Water-Mediated One-pot Three-Component Synthesis of Hydrazinyl-Thiazoles Catalyzed by Copper Oxide Nanoparticles Dispersed on Titanium Dioxide Support: A Green Catalytic Process

Article abstract of DOI:10.1002/adsc.201701063

The present work describes the catalytic activity of copper oxide nanoparticles dispersed on titanium dioxide in water for one-pot synthesis of a library of hydrazinyl-thiazoles via a three-component reaction of various aldehydes/ketones with thiosemicarbazide and different phenacyl bromides. The structure of the synthesized compound, (E)-4-(4-bromophenyl)-2-(2-(4-methoxybenzylidene) hydrazinyl)thiazole is confirmed by single crystal X-ray diffraction studies. The catalyst prepared by a molten-salt method is characterized by X-ray diffraction, field emission scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, Auger electron spectroscopy and electron spin resonance spectroscopy. The noteworthy advantages of this method include its broad substrate scope, clean reaction profile, short reaction times and high yields at low catalyst loading. Further, the product does not require any chromatographic purification and the method has the potential for large-scale applications in pharmaceutical industries. In addition, the developed catalyst can be recovered and reused for 5 times without significant loss of activity. Mechanistic studies suggest that the reaction begins with the activation of the carbonyl group of both aldehyde/ketone and phenacyl bromide by copper oxide nanoparticles supported on titanium dioxide in water. These studies reveal that the reaction proceeds via the formation of thiosemicarbazone intermediate. (Figure presented.).

Full text of DOI:10.1002/adsc.201701063

Title: Water-Mediated One-pot Three-Component Synthesis of
Hydrazinyl-Thiazoles Catalyzed by Copper Oxide Nanoparticles
Dispersed on Titanium Dioxide Support: A Green Catalytic
Process
Authors: Trivikram Reddy Gundala, Kumar Godugu, and Nallagondu
Chinna Gangi Reddy
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701063
Link to VoR: http://dx.doi.org/10.1002/adsc.201701063

10.1002/adsc.201701063
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Water-Mediated One-pot Three-Component Synthesis of
Hydrazinyl-Thiazoles Catalyzed by Copper Oxide
Nanoparticles Dispersed on Titanium Dioxide Support: A
Green Catalytic Process
G. Trivikram Reddy,a G. Kumar a and N. C. Gangi Reddy*a
a
Department of Chemistry, School of Physical Sciences, Yogi Vemana University, Kadapa-516 003, Andhra Pradesh,
India. E-mail: ncgreddy@yogivemanauniversity.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article (1 H & 13C NMR, HRMS and MS spectra of all compounds and crystallographic
data in CIF format (CCDC 1560154)) is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
and high yields at low catalyst loading. Further, the product
does not require any chromatographic purification and the
Abstract. The present work describes the catalytic
activity of copper oxide nanoparticles dispersed on titanium
method has the potential for large-scale applications in
dioxide in water for one-pot synthesis of a library of
pharmaceutical industries. In addition, the developed
hydrazinyl-thiazoles via a three-component reaction of
various aldehydes/ketones with thiosemicarbazide and
catalyst can be recovered and reused for 5 times without
significant loss of activity. Mechanistic studies suggest that
different phenacyl bromides. The structure of the
the reaction begins with the activation of the carbonyl
synthesized compound, (E)-4-(4-bromophenyl)-2-(2-(4-
methoxybenzylidene) hydrazinyl)thiazole is confirmed by
single crystal X-ray diffraction studies. The catalyst
group of both aldehyde/ketone and phenacyl bromide by
copper oxide nanoparticles supported on titanium dioxide in
water. These studies reveal that the reaction proceeds via
prepared by a molten-salt method is characterized by X-ray
the formation of thiosemicarbazone intermediate.
diffraction, field emission scanning electron microscopy,
transmission electron microscopy, energy dispersive X-ray
spectroscopy, X-ray photoelectron spectroscopy, Auger
electron spectroscopy and electron spin resonance
Keywords: copper oxide nanoparticles; titanium dioxide;
spectroscopy. The noteworthy advantages of this method
water; multi-component reaction; hydrazinyl-thiazoles.
include its broad substrate scope, clean reaction profile,
short reaction times
are considered as ‘privileged scaffolds’ due to their
Introduction
potential biological activities like antimicrobial, anti-
inflammatory, antihypertensive, anti-HIV and
herbicidal activity.[3–7] They are important subunits in
several pharmaceutical drugs, such as Ritonavir,[8]
Bleomycin[9] and Tiazofurin,[10] Fanetizole and
Meloxicam.[11] Some of these thiazoles and its metal
Design and development of organic reactions in water
is an excellent area of research that emphasizes the
spirit of new and innovative green chemistry. Indeed,
it is clear that water has many unique physical and
chemical properties such as extensive hydrogen
bonding, non-toxicity, high heat capacity, large
dielectric constant, non-flammability, environmental
compatibility etc. In addition, water is known to
increase the rates and improve the selectivity of a wide
variety of organic reactions.[1] Among the organic
reactions, multi-component reactions (MCRs) are
powerful tools for the sustainable and diversity-
oriented synthesis of heterocycles[2] by the rapid
construction of several multiple bonds in a single step
operation with minimal waste and energy. MCRs
performed with various heterogeneous catalysts have
undergone remarkable progress in recent years.
