A simple method for the rapid synthesis of 2-amino-7,7-dimethyl-5-oxo-1,4-diaryl-hexahydroquinoline-3-carboxamide derivatives

Article abstract of DOI:10.1007/s13738-020-01920-3

Abstract: Simple synthesis of oxoquinoline carboxamide derivatives via one-pot, multi-component reaction of enaminones derived from the addition of dimedone to various anilines with aromatic aldehydes and cyanoacetamide is described. Optimal reaction cond

Full text of DOI:10.1007/s13738-020-01920-3

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-020-01920-3
ORIGINAL PAPER
A simple method for the rapid synthesis of 2‑amino‑7,7‑dimethyl‑5‑
oxo‑1,4‑diaryl‑hexahydroquinoline‑3‑carboxamide derivatives
Fahimeh Sadat Hosseini1 · Mohammad Bayat1
Received: 22 January 2018 / Accepted: 21 March 2020
© Iranian Chemical Society 2020
Abstract
Simple synthesis of oxoquinoline carboxamide derivatives via one-pot, multi-component reaction of enaminones derived
from the addition of dimedone to various anilines with aromatic aldehydes and cyanoacetamide is described. Optimal reac-
tion conditions for the synthesis of products were obtained, when EtOH/H2O (1:1) was used as the solvent at 80 °C, in the
presence of piperidine as the catalyst. The reactions are completed within 5–25 min, in good to high yields (74–85%). This
protocol involves Michael reaction, imine-enamine tautomerization, and cyclization sequences. The structures of products
were deduced from their IR, mass, 1H NMR, and 13C NMR spectra. This method includes some important aspects including
simple operation under mild conditions, easy accessibility of reactants, workup procedure, high atom economy, and the use
of ethanol/water as a green media.
Graphic abstract
Keywords Oxoquinoline carboxamide · Dimedone · Anilines · Aromatic aldehydes · Cyanoacetamide
Introduction
Multi-component reactions (MCRs) occupy an outstand-
Electronic supplementary material The online version of this
ing position in organic and medicinal chemistry [1]. These
article (https://doi.org/10.1007/s13738-020-01920-3) contains
reactions are characterized by their convergence, ease of
supplementary material, which is available to authorized users.
execution, high yields, efciency, reducing waste, and atom
economy [2]. Also, the range of readily available starting
materials and the simplicity of one-pot procedures make it
a very powerful tool in achieving such synthetic efciency
[3–7]. Among these, the multi-component synthesis of poly-
functionalized heterocyclic compounds has become more
challenging in organic and medicinal chemistry [8–10].
* Mohammad Bayat
m.bayat@sci.ikiu.ac.ir; bayat_mo@yahoo.com
Fahimeh Sadat Hosseini
f.hosseini_64@yahoo.com
1
Department of Chemistry, Faculty of Science, Imam
Khomeini International University, Qazvin, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
Table 1 Optimization of reaction conditions for the synthesis of 5a
The presence of the quinoline skeleton in the frame-
works of pharmacologically active compounds and natu-
ral products has spurred on the development of diferent
strategies for their synthesis [11]. The quinolines and their
derivatives are known to possess useful biological activi-
ties such as antibacterial, antimalarial, antiplasmodial,
anticancer, cytotoxic [12–14], anti-infammatory, antihy-
pertensive [15–17], antitumor [18, 19], antituberculosis
[20, 21], and antiamoebic [22]. Therefore, the synthesis of
these compounds has attracted much attention in organic
synthesis.
Entry Reaction condi-
tions
Catalyst
Time (min) Yield (%)
1
2
3
4
EtOH, 80 °C
CH3CN, 80 °C
H2O, 80 °C
–
–
–
–
Overnight No reaction
Overnight No reaction
Overnight No reaction
Overnight No reaction
EtOH/H2O (1:1),
80 °C
5
6
7
8
EtOH, 80 °C
CH3CN, 80 °C
H2O, 80 °C
Piperidine
Piperidine
Piperidine
180
150
76
80
Overnight No reaction
10
To this day, extensive libraries of quinoline derivatives
are reported [23–41]. For example, in 2012, Singh et al.
reported the synthesis of N-arylquinoline derivatives via
an efcient one-pot, multi-component reaction of aromatic
aldehydes, 3-arylamino-5,5-dimethylcyclohex-2-enone,
and active methylene compounds utilizing 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) as a catalyst in ethanol
under microwave irradiation [42]. In 2017, Dai et al. devel-
oped the Cu(OAc)2.H2O catalyzed domino reaction of pri-
mary arylamines and electron-defcient terminal alkynes
at room temperature. It provides convenient access to a
variety of 2,4-disubstituted quinolines in good to excel-
lent yields without protection from moisture or air [43].
In 2018, Jiang et al. described a new method to construct
4-hydroxalkyl-quinoline derivatives via Cu(I) and Au(I)
sequential catalyzed cyclization of anilines with aldehyde
derivatives and aliphatic alkynes, respectively [44]. Also,
in 2019, Khan et al. synthesized new quinoline-3-carbon-
itrile derivatives by a one-pot, multi-component reaction
of appropriate aldehyde, ethyl cyanoacetate, 6-methoxy-
1,2,3,4-tetrahydro-naphthalin-1-one, and ammonium ace-
tate in ethanol as a solvent [45].
EtOH/H2O (1:1), Piperidine
80
60
30
58
43
80 °C
9
EtOH/H2O (1:2),
80 °C
Piperidine
Piperidine
240
300
10
11
12
EtOH/H2O (1:3),
80 °C
EtOH/H2O (1:1),
80 °C
Diethylamine 10
Triethylamine 40
EtOH/H2O (1:1),
80 °C
The best results are shown in bold
cyanoacetamide, respectively, in melt conditions and then
in ethanol/water as a green media.
Results and discussion
The one-pot, multi-component reaction of enaminones
derived from the addition of dimedone 1 to various anilines
2 under solvent-free conditions at 80 °C, with aromatic alde-
hydes 3 and cyanoacetamide 4 in the presence of catalytic
amount of piperidine, in EtOH/H2O (1:1) as a green solvent
at 80 °C led to the corresponding oxoquinoline carboxamide
derivatives 5a–u, in good to high yields (Scheme 1).
In continuation of our research interests regarding the
development of new methods in heterocyclic compounds
synthesis [46, 47], herein, we report piperidine-catalyzed
rapid preparation of new class of oxoquinoline carboxa-
mide derivatives via one-pot, multi-component reaction
of dimedone, various anilines, aromatic aldehydes, and
In order to optimize the reaction conditions, several
solvents with the absence and presence of catalyst were
Scheme 1 Synthetic scheme for
the products 5a–u
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Journal of the Iranian Chemical Society
examined to set up standard reaction conditions, and the
results are summarized in Table 1. Experimental results
showed that the reaction proceeded cleanly with high yields
and the shortest reaction times when the two components
1 and 2 react in the melt conditions and then by adding 3
and 4 in ethanol/water (1:1) in the presence of piperidine as
a catalyst at 80 °C (Table 1, Entry 8). The reaction did not
work in the absence of catalyst and also in H2O as reaction
media. When the EtOH or CH3CN was used as a solvent in
the presence of piperidine at 80 °C, the yield of product was
good at longer reaction time (Table 1, Entries 5 and 6). Also,
the yield of the product was low when ethanol/water (1:1)
was used as a solvent in the presence of diethylamine or
triethylamine as a catalyst at 80 °C (Table 1, Entries 11 and
12). We explored the scope of this reaction by varying the
structure of the aromatic aldehyde and aniline components.
The reaction proceeded very cleanly under the same reac-
tion conditions to aford a series of fused quinolines 5a–u in
74–85% yields. The results are shown in Table 2.
and CONH2 (amide) groups (δ 6.35, 7.08, respectively), and
multiplets for the aromatic moieties (δ 7.25–7.61).
The mass spectrum of 5a displayed the molecular ion
peak at m/z 456, which was in agreement with the proposed
1
structure. The H-decoupled 13C NMR spectrum of 5a
showed 20 distinct resonances, which confrmed the pro-
posed structure. The IR spectrum of 5a displayed character-
istic absorption bands (3471, 3355, 1626, 1483, 1267 cm−1)
due to the NH2, C=O, Ar, and C–N groups.
A plausible mechanism for the formation of product 5 is
shown in Scheme 2. It is reasonable to assume that the reac-
tion involves the initial formation of enaminone intermedi-
ate 6 between the dimedone 1 and aniline 2. Apparently,
the reaction proceeds by activation of the CH acid 4 with
piperidine for the Knoevenagel condensation with aromatic
aldehyde 3 to form the corresponding Knoevenagel interme-
diate 7. Intermediate 6 is also activated by piperidine for the
next Michael-type addition reaction to aford 8. Then, inter-
mediate 8 undergoes successive imine-enamine tautomeriza-
tion, followed by cyclization by nucleophilic addition of the
secondary amino group to CN group, and then, dehydration
led to the formation of product 5.
