Synthesis of pyridopyranoquinolines by the Skraup reaction of amino-5H- benzopyrano[2,3-b]pyridin-5-ones

Article abstract of DOI:10.3987/COM-99-8753

7-, 8- and 9-Amino-5H-[1]benzopyrano[2,3-b]-pyridin-5-ones were synthesized. Skraup reaction of 6-Amino-, 7-amino-, 8-amino- and 9-Amino-5H- [1]benzopyrano[2,3-b]pyridin-5-ones in the presence of glycerol, fuming sulfuric acid, nitrobenzene, iron(II) sulf

Full text of DOI:10.3987/COM-99-8753

HETEROCYCLES, Vol. 53, No. 2, 2000, pp. 409 - 417, Received, 13th September, 1999
SYNTHESIS OF PYRIDOPYRANOQUINOLINES BY THE SKRAUP
REACTION OF AMINO-5H-BENZOPYRANO[2,3-b]PYRIDIN-5-ONES
Hidetoshi Fujiwara＊ and Kouki Kitagawa
Niigata College of Pharmacy, 5-13-2 Kamishin,ei-cho,
Niigata, 950-2081, Japan
Abstract - 7-, 8- and 9-amino-5H-[1]benzopyrano[2,3-b]-
pyridin-5-ones were synthesized.
Skraup reaction of
6-amino-, 7-amino-, 8-amino- and 9-amino-5H-[1]benzo-
pyrano[2,3-b]pyridin-5-ones in the presence of glycerol,
fuming sulfuric acid, nitrobenzene, iron(II) sulfate
and boric acid gave 12H-pyrido[3’,2’:5,6]pyrano[2,3-h]-
quinolin-12-one, 12H-pyrido[3’,2’:5,6]pyrano[3,2-f]-
quinolin-12-one, 7H-pyrido[3’,2’:5,6]pyrano[2,3-f]quin-
olin-7-one and 7H-pyrido[3’,2’:5,6]pyrano[3,2-h]quino-
lin-7-one, respectively.
INTRODUCTION
In recent years, a number of heteroaromatic antitumor compounds have been
prepared with the hope of increasing their pharmacological effects or to
find new derivatives with reduced side effects.1-3
DNA intercalating
agents, which are a very important classes of antitumor drugs, usually
possess planar aromatic and heteroaromatic polycyclic systems. Some
thioxanthene derivatives are effective against tumors.4-6 As an extension
of our synthetic studies of xanthene derivatives, we prepared xanthene
analogues consisting of a tetracyclic system containing two pyridine
rings.7-9
In this note we describe the synthesis of 12H-pyrido[3’,2’:
5,6]pyrano[2,3-h]quinolin-12-one(10), 12H-pyrido[3‘,2’:5,6]pyrano[3’2-f]-
quinolin-12-one(11), 7H-pyrido[3’,2’:5,6]pyrano[2,3-f]quinolin-7-one (12),
and 7H-pyrido[3’,2’:5,6]pyrano[3,2-h]quinolin-7-one(13) by the Skraup
reaction10,11 of amino-5H-[1]benzopyrano[2,3-b]pyridin-5-ones.

RESULTS AND DISCUSSION
The synthesis of 6-amino-5H-benzopyrano[2,3-b]pyridin-5-one(1) was
described previously.12
The synthetic route of 7-amino-5H-benzopyrano[2,3-b]pyridin-5-one(2) is
summarized in Scheme 1.
COOH
PPA
COOH
K CO
NHCOCH
NHCOCH
3
2 3
3
+
DMF
74%
76%
N Cl
HO
N O
5
O
O
NH
NHCOCH
2
47%HBr
89%
3
N O
N O
2
6
Scheme 1
The Ullmann reaction of 2-chloronicotinic acid with 4-hydroxyacetanilide
in the presence of K2CO3 in DMF under reflux for 2 h gave 2-(4-acet-
aminophenoxy)nicotinic acid (5)(yield 74%).
This acid (5) was heated with
PPA at 120oC for 3 h and then hydrolyzed with hydrobromic acid in the
presence of phenol for 1 h to give 7-amino-5H-benzopyrano[2,3-b]pyridin-5-
one (2)(yield 68% from 5).
In a similar way, the reaction of 2-chloro-
nicotinic acid with 3-hydroxyacetanilide afforded 2-(3-acetaminophenoxy)-
nicotinic acid (7) (yield 69%), which was cyclized with PPA and then
hydrolyzed with hydrobromic acid to give a mixture of 6- (1) and 8-amino-
5H-benzopyrano[2,3-b]pyridin-5-ones (3) (Scheme 2).
The mixture was separated by column chromatography to give 3 (yield 35%
from 7).
Although the Ullmann reaction of 2-chloronicotinic acid with o-hydroxy-
acetanilide or o-nitrophenol was attempted, it failed.
One of synthetic
method of amino-9H-xanthen-9-ones is direct amination using sulfuric acid
and hydroxylamine.13 Thus, this direct amination method was similarly
applied to the amination of 5H-benzopyrano[2,3-b]pyridin-5-one to afford a
mixture of 6-amino- (1)(yield 22%),7-amino- (2)(yield 14%), 8-amino- (3)
(yield 5%) and 9-amino-5H-benzopyrano[2,3-b]pyridin-5-ones (4)( yield 5%)
(Scheme 3).

