Catalyst- and solvent-free synthesis of highly functionalized octahydro-imidazo[1,2-a]quinolin-6-ones via a one-pot sequential four-component reaction in melt conditions

Article abstract of DOI:10.1016/j.crci.2013.05.018

This is a report of an innovative, one-pot, catalyst-free, four-component synthesis of octahydro-imidazo[1,2-a]quinolin-6-ones from aromatic aldehydes, cyclic 1,3-diones, diamines, and nitro ketene dithioacetal in stoichiometric melt conditions. The protocol avoids the use of expensive catalysts, toxic organic solvents and anhydrous conditions, and affords potentially bioactive compounds in excellent to high yields.

Full text of DOI:10.1016/j.crci.2013.05.018

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´
Full paper/Memoire
Catalyst- and solvent-free synthesis of highly functionalized
octahydro-imidazo[1,2-a]quinolin-6-ones via a one-pot
sequential four-component reaction in melt conditions
*
Abdolali Alizadeh , Atieh Rezvanian
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
This is a report of an innovative, one-pot, catalyst-free, four-component synthesis of
octahydro-imidazo[1,2-a]quinolin-6-ones from aromatic aldehydes, cyclic 1,3-diones,
diamines, and nitro ketene dithioacetal in stoichiometric melt conditions. The protocol
avoids the use of expensive catalysts, toxic organic solvents and anhydrous conditions, and
affords potentially bioactive compounds in excellent to high yields.
Received 31 March 2013
Accepted after revision 28 May 2013
Available online xxx
Keywords:
ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Octahydro-imidazo[1,2-a]quinolin-6-one
Aromatic aldehyde
Cyclic 1,3-diones
Diamine
Nitro ketene dithioacetal
Melt conditions
1. Introduction
2-aminoquinolines are the most popular. Thus, their
reactions with
a-halo carbonyl compounds [2a,4], and
Imidazo[1,2-a]quinoline is a synthetically designed
scaffold with a broad spectrum of biological activities. Its
derivatives have been claimed to be contraceptive [1a],
hypotensive [1b], anti-allergic and anti-asthmatic agents
[1c]. Moreover, several prospective non-sedative anxio-
lytic agents with the imidazoquinoline structure have
been discovered [2a], and one of them, referred to as Ru
31719, is now under clinical evaluation. Its affinity to
GABA receptors in the brain is being studied intensively in
order to evidence its action mechanism [2b–d]. In
addition, imidazoquinolines have been explored as novel
immunostimulant drugs [3]. The known syntheses of
imidazo[1,2-a]quinolines usually utilize various quino-
line derivatives as the starting materials. Among them,
related 1,2-bielectrophiles [5] lead to the target system.
Furthermore, 2-aminoquinolines have been employed in
Strecker–Ugi reactions, also, resulting in imidazoquino-
lines [6,7]. As for other quinoline precursors, the
transformation of 1-phenacylquinolinium salts into the
title system upon treatment with primary amines [8a],
hydroxylamines [8b] and hydrazine derivatives [8c], as
well as the condensation of 2-chloro- or 2-alkoxyquino-
lines with
a-amino carbonyl compounds [9], should be
mentioned. Finally, a few less general approaches to
imidazoquinolines have been reported [10]. However,
many of these procedures are not fully satisfactory with
regard to operational simplicity, cost of the reagent,
drastic reaction conditions, and they afford the products
in relatively low yields. Therefore, a simple, general, and
efficient procedure is still in demand for the preparation of
these important heterocyclic compounds and research is
still in progress to find out a better and improved
methodology.
*
Corresponding author.
E-mail addresses: aalizadeh@modares.ac.ir, abdol_alizad@yahoo.com
(A. Alizadeh).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.05.018
Please cite this article in press as: Alizadeh A, Rezvanian A. Catalyst- and solvent-free synthesis of highly functionalized
octahydro-imidazo[1,2-a]quinolin-6-ones via a one-pot sequential four-component reaction in melt conditions. C. R.
Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.018

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CRAS2C-3782; No. of Pages 5
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A. Alizadeh, A. Rezvanian / C. R. Chimie xxx (2013) xxx–xxx
Table 1
2. Results and discussion
Optimization of reaction conditions.
