Preparation of 23-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-1 ,5-dione derivatives

Article abstract of DOI:10.1002/jhet.5570420439

The 2,3-dihydro-7-methyl-1H,5H-pyrido[3,2,1-ij]quinoline-1,5-dione derivatives 9 and 10 were prepared from 3-(5,7-dimethoxy-4-methyl-2-oxo-2H- quinolin-1-yl)propionitrile (6). Cyclodehydration of the amide 8 gave 1,2-dihydro-7,9-dimethoxy-6-methylpyimido[1,2-a]quinolin-3-one (11).

Full text of DOI:10.1002/jhet.5570420439

May-Jun 2005
723
Preparation of 2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-1,5-dione
Derivatives
Stephen P. Stanforth
School of Applied Sciences, University of Northumbria, Newcastle upon Tyne, NE1 8ST, UK
Received October 25, 2005
The 2,3-dihydro-7-methyl-1H,5H-pyrido[3,2,1-ij]quinoline-1,5-dione derivatives 9 and 10 were prepared
from 3-(5,7-dimethoxy-4-methyl-2-oxo-2H-quinolin-1-yl)propionitrile (6). Cyclodehydration of the amide
8 gave 1,2-dihydro-7,9-dimethoxy-6-methylpyimido[1,2-a]quinolin-3-one (11).
J. Heterocyclic Chem., 42, 723 (2005).
We have previously reported the synthesis of the cross-
OMe) has been reported as part of a study of the anti-tumor
activity of 3-aryl-2-quinolone derivatives [3].
conjugated heterocyclic mesomeric betaine, 3-oxo-2-
5
phenyl-3aλ -azaphenalen-3a-ium-1-olate 2 (R = Ph) and
Cyanoethylation of 5,7-dimethoxy-4-methylquinol-2-
one 5 [4] using acrylonitrile in the presence of tetrabutyl-
ammonium hydroxide afforded the cyano derivative 6 in
good yield (80 %). When compound 6 was heated with
dilute sulphuric acid at 110°, the carboxylic acid derivative
7 was formed in 94 % yield rather than the tricyclic product
10. It had been anticipated that the acid 7, once formed,
would undergo cyclisation onto the electron-rich
dimethoxy-substituted ring but the proton nmr spectrum of
the reaction product showed three aromatic signals indicat-
ing that cyclisation had not occurred. However, compound
10 could be prepared in 63 % yield from the acid derivative
7 when it was heated with a mixture of phosphoric acid and
phosphorus pentoxide in hot toluene. Thus, the proton nmr
spectrum of compound 10 showed only two aromatic sig-
nals indicating the desired reaction had occurred. Other
cyclisation reagents were also investigated. In an attempt to
induce cyclisation directly, compound 6 was heated with 49
% hydrobromic acid. However, under these conditions both
cyclisation and demethylation occurred concomitantly and
the phenolic derivative 9 was produced in 91 % yield.
Milder conditions that might effect cyclisation were also
described a dipolar cycloaddition of this compound [1].
The tricyclic system 1 (R = Ph) was readily constructed by
heating 1,2,3,4-tetrahydroquinoline with diethyl phenyl-
malonate and the mesomeric betaine 2 (R = Ph) was subse-
quently obtained from compound 1 (R = Ph) in several
steps. We were also interested in the preparation of other
cross-conjugated mesomeric betaine isomers of the parent
heterocycle 2 (R = H), for example derivatives of com-
pound 3 (R = H). A potential synthetic route to derivatives
of compound 3 (R = H) might involve the tricyclic system,
8,10-dimethoxy-2,3-dihydro-1H,5H-pyrido[3,2,1-
ij]quinoline-1,5-dione (4) (R = OMe) in which the two
methoxy groups would eventually provide the two oxygen
atoms of the heterocyclic mesomeric betaine 3 (R = H).
This paper describes the synthesis of 2,3-dihydro-1H,5H-
pyrido[3,2,1-ij]quinoline-1,5-dione derivatives 9 and 10.
2,3-Dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-1,5-dione 4
(R = H) has been reported previously and this compound
was obtained in moderate yield by heating 2-(2-carboxy-
ethylamino)cinnamic acid with polyphosphoric acid [2].
The 6-(4-methoxyphenyl) derivative of heterocycle 4 (R =

