Studies with quinolines: New synthetic routes to 4H,5H,6H,9H-benzo[ij] pyrano[2,3-b]quinolizine-8-one, 4H-pyrano[2,3-b]pyridine, 2H-pyran-2-one and pyranopyridoquinoline derivatives

Article abstract of DOI:10.1002/jhet.5570420529

Several new benzo[ij]pyrano[2,3-b]quinolizine-8-ones 5 and 4H-pyrano[2,3-e]pyridine 8 derivatives were synthesized from 4-hydroxyquinolines 1. Reacting 3-acetyl-4-hydroxy-1-phenyl-1H-quinoline-2-one with dimethylformamide dimethylacetal afforded 3-(3-Dimethylamino-acryloyl)-4- hydroxy-1-phenyl-1H-quinolin-2-one 9. This reacted with hippuric acid and diethyl 3-oxoglutarate to give 2H-pyran-2-one 13 and pyranopyridoquinoline 17 respectively.

Full text of DOI:10.1002/jhet.5570420529

Jul-Aug 2005
943
Studies With Quinolines: New Synthetic Routes to 4H,5H,6H,9H-
Benzo[ij]pyrano[2,3-b]quinolizine-8-one, 4H-Pyrano[2,3-b]pyridine,
2H-Pyran-2-one and Pyranopyridoquinoline Derivatives
Fathy Mohamad Abdel Aziz El-Taweel
Department of Chemistry, Faculty of Science, New Damietta City, A. R. Egypt
Received September 29, 2004
Several new benzo[ij]pyrano[2,3-b]quinolizine-8-ones 5 and 4H-pyrano[2,3-b]pyridine 8 derivatives
were synthesized from 4-hydroxyquinolines 1. Reacting 3-acetyl-4-hydroxy-1-phenyl-1H-quinoline-2-one
with dimethylformamide dimethylacetal afforded 3-(3-Dimethylamino-acryloyl)-4-hydroxy-1-phenyl-1H-
quinolin-2-one 9. This reacted with hippuric acid and diethyl 3-oxoglutarate to give 2H-pyran-2-one 13 and
pyranopyridoquinoline 17 respectively.
J. Heterocyclic Chem., 42, 943 (2005).
Introduction.
attention has been paid to the corresponding enaminones
containing the quinolinyl moiety. In continuation of our
studies in exploring the utilization of substituted quino-
lines as versatile precursors for synthesis of a variety of
heteroaromatics like 3-substituted quinolines and pyra-
noquinolines, we report here new accesses to 3-subtituted
quinolines and pyrano[3,2-c]quinoline derivatives.
4-Hydroxy-1H-quinolin-2-ones are versatile reagents
and their utility in synthesis of different heterocycles has
recently received considerable interest [1-6]. Also, they
have occupied a unique place in medicinal and biological
chemistry due to their diverse pharmacological displays as
antitumor [7], antimicrobial [8], antidepressant [9] and
antiseptic agents [10]. They are also useful intermediates
in the manufacture of dyestuffs [11]. Although a large
number of substituted derivatives of the above mentioned
biologically interesting quinolines have been prepared, no
simple general route for derivatives of these ring systems
is available.
Enaminones are an interesting class of compounds that
are versatile and readily available intermediates and play
an important role as building blocks in the synthesis of
many aromatic and heteroaromatic systems [12-16]. In
spite of the many literature reports on enaminones, little
Results and Discussion.
It has been found that, 1-hydroxy-2-acetyl-6,7-dihydro-
5H-benzo[i,j]quinolin-3-one (1a) reacted readily with
arylidenemalononitriles (2a,b) in ethanol with a piperidine
catalyst affords 9-aryl-11-amino-10-cyano-4H,5H,6H,9H-
benzo[ij]pyrano[2,3-b]quinolizin-8-ones (5a,b) Structures
1
5a,b were established on the basis of their H-nmr spectra
which displayed 4H-pyran protons at δ ≈ 4.5 ppm.