The structures of compounds 5a–u were deduced from
their IR, mass, 1H NMR, and 13C NMR spectra (see the Sup-
porting Information). For example, the 1H NMR spectrum
of 5a showed two singlets for the CH3 groups (δ 0.57, 0.84),
multiplets for the two CH2 groups (δ 1.53–2.22), one singlet
for the CH group (δ 4.84), two singlets for the NH2 (amine)
Table 2 Products 5a-u
Entry
Ara
Ar’a
Product 5
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
3,4-Cl2C6H4
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
C6H5
4-ClC6H4
3-ClC6H4
4-BrC6H4
3-FC6H4
4-NO2C6H4
4-ClC6H4
3-ClC6H4
4-BrC6H4
3-FC6H4
4-ClC6H4
3-ClC6H4
4-BrC6H4
4-FC6H4
4-NO2C6H4
4-ClC6H4
3-ClC6H4
4-BrC6H4
3-FC6H4
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
10
10
10
20
10
10
10
5
20
10
10
5
25
10
5
5
5
80
78
82
75
78
78
76
80
74
82
83
85
78
80
78
78
79
74
75
75
78
9
10
11
12
13
14
15
16
17
18
19
20
21
10
10
10
5
4-ClC6H4
3-ClC6H4
4-BrC6H4
C6H5
C6H5
5t
5u
aDimedone (1 mmol), aniline (1 mmol), aromatic aldehyde (1 mmol), and cyanoacetamide (1 mmol) were
used in H2O/EtOH as a solvent at 80 °C, in the presence of piperidine as a catalyst
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Journal of the Iranian Chemical Society
Scheme 2 Plausible mechanism for the formation of product 5
General procedure for the synthesis of product 5
Conclusion
A mixture of dimedone 1 (1 mmol, 0.140 g) and aniline 2
(1 mmol) was melted at 80 °C for 5–10 min. Then, ethanol/
water (1:1, 5 mL) was added, and the solution was stirred
for 5 min at 80 °C. Next, aromatic aldehyde 3 (1 mmol),
cyanoacetamide 4 (1 mmol, 0.084 g), and one drop of piperi-
dine were added and the solution was stirred at refux for the
time given in Table 2. Upon completion as monitored by
TLC, the reaction mixture was allowed to cool to room tem-
perature, and the precipitate was fltered and washed with
ethanol/water (1:1) to give product 5 in high yields.
In conclusion, this work represents an efcient methodol-
ogy for the rapid preparation of a new class of oxoquino-
line carboxamide derivatives via a one-pot, multi-com-
ponent reaction of dimedone, various anilines, aromatic
aldehydes, and cyanoacetamide in melt condition and then
in ethanol/water as a green media at 80 °C, respectively.
The mild reaction conditions, high yields, its experimental
simplicity, short reaction times, simple purifcation pro-
cess involving no chromatographic process, and compat-
ibility with various functional groups make this approach
attractive for the synthesis of a variety of such derivatives.
2‑Amino‑1,4‑bis(4‑chlorophenyl)‑1,4,5,6,7,8‑hexahy-
dro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide (5a) Yellow
powder, mp: 249–253 °C, 0.364 g, yield: 80%. IR (KBr)
(νmax/cm−1): 3471 (NH2), 3355 (NH2), 1626 (C=O), 1483
(Ar), 1267 (C–N).1H NMR (300 MHz, DMSO): δ 0.57 (3H,
s, CH3), 0.84 (3H, s, CH3), 1.53–2.22 (4H, m, 2CH2), 4.84
(1H, s, CH), 6.35 (2H, s, NH2), 7.08 (2H, s, NH2), 7.26 (2H,
d, 3JHH =8.4 Hz, Ar), 7.34–7.41 (4H, m, Ar), 7.60 (2H, d,
3JHH =8.4 Hz, Ar). 13C NMR (75.4 MHz, DMSO): δ 26.0,
29.8, 32.2, 34.1, 41.4, 49.9, 80.8, 113.6, 128.1, 129.7, 130.5,
132.5, 134.5, 135.8, 138.5, 146.8, 150.2, 151.2, 171.9, 195.0.
MS (EI, 70 eV): m/z (%)=456 (M+, 5), 411 (100), 344 (44),
111 (15), 44 (9). Anal. Calcd (%) for C24H23N3O2Cl2 (456.36
gr): C, 63.16; H, 5.08; N, 9.21. Found: C, 63.5; H, 5.4, N,
9.1.
Experimental
General
The dimedone, various anilines, aromatic aldehydes,
cyanoacetamide, and other chemicals and solvents were
obtained from Merck and Aldrich and were used without
further purifcation. NMR spectra were recorded with a
Bruker DRX-300 Avance instrument (300 MHz for 1H and
75.4 MHz for 13C) with DMSO and CDCl3 as solvents.
Chemical shifts are given in ppm (δ), and coupling con-
stant (J) is reported in hertz (Hz). Melting points were
measured with an electrotherma1 9100 apparatus. Mass
spectra were recorded with an Agilent 5975C VL MSD
with Triple-Axis Detector operating at an ionization poten-
tial of 70 eV. IR spectra were measured with Bruker Ten-
sor 27 spectrometer.