Among the heterocycles, thiazole and its derivatives
complexes are also used as semiconducting
[13]
materials,[12] fluorescent chemosensors
and organic
light-emitting diodes.[14] Extensive literature study
reveals that there are only two ways for the synthesis
of hydrazinyl-thiazoles. First one is the homogeneous
acid catalyzed conventional two-step process which
involves the reaction of carbonyl compounds with
thiosemicarbazide to produce thiosemicarbazones
which subsequently undergo cyclization with α-
halocarbonyl compounds.[15] But, this procedure
suffered from disadvantages such as limited substrate
scope, use of organic solvents, low yields, lengthy
reaction times and complicated workup procedures.
One-pot methods reported so far have been very
limited. This method involves the reaction of carbonyl
1
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10.1002/adsc.201701063
Advanced Synthesis & Catalysis
compounds, thiosemicarbazide and α-halo carbonyl
compounds in a single-step operation.[16] Though the
reported one-pot methods are efficient to provide the
desired hydrazinyl-thiazoles, there are still some
drawbacks such as narrow substrate scope and use of
expensive techniques; The method generates unwanted
side products and the products require column
chromatographic purification. Further, there is no
mechanistic evidence for the reaction pathway and the
method is unsuitable for large-scale applications.[16c,e]
support and the CuO nanoparticles increases the
stability and catalytic activity of CuONPs on TiO2.
The TiO2 supported CuNPs are widely used as
heterogeneous catalysts in a variety of organic
reactions.[21e-h,q] Inspired by the importance of
CuNPs/TiO2 in organic synthesis, we aimed to prepare
economically viable and environmentally benign
heterogeneous TiO2 supported CuO nanocatalysts and
explore their catalytic performance in organic
transformations. To the best of our knowledge, there
are no reports on CuONPs/TiO2 catalyzed one-pot
synthesis of a library of hydrazinyl-thiazoles in water.
Nowadays, nanocatalysis is an attractive and
highly demanding area of research which involves the
use of nanomaterials as catalysts in a variety of
organic transformations.[17] This may be due to their
unique characteristics like smaller size, high surface
area, high density of defect sites, increased efficiency
and selectivity and reusability.[18] The high surface
energy of nano-size particles favors agglomeration.
Therefore the nanocatalysis is considered as a
sustainable and competitive alternative to conventional
catalysis. Transition metal-based nanoparticles are
employed as catalysts in many important organic
conversions.[19] Among them, copper nanoparticles are
considered as clean and abundant catalysts due to their
low-cost, high stability, non-toxicity, recyclability,
reusability and environmental friendly nature for
several organic transformations.[20] Hence, several
solid supported copper nanocatalysts such as silica,
zeolites, metal oxides and carbon materials are utilized
in a variety of organic reactions.[21] For example,
copper nanoparticles supported on various solid
supports such as TiO2 (CuNPs/TiO2),[21e-h] activated
carbon (CuONPs/C),[21i,j] silica coated maghemite
(CuNPs/MagSilica)[21k] zeolite (CuONPs/Zy),[21l] and
graphene oxide (CuONPs/GO)[21m] are used for the
catalytic activation of the C–H bond of terminal
alkynes. Copper nanoparticles supported on silica
CuNPs (CuNPs/Silica)[21n] and Hexagonal mesoporous
silica (HMS) (CuO/HMS)[21o] are also utilized for the
activation of aldehydes. Copper nanoparticles on silica
(CuNPs/Silica)[21p] are used for the C–N cross-
coupling reaction. Further, Copper nanoparticles
supported on mesoporous titanium oxide and cobalt
ferrite are successfully used in a variety of organic
reactions like epoxidation, reduction, click reaction
and Biginelli reaction.[21q] Among various catalysts
supports, TiO2 has been identified as an attractive
In this paper, we report a CuONPs/TiO2 catalyzed
one-pot three-component synthesis of a series of
hydrazinyl-thiazoles (4a-u & 6a-s) from various
aldehydes (1a-c)/ ketones (5a-s), thiosemicarbazide
(2) and different phenacyl bromides (3a-g) in water
under ambient reaction conditions (Scheme 1). Further,
this study focuses on the explanation of reaction
pathway; the intermediate (I) is isolated and confirmed
by spectral studies.
Scheme 1. CuONPs/TiO2 catalyzed multi-component
synthesis of diversified hydrazinyl-thiazoles(4a-u & 6a-s)
in water.