Continuing our research work on MCR of aminals and
enamines [11] with a view to the synthesis of fused
polycyclic N-heterocycles, we evidence in this paper a very
efficient and environmentally benign strategy for the
synthesis of new imidazo[1,2-a]quinolin-6-one derivatives
Entry Reaction conditions Catalyst T (8C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
EtOH
CH3CN
EtOH
THF
TsOH
Et3N
TsOH
Et3N
TsOH
Et3N
–
RT
28
24
14
20
16
15
3
31
37
55
32
44
59
87
91
RT
80
60
CH3CN
EtOH
Melt
70
by
a one-pot, four-component reaction of aromatic
80
aldehyde, cyclic 1,3-dione, diamine, and nitro ketene
dithioacetal under melt conditions with excellent yields
(Scheme 1).
100
110
Melt
–
2
RT: room temperature.
The reactions between aromatic aldehydes and cyclic
1,3-diones are too slow at room temperature and require a
basic or acidic catalyst; on the other hand, according to our
previous experiments, the formation of ketene aminal
from diamine and nitro ketene dithioacetal requires reflux
at high temperature. Further investigation led us to the
conclusion that both solvent and catalyst can be avoided.
To avoid disadvantages such as volatility and toxicity
inherent to many organic solvents, we applied the melt
octahydro-imidazo[1,2-a]quinoline derivatives
obtained in good yields at 110 8C in melt conditions
without any catalyst.
4
were
The structures of compounds 4a–i were deduced
from their elemental analysis, IR, and high-field 1H, and
13C NMR spectra. The mass spectrum of 4a displayed the
molecular ion peak at m/z 339, which is in agreement
with the proposed structure. The IR spectrum of this
compound showed an absorption band due to NH
stretching at 3336 cmÀ1. Absorption bands at 1641,
1532 and 1350 cmÀ1 are due to the C5O and C–NO2
groups. The 1H NMR spectrum of 4a showed two singlets
method to the four-component reaction as
a green
medium. Initially, the four-component reaction of 4-
nitrobenzaldehyde, dimedone, ethylenediamine and nitro
ketene dithioacetal as a simple model substrate was
investigated to establish the feasibility of the strategy and
to optimize the reaction conditions.
for CH3 groups (d = 0.83, 1.03 ppm), four doublets for the
The effects of solvents and reaction temperature were
evaluated for this model reaction, and the results are
summarized in Table 1.
The melt method provided higher yields and shorter
reaction times than those using organic solvents. The
optimized reaction conditions were then tested for library
construction with nine derivatives. The corresponding
two CH2 groups because these H-atoms are diastereo-
topic
(
d
= 1.98 ppm,
2JHH = 16.10 Hz,
d
= 2.18 ppm,
2JHH = 16.05 Hz,
d
= 2.50 ppm,
2JHH = 17.55 Hz,
2
d
= 2.59 ppm, JHH = 14.30 Hz), three multiplets for the
CH2 groups of the imidazole ring (
4.04, 4.15–4.20 ppm), two singlets for the CH and NH
groups ( = 5.06 and 9.38 ppm), and the phenyl moiety
d = 3.80–3.83, 3.98–
d
Me
Me
S
S
NO2
H
O
Ar
N
O
+
NO2
R
melt
O
O
1
H2N
H2N
R"
R'
2 h
NH
R"
R'
+
4
R'
R'
2
3
Entry Product 4 Aldehyde 1
1,3-Cyclic dione 2
Diamine 3
Yield %
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
Benzaldehyde
Benzaldehyde
4-Nitrobenzaldehyde
4-Nitrobenzaldehyde
4-Chlorobenzaldehyde Dimedone
Benzaldehyde
Benzaldehyde
4-Nitrobenzaldehyde
4-Chlorobenzaldehyde 1,3-cyclohexandione
Dimedone
Dimedone
Dimedone
Dimedone
Ethylenediamine
1,2-Propandiamine
Ethylenediamine
1,2-Propandiamine
Ethylenediamine
Ethylenediamine
1,2-Propandiamine
Ethylenediamine
Ethylenediamine
83
79
91
84
73
80
71
87
85
1,3-cyclohexandione
1,3-cyclohexandione
1,3-cyclohexandione
Scheme 1. Synthesis of imidazo[1,2-a]quinolin-6-one derivatives 4.
Please cite this article in press as: Alizadeh A, Rezvanian A. Catalyst- and solvent-free synthesis of highly functionalized
octahydro-imidazo[1,2-a]quinolin-6-ones via a one-pot sequential four-component reaction in melt conditions. C. R.
Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.018

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3
O
O
R'
R'
Me
Me
S
S
NO2
H
NH2
Knoevenagel
condensation
-2MeSH
ArCHO
H2N
R"
O
R"
O
O2N
HN
H
N
Ar
Ar
+
R'
R'
R'
NH
R"
N
H
O
O
R'
NO2
5
6
Michael reaction
R"
R"
O
Ar
N
O
Ar HN
NO2
O
Ar
N
NO2
Condensation
Ring closure
N
H
N
H
R'
imine-enamine
tautomerizatiom
R'
R'
NO2
NH
R"
O
O
R'
R'
R'
4
7
Scheme 2. Proposed mechanism for the formation of octahydro-imidazo[1,2-a]quinolin-6-ones.
gave rise to characteristic signals in the aromatic region
of the spectrum. The 1H-decoupled 13C NMR spectrum of
4a showed 17 distinct resonances, in agreement with the
suggested structure.
cyclo-adducts were quite stable and easy to handle
under standard conditions.
4. Experimental
A possible mechanism route for the described four-
component reaction is outlined in Scheme 2.
4.1. Materials and techniques
Firstly, we assume that the initial step is a Knoevenagel
condensation between the aldehyde and the cyclic 1,3-
dione, resulting in the adduct 5, then the reaction between
intermediate 5 and the ketene aminal 6 (which is derived
from the addition of diamine to nitro ketene dithioacetal)
The aldehydes, cyclic 1,3-diones, diamines and
nitro ketene dithioacetal were obtained from Merck
(Germany) and Fluka (Switzerland) and were used
without further purification. Melting points were
measured on an Electrothermal 9100 apparatus. Ele-
mental analyses for C, H and N were performed using a
Heraeus CHN–O–Rapid analyzer. Mass spectra were
recorded on a FINNIGAN-MATT 8430 mass spectrometer
operating at an ionization potential of 70 eV. 1H and 13C
NMR spectra were measured (CDCl3 solution) with a
Bruker DRX-500 AVANCE spectrometer at 500.13 and
125.8 MHz, respectively. IR spectra were recorded on a
Shimadzu IR-460 spectrometer; absorbencies are
gives the Michael adduct 7. The Michael adduct
7
undergoes a cyclocondensation reaction through amino
and carbonyl to afford compound 4.
Two products for propane-1,2-diamine were expected,
but when 1,n-diamine was applied in the reaction, only
one of the two possible products was obtained stereo-
specifically.
3. Conclusions
reported in cmÀ1
.
In conclusion, we have recently disclosed a novel and
convenient one-pot synthesis of multisubstituted octa-
hydro-imidazo[1,2-a]quinolin-6-ones via four-compo-
nent reactions. This catalyst-free sequential reaction
proceeded smoothly in excellent yields and offered
several other advantages, including short reaction time,
simple experimental workup procedures, and no toxic
byproducts. This approach to octahydro-imidazo[1,2-
a]quinolin systems presented herein avoids the use of a
catalyst, toxic organic solvents, and anhydrous condi-
4.2. General procedure for the preparation of compounds 4a–
i, exemplified on 4a
The mixtures of benzaldehyde (0.106 g, 1 mmol),
dimedone (0.140 g, 1 mmol), were melted under vacuum
in a 50-mL flask in a drying oven at 110 8C for 1 h. Then
ethylenediamine (0.60 g, 1 mmol) and nitro ketene
dithioacetal (0.165 g, 1 mmol) were added. After comple-
tion, the mixture was dried at 110 8C under a vacuum and
the precipitate was washed with ethanol to afford the pure
product 4a.
tions. This protocol represents
a promising green
route to the class of compounds. In addition, all of the
Please cite this article in press as: Alizadeh A, Rezvanian A. Catalyst- and solvent-free synthesis of highly functionalized
octahydro-imidazo[1,2-a]quinolin-6-ones via a one-pot sequential four-component reaction in melt conditions. C. R.
Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.018

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4.3. Spectral data
C
19H20N4O5 (384.38): C, 59.37; H, 5.24; N, 14.58%.
Found: C, 59.33; H, 5.23; N, 14.61%.