Formation of 5a,b from 1a and 2a,b is assumed to proceed
via initial addition of quinolizinyl C-2 in 1a to the π-defi-
cient double bond in 2 to give the adducts 3, which then
converted into the intermediates 4 via deacetylation as has
been previously reported [6]. The intermediates 4 were
cyclized to yield the final isolable products 5. It is of value
to note that quinolizinyl C-2 in 1a is more acidic than its
acetyl group. Moreover, the steric effect in the adducts 3
facilitate the deacetylation process. This mechanism is
supported further from the finding that 5a,b are formed
from 1-hydroxy-6,7-dihydro-5H-benzo[i,j]quinolin-3-one
(1d) with the same reagents.
Also, 11-amino-10-cyano-4H,5H,6H,9H-benzo[ij]-
pyrano[2,3-b]quinolizin-8-one (5c) was prepared via the
reaction of 2-acetyl-1-hydroxy-6,7-dihydro-5H-pyrido-
[3,2,1-ij]quinolin-3-one (1a) with methylenemalononitrile
(2c), prepared in situ from a mixture of formaldehyde and
malononitrile. The structure of 5c was assigned based on
elemental composition and spectral data and is consistent
with the product expected from the reaction of 1c with
methylenemalononitrile 2c (Scheme 1).
In contrast to the behaviour of compound 1a towards aryli-
denemalononitriles 2, 3-acetyl-4-hydroxy-1-substituted-
2(1H)-quinolones (1b,c) reacted with arylidenemalononi-

944
F. M. A. A. El-Taweel
Vol. 42
triles 2a,b in ethanol/piperidine in a molar ratio (1:1) or (1:2)
to yield pyrano[2,3-b]pyridine derivatives 8a-c. Elemental
analysis and spectral data are in full agreement with the pro-
posed structures 8 (cf. Experimental). Compounds 8 are
likely formed via Michael type addition of the enolate ion of
the acetyl function in 1b,c to the activated double bond in 2
to give the acyclic adducts 6, which cyclized into the inter-
mediates 7. The intermediates 7 then add one molecule of
malononitrile, which exists in equilibrium with 2 especially
under basic conditions [6] to afford compounds 8.
In conjunction of our investigations on the synthesis of
quinoline derivatives of potential interest using N,N-
dimethylformamide dimethylacetal (DMFDMA) as versatile
starting material, we have studied the condensation of 3-
acetyl-4-hydroxy-1-phenyl-2(1H)-quinolone (1b) with N,N-
dimethylformamide dimethylacetal followed by reaction with
different reagents. Thus, treatment of 3-acetyl-4-hydroxy-1-
phenyl-2(1H)-quinolone (1b) with N,N-dimethylformamide
dimethylacetal in dry xylene/ dimethylformamide mixture
(1:1) at reflux temperature afforded a product with molecular
+
formula C H N O (M = 334 m/z), which is consistent
20 18
2 3
with 1-(4-hydroxy-2-one-1-pheny-qninolin-3-yl)-3-
dimethylaminoprop-2-ene-1-one (9) as the reaction product.

Jul-Aug 2005
Studies With Quinolines: New Synthetic Routes
945
Anal. Calcd. For C
11.82. Found: C, 74.41; H, 4.76; N, 11.90.
H
N O (355.4): C, 74.35; H, 4.82; N,
Reacting compound 9 with hippuric acid 10 in acetic
anhydride afforded N-[6-(4-hydroxy-2-oxo-1-phenyl-1,2-
dihydroquinolin-3-yl)-2-oxo-2H-pyran-3-yl]-benzamide
(13). These were assumed to be formed via initial cycliza-
tion of hippuric acid 10 into oxazolone 11 which then adds
to the activated double bond system of the enaminone 9
yielding 12 followed by further rearrangement of 12 to
give 13. Similar sequence has been recently reported for
the reaction of enaminones with hippuric acid [14].
22 17
3 2
11-Amino-10-cyano-9-(4-hydroxyphenyl)-4H,5H,6H,9H-benzo-
[ij]pyrano[2,3-b]quinolizin-8-one (5b).
Compound 5b was obtained as yellow crystals in 65% yield
m.p. 290 °C; ir (KBr): ν 3444, 3290 (NH ), 2188 (CN), 1670
2
-1
1
(CO) cm ; H-nmr (DMSO): δ 1.94 (m, 2H, CH ), 2.94 (t, J =
2
6Hz, 2H, Ar-CH ), 3.94 (t, J = 6Hz, 2H, N-CH ), 4.4 (s, 1H,
2
2
pyran H-4), 6.6 (d, J = 9Hz, 2H, Ar-H), 6.85 (d, J = 9Hz, 2H, Ar-
H), 7.19 (s, 2H, NH ), 7.42 (t, J = 8Hz, 1H, quinolizine H-9),
The enaminone 9 was also reacted with diethyl acetonedi-
carboxylate (14) in acetic acid with ammonium acetate cata-
2
7.42 (d, J = 8Hz, 1H, quinolizine H-8), 7.83 (d, J = 8Hz, 1H,
quinolizine H-10) 9.72 (s, 1H, OH); ms: 371 (M ).
+
lyst to give a product with molecular formula C H N O
25 18
2 5
Anal. Calcd. For C
H N O (371.4): C, 71.15; H, 4.61; N,
22 17 3 3
+
(M = 426). The IR spectrum of the reaction product
showed absorption bands at ν = 1739 cm (CO ester), 1713
cm (CO pyridine), 1637 cm (CO amide). Consequently,
2-ethoxycarbonylmethyl-3,7,8-trihydro-8-phenyl-
pyrano[3,4-b]pyrido[4,3-b]quinoline-3,7-dione (17) was
assigned as a reaction product.
11.31. Found: C, 71.31; H, 4.57; N, 11.23.
-1
-1
-1
11-Amino-10-cyano-4H,5H,6H,9H-benzo[ij]pyrano[2,3-b]-
quinolizin-8-one (5c).
Compound 5c was obtained as colorless crystals in 70% yield
m.p. > 300 °C; ir (KBr): ν 3323, 3300 (NH ), 2192 (CN), 1677
2
-1
1
(CO) cm ; H-nmr (DMSO): δ 1.96 (m, 2H, CH ), 2.91 (t, J =
2
Compound 17 is thought to be formed via condensation of
the active methylene in 14 with the carbonyl function in 9
with water elimination forming the intermediate 15. The later
was cyclized in presence of ammonium acetate via elimina-
tion of molecule of and water to afford the final product 17.
6Hz, 2H, Ar-CH ), 3.34 (s, 2H, pyran H-4), 4.02 (t, J = 6Hz, 2H,
2
N-CH ), 7.11 (s, 2H, NH ), 7.21 (t, J = 7Hz, 1H, quinolizine H-
2
2
9), 7.41 (d, J = 7Hz, 1H, quinolizine H-8), 7.7 (d, J = 7Hz, 1H,
quinolizine H-10); ms: 279 (M ).
+
Anal. Calcd. for C
H N O (279.3): C, 68.81; H, 4.69; N,
16 13 3 2
15.05. Found: C, 68.76; H, 4.73; N, 15.21.
EXPERIMINTAL
Preparation of 5,7-Diamino-4-aryl-2-(1-aryl-4-hydroxy-2-oxo-
1,2-dihydroquinolin-3-yl)-4H-pyrano[2,3-b]pyridine-6-carboni-
triles (8a-c).
All melting points are uncorrected. IR spectra were recorded
for KBr disks on a Shimadzu IR-740 spectrometer. H-nmr spec-
tra were obtained on a Bruker AC-80 spectrometer with DMSO-
d as solvent and TMS as an internal standard and chemical shifts
are expressed as δ ppm. Mass spectra were measured on GC-
MSINCOS XL Finnigan MAT. Elemental analyses were per-
formed on LECO CHNS-932.
