TEMPO supported amine functionalized magnetic titania: a magnetically recyclable catalyst for the aerobic oxidative synthesis of heterocyclic compounds

Article abstract of DOI:10.1007/s00706-020-02714-2

Abstract: The present protocol uncover a new strategy to synthesize highly efficient solid TEMPO based catalyst in which 4-oxo-TEMPO was covalently tethered to the surface of amine functionalized magnetic titania. The chemical nature and structure of the

Full text of DOI:10.1007/s00706-020-02714-2

Monatshefte für Chemie - Chemical Monthly (2021) 152:83–94
https://doi.org/10.1007/s00706-020-02714-2
ORIGINAL PAPER
TEMPO supported amine functionalized magnetic titania:
a magnetically recyclable catalyst for the aerobic oxidative synthesis
of heterocyclic compounds
Sukanya Sharma1 · Anu Choudhary1 · Shally Sharma1 · Tahira Shamim1 · Satya Paul1
Received: 17 February 2020 / Accepted: 19 November 2020 / Published online: 2 January 2021
© Springer-Verlag GmbH Austria, part of Springer Nature 2021
Abstract
The present protocol uncover a new strategy to synthesize highly efcient solid TEMPO based catalyst in which 4-oxo-
TEMPO was covalently tethered to the surface of amine functionalized magnetic titania. The chemical nature and structure
of the synthesized catalyst was authenticated by various techniques such as Fourier transform infrared spectroscopy, thermo-
gravimetric analysis, X-ray powder difraction, feld emission gun scanning electron microscopy, high resolution transmission
electron microscopy, energy dispersive X-ray spectroscopy, elemental analysis, and vibrating sample magnetometer. FT-IR
confrmed the immobilization of titania, APTES, and TEMPO on the magnetic nanoparticles. Thermal behaviour of the
catalyst was studied by TGA. Morphology of the catalyst was investigated by FEG-SEM and HR-TEM analysis. Furthermore,
loading content of TEMPO on the catalyst was quantifed by elemental analysis and found to be 0.61 mmol/g. Magnetic
properties of the catalyst were investigated by VSM analysis. The catalytic performance of the synthesized catalyst has been
investigated for the oxidative synthesis of benzimidazoles, oxidative aromatization of 1,4-dihydropyridines, and oxidative
trimerization of indoles using molecular oxygen. In addition, the catalyst could be successfully recycled and reused up to
fve times without the prominent loss of catalytic activity.
Graphic abstract
Keywords TEMPO · Magnetic titania · Oxidative synthesis · N-Heterocycles · Molecular oxygen
Introduction
Selective oxidation of organic molecules is potentially an
attractive transformation which provides the basis for stream-
Supplementary Information The online version contains
lined conversion of simple precursors into fne chemicals
and intermediates [1]. In particular, the oxidative synthesis
of heterocyclic compounds has been intensively explored in
the chemical industry. Among heterocycles, N-heterocycles
are of extensive interest because these are pivotal building
blocks in natural products and pharmaceuticals [2]. Various
supplementary material available at https://doi.org/10.1007/s0070
6-020-02714-2.
* Satya Paul
paul7@redifmail.com
1
Department of Chemistry, University of Jammu,
Jammu 180006, India
Vol.:(0123456789)
1 3

84
S. Sharma et al.
methods have been developed for carrying out the oxidative
synthesis of N-containing heterocyclic compounds. How-
ever, most of these methods sufer from drawbacks such as
drastic reaction conditions, low yields, and co-occurrence of
several side reactions. In recent times, lot of work is being
carried out for methodology improvement, especially in
terms of waste product minimization and the use of renewa-
ble materials. In this context, molecular oxygen has emerged
as one of the most favourable oxidants due to its remark-
able advantages, including its abundance, safe use, low cost,
and high atom economy. Many catalytic systems have been
developed for catalysing the synthesis of heterocyclic com-
pounds in the presence of molecular oxygen [3, 4] and one
of the most impressive approaches involves the use of stable
nitroxyl radicals.
activated carbon in acetic acid [28]; and oxidative trimeriza-
tion of indoles making use of TEMPO/CuCl2 and benzoic
acid at 60 °C [29], TEMPO and benzoic acid at 65 °C [30].
However, most of these methods sufer from drawbacks
such as use of transition metal catalyst, long reaction time,
harsh reaction conditions, low yields, and tedious workup.
