InBr3-promoted divergent approach to polysubstituted indoles and quinolines from 2-ethynylanilines: Switch from an intramolecular cyclization to an intermolecular dimerization by a type of terminal substituent group

Article abstract of DOI:10.1021/jo800464u

(Chemical Equation Presented) Use of a 2-ethynylaniline having an alkyl or aryl group on the terminal alkyne selectively produced a variety of polyfunctionalized indole derivatives in moderate to excellent yields via indium-catalyzed intramolecular cyclization of the corresponding alkynylaniline. In contrast, employment of a substrate with a trimethylsilyl group or with no substituent group on the terminal triple bond, exclusively afforded polysubstituted quinoline derivatives in good yields via indium-promoted intermolecular dimerization of the ethynylaniline. This indium catalytic system successfully accommodated the intramolecular cyclization of other arylalkyne skeletons involving a carboxylic acid and an amide group.

Full text of DOI:10.1021/jo800464u

InBr3-Promoted Divergent Approach to Polysubstituted Indoles and
Quinolines from 2-Ethynylanilines: Switch from an Intramolecular
Cyclization to an Intermolecular Dimerization by a Type of
Terminal Substituent Group
Norio Sakai,* Kimiyoshi Annaka, Akiko Fujita, Asuka Sato, 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
ReceiVed February 28, 2008
Use of a 2-ethynylaniline having an alkyl or aryl group on the terminal alkyne selectively produced a
variety of polyfunctionalized indole derivatives in moderate to excellent yields via indium-catalyzed
intramolecular cyclization of the corresponding alkynylaniline. In contrast, employment of a substrate
with a trimethylsilyl group or with no substituent group on the terminal triple bond, exclusively afforded
polysubstituted quinoline derivatives in good yields via indium-promoted intermolecular dimerization of
the ethynylaniline. This indium catalytic system successfully accommodated the intramolecular cyclization
of other arylalkyne skeletons involving a carboxylic acid and an amide group.
Introduction
consisting of a Pd/Cu-catalyzed Sonogashira reaction between
an aryl halide and a terminal alkyne, and the subsequent
intramolecular cyclization of the formed 2-ethynylaniline de-
rivative with a palladium catalyst,4 and the procedure using
intramolecular cyclization of a 2-ethynylaniline derivative in
the presence of various metal catalysts and metal complexes
involving copper, gold, iridium, mercury, molybdenum, plati-
num, and rhodium also has been reported.5 Moreover, an
approach with bases, such as NaOEt,6 t-BuOK,7 KH,8 and
Polysubstituted indoles and quinolines have played an
important and central role in biologically active substances and
natural products.1 Thus, development of facile and practical
approaches to the synthesis of those skeletons has been
investigated by a number of organic and pharmaceutical
chemists.2 Since development of the practical synthesis of
indoles by Fischer et al., a number of the synthesis of indole
derivatives has been widely investigated.2 Particular attention
has been paid to intramolecular cyclization of 2-alkynylanilines-
one of the most convenient tools for preparation of polysub-
stituted indole derivatives.3 For example, a combined method
10
Et2Zn,9 and Lewis acidic iodine complexes, such as I2 and
I(Py)2BF4,11 via intramolecular cyclization also has been suc-
cessful in the synthesis of an indole skeleton. On the other hand,
facile and practical synthesis of the quinoline derivative, a basic
(1) (a) Glasby, J. S., Ed. In Encyclopedia of the Alkaloids; Plenum Press:
New York, 1975. (b) Mitscher, L. A. Chem. ReV. 2005, 105, 559. (c) Yokoshima,
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J. Am. Chem. Soc. 2002, 124, 2137. See also refs 2 and 3.
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hensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Pergamon Press: Oxford, 1996. (c) Sundberg, R. J. Indoles;
Academic Press: San Diego, 1996.
(3) For selected reviews for the synthesis of indoles, see: (a) Humphrey,
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1 2000, 1045.