Results and Discussion
In the present study, we aimed to fulfill three
major objectives: i) development of a new
catalytic system ii) investigation of reaction
mechanism and iii) establishing clean, economic
and environmental friendly reaction conditions for
the one-pot multi-component synthesis of
hydrazinyl-thiazoles. Initially, a variety of TiO2
supported copper catalysts were prepared by a
molten-salt method using mixture-i (NaCl and
commercial P-25 TiO2) and mixture-ii (NaCl and
Cu (NO3)2.3H2O) as indicated in Table 1. Briefly,
mixture-i and mixture-ii were mixed in an alumina
crucible, calcined, washed with distilled water and
dried. The obtained TiO2 supported CuO
support because of its unique physico-chemical nanoparticles were labelled as CT-1, CT-2, CT-3,
CT-4, CT-5, CT-6 and CT-7 (Table 1).
properties such as high surface area, non- toxicity and
high chemical and thermal stability in both acidic and
oxidative environments. In addition, the surface of
TiO2 is highly hydrophilic which stabilizes the
dispersion of the TiO2 in water thus enabling the
deposition of metal or metal oxide NPs on the TiO2
surface.[22] Furthermore, the synergetic activity of TiO2
Table 1. Chemical composition for the preparation of
catalysts (CT-1 to CT-7).
2
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10.1002/adsc.201701063
Advanced Synthesis & Catalysis
Catalyst Mixture-i
Entry Code Wt. of Wt. of Wt. of
Mixture-ii
Wt. of
3
4
TiO2
CT-1
CT-2
CT-3
CT-4
CT-5
CT-6
CT-7
EtOH
Acetone
Isopropanol 60
H2O 60
Acetonitrile 60
EtOH
Acetone
Isopropanol 60
H2O 60
Acetonitrile 60
EtOH
Acetone
Isopropanol 20
H2O 20
Acetonitrile 20
EtOH
Acetone
Isopropanol 20
H2O 20
Acetonitrile 20
EtOH
Acetone
Isopropanol 20
H2O 20
Acetonitrile 20
EtOH
Acetone
Isopropanol 20
H2O 20
Acetonitrile 20
EtOH
Acetone
Isopropanol 20
H2O 20
Acetonitrile 20
EtOH
Acetone
Isopropanol 20
H2O 20
Acetonitrile 20
60
60
4a
4a
4a
4a
4a
4a
4a
4a
20
-
10
-
-
30
-
Wt.-%
NaCl TiO2 NaCl Cu(NO3)2. of Cu
(mg) (mg) (mg) 3H2O (mg)
1
2
3
4
5
6
7
CT-1
CT-2
CT-3
CT-4
CT-5
CT-6
CT-7
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
9.5
0.5
1.0
1.3
1.5
1.7
2.0
2.5
19.0
24.7
28.5
32.3
38.0
47.5
60
60
30
35
10
35
-
20
45
10
40
-
30
60
10
60
-
45
85
10
55
-
40
80
15
50
-
40
78
25
55
-
5
20
20
The prepared catalysts (CT-1 to CT-7) were
examined for their potency along with commercially
available CuO and TiO2 catalysts for the one-pot
synthesis
of
(E)-4-(4-bromophenyl)-2-(2-(4-
6
20
20
methoxybenzylidene) hydrazinyl)thiazole (4a) from 4-
methoxybenzaldehyde (1a), thiosemicarbazide (2) and
2-bromo-1-(4-bromophenyl)ethanone (3a) as model
substrates (Table 2). A control experiment was
conducted in ethanol at RT in the absence of catalyst
for 60 min; the yield obtained was 20 % only (Table 2,
entry 1/C2H5OH). It was also observed that the
reaction did not proceed in water (Table 2, entry
1/H2O). To improve the yield, the same reaction was
repeated with the aforementioned catalysts in different
solvents at RT (Table 2). After examining these
catalysts and solvents, it was found that the 25 mg of
CT-4 catalyst in water was the best option to obtain
better yield (85%) of product (4a) (Table 2, entry
7/H2O) and other catalysts in different solvents
afforded low to moderate yields of 4a (Table 2, entries
2-6 and 8-10). From this study, it was observed that
the of CT-4 catalyst in water was the most suitable
medium for the synthesis of 4a. The high catalytic
activity of CuONPs/TiO2 might be due to the high
dispersity of TiO2 supported CuO nanocatalyst in
water followed by the interaction of organic substrates
with CuONPs.[23]
7
20
20
8
20
20
9
20
20
10
20
20
45
75
30
[a]Reagents and conditions: 4-methoxy benzaldehyde
Table 2 Screening of suitable catalyst and solvent for the
(1a) (10.0 mmol), thiosemicarbazide (2) (10.0 mmol),
one-pot
three-component
synthesis
of
(E)-4-(4-
2-bromo-1-(4-bromophenyl)ethanone (3a) (10.0 mmol),
catalyst (25 mg), solvent (25 mL), RT.