Subsequently, the development of a convenient and an eco-
friendly method for the synthesis of these N-heterocycles
compounds would be highly enviable. Herein, stable radical
based heterogeneous catalytic system has been developed,
where TEMPO was supported onto amine functionalized
magnetic titania and was fully characterized with diferent
techniques such as Fourier transform infrared (FT-IR) spec-
troscopy, thermogravimetric analysis (TGA), X-ray powder
difraction (XRD), feld emission gun scanning electron
microscopy (FEG-SEM), high resolution transmission elec-
tron microscopy (HR-TEM), energy dispersive X-ray (EDX)
spectroscopy, elemental analysis (CHN), and vibrating sam-
ple magnetometer (VSM). To the best of our knowledge, the
catalytic activity of heterogeneous TEMPO for the oxidative
synthesis of heterocycles has not been reported yet. This
fact made us to study the activity of TEMPO based catalyst
for carrying out the oxidative synthesis of benzimidazoles,
oxidative aromatization of 1,4-dihydropyridines, and oxida-
tive trimerization of indoles using O2 as the green oxidant.
Among the various persistent nitroxyl radicals,
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) is the most
prominent free radical which is stabilized by both thermo-
dynamic and kinetic efects [5]. TEMPO has attracted accu-
mulative consideration not only because of its versatility and
unique redox properties, but also due to its application in
various strategic domains [6–9]. Although TEMPO based
systems show high efciency for various organic transfor-
mations, but its recovery from the reaction medium is inher-
ently difcult due to its unique physicochemical properties
which leads to industrial wastes and additional costs. Keep-
ing in view the above mentioned limitations and increasing
concerns about the environment, various organic or inor-
ganic supports such as polymers [10–12], silica [13, 14],
ionic liquids [15], graphene oxide [16], microporous organic
nanotubes [17], C-60 [18], magnetic core–shell nanoparti-
cles [19], and carbon-coated Co ferromagnetic nanoparti-
cles [20] are being used to immobilize TEMPO. The most
frequently used support is silica, but the problem associated
with silica is its instability under basic conditions that leads
to loss of active phase during chemical reactions [21]. Mag-
netic titania has attracted a considerable amount of attention
as a new type of catalyst support because of its merits like
magnetic property, easy modifcation, non-toxicity, good
bio-compatibility, cost-efectiveness, and also its stability
in diferent chemical environment. Also, the use of tita-
nia as support for the immobilization of TEMPO has been
described only one time in literature [22]. Further enhance-
ment of the multifunctional properties of the magnetic tita-
nia was done by (3-aminopropyl)triethoxysilane (APTES),
which proved to be highly signifcant for the coupling of
TEMPO to the surface of the magnetic titania.
Results and discussion
Characterization of TEMPO@APTES–TiO2–Fe3O4
In the present work, magnetically recoverable heterogene-
ous TEMPO based catalyst, TEMPO@APTES–TiO2–Fe3O4
was successfully synthesized (Scheme 1). Initially, Fe3O4
nanoparticles were synthesized by the co-precipitation of
aq. solution of FeSO4.7H2O and Fe2(SO4)3 and then titania
was in situ coated onto the surface of Fe3O4, which helps
in stabilizing magnetite nanoparticles from oxidation and
provides the surface charges needed to prevent aggregation.
The magnetic titania nanoparticles were then functional-
ized with APTES, which acted as an excellent inter-particle
linker for the immobilization of TEMPO. The amino group
present in APTES enables the magnetic titania material to be
modifed with TEMPO by interacting with the correspond-
ing oxo group of TEMPO. The prepared catalyst was sepa-
rated magnetically, washed successively with ethanol, and
dried under vacuum. The TEMPO@APTES–TiO2–Fe3O4
was characterized by various techniques like FT-IR, TGA,
XRD, FEG-SEM, HR-TEM, EDX, CHN, and VSM.
Various aerobic oxidation pathways have been reported in
the literature for the oxidative synthesis of benzimidazoles
using Co/SBA-15 nanocatalyst [23], CuI nanoparticles [24],
Fe(NO3)3/TEMPO [25]; oxidative aromatization of 1,4-dihy-
dropyridines catalysed by heterogeneous cobalt catalyst at
90 °C [26], Co-naphthenate in chloroform at 61 °C [27],
The investigation about the presence of diferent func-
tional groups in the catalyst was done with FT-IR spec-
troscopy (S1). It showed broad peak at 3468 cm−1, which
was attributed to the O–H stretching mode of the hydroxyl
1 3

TEMPO supported amine functionalized magnetic titania: a magnetically recyclable catalyst…
85
groups present on the surface, whereas peak at 3404 cm−1
corresponds to N–H stretching vibrations [31]. The peak
at 2926 cm−1 was assigned to the C–H stretching vibra-
tion of the propyl group present in APTES, which confrms
the immobilization of APTES onto Fe3O4-TiO2 [32]. The
immobilization of TEMPO was confrmed by the peaks in
the region 1400–1340 cm–1 corresponding to the bending
modes of CH3 group (1480 cm−1) and stretching vibra-
tions of N–O radical (1400–1340 cm–1) [33–35]. The peak
at 894 cm−1 was presumably due to the stretching vibra-
tions of the Ti–O–Si bond [36], whereas the broad peak
centred at 626 cm–1 is an envelope of stretching vibrations
due to Ti–O of the TiO2 and Fe–O of Fe3O4 nanoparticles.