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1594. (e) Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122,
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7652. (g) Cacchi, S.; Fabrizi, G.; Pace, P. J. Org. Chem. 1998, 63, 1001. (h)
Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689. (i) Rudisillt,
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4160 J. Org. Chem. 2008, 73, 4160–4165
10.1021/jo800464u CCC: $40.75 2008 American Chemical Society
Published on Web 04/29/2008

InBr3-Promoted DiVergent Approach
SCHEME 1. Representative Synthesis of the Substrates
framework widely found in naturally occurring products,
biologically active substances, and clinical drugs, also has
attracted considerable interest.12 Therefore, a number of reac-
tions involving the Conrad-Limpach-Knorr synthesis,13 the
Skraup synthesis,14 and the Friedla¨nder synthesis15 have been
developed for the preparation of this skeleton. Recently, the
development of a modified Friedla¨nder-type reaction using a
Lewis acid has proven promising.16 During the ongoing
exploration of the novel synthetic process of nitrogen-containing
heterocycles using an indium catalyst,17 we also found that the
structure of a terminal substituent on the triple bond bonded to
an o-alkynylaniline directly has an effect on the selectivity of
TABLE 1. Examination of a Catalyst
run
Lewis acid
time (h)
yield (%)a
(5) Cu: (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) Cacchi,
S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843. (d) Hiroya, K.; Itoh, S.;
Ozawa, M.; Kanamori, Y.; Sakamoto, T. Tetrahedron Lett. 2002, 43, 1277. (e)
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. Au: (f) Ambrogio, I.;
Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2007, 1775. (g) Zhang,
Y.; Donahue, J. P.; Li, C. J. Org. Lett. 2007, 9, 627. Ir: (h) Li, X.; Chianese,
A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005, 7, 5437. Hg: (I) Kurisaki, T.;
Naniwa, T.; Yamamoto, H.; Imagawa, H.; Nishizawa, M. Tetrahedron Lett. 2007,
48, 1871. Mo: (j) McDonald, F. E.; Chatterjee, A. K. Tetrahedron Lett. 1997,
38, 7687. Pt: (k) Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc.
2004, 126, 10546. Rh: (l) Trost, B. M.; McClory, A. Angew. Chem., Int. Ed.
2007, 46, 2074.
1
2
3
4
5
6
7
8
9
BF3•OEt2
B(C6F5)3
AlCl3
Cu(OTf)2
PdCl2(PPh3)2
InBr3
InCl3
InI3
InBr3 (1 equiv)
none
12
12
12
12
12
1
3
3
0.1
24
(22)
(29)
(31)
9
75
(95)
90
6
98
18
10
a NMR yield (isolated yield).
(6) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Yamanaka, H. Chem. Pharm.
Bull. 1987, 35, 1823.
(7) (a) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3307.
(b) Dai, W.-M.; Sun, L.-P.; Guo, D.-S. Tetrahedron Lett. 2002, 43, 7699.
(8) Sun, L.-P.; Huang, X.-H.; Dai, W.-M. Tetrahedron 2004, 60, 10983.
(9) (a) Yin, Y.; Ma, W.; Chai, Z.; Zhao, G. J. Org. Chem. 2007, 72, 5731.
(b) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Angew. Chem., Int. Ed.
2006, 45, 944.
the subsequent reaction path, resulting in the selective prepara-
tion of two quite different heterocycles.18 Namely, a terminal
group, such as an alkyl and an aryl group, predominately
produces the corresponding indole derivatives via the indium-
catalyzed intramolecular cyclization of the alkynylaniline. In
contrast, the reaction using the substrate with a trimethylsilyl
group or with no substituent group on the terminal triple bond
exclusively produced the multifunctionalized quinoline deriva-
tives through indium-promoted intermolecular dimerization of
the ethynylaniline derivative. Thus, the focus of our group’s
moved to the scope and limitations of both intramolecular
cyclization and intermolecular dimerization from the original
substrate. This paper details the results of a reinvestigation of
indium-promoted reactions.
(10) (a) Hessian, K. O.; Flynn, B. L. Org. Lett. 2006, 8, 243. (b) Amjad,
M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 539. (c) Yue, D.; Larock, R. C.
Org. Lett. 2004, 6, 1037.
(11) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzaˆlez, J. M. Angew. Chem.,
Int. Ed. 2003, 42, 2406.
(12) Erian, A. W. Chem. ReV. 1993, 93, 1991. and references therein.
(13) (a) Curran, A. C. W. J. Chem. Soc., Perkin Trans. 1 1976, 975. (b)
Misani, F.; Bogert, M. T. J. Org. Chem. 1945, 10, 347.
