Synthesis of 2-substituted indoles by palladium-catalyzed heteroannulation with Pd-NaY zeolite catalysts

Article abstract of DOI:10.1016/j.tetlet.2003.11.075

Various 2-substituted indoles were prepared by heteroannulation of o-iodoanilines and terminal alkynes in a one-pot reaction with a Pd(II)-NaY zeolite catalyst. The product formation largely depended on the solvent, base, and reaction temperature. The recycled catalyst showed good reusability in the heteroannulation reaction.

Full text of DOI:10.1016/j.tetlet.2003.11.075

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 693–697
Synthesis of 2-substituted indoles by palladium-catalyzed
heteroannulation with Pd–NaY zeolite catalysts
a
Ki Bum Hong, Chul Wee Lee and Eul Kgun Yum
b
a,
*
a
Department of Chemistry, Chungnam National University, Yusung, Taejon 305-764, South Korea
b
Advanced Chemical Technology Division, Korea Research Institute of Chemical Technology,
PO Box 107, Yusung, Taejeon 305-600, South Korea
Received 3 October 2003; revised 7 November 2003; accepted 14 November 2003
Abstract—Various 2-substituted indoles were prepared by heteroannulation of o-iodoanilines and terminal alkynes in a one-pot
reaction with a Pd(II)–NaY zeolite catalyst. The product formation largely depended on the solvent, base, and reaction temperature.
The recycled catalyst showed good reusability in the heteroannulation reaction.
Ó 2003 Elsevier Ltd. All rights reserved.
8
The indole nucleus is found in many natural products,
1
acids. By contrast, LarockÕs annulation reaction of 2-
iodoaniline derivatives with internal alkynes has pro-
vided a variety of 2,3-disubstituted indoles in one-pot
reactions. The annulation method is an effective way to
pharmaceutical agents, and material polymers. The
interesting chemical properties of indole have inspired
chemists to design and synthesize a variety of indole
2
9
derivatives. Although many synthetic methods have
been developed for indoles, palladium-mediated indole
prepare a variety of heterocycles. Our group has also
applied the annulation method to the synthesis of het-
erocyclic azaindoles and pyrroloquinolines. Several
groups have reported using Pd-zeolite to catalyze the
3
10
11
synthesis is one of the most active research fields.
Specifically, the palladium-catalyzed annulation of
o-haloanilines with alkynes has received much attention,
as it is a very convenient way to synthesize 2 or 2,3-
12
Heck reaction. Those papers described the following
reaction characteristics: (i) Palladium complexes immo-
bilized in zeolite supercages have almost the same
activity as the free complexes in solution. (ii) Molecules
or small metal particles immobilized in zeolite cavities
are stable. (iii) The zeolite microstructure could help to
overcome the problems of leaching present with a het-
erogeneous catalyst in solution. (iv) Zeolites are capable
of stabilizing active intermediate species in their cavities
and controlling the reaction pathway via shape selec-
tivity. In spite of these interesting properties of zeolites,
there are no reports on recycling the catalyst or catalyst
reusability in palladium-catalyzed heteroannulation.
This paper examines the annulation of o-haloanilines
and terminal alkynes using a Pd-modified zeolite. Zeo-
lites entrapped with different Pd species were prepared
4
;5
substituted indoles (Scheme 1).
R
3
X
R
2
H
R
2
R
3
R
2
R
2
N
Pd-CuI, Base
Pd (0)
N
R
NH
R
1
R
1
1
X = I, Br.
R
1
R
2
= H, Ac. Boc, CO
2 2
Et,SO Ar, Alkyl,
, R = H, Alkyl, Aryl, etc
3
Scheme 1.
The Sonogashira cross-coupling reaction of o-haloani-
lines with terminal alkynes in the presence of Pd(0)–
Cu(I) gives 2-alkynylanilines. The resulting coupling
products have been cyclized to give 2-substituted indoles
13;12a
according to reported methods
of NaY zeolite (Aldrich No 33,444-8) using a 0.1 M
aqueous solution of [Pd(NH ]Cl at room temperature
by the ion exchange
4h;6
7
using various metal alkoxides,
fluorides, and Lewis
3
)
4
2
2
þ
for 24 h to produce [Pd(NH ) ] –NaY. Calcination of
3
4
2
þ
the ion-exchanged [Pd(NH
for 4 h under O
subsequent treatment at 300 °C for 4 h with 5% H
3
)
4
] –NaY zeolites at 500 °C
Keywords: 2-Substituted indole; Pd-Zeolite; Catalyst; Heteroannual-
tion; Terminal alkynes.
2
gave the Pd(II)–NaY zeolite, and
(N
balance) gave Pd(0)–NaY. These Pd-containing
*
Corresponding author. Tel.: +82-42-821-5474/94; fax: +82-42-823-
360; e-mail: ekyum@cnu.ac.kr
2
2
12a
1
0
040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.075