These results confrmed the immobilization of APTES and
TEMPO onto magnetic titania. The thermal stability of
TEMPO@APTES–TiO2–Fe3O4 was determined by thermo-
gravimetric analysis (TGA). The TGA graph of TEMPO@
Fig. 1 XRD spectrum of TEMPO@APTES–TiO2–Fe3O4
APTES–TiO2–Fe3O4 (S2) showed an initial weight loss
of 3.14% up to 100 ℃ due to the desorption of adsorbed
water from the catalyst surface, while the weight loss from
100–300 ℃ may be due to the thermal crystal phase transfor-
mation from Fe3O4 to γ-Fe2O3 and also due to loss of some
organic functionalities. Thus, from the TGA curve, it can be
concluded that the catalyst is stable up to 100 ℃ and thus, it
is safe to carry out the reactions up to 100 ℃.
and 53.8° correspond to the (101), (200), and (105) planes
of the cubic phase TiO2 [38]. The sharp and strong peaks
showed that the synthesized catalyst is crystalline in nature,
which has been further confrmed by HR-TEM image. Thus,
XRD spectra suggested the successful coating of titania onto
Fe3O4 nano-particles.
The information about the phase purity was determined
by X-ray difraction patterns. XRD pattern of TEMPO@
APTES–TiO2–Fe3O4 (Fig. 1) exhibited difraction patterns at
2θ=30.2°, 35.4°, 42.3°, 57.3°, and 62.3°, which corresponds
to (111), (220), (311), (440), and (511) planes of cubic phase
of Fe3O4 lattice [37]. Further, peaks at 2θ = 25.2°, 48.1°,
The shape and surface morphology of TEMPO@
APTES–TiO2–Fe3O4 was examined by scanning electron
microscopy (Fig. 2). SEM images showed the formation of
well-dispersed particles showing foccules like structure and
most of the particles assumed quasi-spherical shape. On the
other hand, the surface of the composite was non-smooth,
1 3

86
S. Sharma et al.
Fig. 2 FEG-SEM images of
TEMPO@APTES–TiO2–Fe3O4
which is responsible for increase in the surface area of the
catalyst and, thus the increased catalytic efciency.
responsible for the better anchoring of TEMPO onto the
support material. The black spots refer to the Fe3O4–TiO2
composite, whereas light grey colour appeared around the
Fe3O4–TiO2 composite indicated its covering with APTES.
Additionally, HR-TEM images showed the lattice fringes
with an inter-planar spacing of approximately 0.485 nm
corresponding to the (111) lattice plane of cubic Fe3O4
(Fig. 3c). The selected area diffraction pattern (SAED,
The HR-TEM images were recorded to obtain the
information about particle size and fne microstructure of
TEMPO@APTES–TiO2–Fe3O4. HR-TEM micrographs
(Fig. 3) revealed that the catalyst has composite type nature.
Moreover, it was also deciphered that APTES forms uni-
form covering over the Fe3O4–TiO2 composite and thus,
Fig. 3 HR-TEM images and
particle size histogram of
TEMPO@APTES–TiO2–Fe3O4
1 3

TEMPO supported amine functionalized magnetic titania: a magnetically recyclable catalyst…
87
Fig. 4 EDX spectrum of
TEMPO@APTES–TiO2–Fe3O4
Table 1 Elemental analysis and TEMPO loading
Entry
Sample
N/wt%
TEMPO
loading /
mmol g−1
1
2
APTES–TiO2–Fe3O4
TEMPO@APTES–TiO2–Fe3O4
1.150
2.054
–
0.61
Fig. 3d) showed small spots forming concentric rings,
thereby confrming the polycrystalline nature of the catalyst.
The average particle size of the composite was 12–14 nm as
depicted by the histogram.
The elemental composition of TEMPO@
APTES–TiO2–Fe3O4 as well as its chemical purity was ana-
lysed by using energy dispersive X-ray spectroscopy (EDX).
The EDX spectrum of TEMPO@APTES–TiO2–Fe3O4
(Fig. 4) confirms the presence of C, Ti, O, Si, and Fe
elements.
Fig. 5 Room temperature magnetization curves of TEMPO@
APTES–TiO2–Fe3O4 (fresh and reused)
To determine the loading of TEMPO on the catalyst, ele-
mental analysis has been undertaken which showed that the
catalyst (TEMPO@APTES–TiO2–Fe3O4) has an appreciably
higher nitrogen content than APTES–TiO2–Fe3O4 (Table 1).
