Chitosan hydrochloride mediated efficient, green catalysis for the synthesis of perimidine derivatives

Article abstract of DOI:10.1002/jhet.3700

Chitosan hydrochloride as biopolymer-based, renewable, and recyclable heterogeneous catalyst was used for efficient one-pot synthesis of perimidine derivatives. This newly developed greener methodology provides a very simple and greener route for the synt

Full text of DOI:10.1002/jhet.3700

Received: 27 May 2019
DOI: 10.1002/jhet.3700
Revised: 8 August 2019
Accepted: 12 August 2019
A R T I C L E
Chitosan hydrochloride mediated efficient, green catalysis
for the synthesis of perimidine derivatives
1
2
2
Premchand B. Shelke | Suraj N. Mali
| Hemchandra K. Chaudhari |
1
Amit P. Pratap
1
Department of Oils, Oleochemicals, and
Abstract
Surfactants Technology, Institute of
Chemical Technology, Mumbai, India
Chitosan hydrochloride as biopolymer‐based, renewable, and recyclable het-
erogeneous catalyst was used for efficient one‐pot synthesis of perimidine
derivatives. This newly developed greener methodology provides a very simple
and greener route for the synthesis of perimidines in short time with excellent
yield.
2
Department of Pharmaceutical Sciences
and Technology, Institute of Chemical
Technology, Mumbai, India
Correspondence
Amit P. Pratap, Department of Oils,
Oleochemicals, and Surfactants
Technology, Institute of Chemical
Technology, Matunga (E), Mumbai 400
019, India.
Email: ap.pratap@ictmumbai.edu.in
1
| INTRODUCTION
alkaline deacetylation yields chitosan. Chitosan, a linear
polyamine, is nontoxic, biodegradable, and biocompatible
The basis of a green chemistry approach depends on the
chemical process in which there is an elimination of haz-
ardous substances and proper utilization of input raw
materials. To recent, there are a large number of litera-
tures available showing applications of solid catalyst in
reactions. The heterogeneous catalyst has its own benefits
than the homogeneous catalyst as they minimize the for-
mation of waste, show reusability, and ease of recovery.
In recent years, the researchers are exploring the hetero-
geneous biopolymer–based catalysts for several chemical
reactions because of the simplicity of the process, low
contamination of the product, and avoiding usage of toxic
substance, and it can be effectively used in green catalysis
as it acts as solid catalyst because of the presence of two
[
1]
functionalities viz hydroxyl and amino.
Literature
shows that chitosan has large number of applications in
[
5–8]
[9,10]
various fields such as drug delivery,
cosmetics,
[
11,12]
[13]
[14]
food packaging,
medicine,
water treatment,
and hydrogels, membranes, and adhe-
Chitosan‐based solid catalysts
[
15]
fuel cells,
[
16]
[17,18]
sives.
are reported
for number of organic transformations [3 + 2] Huisgen
[
19]
[20]
cycloaddition,
addition reaction,
tion,
Suzuki cross‐coupling,
Michael
[
21]
[22]
Heck reaction,
Ullmann reac-
[
23]
[24]
and aldol and Knoevenagel reaction.
The pres-
[1]
solvents. Recently, several biopolymers like starch, cel-
lulose, chitosan, and wool have been reported as hetero-
ence of free NH group and insolubility in most of organic
2
compounds and pure water signifies the importance of
chitosan for utilization as heterogeneous catalysis in the
chemical industry. Since this biopolymer has two func-
tionalities, it can be adapted into many forms by utiliza-
tion of suitable support. Generation of complexity in a
one‐pot reaction, convergence, selectivity, and high atom
efficiency are the key features of multicomponent reac-
[2–4]
geneous catalytic system.
There will be a good
approach to design more sustainable chemical process if
we used biopolymers with little further modification. In
this context, chitosan that is the second most abundant
organic resource next to cellulose has been proved a very
[1]
good catalyst. Several organic transformations are also
