ZnO nanoparticle-β-cyclodextrin: A recyclable heterogeneous catalyst for the synthesis of 3-aryl-4: H -benzo[1,4]thiazin-2-amine in water

Article abstract of DOI:10.1039/c5nj03273c

A combination of ZnO nanoparticles and β-cyclodextrin was used as an efficient and green catalytic system for the synthesis of 3-aryl-4H-benzo[1,4]thiazin-2-amine via a one-pot, three-component reaction of an o-amino thiophenol, aromatic aldehydes and isocyanides in good to excellent yields at 60 °C in water. The nano size of ZnO was confirmed by transmission electron microscopy (TEM), XRD and UV-visible spectral techniques. A high catalytic activity and easy recovery and reuse for several cycles with consistent activity are additional eco-friendly attributes of this catalytic system.

Full text of DOI:10.1039/c5nj03273c

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ZnO nanoparticle-βcyclodextrin: a recyclable heterogeneous
catalyst for synthesis of 3- aryl-4H-benzo[1,4]thiazin-2-amine in
water
Received 00th January 20xx,
Accepted 00th January 20xx
Hozeyfa Sagira, Rahilaa, Pragati Raia, Prashant Kumar Singhb and I.R.Siddiqui*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Combination of ZnO nanoparticles -β Cyclodextrinwas used as an efficient and green catalytic system for the synthesis of
3- aryl-4H-benzo[1,4]thiazin-2-amine via one-pot, three-component reaction of an o-amino thiophenol , aromatic
aldehyde and isocyanides in good to excellent yields at 60 °C in water.Nano size of ZnO was confirmed by transmission
electron microscopy (TEM), XRD and UV-visible spectral techniques. A high catalytic activity, easy recovery and reuses for
several cycles with consistent activity are additional eco-friendly attributes of this catalytic system.
reaction is often limited in scope due to poor solubility of the
organic precursors. To address this solubility issue, we sought
to utilize β-cyclodextrin (β-CD) a well-known phase transfer
INTRODUCTION
The fusion of two emergent areas of twenty first century,
nanotechnology and green chemistry holds the answer of
environmentally sustainable society1.Catalysts build the main
strategy for innumerable organic reactions via modulation of
energy. Recently, metal or metal oxide nanoparticles find vast
application in catalysis because of their novel properties that
are different from corresponding bulk materials2,3. Nano size
of these materials provides immense surface areas that
translate into an enhanced contact between reactants and
catalyst which maximizes the reaction rates, minimizing the
catalyst in water.11 β-Cyclodextrins is cyclic oligosaccharides
possessing hydrophobic cavities, which by formation of a
reversible complex enhance dissolution properties of poorly
soluble organic molecules12.Moreover being nontoxic, safe,
readily recoverable and reusable β-CD is often very attractive
both from an economic and environmental point of view13.
From the literature we realized that benzo fused heterocycles
possessing a sulfur moiety exhibit a plethora of important
biological activities such as vasodilator,14 anticataract,15
antidiabetic,16 and anti arrhythmic activities17. In particular
benzothiazine find useful applications as calcium channel
blockers,18 5-HT3 antagonists, phosphodiesterase inhibitor,19
anti cataract agents and dopamine D4 inhibitors. Moreover,
some of them have been reported as Na+/H+ exchange
inhibitor,20 coagulation factor Xa21 inhibitors and matrix
metalloproteinase inhibitors22. For these important reasons,
considerable efforts23,24 has been focused on the
development of new methodologies to synthesize this
important ring system. Recently, Nano-MnO2@cellulose–
SO3H catalyzed three component reaction25; Cellulose-SO3H
catalyzed oxidative Ugi-type reaction26 and PTSA27 catalyzed
synthesis are appeared in literature but not without
limitations. The use of toxic and volatile organic solvents,
harmful catalyst, discharge of waste, harsh conditions and
non-recoverability of the catalyst make these procedures of
limited utility and applicability in large scale applications.