2‑Amino‑4‑(3‑chlorophenyl)‑1‑(4‑chlorophenyl)‑1,4,5,6,7,
8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5b) Yellow powder, mp: 241–245 °C, 0.355 g, yield:
78%. IR (KBr) (νmax/cm−1): 3471 (NH2), 3358 (NH2),
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Journal of the Iranian Chemical Society
1623 (C=O), 1483 (Ar), 1267 (C–N). 1H NMR (300 MHz,
CDCl3): δ 0.69 (3H, s, CH3), 0.93 (3H, s, CH3), 1.65–2.23
(4H, m, 2CH2), 4.88 (1H, s, CH), 5.03 (2H, s, NH2), 6.68
(2H, s, NH2), 7.12–7.51 (8H, m, Ar). 13C NMR (75.4 MHz,
CDCl3): δ 26.3, 29.5, 32.2, 34.8, 41.7, 49.9, 80.2, 114.2,
125.6, 126.5, 127.4, 129.7, 130.6, 131.3, 134.1, 134.6,
136.0, 147.9, 149.1, 151.2, 171.9, 195.4. MS (EI, 70 eV):
m/z (%) = 456 (M+, 5), 411 (100), 344 (67), 111 (18), 44
(15). Anal. Calcd (%) for C24H23N3O2Cl2 (456.36 gr): C,
63.16; H, 5.08; N, 9.21. Found: C, 63.4; H, 4.7, N, 9.5.
2‑Amino‑1‑(3‑chlorophenyl)‑4‑(4‑chlorophenyl)‑1,4,5,6,7,
8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5f) Yellow powder, mp: 252–256 °C, 0.355 g, yield:
78%. IR (KBr) (νmax/cm−1): 3425 (NH2), 3346 (NH2),
1640 (C=O), 1478 (Ar), 1263 (C–N). 1H NMR (300 MHz,
DMSO): δ 0.57 (3H, s, CH3), 0.84 (3H, s, CH3), 1.52–2.25
(4H, m, 2CH2), 4.84 (1H, s, CH), 6.36 (2H, s, NH2), 7.08
3
(2H, s, NH2), 7.27 (2H, d, JHH = 8.4 Hz, Ar), 7.41 (2H,
3
d, JHH = 8.4 Hz, Ar), 7.53–7.63 (4H, m, Ar). 13C NMR
(75.4 MHz, DMSO): δ 26.1, 29.8, 32.3, 34.2, 41.4, 49.9,
81.0, 113.6, 128.1, 129.6, 129.8, 130.2, 130.5, 130.8, 131.9,
134.4, 138.3, 146.8, 150.0, 151.1, 171.9, 195.0.
2‑Amino‑4‑(4‑bromophenyl)‑1‑(4‑chlorophenyl)‑1,4,5,6,7,
8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5c) Yellow powder, mp: 259–263 °C, 0.410 g, yield:
82%. IR (KBr) (νmax/cm−1): 3470 (NH2), 3348 (NH2),
1622 (C=O), 1484 (Ar), 1268 (C–N). 1H NMR (300 MHz,
DMSO): δ 0.57 (3H, s, CH3), 0.84 (3H, s, CH3), 1.53–2.22
(4H, m, 2CH2), 4.82 (1H, s, CH), 6.34 (2H, s, NH2), 7.07
(2H, s, NH2), 7.32–7.63 (8H, m, Ar). 13C NMR (75.4 MHz,
CDCl3): δ 26.3, 29.5, 32.2, 34.6, 41.7, 49.9, 80.2, 114.2,
120.1, 129.1, 130.7, 131.3, 131.4, 134.6, 136.1, 144.8, 149.0,
151.2, 171.9, 195.6. Anal. Calcd (%) for C24H23N3O2ClBr
(500.82 gr): C, 57.56; H, 4.63; N, 8.39. Found: C, 57.9; H,
4.2, N, 8.1.
2‑Amino‑1,4‑bis(3‑chlorophenyl)‑1,4,5,6,7,8‑hexahy-
dro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide (5g) Yellow
powder, mp: 235–239 °C, 0.346 g, yield: 76%. IR (KBr)
(νmax/cm−1): 3471 (NH2), 3363 (NH2), 1627 (C=O), 1483
(Ar), 1268 (C–N). 1H NMR (300 MHz, DMSO): δ 0.58 (3H,
s, CH3), 0.85 (3H, s, CH3), 1.54–2.25 (4H, m, 2CH2), 4.86
(1H, s, CH), 6.43 (2H, s, NH2), 7.10 (2H, s, NH2), 7.13–7.61
(8H, m, Ar). 13C NMR (75.4 MHz, DMSO): δ 26.1, 29.8,
32.3, 34.4, 41.4, 49.9, 80.9, 113.5, 126.0, 126.4, 127.9,
129.4, 130.2, 130.4, 130.7, 132.0, 132.6, 134.5, 138.3,
150.2, 150.3, 151.1, 171.9, 195.0. MS (EI, 70 eV): m/z
(%)=456 (M+, 5), 411 (100), 344 (67), 111 (21), 44 (14).