The loading of TEMPO on the catalyst is estimated to be
0.61 mmol/g. Thus, CHN study showed the evidence for
the successful grafting of APTES and TEMPO over the
Fe3O4–TiO2 support.
coating of TiO2 onto Fe3O4 NPs protects them from oxida-
tion, reinforces the magnetic stability and enables it to dis-
perse rapidly when the magnetic feld is removed. As seen
from Fig. 5, the curves intersect the origin which means
that the catalyst exhibit superparamagnetic behaviour [39].
Catalytic activity of TEMPO@APTES–TiO2–Fe3O4
for the synthesis of 2‑substituted benzimidazoles
The magnetic properties of the synthesized and reused
catalysts (after 5th run) were investigated by using vibrating
sample magnetometry (VSM) at room temperature. VSM
curves of fresh and reused TEMPO@APTES–TiO2–Fe3O4
are shown in Fig. 5. The magnetization curve unveils the
value of saturation magnetization (Ms) of~20.49 emu/g for
the fresh and ~ 16.69 emu/g for the reused solid TEMPO.
There is small decrease in the saturation value of reused
catalyst, but still the catalyst show fast response to the exter-
nal magnet and can be readily separated magnetically. The
Considering the immense biological signifcance of 2-substi-
tuted benzimidazoles, our main focus was to develop a sim-
ple and greener approach for their synthesis using TEMPO@
APTES–TiO2–Fe3O4. To optimize the reaction conditions
for the synthesis of 2-substituted benzimidazoles, the reac-
tion between o-phenylenediamine (1 mmol) and 4-methoxy-
benzaldehyde (1 mmol) was selected as the model reaction.
To optimize the appropriate catalyst amount, the model
1 3

88
S. Sharma et al.
reaction was performed by varying the catalyst amount to
0.05 g, 0.1 g, 0.15 g, and 0.2 g, and the best results were
obtained with 0.1 g of the catalyst. Further decrease in the
amount of the catalyst from 0.1 g to 0.05 g led to decrease in
yield of the product (entry 2, Table 2) and also with increas-
ing the catalyst amount did not increase the yield consider-
ably (entries 4, 5, Table 2). To compare the catalytic activ-
ity of solid TEMPO with its precursors, the model reaction
was performed using 0.1 g of precursors of the developed
catalyst while keeping the other conditions unaltered. Unfor-
tunately, the yields obtained with the precursors were not
satisfactory (entries 6–8, Table 2). To select the best solvent,
the model reaction was carried out in diferent solvents such
as ethanol, toluene, and acetonitrile, wherein the reaction
in ethanol gave low yield (entries 1, 2, Table 3). Further,
the yield has been improved in acetonitrile (entries 3, 4,
Table 3), but the best results were obtained in toluene (entry
6, Table 3). Also, among oxidants i.e., air and O2, the good
results in terms of time, yield, and selectivity were obtained
with O2. Thus, toluene was selected as the optimized solvent
and O2 as the oxidant to carry out the oxidative synthesis
of 2-substituted benzimidazoles. With optimal conditions
in hand, the scope of the catalytic system was explored for
the reaction between o-phenylenediamine and diversely
substituted aldehydes (Table 4). The reactions were equally
facile with both electron-donating and electron-withdrawing
groups present in aldehyde.