(14) (a) Sakai, N.; Aoki, D.; Hamajima, T.; Konakahara, T. Tetrahedron
Lett. 2006, 47, 1261. (b) Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006,
71, 1668. (c) Kobayashi, K.; Takanohashi, A.; Watanabe, S.; Morikawa, O.;
Konishi, H. Tetrahedron Lett. 2000, 41, 7657. (d) Robinson, J. M.; Brent, L. W.;
Chau, C.; Floyd, K. A.; Gillham, S. L.; McMahan, T. L.; Magda, D. J.; Motycka,
T. J.; Pack, M. J.; Roberts, A. L.; Seally, L. A.; Simpson, S. L.; Smith, R. R.;
Zalesny, K. N. J. Org. Chem. 1992, 57, 7352. (e) Case, F.; Buck, C. J. Org.
Chem. 1956, 21, 697.
Results and Discussion
(15) (a) Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan,
K. V. J. Org. Chem. 2003, 68, 9371. (b) Dormer, P. G.; Eng, K. K.; Farr, R. N.;
Humphrey, G. R.; McWilliams, J. C.; Reider, P. J.; Sager, J. W.; Volante, R. P.
J. Org. Chem. 2003, 68, 467. (c) Gladiali, S.; Chelucci, G.; Mudadu, M. S.;
Gastaut, M. A.; Thummel, R. P. J. Org. Chem. 2001, 66, 400. (d) Breitmaier,
E.; Gassenmann, S.; Bayer, E. Tetrahedron 1970, 26, 5907. (e) Breitmaier, E.;
Bayer, E. Tetrahedron Lett. 1970, 11, 3291. (f) Breitmaier, E.; Bayer, E. Angew.
Chem., Int. Ed. 1969, 8, 765. (g) Fehnel, E. A. J. Org. Chem. 1966, 31, 2899.
(16) For selected papers on modified Friedla¨nder reactions using a metal
catalyst, see: (a) Mart´ınez, R.; Ramo´n, D. J.; Yus, M. Eur. J. Org. Chem. 2007,
1599. (b) Wu, J.; Xia, H.-G.; Gao, K. Org. Biomol. Chem. 2006, 4, 126. (c)
Wu, J.; Zhang, L.; Diao, T.-N. Synlett 2005, 2653. (d) Yadav, J. S.; Reddy,
B. V. S.; Premalatha, K. Synlett 2004, 963. (e) Arcadi, A.; Chiarini, M.; Giuseppe,
S. D.; Marinelli, F. Synlett 2003, 203.
In-Catalyzed Intramolecular Cyclization Leading to
Indole Derivatives. Initially, a series of 2-ethynylaniline
derivatives 1a-n as a reaction substrate were prepared via a
Sonogashira-coupling reaction between 2-iodoaniline derivatives
and several types of terminal alkynes (Scheme 1).19
To confirm the highly catalytic activity of an indium salt for
the intramolecular cyclization of 2-phenylethynylaniline (1a),
we then reinvestigated several types of Lewis acid for optimal
conditions. For example, when the reaction using a catalytic
amount of typical Lewis acids, such as BF3•OEt2, B(C6F5)3, and
AlCl3, was examined, the desired cyclization produced 2-phe-
nylindole (2a), though the yield was rather low (Table 1, runs
1-3). Cu(OTf)2, which promoted a similar cyclization of an
N-protected ethynylaniline,20 did not show a catalytic effect to
(17) For selected reviews and papers on the reaction using indium, see: (a)
Auge´, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007, 1739. (b) Loh, T.-P.;
Chua, G.-L. Chem. Commun. 2006, 2739. (c) Podlech, J.; Maier, T. C. Synthesis
2003, 633. (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) Kawata, A.;
Takata, K.; Kuninobu, Y.; Takai, K. Angew. Chem., Int. Ed. 2007, 46, 7793. (g)
Obika, S.; Kono, H.; Yasui, Y.; Yanada, R.; Takemoto, Y. J. Org. Chem. 2007,
72, 4462. (h) Sakai, N.; Hirasawa, M.; Konakahara, T. Tetrahedron Lett. 2005,
46, 6407. (i) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003,
125, 13002. (j) Yadav, J. S.; Reddy, B. V. S.; Raju, A. K.; Rao, C. V. Tetrahedron
Lett. 2002, 43, 5437. (k) Bandini, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi,
A. Synthesis 2002, 1110. (l) Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba,
A. J. Org. Chem. 2001, 66, 7741. (m) Loh, T.-P.; Wei, L.-L. Tetrahedron Lett.
1998, 39, 323. (n) Yasuda, M.; Miyai, T.; Shibata, I.; Baba, A.; Nomura, R.;
Matsuda, H. Tetrahedron Lett. 1995, 36, 9497. (o) Marshall, J. A.; Hinkle, K. W.
