Synthesis through three-component reactions catalyzed by FeCl3 of fused pyridocoumarins as inhibitors of lipid peroxidation

Article abstract of DOI:10.1002/jhet.1791

2,4-Diphenyl substituted fused pyridocoumarins have been synthesized by one-pot three-component domino reactions of aminocoumarins, benzaldehyde, and phenylacetylene by using FeCl₃ (10%) as catalyst under reflux or MW irradiation. The new compo

Full text of DOI:10.1002/jhet.1791

Month 2014
Synthesis Through Three-Component Reactions Catalyzed by FeCl3 of
Fused Pyridocoumarins as Inhibitors of Lipid Peroxidation
Theodoros S. Symeonidis, Dimitra J. Hadjipavlou-Litina, and Konstantinos E. Litinas
a
b
a
*
aLaboratory of Organic Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
bDepartment of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of
Thessaloniki, Thessaloniki 54124, Greece
*
E-mail: klitinas@chem.auth.gr
Received June 22, 2012
DOI 10.1002/jhet.1791
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
Preliminary communication presented at 21th Panhellenic Chemistry Conference, December 9–12,
2011, Thessaloniki, Greece, Cd of Abstrs., Part V.
Ph
Ph
+ PhCH=O
Ph
H2N
N
N
+ PhC CH
+
FeCl3 (10 mol %)
O
O
O
O
O
O
Ph
2,4-Diphenyl substituted fused pyridocoumarins have been synthesized by one-pot
three-component domino reactions of aminocoumarins, benzaldehyde, and phenylacety-
lene by using FeCl3 (10%) as catalyst under reflux or MW irradiation. The new compounds
were tested as inhibitors of lipid peroxidation. The 7,9-diphenyl-2H-pyrano[2,3-g]quinolin-
2-one presents interesting results and could serve as lead compound.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
of the pyranone moiety is realized from quinolinols by
Pechmann condensation [26,27] or reactions [28] with
dimethyl acetylene dicarboxylate (DMAD) and PPh3, from
quinolinequinones via Wittig reactions [28] or condensation
with diethyl aminofumarate, [29] by the oxidation of a
pyran ring, formed in situ by electrocyclization of cis-dienals,
[30] and demethylation and condensation of o-substituted
(20-methoxyphenyl)pyridine carboxylic acids. [31,32]
Coumarin derivatives are an interesting class of heterocy-
clic systems because the coumarin ring is an essential
core moiety in a variety of natural and synthetic biologically
active compounds. [1–7] In particular, fused coumarins,
among them pyridocoumarins, have been reported to
possess antiallergic, [8] antidiabetic, [9] analgesic, [10,11]
anti-inflammatory, [11] and antimicrobial [11] properties.
The synthesis of pyridocoumarins has been achieved
either by formation of the pyridine [7,9–22] or the pyranone
[7,23–29] moieties. Construction of the pyridine moiety
involves the iodocyclization of 6-(but-2-ynyl)aminocou-
marin in the presence of I2, developed by Majumdar et al.
[12]; the Pd-catalyzed Heck cyclization [13–15] of
(20-bromo)benzylaminocoumarins to dihydropyrido[3,2-g]-
or [2,3-c]coumarins, the Skraup reaction [16] on 6-nitrocou-
marin, the reactions of aminocoumarins with glycerol, [17]
malondialdehyde, [18] ethyl benzoylacetate, [19] alkyl
vinyl ketones [10] or under Vilsmeier conditions, [20]
the Diels–Alder reactions of the O-methyl imine of
2-oxo-2H-chromene-4-carboxaldehyde with dienophiles,
[21] and reactions of 4-oxo-4H-chromene-3-carbalde-
hyde with enamines. [9,22] Very recently, the synthesis of
pyridine skeleton was obtained in the presence of BF3.Et2O
through aza-Claisen rearrangement followed by in situ
cyclization of propargylaminocoumarins under microwave
irradiation [23] or via three-component domino reaction [24]
from aminocoumarin, benzaldehyde, and phenylacetylene.
