Palladium-catalyzed coupling reaction of terminal alkynes with aryl iodides in the presence of indium tribromide and its application to a one-pot synthesis of 2-phenylindole

Article abstract of DOI:10.1021/ol036499u

The use of a novel PdCl₂(PPh₃)₂-InBr ₃ reagent system to catalyze cross-coupling reactions of a variety of aryl iodides with several terminal alkynes is described. The corresponding functional alkyne derivatives were produced in good to excellent yields. Moreover, a catalytic amount of InBr₃ effectively catalyzes the intramolecular cycloaddition of 2-phenylethynylaniline to form an indole skeleton in high yield.

Full text of DOI:10.1021/ol036499u

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1527-1530
Palladium-Catalyzed Coupling Reaction
of Terminal Alkynes with Aryl Iodides in
the Presence of Indium Tribromide and
Its Application to a One-Pot Synthesis
of 2-Phenylindole
Norio Sakai,* Kimiyoshi Annaka, and Takeo Konakahara*
Department of Pure and Applied Chemistry, Faculty of Science and Technology,
Tokyo UniVersity of Science, Noda, Chiba 278-8510, Japan
sakachem@rs.noda.tus.ac.jp
Received December 24, 2003
ABSTRACT
The use of a novel PdCl2(PPh3)2−InBr3 reagent system to catalyze cross-coupling reactions of a variety of aryl iodides with several terminal
alkynes is described. The corresponding functional alkyne derivatives were produced in good to excellent yields. Moreover, a catalytic amount
of InBr3 effectively catalyzes the intramolecular cycloaddition of 2-phenylethynylaniline to form an indole skeleton in high yield.
The transition metal-catalyzed cross-coupling reaction of
metal acetylides with vinyl/aryl halides is one of the most
important reactions in organic synthesis, since it provides a
useful method for direct sp-sp2 carbon-carbon bond forma-
tion.1 Palladium-catalyzed cross-coupling reactions of ter-
minal alkynes with vinyl/aryl halides in the presence of CuI
(Sonogashira-Hagihara alkynylation)2a-e or in the absence
of any cocatalyst (Heck alkynylation)2f,g are more useful
synthetically and have been widely used in the synthesis of
a variety of polyfunctional alkynes. Since the initial report
describing both reactions,2 many chemists have reported the
use of novel metal acetylides, which function as a syntheti-
cally more useful tool than copper acetylide,1c,3 and the
development of a more active palladium catalyst for cross-
coupling with unactivated arenes such as aryl bromides and
chlorides.4 On the other hand, indium(III) halide has recently
(1) For selected reviews of metal-catalyzed coupling reactions, see: (a)
Negishi, E. Xu, C. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Eds.; Wiley-Interscience: New York, 2002; p 531.
(b) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol 3, p 521. (c) Negishi,
E.; Anastasia, L. Chem. ReV. 2003, 103, 1979 and refs cited therein.
(2) For selected reviews and papers on the Sonogashira alkynylation and
the Heck alkynylation, see: (a) Sonogashira, K. In Handbook of Organo-
palladium Chemistry for Organic Synthesis; Negishi, E., Eds.; Wiley-
Interscience: New York, 2002; p 493. (b) Tykwinski, R. R. Angew. Chem.,
Int. Ed. 2003, 42, 1566 and refs cited therein. (c) Sonogashira, K. J.
Organomet. Chem. 2002, 653, 46. (d) Takahashi, S.; Kuroyama, K.;
Sonogashira, K. Hagihara, N. Synthesis 1980, 627. (e) Sonogashira, K.;
Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467. (f) Dieck, H. A.;
Heck, F. R. J. Organomet. Chem. 1975, 93, 259. (g) Cassar, L. J.
Organomet. Chem. 1975, 93, 253.
(3) For selected papers and reviews of the Pd-catalyzed coupling reaction
of alkynylmetal compounds with aryl halides, see the following. For Zn:
(a) Negishi, E.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski, D. Org. Lett.
2003, 5, 1597. (b) Crisp, G. T.; Turner, P. D.; Stephens, K. A. J. Organomet.
Chem. 1998, 570, 219. (c) Negishi, E.; Kotora, M.; Xu, C. J. Org. Chem.