Catalyst testing for oxidative aromatization of 1,
4‑dihydropyridines
For the oxidative aromatization of 1,4-dihydropyridines,
the reaction conditions were optimized using diethyl
4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate as the test substrate at room tempera-
ture and results revealed that oxidative aromatization of
Table 2 Optimization of the reaction conditions for the oxidative synthesis of N-containing heterocyclic compounds using molecular oxygen
Entry
Catalyst
Amount/g
Benzimidazolesa
Pyridinesb
Indolin-3-onec
Time/h
Yield/%d
Time/h
Yield/%d
Time/h
Yield/%d
1
2
3
4
5
6
7
8
No catalyst
–
12
5
5
5
NR
80
92
93
7
NR
80
94
95
24
19
19
19
19
24
24
24
NR
70
85
86
TEMPO@APTES–TiO2–Fe3O4
TEMPO@APTES–TiO2–Fe3O4
TEMPO@APTES–TiO2–Fe3O4
TEMPO@APTES–TiO2–Fe3O4
Fe3O4
Fe3O4–TiO2
Fe3O4–TiO2–APTES
0.05
0.1
0.15
0.2
0.1
0.1
0.1
3.5
3.5
3.5
3.5
7
7
7
5
93
95
86
12
12
12
10e
15e
25e
Traces
15e
20e
Traces
15e
25e
a
Reaction conditions: 0.13 g 4-methoxybenzaldehyde (1 mmol), 0.10 g o-phenylenediamine (1 mmol) at 100 °C in 5 cm3 toluene under O2
atmosphere. b0.359 g diethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1 mmol), 0.013 g FeCl3‧6H2O
(0.05 mmol), 0.0034 g NaNO2 (0.05 mmol), 5 cm3 acetonitrile under O2 atmosphere at room temperature. c0.117 g Indole (1 mmol), 0.06 g ben-
zoic acid (0.5 mmol), 5 cm3 acetonitrile under O2 atmosphere at room temperature. dIsolated yield. eColumn chromatography yield
Table 3 Efect of solvent and
oxidant on the TEMPO@
APTES–TiO2–Fe3O4
Entry
Solvent
Oxidant
Benzimidazolesa
Pyridinesb
Time/h
Indolin-3-onec
Time/h
Yield/%d
Yield%d
Time/h
Yield/%d
catalysed oxidative synthesis
of N-containing heterocyclic
compounds
1
2
3
4
5
6
Ethanol
Ethanol
Acetonitrile
Acetonitrile
Toluene
Air
O2
Air
O2
Air
O2
5
5
5
5
5
5
30
39
70
77
82
92
3.5
3.5
3.5
3.5
3.5
3.5
25
35
85
94
65
70
19
19
19
19
19
19
30
40
78
85
60
69
Toluene
Reaction conditions: a0.13 g 4-methoxybenzaldehyde (1 mmol), 0.10 g o-phenylenediamine (1 mmol),
and 0.1 g TEMPO@APTES–TiO2–Fe3O4 (0.06 mmol TEMPO) at 100 °C in 5 cm3 toluene under O2
atmosphere. b0.359 g diethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
(1 mmol), 0.013 g FeCl3‧6H2O (0.05 mmol), 0.0034 g NaNO2 (0.05 mmol), 0.1 g TEMPO@APTES–
TiO2–Fe3O4 (0.06 mmol TEMPO), and O2 atmosphere in 5 cm3 acetonitrile at room temperature. c0.117 g
Indole (1 mmol), 0.06 g benzoic acid (0.5 mmol), 0.1 g TEMPO@Fe3O4–TiO2–APTES (0.06 mmol
TEMPO), and O2 atmosphere in 5 cm3 acetonitrile at room temperature. dIsolated yield
1 3

TEMPO supported amine functionalized magnetic titania: a magnetically recyclable catalyst…
89
1,4-dihydropyridines using 0.1 g of catalyst with O2 as an
oxidant in acetonitrile gave 75% yield in 5 h. However, it
has been reported in the literature that the combination of
TEMPO with some metallic and non-metallic elements
results in increased catalytic activity [40, 41]. In this con-
text, we attempted to improve the yield and reduce the time
of the oxidative aromatization by using catalytic amount
of ferric chloride and sodium nitrite. It was found that the
yield of the corresponding product was increased to 94% in
3.5 h (entry 3, Table 2). This indicates that FeCl3‧6H2O and
NaNO2 plays an important role in promoting the catalytic
activity of TEMPO for the aromatization of 1,4-DHPs. To
demonstrate the generality of the developed protocol, vari-
ous 1,4-dihydropyridines substituted with electron-releasing
and electron-withdrawing groups were subjected to oxida-
tion under the optimized conditions and excellent results
were obtained (Table 5). The presence of electron-withdraw-
ing or electron-donating substituents on the 1,4-DHP did not
afect the course of the reaction.
water take place leading to the formation of 2-aminobenzo-
imine [A]. TEMPO present in the catalyst then interacts with
A and initiate the reaction by a hydrogen abstraction from the
N–H bond of the amine moiety to produce radical [B] and
TEMPOH, which was further reoxidized to TEMPO radical
by oxygen. The radical [B] so formed then undergoes intra-
molecular cyclization to form corresponding aminyl radical
[C]. The driving force for the aromatization allows the sec-
ond hydrogen abstraction between C and TEMPO to yield
benzimidazole and TEMPOH, which undergoes reoxidation
to TEMPO radical by oxygen. A plausible mechanism for the
oxidative aromatization of Hantzsch 1,4-dihydropyridines is
proposed in Scheme 2b, which is a sequential cascade of dou-
ble-cycle redox reaction. In the 1st step, one electron oxidation
of TEMPO by Fe3+ produces a highly electrophilic N-oxoam-
monium species [A] which convert 1,4-DHP to its correspond-
ing pyridine and itself gets reduced. The reduced derivative
of TEMPO [B] then undergoes oxidation to TEMPO [A] by
−
NO2 , which itself get reduced to NO and then NO undergoes
reoxidation to NO2− by O2 or in other words, NO2− is formed
via rapid oxidation of NO with O2. A plausible mechanism for
the synthesis of 2,2-disubstituted indolin-3-ones is proposed
in Scheme 2c. In the 1st step, TEMPO present in the catalyst
in the presence of molecular oxygen interacts with the indole-
nine tautomer A, leading to the formation of C3 located indole
hydroperoxide B, which after loss of water lead to indol-3-one
(C). Then the rapid nucleophilic addition of second indole
molecule on the C=N bond of this highly reactive species C in
the presence of benzoic acid gave dimer D, which was further
oxidized by O2, resulting in the formation of dimer E. Again
nucleophilic addition of third indole molecule to dimer E take
place in the presence of benzoic acid leading, fnally to trim-
erization of indole.