NHCOCH
COOH
3
COOH
K CO
2 3
PPA
76%
+
DMF
69%
N O NHCOCH
N Cl
3
HO
7
O
O
O NHCOCH
3
47%HBr
+
+
1
N O NHCOCH
46%
N O NH
N O
3
2
3
9
8
Scheme 2
O
O
Direct amination
NH OH
1
2
3
+
+
+
N O
N O
2
5%
14%
NH
c-H SO
22%
2 4
2
4
.
FeSO 7H O
4
2
5%
Scheme 3
Skraup reactions of amino-5H-benzopyrano[2,3-b]pyridin-5-ones (1-4) with
glycerol, fuming sulfuric acid, and nitrobenzene were conducted in the
presence of iron(II) sulfate and boric acid, and all obtained products
were found to have the molecular formula C15H8N2O2 based on the elemental
analytical data and the MS spectra [m/z 248 (M+.)]. The Skraup reaction
products are summarized in Scheme 4. The Skraup reaction of 1 gave 12H-
pyrido[3’,2’:5,6]pyrano[2,3-h]quinolin-12-one (10) in 71 % yield.
The
structure of 10 was determined by 1H-NMR. The 1H-NMR showed proton signals
of the new pyridine ring at δ 7.56 (dd, J=4.4, 8.3 Hz, 3-H), 8.25 (dd,
J=1.9, 8.3 Hz, 4-H) and 9.29 (dd, J=1.9, 4.4 Hz, 2-H), and proton signals
of the 5H-benzopyrano[2,3-b]pyridin-5-one skeleton at δ 7.79 (d, J=8.3 Hz,
6-H) and 8.16 (d, J=8.3 Hz, 5-H). The Skraup reaction of 2 afforded only
12H-pyrido[3’,2’:5,6]pyrano[3,2-f]quinolin-12-one (11) in 82% yield. The
1H-NMR spectrum of 11 demonstrated a new pyridine ring and two doublet
proton signals of the 5H-benzopyrano[2,3-b]pyridin-5-one skeleton as in
the case of 2.

Similarly, the Skraup reaction of 3 produced one product, 7H-pyrido [3’,
2’:5,6]pyrano[2,3-f]quinolin-7-one (12), in 75 % yield, and the structure
of 12 was confirmed by 1H-NMR spectrum as in the case of 11. Based on the
present results, the Skraup reaction of 3 affored the corresponding angu-
lar-type product (12) without the linear-type product. Skraup reaction of
4 gave 7H-pyrido[3’,2’:5,6]pyrano[3,2-h]quinolin-7-one (13) in 84 % yield.
O NH
2
O N
N O
glycerol
N O
1
10
O
O
glycerol
NH
N
2
N O
2
N O
11
O
O
glycerol
N O NH
3
N O N
12
2
O
O
glycerol
N O
N O
N
NH
2
4
13
Scheme 4
EXPERIMENTAL
Melting points were measured on a Yanagimoto micro-melting point apparatus
and are uncorrected. IR spectra were recorded with a Hitachi 260-10

