Direct synthesis of polysubstituted quinoline derivatives by InBr 3-promoted dimerization of 2-ethynylaniline derivatives

Article abstract of DOI:10.1021/jo060245f

InBr₃ promotes the dimerization of 2-ethynylaniline derivatives containing an unsubstituted terminal carbon leading to the production of polysubstituted quinoline derivatives in good yield.

Full text of DOI:10.1021/jo060245f

SCHEME 1
Direct Synthesis of Polysubstituted Quinoline
Derivatives by InBr3-Promoted Dimerization of
2-Ethynylaniline Derivatives
Norio Sakai,* Kimiyoshi Annaka, and Takeo Konakahara*
Department of Pure and Applied Chemistry, Faculty of Science
and Technology, Tokyo UniVersity of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
sakachem@rs.noda.tus.ac.jp
SCHEME 2
ReceiVed February 6, 2006
InBr3 promotes the dimerization of 2-ethynylaniline deriva-
tives containing an unsubstituted terminal carbon leading to
the production of polysubstituted quinoline derivatives in
good yield.
(III) halide as a model reaction. Table 1 shows the results of
the search for optimized conditions. In a preliminary investiga-
tion,5 methanol was found to be the best solvent for this reaction.
When the reaction was conducted using a catalytic amount of
indium bromide in 1 M methanol solution, the yield of the
desired product, 3a, was moderate (entries 1 and 2). However,
when a stoichiometric amount of InBr3 was used, the reaction
proceeded cleanly without any byproducts being produced, and
the yield was further improved to 90% (entry 3). On the other
hand, changing the In catalyst to either InCl3, InI3, or In(OTf)3
resulted in slightly lower yields (entries 4-6). Needless to say,
in the absence of the indium salt, no cyclization occurred (entry
7). Consequently, we found that refluxing methanol in the
presence of a stoichiometric amount of InBr3 gave the best
results for the mutual cyclization. In this context, when the
reaction was performed with a substrate having a trimethylsilyl
group at a terminal alkyne carbon in the presence of the indium
salt, the same product 3a was produced in 50% yield.6
In a previous study,1 we reported on the InBr3-catalyzed
intramolecular cyclization of a variety of 2-ethynylanilines
leading to the preparation of 2-substituted indole derivatives
(path a in Scheme 1). However, when the reaction was carried
out using a substrate with a trimethylsilyl group or with no
substituent group on the terminal carbon under optimal condi-
tions, the desired indole product was not produced. Instead, a
small amount of an unidentified product was isolated. To
determine its structure, the crystalline product was subjected to
an X-ray crystallographic analysis. The X-ray analysis of the
crystalline product indicated the quinoline skeleton, formed by
the dimerization of the ethynylaniline derivative (see Figure 1
in Supporting Information).2 Herein, we report on a further study
of this reaction, which led to the development of a facile
synthesis of quinoline derivatives from this type of ethynyl-
aniline derivative via the use of an indium salt (path b in Scheme
1).3 The synthesis of polysubstituted quinolines is of consider-
able interest in the fields of organic and pharmaceutical
chemistry.4
(3) For selected reviews and papers on reactions mediated by indium,
see: (a) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1995, 60, 1920. (b)
Yasuda, M.; Miyai, T.; Shibata, I.; Baba, A.; Nomura, R.; Matsuda, H.
Tetrahedron Lett. 1995, 36, 9497. (c) Loh, T.-P.; Wei, L.-L. Tetrahedron
Lett. 1998, 39, 323. (d) Chauhan, K. K.; Frost, C. G. J. Chem. Soc., Perkin
Trans. 1 2000, 3015. (e) Ranu, B. C. Eur. J. Org. Chem. 2000, 2347. (f)
Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org. Chem. 2001,
66, 7741. (g) Bandini, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A.
Synthesis 2002, 1110. (h) Yadav, J. S.; Reddy, B. V. S.; Raju, A. K.; Rao,
C. V. Tetrahedron Lett. 2002, 43, 5437. (i) Sakai, N.; Hirasawa, M.;
Konakahara, T. Tetrahedron Lett. 2003, 44, 4171. (j) Sakai, N.; Hirasawa,
M.; Konakahara, T. Tetrahedron Lett. 2005, 46, 6407. (k) Sakai, N.; Kanada,
R.; Hirasawa, M.; Konakahara, T. Tetrahedron 2005, 61, 9298.
Initially, 2-ethynylaniline derivatives, 2a-f, as reaction
substrates were prepared via a Sonogashira-coupling reaction
between 2-iodoaniline derivatives and trimethylsilylacetylene
and a subsequent deprotection of the TMS group from the
anilines, 1a-f, obtained (Scheme 2). We then investigated the
dimerization of 2-ethynylaniline (2a) in the presence of indium-
(4) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell
Science, Ltd.: Oxford, 2000; pp 121-150. (b) Balasubramanian, M.; Keay,
J. G. ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C.
W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 5, pp
245-300. (c) Erian, A. W. Chem. ReV. 1993, 93, 1991.
(5) When the reaction ran with other solvents in the presence of 5 mol
% of InBr3 for 24 h, the quinoline was produced in 28 (PhMe), 2 (Et2O),
45 (1,4-dioxane), and 50% (MeOH) yields.
(1) Sakai, N.; Annaka, K.; Konakahara, T. Tetrahedron Lett. 2006, 47,
631.
(2) See details in Supporting Information. Crystal data for 3a: C16H14N2,
MW ) 234.29, orthorhombic, a ) 9.7558(9) Å, b ) 9.0365(9) Å, c )
26.814(3) Å, U ) 2363.8(4) Å3, T ) 273 K, space group Pbca, Z ) 8,
µ(Mo-KR) ) 0.069 mm-1, 12 610 reflections measured, 2763 independent
reflections (Rint ) 0.0300), R1 ) 0.0539, wR2 ) 0.2075.
10.1021/jo060245f CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/30/2006
J. Org. Chem. 2006, 71, 3653-3655
3653