Thus there is an urgent need to develop environmentally and
economically more viable procedures for the synthesis of
benzothiazines. As a part of our continuing efforts to
synthesize heterocyclic scaffolds in an environmentally
benign fashion,28 we have applied upbringing nanotechnology
in combination with the phase transfer catalysis for the
amount of the catalyst required4,5
. Moreover, these
nanoparticles (NPs) are generally insoluble in the reaction
mixture, therefore can be separated easily as in the case of
heterogeneous catalysts6. Among various metal oxides, ZnO
NPs have turn out to be very popular in the past few years as
it is non-toxic, less corrosive, recyclable and can be prepared
easily from inexpensive starting materials7. Apart from these
benefits ZnO NPs are environmentally advantageous in the
context of catalyst disposal8 and in the removal of chemical
and biological contaminants thus contributing to the waste
water treatment9. Therefore may be considered as a safer as
well as greener compared to traditionally used catalysts.
Together with catalyst, the design of more environmentally
benign protocols also needs a cautious selection of the
medium and the use of water as the reaction medium
represent the most promising options in the search for
cleaner, cheaper and more efficient technologies for organic
transformations10. However, their implementation in organic
a.Laboratory of Green Synthesis, Department of Chemistry University of
Allahabad, Allahabad-211002, India, E-mail: dr.irsiddiqui@gmail.com
b.Nanotechnology Application Centre, University of Allahabad, Allahabad, India.
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efficient preparation of the desired benzothiazines.
Considering the use of ZnO NPs as an effective catalyst for
nature having diameters ranging from 15 to 25 nm. Fig. 2
clearly shows that the diameters of these spherical
nanoparticles were in agreement with those obtained using
XRD results. Inset of the Fig. 2 shows the representative
selected area electron diffraction (SAED) pattern for
synthesized ZnO samples and showed that the prepared ZnO
NPs were polycrystalline in nature.
various transformations29 herein, we report
a novel
heterogeneous ZnO NP-β-CD green catalytic system under
aqueous condition which makes the synthetic process more
applicable. To the best of our knowledge this type of catalytic
system has not been documented so far for present
transformation.
H
N
Ar
np
ZnO
10 mol %
NH2
R2NC
R1
H2O, 60oC
R1
ArCHO
S
NHR2
SH
CD
4
2
1
3
Scheme 1: Synthesis of 3-aryl-4H-benzo[1,4]thiazin-2-amines
catalyzed by ZnO NP-β-CD catalytic system in water.
RESULT AND DISCUSSION
Preparation and characterization of ZnO NPs
Firstly we prepared ZnO nanoparticles (ZnO NPs) by using the
30
“bottom up”procedure with little modification. To confirm
the formation of nano sized ZnO under aqueous condition a
UV-Vis study was performed which shows excitonic
absorption peak at 361 nm which is blue shifted compared to
bulk ZnO (due to the lower particle size of ZnO) indicate the
formation of desired nanoparticles (Fig. S1 of supplementary
information).
Fig 2: TEM Image of Synthesised ZnO Nanoparticles (inset: SEAD pattern of
ZnO Nanoparticles under study).
No impurities were involved in the freshly prepared ZnO NPs,
which was synthesized by aqueous chemical method
following a well establish protocol using potassium hydroxide
and zinc acetate dihydrate as source material. The entire
process involved the use of deionized water due to its
endogenous advantages. The method was simple, economic,
environmentally friendly and scalable for large scale
synthesis. Furthermore, there is no need to use high pressure
and toxic material for the synthesis of these nanopaticles.
Catalytic application of nanoZnO
The obtained nanoparticles were characterized by X-ray
powder diffraction (Fig. 1). The XRD pattern of the
synthesized nanoparticles showed the presence of broad
peaks at the positions of 31.69°, 34.27°, 36.13°, 47.50°,
56.60°, 62.71°, 67.87° and 79.91°, which are in good
agreement with the standard JCPDS file for ZnO (JCPDS 36–
1451, a=b=3.249 Å, c=5.206 Å) and corresponds to hexagonal
wurtzite structure of ZnO having space group P63mc. All the
available reflections of the XRD phases have been fitted with
Gaussian distribution. The broadening of XRD peaks (i.e.