Catalyst testing for the oxidative trimerization
of indoles
The excellent catalytic activity of catalyst for the oxida-
tive synthesis of 2-substituted benzimidazoles and oxida-
tive aromatization of 1,4-dihydropyridines motivated us
to extend the application of the developed catalyst for the
oxidative trimerization of indoles to give 2,2-disubstituted
indolin-3-ones. Initially, oxidative trimerization of indole
was selected as the model reaction to select the optimum
reaction conditions. The reaction was performed using vari-
ous precursors of the catalyst as well as diferent amounts
of the catalyst and the results revealed that 0.1 g of catalyst
under O2 atmosphere gave 12% yield in 24 h. After carrying
out diferent experiments and also from the literature data
[30], it has been found that benzoic acid is critical for the
success of trimerization reaction. It was found that the yield
of the trimerization product was increased to 85% in 19 h
using 0.5 mmol of benzoic acid (entry 3, Table 2). We fur-
ther screened various solvents such as ethanol, toluene, and
acetonitrile under oxygen and air atmosphere. The results
revealed that the conversion was not good in ethanol and
toluene, however acetonitrile under oxygen atmosphere
gave high yield of the desired product. After optimization
of the reaction conditions, the scope and generality of the
developed protocol was studied with respect to 5-substi-
tuted indoles and the products were obtained in good yield
(Table 6).
Recyclability
To confrm the reusability of the catalyst, diferent experi-
ments were carried out in case of 3c (Table 4), 5a (Table 5),
and 7a (Table 6) using TEMPO@APTES–TiO2–Fe3O4 under
the optimum reaction condition. After completion of the reac-
tion, catalyst was separated via magnet, washed with deionized
water (2×20 cm3) and ethanol (2×15 cm3) and dried under
vacuum. Then a fresh reaction was carried out with the used
catalyst. A very small decrease in the catalytic activity of the
synthesized catalyst was observed up to 5 runs for each reac-
tion and hence the catalyst could be used at least fve times
without any change in activity (Fig. 6).
Proposed mechanism
A plausible mechanism for the synthesis of 2-substituted benz-
imidazoles is proposed in Scheme 2a. In the 1st step, loss of
1 3

90
S. Sharma et al.
Table 4 TEMPO@APTES–TiO2–Fe3O4 catalysed synthesis of 2-substituted benzimidazoles
H
O
R
NH2
NH2
N
TEMPO@Fe3O4-TiO2-APTES
toluene, O2, 100 oC
+
N
H
R
1
3
2
Entry
R
H
4-Me
4-OMe
4-Br
4-Cl
2-Cl
3-OMe
2-NO2
3-NO2
4-NO2
Product
Time/h
Yield/%
TON
Melting point/℃
Measured
Literature
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
6
5.5
5
5.5
5.5
6
89a
90a
92a
90a
90a
89a
90a
88b
89b
90a
14
14
14
14
14
14
14
13
14
14
292–294
267–269
224–226
298–299
293–294
232–233
206–208
262–264
206–208
310–312
292–293 [43]
268–270 [44]
225–226 [44]
299–300 [43]
292–294 [43]
233–234 [43]
204–206 [44]
264–266 [44]
206–207 [43]
312–314 [44]
3g
3h
3i
6
6.5
6.5
6
10
3j
Reaction conditions: aldehyde (1 mmol), 0.10 g o-phenylenediamine (1 mmol), and 0.1 g TEMPO@APTES–TiO2–Fe3O4 (0.06 mmol TEMPO)
at 100 ˚C in 5 cm3 toluene under O2 atmosphere
aIsolated yield
bColumn chromatography yield
rate of 10 °C min−1. X-ray difraction (XRD) was recorded
Conclusion
in the 2θ range of 10–80° on a Bruker AXSD8 ADVANCE
X-ray difractometer using Cu Kα radiations. Scanning elec-
tron microscopy (SEM) images were recorded using a FEG
SEM JSM7600F scanning electron microscope and high-res-
olution transmission electron microscopy (HRTEM) images
were recorded using a FEG, Tecnai G2, F30 transmission
electron microscope. Energy-dispersive X-ray analysis
(EDX) analysis was carried out using Oxford X-Max Model
JSM-7600F and the extent of magnetism (magnetic moment)
of the synthesized catalyst was measured using a vibrating
sample magnetometer (VSM) bearing Model: 7410 series,
Lakeshore at room temperature from -10,000 to+15,000 Oe.
