Uncommon intramolecular palladium-catalyzed cyclization of indole derivatives

Article abstract of DOI:10.1016/S0040-4039(03)00116-3

A novel synthetic strategy based on the intramolecular palladium-catalyzed oxidative cyclization reaction, allows the formation of C-C bond and the synthesis of β-carbolinones. The reaction has been performed in the presence of catalytic amount of PdCl

Full text of DOI:10.1016/S0040-4039(03)00116-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1919–1921
Uncommon intramolecular palladium-catalyzed cyclization of
indole derivatives
Egle M. Beccallia,* and Gianluigi Brogginib
aIstituto di Chimica Organica, Universita` degli Studi di Milano, via Venezian 21, 20133 Milano, Italy
bDipartimento di Scienze Chimiche, Fisiche e Matematiche dell’Universita` dell’Insubria, via Lucini 3, 22100 Como, Italy
Received 4 October 2002; accepted 7 January 2003
Dedicated to the memory of Professor Alessandro Marchesini
Abstract—A novel synthetic strategy based on the intramolecular palladium-catalyzed oxidative cyclization reaction, allows the
formation of C–C bond and the synthesis of b-carbolinones. The reaction has been performed in the presence of catalytic amount
of PdCl2(CH3CN)2 and benzoquinone as a reoxidant. © 2003 Elsevier Science Ltd. All rights reserved.
The catalytic processes which allow the formation of
carbon–carbon bonds based on the oxidative addition
of carbon–hydrogen bonds are of considerable interest
with respect to the potential use in organic synthesis.1
The literature data report oxidative inter- or
intramolecular coupling like arylation of aromatic
heterocycles2 and alkenylation of arenes3,4 with olefins
with the cleavage of sp2-C–H bond in the presence of
palladium compounds. Cyclization to carbazoles from
diphenylamine derivatives5 and conversion of aryl-
aminoquinones to carbazoloquinones6 have also been
reported as well as cyclization of bisindolyl systems to
indolocarbazole derivatives7 and cyclization leading to
the synthesis of indole alkaloids.8
Most of the applications of palladium described above
use a stoichiometric amount of expensive Pd(OAc)2.
The oxidative process would be of much greater syn-
thetic utility if one could use only a catalytic amount of
palladium. In the catalytic reactions, in situ regenera-
tion of palladium(II) from palladium(0) is the crucial
step for catalytic cycle. Progress has been made towards
the catalytic oxidative pathway. Several reoxidation
reagents have been reported such as copper acetate,6a,b
tert-butyl hydroperoxide,6c and more recently oxygen6d
or
a
mixture of benzoquinone and tert-butyl
hydroperoxide.3
As a part of our ongoing interest in developing novel
synthetic strategies for the construction of condensed
aromatic heterocyclic derivatives,9 we focused our
attention on the intramolecular Heck reaction10 and
subsequently on the intramolecular oxidative cycliza-
tion reaction.
We report here
a very efficient example of an
intramolecular palladium-catalyzed oxidative cycliza-
tion reaction of an indolic substrate bearing a non-acti-
vated double bond in the 2 position. On the contrary,
the reported coupling reactions of aromatic compounds
with olefins were efficient for the unsaturated systems
bearing an electron-withdrawing substituent at the a-
carbon. Starting from indole-2-carboxylic acid 1, the
reaction with oxalyl chloride and the suitable allyl-
Scheme 1.
Keywords: Pd catalyst; intramolecular cyclization; indoles; carboli-
nones.
* Corresponding author. Tel.: +39-2-50314479; fax: +39-2-50314476;
e-mail: egle.beccalli@unimi.it
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00116-3