reported in the literature. Naturally occurring chitin upon
[
18]
tions (MCRs).
All reported reactions for synthesis of
perimidine derivatives utilize expensive catalyst, tedious
procedures, and high temperature conditions. To
Premchand B. Shelke and Suraj N. Mali have equal contributions.
J Heterocyclic Chem. 2019;1–7.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
SHELKE ET AL.
overcome these issues herein, we wish to report chitosan
hydrochloride as biopolymer‐based, renewable, and recy-
clable heterogeneous catalyst for efficient one‐pot synthe-
sis of perimidine derivatives (Scheme 1). To our best
knowledge, the synthesis of perimidine derivatives is not
reported using the chitosan hydrochloride as a catalyst.
Perimidines compounds exhibit an important class of nat-
catalyst, catalyst loading, temperature, and solvents on
the reaction rate catalyzed by chitosan hydrochloride to
yield desired product. The results for reaction(s) are sum-
marized in Tables 1–4. We have selected water as reaction
solvent for our model reaction (Scheme 1) as it afforded
high yield of desired product with good reaction rate.
We have also investigated the scope of this methodology
by using number of aromatic, aliphatic, and heterocyclic
ketones besides the acetophenone (Table 4). Currently,
our research group is working on synthesis of novel
antiinfective agents using chitosan hydrochloride as
greener catalyst along with further molecular modeling
[25]
ural and synthetic products.
They are having wide
range of bioactivities including antifungal, antimicrobial,
antiulcer, and antitumor agents. They are also used as
dyes, catalyst, photochromic compounds, and antioxi-
dants. Literature shows that there are several reports on
the use of metal chlorides (RuCl and BiCl ), triflates
[
31]
studies.
3
3
(
Ytterbium (III) triflate, a mild Lewis acid), Cu (NO ) ,
3 2
zeolite NaY, CMK‐5‐SO H nanocatalyst, InCl , BF ‐H O,
3
3
3
2
and Zn (OAc) .2H O for synthesis of perimidine deriva-
2 | RESULTS AND DISCUSSION
2
2
[26–30]
tives.
Although these compounds have been synthe-
sized efficiently, the reported methodology suffers major
disadvantages such as long reaction time, use of
nonreusability of catalyst, harsh conditions, and genera-
tion of side reactions. We have investigated the effect of
2.1 | Model reaction condition
optimization and study of reactions of
naphthalene‐1,8‐diamine with various
ketones
In order to evaluate the scope and generality of our newly
developed protocol, we carried out reactions with aro-
matic as well as aliphatic ketones (Table 4).We observed
that aliphatic ketones were giving more product yield
than the aromatic ketones (Table 4, entries 1 and 2). In
particular, the reactions with aromatic ketones
SCHEME 1 Synthesis of perimidine (model reaction)
[26]
TABLE 1 Comparison of effect of different reported
catalytic systems in the synthesis of 2‐phenyl‐2,3‐dihydro‐1H‐perimidine
Entry Catalyst
Solvent
Time
Yield, %
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
CuY‐zeolite
Fe /SiO (CH
AcOH
Ytterbium (III) trifluromethanesulfonate
EtOH
25 min/RT
81
93
52
88
84
70
83
80
80
3
O
4
2
)
3
N + MeBr
3
core shell nanoparticles
No solvent 12 min/80°C
EtOH
MeCN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
24 h/RT
24 h/20°C
0.66 h/RT
45‐50 h/RT
10 min/RT
12 h/RT
I
2
NaY zeolite
Cu (NO ).2H
FePO
Thiocarbohydrazide/nickel–based nanocomposite supported on SBA‐15
Sulfonic functionalized ordered mesoporous carbon (CMK‐5‐SO H)
Polyionene layered tribromide modified silica‐coated magnetic Fe
Benzyl tributylammonium chloride‐FeCl
3
2
O
4
0.25 h/20°C
0
1
2
3
4
5
3
0.083 333 3 h/20°C 91
3
O
4
nanoparticles Neat
Neat
0.166 h/110°C
0.0166 h/25°C
93
90
90
90
90
3
(Triazinediyl)bis sulfamic acid–functionalized silica‐coated magnetite nanoparticle EtOH/water 0.416667 h/50°C
Fe
3
O
4
magnetic nanoparticle–supported β‐CD‐ZrO complex
EtOH
Water
0.166 h/20°C
1 h/90°C
Chitosan hydrochloride (20 wt%)

