Electrospun copper oxide nanoparticles as an efficient heterogeneous catalyst for N-arylation of indole

Article abstract of DOI:10.1016/j.tetlet.2014.08.120

The N-arylation of indoles with a variety of aryl bromides is reported using copper oxide nanoparticles as a heterogeneous catalyst. These copper oxide nanoparticles, which were produced in a novel, facile, and scalable fashion via an electrospinning tech

Full text of DOI:10.1016/j.tetlet.2014.08.120

Accepted Manuscript
Electrospun copper oxide nanoparticles as an efficient heterogeneous catalyst
for N-arylation of indole
Abdullah Khalil, Aziz Fihri, Mustapha Jouiad, Raed Hashaikeh
PII:
S0040-4039(14)01473-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.120
TETL 45087
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
6 July 2014
16 August 2014
28 August 2014
Please cite this article as: Khalil, A., Fihri, A., Jouiad, M., Hashaikeh, R., Electrospun copper oxide nanoparticles
as an efficient heterogeneous catalyst for N-arylation of indole, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.08.120
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Electrospun copper oxide nanoparticles as an efficient heterogeneous catalyst
for N-arylation of indole
Abdullah Khalila, Aziz Fihrib, Mustapha Jouiadc*, Raed Hashaikeha*
aInstitute Center for Water and Environment (iWATER), cInstitute Center for Energy
(iENERGY), Department of Mechanical and Materials Engineering, Masdar Institute of Science
and Technology, Abu Dhabi-54224, UAE
bMAScIR Foundation, VARENA Center, Rabat Design, Rue Mohamed El Jazouli, Madinat Al
Irfane, Rabat-10100, Morocco
(*Corresponding Authors.mjouiad@masdar.ac.ae, Phone:
+9718109235.rhashaikeh@masdar.ac.ae, Phone: +97128109152.)
Abstract – The N-arylation of indoles with a variety of aryl bromides is reported using copper
oxide nanoparticles as a heterogeneous catalyst. These copper oxide nanoparticles, which were
produced in a novel, facile and scalable fashion via an electrospinning technique, resulted in an
excellent product yield under mild conditions. Moreover, the catalyst was easily recovered and
reused several times without significant loss of activity.
Keywords: Copper oxide nanoparticles; electrospinning; scalable catalyst; N-arylation; reusable
catalyst.
Metal oxide nanoparticles possess significant technological potential in several commercial
applications such as cosmetics,1 energy management2 and catalysis.3,4 According to an
international survey, a conservative market estimate of metal oxide nanoparticles in 2012 was
around 270,041 tons with a projected growth to 1,663,168 tons by 2020.5 Among various metal
oxides, copper oxide (CuO) nanoparticles are of major importance because of their applications
which include sensing,6 heat transfer,7 antibacterial uses8 and catalysis.9 Based on these reports,
there is a need to develop facile, economic and industrially scalable techniques for the mass-
production of CuO nanoparticles. Several chemical methods such as alcohothermal10 and quick-

precipitation,11 and physical methods such as laser ablation12 and microwave irradiation,13 have
been employed for synthesizing CuO nanoparticles. We have recently reported electrospinning,
for the first time, as a novel and alternative route for the continuous and large-scale synthesis of
CuO nanoparticles.14 This method is not only simple and low-cost, but can also be easily scaled
at the industrial level based on the desired product yield.15 Moreover, through a suitable choice
of precursor chemicals and adjustment of electrospinning parameters, nanoparticles of any metal
oxide can be easily synthesized. Herein, we report the potential of electrospun CuO nanoparticles
as highly efficient heterogeneous catalytic agents for the N-arylation of indole, an organic
compound commonly used as a fragrance in various cosmetic products and also as a precursor of
many pharmaceuticals.16
The arylation of indole and similar compounds is usually carried out by Ullmann-type coupling
reactions.17 However, these reactions have limitations such as high-temperature reaction
conditions, moderate yields, the use of highly polar solvents as well as the use of large amounts
of copper-based catalysts; and these aspects greatly limit their applications.18 To overcome these
drawbacks, a breakthrough was achieved by Buchwald et al. who reported the combination of
copper iodide with N,N-bidentate ligands as effective catalyst systems for the N-arylation of
nitrogen-containing heterocycles with aryl halides. Under mild conditions, they obtained good
product yields using these catalyst systems.19–21 However, an efficient separation and subsequent
recycling of these homogeneous transition metal catalysts remains a challenge and an economic
concern. One of the best ways to overcome these difficulties is to employ heterogeneous
catalysis, as it enables a convenient recovery and reuse of the catalyst from the reaction mixture
through simple filtration or decantation.22-30 Therefore, in this context, we have developed CuO
nanoparticles through a simple fabrication route based on an electrospinning technique, and
analyzed their potential as a simple and efficient reusable heterogeneous catalyst for the N-
arylation of indole under mild conditions.
The CuO nanoparticles were synthesized via an electrospinning technique in a novel manner.
The method is based on producing rough and discontinuous electrospun nanofibers from a
precursor based on copper acetate and a poly(vinyl alcohol) (PVA) polymer. Selectively
removing the polymeric phase from the fibers produces highly rough and discontinuous CuO
nanofibers. The nanofibers consist of nanoparticles that are weakly held together in a one-
dimensional (1D) manner. Sonication, in a suitable liquid under controlled conditions,
completely disintegrated the nanofibers into nearly spherical nanoparticles (diameter ~30-70 nm)
resulting in the formation of a uniform and relatively well-dispersed nanoparticle suspension.
The detailed description of the nanoparticle synthesis procedure can be found in our previous
work.14 High-resolution scanning electron microscopy (SEM) and transmission electron
microscopy (TEM) were employed for examining the morphology and structure of the CuO
nanoparticles, whereas X-ray diffraction (XRD) and energy dispersive spectroscopy (EDS) were
employed for determining the phase purity and composition of the CuO nanoparticles.
The morphology of the CuO nanoparticles, as revealed from high-resolution SEM, was found to
be nearly spherical with an average size below 100 nm, Figure 1(a). The relatively large particles
may be representative of several smaller nanoparticle clusters. Further, the high-resolution TEM
image of a single nanoparticle, shown in Figure 1(b) (nanoparticle highlighted in color to
differentiate from the amorphous carbon film) reveals a nearly single crystal nature (d-spacing =
2.87 Å), also reflected via the Fast-Fourier Transform (FFT) shown in the inset. The XRD

