InBr3-catalyzed intramolecular cyclization of 2-alkynylanilines leading to polysubstituted indole and its application to one-pot synthesis of an amino acid precursor

Article abstract of DOI:10.1016/j.tetlet.2005.11.121

We describe InBr₃-catalyzed cyclization of 2-alkynylaniline derivatives having a variety of functional groups producing polysubstituted indoles. This methodology could be applied to the one-pot synthesis of an amino acid precursor by the addition of a catalytic amount of the indium salt, an imine, and TMSCl.

Full text of DOI:10.1016/j.tetlet.2005.11.121

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 631–634
InBr3-catalyzed intramolecular cyclization of
2-alkynylanilines leading to polysubstituted indole and
its application to one-pot synthesis of an amino acid precursor
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
Received 2 November 2005; revised 18 November 2005; accepted 24 November 2005
Abstract—We describe InBr3-catalyzed cyclization of 2-alkynylaniline derivatives having a variety of functional groups producing
polysubstituted indoles. This methodology could be applied to the one-pot synthesis of an amino acid precursor by the addition of a
catalytic amount of the indium salt, an imine, and TMSCl.
Ó 2005 Elsevier Ltd. All rights reserved.
Practical syntheses of substituted indole derivatives have
attracted considerable attention in organic, pharmaceu-
tical, or medical chemistry, since this basic skeleton is
broadening in natural products and biologically active
substances.1a,b Among them, palladium,2 copper,3 other
metal,4 and base5,6 mediated cyclization of 2-alkynyl-
anilines is one of the most convenient methods for the
preparation of polysubstituted indoles. Although a
number of the examples have been reported in this com-
munity,1c,d there are still several disadvantages involving
an introduction of a substituted group, such as an elec-
tron-withdrawing group on the nitrogen atom, a large
amount of a loading catalyst, and limitation of a reac-
tion substrate, which is sensitive to a strong base. On
the other hand, we previously reported that InBr3 effec-
tively catalyzes Sonogashira-type coupling reaction to
produce a variety of alkynes derivatives, and that the
coordination of the indium to the alkyne p bond assists
an intramolecular nucleophilic attack by the tethered
amino group of o-alkynylaniline leading to 2-substituted
indole.4,7 In the previous work, we found that a catalytic
activity of the indium was not lost by the unsubstituted
amino group during the reaction. However, the cycliza-
tion reaction examined was only limited to one example.
Hence, we became interested in the scope and limitation
of the intramolecular cyclization of a 2-ethynylaniline
derivative by the indium catalyst. We report herein the
results of the indium-catalyzed cyclization of 2-ethynyl-
aniline derivatives leading to the synthesis of polysubsti-
tuted indoles. We also disclose an efficiently one-pot
synthesis of an amino acid precursor by sequential intra-
molecular cyclization of a tethered amino group, inter-
molecular addition of an imine.
Table 1 shows the results of the cyclization of 2-phenyl-
ethynylaniline (1a), which was prepared by the
Table 1. Examination of indium(III)-catalyzed intramolecular cycli-
zation of 1a leading to 2-phenylindole 2aa
Ph
InX3
PhMe, reflux
Ph
N
H
NH2
1a
Cat (equiv)
2a
Run
Time (h)
Yield (%)b
1
2
3
4
5
6d
InBr3 (0.05)
InCl3 (0.05)
InI3 (0.05)
InBr3 (1)
—
1
4
3
0.2
24
24
95c
90
6
98
18
15
InBr3 (0.05)
a Reaction was carried out using 2-phenylethynylaniline (0.5 mmol)
and indium trihalide (0.05 equiv) in toluene (2 mL).
b NMR yield.
c Isolated yield.
d Reaction was carried out at room temperature.
Keywords: Indium bromide; Indole; Intramolecular cyclization;
2-Ethynylaniline.
*
Corresponding authors. E-mail: sakachem@rs.noda.tus.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.121

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N. Sakai et al. / Tetrahedron Letters 47 (2006) 631–634
procedure previously reported,8 under several condi-
tions for optimized conditions.9 On the basis of previous
work, when the reaction using InBr3 ran, the desired
indole 2a was obtained in nearly quantitative yield within
1 h (run 1). InCl3 also showed a similar effect for the
reaction, however, the reaction time slightly prolonged
(run 2). In contrast, employment of InI3 resulted in
the formation of a complex mixture (run 3). The cycliza-
tion using a stoichiometric amount of indium bromide
was completed faster than while using a catalytic
amount of that (run 4). On the other hand, the reaction
without an indium catalyst, or the reaction at room tem-
perature did not afford the desired product in practical
yield (runs 5 and 6). Consequently, we found that the
toluene reflux conditions using 0.05 equiv of indium
bromide from the viewpoints of reactivity and an
economical cost showed the best result for the
cyclization.10,11
indoles 2n and 2o in good yields (runs 14 and 15).12
These results strongly support the fact that the coordina-
tion of the indium to the alkyne p bond increases the
electrophilicity of the triple bond facilitating the sub-
sequent nucleophilic attack of the tethered amino group
to form the desired indole.13
We then attempted to develop a simple method for a
one-pot synthesis of an amino acid precursor involving
an indolyl group via sequential intramolecular cycliza-
tion, intermolecular addition. After several examina-
tions, we found a proper procedure for the desired
reaction.14 Thus, a catalytic amount of indium bromide
initially undertook an intramolecular cyclization of eth-
ynylaniline 1 producing in situ indole; the addition reac-
tion of the indole with imine 3 in the presence of the
further added indium salt and TMSCl occurred to pro-
duce indolyl amine derivative 4.15,16 Table 3 shows the
results of one-pot synthesis using four types of ethynyl-
aniline 1 and imine 3 having a trichloromethyl group,17
the group of which is not only broadly found in a num-
ber of biologically active molecules, but also could be
hydrolyzed by an alkaline solution to produce the ester.
Next, to extend the generality of this reaction, cycliza-
tion of various N-unsubstituted ethynylaniline prepared
was carried out under optimized conditions, the results
are displayed in Table 2. Cyclization of the ethynylani-
line having not only an electron-donating group but also
an electron-withdrawing group on a benzene unit was
complete in a short time, producing the corresponding
indole derivatives 2 in good to excellent yields (runs 1–
6). In addition, when the reaction of substrates 1 con-
taining an alkyl group, such as a hexyl and tert-butyl
group next to a triple bond also underwent the reaction
to produce the desired polysubstituted indole derivatives
in good yields (runs 7–13). Moreover, attempts to
cyclize N-substituted ethynylaniline having a benzyl or
an acetyl group in the presence of the indium catalyst
also were highly successful to produce N-substituted
In conclusion, we have reported that quite a small
amount of InBr3 efficiently catalyzes the cyclization of
2-alkynylaniline derivatives having a variety of func-
tional groups to produce polysubstituted indoles in
good to excellent yields. This simple catalytic system is
remarkably tolerant to a variety of functional groups
on the o-ethynylaniline and the unsubstituted amino
group. We also succeeded in development for the one-
pot synthesis of an amino acid precursor by the addition
of a catalytic amount of the indium salt, the imine, and
TMSCl. Further investigations toward the synthesis of
Table 2. Intramolecular cyclization of ethynylaniline 1 leading to 2-substituted indole 2
R4
R1
R2
R1
R2
InBr3 (0.05 equiv)
toluene, reflux
R4
N
R3
NH
R3
2
1
Run
Ethynylaniline 1
Time (h)
Yield (%)a
R1
R2
R3
R4
1
2
3
4
5
6
7
8
H
H
H
Me
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Bn
Ac
Ph
Ph
Ph
Ph
Ph
Ph
C6H13
C6H13
C6H13
C6H13
C6H13
t-Bu
t-Bu
Ph
1a
1
0.5
1
2
2
2a
2b
2c
2d
2e
2f
95
98
90
90
91
98
62
52
77
86
89
59
59
78
71
Me
Me
NO2
F
CN
Me
Me
NO2
F
CN
Me
H
H
H
1b
1c
1d
1e
1f
2
1g
1h
1i
1.5
1.5
8.5
8.5
7
4
4
0.5
2.5
2g
2h
2i
9
10
11
12
13
14
15
1j
2j
1k
1l
2k
2l
H
H
H
H
1m
1n
1o
2m
2n
2o
Ph
a Isolated yield.