SHELKE ET AL.
3
TABLE 2 Comparison of effect of amount of chitosan hydro-
chloride catalyst in the naphthalene‐1,8‐diamine and
acetophenone
aryl is due to steric hindrance exerted by phenyl motifs.
We have also experimentally calculated the optimum
amount of catalyst required for these transformations
a
(
Table 2) and also compared with literature (Table 1).
We studied the effect of catalyst amount on reaction rate
for our model reaction (Scheme 1). We found that with-
out catalyst reaction was not progressed to product even
after 50 hours. We optimized the catalytic load at
a
b
Entry
Catalyst Load, wt%
Time, h
Yield, %
1
2
3
4
5
6
None
5
50
0
2
0 wt%. We further found that even after increments of
1.5
1.3
1.2
1.0
1.0
60
75
80
96
95
catalyst load beyond 20 wt% did not improve the yield
of final product (see Table 2). Our typical protocol
includes the cooling of reaction mixture at room temper-
ature and further filtration of precipitated product. The
catalyst can be recovered easily and reused up to five
times (Figure 2). The solvent screening studies (Table 3)
showed that the yield of product was high when we use
water (5 mL) as solvent. The optimized reaction condi-
tions for our model reaction utilize the acetophenone
10
15
20
25
a
All reactions (except entry 1) were performed at a 1‐mmol scale using chito-
san hydrochloride in 5 mL of water at 90°C temperature.
b
Column isolated yields.
(
1.2 mmol), naphthalene‐1,8‐diamine (1 mmol), and
(
acetophenone like), we observed that electron‐
20 wt% catalytic load of chitosan hydrochloride heated
with water as solvent at 90°C temperature. The reaction
may plausibly process through imine formation and sub-
sequent loss of water (Figure 1).
withdrawing substituents on phenyl ring play important
role in order to decrease the reaction time (Table 4,
entries 6‐8).
The aromatic ketones with electron‐donating substitu-
ents on phenyl ring increase the reaction time. We fur-
ther extended our study by using bi‐aryl ketones like
benzophenone (Table 4, entry 11). We found that the
reaction was yielded less, which might be due to the con-
jugation effect and steric hindrance of the two phenyl
rings. The higher reactivity of dialkyl ketone over alkyl‐
2
.2 | Recyclability and scale up studies
The model reaction (Scheme 1) was studied for recyclabil-
ity by performing on 3g scale. The catalyst was recovered
by addition of sufficient amount of ethyl alcohol to
a
TABLE 3 Solvent screening and optimization of reaction parameters
a
a
b
Entry
Solvent
OH
Catalyst
Cat Amount, wt%
Temperature, °C
Time, h
Yield, %
1
2
3
4
5
6
7
8
9
C
2
H
5
Chitosan hydrochloride
Chitosan hydrochloride
Chitosan hydrochloride
Chitosan hydrochloride
Chitosan hydrochloride
Chitosan hydrochloride
Chitosan hydrochloride
Chitosan hydrochloride
Chitosan hydrochloride
Chitosan hydrochloride
Chitosan hydrochloride
Chitosan hydrochloride
Chitosan hydrochloride
20
20
20
20
20
20
20
20
20
20
20
20
20
90
90
90
90
90
90
90
90
90
50
40
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
70
40
5
THF
CH
CH
CH
3
3
2
CN
OH
Cl
60
c
2
NR
c
DMF
NR
c
PhCH
3
NR
c
Et
2
O
NR
Water
Water
Water
Water
Neat
96
70
45
10
11
12
13
b
c
RT
NR
100
60
a
Reaction conditions: naphthalene‐1,8‐diamine (1 mmol), acetophenone (1.2 mmol), and solvent (5 mL).
b
RT, room temperature (30°C‐32°C).
c
No reaction.

4
SHELKE ET AL.
TABLE 4 Reaction of naphthalene‐1,8‐diamine with various ketones
a
b
c
[26–30]
Entry
Ketone
Time, h
Product
Yield, %
MP (°C) Observed (Literature)
1
0.5
80
112‐116
(
115‐116)
2
3
0.5
0.6
70
86
92‐96
94‐95)
(
106‐110
110‐111)
(
4
5
6
1
90
96
86
100‐104
100‐101)
(
1
132‐136
136‐138)
(
0.9
128‐132
129‐130)
(
7
8
0.9
0.6
85
92
156‐158
157‐158)
(
122‐126
126‐128)
(
9
2
83
95
117‐121
117‐118)
(
1
1
1
1
0
1
2
3
0.6
193‐197
193‐194)
(
5
71
83
16
190‐194
3
178‐182
(
178‐180)
50
209‐212
209‐210)
(
1
4
1.5
90
164‐165
164‐165)
(
(Continues)