We have developed a novel non-toxic, low-cost, and stable
radical based catalyst with good activity via immobiliza-
tion of TEMPO onto the surface of the amine functionalized
magnetic titania. The introduction of amino functionalized
silanes onto the surface of magnetic titania improve the
adhesion between the radical and the titania. The resultant
heterogeneous catalyst has been explored for the very frst
time for catalysing the oxidative synthesis of heterocyclic
compounds. All the reactions were performed under oxygen
atmosphere, which is suitable from a green and sustainable
chemistry point of view. The easy recovery, together with the
intrinsic stability of the support material, allows the catalyst
to be recycled fve times without any discernible loss in its
activity.
Synthesis of TEMPO@Fe3O4–TiO2–APTES
For the synthesis of TEMPO@Fe3O4–TiO2–APTES, 1 g
Fe3O4 prepared by co-precipitation method [42] was sus-
pended in 40 cm3 EtOH followed by the addition of 5 cm3
of ammonia solution and sonication up to 1 h. The solu-
tion was then transferred to round bottom fask (100 cm3),
followed by addition of 4 cm3 titanium butoxide in 30
cm3 ethanol, which was then stirred at 45 °C for 12 h. The
resultant Fe3O4–TiO2 colloid was separated with magnet
and washed repeatedly with distilled water (3 × 20 cm3)
Experimental
All of the chemical materials used were purchased from
Aldrich or Merck Chemical Company. To determine the
thermal stability of the synthesized catalyst, thermogravi-
metric analysis (TGA) was recorded on a PerkinElmer, Dia-
mond TG/diferential thermal analysis (DTA) with a heating
1 3

TEMPO supported amine functionalized magnetic titania: a magnetically recyclable catalyst…
91
Table 5 TEMPO@APTES–TiO2–Fe3O4 catalysed oxidative aromatization of 1,4-DHPs
Entry
R
Product
Time/h
Yield/%a
TON
Melting point/℃
Measured
Literature
1
2
3
4
5
6
7
8
9
4-OMe
4-Me
4-Br
4-Cl
H
2-OMe
2-NO2
3- NO2
4- NO2
5a
5b
5c
5d
5e
5f
5g
5h
5i
3.5
3
3
4
3
3.5
4
4.5
4
94
92
92
90
90
89
85
88
88
14
14
14
14
14
14
13
14
14
57–58
73–74
–
65–66
63–64
56–58
72–73
61–62
115–116
55–57 [45]
72–73 [46]
–
63–65 [45]
62–64 [45]
55–57 [47]
73–75 [48]
61–63 [45]
114–116 [45]
Reaction conditions: 1,4-dihydropyridine (1 mmol), 0.013 g FeCl3‧6H2O (0.05 mmol), 0.0034 g NaNO2 (0.05 mmol), and 0.1 g TEMPO@
APTES–TiO2–Fe3O4 (0.06 mmol TEMPO) in 5 cm3 acetonitrile at room temperature under O2 atmosphere
aIsolated yield
Table 6 TEMPO@APTES–TiO2–Fe3O4 catalysed oxidative trimerization of indole
R
H
N
O
R
R
TEMPO@Fe3O4-TiO2-APTES
O2, RT, CH3CN, benzoic acid
N
H
N
H
H
N
6
R
7
Entry
R
H
NO2
OMe
Br
Product
Time/h
Yield/%
TON
Melting point/℃
Measured
Literature
1
2
3
4
7a
7b
7c
7d
19
25
22
20
85a
70a
76a
79b
13
11
12
12
242–244
215–217
224–226
247–249
243–245 [30]
214–216 [29]
226–228 [30]
247–249 [30]
Reaction conditions: indole (1 mmol), 0.06 g benzoic acid (0.5 mmol), and 0.1 g TEMPO@APTES–TiO2–Fe3O4 (0.06 mmol TEMPO) in 5 cm3
acetonitrile at room temperature under O2 atmosphere
aIsolated yield
bColumn chromatography yield
1 3