1997, 62, 8957. (d) Yoneda, N.; Matsuoka, S.; Miyaura, N.; Fukuhara, T.;
Suzuki, A.; Bull. Chem. Soc. Jpn. 1990, 63, 2124. For Sn: (e) Hatanaka,
Y.; Matsui, K.; Hiyama, T. Tetrahedron Lett. 1989, 30, 2403. (f) Kosugi,
M.; Tamura, H.; Sano, H.; Migita, T. Chem. Lett. 1987, 193. (g) Stille, J.
K.; Simpson, J. H. J. Am. Chem. Soc. 1987, 109, 2138. For B: (h) Oh, C.
H.; Jung, S. H.; Tetrahedron Lett. 2000, 41, 8513. (i) Fu¨rstner, A.; Seidel,
G. Tetrahedron 1995, 51, 11165. For Al: (j) Gelman, D.; Tsvelikhovsky,
D.; Molander, G. A.; Blum, J. J. Org. Chem. 2002, 67, 6287. (k) Negishi,
E. Acc. Chem. Res. 1982, 15, 340. For Si: (l) Nishihara, Y.; Ikegashira,
K.; Hirabayashi, K.; Ando, J.-I.; Morio, A.; Hiyama, T. J. Org. Chem. 2000,
65, 1780.
10.1021/ol036499u CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/09/2004

attracted considerable attention in synthetic organic chemistry
due to the fact that it has a lower toxicity than organic tin
compounds, a high stability under aqueous conditions, and
a strong tolerance to oxygen- and nitrogen-containing reac-
tion substrates and functional groups.5 Although a number
of synthetic applications using indium halide have been
reported,6 the transition metal-catalyzed cross-coupling reac-
tion of terminal alkynes with organic halides in the presence
of a catalytic amount of an indium halide as a typical
Sonogashira reaction has not been extensively studied.7 In
this regard, Alami and Linstrumelle et al. reported the simple
and efficient coupling of terminal alkynes with aryl halides
using Pd(PPh3)4 in a cyclic secondary amine,8 and we have
also reported that indium tribromide readily promotes the
alkynylation of a variety of aldehydes with several terminal
alkynes in the presence of triethylamine to give the corre-
sponding propargylic alcohols.9 To expand on this approach
further, we attempted to apply the method to the novel
transition metal-catalyzed cross-coupling of 1-alkynes with
aryl halides in the presence of an indium catalyst. In this
communication, we describe some preliminary results, in
which a novel PdCl2(PPh3)2-InBr3 reagent system effectively
catalyzes the cross-coupling of terminal alkynes with aryl
iodides leading to the corresponding functional alkyne
derivatives in excellent yields. We also disclose herein that
indium(III) bromide catalyzes the smooth intramolecular
cyclization of 2-phenylethynylaniline, directly producing
2-phenylindole in good yield.
We initially examined the Pd-catalyzed cross-coupling
reaction of phenylacetylene (1a) with p-iodotoluene (2a) in
the presence of a catalytic amount of indium tribromide.
When the terminal alkyne 1a was treated with InBr3 (20 mol
%) in piperidine at room temperature for 2.5 h, followed by
the addition of a piperidine solution of Pd(PPh3)4 (5 mol %)
and p-iodotoluene, the expected coupling adduct 3aa was
produced in 94% yield within 1 h (run 1 in Table 1).10
A
Table 1. Examination of Indium Bromide and Reaction
Conditionsa
1a
InBr3
time
(h)
yield
(%)b
run
(equiv)
(equiv)
Pd
1
2
3
4
5
6
7
1
1
1
1.2
1.2
1
0.2
0.05
0.2
Pd(PPh3)4
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(PPh3)2
P d Cl2(P P h 3)2
Pd(PPh3)4
1
2
2
94
72
87
99
95
70
89
0.2
<0.2
<0.2
2
0.05
none
none
(4) For selected recent advantages of the Sonogashira-type reaction, (a)
see ref 2b. (b) Soheili, A.; Albaneze-Walker, J.; Murry, J. A.; Dormer, P.
G.; Hughes, D. L. Org. Lett. 2003, 5, 4191. (c) Me´ry, D.; Heuze´, K.; Astruc,
S. Chem. Commun. 2003, 1934. (d) Ko¨llhofer, A.; Pullmann, T.; Plenio,
H. Angew. Chem., Int. Ed. 2003, 42, 1056. (e) Eckhardt, M.; Fu, G. C. J.
Am. Chem. Soc. 2003, 125, 13642. (f) Remmele, H.; Ko¨llhofer, A.; Plenio,
H. Organometallics 2003, 22, 4098. (g) Yang, C.; Nolan, S. P. Organo-
metallics 2002, 21, 1020. (h) Batey, R. A.; Shen, M.; Lough, A. Org. Lett.
