A one-pot synthesis of the 1-benzopyrano[2,3-b]pyridine moiety from 2-(alkyl/arylamino)-4-oxo-4H-1-benzopyran-3-carbaldehyde

Article abstract of DOI:10.1002/jhet.397

2-(Alkyl/arylamino)chromone-3-carbaldehyde reacts with Meldrum's acid, hippuric acid, 4-hydroxycoumarin, diethyl malonate, ethyl acetoacetate, or ethyl benzoylacetate to produce 1-benzopyrano [2,3-b]pyridine-2,5-dione moiety, but ethyl cyanoacetate and malononitrile react differently.

Full text of DOI:10.1002/jhet.397

July 2010
A One-Pot Synthesis of the 1-Benzopyrano[2,3-b]pyridine Moiety
from 2-(Alkyl/arylamino)-4-oxo-4H-1-Benzopyran-3-Carbaldehyde
973
Sourav Maiti, Suman Kalyan Panja, and Chandrakanta Bandyopadhyay*
Department of Chemistry, R. K. Mission Vivekananda Centenary College, Rahara, Kolkata,
West Bengal 700 118, India
*E-mail: kantachandra@rediffmail.com
Received September 22, 2009
DOI 10.1002/jhet.397
Published online 24 June 2010 in Wiley InterScience (www.interscience.wiley.com).
2-(Alkyl/arylamino)chromone-3-carbaldehyde reacts with Meldrum’s acid, hippuric acid, 4-hydroxy-
coumarin, diethyl malonate, ethyl acetoacetate, or ethyl benzoylacetate to produce 1-benzopyrano[2,3-
b]pyridine-2,5-dione moiety, but ethyl cyanoacetate and malononitrile react differently.
J. Heterocyclic Chem., 47, 973 (2010).
INTRODUCTION
trile by reaction either with acetylacetone in the pres-
ence of piperidine [9] or with 1-ethoxy-1,3-bis(trime-
thylsilyloxy)-1,3-butadiene in the presence of Me3SiOTf
[10], (b) from chromone-3-carbaldehyde by the reaction
of 2-aminochromone [11] or with aniline in the presence
of TMSCl in DMF [12]. 2-Aminochromone-3-carbalde-
hyde 3 (R2 ¼ H) has also been used for the synthesis of
1(R2 ¼ H) [13].
1-Benzopyranopyridine derivatives have found diverse
application in the field of medicinal chemistry. 1-Benzo-
pyrano[3,4-c]pyridine-5-ones act as human dopamine D4
receptor antagonists and serve as potential antipsychotic
agents [1]. Some nonsteroidal human androgen receptor
agonists were synthesized based on 4-(trifluoromethyl)-
2H-pyrano[3,2-g]-2-quinolone [2]. 1-Benzopyrano[2,3-
b]pyridine-2,5-dione 1 (R2 ¼ H, G ¼ COCH2COCH3)
functions as a polyketide, which are involved in the bio-
synthesis of natural products [3]. Some chromenopyri-
dines are designed and synthesized as an analogue of
tetracycline [4]. 5-Salicyloyl-2-oxopyridine-3-carboni-
triles play comparable roles as the nonglycosidic cardio-
tonic agents milrinone or amrinone [5]. Compounds
1(R2 ¼ H, G ¼ CN, CO2R, CO2H) exhibit antiallergic
properties and are used in the preparation of bronchodia-
lators [6]. 1-Benzopyrano[2,3-b]pyridine-4,5-dione hav-
ing a CO2H group at 3-position provides 100% inhibi-
tion in the passive cutaneous anaphylaxis screen when
applied in a dose of 0.9 mg/kg [7]. Recently, some chro-
menopyridines are proved to be effective sensitizers for
europium and terbium luminescence [8].
Although the reactions of 2-aminochromone-3-carbal-
dehyde 3 (R2 ¼ H) and 2-(N,N-dialkylamino)chromone-
3-carbaldehyde 3 (NR2 in place of NHR2) have been
studied in detail [13], the chemistry of 2-(mono substi-
tuted amino)chromone-3-carbaldehyde 3 has only been
little explored. Most of its reactions were carried out by
converting it into N,N-disubstituted analogue [14a,b].
Reaction of 3 with primary amine produces correspond-
ing Schiff base [14], but with aliphatic secondary
amines like diethylamine or piperidine compound 3 (R2
¼ aryl) produces 1-benzopyranoquinolones (A) (Scheme
1) [15]. Recently, diethyl 1-benzopyrano[2,3-b]pyridine-
2,3-dicarboxylate has been synthesized from 3 and
diethyl acetylenedicarboxylate in the presence of Ph3P
[16]. Synthesis of 2-pyridone moiety having ester or car-
bamoyl functionality at its 3-positions from b-formyl-b-
nitroenamine has recently been reported [17].
Synthesis of the 1-Benzopyrano[2,3-b]pyridine motif
have been accomplished (a) from chromone-3-carboni-
C
V
2010 HeteroCorporation