J. Org. Chem. 1995, 60, 1920.
(18) (a) Sakai, N.; Annaka, K.; Konakahara, T. J. Org. Chem. 2006, 71,
3653. (b) Sakai, N.; Annaka, K.; Konakahara, T. Tetrahedron Lett. 2006, 47,
631. (c) Sakai, N.; Annaka, K.; Konakahara, T. Org. Lett. 2004, 6, 1527.
(19) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,
446.
(20) For a copper-promoted reaction of a similar ethynylaniline derivative
resulted in the formation of an indole derivative, see: Dai, W.-M.; Guo, D.-S.;
Sun, L.-P. Tetrahedron Lett. 2001, 42, 5275.
J. Org. Chem. Vol. 73, No. 11, 2008 4161

Sakai et al.
TABLE 2. In-Catalyzed Intramolecular Cyclization of
Ethynylanilines 2 Leading to Indoles 3
TABLE 3. Synthesis of a Variety of Indole Derivatives
run
R1
R2
R3
X
time (h)
yield (%)a
run
R1
R2
R3
time (h) yield (%)a
1
2
3
4
5
6
PhCH2 Ph
MeCO Ph
EtCO2 Ph
H
H
H
H
H
Me
CH (3a)
CH (3b)
CH (3c)
CH (3d)
CH (3e)
1
2
20
8
72
72
78 (4a)
71 (4b)
70 (4c)
1
2
3
4
5
6
7
8
H
H
H
Ph
Ph
(1a)
(1b)
(1c)
(1d)
(1e)
(1f)
0.5
0.5
0.5
2
2
2
6
1
1
8
95
98
90
90
91
98
48
62
52
77
86
89
59
59
(2a)
(2b)
(2c)
(2d)
(2e)
(2f)
(2g)
(2h)
(2i)
(2j)
(2k)
(2l)
(2m)
(2n)
Me
Me
NO2
F
CN
H
Me
Me
NO2
F
CN
Me
H
Me Ph
H
H
H
(CH2)4OH
2-Py
Ph
70 (4d)
H
H
H
H
H
Ph
Ph
Ph
23 (41)b (4e)
27 (46)b (4f
N
(3f)
a Isolated yield. b InBr3 (0.2 equiv) was used.
4-BuC6H4 (1g)
C6H13
(1h)
(1i)
(1j)
(1k)
(1l)
(1m)
(1n)
9
Me C6H13
sponding indoles in moderate yields, due to the steric effect
between the bulky group and the amino group (runs 13 and
14).
10
11
12
13
14
H
H
H
H
H
C6H13
C6H13
C6H13
t-Bu
8
7
4
4
We then applied the present method to cyclize N-protected
ethynylaniline that had a benzyl, an acetyl, and an ester group
in the presence of the indium catalyst (Table 3). Initially,
treatment of the reaction substrate having a benzyl group, with
a 0.05 equivalent of InBr3 produced the desired indole 4a in a
78% yield (run 1). Similarly, when the reaction using the
substrate with an acetyl group was also conducted, the cyclized
product 4b was obtained in a 71% yield within 2 h (run 2).
Although cyclization with the ethynylaniline, which was
substituted by a strong electron-withdrawing group, required a
longer reaction time (>20 h) for the completion of the reaction,
the reaction proceeded cleanly, producing the expected indole
4c in a 70% yield (run 3). Interestingly, it was found that the
introduction of a hydroxy group, which typically deactivates a
common Lewis acid, on the terminal alkyne hardly affects the
yield (run 4). Unfortunately, when the reaction was conducted
with substrates 3e,f having a pyridine ring, both cyclizations
did not proceed smoothly, and the yields were extremely reduced
to about 20% (runs 5 and 6). It seemed that InBr3 prefers
coordination on the more basic nitrogen atom in the pyridine
ring to a softer base part, the Ct C triple bond, resulting in the
loss of its catalytic effect. Therefore, using a stoichiometric
amount of InBr3 unexpectedly resulted in the reaction leading
to the formation of a complex mixture. Then, reducing the
indium to a 0.2 equivalent in the intramolecular cyclization
improved the yields to about 40%.21
Moreover, indium-promoted annulation of trialkynyltriamine
was attempted (Scheme 2). Initially, o-iodoaniline was subjected
to a Sonogashira-coupling reaction with trialkynylbenzene to
produce the corresponding trialkynyltriamine 5 in a 40% yield.