Scherrer's broadening) attributes nano sized formation of
ZnO. The particle size d of ZnO NP were estimated by Debye–
Scherrer's equation and estimated around ~15 nm in size.
After successful preparation and characterization of the ZnO
NPs we evaluated its effectiveness for synthesis of 3-aryl-4H-
benzo[1,4]thiazin-2-amines. With the aim of developing a
green protocol with almost no waste generation a set of
experiments were performed, employing benzaldehyde (1
mmol), cyclohexyl isocyanide (1 mmol) and o-
aminothiophenol (1 mmol) as a model reactant to optimize
the reaction parameters like temperature, time, solvent as
well as catalyst. Initially, we carried out the reaction in the
absence of catalyst and observed that reaction did not
proceed efficiently and only trace amount of product was
formed even after 12 h (Table 1, Entry 1). This negative result
highlighted the necessity of catalytic assistance for present
transformation. In search of a suitable catalyst for synthesis
of 4a initially we chose BF3 a non-metal Lewis acid catalyst to
promote the reaction. We observed that BF3 displayed poor
activity and yielded just 37% of the product (Table 1, Entry 2).
Then we employed metal Lewis acids such as TiCl4 and InCl3
but no significant improvement in the yield was observed
(Table 1, Entry 3, 4). After screening of Lewis acids we
catalyze the reaction with metal oxides.
Fig 1: Comparative XRD patterns of fresh ZnO nanoparticles(blue line) and
after the fifth catalytic cycle(red line)
Fig. 2 shows the representative TEM image of the prepared
ZnO NPs. The morphology of ZnO was found to be spherical in
2 | J. Name., 2012, 00, 1-3
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In comparison, metal oxide (bulk-ZnO) seemed slightly better
than the Lewis acid (Table 1, Entry 5). Keeping in view of
various inherent advantages of nanocatalyst we turned our
attention towards the use of metal oxide nanoparticle as a
heterogeneous catalyst. Fortunately, among the catalysts
evaluated ZnO nanoparticles was proved to be the superior
and generated the high yield of the desired product 4a (Table
1, Entry 6).The optimal catalyst amount was found to be 10
mol %. The use of lesser amounts of the ZnO-NPs afforded
inferior product yield (Table 1, Entry 9, footnote e). On the
other hand, the use of higher quantities of ZnO did not
provide any significant improvement in the yield (Table 1,
Entries 7 and 8, footnote c, d).
Table 2: Effect of different solvents and β-CD concentration on the yield of the
product 4aa
Entry Solvent
Catalystb
Additive
Time
(min)
50
Yield
(%)c
88
1
H2O
H2O
Nano ZnO
Nano ZnO
Nano ZnO
Nano ZnO
Nano ZnO
Nano ZnO
Nano ZnO
Nano ZnO
β-CD (1mol%)
β-CD (2.5mol%)
β-CD (10 mol%)
CTAB (10 mol%)
TTAB (10 mol%)
β-CD (2.5 mol%)
β-CD (2.5 mol%)
β-CD (2.5 mol%)
2.
3.
4.
5.
6.
7.
8.
40
92
H2O
30
83
H2O
40
86
H2O
50
84
DMSO
DMF
CH3CN
45
88
45
88
40
78
aReaction conditions : benzaldehyde (1 mmol), cyclohexyl isocyanide(1 mmol),
and o-aminothiophenol (1 mmol) at 60oC. b10 mol% catalyst. c Isolated yield.
Table 1: Effect of different catalysts and its concentration on the yield of the product
4aa
Pleasingly, now the reaction was completed in 40 min and the
isolated yield was obtained up to 92%.However, on further
raising the concentration of β-CD (10 mol %) reaction time
was reduced, but the yield of desired product was lower than
the expected yields (Table 2, Entry 3).This is probably due to
the reason that, at very high concentration, product was
inserted into the cavity of β-CD and formed an inclusion
complex which is water-soluble. The reaction was also
screened in different organic solvents as well. It was observed
that variation of solvents did not lead to significant
improvement regarding the yield and reaction time of the
desired compound 4a (Table 2, Entries 6-8).