4.3.1. 8,8-Dimethyl-4-nitro-5-phenyl-1,2,3,5,6,7,8,9-
octahydro-imidazo[1,2-a]quinoline-6-one (4a)
4.3.4. 1,8,8-Trimethyl-4-nitro-5-(4-nitrophenyl)-
1,2,3,5,6,7,8,9-octahydro-imidazo[1,2-a]quinoline-6-one
(4d)
Yellow powder (yield 83%); mp: 270 8C (decomp); IR
(KBr) (n
max, cmÀ1): 3336 (NH), 1641 (C5O), 1541 and
1350 (C–NO2). 1H NMR (500.1 MHz, CDCl3): dH (ppm)
Yellow powder (yield 84%); mp: 273 8C (decomp); IR
0.83 (3 H, s, CH3), 1.03 (3 H, s, CH3), 1.98 (1 H, d,
(KBr) (n
max, cmÀ1): 3359 (NH), 1632 (C5O), 1518 and
2
2JH,H = 16.1 Hz, CH2), 2.18 (1 H, d, JH,H = 16.0 Hz, CH2),
1353 (C–NO2). 1H NMR (500.1 MHz, CDCl3):
dH (ppm) 1.01
2
2.50 (1 H, d, JH,H = 17.5 Hz, CH2), 2.59 (1 H, d,
(3 H, s, CH3), 1.11 (3 H, s, CH3), 1.34 (3 H, d, 2JH,H = 10.0 Hz,
2JH,H = 14.3 Hz, CH2), 3.80–3.83 (2 H, m, CH2NH),
3.98–4.04 (1 H, m, CH2N), 4.15–4.20 (1 H, m, CH2N),
5.06 (1 H, s, CH), 7.08–7.19 (5 H, m, 5 CH of Ph), 9.38
CH3), 1.96 (1 H, d, JH,H = 16.2 Hz, CH2), 2.18 (1 H, d,
2
2JH,H = 16.2 Hz, CH2), 2.48–2.54 (2 H, m, CH2), 3.62–3.78 (1
H, m, CH2N), 4.11–4.22 (2 H, m, CH2N and CHNH), 5.13 (1
H, s, CH), 7.46 (2 H, d, 2JH,H = 14.0 Hz, 2 CH of Ar), 8.05 (2 H,
d, 2JH,H = 13.52 Hz, 2 CH of Ar), 9.68 (1 H, s, NH). 13C NMR
(1 H, s, NH). 13C NMR (125.7 MHz, CDCl3):
dC (ppm) 29.80
(2 CH3), 32.22(C), 37.54 (CH2), 38.69 (CH), 43.83
(CH2NH), 45.22 (CH2N), 49.89 (CH2), 107.74 (CCO),
114.18 (C–NO2), 126.45 (CH of Ph), 128.03 (2 CH of
Ph), 128.23 (2 CH of Ph), 144.72 (Cipso of Ph),
149.41 (NCN), 152.12 (C–N), 193.63 (CO). MS: m/z
(%) = 339 (M+, 8), 293 (36), 262 (100), 216 (36), 132
(33), 77 (77), 51 (46). Anal. calcd for C19H21N3O3
(339.39): C, 67.24; H, 6.24; N, 12.38%. Found: C,
67.19; H, 6.22; N, 12.41%.
(125.7 MHz, CDCl3): dC (ppm) 21.13 (CH3), 26.66 (2 CH3),
29.77 (C), 32.25 (CH2), 38.67 (CH), 49.74 (CH2N), 51.74
(CH2), 51.95 (CH), 106.52 (CCO), 112.73 (C–NO2), 123.42
(2 CH of Ar), 129.66 (2 CH of Ar), 146.30 (NCN), 150.26
(Cipso of Ar), 151.14 (Cipso of Ar), 152.37 (C–N), 193.74 (CO).
MS: m/z (%) = 339 (M+, 8), 293 (36), 262 (100), 216 (36),
132 (33), 77 (77), 51 (46). Anal. calcd for C20H22N4O5
(398.41): C, 60.29; H, 5.57; N, 14.06%. Found: C, 60.28; H,
5.55; N, 14.08%.