When the cyclization of 5 was then carried out using 1
equivalent of InBr3 under the toluene reflux conditions, the
expected triple-annulation proceeded simultaneously and cleanly
to produce the desired 1,3,5-tris(2-indolyl)benzene 6 in a nearly
quantitative yield.
In-Catalyzed Cyclization of Other Types of Reaction
Substrates. These successes prompted us to apply the present
protocol to the cyclization of other substrates having a carboxylic
acid and an amide group (Scheme 3). Thus, methyl 2-iodoben-
zoate was initially subjected to the Sonogashira coupling with
phenylacetylene, followed by hydration under basic conditions
t-Bu
a Isolated yield.
the cyclization at all (run 4). However, in the case of Pd(II)
instead of Cu(II), the yield of indole 2a increased to 75% (run
5). In contrast, when the reaction was conducted with InBr3
under standard conditions, the desired cyclization was cleanly
completed within an hour to produce indole 2a in an excellent
yield (run 6). InCl3 also showed a similar catalytic effect for
the reaction, though the reaction time was slightly prolonged
(run 7). These results strongly indicate that indium bromide/
chloride prefers coordinating on an alkyne π-bond to a basic
primary amino group. On the other hand, employment of InI3
remarkably reduced the chemical yield (run 8). The cyclization
using a stoichiometric amount of indium bromide was quanti-
tatively completed within 10 min (run 9). Without the indium
catalyst, the reaction did not produce the desired product in a
practical yield (run 10). Thus, we found that the indium salt
highly and effectively promotes this type of intramolecular
cyclization without the loss of the catalytic activity, and the
toluene reflux conditions using 0.05 equiv of indium bromide
shows the best result.
To extend the generality of this reaction, the cyclization of
various N-unsubstituted ethynylaniline produced was carried out,
and the results are summarized in Table 2. The cyclization of
ethynylanilines having an electron-donating group, such as a
methyl group, was completed in a very short time, producing
the corresponding indole derivatives 2 in good to excellent yields
(runs 1-3). When the substrates having an electron-withdrawing
group, such as a nitro, a fluoro, and a cyano group on the
benzene moiety, were employed, the reaction time was slightly
prolonged due to a lowering of the nucleophilicity of the amino
group, but the yields showed excellent results (runs 4-6). Thus,
it was found that a sort of a substituted group on the benzene
ring was ineffective for the yield of the intramolecular cycliza-
tion. On the other hand, a substrate having an aliphatic group
on the terminal phenyl group reduced the yield to 48% (run 7).
Although the reaction of substrates 1, containing a hexyl group
as a terminal substituent instead of the phenyl group, underwent
cyclization to produce the desired polysubstituted indole deriva-
tives in good yields (runs 8-12), the cyclization using a more
bulky group, such as a tert-butyl group, produced the corre-
(21) When the intramolecular cyclization of 3f ran with 1 equiv of InBr3,
the corresponding 7-azaindole derivative 4f was obtained in an 18% yield, due
to a decline in the nucleophilicity of the tethered amino group by the coordination
of the indium catalyst.
4162 J. Org. Chem. Vol. 73, No. 11, 2008

InBr3-Promoted DiVergent Approach
SCHEME 2
SCHEME 4
TABLE 4. Examination of Catalyst Effect
run
LA (equiv)
time (h)
yield (%)a
1
2
3
4
5
6
7
8
Cu(OAc)2 (0.2)
InBr3 (0.05)
InBr3 (0.2)
InBr3 (1)
InCl3 (1)
InI3 (1)
24
36
48
24
24
24
24
24
trace
(58)b
62
(89)
76
SCHEME 3
69
In(OTf)3 (1)
none
71
0c
a NMR yield (isolated yield). b Average of two runs. c Recovery
(78%) of 12a.
results reported by several other groups,20 our group initially
examined the dimerization of ethynylaniline with copper salts
(0.2 equiv) under toluene reflux conditions. However, the desired
dimerization barely proceeded, resulting in a 95% recovery of
the starting material (run 1). On the other hand, increasing the
amount of the indium catalyst to 1 equivalent for the ethyny-
laniline highly improved the yield to an excellent 89% (run 4).