[b]Isolated yield.
bromophenyl)-2-(2-(4-methoxybenzylidene)hydra
zinyl)thiazole(4a).[a]
[c]In the absence of catalyst.
Further, the amount of loading of CT-4
catalyst (5, 25, 50, 75, 100 and 125 mg) was
varied to optimize the yield of product 4a (Table
3). From this study, it was found that 50 mg of
CT-4 catalyst (1.12 mol.% of Cu) was the
optimum amount to achieve maximum yield of
product 4a (98%) for the stated quantity of
substrates within a short period of time (10 min)
(Table 3, entry 3); However, further increase in the
amount of catalyst (i.e. 75, 100 and 125 mg), did
Entry Catalyst
Solvent Time Product Yieldb
(min)
60
60
(%)
20
-
1c
---
EtOH
Acetone
4a
Isopropanol 60
H2O 60
Acetonitrile 60
10
-
-
2
CuO
EtOH
Acetone
60
60
4a
25
-
Isopropanol 60
H2O 60
Acetonitrile 60
15
20
10
3
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10.1002/adsc.201701063
Advanced Synthesis & Catalysis
not show any significant effect on the product
yields (Table 3, entries 4-6).
Table 3. Effect of amount of catalyst (CT-4) loading in
the one-pot three-component synthesis of 4a [a]
.
Entry Amount of Copper Solvent Time Yieldc
CT-4 catalyst content
(min) (%)
(mg)
(mol-%)b
1
2
3
4
5
6
5
25
50
75
100
125
0.11
0.56
1.12
1.68
2.23
2.79
H2O
H2O
H2O
H2O
H2O
H2O
60
20
10
10
10
10
75
85
98
97
96
96
[a]Reagents and conditions: 4-methoxy benzaldehyde
(
1a) (10.0 mmol), thiosemicarbazide (2) (10.0 mmol),
2-bromo-1-(4-bromophenyl)ethanone (3a) (10.0 mmol),
CT-4 catalyst (5.0 to 125 mg), water (25 mL), RT.
[b] Referred to the substrates.
[c]Isolated yield.
To test the generality and scope of this MCR,
various aromatic aldehydes (1a-c) and phenacyl
bromides (3a-g) were employed in this reaction
separately (Table 4)
.
At first, 4-methoxy
benzaldehyde (1a) underwent the reaction with
thiosemicarbazide (2) and a variety of phenacyl
bromides (3a-g) to afford the corresponding
hydrazinyl-thiazoles (4a-g) in good yields that
ranged from 92 to 98 %. Next, 2, 4-dimethoxy
benzaldehyde (1b) also showed good reactivity
towards thiosemicarbazide (2) and different
phenacyl bromides (3a-g) to produce the
corresponding hydrazinyl-thiazoles (4h-n) in good
yields that ranged from 91 to 97 %. Further, 3-
ethoxy-4-hydroxybenzaldehyde (1c) reacted with
thiosemicarbazide (2) and a range of phenacyl
bromides (1a-g) to yield the corresponding
hydrazinyl-thiazoles (4o-u) in good yields that
ranged from 90 to 96%. From this study, it was
observed that the substrates with diverse
functional groups on the aromatic ring proceeded
well to provide the desired products in high yields
under the optimized reaction conditions.
[a]Reagents and conditions: Aromatic aldehydes (1a-c
(10.0 mmol), thiosemicarbazide (2) (10.0 mmol),
phenacyl bromides (3a-g) (10.0 mmol), CT-4 catalyst
(50 mg; 1.12 mol-% of Cu), water, RT.
[b]Isolated yield.
)
Table 4. Synthesis of hydrazinyl-thiazole derivatives
The structure of 4a was confirmed by a single
crystal X-ray crystallography (Figure.1). The
compound 4a obtained was monoclinic with P21/c
space group and one molecule in the asymmetric
unit (Z = 4, Z’ = 0) (Figure 2). In the crystal
packing (Figure. 2a), the molecules were linked by
N(2)—H……N(1) with a significant bond length
of 3.009 Å. The interactions propagated in a 3D
network packing with respect to the a & c axes as
(
4a-u) using various aldehydes, thiosemicarbazide and
phenacyl bromides.[a]
4
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10.1002/adsc.201701063
Advanced Synthesis & Catalysis
shown in Figure S1 (See the Supporting corresponding products 6n (91%) and 6o (90%)
.
Information).
Acetonaphthones such as 2-acetyl and 1-acetyl
naphthalenes (5p & 5q) afforded the products, 6p
and 6q in good isolated yields of 94 and 92%,
respectively. From the above study, it was
observed that the reaction proceeded well,
irrespective of the substituents present on the aryl
ring of ketones. This MCR was also successfully
applied to hetero aromatic ketones such as 2-acetyl
pyridine and 2-acetylthiophene (5r & 5s) which
afforded good yields of the corresponding
products 6r (84%) and 6s (85%).
