SBA-15-functionalized melamine-pyridine group-supported palladium(0) as an efficient heterogeneous and recyclable nanocatalyst for N-arylation of indoles through Ullmann-type coupling reactions

Article abstract of DOI:10.1002/aoc.3296

SBA-15-functionalized melamine-pyridine group-supported palladium(0) was found to serve as a heterogeneous and recyclable nanocatalyst for N-arylation of indoles with aryl iodides under a low catalyst loading (0.3mol% of Pd) through Ullmann-type C￡N coupling reactions. A variety of aryl iodides could be aminated to provide the N-arylated products in good to excellent yields without the need of an inert atmosphere. Also, this catalyst was found to be an efficient system for the N-arylation of other nitrogen-containing heterocycles with aryl iodides. The heterogeneous palladium catalyst could be recovered by simple filtration of the reaction solution and reused for six cycles without significant loss in its activity.

Full text of DOI:10.1002/aoc.3296

Full Paper
Received: 23 December 2014
Revised: 17 January 2015
Accepted: 21 January 2015
Published online in Wiley Online Library: 12 March 2015
(wileyonlinelibrary.com) DOI 10.1002/aoc.3296
SBA-15-functionalized melamine–pyridine
group-supported palladium(0) as an efficient
heterogeneous and recyclable nanocatalyst for
N-arylation of indoles through Ullmann-type
coupling reactions
Hojat Veisi*, Mohammad Reza Poor Heravi and Mona Hamelian
SBA-15-functionalized melamine–pyridine group-supported palladium(0) was found to serve as a heterogeneous and recyclable
nanocatalyst for N-arylation of indoles with aryl iodides under a low catalyst loading (0.3mol% of Pd) through Ullmann-type
C–N coupling reactions. A variety of aryl iodides could be aminated to provide the N-arylated products in good to excellent
yields without the need of an inert atmosphere. Also, this catalyst was found to be an efficient system for the N-arylation of
other nitrogen-containing heterocycles with aryl iodides. The heterogeneous palladium catalyst could be recovered by simple
filtration of the reaction solution and reused for six cycles without significant loss in its activity. Copyright © 2015 John Wiley &
Sons, Ltd.
Keywords: Ullmann coupling; indole; C–N bond formation; palladium; nanocatalyst
[
19]
molecular heterogeneous catalyst, is essential.
Heterogeneous
Introduction
catalysis also helps to minimize wastes derived from reaction
workup, contributing to the development of green chemical
processes. So, encouraged by our previous works on C–C, C–N
The indole ring system is present in numerous natural products, phar-
maceuticals, agrochemicals and other compounds of importance.
Particularly, N-arylated indole motifs are very important as they
[1–8]
[20]
[
21–24]
and C–O coupling reactions,
we designed and prepared an
exhibit nanomolar affinity for α -adrenoceptors in addition to