2002, 4, 1411. (i) Eberhard, M. R.; Wang, Z.; Jensen, C. M. Chem. Commun.
2002, 818. (j) Alami, M.; Crousse, B.; Ferri, F. J. Organomet. Chem. 2001,
624, 114. (k) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C.
Org. Lett. 2000, 2, 1729. (l) Thorand, S.; Krause, N. J. Org. Chem. 1998,
63, 8551.
(5) (a) Bandini, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A.
Synlett 2002, 1110. (b) Onishi, Y.; Ito, T.; Yasuda, M.; Baba, A. Eur. J.
Org. Chem. 2002, 1578. (c) Nagarajan, R.; Perumal, P. T. Tetrahedron
2002, 58, 1229. (d) Yadav, J. S.; Abraham, S.; Reddy, B. V. S.; Sabitha,
R. G. Synthesis 2001, 2165. (e) Takami, K.; Yorimitsu, H.; Shinokubo, H.;
Matsubara, S.; Oshima, K. Org. Lett. 2001, 3, 1997. (f) Chauhan, K. K.;
Frost, C. G. J. Chem. Soc., Perkin Trans. 1 2000, 3015. (g) Tsuchimoto,
T.; Maeda, T.; Shirakawa, E.; Kawakami, Y. Chem. Commun. 2000, 1573.
(h) Ranu, B. C. Eur. J. Org. Chem. 2000, 2347. (i) Araki, S.; Kamei, T.;
Hirashita, T.; Yamamura, H.; Kawai, M. Org. Lett. 2000, 2, 847. (j) Yasuda,
M.; Miyai, T.; Shibata, I.; Baba, A.; Nomura, R.; Matsuda, H. Tetrahedron
Lett. 1995, 36, 9497. (k) Marshall, J. A.; Hinkle, K. W. J. Org. Chem.
1995, 60, 1920.
1.2
PdCl2(PPh3)2
5
a Reaction was carried out using phenylacetylene (1a, 0.48 mmol),
p-iodotoluene (2a, 0.4 mmol), Pd catalyst (0.02 mmol), InBr3 (0-0.2 equiv
per equiv of 2a), and piperidine (2.5 mL). b NMR yields based on
p-iodotoluene.
catalytic amount of the indium catalyst (5 mol %) permitted
the desired coupling reaction to proceed, but the product yield
was decreased slightly (run 2). Similarly, when the coupling
was carried out using PdCl2(PPh3)2 in place of Pd(PPh3)4,
the corresponding alkyne was obtained in good yield (run
3).11 By increasing the amount of alkyne 1a used to 1.2 equiv
per equivalent of the halide, the yield of bisarylalkyne 3aa
was increased to near quantitative. Moreover, in the case of
PdCl2(PPh3)2, the presence of only 5 mol % indium bromide
led to a smooth reaction that was complete within 15 min,
to afford the expected product in excellent yield (run 5).12
On the other hand, when Pd-catalyzed cross-coupling reac-
tions were conducted without the indium catalyst under the
above conditions, the reaction time needed to be extended,
and the product yield was clearly reduced (runs 6 and 7).8b
This result clearly shows that indium bromide functions as
an effective cocatalyst in promoting this coupling reaction.13
(6) (a) Lee, P. H.; Lee, S. W.; Seomoon, D. Org. Lett. 2003, 5, 4963.
(b) Lehman, U.; Awasthi, S.; Minehan, T. Org. Lett. 2003, 5, 2405. (c)
Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. J. Org.
Chem. 2003, 68, 6627. (d) Rodr´ıguez, D.; Sestelo, J. P.; Sarandeses, L. A.
J. Org. Chem. 2003, 68, 2518. (e) Lee, K.; Lee, J.; Lee, P. H. J. Org. Chem.
2002, 67, 8265. (f) Pena, M. A.; Pe´rez, I.; Pe´res Sestelo, J.; Sarandeses. L.
A. Chem. Commun. 2002, 2246. (g) Pe´rez, I.; Pe´res Sestelo, J.; Sarandeses,
L. A. J. Am. Chem. Soc. 2001, 123, 4155. (h) Pe´res, I.; Pe´res Sestelo, J.;
Sarandeses. L. A. Org. Lett. 1999, 1, 1267.
