C[sbnd]N bond formation in alicyclic and heterocyclic compounds by amine-modified nanoclay

Article abstract of DOI:10.1016/j.molstruc.2017.05.004

In the current protocol, amine functionalized montmorillonite K10 nanoclay (NH₂-MMT) was applied to catalyze the formation of C[sbnd]N bonds in the synthesis of azines and 2-aminothiazoles at room temperature. In comparison with the current methods of C[sbnd]N bond formation, this approach displays specific advantages include atom economy, clean conversion, design for energy efficiency, the use of nontoxic and heterogeneous catalyst, higher purity and yields, safer solvent and reagents for this organic transformation.

Full text of DOI:10.1016/j.molstruc.2017.05.004

Accepted Manuscript
C–N bond formation in alicyclic and heterocyclic compounds by amine-modified
nanoclay
Zohre Zarnegar, Roghayeh Alizadeh, Majid Ahmadzadeh, Javad Safari
PII:
S0022-2860(17)30586-0
10.1016/j.molstruc.2017.05.004
MOLSTR 23745
DOI:
Reference:
To appear in:
Journal of Molecular Structure
Received Date:
Accepted Date:
26 March 2017
02 May 2017
Please cite this article as: Zohre Zarnegar, Roghayeh Alizadeh, Majid Ahmadzadeh, Javad Safari,
C–N bond formation in alicyclic and heterocyclic compounds by amine-modified nanoclay, Journal
of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.05.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form.
Please note that during the production process errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
C–N bond formation in alicyclic and heterocyclic compounds by amine-
modified nanoclay
Javad Safari, Zohre Zarnegar, Roghayeh Alizadeh, Majid Ahmadzadeh
The NH2-MMT as a green nanocatalyst was used for the C–N bond formation in the synthesis of
azines and 2-aminothiazoles in accordance with the principles of green chemistry.
GREEN METHOD
GREEN METHOD
GREEN NANOCATALYST
R1
R1
R2
2
R
N
N
N
2
NH2
S
R
R1
C=N
Azines
2-Aminothiazoles

ACCEPTED MANUSCRIPT
Highlights
 NH2-MMT nanoclayas an excellent catalytic system in organic reaction.
 Introducing NH2-MMT for the synthesis of azine and 2-aminothiazole derivatives.
 Transition-metal-free C–N bond formation at room temperature.
 The method conforms to several of the guiding principles of green chemistry.

ACCEPTED MANUSCRIPT
C–N bond formation in alicyclic and heterocyclic compounds by amine-
modified nanoclay
Zohre Zarnegar,٭ Roghayeh Alizadeh, Majid Ahmadzadeh, Javad Safari
Laboratory of Organic Compound Research, Department of Organic Chemistry, College of Chemistry,
University of Kashan, P.O. Box: 87317-51167, Kashan, I.R., Iran
Abstract
In the current protocol, amine functionalized montmorillonite K10 nanoclay (NH2-MMT) was
applied to catalyze the formation of C–N bonds in the synthesis of azines and 2-aminothiazoles
at room temperature. In comparison with the current methods of C–N bond formation, this
approach displays specific advantages include atom economy, clean conversion, design for
energy efficiency, the use of nontoxic and heterogeneous catalyst, higher purity and yields, safer
solvent and reagents for this organic transformation.
Keywords: Montmorillonite, Clay, Azines, C–N bonds, 2-aminothiazole.
1. Introduction
The developments of carbon–heteroatom bonds formation reactions, especially C–N bonds, are
extremely important in the chemical sciences because of their abundance in various biologically
active natural products and medicinally important compounds [1]. Alicyclic azines and 2-
aminothiazole heterocycles with the C–N bonds in their structure have attracted great attention for
various chemical and biological applications [1.2].
Azine derivatives have been suggested for several pharmacological applications [3] and
extensively used in polymerization [4], bond formation reaction [5], in the generation of
٭Corresponding author. E-mail addresses: z_zarnegar@yahoo.com, Tel: +98 31 5591 2320; Fax: +98 31
5591 2397.
1