Silver-catalyzed cycloisomerization of propargylaminocou-
marins resulted also in pyridocoumarins. [25] The formation
Generally, quinolines have been accessed in recent years
through the three-component domino reactions of anilines,
aromatic aldehydes, and terminal alkynes via the intermedi-
ate propargylamines [33–38] or imines. [24] One-pot
multicomponent reactions (MCRs) constitute a powerful
tool in synthesis, and they also have considerable advan-
tages for the environment in reducing the reaction steps
and minimizing the formation of waste. [39–43] The transi-
tion metal-catalyzed MCRs possess a special interest among
them. Palladium, [44] silver, [45] gold, [33] copper, [34]
zinc, [46] iron, [35,36] and nickel [47] catalysts have been
employed for the MCRs. Recently, iron has been attracting
increasing research interest in homogeneous catalysis
because of its environmentally friendly character, low price,
and nontoxicity. [48–50] In the course of our interest on the
synthesis [21,23,28] of fused pyridocoumarin derivatives,
we wish to report here the application of FeCl3 catalysis
[35,36] in the synthesis of the title compounds by using the
three-component domino reactions with aminocoumarins,
benzaldehyde, and phenylacetylene. On the basis of our
previous experience [51–54] on the antioxidant and antilipid
peroxidation properties of coumarin derivatives, we screened
the synthesized compounds in vitro for their antioxidant
© 2013 HeteroCorporation

T. S. Symeonidis, D. J. Hadjipavlou-Litina, and K. E. Litinas
Vol 000
Scheme 1. Reagents and conditions: (i) FeCl3 (10 mol%), toluene, reflux, air, 24 h (A). (ii) FeCl3 (10 mol %), toluene, MW, 170ꢀC, 15 min (B) or FeCl3
(10 mol %), toluene, o-benzoquinone, MW, 170ꢀC, 5 min (C), or FeCl3 (10 mol %), toluene, O2, MW, 170ꢀC, 3 min (D).
Ph
R1
Ph
R1
R1
O
H
N
PhCH=O (2)
CH (3)
H2N
R2
Ph
N
Ph
N
PhC
+
+
O
O
FeCl3
(i) or (ii)
O
O
O
O
R2
O
R2
R3
R3
4a-d
R3
Ph
5
1a-d
6a,d
1,4,6 a: R1=R2=R3=H
b: R1=R3=H, R2=CH3
c: R1= COOCH3, R2-R3= CH2CH2CH2CH2
d: R1= COOCH3, R2-R3= CH=CH-CH=CH
Scheme 2. Reagents and conditions: (i) FeCl3 (10 mol %), toluene, reflux, air, 24 h (A); (ii) FeCl3 (10 mol %), toluene, MW, 170ꢀC, 15 min (B).
R2 R1
R2
CH3
R1
Ph
CH3
PhCH=O (2)
CH (3)
R3
N
R3
PhC
+
+
O
O
O
Ph
N
O
O
O
FeCl3
(i) or (ii)
O
Ph
N
O
H2N
H
Ph
Ph
8a,b
10
9
7a,b
7,8 a: R1=CH3, R2=R3=H
b: R1= H, R2-R3= CH2CH2CH2CH2
profile. The reactions studied and the products obtained are
depicted in Schemes 1 and 2.
5–7). When we apply this procedure to 7-amino-4-methyl-
coumarin (7a), the linear pyridocoumarin 9 (18%) followed
by the angular analog 8a (54%) and benzylaminocoumarin
10 (26%) were isolated (Scheme 2, Table 1, entry 9). The
reaction between aminocoumarin 7b, benzaldehyde (2),
and phenylacetylene (3) resulted to the expected angular
pyridocoumarin 8b (75%) (Table 1, entry 11).
In connection with our efforts in sustainable synthesis
development, by using MW irradiation, [23,54,56] we
tried subsequently the initial three-component reaction of
aminocoumarin 1a with 2 and 3 in the presence of FeCl3
(10%) under MW irradiation at 170ꢀC for 15 min (Table 1,
entry 2, conditions B). The products were again 4a (40%),
5 (27%), and 6-benzylaminocoumarin (6a) (26%). The
application of MW irradiation in the cases of amines 1d
and 7a gave the products 4d (60%), benzylaminocoumarin
6d (31%), and 8a (35%), 9 (15%), 6-benzylamino-4-
RESULTS AND DISCUSSION
The reaction of 6-aminocoumarin (1a) with benzaldehyde
(2) and phenylacetylene (3) in toluene in the presence [36] of
10% FeCl3 under reflux for 24 h (Scheme 1) resulted to the
synthesis of angular pyridocoumarin 4a (50%), the linear
pyridocoumarin 5 (28%), and 6-benzylaminocoumarin (6a)
(15%) (Table 1, entry 1, conditions A). The formation of
the aforementioned regio pyridocoumarins is analogous to
the formation of regio isomers, seselin, and xanthyletin,
from the cycloisomerization of 7-propargyloxycoumarin by
Au/TiO2. [55] The similar reactions of 6-aminocoumarins
1b–d led to the angular 2,4-diphenyl substituted pyridocou-
marins 4b–d, respectively, in good yields (Table 1, entries
Table 1
Synthesis of fused pyridocoumarins by FeCl3-catalyzed three-component reactions of aminocoumarins, benzaldehyde, and phenylacetylene under heating
or MW irradiation.
Entry
Aminocoumarin
Conditions
Products (yields %)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1c
1d
1d
7a
7a
7b
A: toluene, air, 110ꢀC, 24 h
4a (50), 5 (28), 6a (15)
4a (40), 5 (27), 6a (26)
4a (45), 5 (26), 6a (15)
4a (49), 5 (21), 6a (22)
4b (81)
4c (77)
4d (88)
4d (60), 6d (31)
8a (54), 9 (18), 10 (26)
8a (35), 9 (15), 10 (40)
8b (75)
B: toluene, MW, 170ꢀC, 15 min
C: toluene, MW, o-benzoquinone, 170ꢀC, 5 min
D: toluene, MW, O2, 170ꢀC, 3 min
A
A
A
B
A
B
A
9
10
11
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DOI 10.1002/jhet

Month 2014
Synthesis Through Three-Component Reactions Catalyzed by FeCl3 of Fused Pyridocoumarins
methylcoumarin (10) (40%), respectively (Table 1, entries
8 and 10). In all the aforementioned efforts, there is an increase
of the amounts for benzylaminocoumarins 6a,d and 10.
When we performed the reaction of 1a under MW irradi-
ation in the presence of equivalent amount of o-benzoqui-
none (Table 1, entry 3, conditions C), the isolated yields
for the products 4a, 5, and 6 were quite similar to the yields
during the reflux (Table 1, entry 1). A decrease of the amount
of 6-benzylaminocoumarin 6a (22%) is observed by bub-
bling O2 inside the mixture of the reaction before the applica-
tion of microwaves (Table 1, entry 4, conditions D).
aminocoumarins, there is no any benzylaminocoumarin
isolated under heating, and this is possibly because of ste-
ric hindrance for the attack of imine A to the dihydropyri-
docoumarin E (Table 1, entries 5–7 and 11).
To avoid the consumption of the intermediate imine A,
as an oxidizing reagent, we utilized the o-benzoquinone
in the microwaves, and so the amount of benzylamine 6a
was decreased (Table 1, entries 2 and 3). The use of O2
also seems to have similar results.
From the biological experiments found, the antioxidant
activity of pyridocoumarins was very low (8–15%, Table 2)
A possible mechanism for the one-pot FeCl3-catalyzed
three-component reaction for the formation of pyridocou-
marins is presented in Scheme 3. The imine A formed in
situ from aminocoumarin 1a–d and benzaldehyde (2)
underwent nucleophilic addition from the intermediate
alkynylate complex B [35] of phenylacetylene (3) and
FeCl3 to give the propargylamine complex C. The latter
through an intramolecular hydroarylation [36] generates
the vinylate complex D, [35] which on decomposition
regenerate the catalyst and lead to the dihydropyridocou-
marin E. The intermediate E is oxidized by the air to give
the products 4a–d or 5. In that case, the formation of
benzylamine 6a could be explained by the participation
of imine A as oxidizing agent [34] in the transformation
of E to the products. The amount of the benzylamines 6a,
d and 10 is higher in the case of MW irradiation, where
the air is not enough for the whole process (Table 1, entries
2, 8, and 10). In the cases of o-substituted or fused
Table 2
Interaction % with DPPH (RA %); in vitro inhibition of soybean lipoxygenase
(LOX); % inhibition of lipid peroxidation (LP) (AAPH %).
DPPH %
% Inhibition LOX
at 0.1 mM
LP %
0.1 mM
Compounds
0.1 mM, 20 min
4a
4b
4c
4d
5
8a
8b
9
No
8
No
No
15
6
64
5
No
No
84
100
23
100
22
100
54
No
40
15
No
No
No
4
No
93
NDGA
Trolox
63
No, no activity under the reported experimental conditions. Each value
represents the mean obtained from 3–6 values in two independent
experiments (ꢁSD < 10%).
Scheme 3. Possible mechanism for the formation of pyridocoumarins through the FeCl3-catalyzed three-component reaction of aminocoumarins,
benzaldehyde (2), and phenylacetylene (3).
R1
H2N
+ PhCH=O (2)
O
O
R2
Ph
R3
Cl3Fe
1a-d
R1
O
H
N
PhHC
-H2O
R1
O
R2
PhHC
N
R3
Cl2Fe
C
Ph
R1
O
O
R2
Ph
R3
HN+
A
R1
O
H
N
Ph
FeCl2
Ph
O
O
R2
B
R3
O
R2
D
R3
6a,d
FeCl3
Ph
H
A
(3)
Ph
Ph
R1
Ph
Ph
R1
N
N
Air
O
O
O
R2
O
R2
R3
R3
4a-d
E
O
O
HO
OH
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. S. Symeonidis, D. J. Hadjipavlou-Litina, and K. E. Litinas
Vol 000
Compound 5: light-yellow solid, mp 245–247ꢀC (DCM); IR
(Nujol): 3040, 1725, 1635, 1570, 1500 cmꢂ1 1H NMR
as it is measured by the interaction with the stable free rad-
ical 1,1-diphenyl-2-picrylhydrazyl (DPPH). The com-
pounds 4a, 4c, and 5 presented 100% inhibition of
antilipid peroxidation at 0.1 mM, as it is tested by the
2,20-azobis(2-amidinopropane) dihydrochloride (AAPH)
protocol (Table 2). Compounds 8a and 9 showed 54%
and 40% inhibition, respectively. Only compound 5
presented 64% inhibition of soybean lipoxygenase at
0.1 mM.
In conclusion, we have demonstrated a novel and
efficient strategy for the synthesis of fused pyridocoumar-
ins under heating or MW irradiation. The preliminary
biological assays pointed that compound 5 with its high
antilipid peroxidation and antilipoxygenase inhibitory
activity might be an interesting lead compound.
;
(300 MHz, CDCl3): d = 6.52 (d, 1H, J = 9.7 Hz), 7.48–7.63 (m,
8H), 7.80 (s, 1H), 7.91 (s, 1H), 7.92 (d, 1H, J = 9.7 Hz), 8.21 (dd,
2H, J1 = 1.7 Hz, J2 = 8.2 Hz), 8.39 (s, 1H); 13C NMR (75 MHz,
CDCl3: d = 111.4, 118.4, 120.7, 121.6, 127.5, 127.7, 128.8, 128.9,
129.0, 129.4, 129.7, 129.8, 137.5, 139.0, 142.9, 145.3, 148.9,
150.5, 157.3, 160.1; MS (ESI): 350 [M+ H]+, 372 [M+ Na]+, 388
[M+ K]+, 494 [M+ Na+ MeOH]+. HRMS (ESI): m/z [M + Na]+
Calcd for C24H15NO2: 372.0995; found, 372.0994. Anal. Calcd
for C24H15NO2: C, 82.50; H, 4.33; N, 4.01. Found: C, 82.43; H,
4.62; N, 4.14.
Compound 6a: dark-yellow solid, mp 112–114ꢀC (DCM); IR
;
(Nujol): 3340, 3030, 1675, 1640, 1550 cmꢂ1 1H NMR
(300 MHz, CDCl3): d = 4.35 (s, 2H), 6.35 (d, 1H, J = 9.5Hz), 6.58
(d, 1H, J = 2.8 Hz), 6.84 (dd, 1H, J1 = 2.8 Hz, J2 = 8.9 Hz), 7.15 (d,
1H, J = 8.9 Hz), 7.33–7.38 (m, 5H), 7.55 (d, 1H, J = 9.5 Hz); 13C
NMR (75MHz, CDCl3: d = 48.7, 108.7, 116.8, 117.6, 118.3,
119.4, 127.4, 127.5, 128.8, 138.6, 143.3, 144.8, 147.0, 161.2; MS
(ESI): 252 [M+ H]+, 274 [M + Na]+, 306 [M+ Na + MeOH]+.
Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57. Found:
C, 76.53; H, 5.09; N, 5.17.
EXPERIMENTAL
General. Melting points were determined on a Kofler hot-
stage apparatus and are uncorrected. IR spectra were obtained
with a Perkin-Elmer 1310 spectrophotometer (Perkin-Elmer
Inc., Buckinghamshire, U.K.) as Nujol mulls. NMR spectra
were recorded on a Bruker AM 300 (300 MHz and 75 MHz for
1H and 13C, respectively) using CDCl3 as solvent and TMS as
an internal standard. J values are reported in Hz. Mass spectra
were determined on an LCMS-2010 EV Instrument (Shimadzu)
under electrospray ionization (ESI) conditions. HRMS (ESI)
were received on a Bruker Daltonics APEX II (Bruker Biospin
GMBH, Rheinstetten, Germany). Microanalyses were obtained
Procedures for the synthesis of pyridocoumarins under MW
irradiation: compounds 4a, 5, and 6.
Conditions B: In a special vial for Biotage Initiator 2.0 ME (Biotage
AB, Yppsala, Sweden) reactor were added toluene (1.5 mL), FeCl3
(3 mg, 0.019 mmol), benzaldehyde (2) (20 mg, 0.02 mL, 0.19 mmol),
phenylacetylene (3) (20 mg, 0.021 mL, 0.19 mmol), and 6-
aminocoumarin (1a) (30.5 mg, 0.19mmol). The mixture was irradi-
ated under microwaves at 170ꢀC for 15 min (consumption of
starting material). After cooling, CH2Cl2 and then acetone were
added; the solid was removed, and the remaining solution was
evaporated, and the residue was separated by column chromatogra-
phy (silica gel No 60, hexane/AcOEt 8:1 to 4:1) to give, from the
faster moving band, compound 4a (26.5 mg, 40%) followed by
compound 5 (18mg, 27%) and 6-benzylaminocoumarin (6a)
(12.5 mg, 26%).
Conditions C: In a special vial for Biotage Initiator 2.0 ME
reactor were added toluene (1.5 mL), FeCl3 (3 mg, 0.019 mmol),
benzaldehyde (2) (20 mg, 0.02 mL, 0.19 mmol), phenylacetylene
(3) (20 mg, 0.021 mL, 0.19 mmol), 6-aminocoumarin (1a)
(30.5 mg, 0.19 mmol), and o-benzoquinone (22 mg, 0.2 mmol).
The mixture was irradiated under microwaves at 170ꢀC for
5 min (consumption of starting material). After cooling, CH2Cl2
and then acetone were added; the solid was removed, and the
remaining solution was evaporated, and the residue was separated
by column chromatography (silica gel No 60, hexane/AcOEt
8:1 to 4:1) to give, from the faster moving band, compound
4a (30 mg, 45%) followed by compound 5 (17 mg, 26%) and
6-benzylaminocoumarin (6a) (7 mg, 15%).
on
a Perkin-Elmer 2400-II Element analyzer (Shimadzu
Corporation, Kyoto, Japan). Silica gel No 60, Merck A.G. was
used for column chromatography. The MW experiments were
performed in a Biotage (Initiator 2.0) scientific MW oven.
Procedure for the synthesis of pyridocoumarins under heating
(conditions A): 8,10-diphenyl-3H-pyrano[3,2-f]quinolin-3-
one (4a), 7,9-diphenyl-2H-pyrano[2,3-g]quinolin-2-one (5), and
6-(benzylamino)-2H-chromen-2-one (6a). FeCl3 (8 mg, 0.05 mmol),
benzaldehyde (2) (53 mg, 0.0516mL, 0.5 mmol), phenylacetylene
(3) (51 mg, 0.055mL, 0.5 mmol), and 6-aminocoumarin (1a)
(80 mg, 0.5 mmol) were added in toluene (2 mL), and the mixture
was refluxed for 24h. After cooling, CH2Cl2 and then acetone
were added; the solid was removed, and the remaining solution
was evaporated, and the residue was separated by column
chromatography (silica gel No 60, hexane/AcOEt 8:1 to 4:1)
to give, from the faster moving band, compound 4a (0.174g,
50%) followed by compound
benzylaminocoumarin (6a) (38 mg, 15%).
Compound 4a: yellow solid, mp 216–218ꢀC (DCM); IR (Nujol):
3050, 1725, 1635, 1535cmꢂ1 1H NMR (300 MHz, CDCl3):
5 (98 mg, 28%) and 6-
Conditions D: In a special vial for Biotage Initiator 2.0 ME reactor
were added toluene (1 mL), FeCl3 (2mg, 0.012mmol), benzaldehyde
(2) (13mg, 0.013 mL, 0.124 mmol), phenylacetylene (3) (13 mg,
0.014mL, 0.124mmol), and 6-aminocoumarin (1a) (20 mg,
0.124mmol). O2 was bubbled inside this mixture, and it was irradi-
ated under microwaves at 170ꢀC for 3min (consumption of starting
material). After cooling, CH2Cl2 and then acetone were added; the
solid was removed, and the remaining solution was evaporated,
and the residue was separated by column chromatography (silica
gel No 60, hexane/AcOEt 8:1 to 4:1) to give, from the faster moving
band, compound 4a (21mg, 49%) followed by compound 5 (9 mg,
21%) and 6-benzylaminocoumarin (6a) (7mg, 22%).
;
d = 6.05 (d, 1H, J = 10.1 Hz), 7.32 (d, 1H, J = 10.1Hz), 7.43–7.59
(m, 8H), 7.72 (d, 1H, J = 9.2 Hz), 7.85 (s, 1H), 8.20 (dd, 2H,
J1 = 1.5 Hz, J2 = 8.0 Hz), 8.39 (d, 1H, J = 9.2 Hz); 13C NMR
(75 MHz, CDCl3: d = 113.4, 113.8, 121.5, 122.3, 122.6, 127.4,
128.4, 128.9, 129.0, 129.5, 129.8, 135.3, 138.4, 141.1, 141.6,
146.9, 148.0, 155.0, 156.0, 160.0; MS (ESI): 350 [M+ H]+, 372
[M+ Na]+, 404 [M+ Na+ MeOH]+. HRMS (ESI): m/z [M + Na]+
Calcd for C24H15NO2: 372.0995; found, 372.0995. Anal. Calcd
for C24H15NO2: C, 82.50; H, 4.33; N, 4.01. Found: C, 82.65; H,
4.61; N, 3.77.
6-Methyl-8,10-diphenyl-3H-pyrano[3,2-f]quinolin-3-one (4b)
(conditions A).
(DCM); IR (Nujol): 3020, 1720, 1640, 1530cmꢂ1;1H NMR
81% yield, yellow solid, mp 206–208ꢀC
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Synthesis Through Three-Component Reactions Catalyzed by FeCl3 of Fused Pyridocoumarins
(300MHz, CDCl3): d = 3.01 (s, 3H), 5.96 (d, 1H, J = 10.1Hz),
7.41–7.62 (m, 10H), 7.86 (s, 1H), 8.27 (d, 2H, J = 6.9 Hz); 13C
NMR (75 MHz, CDCl3: d = 19.2, 111.8, 112.6, 120.9, 122.0,
122.1, 127.3, 128.5, 128.8, 128.9, 129.4, 129.7, 138.6, 141.4,
141.9, 144.5, 145.9, 148.1, 154.2, 154.8, 160.3; MS (ESI): 364
[M+ H]+, 386 [M+ Na]+, 418 [M + Na + MeOH]+. HRMS (ESI):
m/z [M+ Na]+ Calcd for C25H17NO2: 386.11515; found,
386.1155. Anal. Calcd for C25H17NO2: C, 82.63; H, 4.72; N,
3.85. Found: C, 82.49; H, 4.90; N, 3.57.
119.1, 120.3, 122.8, 122.9, 127.8, 128.9, 129.0, 129.4, 130.1,
137.9, 139.0, 149.8, 149.9, 151.5, 153.1, 155.7, 159.3, 160.4; MS
(ESI): 364 [M + H]+, 386 [M + Na]+, 418 [M + Na + MeOH]+.
HRMS (ESI): m/z [M + Na]+ Calcd for C25H17NO2: 386.11515;
found, 386.1153. Anal. Calcd for C25H17NO2: C, 82.63; H, 4.72;
N, 3.85. Found: C, 82.77; H, 4.94; N, 3.62.
Compound 8a: 54% yield, light-yellow solid, mp 267–269ꢀC
(DCM); IR (Nujol): 3060, 1710, 1590, 1535 cmꢂ1 1H NMR
;
(300 MHz, CDCl3): d = 2.50 (s, 3H), 6.22 (s, 1H), 7.41–7.59
(m, 8H), 7.84 (s, 1H), 7.87 (d, 1H, J= 9.0 Hz), 8.12 (d, 1H,
J= 9.0 Hz), 8.22 (dd, 2H, J1 =1.6Hz, J2 =8.0Hz); 13C NMR
(75 MHz, CDCl3: d = 19.3, 114.6, 115.9, 116.1, 122.3, 124.2, 126.5,
127.7, 128.0, 128.1, 128.9, 129.4, 130.0, 138.5, 141.1, 149.3, 150.7,
150.9, 152.3, 158.1, 159.0; MS (ESI): 364 [M + H]+, 386 [M + Na]+,
402 [M + K]+. HRMS (ESI): m/z [M + Na]+ Calcd for C25H17NO2:
386.11515; found, 386.1151. Anal. Calcd for C25H17NO2: C, 82.63;
H, 4.72; N, 3.85. Found: C, 82.62; H, 4.74; N, 3.75.
Methyl 2-oxo-5,7-diphenyl-9,10,11,12-tetrahydro-2H-benzo
[h]pyrano[3,2-f]quinoline-4-carboxylate (4c1) (conditions A).
77% yield, dark-yellow solid, mp 280–282ꢀC (DCM); IR
(Nujol): 3030, 1720, 1640, 1530 cmꢂ1 1H NMR (300 MHz,
;
CDCl3): d = 1.93–2.08 (m, 4H), 3.03–3.12 (m, 2H), 3.43
(s, 3H), 3.54–3.62 (m, 2H), 6.44 (s, 1H), 7.40–7.58 (m, 8H),
7.75 (s, 1H), 8.27(dd, 2H, J1 = 1.9 Hz, J2 = 8.4 Hz); 13C NMR
(75 MHz, CDCl3: d = 22.1, 22.3, 23.8, 26.0, 52.9, 108.1, 114.6,
119.9, 120.1, 127.4, 127.7, 127.9, 128.0, 128.3, 128.8, 129.5,
139.0, 140.5, 143.3, 145.8, 146.1, 148.3, 154.0, 154.9, 160.1,
164.7; MS (ESI): 462 [M + H]+, 484 [M + Na]+, 516
[M + Na + MeOH]+. HRMS (ESI): m/z [M + Na]+ Calcd for
C30H23NO4: 484.1519; found, 484.1522. Anal. Calcd for
C30H23NO4: C, 78.07; H, 5.02; N, 3.03. Found: C, 78.22; H,
4.91; N, 2.90.
Compound 10: 26% yield, yellow solid, mp 171–173ꢀC (DCM); IR
1
(Nujol): 3330, 3050, 1680, 1615, 1550 cmꢂ1; H NMR (300 MHz,
CDCl3): d = 2.33 (s, 3H), 4.39 (s, 2H), 4.61 (brs, 1H), 5.97 (s, 1H),
6.48 (d, 1H, J= 2.3 Hz), 6.54 (dd, 1H, J1 =2.3Hz, J2 = 8.7 Hz), 7.30
(d, 1H, J= 8.7 Hz), 7.33–7.42 (m, 5H); 13C NMR (75 MHz, CDCl3:
d = 18.4, 47.8, 109.8, 110.4, 125.5, 127.4, 127.7, 127.8, 128.0,
128.1, 128.9, 129.0, 151.3, 152.8, 161.8; MS (ESI): 266 [M + H]+,
288 [M + Na]+, 304 [M + K]+. Anal. Calcd for C17H15NO2: C,
76.96; H, 5.70; N, 5.28. Found: C, 76.79; H, 5.77; N, 5.12.
Compounds 9, 8a, and 10 (conditions B).
Methyl 2-oxo-5,7-diphenyl-2H-benzo[h]pyrano[3,2-f]quinoline-4-
carboxylate (4d) (conditions A). 88% yield, dark-yellow solid,
mp 301–303ꢀC (DCM); IR (Nujol): 3040, 1710, 1640,
1
1530cmꢂ1; H NMR (300MHz, CDCl3): d = 3.46 (s, 3H), 6.53
Compound 9: 15% yield.
Compound 8a: 35% yield.
Compound 10: 30% yield.
(s, 1H), 7.43–7.62 (m, 8H), 7.79–7.94 (m, 2H), 7.83 (s, 1H), 8.35
(d, 2H, J = 17.3 Hz), 8.59 (d, 1H, J = 8.7 Hz), 9.51 (d, 1H,
J = 7.7Hz); 13C NMR (75MHz, CDCl3: d = 53.0, 108.1, 115.4,
119.0, 120.5, 122.8, 124.5, 125.5, 127.4, 128.9, 129.0, 129.4,
129.6, 130.5, 134.1, 134.6, 138.8, 140.0, 145.4, 146.4, 148.6,
153.0, 155.3, 159.6, 161.8, 164.4; MS (ESI): 458 [M+ H]+.
HRMS (ESI): m/z [M + Na]+ Calcd for C30H19NO4: 480.1206;
found, 480.1212. Anal. Calcd for C30H19NO4: C, 78.76; H, 4.19;
N, 3.06. Found: C, 78.93; H, 4.02; N, 2.88.