(7) During our submission, Negishi et al. also reported a similar effect
of InCl3 as a cocatalyst in Pd-catalyzed cross-coupling reaction; see: Qian,
M.; Huang, Z.; Negishi, E. Org. Lett. 2004, 6, 1531.
(8) (a) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993,
34, 6403. (b) Leadbeater and Tominack recently reported on the PdCl2-
(PPh3)2 catalyzed-coupling reaction of terminal alkynes with aryl halides/
triflates without CuI in a cyclic amine; see: Leadbeater, N. E.; Tominack,
B. J. Tetrahedron Lett. 2003, 44, 4233.
(10) With amines as the solvent, a reaction using pyrrolidine gave a
similar result (72% under the same conditions in run 1, Table 1), although
coupling reactions using other amines such as triethylamine and diethylamine
did not proceed and the starting materials were recovered.
(11) Other catalysts such as Pd(OAc)2 and NiCl2(PPh3)2 were not
effective for this reaction.
(12) Coupling reaction using CuI instead of InBr3 showed a similar result.
For example, the reaction using 2a was complete within 15 min and the
yield of product 3aa was 98%.
(9) Sakai, N.; Hirasawa, M.; Konakahara, T. Tetrahedron Lett. 2003,
44, 4171.
1528
Org. Lett., Vol. 6, No. 10, 2004

To extend the general applicability of this coupling
reaction, the reaction of several 1-alkynes with various aryl
iodides was carried out under the above-optimized conditions,
the results of which are summarized in Table 2. In most of
Table 3. Examination of the Intramolecular Cyclization of
2-Phenylethynylaniline
Table 2. Pd-In Catalyzed Cross-Coupling of Terminal
Alkynes with Aryl Iodides
catalyst
(equiv)
temp
(°C)
time
(h)
yield
(%)a
run
solvent
1
2
3
4
5
6
7
8
In Br 3 (1)
InBr3 (0.05)
tolu en e
toluene
toluene
r eflu x
reflux
reflux
rt
reflux
reflux
reflux
reflux
<0.2
1
99
95
18
15
9
10
ndb
75
24
24
24
24
10
12
InBr3 (0.05)
InBr3 (0.05)
toluene
piperidine
piperidine
toluene
time
(h)
product,
yield (%)a
run
R1
R2
Cu(OTf) (1)
Pd(II) (0.05)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph 1a
Ph
p-Me-C6H4 2a
o-Me-C6H4 2b
p-NH2-C6H4 2c
o-NH2-C6H4 2d
p-MeO-C6H4 2e
p-NO2-C6H4 2f
p-F-C6H4 2g
p-Me-C6H4 2a
p-NO2-C6H4 2f
p-MeO-C6H4 2e
o-NH2-C6H4 2d
p-NO2-C6H4 2f
p-NO2-C6H4 2f
2-thienyl 2h
<0.2
8
1.5
1
<0.5
<0.5
<0.2
6c
4
6
3
1
3
3a a , 95b
3a b, 55b,d
3a c, 96
3a d , 99b
3a e, 99b
3a f, 99
3a g, 93
3ba , 93b
3bf, 88
3ce, 79e
3cd , 74
3cf, 99
3d f, 95
3a h , 85
toluene
a NMR yield based on 3ad. b nd ) not detected. c Pd(II) ) PdCl2(PPh3)2.
Ph
Ph
Ph
Ph
amount of the indium catalyst to less than 0.05 equiv per
equiv of 3ad also gave a similar result (run 2). A Pd(II)
catalyst also catalyzed the cyclization in mild yield (run 7).15
In contrast, in the case of Cu(OTf)2,16 the formation of
cycloadduct 4 could not be confirmed because of product
decomposition under the reflux conditions employed. These
results imply that an initial coordination of an alkyne π-bond
with InBr3 increases the electrophilicity of the alkyne unit,
facilitating subsequent intramolecular nucleophilic attack
onto the alkyne carbon by the ortho amine group.17
Ph
C6H13 1b
C6H13
Me3Si 1c
Me3Si
Me3Si
t-Bu 1d
Ph 1a
9
a Isolated yields based on aryl halide. b NMR yields based on the aryl
halide. c Reaction temperature ) 60 °C. d Pd-catalyzed coupling reaction
without a cocatalyst, as CuI gave no product; see ref 7b. e Pd-catalyzed
coupling reaction without a cocatalyst, as CuI gave the product in 28%
yield; see ref 8b.