ACCEPTED MANUSCRIPT
conducting materials [6], in the design of liquid crystal [7] and the synthesis of heterocyclic
systems [8]. Although, azines are well-known organic compound ever since 19th century but only
a limited number of synthetic approaches is applied for their preparation [9-12]. Some of the
synthetic methods suffer from disadvantages such as low yields of products, large amounts of
catalyst, a large excess of one of the reagents, byproduct formation, high temperatures, long
reaction time, several hours reactions, and difficult operating conditions.
On the other hands, 2-aminothiazole and its derivatives, as a significant class of heterocycles
possessing a C–N bond, have attracted wide attention in medicinal chemistry due to their broad
spectrums of pharmacological and biological activities. Therefore, in recent times, many efforts
have been made for the preparation of this class of heterocycles [13-15]. Although these methods
reported by others find certain merits of their own, some of these protocols have specific
drawbacks, including high reaction temperatures, the use of expensive or toxic catalysts, reagents
in stoichiometric amounts, harsh reaction conditions, tedious workup, low yields and high
catalytic loading [15,16].
However, to overcome the above mentioned problem and the development of a greener and
milder approach for the preparation of azines and 2-aminothiazoles, we decided to design a new
process for the C–N bond formation in alicyclic and heterocyclic compounds in the presence of
the heterogeneous acid–base combination catalytic system.
The use of montmorillonite-K10 (MMT-K10) has received considerable attention as catalyst or
catalyst support in organic transformations due to its high chemical and thermal stability [17].
MMT as layered alumina silicate is clay that consists of two tetrahedral silicate layers with a
central alumina or magnesia octahedral sheet. The organo-modified MMT widely used in the
catalytic systems because of its ability to reusability, its high surface reactivity, its cheap and
2

ACCEPTED MANUSCRIPT
nonhazardous, and its high surface area [18-20]. In this regard, several studies have been
reported using immobilized amine-modified MMT (NH2-MMT) as catalysts for many organic
reactions such as Ullmann reaction [21], Henry reaction [22], Knoevenagel condensation [23],
C–S coupling reactions [24], the synthesis of organic heterocycles [25], and carbonylative
Sonogashira reaction [26].
There for, in this investigation, we report NH2-MMT as an easily separable, eco-friendly and
highly effective catalyst with acid–base properties for the synthesis of azines and 2-
aminothiazoles in excellent yield under mild condition (scheme 1 and 2).
R1
2
O
R
NH2-MMT
N
R2
N
N2H6.SO4
+
2
R1
2
grinding, solvent-free
R
R1
R1= H, CH3
R2= H, Alkyl
Scheme 1. Synthesis of azines using NH2-MMT.
R1
R2
S
O
NH2-MMT, NIS
N
R2
+
R1
H2N
NH2
r.t. , EtOH
NH2
S
R1
H, R, Ar
R 2
=
H, COR, COOR
=
Scheme 2. Synthesis of 2-aminothiazole using NH2-MMT.
2. Experimental
2.1. Chemicals and apparatus
All chemicals were purchased from the Merck, Aldrich and Sigma Chemical Companies.
Melting points were determined on an Electrothermal MK3 apparatus using an open-glass
capillary and are uncorrected. 1H NMR and 13C NMR spectra were recorded with a Bruker DRX-
3

ACCEPTED MANUSCRIPT
400 spectrometer at 400 and 100 MHz respectively. FT-IR spectra were obtained with KBr
pellets in the range 400-4000 cm-1 with a Perkin-Elmer 550 spectrometer. Nanostructures were
characterized using a Holland Philips Xpert X-ray diffraction (XRD) diffractometer (CuK,
radiation, λ= 0.154056 nm), at a scanning speed of 2°/min from 10° to 100° (2θ). The surface
morphology of chitosan based material was analyzed by field emission scanning electron
microscopy (SEM) (EVO LS 10, Zeiss, Carl Zeiss, Germany).
2.2. Synthesis of NH2-MMT nanoclay
The process for the amino-modification of MMT was performed in the following manner. 0.5 g
MMT was added to a 15 ml solution of 3-aminopropyltrimethoxysilane (APTMS) (1.2 mmol)
using n-hexane, and the suspension was stirred at room temperature for 2 h. Next, the prepared
NH2-MMT were filtered and washed three times with ethanol and n-hexane followed by drying
under vacuum at temperature of 50 ◦C [18].
2.3. General procedure for the synthesis of azines
In a solvent-free grinding procedure, a mixture of the ketone or aldehyde (1 mmol), hydrazine
sulfate (0.5 mmol), and NH2-MMT nanocatalyst (0.2 g) was thoroughly mixed in a mortar at
room temperature till the completion of catalytic process as indicated by TLC (ethyl
acetate/petroleum ether 3:7) for 1-8 min. Then, ethyl acetate was added to the resultant material
and the heterogeneous NH2-MMT was separated by filtration. The solvent was evaporated under
reduced pressure, and solid product was washed with water to remove any unreacted hydrazine
sulfate. The product was purified by recrystallization from ethanol.
2.4. General procedure for the synthesis of 2-aminothiazoles
4

