Organic Electrosynthesis as a New Facile and Green Method for One-pot Synthesis of Nanosized Particles of Octahydro-imidazo[1,2-a]quinolin-6-one Derivatives via a Multicomponent Reaction

Article abstract of DOI:10.1002/jhet.3562

Organic electrosynthesis as a new facile and green method was applied for one-pot synthesis of octahydro-imidazo[1,2-a]quinolin-6-one derivatives, via a three component condensation of a dimedone, an aldehyde and 2-(nitromethylene)imidazolidine in propano

Full text of DOI:10.1002/jhet.3562

Month 2019 Organic Electrosynthesis as a New Facile and Green Method for One-pot
Synthesis of Nanosized Particles of Octahydro-imidazo[1,2-a]quinolin-6-
one Derivatives via a Multicomponent Reaction
*
Rana Sayyar, Somayeh Makarem,
and Behrooz Mirza
Department of Chemistry, Karaj Branch, Islamic Azad University, Karaj, Iran
*E-mail: s_makarem@sbu.ac.ir; s.makarem@kiau.ac.ir
Received December 8, 2018
DOI 10.1002/jhet.3562
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Organic electrosynthesis as a new facile and green method was applied for one-pot synthesis of
octahydro-imidazo[1,2-a]quinolin-6-one derivatives, via a three component condensation of a dimedone,
an aldehyde and 2-(nitromethylene)imidazolidine in propanol in an undivided cell in the presence of sodium
bromide as an electrolyte at room temperature. In this study, the anion of dimedone that was produced on the
cathode reacted with aromatic aldehydes through the Knoevenagel reaction and then the product condensed
with 2-(nitromethylene)imidazolidine that resulted in a highly efficient formation of octahydro-imidazo[1,2-
a]quinolin-6-one with 50–96% substance yields.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
geared toward drug discovery and drug delivery because
applying nanotechnology in drug delivery enhanced drug
properties such as solubility, rate of dissolution, oral
bioavailability, targeting ability, enhanced dosing
requirements, lower dosed administered, and a better side
effect profile. The goal is to make the nanoparticles
multifunctional and controllable by external signals or
local environments in the future [9].
Nowadays, electrosynthesis is used as a new green
methodology for the elimination of hazardous reagents,
green environmental applications, the elimination of
dangerous substances, treatment of pollutions, and atom
economy. In this method, electrons act as catalysts, and
because electrons are clean and renewable reagents, this
methodology can be used to replace toxic or dangerous
oxidizing or reducing reagents. Electro-organic syntheses
have some advantages such as its reaction rate, the nature
of the electrode that can be controlled, reaction
conditions that are mild, and electrolysis that is
performed at room temperature and atmospheric pressure
[10]. Many reactions have been reported using organic
electrosynthesis method such as the synthesis of N-
Imidazoquinolines are classified as diverse and
interesting heterocyclic systems that showed significant
biological and pharmaceutical properties depending on
the position of the fusion and the nature of the
substituents [1,2]. A literature survey has revealed that
different imidazoquinolines have been reported to act as
antimalarial [3], antimicrobial [4], antitumor, and
anticancer agents [5,6]. Some imidazoquinoline
derivatives such as imidazo[2,1-a]isoquinoline-2-
carboxylic acid hydrazide (1) as an inhibitor and
imidazo[2,1-a]isoquinoline-2-carboxylic acid (2) with
antiallergic activity are shown in Figure 1 [7,8].
Considering nanoscale materials, the physical, chemical,
and biological properties differ in fundamental and
valuable ways from the properties of individual atoms
and molecules or the bulk matter. Nanotechnology R&D
is directed toward understanding and creating improved
materials and systems that exploit these new properties,
and these unique phenomena enable novel applications.
Currently, nanoparticle applications in medicine are
© 2019 Wiley Periodicals, Inc.

R. Sayyar, S. Makarem, and B. Mirza
Vol 000
Scheme 1. General schematic for the preparation of octahydro-
imidazo[1,2-a]quinolin-6-one derivatives.
Figure 1. Examples of imidazoquinoline derivatives as biological active
agents.
heterocyclic carbenes precursors [11], 1H-indole [12],
amidation [13], imidazolium carboxylates [14], electro-
oxidation of alcohols [15], bromination reaction [16],
cyclic carbonates [17,18], oxidative esterification [19–
In order to optimize the synthesis conditions, several
parameters such as solvent, anode, temperature, and
current were studied (Table 1).