TABLE 1. Optimization of the Dimerization of 2a Using an
Indium Catalysta
SCHEME 3. Plausible Reaction Path for the Dimerization
entry
InX3 (equiv)
time (h)
yieldb (%)
1
2
3
4
5
6
7
InBr3 (0.05)
InBr3 (0.2)
InBr3 (1)
InCl3 (1)
InI3 (1)
36
48
24
24
24
24
24
70
62
90
76
69
71
0c
In(OTf)3 (1)
a The reaction was carried out in MeOH (0.6 mL) using 2-ethynylaniline
(2a, 0.6 mmol). b NMR yield. c Recovery (78%) of 2a.
substituent group at the terminal carbon would enable the
approach of two molecules of the aniline 2a-d, activated by
InBr3, to lead to the dimerization. In contrast, in the case of
aniline derivatives having an aliphatic/aromatic group,1 a steric
repulsion at the terminal carbon would retard the approach
between two molecules, preferring the intramolecular cyclization
to the dimerization. Moreover, indium bromide seems to be
activated at the alkyne π-bond, leading to the facile inter-
molecular cyclization of 2a-d.7
TABLE 2. InBr3-Promoted Cyclization of Ethynylaniline
Derivative 2 Leading to Quinoline 3
yield (%)
The findings show that InBr3 promotes the dimerization of
substituted 2-ethynylanilines, without a substituent group on the
terminal carbon, to produce polysubstitued quinolines, in
contrast to our previous report. To our knowledge, this is the
first direct synthesis of a quinoline skeleton via a dimerization
of identical molecules.
entry
R1
R2
of 3a
1
2
3
4
5
6
H
H
H
Me
H
H
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
89
79
84
56
81
80
Me
Me
F
CN
NO2
H
a Isolated yield.
Experimental Section
General Procedure for the Dimerization of 2. To a 10 mL
reaction flask under argon, containing freshly distilled methanol
(0.6 mL), 2-(ethynyl)aniline 2 (140 mg, 0.600 mmol) and InBr3
(212 mg, 0.600 mmol) were added. The resulting mixture was
refluxed and monitored by TLC until the starting material had been
consumed. After the usual workup, the crude product was purified
by silica gel column chromatography (hexane/AcOEt ) 7:3) to
afford the polysubstituted quinoline 3 (yields are collected in Table
2).
General Procedure for the Dimerization of 2a in MeOH-d4.
To an NMR tube equipped with a screw cap containing methanol-
d4 (0.75 mL) under argon, 2-ethynylaniline (2a, 87.8 mg, 0.750
mmol) and InBr3 (265 mg, 0.750 mmol) were added. The resulting
mixture was refluxed and monitored by NMR until the starting
material had been consumed. After the usual workup, the crude
product was purified by silica gel column chromatography (hexane/
AcOEt ) 7:3) to afford 3a-d in 63% (55 mg) yield.
Cyclization reactions of several ethynylanilines were similarly
run under the above optimal conditions, and the results are
shown in Table 2. For example, the use of a substrate containing
an electron-rich group afforded the desired product 3b in 79%
yield (entry 2). The use of 2c gave the 2,4,6,7-tetrasubstituted
quinoline 3c in good yield (entry 3). With the exception of the
4-fluoro-substituted aniline 2d, the use of an ethynylaniline
derivative containing an electron-withdrawing group also gave
the corresponding product (entries 5 and 6). In any case, all
entries successfully underwent the desired dimerization, produc-
ing the corresponding quinoline derivatives in good to excellent
yields.
To better understand the reaction pathway for the cyclization,
a deuterium-labeling experiment was conducted. When the
reaction with 2-ethynylaniline (2a) was carried out in MeOH-
d4 at 65 °C, quinoline 3a-d with a deuterated 4-methyl group
and a deuterated 3-position was obtained, after purification.
During the reaction, NMR showed a rapid in situ H-D exchange
on the terminal carbon of 2a. On the basis of the deuterium-
labeling results, a plausible mechanism for the dimerization is
shown in Scheme 3. A reaction using ethynylaniline with no
Acknowledgment. This work was partially supported by a
fund for “High-Tech Research Center” Project for Private
Universities: a matching fund subsidy from MEXT, 2000-
2004 and 2005-2007.
(6) A copper(II)-promoted reaction of a similar ethynylaniline derivative
resulted in the formation of an indole derivative, see: (a) Ezquerra, J.;
Pedregal, C.; Lamas, C.; Barluenga, J.; Pe´rez, M.; Garc´ıa-Mart´ın, M. A.;
Gonza´lez, J. M. J. Org. Chem. 1996, 61, 5804. (b) Hiroya, K.; Itoh, S.;
Ozawa, M.; Kanamori, Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43, 1277.
(c) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126.
(7) For examples of indium salts activating alkyne π electrons, see: (a)
Tsuchimoto, T.; Maeda, T.; Shirakawa, E.; Kawakami, Y. Chem. Commun.
2000, 1573. (b) Tsuchimoto, T.; Hatanaka, K.; Shirakawa, E.; Kawakami,
Y. Chem. Commun. 2003, 2454. (c) Sakai, N.; Annaka, K.; Konakahara,
T. Org. Lett. 2004, 6, 1527. (d) Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima,
T.; Shibasaki, M. Org. Lett. 2005, 7, 1363.
3654 J. Org. Chem., Vol. 71, No. 9, 2006

Supporting Information Available: Detailed Procedures and
spectroscopic data for compounds 1, 2, and 3, copies of H NMR
for 3a. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
spectra for 1a-f, 2a-f, and 3a-d, ORTEP of 3a, and X-ray data
JO060245F
J. Org. Chem, Vol. 71, No. 9, 2006 3655