ACCEPTED MANUSCRIPT
A mixture of methylcarbonyl (2 mmol), thiourea (3 mmol), NIS (2 mmol), and NH2-MMT (0.10
g) in EtOH (5 mL) at room temperature was stirred until completion of reaction. The progress of
the reaction was monitored by TLC (petroleum ether–ethyl acetate 4:1). After completion of the
reaction, the NH2-MMT was separated by filtration. After evaporation of EtOH under vacuum,
the crude product was dissolved in boiling water and adjusted to pH=8 with the amount of
ammonia to give the solid products. The solid obtained was recrystallized from a mixture of
ethanol-water.
3. Results and discussion
3.1. Characterization of catalyst
The grafting of MMT with organic moieties containing amine was performed with APTES via
silanization procedure (scheme 3) and was characterized by X-ray diffraction (XRD), energy-
dispersive analysis of X-ray (EDAX), scanning electron microscopy (SEM), and fourier
transform infrared spectroscopy (FT-IR). NH2-MMT has been used as nanocatalyst for the
synthesis of symmetrical azine derivatives.
OH
O
Si
Si
NH2
NH2
OEt
EtO Si
O
n-hexane
r.t., 2h
MMT OH
NH2
MMT
O
+
OEt
O
OH
NH2
O
Si
NH2-MMT
Scheme 3: Preparation of NH2-MMT nanocatalyst.
SEM images of MMT and NH2-MMT are shown in Fig. 1. The neat MMT possesses a layered
morphology consisting of broken plates. It is clear that layered structure of MMT after
modification is similar to that of the parent nanoclay.
5

ACCEPTED MANUSCRIPT
(b)
(a)
(c)
(d)
Fig. 1. SEM images of (a) and (b) MMT nanoclay; (c) and (d) NH2-MMT.
The EDAX of the NH2-MMT are shown in Fig. 2. It can be obviously seen that the NH2-MMT
contained main elements O (54.50 W%), Si (30.77 W%), Al (6.41 W%), and N (4.96 W%).
These results indicate that organosilane was successfully grafted on the MMT.
6

ACCEPTED MANUSCRIPT
4000
3500
3000
2500
2000
1500
1000
500
Si
O
Al
Cu
Mg
FeNa
S
S
N
K
Fe
K
Fe
Cu
Cu
keV
0
0
5
10
Fig. 2. The EDAS spectrum of NH2-MMT.
In Fig. 3, the XRD pattern of unmodified MMT and NH2-MMT showed that the diffraction
peaks of MMT were observed at 2θ = 12.25, 20.94, 35.06, and 61.89 which are assigned to the
diffractions of the (002), (110, 220), (200, 130), and (060, 330) reflections, respectively [18]
Furthermore, the similarity in the XRD pattern of the two samples suggests the clay structure in
the MMT matrix is retained after modification.
(b)
(a)
Fig. 3. XRD patterns of (a) MMT and (b) NH2-MMT.
7