Finally, we applied the present method to a one-pot
synthesis of 2-phenylindole (4). As shown in Scheme 1, the
the cases where phenylacetylene (1a) was used, the Pd-
coupling reactions were complete in a short time (<1.5 h),
and the corresponding alkynes 3 were produced in high yields
(runs 1, 3-7, and 14), except for the reaction in which
o-iodotoluene was used (2b) (run 2). In addition, the catalytic
system described here could be adapted to reactions em-
ploying other alkynes such as 1-octyne (1b), trimethyl-
silylacetylene (1c), and tert-butylacetylene (1d) (runs 8-13).
It is noteworthy that utilizing this improved procedure
dramatically improved the yields of the coupling adducts 3ab
and 3ce in comparison to those reported in the recent
literature (3ab, 0%; 3ce, 28%) (runs 2 and 10).8b
Scheme 1. One-Pot Synthesis of 2-Phenylindole
The intramolecular cyclization of 2-phenylethynylaniline
(3ad) in the presence of indium bromide or other catalysts
was next examined, and the results are listed in Table 3. As
a result of these experiments, we found that when 1 equiv
of indium bromide per equiv of 3ad is used in toluene, the
intramolecular cyclization of 3ad is essentially complete
within 10 min, producing a nearly quantitative yield of
2-phenylindole (4) (run 1).14 Moreover, decreasing the
Pd-catalyzed reaction of phenylacetylene (1a) with o-
iodoaniline (2d) in the presence of InBr3 (5 mol %) was
initially carried out under the optimized conditions. The
bisarylalkyne 3ad formed was not isolated, and the solvent
(14) Intramolecular cycloaddition of 3cd did not proceed at all.
(15) (a) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843.
(b) Hiroya, K.; Itoh, S.; Ozawa, M.; Kanamori, Y.; Sakamoto, T.
Tetrahedron Lett. 2002, 43, 1277. (c) 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. (d) Villemin, D.; Goussu, D. Heterocycles 1989,
29, 1255.
(13) When the reaction using InCl3 instead of InBr3 was carried out, the
reaction time was prolonged (5 h) and the product yield of 3aa was
decreased to 68%.
Org. Lett., Vol. 6, No. 10, 2004
1529

was replaced with toluene. To this solution was added 1
equiv of indium bromide, and the toluene solution was
refluxed for 17 h, giving the expected indole derivative 4 in
54% yield.
coupling reaction of terminal alkynes with aryl iodides
leading to the corresponding functionalized alkyne deriva-
tives in excellent yields. Thus, the indium catalyst is a quite
useful cocatalyst for promoting this type of coupling reaction.
In addition, it was found that indium(III) bromide catalyzes
the smooth intramolecular cyclization of ethynylaniline
derivatives without the need for a protecting group on a
nitrogen atom, directly producing an indole skeleton. Further
investigation of the mechanism of this reaction is now in
progress.
Although there is no clear explanation for the actual role
of indium bromide at present, we assume that InBr3 initially
coordinates to the alkyne π bond to increase the acidity of
the terminal hydrogen, followed by abstraction of the proton
by a mild base such as piperidine to facilitate formation of
alkynylindium species.17 The evidence for the initial com-
plexation/coordination process of Lewis acidic InBr3 to the
alkyne π bond is supported by the fact that the smooth InBr3-
catalyzed intramolecular cyclization of coupled product 3ad
led to indole 4.
Acknowledgment. This work was partially supported by
a grant from the Japan Private School Promotion Foundation
and a grant for High Technology Research Centers of Private
Universities.
In summary, we demonstrate herein that a novel PdCl2-
(PPh3)2-InBr3 reagent system effectively catalyzes the cross-
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of compounds 3 and 4. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) (a) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989,
30, 2581. (b) Iritani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett. 1988,
29, 1799.
(17) Sirakawa et al. reported that In(OTf)3 coordinates onto alkyne
π-electrons to activate subsequent nucleophilic reaction by aromatics; see:
Tsuchimoto, T.; Maeda, T.; Sirakawa, E.; Kawakami, Y. Chem. Commun.
2000, 1573.
OL036499U
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Org. Lett., Vol. 6, No. 10, 2004