Ligand-free copper nanoparticle promoted N-arylation of azoles with aryl and heteroaryl iodides

Article abstract of DOI:10.1016/j.tetlet.2013.12.065

A relatively mild, efficient, and inexpensive method for the nucleophilic aromatic substitution of the N-H heterocycles with various aryl and heteroaryl iodides using copper nanoparticles (Cu-NP) is reported. The coupling reaction has been successfully ac

Full text of DOI:10.1016/j.tetlet.2013.12.065

Tetrahedron Letters 55 (2014) 941–944
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ligand-free copper nanoparticle promoted N-arylation of azoles
with aryl and heteroaryl iodides
⇑
Gita Pai, Asoke P. Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741235, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2013
Revised 13 December 2013
Accepted 17 December 2013
Available online 25 December 2013
A relatively mild, efficient, and inexpensive method for the nucleophilic aromatic substitution of the N–H
heterocycles with various aryl and heteroaryl iodides using copper nanoparticles (Cu-NP) is reported. The
coupling reaction has been successfully achieved with moderate to good yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Copper nanoparticles
N-Arylindoles
N-Arylpyrroles
Aryl iodides
Ullmann–Goldberg coupling
N-Arylazoles
(e.g.
N-arylindoles,
N-arylpyrroles
and
are well known,22 the ligand-promoted Cu-catalyzed chemistry be-
came general for the N-arylation of indoles, imidazoles, etc.
We noticed a remarkable success in the recent Cu-catalyzed C–
N coupling reaction in our laboratory. In connection with this, we
wish to report herein a general and efficient arylation of N-hetero-
N-arylimidazoles, etc.) are important compounds widely employed
in organic synthesis, pharmaceutical, and biological areas.
N-Arylazoles are of interest as antiallergic, antipsychotic agents,
1
2
3
5
4
angiotensin II antagonists, melatonin receptor MT1 agonists,
COX-2 inhibitors, herbicides,7 and as selective ligands for the G2
6
cycles using Cu nanoparticles (Cu-NP), recently synthesized in our
8
23
binding sites. Apart from their biological activities they are used
laboratory,
3 4
K PO as base in DMSO at 80 °C. The success of
24
as key intermediates in the synthesis of some biologically active
previously reported Cu-NP promoted C–C coupling reactions
9
compounds. Many synthetic strategies have been developed for
encouraged us to extend the application of Cu-NP to the synthesis
of N-arylazoles. This is in agreement with a large number of obser-
vations worldwide, and is usually explained by the greater surface
to volume ratio for metal nanoparticles, also exposing them to oxi-
the N-arylation of indoles and other heterocycles. In the past few
years, significant advances have occurred in the development of
cross-coupling methodology. Traditionally, the copper-catalyzed
Ullmann–Goldberg coupling is a well-known method for the intro-
duction of amine functionality with the use of aromatic halides,
though the scope of these reactions is limited because of high tem-
peratures (150–200 °C), use of stoichiometric amounts of copper
reagents, and low yield with longer reaction time.10 Therefore their
applications would be restricted. In previous years, great efforts
have been directed toward developing highly efficient methods
2
5
dation, thereby increasing their reactivity.
A set of experiments was carried out to optimize the reaction
conditions. The C–N coupling reaction between aryl halide and
N-heterocycles using Cu-NP was studied with indole (1a) and 1-
iodo-4-(trifluoromethyl) benzene (2a). The results of these experi-
ments are summarized in Table 1.
As expected, in the absence of Cu-NP, the desired product 3a
was not obtained (Table 1, entry 1). From entries 2–4, it is observed
that yield of the desired product is improved by adding Cu-NP 0.1–
1 equiv. Addition of 3 equiv of Cu-NP and carrying out the reaction
at 80 °C for 8 h in DMSO afforded the desired product 3a in a 60%
yield (Table 1, entry 2). However, when similar reaction was car-
ried out with 1.6 equiv of Cu-NP, the desired N-arylindole was
formed in a 68% yield (Table 1, entry 3). On the other hand, when
the reaction time is decreased from 8 h to 5 h, compound 3a was
obtained in 82% yield (entry 4). If temperature of the reaction is
increased to 110 °C, then the yield of the desired product is
11
for constructing N-arylazoles using some low-cost and efficient
12
13
14
ligands such as diamines,
diimines,
amino acids,
b-keto
1
5
16
17
18
esters, diols, aminoarenethiolate, phosphine ligands, hydra-
1
9
20
21
zones, N-hydroxyimides, and hydroxyquinoline under mild
conditions. Although Pd catalyzed C–N bond formation reactions
⇑
Corresponding author. Tel.: +91 33 2582 8750x305/307 (O), +91 33 2582 9699
Res); fax: +91 33 2582 8282.
E-mail addresses: asoke@klyuniv.ac.in, asoke.chattopadhyay@gmail.com
A.P. Chattopadhyay).
(
(
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.065