21],
N-functionalization
[22,23]
and
recently,
synthesizing the nanoparticles of 3-hydroxy-3-(1H-indol-
3-yl)indolin-2-one [24], 2-amino-pyranes, [25] and
spirooxindoles [26]. Based on our strong literature
survey, the synthesis of octahydro-imidazo[1,2-a]
quinolin-6-one derivatives through electro-organic
methods has not been reported until now. We first
investigated the reaction of dimedone (1), 4-
It can be seen from Table 1 that increasing the current to
amounts more than 400 mA decreased the yield of the
reaction (entry 1–6). We also investigated the effect of
temperature on the reaction and found that increasing the
temperature also decreased the reaction yields (entry 7).
Subsequently, several solvents such as propanol, ethanol,
and propanol/dimethylsolfoxide were used to find the
best solvent for the reaction (entry 9). Effect of anode on
time and yield of the reaction was also checked (entry
10). It was found that the best condition for minimizing
the synthesis time and higher production yield is dry
propanol/dimethylsolfoxide (95:5, PrOH/DMSO) at a
current density of 80 mA cmÀ2 (I = 400 mA, electrode
surface = 5 cm2) on magnesium anode and at room
temperature (entry 9).
nitrobenzaldehyde
(2a)
with
2-(nitromethylene)
imidazolidine under various reaction conditions (Table 1).
1
The H and 13C NMR and IR spectra of product showed
the formation of 8,8-dimethyl-4-nitro-5-(4-nitro-phenyl)-
2,3,5,7,8,9-hexahydro-1H-imidazo[1,2-a]quinolin-6-one.
RESULT AND DISCUSSION
In this study, we tried to design and introduce a new
green methodology for the synthesis of octahydro-
imidazo[1,2-a]quinolin-6-one derivatives by the reaction
of dimedone, aldehydes, and 2-(nitromethylene)
imidazolidine in an alcoholic solvent and an undivided
cell in the presence of NaBr as the electrolyte (Scheme 1).
The scope and generality of this protocol was next
examined by employing dimedone, various aromatic
aldehydes,
and
2-(nitromethylene)imidazolidine.
Conscionably, under the optimized condition, a variety of
octahydro-imidazo[1,2-a]quinolin-6-ones (7a–7f) were
obtained in a good to excellent yield (Table 2).
Table 1
Optimization of reaction conditions and effect of solvents, anode, temperature, and current in this procedure.
Entry
Current (mA)
Temperature °C
Solvent
Passed current (F/mol)
Time (min)
Yieldc
1a
2a
3a
4a
5a
6a
7a
8
100
200
300
400
500
600
400
400
400
400
r.t
r.t
r.t
r.t
r.t
r.t
50
r.t
r.t
r.t
n-PrOH
n-PrOH
n-PrOH
n-PrOH
n-PrOH
15.2
30.3
45.4
26.2
33.4
50.1
26.2
37.6
26.2
26.2
240
240
240
105
105
135
105
150
105
105
30
34
38
86
83
40
65
33
96
87
n-PrOH
n-PrOH
EtOH
n-PrOH/DMSO 95/5
n-PrOH/DMSO 95/5
9a
10b
Reaction conditions: dimedone (1, 1.0 mmol), 4-nitro benzaldehyde (2a, 1.0 mmol), 2-(nitromethylene)imidazolidine (3, 1.0 mmol), 0.5-mmol NaBr, and
iron cathode (5 cm2).
aMagnesium (5 cm2) was used as anode.
bGraphite (5 cm2) was used as anode.
cIsolated yield.
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Month 2019
Electrosynthesis of Organic Compounds
Table 2
Electro-organic synthesis of octahydro-imidazo[1,2-a]quinolin-6-ones derivatives.
Productsa
R1
Time (min)
Yield (%)a
Lit. m.p (°C)
m.p (°C)
7a
7b
7c
7d
7e
7f
4-Nitro
4-Hydroxy
2,4-Dimethoxy
4-Chloro
3,4,5-Trimethoxy
4-Methoxy
105
120
150
135
120
135
96
95
63
70
50
94
265 dec.27
258–260 dec.
274–276
260–262
248–250 dec.
240–242
200–202
—
—
254 dec.27
—
—
aReaction conditions: an iron cathode (5 cm2), a magnesium anode (5 cm2), current (0.4 A), electrolyte (NaBr), and n-PrOH/DMSO 95/5 (25 mL), an
undivided cell, and room temperature.
For investigating the effect of anode material on the size
of product, under the optimized condition, we synthesized
7a with both a magnesium and a graphite anode. SEM
images of the template-synthesized nanoparticles,
obtained from powder, are shown in Figure 2.
It is obvious that using magnesium as the anode
decreases the size of product in nanometer. The average
particle size using a magnesium anode (dSEM) is
<100 nm. Based on our previous report [23], we
believed that the existence of Mg2+ ions in the solution
might prevent the coagulation of the product molecules in
the medium.
the cathode leads to the formation of an alkoxide anion.