1
To a solution of 3-acetyl-4-hydroxy-1-substituted-2(1H)-
quinolones (1b,c) (0.01 mol) in ethanol containing few drops of
piperidine, (0.01 mol) of 2a,b were added. The reaction mixture
was refluxed for one hour, and then left to cool at room tempera-
ture. The solid product that formed was collected by filtration and
recrystallized from ethanol/1,4-dioxane to give 8a-c.
6
Synthesis of Quinolones 5a-c.
5,7-Diamino-2-(4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-
3-yl)-4-phenyl-4H-pyrano[2,3-b]pyridine-6-carbonitrile (8a).
Method A.
Compound 8a was obtained as colorless crystals in 75% yield
A mixture of 1-hydroxy-2-acetyl-6,7-dihydro-5H-benzo[ij]-
quinolin-3-one (1a) (0.01 mol ) and (0.01 mol) of 2a-c in ethanol
(50 ml) containing a few drops of piperidine were refluxed for
half an hour, then left to cool. The obtained precipitate was col-
lected by filtration and recrystallized from ethanol/DMF and then
identified as 5a-c.
m.p. > 300 °C; ir (KBr): ν 3450, 3380, 3200 (NH , OH), 2200
2
-1
1
(CN), 1680 (CO) cm ; H-nmr (DMSO): δ 4.53 (s, 1H, pyran H-
4), 6.6 (d, J = 8.5Hz, 1H, Ar-H), 7.1-7.6 (m, 15H, 13H, Ar-H and
4H, 2NH ), 8.1 (d, J = 8.5 Hz, 1H, quinoline H-8); ms: 499 (M ).
+
2
Anal. Calcd. for C
H N O (499.53): C, 72.13; H, 4.24; N,
30 21 5 3
14.02. Found: C, 72.24; H, 4.16; N, 14.13.
Method B.
5,7-Diamino-2-(4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-
3-yl)-4-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-6-carboni-
trile (8b).
Compounds 5a-c were also prepared from 1-hydroxy-6,7-
dihydro-5H-benzo[ij]quinolin-3-one (1d) (0.01 mol) and (0.01
mol) 2a-c utilizing the above reaction conditions.
Compound 8b was obtained as yellow crystals in 70% yield
11-Amino-10-cyano-9-phenyl-4H,5H,6H,9H-benzo[ij]pyrano-
[2,3-b]quinolizin-8-one (5a).
m.p. > 300 °C; ir (KBr): ν 3460, 3338, 3124 (NH , OH), 2210
2
-1
1
(CN), 1636 (CO) cm ; H-nmr (DMSO): δ 4.5 (s, 1H, pyran H-
4), 6.51(d, J = 8.5Hz, quinoline H-7), 6.63 (d, J = 8.5Hz, 2H, Ar-
H), 7.2 (d, J = 8.5 Hz, 2H, Ar-H), 7.4-7.8 (m, 13H, 9H, Ar-H and
Compound 5a was obtained as colorless crystals in 60% yield
m.p. > 300 °C; ir (KBr): ν 3393, 3326 (NH ), 2198 (CN), 1675
2
-1
1
4H, 2NH ), 8.2 (d, J = 8.5 Hz, 1H, Quinoline H-8), 9.5 (s, 1H,
(CO) cm ; H-nmr (DMSO): δ 1.95 (m, 2H, CH ), 2.5 (t, J =
6Hz, 2H, Ar-CH ), 3.95 (t, J = 6Hz, 2H, N-CH ), 4.54 (s, 1H,
2
2
+
OH); ms: 515 (M ).
2
2
Anal. Calcd. for C
13.59. Found: C, 69.89; H, 4.22; N, 13.61.
H N O (515.53): C, 69.90; H, 4.11; N,
pyran H-4), 7.16-7.45 (m, 9H, 7H, Ar-H and 2H, NH ) 7.9 (d, J =
8Hz, 1H, quinolizine H-9); ms: 355 (M ).
30 21 5 4
2
+

946
F. M. A. A. El-Taweel
Vol. 42
5,7-Diamino-2-(1-benzyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-
3-yl)-4-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-6-carbo-
nitrile (8c).
Compound 9 (0.01 mol) and (0.01 mol) of diethyl acetonedi-
carboxylate (14) and (0.01 mol) of ammomium acetate in glacial
acetic acid (30 ml) were refluxed for one hour then left to cool to
room temperature. The material that precipitated upon cooling
was isolated by filtration and recrystallized from ethanol to give
17 as yellow crystals in 60% yield, m.p. 200-202 °C; ir (KBr): ν
Compound 8c was obtained as yellow crystals in 65% yield
m.p. 260-262 °C; ir (KBr): ν 3464, 3310, 3216 (NH , OH), 2200
2
-1
1
(CN), 1680 (CO) cm ; H-nmr (DMSO): δ = 4.6 (s, 1H, pyran
H-4), 5.41(s, 2H, CH ), 6.67 (d, J = 8.5Hz, quinoline H-7), 7.2 (d,
-1
+
1739 (CO ester), 1713 (CO), 1637 (CO) cm ; ms : 426 (M ).
Anal. Calcd. for C N O (426.43): C, 70.42; H, 4.25; N,
2
H
25 18
2 5
J = 8.5 Hz, 2H, ArH), 7.35 (m, 12H, 8H, Ar-H and 4H, 2NH ),
2
6.57; Found: C, 70.51; H, 4.22; N, 6.63.
8.1 (d, J = 8.5 Hz, 1H, quinoline H-8), 9.3 (s, 1H, OH), 10.2 (s,
+
1H, OH); ms: 529 (M ).
Anal. Calcd. for C
H N O (529.56): C, 70.31; H, 4.38; N,
REFERENCES AND NOTES
31 23 5 4
13.23. Found: C, 70.43; H, 4.33; N, 13.44.
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3-(3-Dimethylamino-acryloyl)-4-hydroxy-1-phenyl-1H-quino-
lin-2-one (9).
Dimethylformamide dimethylacetal (0.01 mol) was added to 3-
acetyl-4-hydroxy-1-phenyl-2(1H)-quinolone (1b) (0.01 mol) in dry
xylene (50 ml) and the reaction mixture was refluxed for 6 hours.
Removal of the solvent under reduced pressure yielded the crude
product, which was recrystallized from DMF to give 9 as orange
crystals in 70% yield, m.p. 270-272 °C; ir (KBr): ν 3450, 3137
[4] J. Tois, M. Vahermo and A. Koskinen, Tetrahedron Lett., 46
,735 (2005)
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(1993).
-1
+
(OH), 1680 (CO), 1660 (CO), 1604 (C=C) cm ; ms: 334 (M ).
Anal. Calcd. for C N O (334.38): C, 71.84; H, 5.43; N,
H
20 18
2 3
8.38. Found: C, 71.78; H, 5.51; N, 8.39.
[9]
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(2003).
N-[6-(4-Hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)-2-
oxo-2H-pyran-3-yl]-benzamide (13).
A solution of 9 (0.01 mol) and the appropriate amount of hip-
puric acid 10 (0.01 mol) in acetic anhydride (50 ml), was refluxed
for 3 hours, then left to cool. The deposited solid was isolated by
filtration and recrystallized from ethanol/DMF to give 13 as red
crystals in 65% yield, m.p. 244-246 °C; ir (KBr): ν 3508, 3406
(OH, NH), 1785 (CO pyrone), 1702 (CO), 1668 (CO amide)
-1
+
cm ; ms: 450 (M ).
Anal. Calcd. for C
H N O (450.45): C, 71.99; H, 4.03; N,
27 18 2 5
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Tetrahedron, 60, 4601 (2004).
6.22. Found: C, 71.89; H, 4.13; N, 6.34.
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quinolin-12-yl)-acetic Acid Ethyl Ester (17).
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