2‑Amino‑1‑(4‑chlorophenyl)‑4‑(3‑fluorophenyl)‑1,4,5,6,7,
8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5d) Yellow powder, mp: 238–242 °C, 0.329 g, yield:
75%. IR (KBr) (νmax/cm−1): 3470 (NH2), 3357 (NH2),
1621 (C=O), 1483 (Ar), 1266 (C–N). 1H NMR (300 MHz,
DMSO): δ 0.58 (3H, s, CH3), 0.84 (3H, s, CH3), 1.54–
2.22 (4H, m, 2CH2), 4.87 (1H, s, CH), 6.40 (2H, s, NH2),
7.10 (2H, s, NH2), 6.87–7.31 (3H, m, Ar), 7.37 (2H,
2‑Amino‑4‑(4‑bromophenyl)‑1‑(3‑chlorophenyl)‑1,4,5,6,7,
8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5h) Yellow powder, mp: 244–248 °C, 0.400 g, yield: 80%.
1H NMR (300 MHz, DMSO): δ 0.58 (3H, s, CH3), 0.84 (3H,
s, CH3), 1.52–2.25 (4H, m, 2CH2), 4.82 (1H, s, CH), 6.36
(2H, s, NH2), 7.08 (2H, s, NH2), 7.35 (2H, d, 3JHH =8.1 Hz,
Ar), 7.41 (2H, d, 3JHH =8.1 Hz, Ar), 7.53–7.60 (4H, m, Ar).
13C NMR (75.4 MHz, DMSO): δ 26.1, 29.8, 32.3, 34.2, 41.4,
49.9, 80.9, 113.5, 119.0, 129.6, 130.2, 130.8, 131.1, 131.9,
134.4, 138.3, 145.0, 147.2, 150.0, 151.1, 171.9, 195.0.
3
3
d, JHH = 8.1 Hz, Ar), 7.63 (2H, d, JHH = 8.1 Hz, Ar).
13C NMR (75.4 MHz, DMSO): δ 26.0, 29.8, 32.2, 34.4,
2
41.4, 49.9, 80.7, 112.7 (d, JCF = 21 Hz), 113.5, 114.7 (d,
2JCF = 21 Hz), 123.6, 130.1, 130.6, 132.4, 134.5, 135.8,
150.3, 150.8, 151.2, 162.3 (d, 1JCF =242 Hz), 171.9, 195.0.
MS (EI, 70 eV): m/z (%)=439 (M+, 5), 395 (100), 344 (43),
111 (12). Anal. Calcd (%) for C24H23N3O2ClF (439.91 g):
C, 65.53; H, 5.27; N, 9.55. Found: C, 65.9; H, 5.8, N, 9.1.
2‑Amino‑1‑(3‑chlorophenyl)‑4‑(3‑fluorophenyl)‑1,4,5,6,7,
8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5i) Yellow powder, mp: 238–242 °C, 0.325 g, yield:
74%. IR (KBr) (νmax/cm−1): 3440 (NH2), 3342 (NH2),
1628 (C=O), 1481 (Ar), 1268 (C–N). 1H NMR (300 MHz,
DMSO): δ 0.58 (3H, s, CH3), 0.85 (3H, s, CH3), 1.54–2.25
(4H, m, 2CH2), 4.87 (1H, s, CH), 6.41 (2H, s, NH2), 7.10
(2H, s, NH2), 6.87–7.61 (8H, m, Ar). 13C NMR (75.4 MHz,
DMSO): δ 26.0, 29.8, 32.3, 34.5, 41.4, 49.9, 80.9, 112.7 (d,
2JCF =21 Hz), 113.6, 114.7 (d, 2JCF =21 Hz), 123.7, 129.5,
130.2, 130.7, 132.0, 134.4, 138.3, 150.1, 150.7, 150.8,
151.1, 162.2 (d, 1JCF =242 Hz), 171.9, 195.0.
2 ‑ A m i n o ‑ 1 ‑ ( 4 ‑ c h l o r o p h e n y l ) ‑ 1 , 4 , 5 , 6 , 7 , 8 ‑ h e xa h y -
dro‑7,7‑dimethyl‑4‑(4‑nitrophenyl)‑5‑oxoquinoline‑3‑carbox-
amide (5e) Yellow powder, mp: > 380 °C, 0.363 g, yield:
1
78%. H NMR (300 MHz, DMSO): δ 0.56 (3H, s, CH3),
0.84 (3H, s, CH3), 1.55–2.24 (4H, m, 2CH2), 5.01 (1H, s,
CH), 6.45 (2H, s, NH2), 7.17 (2H, s, NH2), 7.46 (2H, d,
3JHH =8.4 Hz, Ar), 7.64 (2H, d, 3JHH =8.1 Hz, Ar), 7.66 (2H,
d, 3JHH =8.4 Hz, Ar), 8.15 (2H, d, 3JHH =8.1 Hz, Ar). 13
C
NMR (75.4 MHz, DMSO): δ 26.1, 29.8, 32.3, 34.9, 41.5,
49.8, 80.2, 112.8, 123.6, 129.1, 130.5, 132.6, 134.6, 135.6,
146.0, 150.8, 151.3, 155.6, 171.8, 194.9.
2‑Amino‑1‑(4‑bromophenyl)‑4‑(4‑chlorophenyl)‑1,4,5,6,7,
8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5j) Yellow powder, mp: 227–231 °C, 0.410 g, yield:
1 3

Journal of the Iranian Chemical Society
1
82%. H NMR (300 MHz, DMSO): δ 0.57 (3H, s, CH3),
2‑Amino‑1‑(3,4‑dichlorophenyl)‑4‑(4‑chlorophenyl)‑1,4,5,6,
7,8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5o) Yellow powder, mp: 247–251 °C, 0.382 g, yield:
78%. IR (KBr) (νmax/cm−1): 3469 (NH2), 3346 (NH2),
1622 (C=O), 1480 (Ar), 1267 (C–N).1H NMR (300 MHz,
DMSO): δ 0.57 (3H, s, CH3), 0.85 (3H, s, CH3), 1.57–2.27
(4H, m, 2CH2), 4.82 (1H, s, CH), 6.35 (2H, s, NH2), 7.19
0.84 (3H, s, CH3), 1.52–2.22 (4H, m, 2CH2), 4.83 (1H, s,
CH), 6.35 (2H, s, NH2), 7.07 (2H, s, NH2), 7.26 (2H, d,
3JHH =7.8 Hz, Ar), 7.32 (2H, d, 3JHH =8.1 Hz, Ar), 7.39 (2H,
d, 3JHH =7.8 Hz, Ar), 7.75 (2H, d, 3JHH =8.1 Hz, Ar). 13
C
NMR (75.4 MHz, DMSO): δ 26.1, 29.8, 32.2, 34.1, 41.4,
49.9, 80.8, 113.6, 123.2, 125.0, 128.1, 129.7, 130.5, 133.5,
136.3, 146.8, 150.1, 151.1, 171.9, 194.9.
3
(2H, s, NH2), 7.26 (2H, d, JHH = 8.4 Hz, Ar), 7.41 (2H,
3
d, JHH = 8.4 Hz, Ar), 7.37–7.83 (3H, m, Ar). 13C NMR
2‑Amino‑1‑(4‑bromophenyl)‑4‑(3‑chlorophenyl)‑1,4,5,6,7,
8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5k) Yellow powder, mp: 215–219 °C, 0.415 g, yield: 83%.
1H NMR (300 MHz, DMSO): δ 0.58 (3H, s, CH3), 0.84 (3H,
s, CH3), 1.55–2.22 (4H, m, 2CH2), 4.85 (1H, s, CH), 6.41
(75.4 MHz, DMSO): δ 25.9, 29.9, 32.3, 34.2, 41.4, 50.0,
80.9, 113.6, 128.1, 128.2, 129.9, 130.5, 131.2, 132.1, 132.7,
132.9, 136.8, 146.7, 149.9, 151.0, 171.9, 195.0. MS (EI,
70 eV): m/z (%) = 490 (M+, 3), 447 (100), 378 (38), 111
(11), 44 (14).
(2H, s, NH2), 7.10 (2H, s, NH2), 7.12–7.78 (8H, m, Ar). 13
C
NMR (75.4 MHz, DMSO): δ 26.3, 29.8, 32.3, 34.4, 41.4,
49.9, 80.7, 113.4, 123.2, 125.0, 126.0, 126.3, 127.9, 130.3,
132.6, 132.7, 133.5, 136.3, 150.3, 151.1, 171.9, 195.0.
2‑Amino‑1‑(3,4‑dichlorophenyl)‑4‑(3‑chlorophenyl)‑1,4,5,6,
7,8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5p) Yellow powder, mp: 234–238 °C, 0.382 g, yield: 78%.
1H NMR (300 MHz, DMSO): δ 0.58 (3H, s, CH3), 0.86 (3H,
s, CH3), 1.60–2.27 (4H, m, 2CH2), 4.84 (1H, s, CH), 6.43
(2H, s, NH2), 7.12–7.36 (2H, s, NH2), 7.12–7.84 (7H, m,
Ar). 13C NMR (75.4 MHz, DMSO): δ 25.9, 29.8, 32.3, 34.5,
41.3, 49.9, 80.8, 113.5, 126.0, 126.5, 128.0, 130.4, 131.1,
132.2, 132.4, 132.5, 132.7, 132.9, 136.8, 150.1, 150.2,
151.0, 171.9, 195.0.
2‑Amino‑1,4‑bis(4‑bromophenyl)‑1,4,5,6,7,8‑hexahy-
dro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide (5l) Yellow
1
powder, mp: 252–256 °C, 0.463 g, yield: 85%. H NMR
(300 MHz, DMSO): δ 0.57 (3H, s, CH3), 0.84 (3H, s, CH3),
1.52–2.22 (4H, m, 2CH2), 4.82 (1H, s, CH), 6.36 (2H, s,
NH2), 7.08 (2H, s, NH2), 7.26–7.35 (4H, m, Ar), 7.40 (2H,
d, 3JHH =7.5 Hz, Ar), 7.75 (2H, d, 3JHH =7.5 Hz, Ar). 13
C
NMR (75.4 MHz, DMSO): δ 26.1, 29.8, 32.2, 34.1, 41.4,
49.9, 80.8, 113.5, 119.0, 123.2, 130.1, 131.1, 132.8, 133.5,
136.3, 147.2, 150.1, 151.1, 171.9, 195.0.
2‑Amino‑4‑(4‑bromophenyl)‑1‑(3,4‑dichlorophenyl)‑1,4,5,6,
7,8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5q) Yellow powder, mp: 255–259 °C, 0.422 g, yield: 79%.
1H NMR (300 MHz, DMSO): δ 0.58 (3H, s, CH3), 0.85 (3H,
s, CH3), 1.57–2.27 (4H, m, 2CH2), 4.81 (1H, s, CH), 6.36
2‑Amino‑1‑(4‑bromophenyl)‑4‑(4‑fluorophenyl)‑1,4,5,6,7,
8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5m) Yellow powder, mp: 248–252 °C, 0.377 g, yield:
(2H, s, NH2), 7.19 (2H, s, NH2), 7.30–7.83 (7H, m, Ar). 13
C
NMR (75.4 MHz, DMSO): δ 26.0, 29.9, 32.3, 34.3, 41.4,
50.0, 80.8, 113.5, 119.0, 130.3, 131.0, 131.2, 132.1, 132.4,
132.7, 132.9, 136.8, 147.2, 149.9, 151.0, 171.9, 195.0.
1
78%. H NMR (300 MHz, DMSO): δ 0.57 (3H, s, CH3),
0.84 (3H, s, CH3), 1.52–2.22 (4H, m, 2CH2), 4.82 (1H, s,
CH), 6.34 (2H, s, NH2), 6.99 (2H, s, NH2), 6.99–7.77 (8H,
m, Ar). 13C NMR (75.4 MHz, DMSO): δ 26.0, 29.8, 32.2,
33.9, 41.4, 49.9, 81.2, 113.9, 114.8 (d, 2JCF =21 Hz), 123.2,
129.5, 132.8, 133.5, 136.3, 144.0, 149.9, 151.1, 160.8 (d,
1JCF =244 Hz), 172.0, 194.9.
2‑Amino‑1‑(3,4‑dichlorophenyl)‑4‑(3‑fuorophenyl)‑1,4,5,6,
7,8‑hexahydro‑7,7‑dimethyl‑5‑oxoquinoline‑3‑carboxamide
(5r) Yellow powder, mp: 228–232 °C, 0.350 g, yield:
74%. IR (KBr) (νmax/cm−1): 3476 (NH2), 3370 (NH2),
1627 (C=O), 1475 (Ar), 1262 (C–N). 1H NMR (300 MHz,
DMSO): δ 0.58 (3H, s, CH3), 0.86 (3H, s, CH3), 1.59–2.27
(4H, m, 2CH2), 4.85 (1H, s, CH), 6.40 (2H, s, NH2), 7.10
(2H, s, NH2), 6.87–7.83 (7H, m, Ar). 13C NMR (75.4 MHz,
DMSO): δ 25.9, 29.9, 32.3, 34.5, 41.4, 49.9, 80.8, 112.7 (d,
2JCF =21 Hz), 113.5, 114.8 (d, 2JCF =21 Hz), 123.8, 130.1,
130.2, 131.1, 132.2, 132.7, 132.9, 136.8, 150.0, 150.7,
2 ‑ A m i n o ‑ 1 ‑ ( 4 ‑ b r o m o p h e n y l ) ‑ 1 , 4 , 5 , 6 , 7 , 8 ‑ h e xa h y -
dro‑7,7‑dimethyl‑4‑(4‑nitrophenyl)‑5‑oxoquinoline‑3‑carbox-
amide (5n) Yellow powder, mp: > 380 °C, 0.408 g, yield:
1
80%. H NMR (300 MHz, DMSO): δ 0.56 (3H, s, CH3),
0.84 (3H, s, CH3), 1.55–2.24 (4H, m, 2CH2), 5.01 (1H, s,
CH), 6.45 (2H, s, NH2), 7.16 (2H, s, NH2), 7.39 (2H, d,
3JHH =8.1 Hz, Ar), 7.66 (2H, d, 3JHH =8.4 Hz, Ar), 7.76 (2H,
1
151.0, 162.2 (d, JCF = 242 Hz), 171.9, 195.0. MS (EI,
d, 3JHH =8.1 Hz, Ar), 8.15 (2H, d, 3JHH =8.4 Hz, Ar). 13
C
70 eV): m/z (%)=474 (M+, 5), 429 (100), 378 (42), 44 (10).