9
42
G. Pai, A. P. Chattopadhyay / Tetrahedron Letters 55 (2014) 941–944
Table 1
decreased to 49% (entry 5). From entries 6–9, it is apparent that the
solvent has a significant role on the reaction; DMSO was found to
be quite successful for the transformation. Compound 3a was
obtained in 42% yield, when DMF was used instead of DMSO
Optimization of conditions for Cu-NP promoted N-arylation of indoles with 1-iodo-4-
(
trifluoromethyl) benzenea
CF3
Cu-NP, K PO
3
4
N
CF
3
+
I
(Table 1, entry 6). When toluene, 1,4-dioxane, and acetonitrile
o
N
H
DMSO, 80 C, 5h
were used as solvents, the desired product was obtained in only
30%, 27%, and 38% yields, respectively (Table 1, entries 7–9). Differ-
ent bases were also tested in this reaction system (Table 1, entries
2a
Base
3a
1a
Cu-NPc (equiv)
Yieldb (%)
Entry
Solvent
Time (h)/(°C)
t
t
1
0–14) and K
Cs CO , and K
found to be 1.6 equiv Cu-NP and 2 equiv K
at 80 °C for 5 h under an argon atmosphere.
3
PO
4
found to be superior to KO Bu, NaO Bu, Et
. Thus the optimized reaction condition was
PO in DMSO as solvent
3
N,
1
2
3
4
5
6
7
8
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
K
K
K
K
K
K
K
K
K
K
K
K
3
3
3
3
3
3
3
3
3
3
3
3
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
4
4
4
4
4
4
4
4
4
4
4
4
00
8/80
8/80
8/80
8/80
8/80
8/80
5/80
5/110
5/80
5/80
5/80
5/80
5/80
5/80
5/80
5/80
5/80
00
28
45
54
60
68
82
49
42
30
27
38
55
49
24
66
50
2
3
2
CO
3
0.1
0.5
1
3
4
3
After getting optimized reaction conditions, the scope of the
N-arylation of pyrroles, indoles, and azaindoles with various
substituted aryl and heteroaryl iodides has been examined and
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
2
7
the results are summarized in Table 2. Aryl and heteroaryl io-
dides with electron-withdrawing groups in the ortho, meta, or para
position afforded the coupling products in excellent yields (Table 2,
entries 1, 3, 4, 8, 9, 11, 13, 14 and 16). The reaction of 4-iodopyri-
dine 2f with 1a, 1b, 1c, 1d, and 1e afforded the coupling products
in 92%, 94%, 89%, 90%, and 87% yields (Table 2, entries 6, 7, 10, 12
and 15). The electron-donating groups like methyl and methoxy
groups in the para position of the aryl halide provided the coupling
products in good yields (Table 2, entries 2, 5 and 17) but when the
electron donating group is in ortho position, the yield became low-
er because of steric hindrance (Table 2, entry 18).
10
11
12
13
14
15
16
17
Toluene
Dioxane
CH
3
CN
PO
t
DMSO
DMSO
DMSO
DMSO
DMSO
KO Bu
t
NaO Bu
Et
Cs
K
3
N
2
CO
CO
3
2
3
a
Reaction conditions: all reactions were performed with 1 mmol of 1a, 1 mmol
of 2a, 2 mmol of base, in 1 mL of solvent under an argon atmosphere.
b
c
26
Yield based on LCMS analysis
The same reactions were carried out with Cu(I) and Cu(II) also. For details see
.
In conclusion, we have established that Cu-NP is inexpensive
and useful for the synthesis of N-arylindoles and N-arylpyrroles.
Supporting information.
Table 2
Cu-NP promoted reaction of aryl and heteroaryl iodides with pyrrole, indole, and azaindolea
I
R2
1.6 equiv Cu-NP,
Y
R2
N
+
R1
N
H
X
2 equiv K PO DMSO
3
o
4,
X
Y
8
0 C, 5h
2
a-h
3a-r
1
a-e
R1
X = N, R1 = H, Y= CH
1
X= CH, R = H,Y = N
X= CH, R1 = OMe, Y= CH
Entry
1
Indole/pyrrole
ArI
Product
Yieldb (%)
79
I
CF3
N
N
CF3
O
1a
2a
3a19
N
H
I
I
O
2
3
2b
3b19
75
NO2
NO2
3c28
N
84c
2c
NO2
O N
2
N
N
N
86c
4
2d
I
3d29
I
I
5
6
2e
2f
3e19
78
92
N
N
3f30