724
S. P. Stanforth
Vol. 42
261° (from acetone). Compound 10 had: ir (chloroform) 1680,
1660, 1580, 1470 and 1360 cm ; H nmr (trifluoroacetic acid): δ
7.02 (s, 1H, Ar-H), 6.73 (s, 1H, Ar-H), 4.80 (t, 2H, J = 7 Hz, -
investigated. Thus, treatment of the cyano derivative 6 with
a mixture of zinc dichloride and hydrogen chloride gas in
acetic acid gave the amide 7 in 77 % yield rather than the
tricyclic compound 10. Amide 7 could be dehydrated with
phosphorus pentoxide in boiling toluene giving the hetero-
cyle 11 (36 % yield).
-1 1
CH -), 4.19 (s, 3H, -OCH ), 4.17 (s, 3H, -OCH ), 3.08 (t, 2H, J =
2
3
3
7 Hz, -CH -) and 2.89 (s, 3H, -CH ); ms: m/z 273 (100).
2
3
Anal. Calcd. for C
H NO : C, 65.9; H, 5.5; N, 5.1. Found: C,
15 15 4
65.7; H, 5.5; N, 4.8.
In conclusion, various conditions have been investigated
in order to convert the cyano derivative 6 into the tricyclic
derivatives 9 and 10. The dimethoxy derivative 10 is avail-
able via the carboxylic acid 6 whereas the dihydroxy deriv-
ative 9 can be prepared directly from compound 6.
Cyclodehydration of the amide 8 afforded the 1,2-dihy-
dropyimido[1,2-a]quinolin-3-one derivative 11.
3-(5,7-Dimethoxy-4-methyl-2-oxo-2H-quinolin-1-yl)propi-
onamide (8).
A suspension of compound 6 (0.85 g, 3.1 mmol) and zinc
dichloride (0.85 g, 6.3 mmol) in acetic acid (10 mL) was satu-
rated with hydrogen chloride gas. The mixture was allowed to
stand at room temperature overnight, diluted with water and
extracted four times with chloroform. The organic extracts were
dried (sodium sulfate) and evaporated giving a yellow oil. Ether
was added to the oil and compound 8 precipitated as a white solid
(0.7 g, 77 %), mp 211-214°. Compound 8 had: ir (potassium bro-
mide) 3410, 3130, 1690, 1640, 1610, 1590, 1395, 1270 and 1160
EXPERIMENTAL
3-(5,7-Dimethoxy-4-methyl-2-oxo-2H-quinolin-1-yl)propioni-
trile (6).
-1
1
cm
; H nmr (trifluoroacetic acid): δ 7.74 (broad s, 2H,
-CONH ), 7.04 (s, 1H, Ar-H), 6.94 (s, 1H, Ar-H), 6.82 (s, 1H, Ar-
2
A mixture of 5,7-dimethoxy-4-methylquinolin-2-one (5) [4]
(0.2 g, 0.9 mmol), acrylonitrile (0.4 mL, 6.0 mmol) and 40 %
tetrabutylammonium hydroxide (2 drops) in dimethoxymethane
(5 mL) was heated (0.5 hour) under reflux with stirring. After
cooling to room temperature, the mixture was filtered and the
white solid (0.3 g) was washed with ether and recrystallised from
ethanol giving compound 6 (0.2 g, 80 %), mp 188°. Compound 6
H), 5.03 (t, 2H, J = 6 Hz, -CH -), 4.09 (s, 6H, -OCH ), 3.15 (t,
2
3
2H, J = 6 Hz, -CH -) and 2.97 (s, 3H, -CH ); ms: m/z 290 (30)
2
3
and 219 (100).
Anal. Calcd. for C
H
N O : C, 62.1; H, 6.3; N, 9.7. Found:
2 4
15 18
C, 61.7; H, 6.2; N, 9.7.
8,10-Dihydroxy-2,3-dihydro-7-methyl-1H,5H-pyrido[3,2,1-
ij]quinoline-1,5-dione (9).
-1
1
had: ir (chloroform)1650 and 1610 cm ; H nmr (trifluoroacetic
Compound 6 (0.5 g, 1.84 mmol) and 49 % hydrobromic acid
(15 mL) were heated under reflux (oil-bath) overnight. The mix-
ture was allowed to cool to room temperature and then cooled in
ice. The purple solid was collected, washed with a little 49 %
hydrobromic acid and then water and dried under vacuum over
phosphorous pentoxide giving compound 9 (0.41 g, 91 %) as a
pale red solid, mp >300°. Compound 9 had: ir (potassium bro-
acid): δ 6.94 (s, 2H, Ar-H), 6.79 (s, 1H, Ar-H), 5.01 (t, 2H, J = 7