The subsequent reaction between the alkoxide anion and
dimedine (1) gives rise to the dimedone anion (1), and
then, the reaction of aldhyde (2) and dimedone anion (1)
obtains product (5) via Knoevenagel reaction. This
product would undergo the condensation with ketene
diaminal (3) giving intermediate (6). Intermediate (6)
would dehydrate spontaneously to achieve products (7)
[26–28].
The spectral data of products confirmed structure 7. The
IR spectrum of compound (7) exhibited peaks at 3363–
3700 (NH) and 1655–1725 (C═O) for the carbonyl
functional group. The 1H NMR spectrum showed one
singlet at 4.57–5.07 ppm for the hydrogen of CH and one
hydrogen of NH at 9.19–9.32.
A proposed mechanism for the synthesis is depicted in
Scheme 2. Deprotonation of an alcohol on the surface of
EXPERIMENTAL
General electro-organic synthesis procedure for the
preparation of octahydro-imidazo[1,2-a]quinolin-6-ones
derivatives. A mixture of dimedone (1 mmol), aldehyde
(1 mmol), 2-(nitromethylene)imidazolidine (1 mmol), and
NaBr (0.05 g, 0.5 mmol) in propanol (25 mL) was
magnetically stirred and electrolyzed in a cell equipped
with an iron cathode (5 cm2) and a magnesium anode
(5 cm2) at room temperature under a constant current
density of 80 mA/cm2 (I = 400 mA). After completion of
the reaction (monitored by thin-layer chromatography,
ethyl acetate/n-hexane 2:1), the solvent was evaporated
under reduced pressure (about 40 torr), and then, 20-ml
ethanol (80%) was added to the reaction mixture. The
precipitate was separated by centrifugation.
Spectral data for selected new products. 8,8-Dimethyl-4-
nitro-5-(4-nitro-phenyl)-2,3,5,7,8,9-hexahydro-1H-imidazo[1,2-
a]quinolin-6-one (7a).
Yellow crystal; mp 258–260°C;
yield (96%); IR (KBr) (νmax, cmÀ1): 3343 (NH), 1725
1
(C═O), 1617, 1520, 1510. H NMR (300 MHz, CDCl3)
δH (ppm) 1.00 (3H, S, CH3), 1.02 (3H, s, CH3), 1.88
(1H, d, J = 12.2, CH), 1.96 (1H, d, J = 13.50, CH), 2.14
(1H, d, J = 13.8, CH), 2.43 (1H, d, J = 12.6, CH), 3.56,
3.74 (3H, m, CH), 4.41 (1H, d, J = 11.1 CH), 6.30 (1H,
Figure 2. SEM images of 7a compound used (a) magnesium (b) graphite
as anode. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Sayyar, S. Makarem, and B. Mirza
Vol 000
Scheme 2. Plausible mechanism for the condensation of dimedone, aldehydes, and 2-(nitromethylene)imidazolidine. [Color figure can be viewed at
wileyonlinelibrary.com]
s, CH3),7.47 (1H, t, ArH), 9.20 (1H, s, NH). 13C NMR
(75.4 MHz, CDCl3) δC (ppm) 26.0, 29.3, 31.8, 43.4,
44.8, 49.2, 106.5, 112.4, 121.2, 122.5, 129.2, 134.5,
146.4, 147.1, 149.8, 151.3, 193.3. Anal. Calcd for
C19H20N4O5: C, 59.37; H, 5.24; N, 14.58%. Found: C,
J = 6.3, 2.2, ArH) 6.45 (1H, d, J = 2.2, ArH), 6.69 (1H,
d, J = 8.4, ArH), 9.32 (1H, s, NH). 13C NMR 18.5, 29.8,
32.1, 32.8, 43.9, 53.3.55.0, 56.0, 58.4, 84.5, 97.8,103.7,
104.2, 123.1, 128.1, 156.8, 157.0, 158.4, 205.9. Anal.
Calcd for C21H25N3O5: C, 63.15; H, 6.31; N, 10.52%.
59.25; H, 5.34; N, 14.40%.
5-(4-Hydroxy-phenyl)-8,8-dimethyl-4-nitro-2,3,5,7,8,9-
Found: C, 63.28; H, 6.41; N, 10.39%.
8-Methyl-4-nitro-5-(3,4,5-trimethoxy-phenyl)-2,3,5,7,8,9-
hexahydro-1H-imidazo[1,2-a]quinolin-6-one (7b).
Yellow
hexahydro-1H-imidazo[1,2-a]quinolin-6-one (7e).