ACCEPTED MANUSCRIPT
The TGA results of the nanoclays are presented in Fig. 4. As can be seen, the thermogram of
NH2-MMT exhibit significant weight loss at the temperature ranges 50–200 and 200–750 °C.
The weight loss below 200 °C is usually interpreted as the loss of adsorbed water. The other
losses of weight between 200 and 750 ºC (about 12%) are corresponding to the thermal
decomposition of organic components in nanoclay [18].
Fig. 4. TGA curves of pure MMT and silane functionalized NH2-MMT
Fig. 5 shows the FT-IR spectrum of aminated nanoclay. The absorbance bands at 3627 and 1043
cm−1 are related to Al–O–H and O–Si stretching vibration, respectively. The absorption peak at
3434 cm−1 correspond to the NH2 groups stretching mode and a weak peak at 2928 cm−1 is
attributed to the –CH stretching vibration. Moreover, the absorption peaks at 571 and 468 cm−1 is
assigned for the Al-O and Mg-O stretching vibration respectively [18].
8

ACCEPTED MANUSCRIPT
(b)
(a)
Fig. 5. FT-IR spectra of (a) MMT and (b) NH2-MMT.
2.3. Catalytic performance of NH2-MMT in the synthesis of azines
Recently, Dar and et.al reported the grinding-induced approach for the preparation of α-
aminophosphonates using aluminium pillared interlayered clay under solvent free conditions
[17b]. The salient advantages of their research include operational simplicity, greater selectivity,
high yields and clean reaction conditions. Therefore, we studied the efficacy of the NH2-MMT
nanocatalyst on the synthesis of azines by grinding technique. To optimize the reaction
conditions, the reaction of benzaldehyde (2 mmol) and hydrazine sulfate (1 mmol) was used as a
model reaction. First, we investigated the catalytic effect of NH2-MMT and MMT nanoclay in
the synthesis of the azine compounds under grinding method at room temperature and under
reflux condition in EtOH as solvent. As Table 1 shows, NH2-MMT exhibited the highest
catalytic activity as compared with MMT in terms of reaction times and product yield. This may
be due to the base and acid sites in amine functionalized acidified MMT. Meanwhile, pure MMT
acts as a Lewis acid in this process. Another significant observation is that the solvent-free
grinding process is more successful considering time and yield than reflux condition in EtOH
(Table 1, entry 2 and 3). In order to study the effect of quantity of catalyst on the model reaction,
9

ACCEPTED MANUSCRIPT
we carried out the reaction using 0.1, 0.15, 0.20 and 0.25 g of NH2-MMT nanoclay and found
that the optimal NH2-MMT concentration was 0.20 g in this process (Table 1, entry 5). To
demonstrate the efficiency of the chosen nanocatalyst, we carried out a blank reaction (without
catalyst) under solvent-free grinding using amine functionalized catalyst (Table 1, entry 1).
However, we are getting better results using the heterogeneous catalytic system for a shorter
period of time and further increase the yields of products. So we have developed a one-pot
procedure using stable and inexpensive nanocatalyst in a extremely simple, facile, and clean
solvent-free rapid protocol at room temperature, with excellent yields.
Table 1. Optimization of the reaction conditions for the synthesis of azines.a
Time (min)/ Yieldb (%)
Time (min)/Yieldb (%)
Reflux condition
Entry
Catalyst (g)
Solvent-free grinding
1
2
3
4
5
6
-
15
90
90
92
90
25
20
15
15
10
10
70
70
85
80
90
90
MMT (0.15)
5
NH2-MMT (0.15)
NH2-MMT (0.10)
NH2-MMT (0.20)
NH2-MMT (0.25)
2.5
3
2
94
94
2
a benzaldehyde (2 mmol), hydrazine sulfate (1 mmol)
bIsolated yield of the pure compound.
After optimizing the reaction conditions, in order to explore the scope and generality of this
method, various aldehydes and ketones were used for the synthesis of azines. The results are
shown in Tables 2. These results show that aromatic aldehydes (ketones) with electron-
withdrawing group such as 4-Cl afforded the target products in high yields and purity in short
time. Aromatic aldehydes with an electron-donating group such as N(Me)2 reacted sluggishly,
which required comparatively longer reaction time with low yield. The activity of aldehydes is
higher than ketones, because an aldehyde is less sterically. The position of substituent in the
10

ACCEPTED MANUSCRIPT
benzene rings of aldehyde (ketone) influences this reaction. The activity of o-aldehyde is higher
than p- and m-benzaldehyde.
Table 2. Synthesis of azine derivatives using NH2-MMT.a
Entry
Time (min) Yieldb (%) m.p (°C) m.p. (°C) [Rep]
aldehyde/ketone
Product
4a
1
2
benzaldehyde
2
2
2
6
8
8
1
2
7
5
8
94
96
96
9/
93-94
92-93 [30]
4-chlorobenzaldehyde
2-hydroxybenzaldehyde
4-methylbenzaldehyde
4-dimethylamino benzaldehyde
4-methoxybenzaldehyde
2-fluorobenzaldehyde
4b
210-213 213 [31]
213-214 216 [32]
159-108 159-161 [32]
214-215 215 [33]
169-170 171 [34]
134-135 132 [35]
214-217 213 [35]
214-217 133-134 [36]
197-199 196-198 [36]
223-224 223-224 [12]
3
4c
4
4d
5
4e
85
85
98
95
87
82
80
6
4f
7
4g
8
2,4-dichlorobenzaldehyde
4-chloroacetophenone
2-hydroxyacetophenone
4-hydroxyacetophenone
4h
9
4i
10
4j
11
4k
a
aldehyde (2 mmol), hydrazine sulfate (1 mmol), and NH2-MMT (0.20 g) under grinding condition at room
temperature.
bIsolated yield of the pure compound.
In scheme 4, a plausible mechanistic pathway is proposed to illustrate the synthesis of azine
derivatives catalyzed by NH2-MMT. As the first step, the NH2-MMT as base catalyst helps to
generate the hydrazine from hydrazonium sulfate. Then, the reaction proceeds via the
intermediate (I), which is formed by the activation of aldehyde carbonyl group by the MMT as
acid catalyst, which facilitates the nucleophilic attack of hydrazine to promote the formation of
C–N bond to yield intermediate (II). The subsequent elimination of water molecule from
intermediate (II) enhanced by catalyst NH2-MMT eventually yield compound (III) followed by
regeneration of the solid acid-base nanocatalyst. The repetition of catalytic loop for compound
(I) with another aldehyde finally ends up with target azine products.
11

ACCEPTED MANUSCRIPT
H
O
N
Ar
Ar
Ar
N
H
H
NH2-MMT
N-NH2
H
O
NH2-MMT
(III)
Ar
Ar
H
-H2O
NH2-MMT
NH2-MMT
N2H6.SO4
+
OH
H
(II)
O
(I)
H
NH-NH2
Ar
Ar
MMT-NH2
+
..
O
-
NH3-MMT
HSO
NH2-NH2
+
+
4
+
Ar
H
NH3-MMT
..
NH2-NH2
Scheme 4. Plausible mechanistic pathway for the synthesis of target azine derivatives.
This heterogeneous synthetic method is more useful than the protocols published till date,
because it has many advantages, such as decreased byproduct formation or without requirement
to separate the hydrazone intermediate, reduced pollution, lower cost, and simplicity in
processing, which are beneficial to the industry as well as to the environment.
3.3. Catalytic performance of NH2-MMT in the synthesis of 2-aminothiazoles
The excellent catalytic efficiency of NH2-MMT in the preparation of azine derivatives motivated
us to explore their efficacy for the synthesis of 2-aminothiazole heterocycles. Recently, an
efficient method for the synthesis of 2-aminothiazole from thiourea and methylcarbonyls using I2
in the presence MMT-K10 as a catalyst was developed by our research group.16 But the usage of
I2 as a iodinating agent, DMSO as solvent and high reaction temperature were still unavoidable
in this process. To the best of our knowledge, there is no effective methodology for the synthesis
of 2-aminothiazole at room temperature. In this research, we present our studies toward the
conversion of iodomethylcarbonyls, which are easily obtained from methylcarbonyls, to the
12