G. Pai, A. P. Chattopadhyay / Tetrahedron Letters 55 (2014) 941–944
943
Table 2 (continued)
Entry
Indole/pyrrole
ArI
Product
Yieldb (%)
I
N
N
N
N
H
O
3gd
7
1b
2f
94
O
O
NO2
I
O
N
2
N
8
9
2d
3hd
80c
Cl
N
Cl
N
H
3id
3jd
N
1c
N
2g
2f
I
I
77
89
N
N
N
1
1
0
1
N
NO2
I
O N
2
2d
2f
3kd
N
80c
90
N
N
I
N
N
N
1
2
3
1d
N
H
3ld
N
N
NO2
I
O N
2
1
2d
3md
N
79c
NO2
I
O N
2
14
15
16
17
1e
N
H
2d
2f
3n31
3od
83c
87
78
86
N
N
I
N
N
Cl
Cl
2g
2e
3p32
3q31
I
I
N
N
O
I
O
N
1
8
2h
3r33
75
a
b
c
All reactions were carried out using 1 mmol of azoles, 1 mmol of ArI, 2 mmol of K
Isolated yields.
Reaction was carried out at 80 °C for 2 h.
3 4
PO in 1 mL DMSO at 80 °C for 5 h.
d
New compounds. Some information given in Supporting information (representative examples of each class above); for example, data for product 3a are given in Ref. 27.
Such ligand-free C–N bond formation reaction was achieved effi-
ciently, under relatively mild conditions and with moderate to
good yields. This advantage would prompt the synthetic applica-
tions of this Cu-NP mediated C–N bond formation reaction.
Help with laboratory facilities from Prof. T. Basu, Department of
Biochemistry & Biophysics of the same university is acknowledged.
Assistance from DST-PURSE Grant to the University of Kalyani is
hereby acknowledged.
Acknowledgements
Supplementary data
Supplementary data (analytical information and 1H NMR,
NMR and mass spectra of some product compounds)
associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.tetlet.2013.12.065.
The authors wish to record the help provided by the NMR facil-
ity installed in the Department of Chemistry, University of Kalyani,
Kalyani, India under the DST-FIST scheme. Helpful discussion with
Dr. K. Ghosh of the same department is gratefully acknowledged.
13C

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G. Pai, A. P. Chattopadhyay / Tetrahedron Letters 55 (2014) 941–944
2
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