Novel and efficient heterogeneous polymer supported copper catalyst for synthesis of 2-substituted Benzoxazoles from 2-Haloanilides

Article abstract of DOI:10.1016/j.jorganchem.2021.121733

A novel polymer supported copper complex is prepared by the immobilization of copper iodide on chemically modified polyacrylonitrile and its application in heterogeneous catalysis is described. The catalyst was prepared by easy method via synthetic modification of Polyacrylonitrile (PAN) using ethylene diamine followed by the complexation with CuI. After characterization, this complex was explored as a green and efficient heterogeneous catalyst for the synthesis of 2-benzoxazoles from 2-haloanilides. The reaction was performed without adding additional ligand and the catalyst shows activity over a broad range of substrates with quantitative product yields. The catalyst was easily recovered by simple filtration and reused successfully for further cycle.

Full text of DOI:10.1016/j.jorganchem.2021.121733

Journal of Organometallic Chemistry 937 (2021) 121733
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Communication
Novel and efficient heterogeneous polymer supported copper catalyst
for synthesis of 2-substituted Benzoxazoles from 2-Haloanilides
Thachora Venu Saranyaa,c, Pambingal Rajan Sruthia, Veena Rajd, Saithalavi Anasa,b,∗
a School of Chemical Sciences, Mahatma Gandhi University, Kottayam, Kerala, 686560, India
b Institute for Integrated Programmes and Research in Basic Sciences, Mahatma Gandhi University, Kottayam, Kerala, 686560, India
c Postgraduate Department of Chemistry, T. M. Jacob Memorial Government College, Manimalakunnu, Kerala, 686662, India
d Department of Chemistry, Sree Narayana College, Kannur, Kerala, 670007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel polymer supported copper complex is prepared by the immobilization of copper iodide on chem-
ically modified polyacrylonitrile and its application in heterogeneous catalysis is described. The catalyst
was prepared by easy method via synthetic modification of Polyacrylonitrile (PAN) using ethylene diamine
followed by the complexation with CuI. After characterization, this complex was explored as a green and
efficient heterogeneous catalyst for the synthesis of 2-benzoxazoles from 2-haloanilides. The reaction was
performed without adding additional ligand and the catalyst shows activity over a broad range of sub-
strates with quantitative product yields. The catalyst was easily recovered by simple filtration and reused
successfully for further cycle.
Received 5 December 2020
Revised 28 January 2021
Accepted 4 February 2021
Available online 8 February 2021
Keywords:
Benzoxazole
Copper
Haloanilide
© 2021 Elsevier B.V. All rights reserved.
Heterogeneous catalysis
Polymer support
Benzoxazoles and analogous molecules are present as the core
structures in wide variety of natural products and biologically im-
portant compounds [1]. They form key structural component in
many drugs and their structural properties are widely exploited
for pharmaceutical applications to use as anticancer agent NSC-
693,638 [2a], HIV reverse transcriptase inhibitors, l-697, 661 [2b],
cathepsin-S inhibitors [2c], DNA topoisomerase inhibitors [2d], per-
oxisome proliferator-activated receptorγ (PPARγ ) antagonists JTP-
426,467 [2e], estrogen receptor-β agonists [2f]. Therefore, the de-
velopment of general and effective methods for the synthesis of
benzoxazole motifs are of great importance in synthetic chem-
istry. The conventional method for the preparation of benzoxa-
zoles involve the condensation of ortho-aminophenol with either
carboxylic acids [3a] or aldehydes [3b]. Other approaches such as
intramolecular oxidative C-H functionalization of benzanilides [4a-
b], bisaryloxime ethers [4c], tandem cyclization of amidines with
2-halophenols [4d], oxidative cyclization of 2-nitrophenols with
benzyl amines [4e], cylizations of ortho-aminophenols with ben-
zylic alcohols [4f] and β-diketones [4g] are also been adopted for
the synthesis of benzoxazole derivatives. However, most of these
methods are usually suffer from some drawbacks such as harsh re-
action conditions, limited substrate scope etc. Recently transition
metal catalyzed intramolecular cyclisation of 2-haloanilides have
emerged as an important synthetic route towards benzoxazoles,
by limiting some of the drawbacks in conventional methods [5].
Most of the previous reports relied on using homogeneous cop-
per catalysts in combination with commercially available N, N-, N,
O- and O, O- based bidentate ligands for accelerating these reac-
tions. In this regard, our group has reported the synthesis of 2-
benzoxazoles via copper catalyzed intramolecular cyclization of 2-
haloanilides using bipyridine as ligand [6]. However the scope of
these reactions in industrial applications is usually limited by the
stoichiometric use of metal salts, toxicity of ligands and catalysts,
difficulty in recovery and reusability of catalysts. These environ-
mental and safety concerns can pose serious challenges in the area
of homogeneous catalysis. Therefore the development of novel and
efficient reusable catalytic system without the use of chelating lig-
ands that fits the requirements of green chemistry is very impor-
tant approach in organic chemistry.
In contrast to homogeneous catalysis, the development of en-
vironmentally benign novel heterogeneous catalysts that are eas-
ily accessible, easily recoverable and reusable are of great interest
in academic and industrial perspective. In this context, identify-
ing suitable solid supports to immobilize homogeneous metal cat-
alysts on their surface is very crucial and examples for such sup-
ports include zeolites [7], silica [8], organic polymers [9], carbon
nano tubes [10], graphenes [11] etc. Among which organic poly-
mers such as polystyrene are used as important class of solid sup-
port in which the metals can be suitably anchored which will al-
low the easy recovery and reusability of the catalytic system [12].
∗
Corresponding author.
E-mail address: anas@mgu.ac.in (S. Anas).
https://doi.org/10.1016/j.jorganchem.2021.121733
0022-328X/© 2021 Elsevier B.V. All rights reserved.