N. Sakai et al. / Tetrahedron Letters 47 (2006) 631–634
633
Table 3. A one-pot procedure for amino acid precursor 4a
4. Sakai, N.; Annaka, K.; Konakahara, T. Org. Lett. 2004, 6,
1527.
Ph
Ph
5. (a) Yasuhara, A.; Kanamori, Y.; Kaneko, M.; Numata,
A.; Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans.
1 1999, 529; (b) Rodriguez, A. L.; Koradin, C.; Dohle, W.;
Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 2488; (c)
Dai, W.-M.; Sun, L.-P.; Guo, D.-S. Tetrahedron Lett.
2002, 43, 7699; (d) Koradin, C.; Dohle, W.; Rodriguez, A.
L.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571; (e)
Sun, L.-P.; Huang, X.-H.; Dai, W.-M. Tetrahedron 2004,
60, 10983.
1) InBr3 (0.05 equiv)
PhMe, reflux
Cl3C
NH
Ph
R1
R2
R1
R2
2) PhCH2N=CHCCl3
3
InBr3 (0.2 equiv)
TMSCl (1.2 equiv)
PhMe, rt
NH2
N
H
1
4
Run
Ethynylaniline 1
Time (h)b
Yield (%)c
6. For cyclization of an ethynyl aniline via an iodination
process, see: Barluenga, J.; Trincado, M.; Rubio, E.;
Gonzaˆlez, J. M. Angew. Chem., Int. Ed. 2003, 42, 2406.
7. For selected reviews and papers for indium promotes or
catalyzes reaction, see; (a) Chauhan, K. K.; Frost, C. G.
J. Chem. Soc., Perkin Trans. 1 2000, 3015; (b) Ranu, B. C.
Eur. J. Org. Chem. 2000, 2347; (c) Podlech, J.; Maier, T.
C. Synthesis 2003, 633; (d) Marshall, J. A.; Hinkle, K. W.
J. Org. Chem. 1995, 60, 1920; (e) Yasuda, M.; Miyai, T.;
Shibata, I.; Baba, A.; Nomura, R.; Matsuda, H. Tetra-
hedron Lett. 1995, 36, 9497; (f) Loh, T.-P.; Wei, L.-L.
Tetrahedron Lett. 1998, 39, 323; (g) Babu, G.; Perumal, P.
T. Tetrahedron Lett. 1998, 39, 3225; (h) Miyai, T.; Onishi,
Y.; Baba, A. Tetrahedron Lett. 1998, 39, 6291; (i) Yasuda,
M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org.
Chem. 2001, 66, 7741; (j) Onishi, Y.; Ito, T.; Yasuda, M.;
Baba, A. Eur. J. Org. Chem. 2002, 1578; (k) Bandini, M.;
Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Synthesis
2002, 1110; (l) Yadav, J. S.; Reddy, B. V. S.; Raju, A. K.;
Rao, C. V. Tetrahedron Lett. 2002, 43, 5437; (m) Onishi,
Y.; Ito, T.; Yasuda, M.; Baba, A. Tetrahedron 2002, 58,
8227; (n) Bandini, M.; Fagioli, M.; Melloni, A.; Umani-
Ronchi, A. Synthesis 2003, 397; (o) Yadav, J. S.; Reddy,
B. V. S.; Swamy, T. Synthesis 2004, 106; (p) Hayashi, N.;
Shibata, I.; Baba, A. Org. Lett. 2004, 6, 4981; (q) Shibata,
I.; Kato, H.; Ishida, T.; Yasuda, M.; Baba, A. Angew.
Chem., Int. Ed. 2004, 43, 711; (r) Sakai, N.; Kanada, R.;
Hirasawa, M.; Konakahara, T. Tetrahedron 2005, 61,
9298; (s) Sakai, N.; Hirasawa, M.; Konakahara, T.
Tetrahedron Lett. 2005, 46, 6407.
R1
R2
1
2
3
4
H
H
H
Me
H
1a
1b
1c
1e
2.5
1
0.5
7.5
4a
4b
4c
4e
89
75
88
84
Me
Me
F
a Cyclization of ethynylaniline 1 (0.5 mmol) and subsequent addition
of imine 3 (1 mmol) was carried out in toluene (4 mL).
b For a reaction time in the first step, see Table 2.
c Isolated yield based on 2-phenylethynylaniline derivative 1.
biologically active substances by using the present meth-
od are currently in progress.
Acknowledgments
This work was partially supported by a grant from the
Japan Private School Promotion Foundation and a fund
for ꢀHigh-Tech Research Centerꢁ Project for Private
Universities: a matching fund subsidy from MEXT,
2000–2004, and 2005–2007.
References and notes
1. (a) Glasby, J. S. Encyclopedia of the Alkaloids; Plenum
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8. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467.
9. General procedure for the intramolecular cyclization of 1.
To a 10 mL reaction flask containing a freshly distilled
toluene (2 mL) under argon was added 2-ethynylaniline 1a
(96 mg, 0.50 mmol) and InBr3 (0.025 mmol). The resulting
mixture was refluxed and monitored by GC or TLC until
the starting material was consumed. After the usual work-
up, the crude product was purified by silica gel column
chromatography to afford the 2-substituted indole 2a
(91 mg, 95%) as a pale yellow solid.
2. (a) Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.;
McKillop, A. Tetrahedron Lett. 1985, 26, 5963; (b) Iritani,
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Frennesson, D. B.; Deshpande, M. S.; Vyas, D. M.
Tetrahedron Lett. 1995, 36, 7841; (h) Cacchi, S.; Fabrizi,
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3. (a) Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.;
Peˆrez, M.; Garcˆıa-Martˆın, M. A.; Gonzaˆlez, J. M. J. Org.
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1277; (c) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett.
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Org. Chem. 2004, 69, 1126; (e) Hiroya, K.; Itoh, S.;
Sakamoto, T. Tetrahedron 2005, 61, 10958.
10. Other polar solvents, such as CHCl3, THF, and CH3CN
were not effective for the reaction.
11. When the cyclization of 1a ran with other Lewis acids
(5 mol %), such as BF3ÆOEt2, AlCl3, and B(C6F5)3 in
toluene at 110 °C for 12 h, the desired product 2a
was obtained in lower yield (BF3ÆOEt2: 22%, AlCl3:
31%, B(C6F5)3: 29%). Another group investigated a
similar cyclization of an ethynylaniline derivative, see
Ref. 3b.
12. In case of 2-ethynylaniline (R1, R2, R3, and R4 = H), the
corresponding indole product was not obtained under the
present conditions.
13. For examples of indium salt activates alkyne p-electrons,
see: (a) Tsuchimoto, T.; Maeda, T.; Shirakawa, E.;
Kawakami, Y. Chem. Commun. 2000, 1573; (b) Tsuchim-
oto, T.; Hatanaka, K.; Shirakawa, E.; Kawakami, Y.
Chem. Commun. 2003, 2454; (c) Nakamura, M.; Endo, K.;