1
spectrophotometer. H-NMR spectra were measured on a JEOL FX-400
instrument using CDCl3 as a solvent and tetramethylsilane as an internal
standard. MS were taken with a Hitachi M-2500 spectrometer.
2-(4-Acetamidophenoxy)nicotinic acid (5)
A mixture of 2-chloronicotinic acid (7.85 g, 50 mmol), 4-acetamidophenol
(7.55 g, 50 mmol), potassium carbonate (13.8 g, 100 mmol), copper (0.7 g),
cuprous iodide (0.7 g) and DMF (120 mL) was stirred under reflux for 2 h,
cooled and filtered. The filtrate was concentrated. The residue was
mixed with hot water, filtered, and the filtrate was acidified with 10%
hydrochloric acid. The resulting precipitate was collected. The residue
was purified by recrystallization from methanol to give 5 (10.0 g, 74% )
as colorless needles. mp 241-242 oC. Anal. Calcd for C14H12N2O4: C,61.76;
H,4.44; N, 10.29. Found: C, 61.68; H, 4.65; N, 10.13. 1H-NMR(DMSO-d6) δ:
7.03(1H, dd, J=2.0, 8.8 Hz, 2’-H), 7.20(1H, dd, J=4.9, 7.3 Hz, 3-H), 7.59
(1H, dd, J=2.0, 8.8 Hz, 3’-H), 8.22 (1H, dd, J=2.0, 7.3 Hz, 4-H), 8.30 (1H,
dd, J=2.0, 4.9 Hz, 2-H), 9.96 (1H, s, NH). MS: m/z 272 (M+.).
7-Acetamido-5H-[1]benzopyrano[2,3-b]pyridin-5-one (6)
2-(4-Acetamidophenoxy)benzoic acid (10 g, 40 mmol) was heated with PPA
(300 g) at 130oC for 8 h. The hot reaction solution was poured into water,
and the resulting precipitate was collected, washed and recrystallized
from methanol to give 6 (7.2 g, 76%). mp 225-226 oC. Anal. Calcd For
C14H10N2O3: C, 66.13, H, 3.96, N, 11.02. Found: C, 65.89, H, 4.26, N, 11.03.
1H-NMR (CDCl3) δ: 2.10 (3H, s, CH3), 7.63 (1H, dd, J=4.4, 7.8 Hz, 3-H),7.72
(1H, d, J=8.8 Hz, 9-H), 8.03 (1H, dd, J=2.9, 8.8 Hz, 8-H), 8.48 (1H, d,
J=2.9 Hz, 6-H), 8.64 (1H, dd, J=2.0, 7.8 Hz, 4-H), 8.82 (1H, dd, J=2.0,
4.4 Hz, 2-H). MS: m/z 254 (M+.).
7-Amino-5H-[1]benzopyrano[2,3-b]pyridin-5-one (2)
Compound (6, 7.2 g, 30 mmol) heated with 47% hydrobromic acid (100 mL) and
phenol (5.6 g, 60 mmol) under reflux for 2 h. After cooling, the mixture
was basified with 10% aqueous sodium hydroxide to give a yellow solid
which was recrystallized from methanol to afford 2 ( 4.97 g, 89%) as
yellow needles, mp 253-254 oC. Anal. Calcd for C12H8N2O2: C, 67.91; H, 3.80;

N, 13.21. Found: C, 67.83; H, 3.89; N, 13.19. IR (KBr): 1600, 1620 cm-1.
1H-NMR (CDCl3) δ: 7.16 (1H, dd, J=3.0, 8.7 Hz, 8-H), 7.41 (1H, dd, J=4.7,
7.8 Hz, 3-H), 7.47 (1H, d, J=8.3 Hz, 9-H), 7.50 (1H, d, J=3.0, 6-H), 8.71
(1H, dd, J=2.0, Hz, 4-H), 8.73 (1H, dd, J=2.0, 4.7 Hz, 2-H). MS: m/z 212
(M+.).
2-(3-Acetamidophenoxy)nicotinic acid (7)
A mixture of 2-chloronicotinic acid (7.85 g, 50 mmol), 3-acetamidophenol
(7.55 g, 50 mmol), potassium carbonate (13.8 g, 100 mmol), copper powder
(0.7 g), cuprous iodide (0.7 g) and DMF (120 mL) was stirred under reflux
for 2 h, then cooled and filtered. The filtrate was concentrated. The
residue was mixed with hot water, filtered, and acidified with 10%
hydrochloric acid. The resulting precipitate was collected by filtration
and recrystallized from methanol to give 7 (9.33 g, 69% ) as colorless
needles. mp 283-284 oC. Anal. Calcd for C14H12N2O4: C,61.76; H,4.44; N,
1
10.29. Found: C, 61.92; H, 4.59; N, 10.32. H-NMR (DMSO-d6)δ: 2.03 (3H,
s, CH3), 6.77 (1H, dd, J=2.0, 7.3 Hz, 6‘-H), 7.24 (1H, dd, J=4.9, 7.3 Hz,
3-H), 7.27-7.88 (2H, m, 4’-H, 5‘-H), 7.44 (1H, s, 2’-H), 8.25 (1H, dd,
J=2.0, 7.3 Hz, 4-H), 8.28 (1H, dd, J=2.0, 4.9 Hz, 2-H), 9.96 (1H, s, NH).
MS: m/z 272 (M+.).
8-Amino-5H-[1]benzopyrano[2,3-b]pyridin-5-one (3)
Compound (7, 9.33 g, 40 mmol) was heated with PPA (500 g) at 130oC for 6 h.
The hot solution was poured into ice-water. The resulting precipitate was
collected (a mixture of 8 and 9 , 6.60 g, 77%), and then heated with 47%
hydrobromic acid (120 mL) and phenol (7.5 g, 80 mmol) under reflux for 2 h.
After cooling, the mixture was alkalinized with 10% aqueous sodium
hydroxide to give a mixture of 1 and 3 as a yellow solid. This mixture
was separated by silica gel column chromatography (CHCl3) to afford 1 (1.07
g, 14 %) and 3 (1.27 g, 16%). Compound (3) : Pale yellow needles (from
MeOH); mp 272-273 oC. Anal. Calcd for C12H8N2O2: C, 67.91; H, 3.80; N, 13.21.
1
Found: C, 67.95; H, 3.96; N, 13.15. IR (KBr): 1585, 1620 cm-1. H-
NMR(CDCl3) δ: 6.69 (1H, dd, J= 2.0, 8.3 Hz, 7-H), 6.70 (1H, d, J=2.0 Hz, 9-
H), 7.39 (1H, dd, J=4.8, 7.3 Hz, 3-H), 8.11 (1H, d, J=8.3 Hz, 6-H), 8.66
(1H, dd, J=1.9, 4.8 Hz, 2-H), 8.68 (1H, dd, J=1.9, 7.3 Hz, 4-H). MS: m/z

212 (M+.).
9-Amino-5H-[1]benzopyrano[2,3-b]pyridin-5-one (4)
A mixture of 5H-[1]benzopyrano[2,3-b]pyridin-5-one (19.7 g, 100 mmol),
hydroxylamine sulfate (10 g, 50 mmol), ferrous sulfate (37 g, ) and 94 %
sulfuric acid (400 g) was stirred at 140-150 oC for 7 h. The reaction
mixture was poured into water and then filtered. To the filtrate was
added potassium hydrogen tartrate and the mixture was basified with 25%
ammonium hydroxide. The resulting precipitate was collected by filtration
and dried (13.17 g). The products were purified with silica gel (solvent:
benzene) and alumina column chromatography (solvent: chloroform) to give
6-amino- (1) (4.57 g, 22%), 7-amino- (2) (2.88 g, 14 %), 8-amino- (3)
(1.10 g, 5%) and 9-amino-5H-[1]benzopyrano[2,3-b]pyridin-5-one(4)( 1.04 g,
5%).
Compound (4): Yellow needles (from methanol), mp 212-213 oC. Anal. Calcd
for C12H8N2O2: C, 67.91; H, 3.80; N, 13.21. Found: C, 68.01; H, 3.86; N,
1
13.32. IR (KBr): 1580, 1650 cm-1. H-NMR(CDCl3) δ : 7.12 (1H, dd, J= 1.5,
7.8 Hz, 8-H), 7.21 (1H, t, J=7.8 Hz, 7-H), 7.44 (1H, dd, J=3.5, 5.4 Hz, 3-
H), 7.66 (1H, dd, J=1.5, 7.8 Hz, 6-H), 8.72 (1H, dd, J=1.5, 3.5 Hz, 2-H),
8.73 (1H, dd, J=1.5, 5.4 Hz, 4-H). MS: m/z 212 (M+.).
General procedure for the Skraup reaction of amino-5H-benzopyrano[2,3-b]-
pyridin-5-ones (1-4)
̣
A mixture of H2SO4 SO3 (6.0 g, 50 mmol), nitrobenzene (1.23 g, 10 mmol),
̣
FeSO4 7H2O (0.28 g, 1.0 mmol) and H3BO3 (0.31 g, 5.0 mmol) was chilled to 0-
5 oC, and then glycerol (1.84 g, 20 mmol), amino-5H-benzopyrano[2,3-b]-
pyridin-5-one (1.06 g, 5 mmol) and water (2.5 mL) were successively added.
The mixture was heated at 130oC for 5 h. The reaction mixture was
basified with 28 % NH4OH, the resulting precipitate was collected by
filtration, and the precipitate was dissolved in CHCl3. The extract was
dried over Na2SO4, the solvent was evaporated and the residue was
recrystallized from MeOH to give the corresponding pyrido[3’,2’:5,6]-
pyranoquinoline derivative.

’
12H-Pyrido[3 ,2’:5,6]pyrano[2,3-h]quinolin-12-one(10)
Colorless needles, mp 237-238 oC. Yield 71 %. Anal. Calcd for C15H8N2O2:
C,72.56; H, 3.25; N, 11.29. Found: C, 72.60; H, 3.07; N, 11.26. IR (KBr):
1
1580, 1600, 1640 cm-1. H-NMR(CDCl3) δ: 7.51 (1H, dd, J=4.4, 7.8 Hz, 10-H),
7.56 (1H, dd, J=4.4, 8.3 Hz, 3-H), 7.79 (1H, d, J=8.8 Hz, 6-H), 8.14 (1H,
d, J=8.8 Hz, 5-H), 8.25 (1H, dd, J=2.0, 8.3 Hz, 4-H), 8.75 (1H, dd, J=2.0,
4.4 Hz, 9-H), 8.85 (1H, dd, J=2.0, 7.8 Hz, 11-H), 9.29 (1H, dd, J=2.0, 4.4
Hz, 2-H). MS: m/z 248 (M+.).
’
12H-Pyrido[3,2’:5,6]pyrano[3,2-f]quinolin-12-one(11)
Colorless needles, mp 190-191 oC. Yield 82 %. Anal. Calcd for C15H8N2O2: C,
72.56; H, 3.25; N, 11.29. Found: C, 72.72; H, 3.33; N, 11.41. IR (KBr):
1
1580, 1600, 1620 cm-1. H-NMR(CDCl3) δ: 7.69 (1H, dd, J=4.4, 7.8 Hz, 10-H),
7.79 (1H, dd, J=4.4, 8.7 Hz, 2-H), 8.04 (1H, d, J=9.3 Hz, 6-H), 8.49 (1H,
d, J=9.3 Hz, 5-H), 8.79 (1H, dd, J=2.0, 7.8 Hz, 11-H), 8.87 (1H, dd, J=2.0,
4.4 Hz, 9-H), 9.02 (1H, dd, J=1.0, 8.7 Hz, 3-H), 10.27 (1H, dd, J=1.0, 8.7
Hz, 1-H). MS: m/z 248 (M+.).
’
7H-Pyrido[3 ,2’:5,6]pyrano[2,3-f]quinolin-7-one (12)
Colorless needles, mp 218-219 oC. Yield 75 %. Anal. Calcd for C15H8N2O2: C,
72.56; H, 3.25; N, 11.29. Found: C,72.39; H, 3.33; N, 11.22. IR (KBr):
1580, 1600, 1640 cm-1. 1H-NMR(CDCl3) δ: 7.54 (1H, dd, J=4.4, 7.8 Hz, 9-H),
7.64 (1H, dd, J=4.4, 8.3 Hz, 2-H), 8.03 (1H, d, J=8.8 Hz, 5-H), 8.45 (1H,
d, J=8.8 Hz, 6-H), 8.78 (1H, dd, J=1.9, 7.8 Hz, 8-H), 8.81 (1H, dd, J=1.9,
4.4 Hz, 10-H), 9.08 (1H, dd, J=2.0, 8.3 Hz, 1-H), 9.11 (1H, dd, J=2.0, 4.4
Hz, 3-H). MS: m/z 248 (M+.).
’
7H-Pyrido[3 ,2’:5,6]pyrano[3,2-h]quinolin-7-one (13)
Colorless needles, mp 291-292 oC. Yield 84 %. Anal. Calcd for C15H8N2O2: C,
72.56; H, 3.25; N, 11.29. Found: C,72.72; H,3.25; N, 11.39. IR (KBr): 1580,
1
1600, 1630 cm-1. H-NMR (CDCl3) δ: 7.54 (1H, dd, J=4.4, 7.8 Hz, 9-H), 7.69
(1H, dd, J=4.4, 8.3 Hz, 3-H), 7.80 (1H, d, J=8.8 Hz, 5-H), 8.30 (1H, dd,
J=1.5, 8.3 Hz, 4-H), 8.36 (1H, d, J=8.8 Hz, 6-H), 8.80 (1H, dd, J=2.0, 7.8
Hz, 8-H), 8.87 (1H, dd, J=2.0, 4.4 Hz, 10-H), 9.20 (1H, dd, J=1.5, 4.4 Hz,
2-H). MS:m/z 248 (M+).

ACKNOWLEDGEMENT
This work was supported by the Ministry of Education, Science, Sports and
Culture of Japan.
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