SBA-15/CCPy/Pd nanocatalyst by grafting of melamine bearing
pyridine groups on SBA-15 and subsequent deposition of Pd
nanoparticles as a new and stable catalyst which is employed in
the coupling of phenylboronic acid with aryl halides (Suzuki
coupling). The wide scope of this catalyst led us to investigate
the N-arylation of indoles from the corresponding aryl iodides
and indoles under mild conditions (Scheme 1).
1
[
9]
their affinities for dopamine D and serotonin 5-HT receptors.
2
2A
Also, N-arylated indoles are prevalent in compounds that are ma-
[10]
terials of interest.
Of the many methods for the synthesis of N-arylindoles, the
[21]
[
4,11]
Fisher indole synthesis is the best known and most widely used.
Ullmann-type coupling methodology, involving the combination
of an indole with an aryl halide in the presence of base and a
[
12]
copper catalyst at high temperatures, is an important alternative.
Methods that operate under milder conditions and utilize aryl
Experimental
[13]
[14]
bismuth and aryl lead reagents have been developed. Finally,
the synthesis of N-arylindoles may also be achieved by nucleophilic
aromatic substitution in instances in which the aryl halides are
activated by the presence of one or more electron-withdrawing
General Procedure for Synthesis of N-arylindoles
In a typical reaction, 10 mg of the catalyst (10 mg = 0.003mmol Pd)
was placed in a 25 ml flask. Aryl iodide (1.1 mmol) in 5 ml of DMF
[15–17]
groups.
While each of these methods is useful in its own right,
was added with 1 mmol of indole and 2 mmol of Et N. The mixture
3
each suffers from one or more limitations including a lack of
generality, the use stoichiometric quantities of toxic reagents or
the need to employ harsh reaction conditions.
was then refluxed for 2 h at 110 °C. After completion of the reaction
monitored using TLC, the reaction mixture was cooled to room
temperature (the catalyst was recovered by centrifugation) and
was extracted with diethyl ether three times (3 × 10 ml). The
combined organic layers were washed with brine solution and
The palladium-catalysed N-arylation of heterocycles is an
[18]
alternative method under mild reaction conditions.
However,
use of expensive palladium salts and high oxophilicity associated
with phosphine ligands limit the attractiveness of this method for
industrial applications. To overcome these problems, the develop-
ment of highly efficient and recyclable heterogeneous catalysts,
such as immobilization of catalytically active species, e.g.
organometallic complexes, onto a solid support to produce a
*
Correspondence to: Hojat Veisi, Department of Chemistry, Payame Noor
University, Tehran, Iran. E-mail: hojatveisi@yahoo.com
Department of Chemistry, Payame Noor University (PNU), 19395-4697, Tehran,
Iran
Appl. Organometal. Chem. 2015, 29, 334–337
Copyright © 2015 John Wiley & Sons, Ltd.