Figure 1. ORTEP diagram of (E)-4-(4-bromophenyl)-
2-(2-(4-methoxybenzylidene)hydrazinyl)thiazole(4a)
.
Table 5. Synthesis of hydrazinyl-thiazole derivatives
(6a-s) using various ketones, Thiosemicarbazide and 4-
Chlorophenacyl bromide.[a]
Figure 2. Hydrogen bonding pattern of molecule (E)-4-
(4-bromophenyl)-2-(2-(4-methoxybenzylidene)
hydrazinyl)thiazole (4a)
.
Encouraged by these results, we proposed to
extend this MCR for the synthesis of a library of
structurally diverse hydrazinyl-thiazoles (6) from
various ketones (5a-s), thiosemicarbazide (2) and
4-chlorophenacyl bromide (3b). For this purpose,
initially, a reaction was carried out by using
acetophenone (5a), thiosemicarbazide (2) and 4-
chlorophenacyl bromide (3b) in the presence of
CT-4 catalyst (50 mg) in H2O at RT for 2h. It
resulted in a 40 % yield of 6a. The yield of the
product was further increased to 94 % within 10
minutes by increasing the temperature from room
temperature to reflux temperature. To demonstrate
the generality and broad scope of the present
protocol, a variety of ketones were employed
under the optimized reaction conditions (Table 5)
.
A range of functional groups such as electron-
donating (Me, Et, OH and OMe) (5c-5h) and
electron-withdrawing (Cl, Br, F and NO2) (5i-5m)
groups present at different positions on the aryl
ring of ketones provided good to excellent isolated
yields of the corresponding products (6c-6h & 6i-
6m) that ranged from 88 to 96 %. Further, it was
also observed that the presence of 3,4-dimethoxy
(5n) and 2,4-dichloro (5o) substituents on the aryl
ring of ketones gave good isolated yields of the
[a]Reagents and conditions: Aromatic ketones (5a-s
(10.0 mmol), thiosemicarbazide ( ) (10.0 mmol), 2-
bromo-1-(4-chlorophenyl)ethanone (3b) (10.0 mmol),
CT-4 catalyst (50 mg; 1.12 mol-% of Cu) water, RT.
[b]Isolated yield.
)
2
5
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10.1002/adsc.201701063
Advanced Synthesis & Catalysis
The scalability of the optimized procedure was
then studied by the reaction of 4- A plausible mechanism for the one-pot three-
methoxybenzaldehyde (1a), thiosemicarbazide (2) component synthesis of hydrazinyl-thiazoles in the
and 2-bromo-1-(4-bromophenyl)ethanone (3a) in presence of CuONPs/TiO2 as the catalyst is
the presence of CT-4 catalyst in water in different depicted in Scheme
gram scale reactions, 1.0, 5.0, 10.0, 15.0, 20.0 and the activation of
2
. The mechanism begins with
a
carbonyl carbon of
25.0 grams. The yields of product 4a were 98%, aldehyde/ketone by CuONPs on a hydrophilic
98%, 98%, 97%, 97% and 96%, respectively TiO2 surface in water followed by condensation
(Figure. 3). In this investigation, it is found that with NH2 group of thiosemicarbazide to give a
the developed catalytic system is a promising thiosemicarbazone intermediate (I). To investigate
greener alternative for the gram-scale production the reaction mechanism, the obtained intermediate
1
13
of hydrazinyl-thiazoles.
(I) was isolated and confirmed by H & C NMR
and HRMS spectral studies. The NH2-group of
intermediate (I) reacts with the carbonyl carbon of
phenacyl bromide that was activated by
CuONps/TiO2 in the same pot to form diimine (II).
The
obtained
diimine
(II)
undergoes
intramolecular cyclization to give dihydro
hydrazinyl-thiazole (III) via intra molecular SN2
displacement of bromide ion followed by proton
transfer (aromatization) to yield hydrazinyl-
thiazoles (4 & 6).
Figure
3
Gram-scale synthesis of (E)-4-(4-
bromophenyl)-2-(2-(4-methoxybenzylidene)hydrazinyl)
thiazole (4a).
The reusability of the catalyst was also
examined by using the model reaction for the
preparation of 4a from 4-methoxybenzaldehyde
(1a), thiosemicarbazide (2) and 2-bromo-1-(4-
bromophenyl) ethanone (3a) in water. After
completion of the first cycle, the catalyst was
recovered by filtration, dried under vacuum and
was reused in the next cycle. The yields obtained
for product 4a were 98, 98, 98, 97 and 97 % for
first, second, third, fourth and fifth cycles,
respectively (Figure 4). It is noteworthy to
mention that there is no significant loss of catalytic
activity of CuONPs/TiO2 in water up to five
cycles.
Scheme 2. A plausible mechanism for the synthesis of
hydrazinyl-thiazoles (4 & 6) in the presence of
CuONPs/TiO2 in water.
Isolation and characterization of Intermediate
((E)-2-(3-ethoxy-4-droxybenzylidene)
hydrazinecarbothioamide)(I):
A mixture of 3-ethoxy-4-hydroxybenzaldehyde
(1c) (10.0 mmol), thiosemicarbazide (2) (10.0
mmol), 2-bromo-1-(4-bromophenyl)ethanone (3a)
(10.0 mmol) in 25.0 mL H2O was stirred in the
presence of CT-4 catalyst (50 mg) at 25-30 °C for
3-5 min. The progress of the reaction was
monitored by TLC. As per TLC, we noticed that
there was a formation of an intermediate (I) along
with starting materials and product. In order to
identify the reaction pathway, the pure intermediate
was isolated by preparative TLC and it was
characterized by 1H & 13C NMR and HRMS data.
Further, the degradation of the intermediate (I) was
also examined by mass spectral fragmentations
(Figure
5
). The presence of molecular ion 240.0804
Figure 4 Efficiency of a CT-4 catalyst.
6
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10.1002/adsc.201701063
Advanced Synthesis & Catalysis
[M+H]+ C10H14N3O2S of intermediate (
I
) and a
Powder XRD pattern of catalyst was shown in
series of daughter ions i.e., 223.0774 [M+H-OH]+, Figure
6
. The diffraction peaks at 2θ = 25.57,
164.0697[M+H-CH2NS]+ and 149.0835 [M+H- 38.09, 48.30, 54.18, 55.29, 62.99, 69.11 and
CH3N2S]+ in the mass spectrum of intermediate (
70.49° were attributed to the (101), (004), (200),
revealed that the reaction proceeded via a (105), (221), (204), (116) and (220) planes of
I)
thiosemicarbazone intermediate (
I
).
anatase TiO2 (JCPDS 21-1272). The diffraction
peaks at 2θ = 27.71, 36.35, 41.49 and 56.88° were
assigned to the (110), (101), (111) and (220)
planes of rutile TiO2 (JCPDS 21-1276). The XRD
data revealed the presence of highly crystalline
biphasic TiO2. No characteristic peaks owing to
copper species were found in XRD pattern; this
could be ascribed to fine dispersion of CuO
nanoparticles below the detectable limit of X-
rays.[24] FESEM images and EDS analysis of
catalyst showed that the CuO nanoparticles were
distributed on the TiO2 surface (Figures S2 and S3,
Characterization of
(
E)-2-(3-ethoxy-4-
hydroxybenzylidene) hydrazinecarbothioamide:
1
Pale yellow solid; H NMR (500MHz, DMSO-d6):
훿
(ppm) 11.24 (s, 1H, NH), 9.39 (s, 1H, OH), 8.09
(s, 1H, NH), 7.94 (s,1H, NH), 7.92 (s, 1H, H-C=N-
), 7.45 (d, J = 1.5 Hz, 1H, arom H), 7.02 (dd, J =
8.0 Hz, J = 1.5 Hz, 1H, arom H), 6.78 (d, J = 8.0
Hz, 1H, arom H), 4.08 (q, J = 7.0 Hz, 2H, =CH2),
1.34 (t, J = 7.0 Hz, 3H, -CH3). 13C NMR (125
MHz, DMSO-d6):
훿 (ppm) 177.82 (1C), 149.48
(1C), 147.68 (1C), 143.42 (1C), 126.02 (1C),
122.77 (1C), 115.70 (1C), 110.94 (1C), 64.36 (1C),
15.14 (1C). HRMS: m/z calcd for C10H14N3O2S
[M+H]+ 240.0806, found: 240.0804.
see the Supporting Information).
TEM and
HRTEM images further confirmed the particle size
of TiO2 and CuO and dispersion CuO on TiO2 in
CT-4 catalyst (vide infra).
Figure 6. XRD pattern of CT-4 catalyst.
TEM micrograph revealed that the CuO
nanoparticles were randomly dispersed on the
surface of TiO2 (Figure 7a). The particle size of
TiO2 was 40 ± 5 nm (Figure 7a) and CuO was 5 ±
2 nm (Figure 7c). The lattice fringes with d-
spacing values of 0.357 nm and 0.327 nm
confirmed anatase (101) and rutile (110) phases of
TiO2, respectively as shown in high resolution
TEM image (Figure 7b). Further, Figure 7c
provides evidence for CuO nanoparticles dispersed
over a TiO2 support. EDS analysis on various areas
revealed that the presence of copper oxide on TiO2
support as evidenced by the energy bands at 8.01,
8.92 (K lines) and 0.91 keV (L line) (Figure 7d).
Figure
5.
HRMS
of
(E)-2-(3-ethoxy-4-hydroxy
benzylidene)hydrazinecarbothioamide(I).
Characterization of CT-4 catalyst:
The chosen catalyst was characterized by XRD,
FESEM with EDS, TEM with EDS, XPS, AES
and ESR.
7
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10.1002/adsc.201701063
Advanced Synthesis & Catalysis
Further, the elemental composition of catalyst was
determined by EDS analysis (Figure 7d).
Figure 8. XPS spectra of CT-4 catalyst
Figure 7. TEM image (7a) and HRTEM Images
(7b & 7c) and (7d) EDS analysis of CT-4 catalyst.
The CT-4 catalyst surface composition was
determined by XPS. From this study, it was found
that the weight percentages of Ti, O and Cu were
53.95%, 44.63% and 1.42% respectively. The
copper content of 1.42 wt.-% in the catalyst
corresponds to 1.12 mol-% of copper with respect
to the reactants i.e. aldehyde, thiosemicarbazide
and phenacyl bromide. The Ti 2p XPS spectrum of
CT-4 catalyst (Figure 8b) clearly showed two
well-resolved peaks at 458.6 and 464.6 eV. These
were assigned to Ti 2p3/2 and Ti 2p1/2 spin-orbital
components of TiO2, respectively. A peak at 529.9
eV in the O1s XPS spectrum (Figure 8c) was
attributed to O 1s in the CT-4 catalyst. The Cu 2p
XPS spectrum of CT-4 catalyst (Figure 8d) showed
two peaks at 932.8 and 951.8 eV. These were assigned
to Cu 2p3/2 and Cu 2p1/2; However, no corresponding
satellite peaks (941-944 eV) were found. The lower
binding energy values (i.e. slightly higher than that of
Cu2O) and the absence of satellite peaks in the XPS
spectra of Cu 2p might be due to the presence of CuO
in a highly dispersed amorphous state at lower amount
of Cu loadings (1.0-2.6 wt.-% of Cu).[24] From the
above study, it was clear that the copper was present in
the form of Cu(II) in the CT-4 catalyst. Further, the
formation of CuO was also supported by Auger and
ESR spectral analysis. A peak at 917.5 eV in the
Auger spectrum revealed that the presence of Cu(II) in
the CT-4 catalyst This is in good agreement with the
reported data.[25] Finally, the ESR spectrum of the CT-
4 catalyst showed a broad band centered at g = 2.11 [g
(2.11) > ge (2.0036)] without resolved hyperfine
structure (Figure 10). The observed g-value
corresponds to the presence of Cu(II) in an octahedral
geometry.[26]
Figure 9. Auger spectrum of CT-4 catalyst
Figure 10. ESR spectrum of a CT-4 catalyst
Conclusions
A new catalytic system i.e. CuO nanoparticles
dispersed on TiO2 has been developed for the
synthesis of a series of medicinally privileged
hydrazinyl-thiazoles from the reaction of carbonyl
compounds, thiosemicarbazide and α-bromo
8
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10.1002/adsc.201701063
Advanced Synthesis & Catalysis
carbonyl compounds in water via a one-pot multi- 9.66322 GHz), having a 100 kHz field modulation
component reaction. The mechanistic study to obtain a first derivative ESR spectrum. DPPH
revealed that the reaction proceeds via
a
with a g-value of 2.0036 is used for g factor
thiosemicarbazone intermediate formation. The calculations. Thin layer chromatography was
present method has several advantages, such as its performed on 0.25 mm silica gel plates (Merck).
ease of operation, wide substrate scope, clean Millipore double distilled water was used for the
reaction profile, scalability, short reaction times workup process. All phenacyl bromides are
and high yields at ambient conditions. In addition,
all the reactions are performed in water and the
product does not require any chromatographic
purification. The catalyst used at lower amount of
copper loading and could be reutilized for up to
five cycles without significant loss of activity.
Further, the high catalytic performance of
CuONPs/TiO2 might be due to the high dispersity
of the catalyst in water followed by interaction of
organic substrates with CuONPs. The developed
catalyst is superior to other commercially available
heterogeneous copper catalysts and outwardly
operates under heterogeneous conditions.
