Catalytic activity and antibacterial properties of nanopolymer-supported copper complex for C-N coupling reactions of amines and nitrogen-containing heterocycles with aryl halides

Article abstract of DOI:10.1007/s00706-014-1367-6

This paper reports on the antibacterial properties and application of nanopolymer-supported copper complex for the ligand-free C-N coupling reactions of amines and nitrogen-containing heterocycles with aryl halides. This method has the advantages of high yields, simple methodology, and easy workup. The catalyst can be recovered by simple filtration from the reaction mixture and reused several times without significant loss of catalytic activity.

Full text of DOI:10.1007/s00706-014-1367-6

Monatsh Chem
DOI 10.1007/s00706-014-1367-6
ORIGINAL PAPER
Catalytic activity and antibacterial properties of nanopolymer-
supported copper complex for C–N coupling reactions of amines
and nitrogen-containing heterocycles with aryl halides
Mahmoud Nasrollahzadeh
Eslam Pourbasheer
•
Ali Zahraei
•
Received: 12 May 2014 / Accepted: 24 November 2014
Springer-Verlag Wien 2014
ꢀ
Abstract This paper reports on the antibacterial proper-
ties and application of nanopolymer-supported copper
complex for the ligand-free C–N coupling reactions of
amines and nitrogen-containing heterocycles with aryl
halides. This method has the advantages of high yields,
simple methodology, and easy workup. The catalyst can be
recovered by simple filtration from the reaction mixture
and reused several times without significant loss of cata-
lytic activity.
amounts of homogeneous copper catalysts that make scale-
up unfeasible and ecologically unfriendly, and the use of
strong bases, toxic and expensive ligands, and thus limited
their large scale applications in industry, the use of toxic
and air-sensitive aryl coupling reagents that can be difficult
to access, and excess aryl halide starting materials to
achieve reasonable product yields [5–12]. Although the C–
N coupling reactions catalyzed by the palladium catalysts
with bulky phosphine ligands can be performed at mild
conditions, the phosphine ligands are normally not easily
available, air sensitive, and expensive [13–15]. The toxicity
and high cost of palladium catalysts restrict their use on the
industrial applications. Thus, researchers have turned their
attention toward the use of less expensive, less toxic, and
more efficient metals to replace Pd. Due to safety consid-
erations, it is desirable to develop a more efficient and
convenient method for the copper-catalyzed synthesis of
compounds bearing an arylated nitrogen moiety under
heterogeneous conditions that reduce or eliminate the use
and generation of hazardous compounds is essential.
Among various catalysts for the carbon–heteroatom
coupling reactions, homogeneous copper catalysts have
been widely investigated [16–22], while less expensive
heterogeneous copper catalysts received scanter attention.
Thus, the use of ligand-free heterogeneous Cu catalysts is
often desirable from the perspective of process develop-
ment due to their easy handling, simple recovery, and
recycling.
Keywords Nanopolymer Á Copper Á Complex Á
Amine Á Nitrogen-containing heterocycles
Introduction
The synthesis of compounds bearing an arylated nitrogen
moiety is an active area in organic synthesis due to their
key role in medically important species, natural products,
and in materials with useful interesting electronic and
mechanical properties [1–4].
The convenient synthetic routes for installing the N-aryl
functionality are based on the aromatic nucleophilic sub-
stitution reaction (S Ar) of nitrogen nucleophiles by
N
activating aryl halides or metal-catalyzed Ullmann-type C–
N coupling reaction at higher temperature [5–8]. The
classical Cu-catalyzed Ullmann coupling reaction suffers
from high reaction temperatures (often 150 ꢁC or as high as
2
00 ꢁC), tedious workups, low to moderate yields, poor
According to the literature, tetrazoles can play an
important role in coordination chemistry for the synthesis
of metal complexes. We recently published synthesis of
various tetrazoles in high yields and their application in
coordination chemistry [23–25].
substrate generality, the requirement of stoichiometric
M. Nasrollahzadeh (&) Á A. Zahraei Á E. Pourbasheer
Department of Chemistry, Payame Noor University (PNU),
P.O. Box 19395-3697, Tehran, Iran
As part of our ongoing interest in heterocyclic chemistry
and application of heterogeneous catalysts [26–33], we
e-mail: mahmoudnasr81@gmail.com
123

M. Nasrollahzadeh et al.
Scheme 1
Scheme 2
Fig. 1 SEM image of PS-tet-Cu(II)
now wish to report the copper-catalyzed N-arylation of
amines and nitrogen-containing heterocycles with aryl
halides using nanopolystyrene-anchored Cu(II) tetrazole
complex (PS-tet-Cu(II), Scheme 1) as a novel and stable
heterogeneous catalyst (Scheme 2).
Results and discussion
The catalyst was characterized using the SEM, TGA-DTG,
and EDS spectroscopy. Scanning electron micrograph
Fig. 2 Thermal studies of PS-tet-Cu(II)
(
SEM) image of PS-tet-Cu(II) is shown in Fig. 1. As
expected, the pure polystyrene bead had a smooth and flat
surface [34, 35], while the anchored complex showed
roughening of the top layer. The presence of Cu has caused
changes, demonstrated by change in the polymer particle
size and roughness of the surface. Thermal stability of
polymer-bound complex was investigated using TGA-DTG
at a heating rate of 10 ꢁC/min in air over a temperature
range of 30–800 ꢁC. The TGA curve of the nanopolysty-
rene-anchored Cu(II) tetrazole complex (PS-tet-Cu(II)) is
shown in Fig. 2. The complex is stable up to 200 ꢁC, and
above this temperature it decomposes. The polymer-sup-
ported Cu(II) complex decomposed at 300 ꢁC. We used
Energy Dispersive X-ray Spectroscopy (EDS) to determine
chemical composition of catalyst. The presence of the
metals is confirmed by EDS. EDS results show that Cu
concentration is about 3.07 wt%.
absence of catalyst, the reactions did not proceed after a
long reaction time (Table 1, entry 7). We believe that na-
nopolystyrene-anchored Cu(II) tetrazole complex (PS-tet-
Cu(II)) can play an important role in the N-arylation of
nitrogen-containing heterocycles. First, several solvents
were screened for the reaction. According to data given in
Table 1, DMSO was the most efficient solvent for this
reaction (Table 1, entry 6). After choosing DMSO as the
solvent, we examined several different bases. The results
indicated that base had a demonstrative effect on the yield
of product. Among the various bases tested, K CO is an
2 3
effective base (Table 1, entry 6). Increasing the amount of
catalyst showed no substantial improvement in the yield.
The best result was obtained with 1.0 mmol phenyl iodide,
1.2 mmol imidazole, 0.05 g PS-tet-Cu(II), 2.0 mmol
3
K
CO
, and 9.0 cm DMF at 120 ꢁC, which resulted the
product in an excellent yield (94 %).
2
3
The catalytic behavior of the PS-tet-Cu(II) was studied
for the N-arylation of aryl amines and nitrogen-containing
heterocycles with aryl halides. Reaction conditions were
optimized for the arylation of imidazole using phenyl
iodide as a substrate and PS-tet-Cu(II) as catalyst in the
presence of various solvents and bases (Table 1). In the
Next, using the optimized procedure, a variety of aryl
halides possessing both electron-releasing and electron-
withdrawing groups were employed (Table 2). According
to Table 2, the nature of the substituent on the benzene ring
did affect the reaction. As shown in Table 2, aryl halides
1
23

Catalytic activity and antibacterial properties
Table 1 The model reaction in N-arylation of imidazole with iodo-
benzene under various reaction conditions
require higher reaction times. The results are shown in
Table 2 and 2-iodotoluene with a bigger steric hindrance
around the reaction site gave a good yield. Thus, the
reactions appeared to be insensitive to the steric hindrance
around the reaction site (Table 2, entry 6).
b
Entry Base
Catalyst/g Solvent Temp./ꢁC Time/h Yield /%
1
2
3
4
5
6
7
8
9
1
1
K
K
K
K
K
K
K
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
0.05
0.05
0.05
0.05
0.05
0.05
0
THF
80
15
15
17
15
12
12
15
12
12
12
12
68
75
62
83
87
94
0
CH CN 80
3
Due to the importance of aryl amines in industry for the
manufacture of pharmaceuticals, polymers, medicinal
compounds and their applications in materials research, we
next turned our attention to applying PS-tet-Cu(II) for the
N-arylation of aryl amines with aryl halides.
DME
NMP
DMF
80
130
120
DMSO 120
DMSO 120
DMSO 120
DMSO 120
DMSO 120
DMSO 120
For optimization of the reaction conditions, we chose
the reaction of aniline with iodobenzene in DMSO in the
presence of 0.05 g of PS-tet-Cu(II) as the model reaction,
and the effects of the base were examined. As shown in
Table 3, the reaction was influenced significantly by the
base employed and the best result obtained in the case of
KOH (Table 3, entry 7). The optimum conditions were
found to be 1.0 mmol of aryl halide, 1.2 mmol of aromatic
amine, 0.05 g of PS-tet-Cu(II), and 1.5 mmol of KOH in
Et
3
N
0.05
0.05
0.05
0.08
37
70
51
93
K
PO
3 4
0
1
Cs
2
CO
3
K
2
CO
3
Reaction conditions: iodobenzene (1 mmol), imidazole (1.2 mmol),
3
base (2.0 mmol), 9.0 cm DMF, pressure tube, N atm
2
b
Yields are after workup
3
having the electron-withdrawing groups (entries 4 and 5)
were completed at 120 ꢁC after 12 h, while the species
bearing the electron-releasing groups (entries 2 and 3)
9.0 cm DMSO at 120 ꢁC. Increasing the amount of cata-
lyst showed no substantial improvement in the yield. Upon
optimization of reaction conditions, the scope of the pro-
Table 2 Copper-catalyzed
b
Entry
1
Substrate
Aryl halide
Time/h
12
Yield /%
N-arylation of various nitrogen-
containing heterocycles with
aryl halides at 120ꢁC
NH
NH
I
94
N
N
I
2
3
4
15
15
12
83
81
95
Me
NH
NH
I
N
N
MeO
I
O
2
N
NH
NH
I
5
6
12
15
94
67
N
N
OHC
I
Me
Br
NH
NH
7
8
12
12
73
81
N
N
Br
O
2
N
NH
N
I
9
12
12
77
80
MeO
NH
N
I
1
0
General reaction conditions:
Het-NH (1.2 mmol), aryl halide
O N
2
(
K
1.0 mmol), 0.05 g Cu source,
3
NH
N
I
2
CO
3
(2.0 mmol), 9.0 cm
11
N
12
81
DMSO, 120 ꢁC, pressure tube,
N
O
2
N
2
atm
b
Yields are after workup
123

M. Nasrollahzadeh et al.
Table 3 Optimization of reaction conditions in reaction of aniline
with iodobenzene
The synthesized catalyst is found to be highly toxic
against Gram-positive bacteria than Gram-negative bacte-
ria. In vitro antibacterial activity of the PS-tet-Cu(II) was
evaluated using the standard well diffusion method. One
species each of a Gram-positive (Staphylococcus aureus)
and Gram-negative bacteria (Escherichia coli) were used
for the antibacterial assay. The results presented in Table 5
showed the antibacterial effects of PS-tet-Cu(II) against
E. coli (Escherichia coli) and S. aureus (Staphylococcus
aureus). The antibacterial activity is estimated by the zone
of inhibition. The diameter of the zone is measured to the
nearest millimeter (mm). The standard error for each assay
is presented in the parenthesis (Table 5). As shown in
Table 5, PS-tet-Cu(II) has shown high antibacterial effect.
The present study clearly indicates that the PS-tet-Cu(II)
has good antibacterial action against Gram-positive
organism than Gram-negative organisms (Table 5). It is
possible that PS-tet-Cu(II) not only interact with the sur-
face of membrane, but can also penetrate inside the
bacteria.
b
Yield /%
Entry
Catalyst/g
Base
1
2
3
4
5
0.05
0.05
0.05
0.05
0.08
K
3
PO
CO
CO
4
61
58
65
85
85
Cs
2
3
K
2
3
KOH
KOH
Reaction condition: 1.0 equiv of iodobenzene, 1.2 equiv of aniline,
3
and 1.5 equiv of base, 120 ꢁC, 9.0 cm DMSO, 12 h, pressure tube,
N
2
atm
b
Isolated yield
tocol was subsequently extended to a range of substituted
aryl iodides and amines as substrates (Table 4).
From an economic point of view, the stability and sustained
activity of the catalysts is of great importance. Thus, the
recovery and reusability of the PS-tet-Cu(II) was examined by
applying it to the C–N coupling of imidazole with iodoben-
zene under the present reaction conditions. After the first run
completed, the catalyst was separated by filtration, washed
with ethyl acetate and dried in a hot air oven at 100 ꢁC for 2 h
and employed for the next run of the reaction. The catalytic
activity did not decrease considerably after five catalytic
cycles (Fig. 3). This reusability demonstrates the high stability
and turnover of catalyst under operating condition.
Experimental
All reagents were purchased from the Merck and Aldrich
chemical companies and used without further purification.
Table 4 Copper-catalyzed
N-arylation of various amines
with aryl iodides at 120 ꢁC
b
Entry
1
Substrate
Aryl halide
Time/h
12
Yield /%
NH
2
2
I
85
NH
I
2
3
4
14
14
16
77
73
70
Me
NH
NH
2
I
MeO
2
I
Me
I
NH
2
5
6
7
8
14
14
16
12
71
72
67
79
Me
I
I
NH
2
NH
2
Br
General reaction conditions:
amine (1.2 mmol), aryl halide
(1.0 mmol), 0.05 g Cu source,
3
KOH (1.5 mmol), 9.0 cm
NH
2
I
MeO
Me
MeO
NH
2
I
9
12
80
DMSO, 120 ꢁC, pressure tube,
N
2
atm
Me
b
Yields are after workup
1
23

Catalytic activity and antibacterial properties
conditions for 24 h. The resulting bright green colored
polymer, impregnated with the metal complex, was filtered,
washed with ethanol and dried at 60 ꢁC to give PS-tet-
Cu(II) [35].
General procedure for the copper-catalyzed
N-arylation of nitrogen-containing heterocycles
with aryl halides
To a mixture of 0.05 g catalyst and aryl halide (1.0 mmol)
3
in 9.0 cm DMSO, Het-NH (1.2 mmol) and K CO
2
3
(
2.0 mmol) was added and the mixture was vigorously
Fig. 3 Reusability of PS-tet-Cu(II) for the N-arylation of imidazole
stirred at 120 ꢁC for the appropriate time under a dry
nitrogen atmosphere. After completion (as monitored by
TLC), the catalyst was filtered, and the filtrate was
Table 5 Zone of inhibition (mm) of PS-tet-Cu(II) against bacterial
pathogens
3
extracted with ethyl acetate (3 9 20 cm ) and the com-
bined organic layers were dried with anhydrous MgSO4,
filtered, and evaporated under reduced pressure. The resi-
due was purified by column chromatography. The purity of
Diameter of inhibition zone/mm
Bacteria
50 ppm
75 ppm
100 ppm 150 ppm
1
the compounds was checked by H NMR and yields are
E. coli (Gram -ve)
20 (± 0.7) 22 (± 0.9) 22 (± 1.0) 25 (± 1.0)
based on aryl bromide. All the products are known and the
spectroscopic data (FT-IR and NMR) and melting points
were consistent with those reported in the literature [36–
41].
S. aureus (Gram 1ve) 22 (± 0.8) 24 (± 1.2) 26 (± 1.5) 28 (± 0.8)
Chloromethylated polystyrene (4–5 % Cl and 2 % cross-
linked with divinylbenzene) was purchased from Merck.
Products were characterized by different spectroscopic
General procedure for the copper-catalyzed
N-arylation of amines with aryl iodides
methods (FT-IR and NMR spectra) and melting points. The
1
NMR spectra were recorded in CDCl . H NMR spectra
3
were recorded on a Bruker Avance DRX 300 MHz
instrument. The chemical shifts (d) are reported in ppm
relative to the TMS as internal standard. J values are given
in Hz. IR (KBr) spectra were recorded on a Perkin-Elmer
To a mixture of 0.05 g catalyst and aryl iodide (1.0 mmol) in
3
.0 cm DMSO, amine (1.2 mmol) and KOH (1.5 mmol)
9
was added and the mixture was vigorously stirred at 120 ꢁC
for appropriate time under a dry nitrogen atmosphere. After
the completion of the reaction, the catalyst was filtered off
and washed with water followed by acetone and dried in
7
81 spectrophotometer. Melting points were taken in open
¨
capillary tubes with a BUCHI 510 melting point apparatus.
TLC was performed on silica gel polygram SIL G/UV 254
plates. Morphology and particle dispersion was investi-
gated by scanning electron microscopy (SEM) (Cam scan
MV2300). The chemical composition of the prepared
nanostructures was measured by EDS performed in SEM.
oven. The filtrate was extracted with ethyl acetate
3
3 9 20 cm ) and the combined organic layers were dried
(
with anhydrous Na SO by vacuum. The filtrate was con-
2
4
centrated by vacuum and the resulting residue was purified
by column chromatography on silica gel to provide the
desired product. All the products are known and the spec-
troscopic data (FT-IR and NMR) and melting points were
consistent with those reported in the literature [26].
Preparation of nanopolystyrene-anchored Cu(II)
tetrazole complex
The reaction was carried out in a round-bottomed flask of
3
50 cm capacity. To the mixture of 2.0 g chloromethy-
Acknowledgments We gratefully acknowledge the Iranian Nano
Council and the Payame Noor University for the support of this work.
2
3
lated polystyrene (1.25 mmol/g of Cl) in 50 cm of DMF,
-phenyl-1H-tetrazole (5.0 mmol) and K CO (5.0 mmol)
5
2
3
References
was added. The mixture was stirred at 100 ꢁC for 24 h.
Then reaction mixture was filtrated, washed with DMF, and
dried in vacuo for 12 h. Phenyltetrazole-functionalized
polymer (1.0 g) was treated with 0.5 g CuCl •2H O in
1
. Katritzky AR, Rees CW (eds) (1996) Comprehensive heterocy-
clic chemistry II. Elsevier, Oxford
2
2
2. Craig PN, Drayton CJ (1991) Comprehensive medicinal chem-
istry, vol 8. Pergamon Press, New York
3
5
0 cm ethanol and the mixture stirred under reflux
123

M. Nasrollahzadeh et al.
3
4
. Southon IW, Buckingham J, Saxton JE (1989) Dictionary of
alkaloids. Chapman and Hall, London
. Negwer M (2002) Organic-chemical drugs and their synonyms,
8th edn. VCH-Wiley, Berlin
. Ullmann F (1903) Ber Dtsch Chem Ges 36:2382
. Ullmann F, Illgen E (1914) Ber Dtsch Chem Ges 47:380
. Jitchati R, Batsanov AS, Bryce MR (2009) Tetrahedron 65:855
. Jiao J, Zhang X-R, Chang N-H, Wang J, Wei J-F, Shi X-Y, Chen
ZG (2011) J Org Chem 76:1180
23. Habibi D, Nasrollahzadeh M, Mehrabi L, Mostafaee S (2013)
Monatsh Chem 144:725
24. Nasrollahzadeh M, Jaleh B, Jabbari A (2014) RSC Adv 4:36713
25. Shahroosvand H, Najafi L, Mohajerani E, Janghouri A, Nasrol-
lahzadeh M (2013) RSC Adv 3:6323
26. Fakhri P, Jaleh B, Nasrollahzadeh M (2014) J Mol Catal A Chem
383–384:17
27. Habibi D, Nasrollahzadeh M, Sahebekhtiari H, Parish RV (2013)
Tetrahedron 69:3082
5
6
7
8
9
. Liu L, Frohn M, Xi N, Dominguez C, Hungate R, Reider PJ
28. Nasrollahzadeh M, Ehsani A, Rostami-Vartouni A (2014)
Ultrason Sonochem 21:275
(2005) J Org Chem 70:10135
1
0. Jerphagnon T, van Klink GPM, de Vries JG, van Koten G (2005)
Org Lett 7:5241
29. Nasrollahzadeh M, Sajadi SM, Khalaj M (2014) RSC Adv
4:47313
1
1
1. Xu L, Zhu D, Wang R, Wan B (2005) Tetrahedron 61:6553
2. Kuil M, Bekedam K, Visser GM, van den Hoogenband A,
Terpstra JW, Kamer PCJ, van Leeuwen PWNM, van Strijdonck
GPF (2005) Tetrahedron Lett 46:2405
30. Nasrollahzadeh M (2014) RSC Adv 4:29089
31. Nasrollahzadeh M (2014) New J Chem 38:5544
32. Nasrollahzadeh M, Sajadi SM, Rostami-Vartooni A, Khalaj M
(2014) RSC Adv 4:43477
1
1
1
3. Hartwig JF, Kawatsura M, Hauck SI, Shaughnessy KH, Alcazar-
Roman LM (1999) J Org Chem 64:5575
4. Wolfe JP, Tomori H, Sadighi JP, Yin J, Buchwald SL (2000) J
Org Chem 65:1158
5. Stauffer SR, Lee S, Stambuli JP, Hauck SI, Hartwig JF (2000)
Org Lett 2:1423
33. Nasrollahzadeh M, Zahraei A, Ehsani A, Khalaj M (2014) RSC
Adv 4:20351
34. Islam SM, Mondal S, Mondal P, Roy AS, Tuhina K, Salam N,
Mobarak M (2012) J Organomet Chem 696:4264
35. Nasrollahzadeh M, Rostami-Vartouni A, Ehsani A, Moghadam M
(2014) J Mol Catal A: Chem 387:123
1
1
6. Nasrollahzadeh M, Ehsani A, Maham M (2014) Synlett 25:505
7. Klapars A, Antilla JC, Huang X, Buchwald SL (2001) J Am
Chem Soc 123:7727
8. Altman RA, Buchwald SL (2006) Org Lett 8:2779
9. Antilla JC, Baskin JM, Barder TE, Buchwald SL (2004) J Org
Chem 69:5578
36. Xi Z, Liu F, Zhou Y, Chen W (2008) Tetrahedron 64:4254
37. Maheswaran H, Krishna GG, Prasanth KL, Srinivas V, Chaitanya
GK, Bhanuprakash K (2008) Tetrahedron 64:2471
38. Chang JWW, Xu X, Chan PWH (2007) Tetrahedron 48:245
39. Inamoto K, Nozawa K, Kadokawa J, Kondo Y (2012) Tetrahe-
dron 68:7794
1
1
2
2
0. Correa A, Bolm C (2007) Adv Synth Catal 349:2673
1. Ali MA, Saha P, Punniyamurthy T (2010) Synthesis 2010:
40. Zhu L, Li G, Luo L, Guo P, Lan J, You J (2009) J Org Chem
74:2200
9
08–910
2. Yang Q, Wang Y, Lin D, Zhang M (2013) Tetrahedron Lett
4:1994
41. Panda N, Jena A, Mohapatra S, Rout SR (2011) Tetrahedron Lett
52:1924
2
5
1
23