Yellow
crystal; mp 274–276°C; yield (95%); IR (KBr) (νmax
,
crystal; mp 240–242°C; yield (50%); IR (KBr) (νmax,
cmÀ1): 3343 (NH), 1725 (C═O), 1520, 1124. H NMR
(300 MHz, CDCl3) δH (ppm) 1.00 (3H, s, CH3), 1.02
(3H, s, CH3), 1.87 (1H, d, J = 12.6, CH), 1.96 (1H, d,
J = 13.1, CH), 2.14 (1H, d, J = 13.50, CH), 2.43 (1H, d,
J = 12.3, CH), 3.31 (3H, s, CH3), 3.62–3.77 (3H, m,
CH2), 4.41 (1H, d, J = 11.4, CH), 6.27 (1H, s, CH), 7.47
(1H, t, J = 8.1, ArH), 7.69 (1H, d, J = 7.8, ArH), 7.96
(2H, d, J = 5.1, ArH), 9.19 (1H, s, NH). 13C NMR
(75.4 MHz, CDCl3) δC (ppm) 27.5, 31.3, 32.8, 34.7,
45.6, 53.2, 59.8, 84.9, 107.2, 147.0, 147.2, 157.0, 204.5.
Anal. Calcd for C19H21N3O4: C, 64.21; H, 5.96; N,
cmÀ1): 3700 (NH), 3376, 2955, 1693 (C═O), 1590,
1
1
1505, 1123. H NMR (300 MHz, CDCl3) δH (ppm) 0.91
(3H, s, Me), 1.05 (3H, s, Me), 2.03 (1H, d, J = 16, CH),
2.21 (1H, d, J = 16.1 CH), 2.52–2.58 (2H, m, CH2), 3.57
(3H, s, CH3), 3.78–3.83 (2H, m, CH2), 3.98–4.01 (1H,
m, CH), 4.13–4.19 (1H, m, CH), 5.07 (1H, s, CH), 6.44
(2H, s, ArH), 9.74 (1H, s, NH). 13C NMR (75.4 MHz,
CDCl3) δC (ppm) 13.8, 39.2, 109.2, 109.8, 113.2, 120.2,
120.9, 123.1, 127.2, 135.3, 140.2, 153.3, 170.8. Anal.
Calcd for C22H27N3O6: C, 61.53; H, 6.34; N, 9.78%.
Found: C, 61.43; H, 6.44; N, 9.63%.
5-(4-Methoxyphenyl)-8,8-dimethyl-4-nitro-2,3,5,7,8,9-
11.82%. Found: C, 64.31; H, 5.85; N, 11.70%.
5-(2,4-Dimethoxy-phenyl)-8,8-dimethyl-4-nitro-2,3,5,7,8,9-
hexahydroimidazo[1,2-a]quinolin-6(1H)-one (7f).
Yellow
hexahydro-1H-imidazo[1,2-a]quinolin-6-one (7c).
Yellow
crystal; mp 200–202°C; yield (94%); IR (KBr) (νmax,
crystal; mp 260–262°C; yield (63%); IR (KBr) (νmax
,
cmÀ1): 3700 (NH), 3371, 3220, 2957, 1655 (C═O),
1606, 1510, 1409. 1H NMR (300 MHz, CDCl3) δH
(ppm) = 0.92 (3H, s, CH3), 1.01 (3H, s, CH3), 1.89–1.94
(4H, s, CH2), 3.55 (3H, s, CH3), 3.64–3.70 (4H, m,
CH2), 4.75 (1H, s, CH), 6.71 (2H, d, J = 6.3, ArH), 7.08
(2H, d, J = 7.08, ArH), 8.41 (1H, s, NH). 13C NMR
cmÀ1): 3273 (NH), 1713 (C═O), 1605, 1503, 1145. H
NMR (300 MHz, CDCl3) δH (ppm) 1.01 (3H, s, CH3),
1.92–2.07 (3H, m, CH), 2.53 (1H, m, CH), 3.38–3.47
(3H, m, CH), 3.51–3.58 (1H, m, CH), 3.68 (3H, s, CH),
3.71 (3H, s, CH3), 5.68 (1H, s, CH) 6.30 (1H, dd,
1
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DOI 10.1002/jhet

Month 2019
Electrosynthesis of Organic Compounds
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Anal. Calcd for C20H23N3O4: C, 65.03; H, 6.28; N,
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In conclusion, a simple electrosynthesis method has
been developed to prepare nanosized particles of
octahydro-imidazo[1,2-a]quinolin-6-ones derivatives via a
multicomponent reaction. The electrosynthesis process is
crucial for the green synthesis of inexpensive and highly
electrocatalytically active intermediate for sustainable
energy production. Albeit, the process can be used for a
myriad of nanoparticles of organic compounds.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet