Green synthetic approach toward new chromeno[4,3-b]quinoline and chromeno[4,3-b]pyridine derivatives

Article abstract of DOI:10.1007/s10593-019-02585-4

[Figure not available: see fulltext.] A facile, convenient, and efficient synthesis of new chromeno[4,3-b]quinoline and chromeno[4,3-b]pyridine derivatives has been accomplished via one-pot three-component reaction of 4-aminocoumarin, 1,3-dicarbonyl compo

Full text of DOI:10.1007/s10593-019-02585-4

DOI 10.1007/s10593-019-02585-4
Chemistry of Heterocyclic Compounds 2019, 55(11±, 1104–1110
Green synthetic approach toward new chromeno[4,3-b]quinoline
and chromeno[4,3-b]pyridine derivatives
1
1
Abolfazl Olyaei *, Reyhaneh Mohammad Ebrahimi ,
1
2
Alireza Adl , Mahdieh Sadeghpour
1
Department of Chemistry, Payame Noor University,
P. O. Box 19395-4697, Tehran, Iran; е-mail: olyaei_a@pnu.ac.ir
2
Department of Chemistry, Takestan Branch, Islamic Azad University,
Takestan, Iran; e-mail: m.sadeghpour@tiau.ac.ir
Submitted June 25, 2019
Accepted after revision September 11, 2019
Published in Khimiya Geterotsiklicheskikh Soedinenii,
019, 55(11±, 1104–1110
2
A facile, convenient, and efficient synthesis of new chromeno[4,3-b]quinoline and chromeno[4,3-b]pyridine derivatives has been accomplished
via one-pot three-component reaction of 4-aminocoumarin, 1,3-dicarbonyl compounds (dimedone and Meldrum's acid±, and substituted
aromatic aldehydes in H O or EtOH under reflux conditions using 10 mol % of guanidine hydrochloride as organocatalyst. Formation of
2
products proceeds through tandem Knoevenagel and Michael reactions, followed by concomitant cyclization and dehydration or
decarboxylation. A wide range of aromatic aldehydes were tolerated by the developed protocol. The advantages of this environmentally
friendly synthetic approach are short reaction times, high atom economy, operational simplicity, application of readily available catalyst,
high yields of products, simple workup procedure, and possibility to purify products by recrystallization.
Keywords: 4-aminocoumarin, chromeno[4,3-b]pyridine, chromeno[4,3-b]quinoline, guanidine hydrochloride.
In recent years, increased attention has been directed
toward synthesis of chromene derivatives owing to their
wide application in various research fields, including
biological sciences and medicinal chemistry. Compounds
with chromene scaffold possess a variety of useful
pharmacological and biological activities, such as anti-
compounds. Thus, in addition to unsubstituted chromeno-
quinolines,17 synthesis of chromenoquinoline derivatives
has been also reported. For example, Paul and Das described
synthesis of 7,10,11,12-tetrahydro-6H-chromeno[4,3-b]-
quinoline derivatives via one-pot three-component cyclocon-
densation of 4-aminocoumarin, aromatic aldehydes, and
dimedone or 1,3-indandione using ethyl L-lactate as green
convulsant, antibacterial, anticancer, antitumor,4 anti-
1
2
3
5
6
7
8
18
vascular, antifungal, antioxidant, anti-inflammatory, and
solvent and (± ±-lactic acid as organocatalyst. Ahmed and
9
10
antitubercular, and may act as apoptosis inducers and
coworkers demonstrated simple and highly efficient method
1
1
inhibitors of Chk1 kinase.
for the synthesis of 7,10,11,12-tetrahydro-6H-chromeno-
19
As an important subclass of nitrogen-containing hetero-
cycles, chromenoquinolines exhibit interesting biological
[4,3-b]quinolines in AcOH. Recently, Pal and coworkers
reported Sc(OTf± -catalyzed synthesis of chromeno[4,3-b]-
3
12
13
15
20
properties, for example, anti-inflammatory, bacteriostatic,
quinolines in MeCN. Furthermore, Foroumadi and coworkers
14
and anticancer, and can be used as selective progesterone
synthesized a series of chromeno[4,3-b]quinolines by
and glucocorticoid1 receptor modulators. Evaluation of
such biological activities is closely related to the efforts of
synthetic chemists to prepare structurally different chromeno-
quinolines and thereby discover new therapeutically active
6
reaction of 4-hydroxycoumarin, aqueous NH
, dimedone,
3
and different aromatic aldehydes in n-PrOH.21
2-Pyridone is another important heterocyclic core in
many complex organic molecules exhibiting different
0
009-3122/19/55(11±-1104©2019 Springer Science+Business Media, LLC
1104

Chemistry of Heterocyclic Compounds 2019, 55(11±, 1104–1110
biological properties, such as antitumor, antiviral,23
22
Table 1. Optimization of reaction conditions for the synthesis
of chromeno[4,3-b]quinoline-6,8-dione 5a*
antibacterial,24 and psychotherapeutic, and is also incor-
25
26
porated in structure of several fungal metabolites. Few
reports devoted to the synthesis of chromeno[4,3-b]-
pyridine-2,5-dione derivatives have been presented in
literature. Saghanezhad and coworkers reported a synthesis of
various chromeno[4,3-b]pyridine-2,5-diones by reaction of
4
-hydroxycoumarin, aqueous NH
3
, Meldrum's acid, and
aromatic aldehydes in refluxing n-PrOH using sulfonic acid-
functionalized mesoporous silica (SBA-15-SO H± as cata-
3
lyst.27 In addition, Foroumadi and coworkers showed that
catalyst-free condensation of 4-hydroxycoumarin, aqueous
NH , Meldrum's acid, and aromatic aldehyde in refluxing
3
n-PrOH produced substituted chromeno[4,3-b]pyridine-
Catalyst,
mol %
Temperature,
°C
Time,
h
Yield,
%
2
8
Entry Solvent
2
,5-diones in moderate yields. However, these previously
reported methods could be improved by reduction of
reaction time as well as application of inexpensive catalyst
and/or solvent-free conditions. Therefore, development of
new synthetic approaches for obtaining chromeno[4,3-b]-
pyridine-2,5-dione derivatives is still of high demand.
In continuation of our research program aimed toward
the design and synthesis of novel heterocyclic systems,29
we describe herein an efficient and green synthetic protocol
for the synthesis of new chromeno[4,3-b]quinoline-6,8-
diones and chromeno[4,3-b]pyridine-2,5-diones by one-pot
three-component reaction of 4-aminocoumarin (1±, dimedone
1
2
3
4
5
6
7
8
9
H
2
2
O
O
–
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
70
2
20
73
88
89
89
61
55
40
48
62
75
68
H
5
3
2
H O
10
15
20
10
10
10
10
10
10
10
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
H
2
2
O
O
H
EtOH
MeOH
THF
MeCN
–
(
2a± or Meldrum's acid (2b±, and aromatic aldehydes 3 in
2
H O or EtOH using guanidine hydrochloride (4± as organo-
1
0
1
2
catalyst. To optimize the reaction conditions, interaction of
equimolar amounts of 4-aminocoumarin (1±, dimedone
1
1
–
90
(
2a±, and benzaldehyde (3a± was chosen as a model
–
120
reaction. First, the chemical transformation was conducted
in refluxing H O in the absence of catalyst 4 for 2 h and
* Amounts of reactants: 4-aminocoumarin (1± (161 mg, 1 mmol±,
dimedone (2a± (140 mg, 1 mmol±, benzaldehyde (3a± (106 mg, 1 mmol±;
solvent (10 ml±.
2
target product 5a was obtained in 20% yield (Table 1, entry 1±.
Furthermore, the reaction was performed in the presence of
catalytic amount of guanidine hydrochloride (4± (10 mol %±
leading to the formation of product 5a in 88% yield after
5a–f with a number of electron-donating and electron-
withdrawing substituents, introduced into the products by
aromatic aldehydes 3a–f. All of the reactions were
conducted for 1.5 h providing products 5a–f in uniformly
high yields (81–92%± without particular effect of the
substituents (Scheme 1±.
1
.5 h (entry 3±. In addition to H O, several other solvents,
2
such as EtOH, MeOH, THF, and MeCN, were also tested.
When the reaction was carried out in organic solvents in
the presence of 10 mol % of guanidine hydrochloride (4±,
significant decrease in the yield of compound 5a was
observed (entries 6–9±. The model reaction was also per-
formed under solvent-free conditions at various tempe-
ratures. However, yield of chromeno[4,3-b]quinoline-6,8-
dione 5a was not significantly improved by increasing the
temperature (entries 10–12±. Finally, the reaction was
We next explored the scope of this domino reaction and
applicability of guanidine hydrochloride (4± as catalyst for
the synthesis of chromeno[4,3-b]pyridine-2,5-dione deriva-
tives by replacing dimedone (2a± with Meldrum's acid (2b±.
To select an appropriate solvent, reaction of equimolar
amounts of 4-aminocoumarin (1±, Meldrum's acid (2b±, and
4-nitrobenzaldehyde (3g± using 10 mol % of guanidine
conducted in H
2
2
O using different amounts (5, 15, and
0 mol %± of guanidine hydrochloride (4±. The results
revealed that application of 5 mol % of catalyst 4 required
prolonged reaction time and afforded product 5a in
moderate yield. On the other hand, amount of guanidine
hydrochloride (4± higher than 10 mol % did not signi-
ficantly increase the yield (entries 2–5±. Hence, application
hydrochloride (4± was examined in H O, EtOH, and MeCN
2
under reflux. In addition, solvent-free synthesis of chromeno-
[4,3-b]pyridine-2,5-dione 6a at 70, 90, and 120°C was also
performed. The highest yield of product 6a (82%± was
obtained when the reaction mixture was refluxed in EtOH
for 1.5 h. Having established optimized conditons for the
synthesis of chromeno[4,3-b]pyridine-2,5-dione deriva-
tives, we determined its scope using aromatic aldehydes
3c,f,g–k with electron-donating and electron-withdrawing
substituents. A wide range of aromatic aldehydes was well-
of H O as solvent and 10 mol % of guanidine hydro-
2
chloride (4± as catalyst was selected as the most appropriate
conditions for the investigated multicomponent reaction.
The optimized reaction conditions were further applied
for the synthesis of chromeno[4,3-b]quinoline-6,8-diones
1
105

Chemistry of Heterocyclic Compounds 2019, 55(11±, 1104–1110
Scheme 1
tolerated, and chromeno[4,3-b]pyridine-2,5-diones 6a–g
were synthesized in high yields (80–86%± (Scheme 1±. All
new products were characterized by melting point, FTIR
and H and C NMR spectroscopy, mass spectrometry, and
elemental analysis. To the best of our knowledge, synthesis
of compounds 5c–f and 6a,c–g has not been previously
reported.
of organic acid provides chromeno[4,3-b]quinoline-6,8-
dione 5 and loss of Me CO and CO from intermediate 10
2
2
leads to chromeno[4,3-b]pyridine-2,5-dione 6 (Scheme 2±.
In summary, a simple and environmentally benign
method for the synthesis of new chromeno[4,3-b]quinoline-
6,8-diones and chromeno[4,3-b]pyridine-2,5-diones in high
yields using guanidine hydrochloride as organocatalyst and
1
13
A possible mechanism for the described one-pot three-
component reaction was proposed. The first step, most
likely, is the Knoevenagel condensation of aromatic
aldehyde 3 and 1,3-dicarbonyl compound 2, catalyzed by
guanidine hydrochloride (4±, to generate intermediate 7,
which may act as a strong Michael acceptor. Further
Michael addition of 4-aminocoumarin (1± to compound 7
provides intermediate 8, which undergoes intramolecular
cyclization to afford intermediate 9 in case of dimedone
H O or EtOH as solvents has been developed. To the best
2
of our knowledge, it is the first example of one-pot three-
component reaction performed in green solvents and
catalyzed by guanidine hydrochloride leading to new
coumarin-fused dihydropyridine scaffolds. This domino
strategy provides a straightforward and facile pathway
toward the target molecules in atom-economic fashion
avoiding the use of strong acid or transition metal catalysts.
Furthermore, environmentally benign reaction conditions,
short reaction times, broad substrate scope, high yields of
products, simple workup procedure, and purification of
(
2a± or intermediate 10 in case of Meldrum's acid (2b±.
Subsequently, dehydration of compound 9 in the presence
1
106

Chemistry of Heterocyclic Compounds 2019, 55(11±, 1104–1110
Scheme 2
NH2
H
O
NH2
O
O
Cl
O
O
O
4
Ar
1
Ar
+
ArCHO
H
O
O
– H2O
O
3
O
8
2
7
Me
Me Me
Me Me
Me
O
O
HO
HN
O
HN
O
O
NH2
H
Ar
–
H O
2
Ar
O
Ar
O
O
O
O
9
5
Me
O
Me Me
Me
O
H
O
HN
O
O
O
O
HN
O
O
NH2
O
H
Ar
–
CO2
2
Ar
Ar
– Me CO
O
O
O
O
O
6
1
0
products by recrystallization make this synthetic approach
attractive for academic and industrial application.
10,10-Dimethyl-7-phenyl-7,10,11,12-tetrahydro-6H-
chromeno[4,3-b]quinoline-6,8(9H)-dione (5a). Yield 320 mg
21
(
88%±, white powder, mp 294–295°C (mp 290–291°C ±.
Experimental
–1
IR spectrum, ν, cm : 3342 (NH±, 3081 and 3026 (C–H Ar±,
IR spectra were obtained on a Shimadzu 4300 spectro-
2957 and 2871 (C–H aliphatic±, 1672 (C=O ketone±, 1644
and 1607 (C=C Ar±, 1508, 1470, 1365, 1311, 1239, 1194,
1
13
meter in KBr pellets. H and C NMR spectra were
1
recorded on a Bruker Avance DRX-300 spectrometer (300
1146, 1046. H NMR spectrum, δ, ppm (J, Hz±: 0.86 (3H, s,
1
and 75 MHz, respectively± in DMSO-d
6
. H NMR chemical
CH ±; 0.96 (3H, s, CH ±; 1.97 (1H, d, J = 16.2± and 2.16
3
3
shifts are reported relative to the residual solvent protons as
internal standard (2.50 ppm±. Solvent carbon atoms served
(1H, d, J = 16.2, 11-CH
2
±; 2.55 (2H, s, 9-CH ±; 4.84 (1H, s,
2
7-CH±; 6.99–7.12 (5H, m, H Ar±; 7.26–7.27 (2H, m, H Ar±;
7.54 (1H, t, J = 8.1, H Ar±; 8.20 (1H, d, J = 8.1, H Ar±; 9.60
(1H, s, NH±.
13
as internal standard for C NMR spectra (39.52 ppm±. Mass
spectra were obtained on an Agilent technologies HP 5973
mass selective detector (EI, 70 eV±. Elemental analyses
were carried out on a Heraeus CHN-O-Rapid elemental
analyzer. Melting points were determined on an
Electrothermal IA9100 apparatus and are uncorrected. The
progress of reactions was followed by TLC (eluent EtOAc–
hexane, 1:2± using pre-coated silica gel plates 60 F254
7-(3-Hydroxyphenyl)-10,10-dimethyl-7,10,11,12-tetra-
hydro-6H-chromeno[4,3-b]quinoline-6,8(9H)-dione (5b).
Yield 313 mg (81%±, white powder, mp 191–193°C
21
–1
(mp 190–192°C ±. IR spectrum, ν, cm : 3322 (NH, OH±,
3093 (C–H Ar±, 2960 and 2869 (C–H aliphatic±, 1648
(C=O ketone±, 1632 and 1604 (C=C Ar±, 1505, 1464, 1364,
1
(
visualization with UV light at 254 nm±.
Starting materials were purchased from commercial
1275, 1200, 1151, 1062. H NMR spectrum, δ, ppm (J, Hz±:
0.85 (3H, s, CH ±; 0.96 (3H, s, CH ±; 1.99 (1H, d, J = 15.6±
3
3
sources and were used without additional purification.
Synthesis of chromeno[4,3-b]quinoline-6,8-diones 5a–f
and chromeno[4,3-b]pyridine-2,5-diones 6a–g (General
method±. A 25-ml round-bottom flask was charged with
and 2.16 (1H, d, J = 15.6, 11-CH ±; 2.54 (2H, s, 9-CH ±;
2
2
4.77 (1H, s, 7-CH±; 6.37 (1H, d, J = 7.8, H Ar±; 6.53–6.57
(2H, m, H Ar±; 6.86 (1H, t, J = 7.8, H Ar±; 7.27–7.37 (2H,
m, H Ar±; 7.54 (1H, t, J = 8.1, H Ar±; 8.19 (1H, d, J = 8.1,
H Ar±; 9.08 (1H, s, OH±; 9.58 (1H, s, NH±.
4
3
1
-aminocoumarin (1± (161 mg, 1 mmol±, aromatic aldehyde
a–k (1 mmol±, guanidine hydrochloride (4± (10 mg,
0 mol %±, dimedone (2a± (140 mg, 1 mmol± or Meldrum's
7-(2,3-Dimethoxyphenyl)-10,10-dimethyl-7,10,11,12-
tetrahydro-6H-chromeno[4,3-b]quinoline-6,8(9H)-dione
(5c). Yield 396 mg (92%±, pale-yellow powder, mp 298–
acid (2b± (144 mg, 1 mmol±, and H O (10 ml± or EtOH
2
–1
(10 ml±, respectively. The reaction mixture was refluxed
300°C. IR spectrum, ν, cm : 3299 (NH±, 3077 (C–H Ar±,
2948 and 2835 (C–H aliphatic±, 1710 (C=O lactone±, 1647
(C=O ketone±, 1632 and 1602 (C=C Ar±, 1500, 1472, 1364,
for 1.5 h. After completion of the reaction (confirmed by
TLC±, the mixture was gradually cooled to room tempe-
rature. The obtained solid was filtered off, air-dried, and
recrystallized from EtOH.
1
1307, 1288, 1255, 1200, 1153, 1072. H NMR spectrum,
δ, ppm (J, Hz±: 0.84 (3H, s, CH ±; 0.94 (3H, s, CH ±; 1.93
3
3
1
107

Chemistry of Heterocyclic Compounds 2019, 55(11±, 1104–1110
(
(
1H, d, J = 15.2± and 2.08 (1H, d, J = 15.2, 11-CH
2H, s, 9-CH ±; 3.56 (3H, s, OCH ±; 3.61 (3H, s, OCH
.01 (1H, s, 7-CH±; 6.65–6.75 (3H, m, H Ar±; 7.23–7.35
2
±; 2.50
H Ar±; 7.29–7.37 (2H, m, H Ar±; 7.54 (1H, t, J = 7.8,
H Ar±; 7.68 (2H, d, J = 8.1, H Ar±; 8.21 (1H, d, J = 7.8,
2
3
3
±;
5
H Ar±; 9.65 (1H, s, NH±; 12.67 (1H, s, CO
H±. 13C NMR
2
(
2H, m, H Ar±; 7.51 (1H, t, J = 7.8, H Ar±; 8.19 (1H, d,
spectrum, δ, ppm: 26.9; 29.4; 30.1; 32.6; 35.3; 50.4; 101.6;
110.8; 113.3; 117.3; 123.5; 124.5; 128.5; 129.2; 129.6;
132.5; 142.8; 150.4; 150.9; 152.5; 160.6; 167.6; 195.1.
1
3
J = 7.8, H Ar±; 9.50 (1H, s, NH±. C NMR spectrum,
δ, ppm: 27.3; 29.2; 32.1; 32.4; 32.5; 50.7; 55.8; 60.1;
+
1
1
1
4
2
01.9; 111.0; 111.4; 113.5; 117.1; 122.8; 123.2; 123.5;
24.3; 132.2; 138.9; 142.8; 147.5; 150.0; 152.4; 152.7;
Mass spectrum, m/z (Irel, %±: 415 [M] (0.2±, 272 (30±, 271
(11±, 263 (27±, 262 (100±, 234 (20±, 227 (53±, 205 (14±, 176
(16±, 171 (10±. Found, %: C 72.34; H 5.08; N 3.44.
+
60.4; 194.8. Mass spectrum, m/z (Irel, %±: 431 [M] (63±,
+
+
01 [M–CH
2
O] (27±, 400 [M–OCH
3
] (100±, 294 (44±,
C
25
H
21NO . Calculated, %: C 72.28; H 5.10; N 3.37.
5
38 (10±, 210 (15±. Found, %: C 72.30; H 5.72; N 3.30.
4-(4-Nitrophenyl)-3,4-dihydro-2H-chromeno[4,3-b]-
C
26
H
25NO
5
. Calculated, %: C 72.37; H 5.84; N 3.25.
pyridine-2,5(1H)-dione (6a). Yield 275 mg (82%±, pale-
–1
1
0,10-Dimethyl-7-[4-(dimethylamino)phenyl]-7,10,11,12-
yellow powder, mp 265–267°C. IR spectrum, ν, cm : 3265
(NH±, 3077 (C–H Ar±, 2976 and 2905 (C–H aliphatic±,
1712 (C=O lactone±, 1684 (C=O lactam±, 1627 (C=C Ar±,
tetrahydro-6H-chromeno[4,3-b]quinoline-6,8(9H)-dione
(
5d). Yield 347 mg (84%±, pale-yellow powder, mp 303–
–
1
3
2
04°C. IR spectrum, ν, cm : 3288 (NH±, 3072 (C–H Ar±,
1515 (NO
2
±, 1458, 1346 (NO
1000. H NMR spectrum, δ, ppm (J, Hz±: 2.60 (1H, d,
J = 16.5± and 3.21 (1H, s, 3-CH ±; 4.45 (1H, d, J = 7.5,
2
±, 1278, 1196, 1155, 1112,
1
961 and 2880 (C–H aliphatic±, 1703 (C=O lactone±, 1634
and 1604 (C=C Ar±, 1509, 1477, 1366, 1240, 1195, 1147,
2
1
1
042. H NMR spectrum, δ, ppm (J, Hz±: 0.86 (3H, s,
CH ±; 0.97 (3H, s, CH ±; 1.96 (1H, d, J = 16.2± and 2.15
1H, d, J = 16.2, 11-CH ±; 2.54 (2H, s, 9-CH ±; 2.68 (6H, s,
N(CH ±; 4.71 (1H, s, 7-CH±; 6.44 (2H, d, J = 8.7, H Ar±;
4-CH±; 7.31–7.39 (2H, m, H Ar±; 7.43 (2H, d, J = 8.4,
H Ar±; 7.61 (1H, t, J = 7.8, H Ar±; 8.07 (2H, d, J = 8.4,
H Ar±; 8.19 (1H, d, J = 7.8, H Ar±; 11.03 (1H, s, NH±.
3
3
(
2
2
1
3
3
±
2
C NMR spectrum, δ, ppm: 36.0; 37.9; 102.6; 113.5;
6
.92 (2H, d, J = 8.7, H Ar±; 7.25–7.35 (2H, m, H Ar±; 7.52
117.4; 123.7; 124.4; 124.8; 128.6; 133.1; 146.6; 147.1;
(
(
1H, t, J = 7.5, H Ar±; 8.18 (1H, d, J = 7.5, H Ar±; 9.51
149.6; 153.3; 160.7; 170.3. Mass spectrum, m/z (Irel, %±:
1H, s, NH±. 13C NMR spectrum, δ, ppm: 27.0; 29.6; 32.6;
336 [M] (100±, 319 (95±, 307 (25±, 290 [M–NO
+
] (14±,
+
2
3
1
1
3.6; 33.7; 40.6; 50.6; 102.9; 111.6; 112.5; 113.6; 117.2;
23.2; 124.4; 128.6; 132.1; 134.5; 141.9; 149.4; 149.5;
289 (46±, 261 (12±, 214 (50±, 186 (23±, 115 (17±. Found, %:
C 64.22; H 3.60; N 8.39. C18
C 64.29; H 3.60; N 8.33.
H
12
N
2
5
O . Calculated, %:
+
52.4; 160.7; 195.1. Mass spectrum, m/z (Irel, %±: 414 [M]
(
(
43±, 397 (12±, 330 (11±, 293 (100±, 278 (18±, 265 (21±, 250
4-(2-Nitrophenyl)-3,4-dihydro-2H-chromeno[4,3-b]-
pyridine-2,5(1H)-dione (6b). Yield 268 mg (80%±, pale-
+
10±, 237 (87±, 209 (15±, 153 (14±, 120 (60±, 77 [Ph] (14±.
28
Found, %: C 75.40; H 6.22; N 6.79. C26
Calculated, %: C 75.34; H 6.32; N 6.76.
H
26
N
2
O
3
.
yellow powder, mp 245–247°C (mp 244°C ±. IR spectrum,
–1
ν, cm : 3251 (NH±, 3041 (C–H Ar±, 2982 and 2927 (C–H
1
0,10-Dimethyl-7-(pyridin-3-yl)-7,10,11,12-tetrahydro-
aliphatic±, 1716 (C=O lactone±, 1691 (C=O lactam±, 1630
6
H-chromeno[4,3-b]quinoline-6,8(9H)-dione (5e). Yield
and 1610 (C=C Ar±, 1574, 1526 (NO
2
±, 1463, 1312 (NO ±,
2
1
3
27 mg (88%±, pale-yellow powder, mp 290–292°C.
1203, 1005. H NMR spectrum, δ, ppm (J, Hz±: 2.53 (1H,
d, J = 16.5± and 3.36 (1H, dd, J = 16.5, J = 9.0, 3-CH ±;
–
1
IR spectrum, ν, cm : 3274 (NH±, 3073 (C–H Ar±, 2954 and
2
2
869 (C–H aliphatic±, 1706 (C=O lactone±, 1633 and 1604
4.63 (1H, d, J = 9.0, 4-CH±; 7.19 (1H, d, J = 7.5, H Ar±;
7.32–7.45 (3H, m, H Ar±; 7.51 (1H, t, J = 7.5, H Ar±; 7.61
(1H, t, J = 8.1, H Ar±; 7.90 (1H, d, J = 8.1, H Ar±; 8.21
(
C=C Ar±, 1509, 1476, 1365, 1242, 1196, 1149, 1026.
1
H NMR spectrum, δ, ppm (J, Hz±: 0.82 (3H, s, CH
3H, s, CH ±; 1.98 (1H, d, J = 16.2± and 2.12 (1H, d,
±; 2.57 (2H, s, 9-CH ±; 4.85 (1H, s, 7-CH±;
.19–7.58 (5H, m, H Ar±; 8.22–8.24 (2H, m, H Ar±; 8.41
3
±; 0.97
13
(
3
(1H, d, J = 8.1, H Ar±; 11.08 (1H, s, NH±. C NMR
spectrum, δ, ppm: 32.3; 37.6; 102.5; 113.4; 117.4; 123.8;
124.8; 125.5; 128.5; 129.2; 133.2; 134.5; 135.9; 147.2;
149.0; 153.3; 160.5; 169.9.
J = 16.2, 11-CH
2
2
7
(
1
3
1H, d, J = 1.2, H Ar±; 9.69 (1H, s, NH±. C NMR
spectrum, δ, ppm: 26.4; 27.0; 29.3; 32.6; 33.3; 50.3; 101.3;
10.3; 113.3; 117.3; 123.6; 124.2; 124.5; 132.6; 136.6; 141.9;
43.0; 147.1; 148.7; 150.7; 152.5; 160.6; 195.1. Mass
4-(2,3-Dimethoxyphenyl)-3,4-dihydro-2H-chromeno-
[4,3-b]pyridine-2,5(1H)-dione (6c). Yield 294 mg (84%±,
1
–
1
1
pale-yellow powder, mp 234–235°C. IR spectrum, ν, cm :
3229 (NH±, 3128 (C–H Ar±, 2937 and 2832 (C–H
aliphatic±, 1721 (C=O lactone±, 1696 (C=O lactam±, 1635
and 1610 (C=C Ar±, 1585, 1517, 1479, 1366, 1282, 1198,
+
spectrum, m/z (Irel, %±: 372 [M] (46±, 295 (21±, 294
+
[M–Py] (100±, 210 (11±. Found, %: C 74.11; H 5.41; N 7.60.
C
23
4
H
20
N
2
O
3
. Calculated, %: C 74.18; H 5.41; N 7.52.
1
-(10,10-Dimethyl-6,8-dioxo-7,8,9,10,11,12-hexahydro-
1165, 1069. H NMR spectrum, δ, ppm (J, Hz±: 2.30 (1H,
6
H-chromeno[4,3-b]quinolin-7-yl)benzoic acid (5f). Yield
61 mg (87%±, pale-yellow powder, mp 309–311°C.
d, J = 16.2± and 3.15 (1H, dd, J = 16.2, J = 8.7, 3-CH
2
±;
3
3.70 (3H, s, OCH
3
±; 3.71 (3H, s, OCH
3
±; 4.50 (1H, d,
–
1
IR spectrum, ν, cm : 3189 (NH±, 3092 (C–H Ar±, 2952 and
J = 8.7, 4-CH±; 6.39–6.41 (1H, m, H Ar±; 6.78–6.86 (2H,
m, H Ar±; 7.30–7.37 (2H, m, H Ar±; 7.58 (1H, t, J = 7.8,
H Ar±; 8.16 (1H, d, J = 7.8, H Ar±; 10.90 (1H, s, NH±.
2
872 (C–H aliphatic±, 1717 (C=O lactone±, 1666 (br, C=O
ketone, C=O acid±, 1602 (C=C Ar±, 1508, 1477, 1369,
1
13
1
314, 1235, 1197, 1154, 1051. H NMR spectrum, δ, ppm
J, Hz±: 0.82 (3H, s, CH ±; 0.96 (3H, s, CH ±; 1.97 (1H, d,
J = 16.2± and 2.17 (1H, d, J = 16.2, 11-CH ±; 2.56 (2H, s,
-CH ±; 4.90 (1H, s, 7-CH±; 7.24–7.26 (2H, d, J = 8.1,
C NMR spectrum, δ, ppm: 31.0; 37.9; 56.1; 60.5; 103.3;
(
3
3
112.5; 113.5; 117.3; 118.7; 123.5; 124.5; 124.7; 132.8;
134.9; 146.3; 146.5; 153.1; 153.2; 160.5; 170.5. Mass
spectrum, m/z (Irel, %±: 351 [M] (100±, 336 [M–CH
2
+
+
9
2
3
]
1
108

Chemistry of Heterocyclic Compounds 2019, 55(11±, 1104–1110
+
+
–1
(
13±, 321 [M–CH
2
O] (25±, 320 [M–OCH
3
] (92±, 304 (11±,
powder, mp 330–332°C. IR spectrum, ν, cm : 3247 (NH±,
3041 (C–H Ar±, 2972 and 2927 (C–H aliphatic±, 1717
(C=O lactone±, 1686 (C=O lactam±, 1633 (C=C Ar±, 1570,
2
14 (14±. Found, %: C 68.42; H 4.85; N 3.90. C20
Calculated, %: C 68.37; H 4.88; N 3.99.
-(2,4-Dichlorophenyl)-3,4-dihydro-2H-chromeno[4,3-b]-
pyridine-2,5(1H)-dione (6d). Yield 309 mg (86%±, white
H
17NO .
5
1
4
1516, 1463, 1365, 1200, 1005. H NMR spectrum, δ, ppm
(J, Hz±: 2.44 (1H, d, J = 17.1± and 3.20 (1H, dd, J = 17.1,
–
1
powder, mp 301–303°C. IR spectrum, ν, cm : 3241 (NH±,
041 (C–H Ar±, 2972 and 2923 (C–H aliphatic±, 1724
J = 7.8, 3-CH ±; 4.56 (1H, d, J = 7.8, 4-CH±; 6.91 (1H, dd,
2
3
J = 7.2, J = 1.8, H Ar±; 7.09–7.18 (2H, m, H Ar±; 7.32–7.39
(
C=O lactone±, 1693 (C=O lactam±, 1633 and 1610 (C=C Ar±,
(2H, m, H Ar±; 7.59–7.64 (2H, m, H Ar±; 8.19 (1H, d,
1
13
1
517, 1463, 1363, 1198, 1050. H NMR spectrum, δ, ppm
J = 8.1, H Ar±; 11.03 (1H, s, NH±. C NMR spectrum,
(
J, Hz±: 2.44 (1H, d, J = 15.9± and 3.20 (1H, dd, J = 15.9,
δ, ppm: 36.2; 37.0; 102.6; 113.5; 117.4; 123.8; 123.9;
J = 8.4, 3-CH
J = 8.4, H Ar±; 7.19 (1H, dd, J = 8.1, J = 1.8, H Ar±; 7.32–
2
±; 4.55 (1H, d, J = 8.4, 4-CH±; 6.96 (1H, d,
124.8; 127.7; 128.8; 129.8; 133.1; 133.9; 139.6; 147.3;
+
153.3; 160.4; 170.0. Mass spectrum, m/z (Irel, %±: 372 [M]
+
+
+
7
.39 (2H, m, H Ar±; 7.61 (2H, t, J = 8.1, H Ar±; 8.18 (1H,
(1.5±, 371 [M] (1.2±, 370 [M] (1.6±, 291 (48±, 290 [M–Br]
(100±, 263 (11±, 262 (39±, 250 (14±, 249 (72±, 248 (81±.
1
3
d, J = 8.1, H Ar±; 11.05 (1H, s, NH±. C NMR spectrum,
δ, ppm: 33.5; 36.6; 102.0; 113.5; 117.4; 123.8; 124.8;
Found, %: C 58.40; H 3.20; N 3.81. C18
H
12BrNO .
3
1
1
(
[
[
28.3; 129.2; 130.0; 133.1; 133.2; 133.9; 137.3; 147.4;
Calculated, %: C 58.40; H 3.27; N 3.78.
+
53.3; 160.4; 169.9. Mass spectrum, m/z (Irel, %±: 363 [M]
+
+
Supplementary information file containing 1H and
13
0.06±, 361 [M] (0.36±, 359 [M] (0.54±, 327 (27±, 326
M–Cl]+ (100±, 324 [M–Cl] (77±, 284 (40±, 282
+
C NMR spectra of compounds 5a–f and 6a–g is available
+
M–Ph] (92±, 214 (14±, 115 (10±. Found, %: C 60.08;
at the journal website http://link.springer.com/journal/10593.
H 3.01; N 3.95. C18
H 3.08; N 3.89.
H
11Cl
2
NO . Calculated, %: C 60.02;
3
The authors thank Research Council of the Payame
Noor University for financial support.
4
-(2,5-Dioxo-1,3,4,5-tetrahydro-2H-chromeno[4,3-b]-
pyridin-4-yl)benzoic acid (6e). Yield 271 mg (81%±,
–1
References
white powder, mp 340–341°C. IR spectrum, ν, cm : 3235
1
. Angelova, V. T.; Andreeva-Gateva, P. A.; Vassilev, N. G.;
Tafradjiiska-Hadjiolova, R.; Surcheva, S.; Tchekalarova, J.
C. R. Acad. Bulg. Sci. 2016, 69, 513.
2. (a± Kidwai, M.; Saxena, S.; Khan, M. K. R.; Thukral, S. S.
Bioorg. Med. Chem. Lett. 2005, 15, 4295. (b± Kumar, D.;
Reddy, V. B.; Sharad, S.; Dube, U.; Kapur, S. Eur. J. Med.
Chem. 2009, 44, 3805. (c± Gholipour, S.; Davoodnia, A.;
Nakhaei-Moghaddam, M. Chem. Heterocycl. Compd. 2015,
51, 808. [Khim. Geterotsikl. Soedin. 2015, 51, 808.]
3. Shestopalov, A. M.; Litvinov, Yu. M.; Rodinovskaya, L. A.;
Malyshev, O. R.; Semenova, M. N.; Semenov, V. V. ACS
Comb. Sci. 2012, 14, 484.
4. Wang, J.-L.; Liu, D.; Zhang, Z.-J.; Shan, S.; Han, X.;
Srinivasula, S. M.; Croce, C. M.; Alnemri, E. S.; Huang, Z.
Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 7124.
. Gourdeau, H.; Leblond, L.; Hamelin, B.; Desputeau, C.;
Dong, K.; Kianicka, I.; Custeau, D.; Boudreau, C.; Geerts, L.;
Cai, S.-X.; Drewe, J.; Labrecque, D.; Kasibhatla, S.; Tseng, B.
Mol. Cancer Ther. 2004, 3, 1375.
6. (a± Thareja, S.; Verma, A.; Kalra, A.; Gosain, S.; Rewatkar, P. V.;
Kokil, G. R. Acta Pol. Pharm. 2010, 67, 423. (b± Ashok, D.;
Lakshmi, B. V.; Ravi, S.; Ganesh, A.; Adam, S. Chem.
Heterocycl. Compd. 2015, 51, 462. [Khim. Geterotsikl.
Soedin. 2015, 51, 462.]
(
NH±, 3079 (C–H Ar±, 2982 and 2827 (C–H aliphatic±,
1
1
1
710 (C=O lactone±, 1688 (br, C=O lactam, C=O acid±,
633 and 1610 (C=C Ar±, 1572, 1517, 1461, 1368, 1294,
1
197. H NMR spectrum, δ, ppm (J, Hz±: 2.56 (1H, d,
J = 16.2± and 3.20 (1H, dd, J = 16.2, J = 7.8, 3-CH
2
±; 4.35
(
7
1H, d, J = 7.8, 4-CH±; 7.25 (2H, d, J = 8.1, H Ar±; 7.29–
.38 (2H, m, H Ar±; 7.59 (1H, t, J = 8.1, H Ar±; 7.76 (2H,
d, J = 8.1, H Ar±; 8.16 (1H, d, J = 8.1, H Ar±; 10.97 (1H, s,
1
3
NH±; 12.81 (1H, s, CO
2
H±. C NMR spectrum, δ, ppm:
6.0; 38.1; 103.2; 113.5; 117.4; 123.6; 124.7; 127.3; 130.1;
30.3; 133.0; 146.3; 146.8; 153.2; 160.7; 167.4; 170.5.
3
1
+
Mass spectrum, m/z (Irel, %±: 335 [M] (81±, 309 (20±, 308
+
+
(
100±, 293 (14±, 291 [M–CO
2
] (20±, 290 [M–CO
2
H] (18±,
2
1
89 (33±, 263 (29±, 262 (11±, 249 (20±, 214 (19±, 121 (25±,
15 (16±, 92 (25±. Found, %: C 68.01; H 3.90; N 4.22.
5
C
19
4
H
13NO . Calculated, %: C 68.06; H 3.91; N 4.18.
5
-(3-Chlorophenyl)-3,4-dihydro-2H-chromeno[4,3-b]-
pyridine-2,5(1H)-dione (6f). Yield 276 mg (85%±, white
–
1
powder, mp 277–278°C. IR spectrum, ν, cm : 3283 (NH±,
069 (C–H Ar±, 2972 and 2907 (C–H aliphatic±, 1713
C=O lactone±, 1678 (C=O lactam±, 1628 (C=C Ar±, 1571,
3
(
1
1
516, 1459, 1367, 1198, 1010. H NMR spectrum, δ, ppm
J, Hz±: 2.55 (1H, d, J = 16.2± and 3.12 (1H, dd, J = 16.2,
J = 7.2, 3-CH ±; 4.29 (1H, d, J = 7.2, 4-CH±; 7.05–7.37 (6H, m,
H Ar±; 7.58 (1H, t, J = 7.2, H Ar±; 8.14 (1H, d, J = 7.2, H Ar±;
7
. Mladenović, M.; Mihailović, M.; Bogojević, D.; Matić, S.;
Nićiforović, N.; Mihailović, V.; Vuković, N.; Sukdolak, S.;
Solujić, S. Int. J. Mol. Sci. 2011, 12, 2822.
(
2
8. Chung, S.-T.; Huang, W.-H.; Huang, C.-K.; Liu, F.-C.;
Huang, R.-Y.; Wu, C.-C.; Lee, A.-R. Res. Chem. Intermed.
2016, 42, 1195.
1
3
1
0.95 (1H, s, NH±. C NMR spectrum, δ, ppm: 35.7; 38.1;
03.2; 117.4; 123.7; 124.7; 125.7; 127.1; 127.6; 131.2; 133.0;
33.8; 144.3; 146.3; 147.7; 153.2; 160.7; 170.6. Mass
1
9
. Kamdar, N. R.; Haveliwala, D. D.; Mistry, P. T.; Patel, S. K.
1
+
+
Med. Chem. Res. 2011, 20, 854.
spectrum, m/z (Irel, %±: 327 [M] (38±, 326 (39±, 325 [M]
+
10. (a± Kemnitzer, W.; Jiang, S.; Wang, Y.; Kasibhatla, S.;
Crogan-Grundy, C.; Bubenik, M.; Labrecque, D.; Denis, R.;
Lamothe, S.; Attardo, G.; Gourdeau, H.; Tseng, B.; Drewe, J.;
Cai, S. X. Bioorg. Med. Chem. Lett. 2008, 18, 603.
(
(
C
100±, 296 (22±, 291 (15±, 290 [M–Cl] (68±, 214 (41±, 186
16±, 115 (13±. Found, %: C 66.40; H 3.70; N 4.35.
18
4
H
12ClNO . Calculated, %: C 66.37; H 3.71; N 4.30.
3
-(2-Bromophenyl)-3,4-dihydro-2H-chromeno[4,3-b]-
(
b± Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Crogan-
Grundy, C.; Labreque, D.; Bubenick, M.; Attardo, G.; Denis, R.;
pyridine-2,5(1H)-dione (6g). Yield 303 mg (82%±, white
1
109

Chemistry of Heterocyclic Compounds 2019, 55(11±, 1104–1110
Lamothe, S.; Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai, S. X.
19. Ahmed, N.; Babu, B. V.; Singh, S.; Mitrasinovic, P. M.
J. Med. Chem. 2008, 51, 417.
Heterocycles 2012, 85, 1629.
1
1. Foloppe, N.; Fisher, L. M.; Howes, R.; Potter, A.;
Robertson, A. G. S.; Surgenor, A. E. Bioorg. Med. Chem.
20. Nandi, S.; Gupta, A.; Pal, A. K. Lett. Org. Chem. 2017, 14, 291.
21. Yahya-Meymandi, A.; Nikookar, H.; Moghimi, S.; Mahdavi, M.;
Firoozpour, L.; Asadipour, A.; Ranjbar, R. P.; Foroumadi, A.
J. Iran. Chem. Soc. 2017, 14, 771.
2
006, 14, 4792.
1
2. Kym, P. R.; Kort, M. E.; Coghlan, M. J.; Moore, J. L.; Tang, R.;
Ratajczyk, J. D.; Larson, D. P.; Elmore, S. W.; Pratt, J. K.;
Stashko, M. A.; Falls, H. D.; Lin, C. W.; Nakane, M.; Miller, L.;
Tyree, C. M.; Miner, J. N.; Jacobson, P. B.; Wilcox, D. M.;
Nguyen, P.; Lane, B. C. J. Med. Chem. 2003, 46, 1016.
22. Curran, D. P.; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863.
23. Williams, D. R.; Lowder, P. D.; Gu, Y.-G. Tetrahedron Lett.
1997, 38, 327.
24. Brickner, S. J. Chem. Ind. 1997, 131.
1
3. Liu, Y.; Ding, Y. Huaxue Yanjiu Yu Yingyong 1995, 7, 430
25. Kozikowski, A. P.; Campiani, G.; Sun, L.-Q.; Wang, S.;
Saxena, A.; Doctor, B. P. J. Am. Chem. Soc. 1996, 118, 11357.
26. Cox, R. J.; O'Hagan, D. J. Chem. Soc., Perkin Trans. 1 1991, 2537.
27. Sayahi, M. H.; Saghanezhad, S. J.; Mahdavi, M. Res. Chem.
Intermed. 2018, 44, 739.
[
in Chinese].
1
4. (a± Sashidhara, K. V.; Palnati, G. R.; Singh, L. R; Upadhyay, A.;
Avula, S. R.; Kumar, A.; Kant, R. Green Chem. 2015, 17,
3
766. (b± Mulakayala, N.; Rambabu, D.; Raja, M. R.;
Chaitanya, M.; Kumar, C. S.; Kalle, A. M.; Krishna, G. R.;
28. Firoozpour, L.; Nikookar, H.; Moghimi, S.; Mahdavi, M.;
Asadipour, A.; Ranjbar, P. R; Foroumadi, A. Heterocycl.
Commun. 2017, 23, 305.
Reddy, C. M.; Rao, M. V. B.; Pal, M. Bioorg. Med. Chem. 2012,
2
0, 759. (c± Goswami, L.; Gogoi, S.; Gogoi, J.; Boruah, R. K.;
Boruah, R. C.; Gogoi, P. ACS Comb. Sci. 2016, 18, 253.
5. Zhi, L.; Tegley, C. M.; Pio, B.; Edwards, J. P.; Motamedi, M.;
Jones, T. D.; Marschke, K. B.; Mais, D. E.; Risek, B.;
Schrader, W. T. J. Med. Chem. 2003, 46, 4104.
29. (a± Olyaei, A.; Sadeghpour, M.; Zarnegar, M. Chem.
Heterocycl. Compd. 2013, 49, 1374. [Khim. Geterotsikl.
Soedin. 2013, 1474.] (b± Olyaei, A.; Rahbarian, F.;
Sadeghpour, M. Chem. Heterocycl. Compd. 2015, 51, 899.
[Khim. Geterotsikl. Soedin. 2015, 51, 899.] (c± Olyaei, A.;
Shafie, Z.; Sadeghpour, M. Tetrahedron Lett. 2018, 59, 3567.
(d± Olyaei, A.; Saraei, M.; Khoeiniha, R. Synlett 2018, 1589.
(e± Olyaei, A.; Shahsavari, M. S.; Sadeghpour, M. Res. Chem.
Intermed. 2018, 44, 943. (f± Khoeiniha, R.; Olyaei, A.; Saraei, M.
Synth. Commun. 2018, 48, 155. (g± Khoeiniha, R.; Olyaei, A.;
Saraei, M. J. Heterocycl. Chem. 2017, 54, 1746. (h± Olyaei, A.;
Javarsineh, S.; Sadeghpour, M. Chem. Heterocycl. Compd.
2018, 54, 934. [Khim. Geterotsikl. Soedin. 2018, 54, 934.]
1
1
6. (a± Elmore, S. W.; Pratt, J. K.; Coghlan, M. J.; Mao, Y.;
Green, B. E.; Anderson, D. D.; Stashko, M. A.; Lin, C. W.;
Falls, D.; Nakane, M.; Miller, L.; Tyree, C. M.; Miner, J. N.;
Lane, B. Bioorg. Med. Chem. Lett. 2004, 14, 1721. (b± Ku, Y. Y.;
Grieme, T.; Raje, P.; Sharma, P.; Morton, H. E.; Rozema, M.;
King, S. A. J. Org. Chem. 2003, 68, 3238.
1
7. (a± Stadlbauer, W. Monatsh. Chem. 1987, 118, 1297.
(
b± Colin, G. M.; Gear, J. R. J. Nat. Prod. 1993, 56, 1402.
1
8. Paul, S.; Das, A. R. Tetrahedron Lett. 2012, 53, 2206.
1
110