Consequently, it was found that a small amount of the indium
salt strongly coordinated to the more basic nitrogen atom on
the formed quinoline skeleton, resulting in a decline of its
catalytic activity. This was strongly supported by the results
that the yields of intramolecular cyclization of a substrate having
a pyridine ring were rather low (runs 5 and 6 in Table 3).
Moreover, like the preparation of indoles, when the reaction
was conducted with another indium salt, the corresponding
quinoline was obtained in moderate to good yields (runs 5-7).22
Cyclization reactions of several ethynylaniline derivatives
were examined under the above optimal conditions, and the
results are shown in Table 5. For example, the use of a substrate
having an electron-donating group, such as a methyl and a
methoxy group, afforded the desired polysubstituted products
13b-d in high isolated yields (runs 2-4). In addition, the use
of an ethynylaniline derivative containing an electron-withdraw-
ing group, such as a fluoro, a cyano and a nitro group, also
gave the corresponding quinoline product 13e-g (runs 5-7).
Surprisingly, when the reaction with a substrate 12h, having
an acetyl group, was conducted under the standard conditions,
the dimerization did not proceed, but led to the formation of
the acetophenone derivative, which was formed by the hydration
of the starting material 12 h (run 8). There is no reasonable
explanation for the result. Furthermore, when the substrate
having an acetyl group on the amino group or having a nitrogen
to produce the corresponding carboxylic acid 7 in a good yield.
Then, treatment of 7 with a catalytic amount of InBr3 underwent
selectively intramolecular 6-endodig cyclization, producing the
isocoumarin derivative 8 in a quantitative yield. Moreover, the
substrate 7 was converted with benzylamine to the corresponding
amide 9. Similarly, when the cyclization of 9 was carried out
under optimal conditions, the cyclic amide 10 via 6-endodig
cyclization was obtained in a 54% yield. Thus, it was found
that our group’s catalytic system using InBr3 accommodated
an intramolecular cyclization of other types of arylalkynes.
In-Catalyzed Intermolecular Dimerization Leading to
Quinoline Derivatives. As described in the introduction, when
the reaction was carried out using a substrate with a trimeth-
ylsilyl group or without a substituent group on the terminal
alkyne under our stated optimal conditions, the desired indole
product was not produced. This result showed a sharp contrast
to the results of other research groups.20 Thus, we reinvestigated
the scope for the dimerization of the ethynylaniline derivative
along with the re-examination of a Lewis acid. Initially, the
preparation of 2-ethynylaniline 12 was accomplished via both
a standard Sonogashira-coupling reaction of 2-iodoaniline with
trimethylsilylacetylene and subsequent deprotection of the TMS
group under basic conditions (Scheme 4).19
The dimerization of 2-ethynylaniline (12a) using a typical
Lewis acid and indium (III) halide was then reinvestigated, and
the results are summarized in Table 4. As a comparison with
(22) When the reaction was ran with 0.2 equiv of InCl3, the corresponding
quinoline 13a was obtained in a 20% yield.
J. Org. Chem. Vol. 73, No. 11, 2008 4163

Sakai et al.
TABLE 5. In-Catalyzed Intermolecular Dimerization of
Ethynylanilines Leading to Quinolines
SCHEME 6
run
R1
R2
R3
R4
X
yield (%)a
1
2
3
4
5
6
7
8
H
H
H
Me
MeO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ac
H
H
H
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
(12a)
(12b)
(12c)
(12d)
(12e)
(12f)
(12g)
(12h)
(12i)
(12j)
(11a)
(11b)
89 (13a)
79 (13b)
84 (13c)
70 (13d)
56 (13e)
81 (13f)
80 (13g)
ND
ND
ND
50 (13a)
42 (13b)
Me
Me
H
F
CN
NO2
Ac
H
Me
H
9
10
11
12
H
H
H
Me3Si
Me3Si
CH
CH
a in Scheme 6). Thus, to support our group’s expected reaction
route via path a, the crossed-dimerization using two different
ethynylanilines, 12a and 12c, was conducted in MeOH-d4 at
60 °C, and the reaction was monitored with 1H NMR. Surpris-
ingly, the formation of the desired crossed products was not
observed, nor was the formation of the original dimerized
products. After 18 h, the reaction mixture led to the decomposi-
tion of both starting materials. The results implied the existence
of another reaction route for a dimerization of the ethynylaniline.