4.3.2. 1,8,8-Trimethyl-4-nitro-5-phenyl-1,2,3,5,6,7,8,9-
octahydro-imidazo[1,2-a]quinoline-6-one (4b)
4.3.5. 5-(4-Chlorophenyl)-8,8-dimethyl-4-nitro-
1,2,3,5,6,7,8,9-octahydro-imidazo[1,2-a]quinoline-6-one
(4e)
Yellow powder (yield 79%); mp: 260 8C (decomp); IR
(KBr) (n
max, cmÀ1): 3349 (NH), 1646 (C5O), 1522 and
1351 (C–NO2). 1H NMR (500.1 MHz, CDCl3): dH (ppm)
Yellow powder (yield 73%); mp: 254 8C (decomp); IR
0.81 (3 H, s, CH3), 1.01 (3 H, s, CH3), 1.32 (3 H, br, CH3),
(KBr) (
(C–NO2). 1H NMR (500.1 MHz, CDCl3):
dH (ppm) 0.82 (3 H,
n
max, cmÀ1): 3351 (NH), 1641 (C5O), 1553 and 1350
2
1.96 (1 H, d, JH,H = 16.0 Hz, CH2), 2.16 (1 H, d,
2JH,H = 16.0 Hz, CH2), 2.47–2.56(2 H, m, CH2), 3.32–3.57
s, CH3), 1.02 (3 H, s, CH3), 1.96–2.08 (2 H, m, CH2), 2.16–
2.26 (1 H, m, CH2), 2.48–2.60 (1 H, m, CH2), 3.81 (2H, br,
CH2NH), 3.98–4.01 (1 H, m, CH2N), 4.16–4.17 (1 H, m,
CH2N), 5.02 (1 H, s, CH), 7.15–7.26 (4 H, m, 5 CH of Ar), 9.42
(2 H, m, CH2N), 4.11–4.26 (1 H, m, CHNH), 5.04 (1 H, s,
CH), 7.08–7.17 (5 H, m, 5 CH of Ph), 9.51 (1 H, s, NH). 13
NMR (125.7 MHz, CDCl3): dC (ppm) 21.13 (CH3), 28.65 (2
CH3), 31.11 (C), 33.56 (CH2), 39.42 (CH), 49.96 (CH2N),
52.75 (CH2), 53.00 (CH), 107.98 (CCO), 114.17 (C–NO2),
127.33 (CH of Ph), 128.56 (2 CH of Ph), 128.97 (2 CH of
Ph), 144.22 (Cipso of Ph), 149.16 (NCN), 151.39 (C–N),
193.42 (CO). MS: m/z (%) = 353 (M+, 2), 348 (4), 262
(100), 216 (22), 137 (18), 77 (67), 51 (53). Anal. calcd for
C
(1 H, s, NH). 13C NMR (125.7 MHz, CDCl3):
dC (ppm) 26.94
(2 CH3), 31.37 (C), 37.35 (CH2), 39.48 (CH), 43.86 (CH2NH),
45.22 (CH2N), 49.89 (CH2), 107.38 (CCO), 113.62 (C–NO2),
127.95 (CH of Ar), 130.15 (2 CH of Ar), 130.96 (Cipso of Ar),
143.71 (Cipso of Ar), 149.61 (NCN), 163.49 (C–N), 193.65
(CO). MS: m/z (%) = 373 (M+, 1), 349 (74), 273 (100), 217
(70), 161 (41), 111 (25). Anal. calcd for C19H20ClN3O3
(373.83): C, 61.05; H, 5.39; N, 9.48%. Found: C, 67.19; H,
6.22; N, 12.41%.
C
20H23N3O3 (353.419): C, 67.97; H, 6.56; N, 11.89%.
Found: C, 67.98; H, 6.54; N, 11.90%.