SHELKE ET AL.
5
TABLE 4 (Continued)
a
b
c
[26–30]
Entry
Ketone
Time, h
Product
Yield, %
MP (°C) Observed (Literature)
15
16
17
6
80
50
92
94‐97
(
96‐97)
10
5
98‐102
99‐101)
(
Isatin
242‐246
244‐246)
(
a
All reactions were performed at a 1‐mmol scale using 20 wt% of chitosan hydrochloride in 5 mL of water at 90°C temperature.
b
Column isolated yields.
cMelting point of all products was compared with reported literature.[26–30]
[17]
FIGURE 1 Plausible mechanistic
pathway for synthesis of perimidine using
chitosan hydrochloride
FIGURE 2 Catalyst recyclability studies [Color figure can be
viewed at wileyonlinelibrary.com]
FIGURE 3 Plot of the green chemistry metrics for the reaction
between naphthalene‐1,8‐diamine and acetophenone in the
presence of chitosan hydrochloride catalyst [Color figure can be
viewed at wileyonlinelibrary.com]
aqueous medium and further filtered. The filtrate was
allowed to dry and recycled five times without any signif-
icant loss in weight and activity giving yields more than
8
5% (Figure 2). We have also calculated the green chem-
3 | CONCLUSIONS
istry matrices as reported earlier in our lab by Jejurkar
et al.
[32]
The reaction has atom economy (AE) of
In conclusion, we have developed a very practical and
easy to do protocol for efficient synthesis of perimidine
derivatives using newly utilized chitosan hydrochloride
as biopolymer‐based, biodegradable, and green catalyst
9
3.52%, reaction mass efficiency (RME) is 96%, E‐factors
value of 0.041 21, and the eco‐scale score for the method
is 80 (Figure 3).

6
SHELKE ET AL.
giving very high yield of desired perimidine compounds.
This reaction does not require any special inert condi-
tions. The present work represents very convenient prac-
tical protocol for synthesis perimidine derivatives. Low
catalyst loading, clean reaction profiles, and the use of a
one pot are the key features of current developed
methodology.
was not completed with desired formation of compound
even after 50 hours monitored using TLC. The catalyst
chitosan hydrochloride was filtered off, and remaining
filtrate was evaporated using the rotary evaporated to
yield crude solid mass. The crude solid mass was further
purified using the column chromatography. The solid
product was washed with ethanol and further dried in
oven at 50°C under vacuum. The purified compounds
1
were further characterized using the representative H‐
4
| EXPERIMENTAL
13
NMR and C‐NMR, and for remaining compound, we
compared their melting points with reported melting
points.
All the necessary reagents and starting materials were
procured from well‐established commercial resources
[26–30]
(
Sigma‐Aldrich and Merck). All the chemicals procured
were used without further purification. Chitosan
MW = 50 000‐190 000 Dalton) was purchased from
Merck. Melting points were recorded on Mettler Toledo
MP‐70) model and were uncorrected. Representative
ACKNOWLEDGMENT
(
Author P.B.S. is thankful to the Institute of Chemical
Technology, Mumbai, for recording of H‐NMR.
1
(
1
13
proton magnetic resonance ( H‐NMR) and C‐NMR
were recorded on well‐conditioned 400 and 100 MHz
respectively on Bruker spectrometer using the deuterated
solvents, and chemical shift values were expressed in δ
ppm using the TMS as an internal standard (see the
Supporting Information). Silica F254–coated aluminium
plates (Merck) were used for conducting thin‐layer chro-
matography (TLC) and were visualized using the ultravi-
olet light or an iodine chamber. The characterization of
chitosan hydrochloride was performed using SEM, TGA,
XRD, and FTIR studies (see the Supporting Information).
ORCID
Suraj N. Mali https://orcid.org/0000-0003-1995-136X
Amit P. Pratap https://orcid.org/0000-0002-8945-6885
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How to cite this article: Shelke PB, Mali SN,
Chaudhari HK, Pratap AP. Chitosan hydrochloride
mediated efficient, green catalysis for the synthesis
of perimidine derivatives. J Heterocyclic Chem.
2019;1–7. https://doi.org/10.1002/jhet.3700
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