NMR (75.4 MHz, DMSO): δ 26.1, 29.8, 32.3, 34.9, 41.5,
49.8, 80.2, 112.8, 123.3, 123.6, 129.1, 132.9, 133.5, 136.1,
146.0, 150.8, 151.3, 155.6, 171.8, 194.9.
2 ‑ A m i n o ‑ 4 ‑ ( 4 ‑ c h l o r o p h e n y l ) ‑ 1 , 4 , 5 , 6 , 7 , 8 ‑ h e xa h y -
dro‑7,7‑dimethyl‑5‑oxo‑1‑phenylquinoline‑3‑carboxamide
(5s) Yellow powder, mp: 247–251 °C, 0.316 g, yield:
1 3

Journal of the Iranian Chemical Society
75%. IR (KBr) (νmax/cm−1): 3436 (NH2), 3343 (NH2),
1634 (C=O), 1483 (Ar), 1264 (C–N).1H NMR (300 MHz,
DMSO): δ 0.57 (3H, s, CH3), 0.82 (3H, s, CH3), 1.51–2.20
(4H, m, 2CH2), 4.86 (1H, s, CH), 6.42 (2H, s, NH2), 7.00
(2H, s, NH2), 7.13–7.58 (9H, m, Ar). 13C NMR (75.4 MHz,
DMSO): δ 26.2, 29.8, 32.2, 34.1, 41.5, 49.9, 80.8, 113.5,
128.1, 129.7, 129.9, 130.1, 130.5, 130.6, 136.9, 146.8,
150.4, 151.3, 172.0, 194.9. MS (EI, 70 eV): m/z (%)=421
(M+, 5), 377 (100), 310 (51), 77 (20).
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2 ‑ A m i n o ‑ 4 ‑ ( 3 ‑ c h l o r o p h e n y l ) ‑ 1 , 4 , 5 , 6 , 7 , 8 ‑ h e xa h y -
dro‑7,7‑dimethyl‑5‑oxo‑1‑phenylquinoline‑3‑carboxamide
(5t) Yellow powder, mp: 237–241 °C (dec.), 0.316 g, yield:
75%. 1H NMR (300 MHz, DMSO): δ 0.57 (3H, s, CH3), 0.83
(3H, s, CH3), 1.52–2.20 (4H, m, 2CH2), 4.86 (1H, s, CH),
6.42 (2H, s, NH2), 6.99 (2H, s, NH2), 7.13–7.61 (9H, m, Ar).
13C NMR (75.4 MHz, DMSO): δ 26.1, 29.7, 32.3, 34.4, 41.5,
49.9, 80.7, 113.4, 126.0, 126.3, 127.9, 130.0, 130.3, 130.4,
130.6, 132.6, 136.9, 150.4, 150.6, 151.3, 171.9, 195.0.
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2 ‑ A m i n o ‑ 4 ‑ ( 4 ‑ b r o m o p h e n y l ) ‑ 1 , 4 , 5 , 6 , 7 , 8 ‑ h e xa h y -
dro‑7,7‑dimethyl‑5‑oxo‑1‑phenylquinoline‑3‑carboxamide
(5u) Yellow powder, mp: 246–250 °C, 0.363 g, yield: 78%.
1H NMR (300 MHz, DMSO): δ 0.57 (3H, s, CH3), 0.82 (3H,
s, CH3), 1.50–2.20 (4H, m, 2CH2), 4.84 (1H, s, CH), 6.36
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(2H, s, NH2), 6.97 (2H, s, NH2), 7.32–7.55 (9H, m, Ar). 13
C
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NMR (75.4 MHz, DMSO): δ 26.2, 29.8, 32.2, 34.2, 41.5,
49.9, 80.8, 113.4, 119.0, 129.9, 130.1, 130.3, 130.5, 131.1,
136.9, 147.3, 150.4, 151.3, 171.9, 194.9.
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29. H.G. Fu, Z.W. Li, X.X. Hu, S.Y. Si, X.F. You, S. Tang, Y.X.
Wang, D.Q. Song, Molecules 24, 548 (2019)
Acknowledgements Financial support of this research from Imam
Khomeini International University, Iran, is gratefully acknowledged.
30. X.Y. Jin, H. Chen, D.D. Li, A.L. Li, W.Y. Wang, W. Gu, J.
Enzyme Inhib. Med. Chem. 34, 955 (2019)
Compliance with ethical standards
31. S.N. Chanquia, F. Larregui, V. Puente, C. Labriola, E. Lom-
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Conflict of interest The authors declare no competing fnancial inter-
est.
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