T.V. Saranya, P.R. Sruthi, V. Raj et al.
Journal of Organometallic Chemistry 937 (2021) 121733
Scheme 1. Synthesis of en-PAN-Cu complex.
Table 1
Polyacrylonitrile and its modified polymers [13] are recently iden-
tified as a suitable support for various metals and its subsequent
catalytic applications [14].
Optimization studies.
Entry
Catalyste
Base
Solvent
Yield (%)
Copper catalyst anchored on polymer supports has been shown
excellent catalytic activities for C-C and C-heteroatom bond form-
ing reactions [15]. In continuation of our research interest on de-
velopment of various polymer supported catalysts for cross cou-
pling reactions, recently our group has reported a novel amidoxime
modified PAN supported copper catalyst for Heck reaction [16]. In
the present study, ethylene diamine modified PAN has been uti-
lized as efficient platform to immobilize CuI on their surface. To
the best of our knowledge, there are no reports on the use of a
heterogeneous ethylene diamine modified PAN supported copper
complex for intramolecular cyclization of 2-haloanilides. This pa-
per deals with the synthesis and characterization of ethylene di-
amine modified PAN supported copper complex and its application
as effective heterogeneous catalyst for the synthesis of a series of
2-benzoxazoles from 2-haloanilides. The details of the synthesis,
characterization, catalytic activities and reusabilities of the modi-
fied PAN supported copper complex are presented.
1
en-PAN-Cu
en-PAN-Cu
en-PAN-Cu
en-PAN-Cu
en-PAN-Cu
en-PAN-Cu
en-PAN-Cu
en-PAN-Cu
en-PAN-Cu
————–
Cs2CO3
K2CO3
DMF
89 (65)b
32
2
DMF
3
Na2CO3
K3PO4
DMF
28
4
DMF
85
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
———–
Cs2CO3
Cs2CO3
DMSO
DMA
57
6
54
7
1,2-DCE
1,4-Dioxane
Toluene
DMF
45
8
30
9
20
10
11
12c
13d
0
en-PAN-Cu
en-PAN-Cu
en-PAN-Cu
DMF
0
DMF
75
DMF
94
aReaction conditions: en-PAN-Cu(10 mol%), Base (2 equiv.), Sol-
vent (2 ml), 140 °C, 16h
b5 mol% catalyst,
cReaction temperature at 120 °C,
dReaction time 24h
emol% of the catalyst was calculated with reference to the mass
of CuI coordinated to a single monomer unit.
Our studies started with the preparation of the polymer sup-
ported copper complex (en-PAN-Cu) in
3 steps as shown in
scheme 1. The synthesis involves the polymerization of acryloni-
trile (AN) [17] followed by the chemical modification of nitrile
group in PAN with ethylene diamine to form en-PAN [18]. Final
step is the complexation of en-PAN with CuI under reflux condi-
tion in CH3CN affording en-PAN-Cu. The primary characterization
of PAN, en-PAN and en-PAN-Cu were done using FTIR, XRD and
XPS analyses.
PAN-Cu was performed in presence of 2 eq. of Cs2CO3 in DMF at
140 °C (Scheme 2). The mol% of the catalyst was calculated with
reference to the mass of CuI coordinated to a single monomer
unit. To our delight, the reaction proceeded without the addition
of any chelating ligand and after 16 hrs of reaction provided 2-
phenyl benzoxazole 4a in 89% yield. After that we have carried out
a set of further optimization studies in search for better results.
Initial studies to understand the effect of catalyst loading on the
C-O coupling reaction revealed that under lower catalyst loading