4.3.3. 8,8-Dimethyl-4-nitro-5-(4-nitrophenyl)-
1,2,3,5,6,7,8,9-octahydro-imidazo[1,2-a]quinoline-6-one (4c)
Yellow powder (yield 91%); mp: 265 8C (decomp); IR
4.3.6. 4-Nitro-5-phenyl-1,2,3,5,6,7,8,9-octahydro-
imidazo[1,2-a]quinoline-6-one (4f)
(KBr) (
n
max, cmÀ1): 3344 (NH), 1626 (C5O), 1523 and
Yellow powder (yield 80%); mp: 248 8C (decomp); IR
1349 (C–NO2). 1H NMR (500.1 MHz, CDCl3): dH (ppm)
0.82 (3 H, s, CH3), 1.03 (3 H, s, CH3), 1.96–1.96 (1 H, m,
CH2), 2.13–2.19 (1 H, m, CH2), 2.43–2.61 (2 H, m, CH2),
3.84 (2 H, br, CH2NH), 4.02–4.04 (1 H, m, CH2N), 4.11–
4.17 (1 H, m, CH2N), 5.14 (1 H, s, CH), 7.48 (2 H, d,
2JH,H = 8.3 Hz, 2 CH of Ar), 8.05 (2 H, d, 2JH,H = 8.3 Hz, 2 CH
of Ar), 9.48 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): dC
(ppm) 26.65 (2 CH3), 29.65 (C), 32.23 (CH2), 39.50 (CH),
43.96 (CH2NH), 45.25 (CH2N), 49.76 (CH2), 107.23 (CCO),
113.41 (C–NO2), 123.27 (2 CH of Ar), 129.65 (2 CH of Ar),
146.30 (NCN), 150.14 (Cipso of Ar), 151.85 (Cipso of Ar),
152.37 (C–N), 193.65 (CO). MS: m/z (%) = 384 (M+, 3), 339
(14), 262 (100), 235 (42), 111(39), 55 (24). Anal. calcd for
(KBr) (
(C–NO2). 1H NMR (500.1 MHz, CDCl3):
n
max, cmÀ1): 3159 (NH), 1649 (C5O), 1582 and 1392
d
H (ppm) 1.83–1.94
(2 H, m, CH2), 2.27–2.49 (2 H, m, CH2), 2.62–2.80 (2 H, m,
CH2), 3.38–4.02 (4 H, m, CH2NH and CH2N), 5.36 (1 H, s,
CH), 7.11–7.68 (5 H, m, 5 CH of Ph), 9.61 (1 H, s, NH). 13C
NMR (125.7 MHz, CDCl3): dC (ppm) 20.30 (CH2), 26.88
(CH2), 31.29 (CH), 36.84 (CH2), 42.34 (CH2NH), 43.45
(CH2N), 102.59 (CCO), 115.99 (C–NO2), 125.92 (CH of Ph),
128.21 (2 CH of Ph), 128.47 (2 CH of Ph), 136.50 (Cipso of
Ph), 144.99 (NCN), 151.93 (C–N), 196.69 (CO). MS: m/z
(%) = 294 (37), 217 (100), 152 (20), 115 (22), 77 (37), 55
(25). Anal. calcd for C17H17N3O3 (311.33): C, 65.58; H, 5.50;
N, 13.50%. Found: C, 65.56; H, 5.51; N, 13.49%.
Please cite this article in press as: Alizadeh A, Rezvanian A. Catalyst- and solvent-free synthesis of highly functionalized
octahydro-imidazo[1,2-a]quinolin-6-ones via a one-pot sequential four-component reaction in melt conditions. C. R.
Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.018

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CRAS2C-3782; No. of Pages 5
A. Alizadeh, A. Rezvanian / C. R. Chimie xxx (2013) xxx–xxx
5
4.3.7. 2-Methyl-4-nitro-5-phenyl-1,2,3,5,6,7,8,9-octahydro-
imidazo[1,2-a]quinoline-6-one (4g)
(C–N), 193.88 (CO). MS: m/z (%) = 328 (90), 293 (66), 217
(100), 152 (25), 111 (27), 77 (16), 20 (46). Anal. calcd for
Yellow powder (yield 71%); mp: 247 8C (decomp); IR
C17H16ClN3O3 (345.78): C, 59.05; H, 4.66; N, 10.25%.
Found: C, 59.10; H, 4.64; N, 110.28%.
(KBr) (
n
max, cmÀ1): 3159 (NH), 1649 (C5O), 1582 and 1392
(C–NO2). 1H NMR (500.1 MHz, CDCl3):
d
H (ppm) 1.47 (3 H,
br, CH3), 1.76–1.93 (2 H, m, CH2), 2.24–2.42 (2 H, m, CH2),
2.57–2.65 (2 H, m, CH2), 3.53–3.66 (2 H, m, CH2N), 4.17–
4.23 (1 H, m, CHNH), 5.38 (1 H, s, CH), 7.10–7.30 (5 H, m, 5
CH of Ph), 8.70 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): dC
(ppm) 20.25 (CH3), 21.14 (CH2), 27.32 (CH2), 31.59 (CH),
37.91 (CH2), 48.34 (CHNH), 50.13 (CH2N), 104.76 (CCO),
116.88 (C–NO2), 126.35 (CH of Ph), 128.04 (2 CH of Ph),
128.32 (2 CH of Ph), 135.83 (Cipso of Ph), 144.33 (NCN),
151.65 (C–N), 196.40 (CO). MS: m/z (%) = 325 (M+, 2), 294
(82), 217 (90), 156 (70), 91 (100). Anal. calcd for
Acknowledgements
We gratefully acknowledge financial support from the
Research Council of Tarbiat Modares University.
References
[1] (a) A. Omodei-Sale, E. Toia, G. Galliani, L. Lerner, J. Ger. Offen. 85 (1997)
192731, 2551868; Chem. Abstr.;
(b) I.R. Ager, P. Ramm, J. Ger. Offen. 89 (1978) 180001, 2802493; Chem.
Abstr;
(c) I.R. Ager, A.C. Barnes, G.W. Danswan, P.W. Hairsine, D.P. Kay, P.D.
Kennewell, S.S. Matharu, P. Miller, P. Robson, D.A. Rowlands, W.R. Tully,
R. Westwood, J. Med. Chem. 31 (1988) 1098.
C18H19N3O3 (325.36): C, 65.58; H, 5.50; N, 13.50%. Found:
C, 65.56; H, 5.51; N, 13.49%.
[2] (a) S. Clements-Jewery, G. Danswan, C.R. Gardner, S.S. Matharu, R.
Murdoch, W.R. Tully, R. Westwood, J. Med. Chem. 31 (1988) 1220;
(b) S. Khom, I. Baburin, E.N. Timin, A. Hohaus, W. Sieghart, S. Hering,
Mol. Pharmacol. 69 (2006) 640;
(c) W. Ogris, A. Po¨ltl, B. Hauer, M. Ernst, A. Oberto, P. Wulff, H. Ho¨ger, W.
Wisden, W. Sieghart, Biochem. Pharmacol. 68 (2004) 1621;
(d) P. Scholze, V. Ebert, W. Sieghart, Eur. J. Pharmacol. 304 (1996) 155.
[3] J.F. Gerster, K.J. Lindstrom, G.J. Marszalek, B.A. Merrill, B.J.W. Mickelson,
M. Rice, J. PCT Int. Appl. 132 (2000) 137381, WO2000006577, Chem.
Abstr..
[4] (a) V.A. Mamedov, I.A. Nuretdinov, F.G. Sibgatullina, Izv. Akad. Nauk
SSSR, Ser. Khim. (1990) 2627;
(b) B. Kickho¨fen, Chem. Ber. 88 (1955) 1114.
[5] (a) A.L. Krasovsky, V.G. Nenajdenko, E.S. Balenkova, Synthesis (2002)
1379;
4.3.8. 4-Nitro-5-(4-nitrophenyl)-1,2,3,5,6,7,8,9-octahydro-
imidazo[1,2-a]quinoline-6-one (4h)
Yellow powder (yield 87%); mp: 245 8C (decomp); IR
(KBr) (
(C–NO2). 1H NMR (500.1 MHz, CDCl3):
n
max, cmÀ1): 3378 (NH), 1654 (C5O), 1532 and 1337
d
H (ppm) 1.73 (1 H,
br, CH2), 1.93 (1 H, br, CH2), 2.17–2.65 (4 H, m, CH2), 3.81–
3.84 (2 H, m, CH2NH), 3.99–4.05 (1 H, m, CH2N), 4.15–4.18
(1 H, m, CH2N), 5.19 (1 H, s, CH), 7.48 (2 H, d, 3JH,H = 7.9 Hz,
2 CH of Ar), 8.04 (2 H, d, 3JH,H = 8.0 Hz, 2 CH of Ar), 9.48 (1 H,
s, NH). 13C NMR (125.7 MHz, CDCl3):
dC (ppm) 20.61 (CH2),
25.67 (CH2), 36.21 (CH), 38.17 (CH2), 43.96 (CH2NH), 45.21
(CH2N), 106.80 (CCO), 113.95 (C–NO2), 123.33 (2 CH of Ar),
129.63 (2 CH of Ar), 146.31 (Cipso of Ar), 151.68 (NCN),
152.14 (C–N), 152.63 (Cipso of Ar), 193.88 (CO). MS: m/z
(%) = 356 (M+, 8), 338 (6), 310 (13), 264 (10), 234 (100), 188
(43), 132 (31), 83 (21), 55 (47). Anal. calcd for C17H16N4O5
(356.33): C, 57.30; H, 4.53; N, 15.72%. Found: C, 57.28; H,
4.55; N, 15.71%.