694
K. B. Hong et al. / Tetrahedron Letters 45 (2004) 693–697
2
zeolites had an SBET of 765 cm /g and an average pore
diameter of 14.6 A. Using AAS, the absolute palladium
vents and reaction times with o-iodoanilides and phenyl
acetylene. The results are summarized in Table 2.
ꢀ
content of these catalysts was determined to be
1
.0 ± 0.1 wt %. First, we investigated the reaction of N-
Table 2. The effects of solvents and reaction time on heteroannulation
acyl 2-iodoaniline with phenylacetylene as a model to
study the intermolecular heteroannulation with 1.0 wt %
Pd-loaded zeolite catalysts. To optimize the reaction
conditions, we varied our previous heteroannulation
conditions, including the halide source, base, temper-
ature, and Pd-zeolite catalyst. As shown in Table 1, the
reaction using LiCl gave a better yield than the reactions
Ph
5
mol % Pd-zeolite
LiCl, 2 Cs CO
H
I
1
2
3
+
2
+
140 oC, DMF
N
H
Ph
NHAc
NHAc
Ph
a
b
10
a
Entry
Solvent
Reaction time (h) Isolated yield (%)
1
2
3
4
5
DMF
DMA
NMP
24
24
24
24
6
80
62
with n-BuN Cl or CsCl as the chloride source (entries 1–
4
3
). The reaction provided 2-phenylindole as the major
59
product instead of N-acetyl 2-phenylindole. The depro-
tection of the acetyl group in the indole likely occurred
as a result of the acidic nature of the zeolite. After the
chloride effects were examined, we tried various bases
using the same reaction conditions (entries 4–7). Using
Cs CO as the base, the desired indole was obtained in
1,4-Dioxane
DMF
DMA
Trace
80
67 (1:6)
b
6
6
a
The reactions were run on a 0.5-mmol scale with 10 mL of DMF.
The reaction provided the Sonogashira coupling product as a major
product.
b
2
3
8
0% yield. A mixture of the desired indole and the
Sonogashira coupling product was obtained using other
carbonate or acetate bases.
On changing the solvent, the reactions using DMF,
DMA, and NMP gave similar yields of 2-phenylindole
after 24 h. Furthermore, we re-examined the effect of
continuing the annulation reaction for 6 h. The reaction
using DMF gave the best yield of the desired product.
Conversely, the reaction using DMA provided the
coupling product as a major product after 6 h, while the
cyclized 2-phenylindole was obtained after a longer
reaction time (entries 2 and 6). These tests showed that
the general reaction conditions for synthesizing indole
derivatives required 2 equiv of the terminal alkyne,
The effect of temperature was also examined with the
1
.0 wt % Pd–NaY catalyst (entries 1 and 8). The desired
product was obtained using LiCl, 1.0 wt % Pd(II)–NaY,
and Cs CO
at 140 °C. By contrast, at 120 °C, the same
reaction did not give any of the desired products (entry
). Finally, we compared the catalytic activity in terms
of Pd loading and Pd species with Pd–NaY catalysts
entries 9–12). The catalytic activity of the Pd-loaded
2
3
8
(
zeolite depended on the palladium concentration and
palladium species. The heteroannulation reaction using
2 3
1 equiv of LiCl, 2 equiv of Cs CO , 5 mol % Pd-loaded
1.0 wt % Pd(II)–NaY catalyst showed good catalytic
activity. We also investigated the effect of different sol-
zeolite, and DMF at 140 °C. To synthesize diverse
2-substituted indoles with Pd-loaded zeolites, the reac-
Table 1. Optimizing the heteroannulation reaction conditions
Ph
5
mol % Pd-zeolite
H
I
1 LiCl, 2 Cs CO
2
3
+
2
+
140 oC, DMF
N
H
Ph
NHAc
NHAc
Ph
a
b
a
Entry
Halide source
LiCl
Base
Pd-zeolite
Reaction yield (%)
b
Time (h)
(a:b)
1
2
3
4
5
6
7
Cs
2
Cs
2
Cs
2
CO
3
3
3
Pd(II)–NaY
Pd(II)–NaY
Pd(II)–NaY
Pd(II)–NaY
Pd(II)–NaY
Pd(II)–NaY
Pd(II)–NaY
Pd(II)–NaY
Pd(II)–NaY
Pd(II)–NaY
Pd(0)–NaY
12
12
12
12
12
12
12
12
24
24
24
12
80
64
n-BuN
CsCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
4
Cl
CO
CO
58
KOAc
Na CO
CO
LiOAc
75 (1:4)
70 (2:1)
78 (3:2)
70 (3:4)
<5
2
3
K
2
3
c
8
d
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
9
66
66
e
1
1
1
0
1
2
78
Pd(NH
3
)
4
–NaY
67
a
b
c
All the reactions were run on a 0.5-mmol scale with 10 mL of DMF.
The yields and ratio of isomeric products were determined by isolation.
The reaction was run at 120 °C.
d
e
The reaction used 0.5 wt % Pd-zeolite.
The reaction used 2.0 wt % Pd-zeolite.