N-Arylation of indoles through Ullmann-type coupling reactions
Initially, various solvents, namely DMF, EtOH, CH
CH Cl , DMSO and H O, were studied in the presence of 0.5mol%
Pd catalyst and 2 equiv. of Et N at 110 °C (Table 1, entries 1–7). As
is evident from Table 1, the best result is obtained in DMF (Table 1,
entry 7). Next, bases, namely Et N, KOH, K PO , Na CO , NaHCO
and K CO , were explored. Et N gives the best yields (Table 1,
entries 1, 12–16). However, a low yield is obtained without any base
3
CN, toluene,
2
2
2
3
3
3
4
2
3
3
2
3
3
(Table 1, entry 10).
It is also found that the reaction temperature has a great
influence on this transformation (Table 1, entries 9, 17, 18). An
obvious improvement in the conversion (98%) is achieved for the
reaction at 110 °C (Table 1, entry 9).
In addition, when the loading of Pd is reduced from 0.5 to 0.3mol
%, an excellent yield is also afforded. However, when 0.2mol% of
Pd is employed, the reaction yield decreases to 70% (Table 1, en-
tries 7–9). It is important to mention that N-arylation of indole does
not take place in the absence of Pd catalyst (Table 1, entry 11). In
summary, the optimal condition for the N-arylation of indole with
iodobenzene involves the use of 0.3mol% of Pd catalyst, 2 equiv.
Scheme 1. SBA-15/CCPy/Pd(0)-catalysed N-arylation of indoles using
various aryl iodides.
of Et N in DMF at 110°C for 2 h (Table 1, entry 9).
3
With these optimum reaction conditions in hand, the scope and
generality of the N-arylation method were investigated with various
aryl iodides and indoles with different substituents. The results are
summarized in Table 2.
dried over anhydrous Na SO and concentrated in vacuo. The crude
2
4
product was purified using column chromatography on silica gel
60–120 mesh) to afford the N-arylindoles.
(
We examined the reaction of indoles with substituted aryl
iodides (Table 2, entries 1–16). All the substituted aryl iodides
react with indoles to afford the coupling products in good to
high yield. We do not observe any limitation as for aryl iodide
derivatives. The reactivity of 2-methylindole is slightly lower than
that of indole and 3-methylindole due to the steric effect (Table 2,
entries 1, 11, 13).
Results and Discussion
In our initial screening experiments, the N-arylation reaction of
indole with iodobenzene was investigated to optimize the reaction
conditions including Pd concentration, solvent, base and
temperature without the protection of an inert gas. The results
are summarized in Table 1.
a
Table 2. Synthesis of N-arylindoles catalysed by SBA-15/CCPy/Pd(0)
Table 1. Optimization of reaction conditions for N-arylation of indole
a
with iodobenzene
b
Entry Pd (mol%)
Base
Solvent T (°C) t (h) Yield (%)
b
Entry
Aryl iodide
Indole
Yield (%)
Ref.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.2
0.3
0.3
0.0
0.3
0.3
0.3
0.3
0.3
0.3
0.3
Et
Et
Et
Et
Et
Et
Et
Et
Et
3
3
3
3
3
3
3
3
3
N
N
N
N
N
N
N
N
N
—
N
CH
3
CN
82
78
12
12
12
12
12
12
3
55
45
70
40
35
85
95
70
98
12
0
EtOH
1
2
3
4
5
6
7
8
9
Iodobenzene
Indole
98
98
98
97
96
92
96
90
95
88
90
92
98
96
92
0
[12d]
[12d]
[12d]
[12e]
[12d]
[12d]
[12d]
[12f]
[12d]
[12f]
[12e]
[18c]
[12d]
[12d]
[12d]
—
Toluene
110
100
40
p-Methoxyiodobenzene Indole
2
H O
p-Chloroiodobenzene
p-Nitroiodobenzene
p-Bromoiodobenzene
p-Acetyliodobenzene
p-Methyliodobenzene
o-Bromoiodobenzene
Indole
Indole
Indole
Indole
Indole
Indole
2 2
CH Cl
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
110
110
110
110
110
110
110
110
110
110
110
25
12
2
0
1
2
3
4
5
6
7
8
12
12
12
12
12
12
12
12
12
o-Methoxyiodobenzene Indole
Et
3
10
11
12
13
14
15
16
m-Nitroiodobenzene
Iodobenzene
Indole
K
2
CO
3
65
45
50
73
60
0
2-Methylindole
2-Methylindole
3-Methylindole
Na
CO
2 3
p-Methyliodobenzene
Iodobenzene
K
3
PO
KOH
NaHCO
4
p-Methoxyiodobenzene 3-Methylindole
3
p-Nitroiodobenzene
3-Methylindole
1-Methylindole
Et
Et
3
N
N
Iodobenzene
3
70
25
a
Reactions were carried out under aerobic conditions in 5 ml of DMF,
N in the
a
Reaction conditions: indole (1.0 mmol), iodobenzene (1.1 mmol), Pd
catalyst, base (2.0 mmol), solvent (5.0 ml).
1.1 mmol aryl iodide, 1.0 mmol indole and 2 mmol Et
3
presence of Pd catalyst (0.010 g, 0.3 mol% Pd) and 110 °C for 2 h.
b
b
Isolated yield.
Isolated yield.
Appl. Organometal. Chem. 2015, 29, 334–337
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