By contrast, in the case of aniline derivatives having an alkyl
or aryl group, a steric repulsion at the terminal carbon would
retard the approach between two molecules, preferring intramo-
lecular cyclization to dimerization (path b in Scheme 6).
Me
a Isolated yield.
SCHEME 5
atom embedded in the benzene ring was used, it did not undergo
the desired dimerization. The result was a byproduct, which
was decomposed by a similar hydration, and the recovery of
the starting material 12i,j (runs 9 and 10). The result of run 9
in Table 5 clarified that a 2-alkynylaniline, which led to the
quinoline skeleton, necessarily needed the underivatized amino
group. On the other hand, when the reaction was performed
with substrates 11a,b having a trimethylsilyl group at a terminal
Ct C bond in the presence of the indium salt, the corresponding
products 13a,b were produced in 50 and 42% yields (runs 11
and 12). Thus, our group’s catalytic system using InBr3 was
successful in undergoing the desired intramolecular dimerization,
producing the corresponding multisubstituted quinoline deriva-
tives in moderate to good yields.
Mechanistic Aspect for Intramolecular Cyclization and
Intermolecular Dimerization. To better understand the reaction
pathway for the dimerization, a deuterium-labeling experiment
was conducted, and the result is shown in Scheme 5. When the
reaction with 2-ethynylaniline (12a) was carried out in MeOH-
d4 at 60 °C, quinoline 13a-d with a deuterated 4-methyl group
and 3-position was obtained in a 63% yield after purification.
Conclusion
In summary, we have demonstrated that a class of terminal
substituents on the triple bond of an ethynylaniline selectively
produces two quite different nitrogen-containing heterocycles.
First, in alkyl/aryl groups, the indium-catalyzed intramolecular
cyclization of the alkynylaniline having the unsubstituted amino
group occurs predominately to produce the corresponding
multifunctionalized indole derivatives. Second, the use of the
substrate with a trimethylsilyl group or with no substituent group
on the terminal triple bond leads to the production of the
polysubstituted quinoline derivative via the intermolecular
dimerization of the ethynylaniline. Finally, we also have found
that the indium catalytic system can be successfully applied to
the intramolecular cyclization of other arylalkyne substrates
having a carboxylic acid and an amide group.
Experimental Section
General Procedure for the Intramolecular Cyclization of
the Arylalkyne. To a 10 mL reaction flask containing a freshly
distilled toluene (2 mL) under argon was added arylalkyne 1, 3, 7,
or 9 (0.5 mmol) and InBr3 (0.025-0.50 mmol). The resulting
mixture was refluxed and monitored by GC or TLC until the starting
material was consumed. After the usual workup, the crude product
was purified by silica gel column chromatography (hexane-AcOEt)
to produce the corresponding cycloaddition products in yields as
shown in Tables 2 and 3 and Scheme 3.
2-Hexyl-5-nitroindole (2j): pale-yellow solids; mp 86-87 °C;
1H NMR (500 MHz, CDCl3) δ 0.87 (brs, 3H), 1.23-1.37 (m, 6H),
1.70-1.73 (m, 2H), 2.76 (t, 2H, J ) 8 Hz), 6.36 (s, 1H), 7.30 (d,
1H, J ) 8.5 Hz), 7.99 (d, 1H, J ) 8.5 Hz), 8.44 (s, 1H), 8.55 (brs,
1H); 13C NMR (125 MHz, CDCl3) δ 14.0, 22.5, 28.1, 28.7, 28.8,
1
Additionally, during the reaction H NMR showed a rapid in
situ H-D exchange on the terminal carbon of 12a, and 13C
NMR did not detect the new peaks, which supported formation
of some intermediates, such as an alkynylindium.23 On the basis
of the deuterium-labeling results, we present a plausible
mechanism for the dimerization as shown in Scheme 6.
Reactions using ethynylaniline with no substituent group at the
terminal carbon would enable the approach of two molecules
of the aniline activated by InBr3 to lead to the dimerization (path
(23) During the dimerization, 13C NMR observed two peaks (81.1 and 83.5
ppm) of the alkyne moiety of 12a.
4164 J. Org. Chem. Vol. 73, No. 11, 2008

InBr3-Promoted DiVergent Approach
31.5, 101.5, 110.1, 116.7, 128.2, 128.3, 139.1, 141.6, 143.7; MS
(FAB): m/z 247 (M++H, 100%); HRMS (FAB): Calcd for
C14H19N2O2: 247.1447, Found: 247.1443; Anal. Calcd for
C14H18N2O2: C, 68.27; H, 7.37; N, 11.37, Found: C, 68.08; H, 7.76;
N, 11.58.
purified by silica gel column chromatography (hexane/AcOEt )
7:3) to produce the polysubstituted quinoline 13 (yields are collected
in Table 5).