K. B. Hong et al. / Tetrahedron Letters 45 (2004) 693–697
695
tions were run with N-substituted 2-iodoaniline and
various terminal alkynes under the optimal reaction
conditions. The results are summarized in Table 3.
One important finding of this study was the reusability
of the Pd-zeolite catalyst. The Pd-zeolite catalyst used
was separated with a membrane filter and then washed
14
with CH
for the same reaction, adding LiCl and Cs
reaction without regenerating the catalyst. The results
are summarized in Table 4.
2
Cl
2
. The recycled catalyst was used five times
CO to each
The reactions using N-acetyl o-iodoanilide with alkyl,
aryl, and heteroaryl substituted terminal alkynes pro-
vided 2-substituted indoles in good to reasonable yields
with deprotection of the N-acetyl group. The reaction
using acetylene also gave indole after purging the acet-
ylene with a balloon (entry 9). The reactions using N-Bn
or N-Ts 2-iodoaniline with a terminal alkyne provided
N-protected 2-substituted indoles in reasonable yields
2
3
Although the recycled catalyst did not have the same
catalytic activity as the fresh catalyst, the recycled cat-
alyst showed good catalytic reusability for heteroannu-
lation, although it required a longer reaction time than
the freshly prepared catalyst. The more times it was
(
entries 10–12).
Table 3. Synthesis of 2-substituted indoles by palladium-catalyzed heteroannulation with terminal alkynes
a
b
Entry
Aryl halide
Alkyne
Product
Yield
82
I
Ph
1
Ph
N
H
NHAc
2
CH OThp
2
3
4
5
6
69
78
52
51
50
N
H
OThp
N
H
Ac
S
Ac
S
N
N
H
N
N
H
N
H
N
N
2 3
CH OCH
7
8
48
72
N
H
OCH3
(
2 4 3
CH ) CH
C H
5
12
N
H
c
9
40
68
52
40
42
N
H
I
Ph
Ph
1
1
1
1
0
1
2
3
Ph
N
NHBn
Bn
N
Bn
I
Ph
N
NHTs
Ts
N
Ts
a
b
c
Reaction conditions: 0.5 mmol aryl halide, 1.0 mmol alkyne, 0.5 mmol LiCl, 1.0 mmol Cs
Isolated yield (%).
2 3
CO with 10 mL of DMF at 140 °C for 6 h.
The acetylene was purged with a balloon.