Entry
Catalystb
Solvent
Time (h)
Yield (%)f
1
-
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
12
5
5
2.
3.
4.
5.
6.
7.
8.
9.
BF3
37
39
41
49
66
66
66
60
TiCl4
6
InCl3
3
Bulk ZnO
Nano ZnO
Nano ZnOc
Nano ZnOd
Nano ZnOe
4
1
1
1
1
aReaction conditions : benzaldehyde (1 mmol), cyclohexyl isocyanide(1 mmol),
ando-aminothiophenol (1 mmol) in water (5 ml) at 60oC.b10 mol% catalyst.c 15
mol% of ZnO(NPs).d 20 mol% ZnO(NPs).e 5 mol% ZnO(NPs).f Isolated yield.
Table 3: Effect of temperature on the yield of the product 4aa
Entry
Catalyst System b
Temp(oC)
Time (min)
Yield (%)c
Next, we screened the effect of the different solvents (Table
2).We started our study with water, because of the solubility
difference of the product from the starting materials water
1
Nano ZnO, β-CD, H2O
Nano ZnO, β-CD, H2O
Nano ZnO, β-CD, H2O
Nano ZnO, β-CD, H2O
15
r.t
40
40
40
40
78
82
92
92
2.
3.
4.
served as
a most suitable solvent for the present
60
transformation, leading to easy separation of product from
the reaction mixture, thus facilitating isolation of solid
product from the reaction mixture. Additionally by
considering the criteria of Green Chemistry, water is a solvent
of choice for this reaction. However under aqueous condition
reaction was not satisfactory possibly due to limited solubility
of the organic reactants in water. To overcome this problem
we sought to utilize β cyclodextrin as an effective phase
transfer catalyst. It is the best option because under aqueous
condition organic reagents which are not soluble in water are
inserted into the cavity of β-cyclodextrin and form a water-
soluble inclusion complex. Although surfactants was also an
efficient phase transfer catalyst and could be a good choice
for this purpose, we discarded it because it is toxic to marine
organisms and very difficult to remove from the reaction
mixture31 (Table 2, Entry 4, 5). Fortunately, result
substantiates our hypothesis and the reaction carried out in
presence of β-cyclodextrin (1mol%) along with ZnO-NP in
water, would not only be faster but would also result in
higher yields as compare to the previous results (Table 2,
Entry 1). With the hope to increase the yield further, we
raised the concentration of β- cyclodextrin from 1 to 2.5 mol
% (Table 2, Entry 2).
reflux
aReaction conditions: benzaldehyde (1 mmol), cyclohexyl isocyanide (1
mmol), and o-aminothiophenol (1 mmol) in water (5 ml).b10 mol%ZnO
and 2.5mol%β-CD.c Isolated yield.
Next, to evaluate the effect of temperature on catalytic
activity of nano ZnO- β-CD system, we performed the model
reaction under diverse range of temperature (Table 3). As
expected when temperature was low catalytic system
showed very poor activity, furnishing the desired product in
low yield (Table 3, Entry 1).However, on further rising the
temperature yield was increased and combination of catalysts
showed outstanding activity, producing the best result
(maximum yield within minimum time) when we carried out
the reaction at 60oC (Table 3, Entry 3). On the other hand,
further rise in temperature did not improve the result to an
appreciable extent (Table 3, Entry 4).
Efficient recovery and reusability of the catalyst is another
important feature of our proposed protocol. After completion
of the reaction catalyst (ZnO) could be recycled easily simply
by washing with ethanol (to remove organic substances)
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Further to explore the potential of this protocol a variety of
structurally diverse o-amino- thiophenol (1), aldehydes ( )and
2
isocyanides (3) were tested under the above optimized
condition. The results are summarized in Table 4.Results
clearly revealed that aldehydes having electron donating and
electron withdrawing functional groups at different position
reacted with varying o-aminothiophenols and isocyanides
smoothly and gave the corresponding product in good to
excellent yield. The products were obtained in pure form
which avoided the complicated purification operations thus
allowing saving of both solvents as well as reagents.
Fig 3: Recyclability of ZnO nanoparticles
On the basis of the above experimental results and the
existing literature report, we propose the plausible
mechanism for the Synthesis of 3-Aryl-4H-benzo[1,4]thiazin-
dried at room temperature and could be reused five
consecutive times with retaining its optimum activity. As
shown in recyclability graph of catalytic efficiency of nano
ZnO the isolated yields were almost similar until the fifth
recycling (Fig 3). Further in order to investigate the stability of
nano ZnO during five consecutive runs, XRD pattern and TEM
micrograph of recovered nano ZnO (after five cycles) was
compared with the fresh sample. As documented in Fig 1 XRD
spectra displayed by recovered catalyst was found to be
almost similar to the fresh one. Furthermore TEM micrograph
of recovered nano ZnO (Fig 4) also shows almost same
morphology and size as freshly prepared ZnO nanoparticles.
2-amine
with the formation of intermediate
aminothiophenol catalyzed by ZnO-NPs. Now the resulting
intermediate was further activated by ZnO-NPs, favouring
the nucleophilic attack of isocyanide to afford the
intermediate which subsequently undergoes
intramolecular trapping by the sulfur nucleophile to yield the
desired product in excellent yield. Compounds and its
4
as shown in Scheme 2. The reaction commences
5
from aldehyde and o-
5
6,
4
4
derivatives are stable solids whose structures were properly
1
confirmed by their spectroscopic (IR, H NMR, 13C NMR and
MS) data and by elemental analysis.
OH
O
O
HO
O
OH
HO
OH
O
Zno
OH
Zno
HO
O
HO
Ar
O
H
N
C
H
Ar
H
R1
OH
R1
3
NH2
O
CH
O
SH
5
2
N
SH
1
OH
O
R2
Hydrophobic
Cavity
Zno
HO
H
N
OH
R1
H
Ar
Fig 4: TEM micrograph of recovered ZnO nanoparticles ( inset: SEAD
pattern of recovered ZnO)
Ar
N
R1
OH
R2
O
S
4
N
H
SH
N
OH
6
Table 4: Scope of substrate for the synthesis of compound 4(a-j)a
R2
H
N
H
[1,3 H] Shift
Ar
N
OH
R1
R2
S
OH
O
Entry
1.
R1
H
R2
Ar
Product
4a
Yield(%)a
92
O
OH
O
7
OH
O
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
t-Bu
Ph
OH
2.
H
4-ClC6H4
4-MeOC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
4-OHC6H4
Ph
4b
4c
93
HO
5.
H
91
O
4.
H
4d
4e
92
OH
5.
H
91
6.
H
4f
89
Scheme 2: Plausible mechanistic pathway for the synthesis of 3-aryl-
4H-benzo[1,4]thiazin-2 amine
7.
H
c-Hex
t-Bu
4g
88
8.
H
4h
4i
89
Finally, to access the “greenness” of our proposed method
with respect to other reported methods for synthesis of
functionalized tetrahydropyridines, a comparison chart is
presented in Table 5.
9.
H
t-Bu
4-O2NC6H4
Ph
93
10.
Me
c-Hex
4j
89
aReaction conditions : aromatic aldehyde (1 mmol), isocynide (1 mmol) and o-
aminothiophenol (1 mmol) in water (5 ml) at 60oC in presence of 10 mol% ZnO
NP and 2.5mol% β-CD.b Isolated yield.
4 | J. Name., 2012, 00, 1-3
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6
7
(a) A. Hu, G. T. Yee, W. B. Lin, J. Am. Chem. Soc., 2005,
127,12486; (b) R. Luque, B. Baruwatiand R. S. Varma, Green.
Chem., 2010, 12, 1540.
(a) G.B. D. Rao, M.P. Kaushik A.K. Halve, Tetrahedron
Lette.,2012, 53, 2741; (b) P. Bhattacharyya, K. Pradhan, S.
Paul, A.R. Das, Tetrahedron Lette., 2012, 53, 4687;(c)P. P.