2,4-Diphenyl-9,10,11,12-tetrahydro-6H-benzo[h]pyrano[2,3-
f]quinolin-6-one (8b) (conditions A). 75% yield, dark-yellow
solid, mp 241–243ꢀC (DCM); IR (Nujol): 3050, 1710,
1
1575 cmꢂ1; H NMR (300 MHz, CDCl3): d = 1.94–2.07 (m, 4H),
2.97–3.07 (m, 2H), 3.46–3.56 (m, 2H), 6.34 (d, 1H, J = 9.8 Hz),
7.38–7.57 (m, 8H), 7.81 (s, 1H), 7.97 (d, 1H, J = 9.8 Hz), 8.27
(dd, 2H, J1 = 1.6 Hz, J2 = 8.1 Hz); 13C NMR (75 MHz, CDCl3:
d = 22.5, 22.8, 25.6, 26.5, 114.2, 114.6, 115.5, 120.9, 127.6,
127.9, 128.0, 128.1, 128.8, 129.9, 132.7, 133.3, 138.9, 139.9,
141.5, 149.0, 149.3, 150.4, 156.2, 159.2; MS (ESI): 404
[M+ H]+. HRMS (ESI): m/z [M+ Na]+ Calcd for C28H21NO2:
426.14645; found, 426.1464. Anal. Calcd for C28H21NO2: C,
83.35; H, 5.25; N, 3.47. Found: C, 83.42; H, 5.05; N, 3.29.
Compound 4d and methyl 6-(benzylamino)-2-oxo-2H-benzo
[h]chromene-4-carboxylate (6d) (conditions B).
Compound 4d: 60% yield.
Compound 6d: 31% yield, brown solid, mp 214–216ꢀC (DCM);
IR (Nujol): 3370, 3060, 1670, 1625, 1530 cmꢂ1 1H NMR
;
(300 MHz, CDCl3): d = 3.96 (s, 3H), 4.52 (s, 2 H), 4.63 (brs,
1H), 6.97 (s, 1H), 7.30 (s, 1H), 7.32–7.42 (m, 3H), 7.48 (d,
2H, J = 6.7 Hz), 7.65 (dd, 2H, J1 = 3.5 Hz, J2 = 6.0 Hz), 7.88 (dd,
1H, J1 = 3.7 Hz, J2 = 6.0 Hz), 7.58 (dd, 1H, J1 = 3.1 Hz,
J2 = 6.0 Hz); 13C NMR (75 MHz, CDCl3: d = 48.9, 53.0, 98.7,
112.6, 118.5, 120.2, 123.4, 123.7, 125.8, 127.2, 127.6, 127.9,
128.4, 128.8, 138.5, 140.2, 143.2, 160.5, 165.2; MS (ESI): 360
[M + H]+, 382 [M + Na]+, 398 [M + K]+. Anal. Calcd for
C22H17NO4: C, 73.53; H, 4.77; N, 3.90. Found: C, 73.66; H,
4.72; N, 3.78.
Biological experiments: in vitro assays.
The compounds
were dissolved in DMSO.
1) Interaction with the stable free radical DPPH (final concentration
0.05 mM) in ethanol absolute (final concentration 0.1 mM).
[52–54]
2) Antilipid peroxidation. The AAPH protocol was performed.
[52,53]
3) Lipoxygenase inhibition. The soybean lipoxygenase/linoleic
sodium protocol was used. [52–54]
4-Methyl-6,8-diphenyl-2H-pyrano[3,2-g]quinolin-2-one (9),
4-methyl-8,10-diphenyl-2H-pyrano[2,3-f]quinolin-2-one (8a),
and 7-(benzylamino)-4-methyl-2H-chromen-2-one (10)
(conditions A, the fractions separated in this row from the column
chromatography).
Acknowledgments. This research has been co-financed by the
European Union (European Social Fund, ESF) and Greek national
funds through the operational program “Education and Lifelong
Learning” of the National Strategic Reference Framework
(NSRF), Research Funding Program: Heracleitus II, investing in
knowledge society through the European Social Fund.
Compound 9: 18% yield, light-yellow solid, mp 281–283ꢀC (DCM);
IR (Nujol): 3030, 1705, 1605, 1525 cmꢂ1 1H NMR (300 MHz,
;
CDCl3): d = 2.37 (s, 3H), 6.33 (s, 1H), 7.48–7.63 (m, 8H), 7.83
(s, 1H), 8.09 (s, 1H), 8.13 (s, 1H), 8.23 (dd, 2H, J1 =1.6Hz,
J2 =7.9Hz); 13C NMR (75MHz, CDCl3: d = 18.6, 115.2, 116.1,
We are grateful to Prof. Dr Athanassios Giannis, University of
Leipzig, Germany for the HRMS spectra.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. S. Symeonidis, D. J. Hadjipavlou-Litina, and K. E. Litinas
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet