A convenient one-pot synthesis of pyrano[3,2-c]quinolin-2,5(6H)-dione and 2H,5H-pyrano[3,2-c]chromene-2,5-dione derivatives

Article abstract of DOI:10.1055/s-2006-926295

The preparation of novel pyrano[3,2-c]quinolin-2,5(6H)-dione and 2H,5H-pyrano[3,2-c]chromene-2,5-dione derivatives starting from 4-hydroxyquinolin-2(1H)-ones and 4-hydroxy-2H-chromene-2-one with chlorocarbonyl ketenes is described. This method provides a new route to produce fused pyrano derivatives in good to excellent yields in a short experimental time. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926295

PAPER
435
A Convenient One-Pot Synthesis of Pyrano[3,2-c]quinolin-2,5(6H)-dione and
2H,5H-Pyrano[3,2-c]chromene-2,5-dione Derivatives
P
yrano[3,2-
c
]quino
a
lin-2,5(6
H
s
)-dione/2
H
s
,5
H
-
Pyr
a
a
no[3,2-c]ch
n
romene-2,5-dionesSheibani,*a Mohammad Hossein Mosslemin,b Soheila Behzadi,b Mohammad Reza Islami,a Kazem Saidia
a
Department of Chemistry, Shahid Bahonar University of Kerman, Kerman 76169, Iran
Fax +98(341)3221452; E-mail: hsheibani@mail.uk.ac.ir
b
Department of Chemistry, Islamic Azad University of Yazd, Yazd 89195, Iran
Received 20 July 2005; revised 23 August 2005
have been used mainly for the synthesis of five- and six-
membered heterocyclic compounds.11,12
Abstract: The preparation of novel pyrano[3,2-c]quinolin-
2,5(6H)-dione and 2H,5H-pyrano[3,2-c]chromene-2,5-dione deriv-
atives starting from 4-hydroxyquinolin-2(1H)-ones and 4-hydroxy-
2H-chromene-2-one with chlorocarbonyl ketenes is described. This
method provides a new route to produce fused pyrano derivatives in
good to excellent yields in a short experimental time.
In continuing our interest in the synthesis of heterocyclic
compounds we wish to report in this paper a one-pot
synthesis of pyrano[3,2-c]quinolin-2,5(6H)-dione and
2H,5H-pyrano[3,2-c]chromene-2,5-dione derivatives us-
ing the reaction of 4-hydroxyquinolin-2(1H)-ones and
4-hydroxy-2H-chromene-2-one with chlorocarbonyl
ketenes and diethyl phenylmalonate in good to excellent
yields.
Keywords: pyrano quinolinones, chromene derivatives, chlorocar-
bonyl ketenes
Development of novel synthetic methods for the construc-
tion of new analogues of bioactive heterocyclic com-
pounds represents a major challenge in synthetic organic
and medicinal chemistry. 4-Hydroxy-2-pyrones fused to
heterocyclic systems represent a very important class of
compounds used mainly as intermediates for the prepara-
tion of heterocyclic tricarbonylmethane derivatives of bi-
ological interest.1,2 The synthesis of such compounds has
been the subject of several reviews which demonstrate the
high importance of this class of compounds.3–5 These
compounds are useful synthons in organic synthesis and
can be used as precursors of a wide variety of biologically
active natural products.6 Although 2-pyrones have some
aromatic character, they undergo Diels–Alder [4+2]cy-
cloaddition reaction with a desired dienophile such as
alkynes and alkenes under suitable reaction conditions.7–9
In the present protocol as exhibited in Scheme 2 the con-
densation of (chlorocarbonyl)phenyl ketene (Method A)
with N-substituted 4-hydroxyquinolinones 1 afforded pyr-
ano[3,2-c]quinolin-2,5(6H)-dione derivatives 2 in excel-
lent yields at room temperature. The compounds 2 were
obtained in low yields when diethyl phenylmalonate was
condensed with 1 in boiling diphenyl ether as solvent
(Method B) (Scheme 2). The reaction conditions of Meth-
od A and Method B are shown in Table 1.
O
Ph
C
C O
OH
Ph
Cl
O
Method A
O
OH
anhyd CHCl3
N
R
O
N
R
O
2
1
We have recently described a new and operationally con-
venient approach to the synthesis of 4-hydroxy-3,5,6-
trisubstituted 2-pyrones (Scheme1) based on the 1,3-dinu-
cleophilic reaction of 1,3-diketones with (chlorocarbon-
yl)phenyl ketene.10
PhCH(CO2Et)2
Ph2O, 250 °C
Method B
Compound
R
2a Et
2b Me
2c Ph
O
OH
Scheme 2
O
O
Ph
O
Ph
anhyd Et2O
R
C
C O
+
Table 1 Reaction Conditions of N-Substituted 4-Hydroxyquino-
linones with (Chlorocarbonyl)phenyl Ketene (Method A) and Di-
ethyl Phenylmalonate (Method B) To Form Pyrano[3,2-c]quinolin-
2,5(6H)-diones 2a–c
Cl
R
R
R
O
O
Scheme 1
Entry
Method
R
Time
20 min
5 h
Temp (°C) Yield (%)
Chlorocarbonyl ketenes have been found to be a very ef-
fective 1,3-bielectrophiles reacting with a variety of nu-
cleophiles under rather mild experimental conditions, and
1
2
3
4
5
6
A
B
A
B
A
B
Et
25
90
65
85
58
92
63
Et
250–300
25
Me
Me
Ph
Ph
20 min
5 h
SYNTHESIS 2006, No. 3, pp 0435–0438
x
x
.
x
x
.2
0
0
5
250–300
25
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926295; Art ID: P09705SS
© Georg Thieme Verlag Stuttgart · New York
30 min
5 h
250–300

436
H. Sheibani et al.
PAPER
O
In a similar manner we have been prepared 2H,5H-py-
rano[3,2-c]chromene-2,5-diones 3a,b from the reaction of
chlorocarbonyl ketenes, (chlorocarbonyl)phenyl ketene
and (chlorocarbonyl)benzyl ketene with 4-hydroxy-2H-
chromene-2-one (Scheme 3).
OEt
OEt
– EtOH
O
>200 °C
O
H
EtO
O
C
C O
R
O
R
OH
OH
O
OH
O
O
O
C
C O
Cl
OH
O
O
O
Ph
3
C
C O
Cl
3a: R = Ph
O
O
3b: R = Benzyl
O
OPh
PhO
Scheme 3
Ph
4
There has been a considerable interest in the 2-oxo-2H-
chromene (coumarin) ring system, both with regard to
natural product chemistry, and to the pharmacological ac-
tivities of several of its derivatives.13 In addition, other 2-
oxo-2H-chromenes are of interest as a result of their tox-
icity,14 carcinogenicity,15 and photodynamic effects.16
Scheme 5
were added to (chlorocarbonyl)phenyl ketene, only corre-
sponding esters were generated (Scheme 5).
The structures of 2a–c, 3a–c and 4 were determined on the
basis of their elemental analyses, mass spectrum, 1H and
13C NMR and IR spectroscopic data.
It should be stressed that all starting materials such as
N-substituted 4-hydroxyquinolinones, 4-hydroxy-2H-
chromene-2-one, (chlorocarbonyl)phenyl ketene and
(chlorocarbonyl)benzyl ketene17a are easily available.
The 1H NMR spectrum of 2a indicated four kinds of pro-
ton signals along with one signal quite down field (d =
15.17 ppm), arising from the proton of enol OH. This as-
signment is consistent with the literature precedents for
closely related products, and two signals at d = 4.57 (q, 2
H) and 1.54 (t, 3 H) ppm were identified as ethyl protons.
The phenyl protons appeared at d = 7.27–7.44 ppm (m, 5
H). The 1H decoupled 13C NMR spectrum of 2a was mea-
sured in CDCl3 and it is in accord with the proposed struc-
ture. The 13C NMR of compound 2a showed two signals
at d = 178.42 and 168.15 ppm which are due to the ester
and amide carbonyl carbons, respectively. The oxo and
hydroxy groups adjacent to double bond strongly polarize
the double bond system. The a-carbons and b-carbons of
these substituents appear at d = 159.04, 155.05 ppm and
d = 97.80, 95.21 ppm, respectively. The aromatic carbons
appeared at d = 115.56–136.94 ppm. The signals that ap-
peared d = 39.79 and 13.42 ppm were identified as ethyl
carbons.