(b) J. Reisch, M. Scheer, J. Heterocycl. Chem. 25 (1988) 677;
(c) T. Kato, Y. Yamamoto, S. Takeda, Yakugaku Zasshi 94 (1974) 627,
Chem. Abstr. 81 (1974) 37514.
[6] S.R. Inglis, R.K. Jones, G.W. Booker, S.M. Pyke, Bioorg. Med. Chem. Lett.
16 (2006) 387.
[7] (a) H. Bienayme, K. Bouzid, Angew. Chem. Int. Ed. 37 (1998) 2234;
(b) S.M. Ireland, H. Tye, M. Whittaker, Tetrahedron Lett. 44 (2003)
4369.
[8] (a) R.F. Cookson, D.P. Nowotnik, R.T.R. Parfitt, J. Chem. Soc., Chem.
Commun. (1974) 911;
(b) V.A. Artyomov, A.M. Shestopalov, V.P. Litvinov, Synthesis (1996)
927;
4.3.9. 5-(4-Chlorophenyl)-4-nitro-1,2,3,5,6,7,8,9-octahydro-
imidazo[1,2-a]quinoline-6-one (4i)
(c) S. Ito, A. Kakehi, T. Miwa, Heterocycles 32 (1991) 2373.
[9] P. Angibaud, X. Bourdrez, D.W. End, E. Freyne, M. Janicot, P. Lezouret, Y.
Ligny, G. Mannens, S. Damsch, L. Mevellec, C. Meyer, P. Muller, I. Pilatte,
V. Poncelet, B. Roux, G. Smets, J. Van Dun, P. Van Remoortere, M. Venet,
W. Wouters, Bioorg. Med. Chem. Lett. 13 (2003) 4365.
[10] (a) A.R. Katritzky, M. Michalska, R.L. Harlow, S.H. Simonsen, J. Chem.
Soc., Perkin Trans. 1 (1980) 354;
(b) R.H. Prager, Y. Singh, Tetrahedron 49 (1993) 8147;
(c) R.H. Prager, Y. Singh, B. Weber, Aust. J. Chem. 47 (1994) 1249;
(d) J. Parrick, R. Wilcox, J. Chem. Soc., Perkin Trans. 1 (1976) 2121.
[11] (a) A. Alizadeh, A. Rezvanian, L.G. Zhu, J. Org. Chem. 77 (2012) 4385;
(b) A. Rezvanian, A. Alizadeh, Tetrahedron (2012) 2526;
(c) A. Alizadeh, A. Rezvanian, Synlett 8 (2011) 1105;
(d) A. Alizadeh, A. Rezvanian, J. Mokhtari, Synthesis 21 (2011) 3491;
(e) A. Alizadeh, A. Zarei, A. Rezvanian, Synthesis 3 (2011) 497.
Yellow powder (yield 85%); mp: 243 8C (decomp); IR
(KBr) (
1348 (C–NO2). 1H NMR (500.1 MHz, CDCl3):
n
max, cmÀ1): 3380 (NH), 1660 (C5O), 1533 and
d
H (ppm) 1–
73–1.94 (2 H, m, CH2), 2.17–2.25 (2 H, m, CH2), 2.48–
2.63 (2 H, m, CH2), 3.79–3.85 (2 H, m, CH2NH), 4.02–4.14
(2 H, m, CH2N), 5.07 (1 H, s, CH), 7.13–7.27 (4 H, m, 5 CH
of Ar), 9.41 (1 H, s, NH). 13C NMR (125.7 MHz, CDCl3): dC
(ppm) 20.26 (CH2), 26.88 (CH2), 36.79 (CH), 37.20 (CH2),
43.87 (CH2NH), 45.21 (CH2N), 107.31 (CCO), 113.62 (C–
NO2), 128.00 (2 CH of Ar), 130.14 (2 CH of Ar), 130.98
(Cipso of Ar), 143.94 (Cipso of Ar), 151.55 (NCN), 151.79
Please cite this article in press as: Alizadeh A, Rezvanian A. Catalyst- and solvent-free synthesis of highly functionalized
octahydro-imidazo[1,2-a]quinolin-6-ones via a one-pot sequential four-component reaction in melt conditions. C. R.
Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.05.018