spectrum shown in Figure 1(c) contains all of the peaks associated with the crystalline planes of
pure CuO (JCPDS card no. 05-0661) confirming the crystallinity and phase purity of the
nanoparticles. The EDS spectrum and the corresponding quantitative results of the CuO
nanoparticles, Figure 1(d), shows a Cu/O ratio of about 78/22 wt/wt which is in a close
stoichiometric ratio to that of pure CuO (79.8/20.2 wt/wt). These results confirm the purity and
single crystal nature of our electrospun CuO nanoparticles.
To explore the potential activity of this heterogeneous catalyst, we evaluated these CuO
nanoparticles as a catalyst for the N-arylation of indole. Initial trials were performed to optimize
the reaction conditions for the N-arylation of indole with 4-bromotoluene. First, the reaction was
conducted without any catalyst and no activity was observed despite a prolonged reaction time.
This was expected because the presence of a base is vital for the catalytic cycle as it removes the
acidic proton from the indole. After screening a range of inorganic and organic bases and
exploring various solvents, this nanocatalyst was found to be most active in DMSO as the
solvent with potassium hydroxide as the base and 1,10-phenanthroline as the ligand.31 Table 1
summarizes the scope of the reactions performed in this study. The N-arylated product was
obtained in good yield under reflux (Entry 1). When 2,2′-bipyridine was used as the ligand
instead of 1,10-phenanthroline, the product yield was reduced to 70% (Entry 2). This difference
in yield was attributed to the difference in spatial distribution of each ligand and to electron
cloud density, which is more important in 1,10-phenanthroline. Another reason is that rotation of
the C-C bond in 2,2′-bipyridine is slow making stabilization of the copper more difficult. In the
absence of any ligand, however, the product yield remained significantly low (Entry 3). Under
identical conditions, the N-arylation of indole with bromobenzene and 1-bromo-4-chlorobenzene
afforded the corresponding N-arylated products in excellent yields (76% and 79%, respectively,
Entries 4 and 5). This system also gave a good yield of 73% in the N-arylation of indole with the
heteroaryl halide, 2-bromopyridine (Entry 6). The recyclability of the catalyst is very important
for industrial applications. After recovery of the CuO nanoparticles by simple filtration followed
by washing with ethanol and drying, we established a set of experiments using the recycled
catalyst for the N-arylation of indole with 4-bromotoluene. The results showed that the catalyst
could be used four times with almost consistent activity. Even in the fourth run, the yield of N-
arylated product was 75% (Entry 5), indicating excellent reusability and chemical stability of the
catalyst. Importantly, the absence of any copper species in the filtrate was confirmed by atomic
absorption spectroscopy, which clearly demonstrated that no leaching of copper had occurred
during the reaction and provided evidence for heterogeneity throughout the reaction.

Figure 1. (a) SEM image, (b) high-resolution TEM image (inset shows the FFT), (c) XRD spectrum and
(d) EDS spectrum of the CuO nanoparticles obtained from the electrospinning technique.

Table 1 CuO Nanoparticle catalyzed N-arylation of indole with aryl bromides.a
Entry
1
Amine
X-Br
Product
Yield(%)b
80
2
3
4
5
6
70c
56d
76
79, 75e
73
aReaction conditions: CuO nanoparticles (5 mol%), 4-bromotoluene (1 mmol), indole (0.5 mmol), KOH (1 mmol),
1,10-phen (0.256 mmol), DMSO (2 mL), reflux, 24 h.
bIsolated yield.
cReaction using 2,2′-bipyridine as the ligand.
dCuO nanoparticles (5 mol%) without any ligand.
eYield after the fourth cycle.

Through the N-arylation of indoles with aryl bromides bearing an electron-donating group, we
have demonstrated that electrospun CuO nanoparticles are efficient heterogeneous catalytic
agents. The high product yields under mild conditions and easy recovery and reuse reflects the
great potential of these electrospun CuO nanoparticles as industrial catalysts. Also, since
electrospinning is an economic, facile and scalable technique, it is possible to produce large
amounts of CuO and other oxide nanoparticles for various catalytic applications to achieve better
product yields with reduced costs.
Acknowledgement
The authors acknowledge the financial support for this work provided by the Masdar Institute of
Science and Technology through grant number 12NAMD1.
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31.
In a typical experiment, a stirred mixture of indole (0.5 mmol), 4-bromotoluene (1
mmol), KOH (1 mmol, 0.08 mmol) and 1,10-phenanthroline (0.256 mmol) was prepared
in a 50 ml round-bottom flask. Next, 5 mol% of the catalyst (CuO nanoparticles) was
added to the stirred mixture followed by heating in 2 ml of dimethylsulfoxide (DMSO)
under reflux. The reaction was monitored by thin-layer chromatography. After 24 hours,
the catalyst was removed by filtration and the mixture was diluted with water and washed
with dichloromethane (3 x 10 ml). The organic phase was dried over anhydrous sodium
sulfate. After concentration of the filtrate, the residue was subjected to column
chromatography leading to the desired product.