(5 mol%) the reaction yield decreases significantly to 65% (Table 1,
entry 1).
The FTIR spectra of PAN, en-PAN, en-PAN-Cu is depicted in
Fig. 1. The strong absorption peak at 2242 cm−1 (Fig. 1a) repre-
senting the stretching vibrations of CN group in PAN disappeared
for en-PAN and new peaks corresponding to N-H, C = N, C-N
stretching vibrations appeared at 3303, 1636, 1320 cm−1 respec-
tively, confirming the modification of PAN with ethylene diamine
(Fig. 1b). In the spectrum of en-PAN-Cu (Fig. 1c), the FTIR bands
of N-H, C=N vibrations shifted to lower frequencies such as 3213,
1632 cm−1 evidencing the complexation of CuI with modified PAN.
The XRD patterns of PAN, en-PAN and en-PAN-Cu are presented
in Fig. 2. The strong diffraction peaks observed at 2Ɵ = 17.28 and
29.32 indicates the semi crystalline nature of PAN (Fig. 2a). How-
ever, XRD spectrum of the modified polymer (en-PAN) exhibited
more amorphous nature. But in the case of en-PAN-Cu, different
peaks at 2Ɵ =22.71, 24.51, 26.92, 37.75, 39.25 and 45.26 are at-
tributed to the planes indicating the presence of crystalline Cu(I)
species.
In the next set of experiments, we have screened different bases
and solvents. A number of inorganic bases such as K2CO3, Na2CO3,
Cs2CO3 and K3PO4 were studied (Table 1, entries 2–4) and bet-
ter result was obtained with Cs2CO3. Among the various solvents
screened, DMF was found to be the best choice for this reaction
and other solvents such as DMA, DMSO, 1,2-DCE 1,4-Dioxan and
toluene gave comparatively lower yields (Table 1, entries 5–9). The
reaction did not work in the absence of catalyst and base showing
the indispensable role of catalyst and base for the reaction (Table 1,
entry 10 and 11). When the reaction was conducted at lower tem-
perature, the yield of the reaction decreased to 75% (Table 1, entry
12). However, increase in the reaction yield (94%) was observed by
further extending the reaction time upto 24 h (Table 1, entry 13).
Based on all these optimization studies, the most suitable condi-
tion for benzoxazole formation was identified as 10 mol% en-PAN-
Cu catalyst with Cs2CO3 (2 eq.) as base in DMF (2 ml) at 140 °C in
air for 24 h.
The XPS spectrum of en-PAN-Cu shows a single Cu2p3/2 peak
at 932.6 eV suggest the presence of Cu(I) species in the complex.
The binding energy values of C1s and N1s were observed at 285.0
and 401.9 eV respectively. These observations clearly revealed the
presence of Cu(I) species in the complex, which are in agreement
with the literature values [19].
Under the optimized reaction conditions, the scope of using
en-PAN-Cu catalyst towards the synthesis of various 2-substituted
benzoxazoles from N-(2-halophenyl) benzamides are investigated
and the results are tabulated (Table 2). It was interesting to note
that, en-PAN-Cu complex is highly efficient for catalyzing the
intramolecular C-O coupling of different 2-haloamides. The in-
After characterization of en-PAN-Cu, we have investigated the
catalytic efficiency of the en-PAN-Cu-Cu for the synthesis of ben-
zoxazoles from 2-haloanilides. In the initial trial, a model reaction
of N-(2-bromophenyl) benzamide 3a (1eq.) with 10 mol% of en-
2