Ghosh, A.R. Das, J. Org. Chem., 2013, 78, 6170.
Table 5: Comparison of our results (Entry 7) with some previously reported
methods.
Entry Catalyst
Solvent
EtOH
TempoC
Reflux
r.t.
Time
5 h
Yield
88%
81%
1.
2.
PTSA(0.05 g)27a
Cellulose-SO3H(0.1
g)26
EtOH
48 h
8
9
F M. Moghaddam, H. Saeidian, Z. Mirjafary and A. Sadeghi,
J. Iran Chem. Soc.2009,6,317.
3.
Nano-MnO2
EtOH
r.t.
48 h
76%
@cellulose –SO3H
or nano-MnO2@
wool–SO3H (0.10
g)25
N.C. Mueller and B. Nowack, “Nanotechnology
Developments for the Environment Sector”. Report of the
Observatory NANO. 2009; (b) S.D. Mamadou and N. Savage,
“Nanoparticles and water quality”. J. Nano. Res.2005, 7,
325.
4.
5.
6.
TEMPO (1.0 eq)27b
DMF
130oC
reflux
12 h
10 h
80%
75%
64%
10 (a) S. K. Rout, S. Guin, J. Nath and B. K. Patel, Green Chem.,
2012, 14, 2491;(b)C.-J. Li and L. Chen, Chem. Soc. Rev.,
2006,35, 68; (c)A. Chanda and V. V. Fokin, Chem. Rev.,
2009,109, 725.
TFA/AcOH27c
CH3CN
Cs2CO3(2 equi),CuI
(20 mol %), 1,10
phenanthro -line
(20 mol %),27d
THF/water, microwave 1 h
v/v = 95:5
irradiation
at 100 °C.
11 T. Ge,C.Zou, and C.Zuo, Ind. Eng. Chem. Res. 2015, 54
,
1723.(b)A. R.Kiasat, S. Sayyahi, Catal. Commun. 2010, 11
484.
,
7.
Nano ZnO, β-CD
H2O
60oC
40min
92%
12 J.A. Shin, Y. G. Lim, and K. H. Lee,J. Org. Chem. 2012, 77
4117.
,
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CONCLUSION
In conclusion a highly efficient and environmentally green
methodology has been developed for synthesis of
functionalized 3-Aryl-4H-benzo[1,4]thiazin-2-amine using an
inexpensive and recoverable nano ZnO-β-CD catalytic system
under aqueous condition, which to the best of our knowledge
has no precedents. This reaction system reveals several
advantages such as novelty, mild reaction conditions, high
atom efficiency, clean reaction profiles, easy workup
procedure and environmental friendliness. Moreover
avoidance of hazardous organic solvent during entire
procedure (synthesis, catalyst preparation and column
chromatography) makes it useful and attractive method for
the synthesis of these important compounds.
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Acknowledgements
We gratefully acknowledge the financial support from
University Grant Commission and Council of Scientific and
Industrial Research. Authors also acknowledge the SAIF,
Punjab University, Chandigarh, for providing all the
spectroscopic data and Nanotechnology Application Centre,
University of Allahabad for powder XRD and UV−vis spectra.
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Graphical Abstract
ZnO nanoparticleꢀβcyclodextrin: a recyclable heterogeneous catalyst for
synthesis of 3ꢀ arylꢀ4Hꢀbenzo[1,4]thiazinꢀ2ꢀamine in water
Hozeyfa Sagira, Pragati Raia, Rahilaa, Prashant Kumar Singhb and I.R.Siddiqui*a
OH
O
O
HO
O
OH
HO
OH
O
OH
HO
HO
O
H
N
OH
Ar
O
R2NC
O
NH2
SH
R1
R1
2
ZnO np -
OH
O
OH
HO
beta-Cyclodextrin
S
NHR2
OH
ArCHO
4
1
O
OH
3
H2O,60oC
OH
OH
O
O
OH
O
OHO
OH
HO
O
OH
Hydrophobic
cavity
Environmentally benign and economic protocol has been developed for one-pot synthesis of 3-
aryl-4H-benzo[1,4]thiazin-2-amine in water.