4-Hydroxyquinolin-2(1H)-ones have also been prepared
by an alternative route involving the condensation of ma-
lonates or malonic acid and phosphoryl chloride with anil-
ides in low yiled.17b
Our new methodology (Scheme 4) involves the reaction
of chlorocarbonyl ketene with anilides as dinucleophiles.
Above 80 °C, malonyl dichlorides lose hydrogen chloride
to form chlorocarbonyl ketene, which is more reactive
than malonyl dichlorides.
OH
COCl
+
– HCl
COCl
NHR
N
R
O
1
Compound
R
Yield
In summary, we have shown that the condensation reac-
tions of chlorocarbonyl ketenes such as (chlorocarbon-
yl)phenyl ketene and (chlorocarbonyl)benzyl ketene with
1,3-dinucleophiles such as 4-hydroxyquinolin-2(1H)-
ones and 4-hydroxy-2H-chromene-2-one occur efficient-
ly at ambient temperature, providing a convenient and
rapid synthesis of pharmacologically active compounds in
high yield, by a simple procedure in a short experimental
time. Furthermore, the products are solid and precipitate
out from the reaction mixture and their purifications are
simple.
1a Et
90
85
85
1b
1c
Me
Ph
Scheme 4
Pyrones and benzoanalogous coumarins have been ob-
tained from enols or phenols and 2-unsubstituted or 2-
monosubstituted diethyl malonates (probably via
arylketene ester intermediate).18 On the other hand, the re-
action of (chlorocarbonyl)phenyl ketene with phenol and
a-naphthol, which act as 1,3 dinucleophile compounds,
did not lead to the corresponding 4-hydroxy-4H-
chromene-2-one derivatives. When phenolic compounds
Synthesis 2006, No. 3, 435–438 © Thieme Stuttgart · New York

PAPER
Pyrano[3,2-c]quinolin-2,5(6H)-dione and 2H,5H-Pyrano[3,2-c]chromene-2,5-diones
437
Melting points were measured on a Gallenkamp melting point ap-
paratus and are uncorrected. IR spectra were measured on a Mattson
1000 FT-IR spectrometer. 1H and 13C NMR spectra were measured
with a Bruker DRX-500 Avance spectrometer at 500 MHz and
125.77 MHz, respectively. Mass spectra were recorded on a MS-
QP2000A Shimadzu mass spectrometer operating at an ionization
potential of 70 eV.
13C NMR (DMSO-d6): d = 179.09 (C=O), 168.13, 158.92, 156.14,
139.66, 135.24, 134.51, 131.37, 130.94, 130.71, 129.24, 128.17,
127.38, 125.69, 125.52, 122.22, 118.35, 97.44, 95.26.
MS (relative intensity): m/z = 381 (80) [parent peak], 353 (100)
[base peak], 296 (40), 195 (28), 165 (30), 77 (20).
Anal. Calcd for C24H15NO4: C, 75.59; H, 3.93; N, 3.67. Found: C,
75.34; H, 3.80; N, 3.59.
6-Ethyl-4-hydroxy-3-phenyl-2H-pyrano[3,2-c]quinoline-
2,5(6H)-dione (2a); Typical Procedure
4-Hydroxy-3-phenyl-2H,5H-pyrano[3,2-c]chromene-2,5-dione
(3a)
Compound 3a was prepared by reaction of 4-hydroxyquinolin-
2(1H)-ones with (chlorocarbonyl)phenyl ketene as described for 2a
(yield: 0.54g, 85%); yellow crystals; mp 222–224 °C (hexane–
EtOAc, 1:5).
Method A: To a magnetically stirred solution of 1-ethyl-4-hy-
droxy-2(1H)-quinolinone (0.38 g, 2 mmol) in anhyd CHCl3 (20 mL)
was added a mixture of (chlorocarbonyl)phenyl ketene (0.36 g, 2
mmol) in CHCl3 (5 mL) at ambient temperature. The solid product
was collected and recrystallized from EtOH. The product 2a was
obtained as light yellow crystals.
IR (KBr): 1741, 1692 (C=O, lactone), 1610 (C=C) cm–1.
1H NMR (DMSO-d6): d = 11.23 (s, 1 H, OH), 7.35–8.09 (m, 9 H,
Method B: A solution of diethyl 2-phenylmalonate (4.72 g, 20
mmol) and 1-ethyl-4-hydroxy-2(1H)-quinolinone (3.78 g, 20
mmol) in diphenyl ether (20 mL) was heated for 3 h to 200–250 °C
in a metal bath. During this time EtOH was liberated. When the lib-
eration of EtOH had stopped, the reaction mixture was heated to an
oil bath temperature of 300 °C for 2 h, during which time further
EtOH (1 mL) was liberated. After cooling, the reaction mixture was
diluted with toluene (30 mL), filtered by suction and washed with
cyclohexane (50 mL). The product 2a was obtained as light yellow
crystals (yield: 0.60 g, 90%); mp 197–199 °C.
arom).
13C NMR (DMSO-d6): d = 162.80, 162.05 (C=O), 161.22, 160.15,
152.52, 135.71, 130.88, 130.73, 128.27, 128.10, 126.51, 124.09,
117.74, 113.28, 104.45, 98.08.
MS (relative intensity): m/z = 306 (10) [parent peak], 305 (20), 278
(15), 225 (100) [base peak], 181 (20), 179 (80), 77 (15).
Anal. Calcd for C18H10O5: C, 70.58; H, 3.27. Found: C, 70.31; H,
3.13.
IR (KBr): 3230 (br, OH), 1740 (C=O, lactone), 1659 (C=O, lactam),
1595 (C=C) cm–1.
1H NMR (CDCl3): d = 15.01 (s, 1 H, OH), 7.28–8.45 (m, 9 H, arom),
4.57 (q, JHH = 7 Hz, 2 H, NCH2), 1.54 (t, JHH = 7 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 178.42, 168.15, 159.04, 155.05, 136.94,
134.67, 130.62, 130.31, 127.93, 127.31, 126.62, 124.96, 123.15,
115.56, 97.80, 95.21, 39.79, 13.42.
3-Benzyl-4-hydroxy-2H,5H-pyrano[3,2-c]chromene-2,5-dione
(3b)
Compound 3b was prepared by reaction of 4-hydroxyquinolin-
2(1H)-ones with (chlorocarbonyl)benzyl ketene as described for 2a
(yield: 0.51 g, 80%); white crystals; mp 252–254 °C.
IR (KBr): 3080 (br, OH), 1734, 1685 (C=O, lactone), 1605 (C=C)
cm–1.
1H NMR (DMSO-d6): d = 11.05 (s, 1 H, OH), 7.14–8.39 (m, 9 H,
arom), 3.73 (s, 2 H, CH2).
MS (relative intensity): m/z = 333 (65) [parent peak], 305 (70), 262
(100) [base peak], 249 (40), 215 (20), 77 (10).
Anal. Calcd for C20H15NO4: C, 72.07; H, 4.50; N, 4.20. Found: C,
71.78; H, 4.28; N; 4.01.
MS (relative intensity): m/z = 320 (70) [parent peak], 291 (40), 215
(80), 121 (100) [base peak], 103 (45), 91 (60), 77 (50), 65 (60).
Anal. Calcd for C19H12O5: C, 71.25; H, 3.75. Found: C, 70.01; H,
3.53.
4-Hydroxy-6-methyl-3-phenyl-2H-pyrano[3,2-c]quinoline-
2,5(6H)-dione (2b)
Yield: 0.54 g (85%); pale yellow crystals; mp 222–224 °C.
4-Hydroxy-1-phenyl-2(1H)quinolone (1c); Typical Procedure
To a boiling solution of malonyl dichlorides (0.28g, 2 mmol) in an-
hyd benzene (30 mL), diphenylamine (0.38 g, 2 mmol) in anhyd
benzene (15 mL) was added dropwise under a N2 atmosphere. The
reaction mixture was heated under a N2 atmosphere for 2 h under re-
flux and then excess benzene was removed by distillation under re-
duced pressure. The residue was triturated with hexane. The solid
product was collected and recrystallized from EtOH–H2O. The
product 1c was obtained as light yellow crystals (yield: 0.40 g,
85%); mp 291 °C.
IR (KBr): 3230 (br, OH), 1756 (C=O, lactone), 1655 (C=O, lactam),
1580 (C=C) cm–1.
1H NMR (DMSO-d6): d = 15.17 (s, 1 H, OH), 7.31–8.31 (m, 9 H,
arom), 3.95 (s, 3 H, CH3).
13C NMR (DMSO-d6): d = 176.15, 167.03, 157.45, 150.20, 133.58,
129.73, 129.14, 126.48, 125.78, 124.65, 123.89, 121.37, 95.85,
93.81, 30.32.
MS (relative intensity): m/z = 319 (30) [parent peak], 304 (10), 291
(100) [base peak], 242 (50), 77 (20).
Spectral data of compounds 1a–c are identical with the reported
Anal. Calcd for C19H13NO4: C, 71.47; H, 4.07; N, 4.38. Found: C,
71.15; H, 3.85; N; 4.21.
data in the literature.17b
Diphenyl 2-Phenylmalonate (4)
4-Hydroxy-3,4-diphenyl-2H-pyrano[3,2-c]quinoline-2,5(6H)-
dione (2c)
Yield: 0.70 g (92%); yellow crystals; mp 256–258 °C (hexane–
EtOAc, 1:5).
(Chlorocarbonyl)phenyl ketene (0.36 g, 2 mmol) was added to phe-
nol (0.18 g, 2 mmol) in anhyd Et2O (20 mL) with stirring at ambient
temperature for 2 h. The solid product was collected and recrystal-
lized from THF. The product 4 was obtained as white crystals
(yield: 0.63g, 95%); mp 86–88 °C.
IR (KBr): 1765, 1741 (C=O), 1600 (C=C) cm–1.
1H NMR (CDCl3): d = 7.17–7.65 (m, 15 H, arom), 5.17 (s, 1 H).
IR (KBr): 3230 (br, OH), 1741 (C=O, lactone), 1666 (C=O, lactam),
1590 (C=C) cm–1.
1H NMR (DMSO-d6): d = 15.25 (s, 1 H, OH), 6.77–8.26 (m, 14 H,
arom).
13C NMR (CDCl3): d = 166.43 (C=O), 150.51, 131.72, 129.52,
129.43, 128.94, 128.74, 126.28, 121.21, 57.92.
Synthesis 2006, No. 3, 435–438 © Thieme Stuttgart · New York

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H. Sheibani et al.
PAPER
MS (relative intensity): m/z = 332 (10) [parent peak], 238 (90), 183
(40) 145 (100) [base peak], 118 (38), 90 (68), 65 (25).
(6) Zhang, X.; Hinkel, B.; Ballantyne, L.; Gonzales, S.; Pena,
M. R. J. Heterocycl. Chem. 1997, 34, 1061.
(7) Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. H.
Tetrahedron 1992, 48, 9111.
(8) Lee, H. S.; Kim, D.; Won, H.; Choi, J. H.; Lee, H.; Cho, C.
G. Tetrahedron Lett. 2002, 43, 5591.
Anal. Calcd for C21H16O6: C, 75.90; H, 4.81. Found: C, 75.79; H,
4.71.
(9) Lacey, N. R. J. Chem. Soc. 1954, 850.
(10) Sheibani, H.; Islami, M. R.; Khabazzadeh, H.; Saidi, K.
Tetrahedron 2004, 60, 5932.
(11) Sheibani, H.; Bernhardt, P. V.; Wentrup, C. J. Org. Chem.
2005, 70, 5859.
Acknowledgment
The authors express appreciation to the Shahid Bahonar University
of Kerman Faculty Research Committee and Islamic Azad Univer-
sity of Yazd for their support of this investigation.
(12) Potts, K. T.; Dery, M. O.; Kullnig, R. J. Chem. Soc., Chem.
Commun. 1987, 840.
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Synthesis 2006, No. 3, 435–438 © Thieme Stuttgart · New York