92
Scheme 2
S. Sharma et al.
a
H
N
NH2
NH2
b
O
TEMPO@Fe3O4-TiO2-APTES
O2, 100 o
R
+
R
H
N
C
N
O
Fe3+
Fe2+
NH2
N
HO
O
N
R
O2
A
R
O
O
O
N
H2O
EtO
Me
OEt
O2
N
NO
N
O
N
H
Me
A
O2
O2
HO
N
R
O
O
H
EtO
Me
OEt
Me
H
N
N
NH
N
NO2
cyclization
N
N
H
OH
R
R
B
C
B
NH
c
O
TEMPO@Fe3O4-TiO2-APTES
O2, CH3CN, benzoic acid, RT
N
NH
N
H
H
H
N
H
H
benzoic acid
N
A
O
N
O
N
NH
E
O2
HO
H
N
O2
O
H2O
O
OOH
N
H
N
H
NH
N
N
benzoic acid
B
D
C
and ethanol (2 × 10 cm3) and dried in an oven at 70 °C
for 8 h. 1 g Fe3O4–TiO2 and 20 cm3 anhydrous toluene
were taken in a round bottom fask (100 cm3) followed by
the addition of APTES (10 mmol). The resulting mixture
was then stirred at 70 °C for 10 h to allow completion
of silanization reaction. The Fe3O4–TiO2–APTES so pre-
pared was separated with magnet, washed with toluene
(3 × 10 cm3) followed by ethanol (2 × 10 cm3) and dried
in an oven at 70 °C. For the anchoring of TEMPO onto
Fe3O4–TiO2–APTES, 2 g Fe3O4–TiO2–APTES, 4-oxo-
TEMPO (1.5 mmol), and 20 cm3 ethanol were added in
a round bottom fask (100 cm3) and the resulting mixture
was stirred at 40 °C for 12 h. After that, 5 cm3 aqueous
solution of NaBH4 (2 mmol) was added to the above reac-
tion mixture during 6 h and the stirring was continued for
another 2 h. Finally, the catalyst so prepared was separated
with an external magnet, washed successively with ethanol
(2 × 10 cm3), and dried in an oven at 40 °C for 8 h.
1 3

TEMPO supported amine functionalized magnetic titania: a magnetically recyclable catalyst…
93
completion, the reaction mixture was diluted with 20 cm3
ethyl acetate and the catalyst was separated with external
magnet, washed with ethyl acetate (2×5 cm3), dried in an
oven, and then used in the next reaction. The organic layer
was washed with water (3×20 cm3) and dried over anhyd.
Na2SO4. The crude product obtained after removal of the sol-
vent under reduced pressure was purifed by crystallization.
General procedure for the synthesis
of 2,2‑disubstituted indolin‑3‑ones using TEMPO@
APTES–TiO2–Fe3O4 as catalyst under O2 atmosphere
To a mixture of indole (1 mmol), 0.06 g benzoic acid
(0.5 mmol), and 0.1 g TEMPO@APTES–TiO2–Fe3O4 in a
round bottom fask (25 cm3), 5 cm3 acetonitrile was added
and the reaction mixture was stirred at room temperature
with an oxygen balloon for the appropriate time. After com-
pletion of the reaction (monitored by TLC), the reaction
mixture was diluted with 20 cm3 ethyl acetate and the cata-
lyst was separated with external magnet, washed with ethyl
acetate, dried in an oven, and then used in the next reaction.
The organic layer was washed with water (3×20 cm3) and
dried over anhyd. Na2SO4. The crude product obtained was
purifed either by crystallization or by passing through col-
umn of silica gel (EtOAc-pet. ether).
Fig. 6 Recyclability of TEMPO@APTES–TiO2–Fe3O4
General procedure for the oxidative synthesis
of 2‑substituted benzimidazoles using TEMPO@
APTES–TiO2–Fe3O4 in the presence of molecular
oxygen
To a mixture of o-phenylenediamine (1 mmol), aro-
matic aldehyde (1 mmol), and 0.1 g TEMPO@
APTES–TiO2–Fe3O4 in a round bottom fask (25 cm3), 5
cm3 toluene was added and the reaction mixture was stirred
at 100 °C under an oxygen atmosphere. When the start-
ing materials were completely consumed as determined by
TLC, the reaction mixture was diluted with 20 cm3 ethyl
acetate and the catalyst was separated with external magnet.
The catalyst obtained was washed with ethyl acetate (3×5
cm3), dried in an oven and then used in the next reaction.
The organic layer was washed with water (3×20 cm3) and
dried over anhyd. Na2SO4. The crude product obtained after
removal of the solvent under reduced pressure was further
purifed either by crystallization or by passing through col-
umn of silica gel using ethyl acetate and petroleum ether as
eluting solvents. 2-substituted benzimidazoles 3a–3j were
synthesized in high yields.
Acknowledgements The author thank the Head, SAIF, IIT Bombay for
FEG-SEM, HR-TEM, and EDX analysis; SAIF Chandigarh for XRD
analysis; CIF, IIT Guwahati for VSM analysis.
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