prepared according to the reported methods.[27]
Preparation of TiO2 supported CuONPs by
molten salt method: A mixture of NaCl (0.5 g)
and TiO2 P-25 (0.5 g) (1:1 ratio) was taken in a
mortar and ground together with a pestle for 10
min. Then the mixed powder was transferred into
a petridish and baked at 150 °C for 12 h. This was
labelled as mixture (i). Another mixture of NaCl
(0.5 g) and different amounts of Cu (NO3)2.3H2O
(to get various amounts i.e. 0.5, 1.0, 1.3, 1.5, 1.7,
2.0 and 2.5 wt.-% of Cu on TiO2) as indicated in
Table 1 was taken in a mortar and ground together
with a pestle for 10 min. This was labelled as
mixture (ii). These two mixtures were then
transferred into an alumina crucible in such a way
Experimental Section
General Material and Methods
as mixture (i) as bottom layer and mixture (ii) as
Aldehydes, ketones, thiosemicarbazide, sodium
chloride and copper nitrate tri-hydrate and solvents
were purchased from Sigma Aldrich, Acros
Organics Ltd., and Merck and were used as
received. Photocatalyst grade titanium dioxide
nanoparticles (TiO2 P-25) composed of anatase
80%, rutile 20%, was procured from Degussa
Corporation, Germany. Melting points were
determined by MR-Vis+ instrument (Labindia)
top layer and calcined at 500 °C for 4 h. Finally,
the calcined powder was washed with distilled
water and dried at 80 °C for 12 h. The obtained
TiO2 supported CuO nanoparticles labelled as
CT-1, CT-2, CT-3, CT-4, CT-5, CT-6, and CT-7.
General procedure for synthesis of Hydrazinyl-
thiazoles (4): A mixture of aldehydes (1) (10.0
mmol), thiosemicarbazide (2) (10.0 mmol),
phenacyl bromides (3) (10.0 mmol) in H2O (25.0
mL) was stirred in the presence of CT-4 catalyst
(50 mg, 1.12 mol-% of Cu) at 25-30°C for 10-15
min. The progress of the reaction was monitored
by TLC. Upon completion of the reaction, the
crude mass was washed with ethyl acetate (25.0
mL) and the catalyst was recovered by filtration
under vacuum. The organic layer was separated,
dried over anhydrous MgSO4 and concentrated
under reduced pressure. The obtained crude
product (4) was purified by recrystallization
(ethanol). The spectroscopic data of the
1
and are uncorrected. The H (500 and 400 MHz)
and 13C (125 and 100 MHz) NMR spectra were
recorded on Bruker NMR spectrometer (500 and
400 MHz). Chemical shifts are reported in (δ)
parts per million and coupling constant(s) (J) in
Hertz. Mass Spectra were recorded on Shimadzu-
LCMS-2010
A
mass spectrometer. High-
Resolution Mass Spectra were recorded on a
Bruker micrOTOF-QII mass spectrometer. XRD
pattern was recorded using a Rigaku Miniflex 600
diffractometer. Field Emission Scanning Electron
Microscopy (FESEM) images were recorded using
Ultra 55 Carl Zeiss instrument with an operating
voltage of 10 kV. Transmission electron
microscopy (TEM) and HRTEM measurements
were carried out by using a JEOL JEM 2100
electron microscope at 200 keV. X-ray
photoelectron spectra and Auger electron spectra
were recorded on Kratos Analytical (AXIS Supra),
UK (SHIMADZU group). ESR spectrum of the
powdered sample was recorded at room
temperature (RT) on Bruker EMX ESR
spectrometer operating at X-band frequencies (ν =
synthesized compounds (4a–4u) are in accordance
with their proposed structures.
General procedure for synthesis of Hydrazinyl-
thiazoles (6): A mixture of ketones (5) (10.0
mmol), thiosemicarbazide (2) (10.0 mmol), 2-
bromo-1-(4-chlorophenyl) ethanone (3b) (10.0
mmol) in H2O (25.0 mL) was stirred in the
presence of CT-4 catalyst (50 mg, 1.12 mol-% of
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701063
Advanced Synthesis & Catalysis
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progress of the reaction was monitored by TLC.
Upon completion of the reaction, the crude mass
was washed with ethyl acetate (25.0 mL) and the
catalyst was recovered by filtration under vacuum.
The organic layer was separated, dried over
anhydrous MgSO4 and concentrated under reduced
pressure. The obtained crude product (6) was
purified by recrystallization (ethanol). The
spectroscopic data of the synthesized compounds
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(E)-4-(4-bromophenyl)-2-(2-(4-
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A
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Acknowledgements
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The authors gratefully acknowledge the Department of Atomic
Energy-Board of Research in Nuclear Sciences (Bhabha Atomic
Research Centre), Mumbai, India for providing the financial
support of this work through a major research project (No.
2011/37C/52/BRNS/2264). The authors are thankful to Prof. M. V.
Shankar, Dept. of MS&NT, YVU for providing catalysts and
scientific discussions. Mr. G T Reddy is thankful to Prof. Samar K.
Das, School of Chemistry and University Grants Commission
Networking Resource Centre (UGC-NRC), School of Chemistry,
University of Hyderabad for providing research fellowship. The
authors also acknowledge the CENTRAL SURFACE
ANALYTICAL FACILITY of IIT BOMBAY for providing the XPS
and Auger spectra. Authors also thank Dr. R.V.J. Kashyap, Dept.
of English, Yogi Vemana University, for critical reading of the
manuscript to ensure linguistic correctness.
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