T.V. Saranya, P.R. Sruthi, V. Raj et al.
Journal of Organometallic Chemistry 937 (2021) 121733
Fig. 1. FTIR spectra of (a) PAN (b) en-PAN (c) en-PAN-Cu.
Fig. 2. XRD spectra of (a) PAN (b) en-PAN (c) en-PAN-Cu.
3

T.V. Saranya, P.R. Sruthi, V. Raj et al.
Journal of Organometallic Chemistry 937 (2021) 121733
Fig. 3. XPS spectra of (a) en-PAN-Cu (b) High resolution analysis of Cu2p signal.
Scheme 2. en-PAN-Cu catalyzed synthesis of Benzoxazole.
tramolecular cyclization of N-(2-bromophenyl) benzamide 3a af-
forded 2-phenyl benzoxazole 4a in 94% yield and the correspond-
ing iodo substrate 3b underwent the reaction to give the product
in 99% yield (Table 2, entry 1 and 2). In general, 2-iodo substrates
afforded higher yields compared to their bromo analogues due to
the higher ease of oxidative addition of iodoarenes. Whereas, cor-
responding chloro substrate, N-(2-chlorophenyl) benzamide 3c ex-
hibited only lower reactivity under the condition to gave the prod-
uct in 41% yield (Table 2, entry 3). N-(2-bromophenyl) benzamide
having 4-CH3 (3d) and 4-F (3e) substituent in the aryl halide moi-
ety worked well to give cyclized products 4b and 4c in 99 and 90%
yields respectively (Table 2, entry 4 and 5). The substrates with
Scheme 3. Plausible mechanism of the reaction.
4

T.V. Saranya, P.R. Sruthi, V. Raj et al.
Journal of Organometallic Chemistry 937 (2021) 121733
Table 2
Substrate scope studies.
electron donating substituents at the para positon of benzamide
moiety 3f-3k were well tolerated under the reaction conditions af-
fording final products 4d-4 h in 86–98% yields (Table 2, entries 6–
11).
product in moderate (60%) yield only (Table 2, entry 16) and the
electron withdrawing 4-NO2 containing substrate (3r) failed to de-
liver the reaction product (Table 2, entry 18). This could be at-
tributed to the less availability of the lone pair electrons of ni-
trogen atom to coordinate with the catalyst during the first step
of the reaction. The isobutyramide derivatives 3s-3v successfully
underwent cyclization reaction to give the products 4n-4p in 42,
50, 76 and 47% yields, respectively (Table 2, entries 19-22). The
substrates 3w-3z afforded 2-ethyl benzoxazoles 4q-4s in moderate
yields (Table 2, entries 23-26 3). The recyclability and reusability of
the en-PAN-Cu catalyst was evaluated for the synthesis of 4a from
3a under the optimized reaction conditions, which is very impor-
tant aspect considering the environmental and economic point of
view. After the completion of the reaction, the catalyst was recov-
ered by simple filtration, dried properly and used for the next run.
The catalyst showed good reusablity after the second run to af-
ford the product in 79% isolated yield (Table 2, entry 1). The metal
leaching in solution during the catalytic process could be the rea-
son for the lose in catalytic activity. However the catalyst possess
Furthermore alkyl amide precursors were also successfully cy-
clized to corresponding 2-alkyl benzoxazoles in slightly lower
yields than aryl analogues under this reaction protocol. It is ob-
served that alkyl substituent on the amide moiety has great influ-
ence on the intramolecular cyclization pathway and the reaction
of ortho-halo alkyl amides follow the order tbutyl>isopropyl>ethyl
under the reaction condition. 2–bromo and iodo pivalamide 3l and
3 m reacted well under this conditions to give tbutylbenzoxazole
4i in good yields (Table 2, entry 12 and 13). While, the reaction
of 2–chloro pivalamide 3n resulted only trace amount of prod-
uct formation (Table 2, entry 14). The substrates with electron do-
nating groups such as CH3 and OCH3 in the para position of 2–
bromo pivalamides 3o and 3q gave the corresponding benzoxa-
zoles 4j and 4l in 79 and 82% yields respectively (Table 2, en-
try 15 and 17). The substrate 3p with 4-F substituent afforded
5

T.V. Saranya, P.R. Sruthi, V. Raj et al.
Journal of Organometallic Chemistry 937 (2021) 121733
good moisture insensitivity and thermal stability even after second
run.
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Eventhough the mechanism for formation of the active cat-
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mechanism for the formation of benzoxazoles using en-PAN-Cu is
presented (Scheme 3). Previous reports on the polymer supported
catalysis hinted out that the active catalytic species in these type
of heterogeneous catalysis are the soluble metal species leached
out from the solid support and partially or completely deposited
back on the support at the end of the reaction. Therefore the cat-
alytic cycle commences with the dissolution of active copper (I)
halide species from the polymer support at higher temperature
which then coordinate with 2-haloanilide 3 in presence of the base
to form intermediate complex A. Then the complex A undergoes
intramolecular oxidative addition to C-X bond leading to the for-
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of the active copper (I) species which in turn involve in the equi-
librium with the supported complex.
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In conclusion, we have developed a highly active and stable het-
erogeneous copper catalyst (en-PAN-Cu) by immobilizing CuI on
suitably functionalized poly acrylonitrile and used for efficient syn-
thesis of benzoxazoles from 2-haloanilides. The catalyst can be eas-
ily prepared by complexing CuI with ethylene diamine modified
polyacrylonitrile and this complex was further explored as a novel
and efficient heterogeneous catalyst for the synthesis of a series
of benzoxazoles from 2-haloanilides. By following this method 2-
aryl and 2-alkyl benzoxazoles were obtained in high yields upto
99%. Compared to our previous report [6], the present method pro-
vides a number of potential advantages in terms of wider substrate
scope, high reaction yields and simple work up procedure. Also,
the catalyst showed reasonable stability and reusability to afford
the product in good yields. To the best of our knowledge, this is
the first report on the use of amidine modified polyacrylonitrile
supported copper complex as a heterogeneous catalyst in benzox-
azole synthesis. Furthermore this heterogeneous catalytic system
provides a great promise and green approach for a series of cop-
per catalyzed homogeneous organic transformations in the future.
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgements
TVS and SPR thank Council of Scientific and Industrial
Research (CSIR, India) for Research Fellowships (Grant No.
09/499(0085)/2014-EMR-I and 09/499(0088)/2015-EMR-I). Authors
thank Institute for Integrated Programmes and Research in Basic
Sciences (IIRBS), Mahatma Gandhi University, Kottayam and So-
phisticated Test and Instrumentation centre (STIC), Cochin Univer-
sity of Science and Technology, Cochin for NMR analyses. We are
thankful to St. Thomas College, Pala for XRD analyses and CSIR-
NIIST, Thiruvananthapuram for XPS analysis. Authors also thank
DST-PURSE Phase (II), Govt. of India (SR/417 and 418/2017) for the
financial assistance.
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Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.jorganchem.2021.
121733.
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