Hz, -CH -), 4.07 (s, 6H, -OCH ), 3.22 (t, 2H, J = 7 Hz, -CH -)
2
3
2
and 2.96 (s, 3H, -CH ).
3
Anal. Calcd. for C
H N O : C, 66.2; H, 5.9; N, 10.3. Found:
15 16 2 3
C, 65.9; H, 5.6; N, 10.4.
3-(5,7-Dimethoxy-4-methyl-2-oxo-2H-quinolin-1-yl)propionic
Acid (7) and 8,10-Dimethoxy-2,3-dihydro-7-methyl-1H,5H-
pyrido[3,2,1-ij]quinoline-1,5-dione (10).
-1
1
mide) 3100 and 1660-1560 (broad) cm ; H nmr (trifluoroacetic
acid): δ 7.22 (s, 1H, Ar-H), 6.83 (s, 1H, Ar-H), 4.96 (t, 2H, J = 6
Hz, -CH -), 3.30 (t, 2H, J = 6 Hz, -CH -) and 3.06 (s, 3H, -CH );
A mixture of compound 6 (1.5 g, 5.5 mmol) and dilute sul-
phuric acid (5 M, 40 mL) was heated on a steam bath (2 hours)
and then allowed to cool to room temperature. The colorless nee-
dles were collected and dried under high vacuum yielding com-
pound 7 (1.5 g, 94 %), mp 116-119° (from acetic acid).
2
2
3
ms: m/z calc. for C
H NO : 245.0688. Found: 245.0678.
13 11 4
Compound 9 gave a dibenzoate, mp 237° (with decomposition)
(from acetone).
Anal. Calcd. for C
H NO : C, 71.5; H, 4.2; N, 3.1. Found:
27 19 6
-1
1
C, 71.6; H, 4.4; N, 3.2.
Compound 7 had: ir (KBr) 2410 (broad) and 1735 cm ; H nmr
(trifluoroacetic acid): δ 7.03 (s, 1H, Ar-H), 6.98 (s, 1H, Ar-H),
1,2-Dihydro-7,9-dimethoxy-6-methylpyimido[1,2-a]quinolin-3-
one (11).
6.68 (s, 1H, Ar-H), 5.05 (2H, t, J = 6 Hz, -CH -), 4.10 (s, 6H, -
2
OCH ), 3.18 (t, 2H, J = 6 Hz, -CH -) and 2.99 (s, 3H, -CH ); ms:
3
2
3
A mixture of amide 8 (0.3 g, 1.0 mmol) and phosphorous pen-
toxide (0.4 g) in dry toluene was heated under reflux (oil-bath)
overnight protected from moisture (calcium chloride guard tube).
The mixture was allowed to cool to room temperature and was
diluted with chloroform. The organic solution was decanted from
the red residue and evaporated giving compound 11 (0.1 g, 36 %)
as a cream solid, mp 188-189° (from toluene). Compound 11 had:
m/z 291 (50) and 219 (100). Compound 7 was cyclised directly to
compound 10 as follows. Compound 7 (0.6 g, 2.1 mmol) was
added to a mixture of phosphorus pentoxide (0.9 g) and phos-
phoric acid (4 mL). The mixture was heated (2 hours) at 100°
(oil-bath) with protection from moisture (calcium chloride guard
tube). The pale orange mixture was allowed to cool to room tem-
perature and was then cooled in an ice-bath. Ice-cold dilute
sodium hydroxide solution was then added cautiously and the
cream coloured precipitate was collected and washed with water.
The solid was partitioned between chloroform and dilute sodium
hydroxide solution. The aqueous layer was extracted three times
with chloroform and the combined chloroform extracts were
washed with water, dried (magnesium sulfate) and evaporated
giving compound 10 (0.35 g, 63 %) as a white solid, mp 259-
-1
1
ir: (chloroform) 1650 and 1610 cm ; H nmr (deuteriochloro-
form): δ 6.54 (s, 1H, Ar-H), 6.32 (s, 1H, Ar-H), 6.27 (s, 1H, Ar-
H), 4.54 (t, 2H, J = 6 Hz, -CH -), 3.94 (s, 3H, -OCH ), 3.88 (s,
2
3
3H, -OCH ), 2.80 (t, 2H, J = 6 Hz, -CH -) and 2.58 (s, 3H, -CH );
3
2
3
ms: m/z 272 (80) and 219 (100).
Anal. Calcd. for C
H N O : C, 66.1; H, 5.9; N, 10.3. Found:
15 16 2 3
C, 65.8; H, 5.8; N, 10.0.

May-Jun 2005
Preparation of 2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-1,5-dione Derivatives
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