhao, J.; Su, L.;
Zhu, Q. Tetrahedron Lett. 2009, 50, 2261. (c) Lee, J. H.; Lee, B. S.; Shin,
H.; Nam, D. H.; Chi, D. Y. Synlett 2006, 65.
yieldb (%)
entry
cat.
solv
tempa (°C) time (h)
3a
4a
1
2
3
4
5
6
7
ꢀ CHCl3
InBr3 CHCl3
CuCl CHCl3
65
65
65
65
65
85
85
18
18
1
ND
5
62
33
51
52
58
ND
ND
ND
CuBr CHCl3
5
CuBr2 CHCl3
24
CuBr2 ClCH2CH2Cl
CuCl2 ClCH2CH2Cl
0.5
0.5
(76) ND
70 ND
a Bath temperature. b NMR (Isolated) yield.
with CuBr2 under 1,2-dichloroethane reflux conditions,
the yield of the quinoline was improved to 76% (entry 6).
Moreover, the reaction time was dramatically shortened.
The use of CuCl2 also showed a similar effect (entry 7).
(11) (a) Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.; Konakahara, T.
J. Org. Chem. 2008, 73, 4160. (b) Sakai, N.; Annaka, K.; Konakahara, T.
J. Org. Chem. 2006, 71, 3653.
(12) (a) Sakai,N.;Watanabe,A.;Ikeda,R.;Nakaike,Y.;Konakahara,T.
Tetrahedron 2010, 66, 8837. (b) Sakai, N.; Sato, A.; Konakahara, T.
Synlett 2009, 1449. (c) Sakai, N.; Asano, J.; Kawada, Y.; Konakahara,
T. Eur. J. Org. Chem. 2009, 917. (d) Sakai, N.; Asano, J.; Shimano, Y.;
Konakahara, T. Synlett 2007, 2675. (e) Sakai, N.; Hirasawa, M.;
Hamajima, T.; Konakahara, T. J. Org. Chem. 2003, 68, 483.
(f) Sakai, N.; Hamajima, T.; Konakahara, T. Tetrahedron Lett. 2002,
43, 4821.
(13) Selected papers for intramolecular cyclization of an ethynylani-
line with a copper catalyst, see: (a) Hiroya, K.; Itoh, S.; Sakamoto, T.
Tetrahedron 2005, 61, 10958. (b) Hiroya, K.; Itoh, S.; Sakamoto, T.
J. Org. Chem. 2004, 69, 1126. (c) Hiroya, K.; Itoh, S.; Ozawa, M.;
Kanamori, Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43, 1277.
Org. Lett., Vol. 14, No. 3, 2012
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