696
K. B. Hong et al. / Tetrahedron Letters 45 (2004) 693–697
Table 4. Reusable catalysts for heteroannulation
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H
5mol % Pd (II)-NaY
eq LiCl
I
1
+
2
eq Cs CO
2
3
NHAc
N
H
n-Bu
n-Bu
°
C
DMF, 140
Entry
Pd(II)–NaY
Fresh
Reaction time (h) Yield (%)
2
001, 42, 4751; (g) Dai, W.-M.; Guo, D.-S.; Sun,
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2
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4
5
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6
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82
72
70
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68
65
Recycled 1 time
Recycled 2 times
Recycled 3 times
Recycled 4 times
Recycled 5 times
5
1
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mechanism for the heteroannulation (Scheme 2).
6. (a) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles
986, 24, 31; (b) Sakamoto, T.; Kondo, Y.; Iwashita, S.;
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D
5 mol % Pd-zeolite
LiCl, 2 Cs CO
I
1
2
3
+
2
1
40 °C, DMF
N
H
Ph
7. Yasuhara, M. C.; Kanamori, Y.; Kaeko, M.; Numata, A.;
Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1
NHAc
Ph
1
999, 529.
Scheme 2.
8
. (a) Saulnier, M. G.; Fennesson, D. B.; Deshpande, M. S.;
Vyas, D. M. Tetrahedron Lett. 1995, 36, 7841; (b) Hiroya,
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Tetrahedron Lett. 2002, 43, 1277.
From the above result, the product would be formed by
Sonogashira cross-coupling and subsequent cyclization.
9
. Review: (a) Larock, R. C. J. Organomet. Chem. 1999, 576,
1
11; (b) Larock, R. C. Pure Appl. Chem. 1999, 71, 1435.
In conclusion, Pd(II)–NaY zeolite catalyst exhibits high
reactivity in the heteroannulation of o-haloanilines and
terminal alkynes. This method provides a convenient
new route to various heteroannulation products in a
one-pot reaction. Furthermore, the Pd-zeolite catalyst is
an interesting alternative to homogeneous catalysis for
heterocyclic synthesis.
1
1
0. (a) Park, S. S.; Choi, J. K.; Yum, E. K.; Ha, D.-C.
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Acknowledgements
This work was supported by a Korea Science Founda-
tion Grant (R01-2003-000-10069-0). The authors thank
Mr. Jung-Nam Park at KRICT for preparing the cata-
lysts.
1
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References and notes
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. Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Compr.
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Chemistry; Pergamon: Amsterdam, 2000; (b) Diederich,
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Reagents and Catalysts; John Wiley & Sons: Chichester,
2
3
13. (a) Michalik, J.; Narayana, M.; Kevan, L. J. Phys. Chem.
1985, 89, 1553; (b) Sachtler, W. M. H.; Cacalcanti, F. A.
Catal. Lett. 1991, 9, 261.
14. General procedure for the synthesis of 2-substituted indole
by palladium-catalyzed heteroannulation with the Pd-
loaded zeolite catalyst.
1995.
4
. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467; (b) Sakamoto, T.; Kondo, Y.;
Yamanaka, H. Heterocycles 1988, 27, 2225, and refer-
ences therein; (c) Arcadi, A.; Cacchi, S.; Marinelli, F.
The Pd-loaded zeolite (0.125 mmol), lithium chloride
(0.5 mmol), cesium carbonate (1 mmol), N-acetyl 2-iodo-
aniline (0.5 mmol), phenyl acetylene (1.0 mmol), and
DMF (10 ml) were added to a sealed tube. The reaction

K. B. Hong et al. / Tetrahedron Letters 45 (2004) 693–697
697
1
mixture was stirred for 6 h at 140 °C. The reaction mixture
was diluted with saturated aqueous ammonium chloride.
The product was isolated with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate. The
reaction mixture was filtered and concentrated. The
product was purified by silica gel column chromatography
using hexane/ethyl acetate. 2-Phenyl indole was obtained
in 82% yield as a brown solid. Mp 189–190 °C; H NMR
(400 MHz, CDCl ) 8.34 (s, br, 1H), 7.62 (m, 3H), 7.42–
7.27 (m, 4H), 7.20–7.09 (m, 2H), 6.80 (dd, 1H, J ¼ 2:0,
3
1
3
0.80 Hz); C NMR (100 MHz, CDCl
132.32, 128.96, 128.22, 127.64, 125.11, 122.28, 120.61,
120.21, 110.91, 99.90. Anal. Calcd for C14 11N: C, 87.01;
H, 5.74; N, 7.25. Found: C, 87.69; H, 5.41; N, 7.65.
3
) 137.85, 136.79,
H