A palladium-catalyzed one-pot procedure for the regioselective dimerization and cyanation of indoles

Article abstract of DOI:10.1016/j.tetlet.2012.01.129

A one-pot method for the regioselective dimerization and cyanation of indoles has been developed. The reaction uses safe and nontoxic K ₄[Fe(CN)₆]·3H₂O as the cyanating agent which introduces selectively a cyano group into

Full text of DOI:10.1016/j.tetlet.2012.01.129

Tetrahedron Letters 53 (2012) 1900–1904
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Tetrahedron Letters
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A palladium-catalyzed one-pot procedure for the regioselective
dimerization and cyanation of indoles
Ebrahim Kianmehr a, , Mohammad Ghanbari a, Nasser Faghih a, Frank Rominger b
⇑
a School of Chemistry, College of Science, University of Tehran, Tehran 1417614411, Iran
b Institute of Organic Chemistry, University of Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot method for the regioselective dimerization and cyanation of indoles has been developed. The
reaction uses safe and nontoxic K4[Fe(CN)6]ꢀ3H2O as the cyanating agent which introduces selectively a
cyano group into the 3-position of biindoles with high efficiency.
Received 13 August 2011
Revised 15 January 2012
Accepted 30 January 2012
Available online 7 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Homogeneous catalysis
Palladium
C–C bond formation
Cyanation
Indoles
Indoles and biindoles constitute an important motif of aromatic
compounds and are found in many natural products and pharma-
ceuticals.1 Despite the development of methods for indole function-
alization at the 2- or 3-positions via C–H activation reactions,2 little
attention has been paid to the development of procedures for direct
2,3-disubstitution of indoles. Due to the unavailability of methods
for direct 2,3-disubstitution of this type of heterocyclic system
and the need for efficient routes to synthesize more elaborate struc-
tures possessing biological activity, the development of convenient
procedures for the preparation of indole derivatives still remains an
active research area.
Aromatic nitriles are not only the key components of numerous
commercial compounds such as natural products, pharmaceuticals,
agrochemicals, pigments, and dyes,3 they are also valuable for the
installation of functional groups, including aldehydes, amines, ami-
dines, tetrazoles, carboxylic acids, and carboxylic acid derivatives.4
The Rosenmund-von Braun and Sandmeyer reactions are two tradi-
tional methods for the synthesis of aromatic nitriles from aryl ha-
lides (Scheme 1).5 On the other hand, direct cyanation of a C–H
bond of heterocyclic systems using, CuCN, K3Fe(CN)6, K4Fe(CN)6,
or a combined source of N,N-dimethylformamide and ammonia
has been reported in recent years.6 Compared to the classic meth-
ods, direct cyanation through C–H bond functionalization is more
attractive due to the use of readily available reactants.
Considering the above reports, and as a part of our current stud-
ies on the development of efficient methods in organic synthesis
and on the preparation of heterocyclic compounds,7 herein, we re-
port a palladium-catalyzed one-pot procedure for the regioselective
dimerization and cyanation of indoles through C–H bond activa-
tion. The reaction uses safe and nontoxic K4[Fe(CN)6]ꢀ3H2O as the
cyanating agent and introduces selectively a cyano group to the
3-position of biindoles with high efficiency.
catalyst
CuCN
Ar
H
Ar
X
Ar CN
+
MCN, oxidant
X = Cl, Br, I , N2
Direct cyanation
Classic methods
Scheme 1. Cyanation methods.
⇑
Corresponding author. Tel.: +98 21 61113301; fax: +98 21 66495291.
E-mail address: kianmehr@khayam.ut.ac.ir (E. Kianmehr).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.129

E. Kianmehr et al. / Tetrahedron Letters 53 (2012) 1900–1904
1901
Pd(OAc) (10 mol%)
2
CN
H
2
1
K [Fe(CN) ].3H O
1
R
4
6
2
R
R
Cu(OAc) (3.6 equiv)
2
N
H
DMSO, Ar, 80 °C
N
N
2
2
R
R
1
2
1
R
CN
CN
Me
N
Et
N
N
N
Me
Et
2a: 93%
2c: 90%
2b: 91%
2d: 87%
CN
CN
Pr
N
Bu
N
N
N
Pr
Bu
CN
CN
R
R
N
N
N
N
R
R
2e:
R= pentyl
77%
R= p-tolylmethyl 2g: 94%
R= i-pentyl 2f: 69%
2h:
R= m-tolylmethyl
86%
CN
CN
Bn
Me
Br
Br
N
N
N
N
Me
Bn
2i: 95%
2j: 71
Br
CN
CN
Et
Pr
Br
Br
N
N
N
Et
N
Pr
2k: 70%
2l:
66%
Br
Br
CN
CN
Bu
Ph
N
N
N
N
Bu
Ph
2m: 65%
2n: 73%
Br
Figure 1. Synthesis of cyanated biindoles. Optimized reaction conditions: 1a (1 mmol), K4[Fe(CN)6]ꢀ3H2O (0.5 mmol), Pd(OAc)2 (10 mol %), Cu(OAc)2 (3.6 equiv), DMSO
(3 ml), 80 °C, 24 h, Ar. Yields are of isolated products.
At the outset of our study, we used N-methylindole (1a) as a
model substrate with K4[Fe(CN)6]ꢀ3H2O in the presence of palla-
dium catalysts. It was found that the dimerization reaction pro-
ceeded with the formation of a C-3 cyanated biindole. Cyanation
took place in the presence of K4[Fe(CN)6]ꢀ3H2O (0.5 equiv),
Pd(OAc)2 (10 mol %), and Cu(OAc)2 (1.8 equiv) in DMSO under an
argon atmosphere at 80 °C (Table 1, entry 1). We investigated the
reaction conditions for the selective formation of cyanated biindole
2a versus 3a as shown in Table 1. The use of DMF, DMAc, and
DMSO-DMF as solvents resulted in lower yields or no reaction (en-
tries 2–4). The yield of the reaction was slightly improved by
increasing the reaction time to 36 h (entry 5). When we performed
the reaction at 120 °C, the yield of 2a decreased (entry 6). It was
found that the amount of oxidant played a key role in the formation
of 2a (entry 7). For example, only 42% of cyanated product was de-
tected when the reaction was performed with 1.8 equiv of

1902
E. Kianmehr et al. / Tetrahedron Letters 53 (2012) 1900–1904
Table 1
Selected optimization screening resultsa
Pd(OAc)2 (10 mol%)
K4[Fe(CN)6].3H2O
Cu(OAc)2
H
CN
Me
Me
N
N
H
+
N
N
N
Me
Me
Me
1a
2a
3a
Entry
Solvent
Cu(OAc)2 (equiv)
Yield of 2ab (%)
Yield of 3ab (%)
1
2
3
4
DMSO
DMF
DMAc
DMF–DMSO (10:1)
DMSO
DMSO
DMSO
DMSO
DMSO
1.8
1.8
1.8
1.8
1.8
1.8
3
42
41
26
23
28
38
29
Trace
–
Trace
Trace
29
45
33
80
93
–
5c
6d
7
8
3.6
3.6
9e
–
a
Reaction conditions: N-methylindole (1a) (1 mmol), K4[Fe(CN)6]ꢀ3H2O (0.5 mmol), Pd(OAc)2 (10 mol %), Cu(OAc)2, anhydrous solvent (3 ml),
80 °C, 24 h, Ar.
b
Isolated yield based on N-methylindole.
The reaction time was 36 h.
The reaction was carried out at 120 °C.
The reaction was carried out in the absence of Pd(OAc)2.
c
d
e
Indoles containing N-alkyl and N-benzyl substituents reacted
smoothly to give the products (2a–d,g–i) in high yields. N-Isopen-
tylindole (2f) and N-pentylindole (2e) gave lower yields, possibly
due to steric hindrance. The presence of bromine on the benzene
ring of the indoles did not change the reaction pathway, and satis-
factory yields of 2 were obtained using these moderately electron-
poor indoles (2j–m). N-Phenylindole tolerated the reaction condi-
tions well and generated the expected product 2n in a good yield.
The structures of the products were characterized by spectroscopic
analysis and further confirmed by an X-ray diffraction study of 2a
as a representative example (Fig. 2).8
Reaction of 1,10-dimethyl-1H,10H-2,30-biindole (3a) with
K4[Fe(CN)6]ꢀ3H2O under the optimized reaction conditions led to
the formation of the 3-cyanated product in an 84% yield (Scheme
2), indicating that the one-pot sequence may proceed through the
formation of a biindole.
Figure 2. X-ray crystal structure of 2a.
On the basis of previous chemistry2a,d,e,g,9 and the results of our
study, a plausible Pd(0)/Pd(II) mechanism for the homocoupling
reaction as shown in Scheme 3 was proposed. Initially, electrophilic
palladation occurs preferentially at the C3-position of the indole
and the subsequent migration of PdX to the 2-position leads to
the formation of intermediate 4, which undergoes electrophilic pal-
ladation with the second indole to form intermediate 5. Next,
reductive elimination generates the 2,30-biindole, and Pd(0) is
oxidized to Pd(II) by the Cu(II) salt to complete the cycle. Electro-
philic palladation of the 2,30-biindole produced may take place
to give intermediate 6, and subsequent transmetallation with
K4[Fe(CN)6]ꢀ3H2O generates intermediate 7, which undergoes
reductive elimination to afford the cyanated biindole. A Pd(II)/
Cu(OAc)2, but the yield of the cyanated product increased to 80%
with 3 equiv of Cu(OAc)2 (entries 1 and 7).
As Table 1 (entry 8) shows, the optimum conditions for the for-
mation of the cyanation product were indole derivative (1 equiv),
K4[Fe(CN)6]ꢀ3H2O (0.5 equiv), Pd(OAc)2 (10 mol %), and Cu(OAc)2
(3.6 equiv) in DMSO (3 ml) at 80 °C for 24 h under an argon atmo-
sphere. Finally, a control experiment demonstrated that no product
2a was detected when the reaction was carried out in the absence
of Pd(OAc)2 (entry 9). Under the optimized conditions, the sub-
strate scope of this reaction was investigated, and the results are
summarized in Figure 1.
CN
Me
Me
Pd(OAc)2 (10 mol%)
Cu(OAc)2
N
N
N
K4[Fe(CN)6].3H2O
N
Me
DMSO, Ar, 80 °C
Me
84% yield
3a
Scheme 2. Direct cyanation of 1,10-dimethyl-1H,10H-2,3-biindole (3a).

E. Kianmehr et al. / Tetrahedron Letters 53 (2012) 1900–1904
1903
N
Me
Pd
N
5
Me
4
PdX
N
N
Me
Pd(0)
[O]
N
N
Me
Me
1
PdX2
N
PdX2
Me
[O]
3
Pd(0)
CN
PdX
N
Me
PdCN
Me
N
Me
6
N
N
N
Me
N
Me
Me
K4[Fe(CN)6].3H2O
2
7
Scheme 3. A plausible mechanism.
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tive oxidative homocoupling reaction.10 Further research is re-
quired to elucidate the precise reaction mechanism.
In summary, we have developed an efficient method for the
dimerization and cyanation of indoles with excellent regioselectiv-
ity. The reaction uses safe and nontoxic K4[Fe(CN)6]ꢀ3H2O as the
cyanating agent. This new protocol provides a facile route to the ti-
tle products via a one-pot sequence.
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Acknowledgments
We gratefully acknowledge the financial support from the Re-
search Council of the University of Tehran. We thank Dr. Karol
Gajewski, Canadian Intellectual Property Office, for helpful com-
ments on this work. We also thank Professor A. Stephen K. Hashmi,
Institute of Organic Chemistry, University of Heidelberg, for pro-
viding access to instrumental facilities.
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