2-(7-Methoxy-4-methyl-2-quinolinyl)-5-methoxyaniline (13d): yel-
low needles; mp 123.5-124.0 °C; 1H NMR (300 MHz, CDCl3) δ
2.66 (s, 3H), 3.81 (s, 3H), 3.94 (s, 3H), 6.28 (d, 1H, J ) 2.4 Hz),
6.32 (brs, 2H), 6.38 (dd, 1H, J ) 9 Hz, 2.4 Hz), 7.13 (dd, 1H, J )
9 Hz, 2.4 Hz) 7.32 (d, 1H, J ) 2.4 Hz), 7.45 (s, 1H), 7.62 (d, 1H,
J ) 9 Hz), 7.82 (d, 1H, J ) 9 Hz); 13C NMR (75 MHz, CDCl3) δ
18.9, 55.1, 55.4, 101.2, 104.1, 107.4, 115.2, 117.9, 118.7, 121.1,
124.6, 131.0, 144.2, 148.4, 149.1, 159.1, 160.4, 161.2; MS (FAB):
m/z 295 (M++H, 100%); HRMS (FAB): Calcd for C18H19N2O2:
295.1446, Found: 295.1458.
2-(1-Hydroxybutyl)indole (4d): yellow oil; 1H NMR (500 MHz,
CDCl3) δ 0.90 (q, 2H, J ) 7 Hz), 1.05 (t, 2H, J ) 7 Hz), 1.50
(brs, 1H), 2.01 (t, 2H, J ) 7 Hz), 2.93 (t, 2H, J ) 7 Hz), 5.53 (s,
1H), 6.41 (m, 2H), 6.56 (d, 1H, J ) 7.5 Hz), 6.84 (d, 1H, J ) 7.5
Hz), 7.50 (brs, 1H); 13C NMR (125 MHz, CDCl3) δ 25.5, 27.8,
31.9, 62.4, 99.3, 110.4, 119.5, 119.7, 120.8, 128.7, 135.9, 139.7;
MS (EI): m/z 189 (M+, 100%); HRMS (EI): Calcd for C12H15NO:
189.1154, Found: 189.1151.
1,3,5-(2-Indolyl)benzene (6): colorless solids; mp >250 °C; 1H
NMR (500 MHz, d6-DMSO) δ 7.05 (t, 3H, J ) 7.5 Hz), 7.15 (m,
6H), 7.47 (d, 3H, J ) 7.5 Hz), 7.62 (d, 3H, J ) 7.5 Hz), 8.33 (s,
3H), 11.68 (br s, 3H); 13C NMR (125 MHz, d6-DMSO) δ 98.9 (d,
J ) 4.8 Hz), 110.8 (d, J ) 6.8 Hz), 119.0, 119.7, 119.9, 121.4,
128.0 (d, J ) 4.8 Hz), 132.8 (d, J ) 6.8 Hz), 136.5 (d, J ) 19 Hz),
136.8 (d, J ) 19 Hz); MS (FAB): m/z 424 (M++H, 25%); HRMS
(FAB): Calcd for C30H22N3: 424.1814, Found: 424.1819.
Acknowledgment. This work was partially supported by a
grant for the “High-Tech Research Center” Project for Private
Universities: a matching fund subsidy from MEXT, 2000-2004,
and 2005-2007. N.S. acknowledges the TORAY Award in
Synthetic Organic Chemistry, Japan. We thank Mr. Kazuyori
Shimamura for his experimental assistance.
General Procedure for the Intermolecular Dimerization of
Ethynylanilines. To a 10 mL reaction flask under argon containing
freshly distilled methanol (0.6 mL) was added 2-(ethynyl)aniline
12 (0.600 mmol) and InBr3 (0.600 mmol). The resulting mixture
was refluxed and monitored by TLC until the starting material had
been consumed. After the usual workup, the crude product was
Supporting Information Available: Detailed procedures and
spectroscopic data for novel compounds. Copies of H NMR
of novel compounds prepared are available. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
JO800464U
J. Org. Chem. Vol. 73, No. 11, 2008 4165