ACCEPTED MANUSCRIPT
corresponding 2-aminothiazoles in good to excellent yields using N-Iodosuccinimide (NIS) as a
halogenating reagent in the presence of NH2-MMT as catalyst. We found that NH2-MMT
provided excellent yields of 2-aminothiazoles by the one-pot of acetophenone, thiourea, and
iodine as a model reaction. The results for the optimization of reaction conditions for the
synthesis of 2-aminothiazoles are presented in Table 3. The optimized yield was obtained in
ethanol medium using 0.1 g NH2-MMT (entry 3, Table 3) at room temperature. The reaction
without nanocatalyst did not provide satisfactory results under the same conditions (entry 1,
Table 3). Althogh, I2 was an efficient iodination agent for this reaction, but it is a hazardous and
toxic reagent and remove it is difficult from the reaction medium.
N-halosuccinimide reagents such as N-bromosuccinimide (NBS) and NIS have some specific
features that determine their broad application in organic transformations and the halogenation of
arenes and heteroarenes under mild conditions. NIS is an iodinating agent that is used for various
electrophilic iodinations and as source for iodine in radical reactions. In next experiment, the
same reaction was carried out with different iodinating agents in the presence of the same
quantity of the NH2-MMT (entreis 15-23, Table 3). Based on these results, the yield increased
with the addition of I2 and NIS. Therefore, NIS is as an efficient and greener iodinating reagent
than others (entry 15, Table 3).
Table 3. Optimization of reaction conditions for the synthesis of 2-aminothiazole using NH2-MMT as a
catalyst.a
Entry
Catalyst (g)
Solvent
EtOH
EtOH
EtOH
EtOH
Reagent
Yieldb (%)
1
2
3
4
-
I2
I2
I2
I2
30
75
97
97
0.05
0.10
0.15
13

ACCEPTED MANUSCRIPT
5
0.20
0.30
EtOH
EtOH
H2O
I2
95
90
65
98
50
85
70
50
10
50
97
75
40
40
50
50
50
20
20
6
I2
7
0.10
I2
8
0.10
DMSO
THF
I2
9
0.10
I2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
0.10
CH3CN
MeOH
EtOAc
CCl4
I2
0.10
I2
0.10
I2
I2
0.10
0.10 (MMT)
0.10
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
I2
NIS
0.10
HI
0.10
NaI
0.10
KI
0.10
KIO3
KIO4
NaIO4
HgI2
CH3(CH2)3NI
0.10
0.10
0.10
0.10
a Reaction conditions: acetophenone (2 mmol), thiourea (3 mmol), and solvent (5 ML) at room temperature for 1h.
bIsolated yield of the pure compound.
Using optimized one-pot reaction conditions, several 2-aminothiazole derivatives were prepared
and the results are given in Table 4. It is clear from results that various methylketones are
suitable for this transformation. In the case of aliphatic substrates and aromatic were obtained in
good to high yields. The results showed that 2-hydroxy acetophenone has the lowest
performance than other methylcarbonyls due to the steric hindrance and the electron donating of
hydroxyl group (–OH).
Table 4. Synthesis of 2-aminothiazole derivatives in the presence of NH2-MMT.a
Entry
ketone
Acetaldehyde
Acetone
Product Time (h)
Yieldb (%)
m.p (°C)
90-92
m.p. (°C) [Rep]
89-90 [15a]
1
2
3a
1
1
90
90
46-48
45-46 [15a]
14

ACCEPTED MANUSCRIPT
3
4
Acetophenone
4-Cl-acetophenone
4-Br-acetophenone
4-OH-acetophenone
2-OH-acetophenone
3-Me-acetophenone
Ethyl acetoacetate
Methyl acetoacetate
Allyl acetoacetate
Acetylacetone
3b
3c
3d
1
1
97
151-153
160-162
180-182
197-200
138-139
85-88
151-153 [15a]
161-162 [15a]
180-183 [15a]
198-200 [15a]
138-139 [15a]
88-91 [15a]
98
98
80
5
1
6
1.5
2.5
1
7
60
93
8
3e
3g
3h
3i
9
1.5
1.5
2
95
92
90
92
98
177-179
224-226
148-150
219-220
277-280
177-179 [15a]
225-226 [15a]
148-149 [15a]
219-220 [15a]
272 [34]
10
11
12
13
3j
2
Morpholinoacetone
1
a
Reaction conditions: methylcarbonyl (2 mmol), thiourea (3 mmol), NIS (2 mmol), and NH2-MMT (0.10 g) in
EtOH at room temperature.
bIsolated yield of the pure compound.
A plausible mechanism for the production of 2-aminothiazoles is presented in scheme 5. In the
first step, the acetophenone undergoes the formation of enolate ion under basic conditions using
NH2-MMT as a basic organocatalyst, and enolate converts to α-iodoacetophenone in the
presence of NIS. Also, thiourea is converted to enol under basic conditions and react with the
iodinated acetophenone for the synthesis of intermediate I. Next, the dehydration of I followed
by the neutralization of H gives the desired [15a].
15