1920
E. M. Beccalli, G. Broggini / Tetrahedron Letters 44 (2003) 1919–1921
amines gave the corresponding indole 2-N-allylcarbox-
amides 2a–d. The intramolecular oxidative cyclization
reaction was performed with PdCl2(CH3CN)2 (10%
mol) as catalyst and benzoquinone (1 equiv.) as reoxi-
dant in a mixture of DMF–THF at 80°C for 45 min., to
give in very good yield b-carbolinones 3a–c. We have
just reported the synthesis of these products by an
intramolecular Heck cyclization.10 Nevertheless in that
case the protection of the 1 position of the indolic
substrate was necessary to prevent the decomposition
of the starting material and the loss of iodine atom. The
monosubstituted amide, indole 2-carboxylic acid allyl-
amide 2d, does not give any cyclization product
(Scheme 1 and Table 1). The in situ reoxidation of
Pd(0) to Pd(II) leads to the subsequent transformation
of benzoquinone to hydroquinone.
Selected spectroscopic data: 2a, mp 101°C; IR: 3230,
1
1605, 1459 cm−1; H NMR (CDCl3): 3.29 (3H, s), 4.34
(2H, br s), 5.32 (2H, m), 5.97 (1H, m), 6.89 (1H, s), 7.15
(1H, dt, J=1.1, 8.1 Hz), 7.29 (1H, dt, J=1.1, 8.1 Hz),
7.46 (1H, dd, J=1.1, 8.1 Hz), 7.68 (1H, d, J=8.1 Hz),
9.48 (1H, br s, exch. with D2O); 13C NMR (CDCl3):
36.5 (CH3), 53.5 (CH2), 105.5 (CH=), 117.6 (CH2=),
112.0, 120.4, 122.0, 124.4, 132.8 (CHAr), 127.8, 129.5,
135.9, 164.0 (C).
General procedure for the synthesis of i-carbolinones
3a–c: to a solution of 1H-indole-2-carboxylic acid allyl-
amide 2 (1 mmol) in a mixture of DMF (6 ml) and
THF (12 ml) PdCl2(CH3CN)2 (26 mg, 10 mol%) and
benzoquinone (108 mg, 1 mmol) were added. The mix-
ture was stirred under N2 for 45 min. at 80°C, then
concentrated in vacuo and the residue poured into
brine to give the b-carbolinone 3 as a solid. The filtrate
was extracted with Et2O (2×20 ml) and the extracted
The reported literature data show for these reactions an
oxidative coupling process that presumably commences
with the direct palladation of the aromatic C–H bond
forming s-aryl palladium(II) complex. Subsequently, in
a manner akin to an intramolecular Heck reaction, the
intermediate undergoes olefin addition and b-hydride
elimination and then results in the coupling product.11
However at present we can not exclude an alternative
pathway for this reaction, based on the nucleophilic
attack of the electron-rich indole ring on a palladium
activated double bond.12
evaporated to give
a residue which was chro-
matographed on silica gel eluent Et2O to give an addi-
tional amount of compound 3.
Selected spectroscopic data: 3a total yield 98%, mp
295°C dec. (from CH2Cl2); IR: 3150, 1651, 1589 cm−1;
1H NMR (C3D6O): 2.60 (3H, d, J=0.7 Hz), 3.66 (3H,
s), 7.08 (1H, d, J=0.7 Hz), 7.24 (1H, dt, J=1.1, 7.3
Hz), 7.46 (1H, t, J=7.3 Hz), 7.71 (1H, d, J=8.0 Hz),
8.13 (1H, d, J=8.0 Hz), 11.18 (1H, bs, exch. with D2O);
13C NMR (DMSO): 16.9, 36.4 (CH3), 113.3, 120.4,
123.0, 126.5, 127.6 (CHAr), 111.4, 123.2, 124.1, 128.1,
140.0, 155.4 (C).
In conclusion, the palladium-catalyzed coupling
described here offers an easy and highly efficient route
to fused aromatic heterocyclic systems. The reaction
utilizes readily available starting materials and is con-
ducted under mild conditions. These facts suggest that
the catalytic method has potential for even a wider
application than that described in the present communi-
cation and further studies are in progress.
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