The palladium-catalyzed cyanation of indole C-H bonds with the combination of NH4HCO3 and DMSO as a safe cyanide source

Article abstract of DOI:10.1039/c1cc11603g

A palladium-catalyzed cyanation of the 3-position of indole sp² C-H bonds by the combination of NH₄HCO₃ and DMSO as the "CN" source was achieved to provide aromatic nitriles in moderate to good yields with excellent regioselectivity. It represents a practical and safe cyanation method.

Full text of DOI:10.1039/c1cc11603g

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The palladium-catalyzed cyanation of indole C–H bonds with the
combination of NH4HCO3 and DMSO as a safe cyanide sourcew
Xinyi Ren, Jianbin Chen, Fan Chen* and Jiang Cheng*
Received 20th March 2011, Accepted 19th April 2011
DOI: 10.1039/c1cc11603g
A palladium-catalyzed cyanation of the 3-position of indole sp2
C–H bonds by the combination of NH4HCO3 and DMSO as the
‘‘CN’’ source was achieved to provide aromatic nitriles in
moderate to good yields with excellent regioselectivity. It
represents a practical and safe cyanation method.
in DMSO under O2 (entry 1, Table 1). Both palladium and
copper species were required for the cyanation (entry 2
and 7, Table 1). Among the Pd sources tested, PdCl2 was the
best and the yield sharply increased to 85% (entries 3–6,
Table 1). Using [Pd(cod)Cl]2 and Pd(dppe)Cl2, or without
palladium, no cyanation product was isolated. As for Cu
sources tested, Cu(OAc)2 was superior to others, such as
CuO, Cu(OTf)2, CuCl2 and CuCl (entries 8–11, Table 1).
Other oxidants such as K2S2O8 were totally ineffective for this
transformation. The use of NMP, toluene and xylene as
solvents resulted in no reaction. The combination of DMF
and NH4HCO3 delivered the cyano product in 35% yield.
Employing NH4F or (NH4)2C2O4 as nitrogen source inhibited
the reaction, while NH3ÁH2O or (NH4)2SO4 provided the
product in poor yields (entries 19 and 20, Table 1). Under
Aryl nitriles are not only key components of pharmaceuticals
and natural products but also basic constituents of dyes and
herbicides.1 In addition, they are valuable in the installation
of functional groups, such as aldehydes, amines, amidines,
tetrazoles, carboxylic acids and their derivatives.2 The
Sandmeyer3 and Rosenmund–von Braun reactions4 are
traditional methods for the synthesis of organo nitriles, but
suffer from multiple-step procedures. The cyanation of aryl
halides catalyzed by Pd,5 Cu6 and Ni7 is a common and useful
transformation in organic synthesis. However, pre-halogenation
is required in these cyanation reactions.
Table 1 Selected results of screening the optimal conditionsa
The direct conversion of C–H bonds into carbon–carbon,
carbon–halogen, carbon-oxygen, carbon–nitrogen and carbon–
sulfur bonds is a very powerful methodology for building
complex molecules.8 Recently, chelation-assisted C–H bond
cyanation using metal-bound precursors of MCN (M = Cu,
K, Na, Zn, TMS) or K3Fe(CN)6 has been reported.9 However,
except for K3Fe(CN)6, the toxicity of the MCN would greatly
decrease the practicality of this transformation. Thus, the
development of a safe cyanide source in the cyanation reaction
still remains a highly desired goal. Very recently, Chang
demonstrated the palladium-catalyzed chelation-assisted
cyanation of 2-arylpyridine C–H bonds using the combination
of ammonia and DMF as a safe cyanide source.10 Our interest
in C–H functionalization and cyanation led us to explore the
possibility of a safe ‘‘CN’’ source for such transformations.9b,c,11
Herein, we report our study in the direct cyanation reaction of
indole C–H bonds using a combination of NH4HCO3 and
DMSO as a safe ‘‘CN’’ source.
Entry Pd source
Cu source N source
Solvent Yield (%)
1
2
Pd(OAc)2
—
Cu(OAc)2 NH4HCO3 DMSO 36
Cu(OAc)2 NH4HCO3 DMSO
0
0
0
3
4
[Pd(cod)Cl]2 Cu(OAc)2 NH4HCO3 DMSO
Pd(dppe)Cl2 Cu(OAc)2 NH4HCO3 DMSO
5
6
PdCl2
PdCl2(PPh3)2 Cu(OAc)2 NH4HCO3 DMSO
Cu(OAc)2 NH4HCO3 DMSO 85 (43b)
0
0
0
0
7
8
9
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
—
NH4HCO3 DMSO
NH4HCO3 DMSO
Cu(Otf)2 NH4HCO3 DMSO
CuO
10
11
12
13
14
15
16
17
18
19
20
CuCl2
CuCl
K2S2O8
NH4HCO3 DMSO 40
NH4HCO3 DMSO
NH4HCO3 DMSO
0
0
0
0
35
0
Cu(OAc)2 NH4HCO3 NMP
Cu(OAc)2 NH4HCO3 Toluene
Cu(OAc)2 NH4HCO3 DMF
Cu(OAc)2 NH4HCO3 xylene
Cu(OAc)2 NH4F
Cu(OAc)2 (NH4)2C2O4 DMSO
Cu(OAc)2 NH3H2O
Cu(OAc)2 (NH4)2SO4 DMSO 38
We first tested the cyanation of 1-methyl-1H-indole as the
model reaction. To our delight, cyanation took place in the
presence of Pd(OAc)2 (10 mol%) and Cu(OAc)2 (1.1 equiv.)
DMSO
0
0
DMSO 50
a
Reaction conditions: N-methyl-1H-indole (0.2 mmol), NH4HCO3
(0.3 mmol, 1.5 equiv.), Pd source (10 mol%), Cu source or other
oxidant (1.1 equiv.), and DMSO (1.5 mL), under O2, 140 1C,
College of Chemistry & Materials Engineering, Wenzhou University,
Wenzhou 325000, People’s Republic of China.
E-mail: jiangcheng@wzu.edu.cn, fanchen@wzu.edu.cn
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c1cc11603g
b
6 h. Under air.
c
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Chem. Commun., 2011, 47, 6725–6727 6725

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Table 2 Palladium-catalyzed cyanation of 3-indole C–H bondsa
was converted to a cyano group (2n, Table 2).12 Notably,
the cyanation of N-methyl-1H-pyrrolo[2,3-b]pyridine led to
nitrile product (2m) in an acceptable 61% yield. Particularly,
the bromo group survived well under the procedure and the
bromo product could be easily further modifiable (2h, Table 2).
In Wang’s protocol, the C2 position should be blocked to
ensure the reaction efficiency.13 However, under this procedure,
whether the C2 positions of indoles were blocked or not, the
cyanation of indoles furnished the corresponding products in
good yields (2a, 2i and 2j, Table 2). Disappointingly, methyl
1-methyl-1H-indole-3-carboxylate, benzofuran and benzimidazole
did not work under the standard condition. Evidently, the
cyanation predominantly took place on the 3-position of
indole. No regioisomeric products were observed by GC-MS
and 1H NMR spectroscopy. In comparison with Chang’s
procedure,10 the reaction time was dramatically shortened to
6 h and avoided ammonia. Disappointingly, free indole failed
to deliver the cyano product. Methylsulfinylbenzene and
ethylsulfinylethane were subjected to the procedure instead
of DMSO and a trace of the cyano product was detected by
GC-MS in each case.
In order to validate the source of the ‘‘CN’’ in this unique
cyanation procedure, a series of experiments were performed
(entries 13–16, Table 1). We found that CuCl2 instead of
Cu(OAc)2 as the oxidant also led to the cyanide product under
the same reaction conditions, which eliminated the possibility
of the carbon atom in the cyano group deriving from
Cu(OAc)2. Moreover, when NH3ÁH2O or (NH4)2SO4 replaced
NH4HCO3 as the nitrogen source, the nitrile product was also
isolated. The results proved that the carbon atom could not
derive from NH4HCO3. Furthermore, the 13C-DMSO labelled
experiment confirmed the carbon in the cyano group came
from DMSO (Scheme 1).
A plausible mechanism for the cyanation of indoles is
proposed in Scheme 2. Step (i) involves the C–H activation
of N-methyl indole to afford a palladated intermediate A. Step
(ii) of the proposed catalytic cycle involves ligand exchange of
CNÀ to form Pd(II) species B. In the presence of Cu(OAc)2, the
combination of DMSO and NH3, which was derived from
the decomposition of NH4HCO3, released the CNÀ.14 Finally,
the reductive elimination of intermediate B delivers the cyanation
product and Pd(0), which is oxidized to Pd(II) by Cu(II) to
regenerate the catalyst. However, the detailed mechanism on
the formation of CNÀ from the combination of DMSO and
NH3 remains unclear at the current stage.
a
Reaction conditions: 1-methyl-1H-indole (0.2 mmol), NH4HCO3
(0.3 mmol), PdCl2(10 mol%), Cu(OAc)2 (1.1 equiv.) in DMSO
b
c
d
(1.5 mL), O2, 140 1C, 6 h. 12 h. Under air. 1n = 1-methyl-1H-
indole-5-carbaldehyde.
In conclusion, we have demonstrated a new protocol for
the generation of a cyano unit from two readily available
precursors. The reaction represents a convenient and safe
method for the cyanation of the 3-position of indole C–H
bonds. This new developed safe cyanide source may have
potential utility in other cyanation reaction.
air atmosphere, only 43% of the product was isolated.
Importantly, this transformation is very practical since it does
not require the use of expensive ligands.
Further investigation showed that N-substituent groups
such as N-phenyl and N-benzyl analogues did not cause any
difficulties for this transformation though long reaction
times were required (2k and 2l, Table 2). N-Methyl indoles
possessing electron-withdrawing groups on the phenyl, such as
formyl, cyano, nitro, bromo and methoxycarbonyl groups,
reacted smoothly under the standard conditions (2h, 2o,
2p and 2q, Table 2). Interestingly, N-methyl-1H-indole-5-
carbaldehyde produced N-methyl-1H-indole-3,5-dicarbonitrile
in 65% yield, and synchronously, the aldehydic carbonyl
Scheme 1 13C-DMSO labelled experiment.
c
6726 Chem. Commun., 2011, 47, 6725–6727
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Scheme 2 Plausible mechanism.
Financial support was provided by the National Natural
Science Foundation of China (No. 20972115) and the Natural
Science Foundation of Zhejiang Province (No. R4110294).
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14 CNÀ was detected by indicator paper when the combination of
NH4HCO3, DMSO and Cu(OAc)2 was heated at 140 1C under O2
for 3 h. However, heating of NH4HCO3, DMSO and Pd(OAc)2 at
140 1C under O2 for 3 h did not produce any detectable CNÀ.
These results indicated the Cu(OAc)2 played an important role in
the in situ formation of CNÀ. See ESIw.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6725–6727 6727