ACCEPTED MANUSCRIPT
O
O
NH2-MMT
CH2
O
O
+
MMT-NH
3I
CH2I
+
CH2
+
O
O
S
O
N
O
N
I
H
S
S
NH2-MMT
H2N
NH2
H2N
NH
H2N
NH
NH2-MMT
NH2
H.N.
O
O
S
S
I
CH2
+
H2N
NH
HI
-
H O
-
2
(I)
NH3
N
N
NH I
-
4
S
NH2.HI
S
NH2
Scheme 5. Proposed mechanism for the synthesis of 2-aminothiazoles using NH2-MMT.
Thus, two present methods for C–N bond formation by NH2-MMT fulfilled the criteria for green
synthesis including: (i) this is transition-metal-free C–N bond formation;(ii) it proceeds faster
and gives excellent yields at room temperature; (ii) it requires a heterogenization of
homogeneous organocatalyst based on MMT clay as a green and eco-friendly nanocatalyst; (iv)
it is applicable to a wide range of chemical transformation; (v) the reactions were performed in
non-hazardous solvents (EtOH or grinding), non-toxic catalyst and reagent (NIS).
4. Conclusions
In the current study, we have demonstrated a simple, green, and a cost effective one-pot
procedure for the synthesis of azines and 2-aminothiazoles in excellent yields at room
temperature using an eco-friendly, nontoxic, inexpensive, and chemically highly stable
16

ACCEPTED MANUSCRIPT
nanocatalyst. The noteworthy advantages of this method are simplicity of performance, easier
work-up procedure, short reaction times and high yields of the products.
Acknowledgments
We gratefully acknowledge the financial support from the Research Council of the University of
Kashan for supporting this work by Grant (No. 256722/18).
References
[1] J. Bariwal, E. Van der Eycken, Chem. Soc. Rev. 42 (2013) 9283-9303.
[2] Q. Wang, Y. Su, L. Lia, H. Huang, Chem. Soc. Rev. 45 (2016) 1257-1272.
[3] C. Liang, J. Xia, D. Lei, X. Li, Q. Yao, J. Gao, Eur.J. Med. Chem. 74 (2013) 742-750.
[4] A. Hashidzume, A. Tsuchiya, Y. Morishima, M. Kamachi, Macromalecules 33 (2000) 2397-
2402.
[5] E.E. Schweizer, Z. Cao, A.L. Rheingold, M. Bruch, J. Org. Chem. 58 (1993) 4339-4345.
[6] E.C. Kesslen, W.B. Euler, Chem. Mater. 11 (1999) 336–340.
[7] R. Centore, C. Garzillo, J. Chem. Soc., Perkin Trans. 2. 1 (1997) 79-84.
[8] K.J. Lee, Y. Her, J.G. Jun, Bull. Korean Chem. Soc. 20 (1999) 341-344.
[9] (a) Cianga, I.; Ivanoiu, M. Eur. Polym. J. 42 (2006) 1922–1933; (b) Kurteva, V. B.;
Simeonov, S. P.; Stoilova-Disheva, M. Pharmacol. Pharm. 2 (2011) 1–9.
[10] J. Safari, S. Gandomi-Ravandi, M. Monemi, Monatsh Chem. 144 (2013) 1375-1380.
[11] J. Safari, S. Gandomi-Ravandi, S. Shariat, J. Iranian Chem. Soc. (2016) DOI:
10.1007/s13738-016-0866-2.
[12] J. Safari, S. Gandomi-Ravandi, Synth. Commun. 41 (2011) 645–651.
[13] K.T. Suji, H. Ishikawa, Bioorg. Med. Chem. Lett. 4 (1994) 1601-1606.
17