H. Veisi et al.
Table 3. SBA-15/CCPy/Pd(0)-catalysed N-arylation of various nitrogen-
a
containing heterocycles with iodobenzene
b
Entry
Het-NH
Yield (%)
Ref.
1
2
3
4
5
1H-benzo[d]imidazole
1H-imidazole
96
98
92
96
96
[25]
[25]
[25]
[25]
[26]
1H-pyrrole
1H-pyrazole
1H-pyrrolo[2–29]pyridine
a
Reactions were carried out under aerobic conditions in 3 ml of DMF,
.1 mmol aryl iodide, 1.0 mmol Het-NH and 2 mmol Et N in the
1
3
presence of Pd catalyst (0.010 g, 0.3 mol% Pd) and 110 °C for 3 h.
b
Isolated yield.
Figure 1. Recycling of the SBA-15/CCPy/Pd(0) for the N-arylation of indole
under similar conditions.
The coupling with p-haloiodobenzenes exhibits interesting selec-
tivities between halogens. The reactions with p-chloroiodobenzene
and p-bromoiodobenzene afford the corresponding products,
N-p-chlorophenyl and N-p-bromophenylindoles, with good
yields of 96 and 98%, respectively, without touching the bromine
and chlorine atoms (Table 2, entries 3, 5). It is very important to
mention that the reaction is very selective to give only N-arylated
product and in none of these cases is C-arylation of indole
observed.
To ensure that there is no C-arylation taking place in the reaction,
the reaction was carried out with 1-methylindole and no product is
formed (Table 2, entry 16). This shows the high selectivity of
SBA-15/CCPy/Pd(0) as catalyst in the N-arylation of indole using
aryl iodides.
Interestingly, less reactive aryl halides such as bromobenzene
and chlorobenzene also couple with indole furnishing C-arylindole
in good to appreciable yields in longer reaction times.
We were pleased to find that the arylation reactions also proceed
with other nitrogen-containing heterocycles such as benzimid-
azoles, imidazole, pyrrole, pyrazole and 7-azaindole in good yields
under the same conditions (Table 3, entries 1–5).
In order to determine whether the catalysis is due to the SBA-15/
CCPy/Pd(0) complex or to a homogeneous Pd complex that comes
off the support during the reaction and then returns to the support
[27]
at the end, we performed the hot filtration test. We focused on
the N-arylation reaction of indole with iodobenzene. We filtered
off the SBA-15/CCPy/Pd(0) complex after 30 min reaction time
and the filtered phase of the reaction mixture was kept under
reaction conditions for another 2 h. The catalyst filtration was
performed at the reaction temperature (110°C) in order to avoid
possible re-coordination or precipitation of soluble palladium upon
cooling. The reaction of indole with iodobenzene at 110 °C for
30min before the hot filtration affords N-phenylindole in 60% yield.
We find that, after this hot filtration, no further reaction is observed.
This result suggests that the Pd catalyst remains on the SBA-15
support at elevated temperatures during the reaction and points to
a process of a heterogeneous nature. Based on these results we pro-
pose a reaction mechanism for Ullmann-type C–N coupling reaction
[
28]
with the prepared nanocatalyst (Scheme 2).
According to the
general mechanism depicted in Scheme 2, the reaction of in-
dole NH with the oxidative addition product A in the presence
of base leads to a novel B complex. When the latter complex un-
dergoes a reductive elimination, the coupled product N-
arylindole is produced, and the catalyst is released to complete
the catalytic cycle.
For a heterogeneous transition metal catalyst, it is important to ex-
amine its ease of separation, recoverability and reusability. The
recycling performance of SBA-15/CCPy/Pd(0) was investigated in the
reaction of iodobenzene and indole. SBA-15/CCPy/Pd(0) was centri-
fuged from the reaction, washed with hot ethanol and water, and
reused in a next reaction. The data presented in Fig. 1 show that
SBA-15/CCPy/Pd(0) can be reused six times without significant
loss of catalytic activity. The high stability and excellent
reusability of the catalyst should result from the chelating action
of bidentate pyridine groups on palladium and the mesoporous
structure of the SBA-15 support. The result is important from a
practical point of view. The high catalytic activity, excellent reus-
ability and easy accessibility of the SBA-15/CCPy/Pd(0) make it a
Scheme 2. Plausible mechanism for N-arylation.
wileyonlinelibrary.com/journal/aoc
Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2015, 29, 334–337

N-Arylation of indoles through Ullmann-type coupling reactions
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solution-phase synthesis of diverse libraries of compounds.
Conclusions
We have demonstrated a simple and efficient procedure for the
synthesis of N-arylindoles through the reaction of indoles with aryl
iodides using SBA-15-immobilized bidentate pyridine palladium
nanoparticles as catalyst under mild reaction conditions. The
reactions generated the corresponding N-arylindoles in good to
excellent yields and were applicable to various indoles and a variety
of aryl iodides. In addition, this methodology offers the competi-
tiveness of recyclability of the catalyst without significant loss of
catalytic activity, and the catalyst could be easily recovered
and reused for at least six cycles, thus making this procedure
environmentally more acceptable.
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Acknowledgments
We are grateful to Payame Noor University (PNU) for partial support
of this work.
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