634
N. Sakai et al. / Tetrahedron Letters 47 (2006) 631–634
Nakamura, E. J. Am. Chem. Soc. 2003, 125, 13002; (d)
15. Although the role of TMSCl is not clear at this stage, it is
known that a coexistence of Lewis acid and TMSCl
promotes reactivity of an addition reaction, see: (a) Corey,
E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6015; (b)
Yamanaka, M.; Nishida, A.; Nakagawa, M. Org. Lett.
2000, 2, 159; (c) Huang, T.; Li, C.-J. Tetrahedron Lett.
2000, 41, 6715; (d) Lee, P. H.; Lee, K.; Sung, S.-Y.; Chang,
S. J. Org. Chem. 2001, 66, 8646; (e) Sakai, N.; Hamajima,
T.; Konakahara, T. Tetrahedron Lett. 2002, 43, 4821; (f)
Tsuji, R.; Yamanaka, M.; Nishida, A.; Nakagawa, M.
Chem. Lett. 2002, 428; (g) Jiang, B.; Si, Y.-G. Tetrahedron
Lett. 2003, 44, 6767; (h) Sakai, N.; Hirasawa, M.;
Hamajima, T.; Konakahara, T. J. Org. Chem. 2003, 68,
483; (i) Yamanaka, M.; Nishida, A.; Nakagawa, M. J.
Org. Chem. 2003, 68, 3112.
16. When the reaction ran with 0.2 equiv of InBr3 in the first
step without an extra load of InBr3 for the second step, the
desired amino acid precursor 4a was produced in 57%
yield.
17. Selected papers for Lewis acid-promoted reaction of
indole with imines, see: (a) Gong, Y.; Kato, K.; Kimoto,
H. Synlett 2000, 1058; (b) Gong, Y.; Kato, K. Tetra-
hedron: Asymmetry 2001, 12, 2121; (c) Gong, Y.; Kato, K.;
Kimoto, H. Bull. Chem. Soc. Jpn. 2002, 75, 2121.
Takita, R.; Fukuta, Y.; Tsuji, R.; Ohshima, T.; Shibasaki,
M. Org. Lett. 2005, 7, 1363; (e) See Ref. 4.
14. General procedure for the one-pot synthesis of 4. To 2 mL
of toluene was added InBr3 (11.3 mg, 0.025 mmol), 2-
ethynylaniline 1a (96.5 mg, 0.50 mmol), and the mixture
was refluxed for the corresponding times shown in Table
1. A toluene solution (2 mL) of InBr3 (45 mg, 0.10 mmol),
imine 3 (1.0 mmol, 236 mg), and TMSCl (0.60 mmol,
65 mg) was also stirred at room temperature for 1 h. The
latter solution was added to the former solution via a
cannula. The resulting mixture was stirred at room
temperature until the starting materials were consumed.
After usual work-up, the crude product was purified by
silica gel column chromatography to afford the corre-
sponding product 4a as a gray solid (191 mg, 89%). mp
(dec) 133 °C; 1H NMR (500 MHz, CDCl3) d 2.81 (br s,
1H), 3.83 (d, 1H, J = 13 Hz), 4.05 (d, 1H, J = 13 Hz), 4.87
(s, 1H), 7.07–7.37 (m, 13H), 8.24 (br s, 1H), 8.26 (d, 1H,
J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) d 51.7, 71.0,
105.4, 107.0, 110.9, 120.2, 122.3, 123.0, 126.6, 127.1, 128.1,
128.3, 128.5, 128.8, 129.0, 132.9, 135.7, 139.6, 140.3; MS
(FAB): m/z 429, 311; Anal. Calcd for C23H19N2Cl3: C,
64.28; H, 4.46; N, 6.52. Found: C, 64.28; H, 4.41; N, 6.43.