ACCEPTED MANUSCRIPT
[14] C. Jaen, L.D. Wise, B.W. Caprathe, H. Tecle, S. Bergmeier, C.C. Humblet, T.G. Heffner,
L.T. Meltzer, T.A. Pugsley, J. Med. Chem. 33 (1990) 311-317.
[15] (a) J. Safari, Z. Abedi-Jazini, Z. Zarnegar, M. Sadeghi, Catal. Commun. 77 (2016) 108-112;
(b) T.M. Potewar, S.A. Ingale, K.V. Srinivasan, Tetrahedron 63 (2007) 11066–11069.
[16] J. Safari, M. Sadeghi, Res. Chem. Intermed. 42 (2016) 8175-8183.
[17] (a) B.S. Kumar, A. Dhakshinamoorthy, K. Pitchumania, Catal. Sci. Technol. 4 (2014) 2378-
2396; (b) B.A. Dar, A. Chakraborty, P.R. Sharma, V. Shrivastava, A. Bhowmik, D. Vyas, P.
Bhatti, M. Sharma, B. Singh. J. Ind. Eng. Chem. 19 (2013) 732–738.
[18] (a) G. B. B. Varadwaj, S. Rana, K. M. Parida, RSC Adv. 3 (2013) 7570–7578; (b) J. Safari,
M. Ahmadzadeh, Z. Zarnegar, Catal. Commun. 86 (2016) 91-95.
[19] T.Y. Wibowo, A.Z. Abdullah, R. Zakaria, Appl. Clay Sci. 50 (2010) 280-281.
[20] H. Wang, S.X. Deng, Z.R. Shen, J.G. Wang, D.T. Ding, T.H. Chen, Green Chem. 11 (2009)
1499-1502.
[21] G.B.B. Varadwaj, S. Rana, K. Parida, J. Phys. Chem. C. 118 (2014) 1640−1651.
[22] G.B.B. Varadwaj, S. Rana, K. Parida, B.B. Nayakc J. Mater. Chem. A. 2 (2014) 7526–7534.
[23] G.B.B. Varadwaj, S. Rana, K.M. Parida, Dalton Trans. 42 (2013) 5122–5129.
[24] G.B.B. Varadwaj, S. Rana, K.M. Parida, RSC Adv. 3 (2013) 7570–7578.
[25] M. Tajbakhsh , M. Bazzar, S.F. Ramzanian, M. Tajbakhsh, Appl. Clay Sci. 88–89 (2014)
178-185.
[26] S.P. Chavana, G.B.B.Varadwaj, K. Paridab, B.M. Bhanagea, Appl. Catal. A: Gen. 506
(2015) 237–245.
[27] E.R. Blout, J. Am, Soc. 67 (1945) 13-17.
18

ACCEPTED MANUSCRIPT
[28] G.F. D'alelio, J.V. Crivello, R. K. Schoenig, T.F. Huemmer, J. Macromol. Sci. Chem. 1
(1967) 1161-1249.
[29] A.M. Stephen, T.G.D. Van Schalkwyk, N. Ravenscroft, ARKIVOC. 2002, 103-111.
[30] H. Loghmani-Khouzami, M.M. Sadeghi, J. Safari, M.S. Abdorrezaie, M. Jafapisheh, J.
Chem. Res. Synop. 2 (2001) 80-81.
[31] B.K. Bandlish, A.W. Garner, M.L. Hodges, J.W. Timberlake, J. Am, Chem. Soc. 97 (1975)
5856-5862.
[32] N.P. Buu-Hoï, G. Saint-Ruf, B Soc Chim Fr. 4 (1968) 2489-2492.
[33] A. Lendl, I. Werner, S. Glasl, C. Kletter, P. Mucaji, A. Presser, G. Reznicek, J. Jurenitsch,
D. W. Taylor, Phytochemistry 66 (2005) 2381-2387.
[34] M. H. M. Helal, M. A. Salem, M.S. A. El-Gaby, M. Aljahdali, Eur. J. Med. Chem. 65
(2013) 517-526.
19