974
S. Maiti, S. K. Panja, and C. Bandyopadhyay
Vol 47
Scheme 1
A literature survey revealed that functionlization at
RESULTS AND DISCUSSION
the 3-position of 1-benzopyrano [2,3-b]pyridine-2,5-
dione made this system medicinally efficacius [6].
1-Benzopyrano[2,3-b]pyridine-2,5-dione (B) having no
functionality at its 3-position had been synthesized by
the reaction of 3 (R2 ¼ Ph) with ethyl (triphenylphos-
phoranylidene)acetate followed by heating in benzene
(Scheme 1) [18].
Meldrum’s acid (4), an active methylene compound
having strong electrophillic centres, has made its posi-
tion in the synthesis of many organic compounds having
use in the fields of drugs and pharmaceuticals [21].
Very recently, its chemical bonding and structure-reac-
tivity relation have been studied both experimentally
and theoretically [22]. Its chemical versatility has also
been discussed in several review articles [23]. We have
used Meldrum’s acid in the synthesis of 1-benzopyr-
ano[2,3-b]pyridine-2,5-dione moiety from 3.
An equimolar mixture of 3 and 4 was heated under
reflux in ethanol in the presence of catalytic amount of
pyridine for 2–4 h. White solids (1a–e) were found to
precipitate under this reaction condition in moderate to
good yields (Table 1, entries 1–5). Compound 3 under-
goes Knoevenagel condensation with Meldrum’s acid to
form 5, which cyclizes to 1a–e under the reaction condi-
tion (Scheme 2, path-a). The structures of the
Our objective was to synthesize 1 with varying sub-
stituents at its 3-position utilizing the C3N1 building
block of the b-amino-a, b-unsaturated aldehyde moiety
of 3. We report herein a few new one-pot syntheses of
compound 1 from 3 by condensation with 2,2-dimethyl-
1,3-dioxan-4,6-dione (Meldrum’s acid), N-benzoylgly-
cine (hippuric acid), 4-hydroxycoumarin, and other
active methylene compounds under suitable reaction
conditions. Compound 3 can readily be obtained from
N-alkyl/aryl-C-(4-oxo-4H-1-benzopyran-3-yl)nitrones
[19] or directly from chromone-3-carbaldehyde [20].
2
Table 1
Results of the reactions of 3 with 4 or 6 or 8 under different conditions.
Entry
R1
R2
Reagent
Reaction condition
Time (h)
Product
Yield (%)
Mps (ꢀC)
1
2
3
H
H
Me
Me
Me
H
Me
Me
H
Me
Me
H
Ph
Ar
Ar
Me
Et
4
4
4
4
4
6
6
6
6
6
8
8
8
A
A
A
A
A
B
B
B
B
B
A
A
A
3
1a
1b
1c
1d
1e
70
68
70
52
50
41
40
45
32
30
85
79
79
>320
>320
298–300
296–298
276–278
>320
4
3
4
5
2
2.5
7
6
7
Ph
Ph
Ar
Et
1f
6
1g
1h
1i
>320
>320
8
7
9
6.5
6
258–260
286–288
284–286
268–270
238–240
10
11
12
13
Et
1j
Ph
Ph
Et
5
6
5.5
10a
10b
10c
H
A, Heated in EtOH under reflux containing catalytic amount of pyridine.
B, Heated a mixture of 3, 6 and fused NaOAc in Ac2O on a water bath.
Ar stands for 4-C6H4Me.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010 A One-Pot Synthesis of the 1-Benzopyrano[2,3-b]pyridine Moiety from 2-(Alkyl/arylamino)-
4-oxo-4H-1-benzopyran-3-carbaldehyde
975
Scheme 2
and 8 in ethanol under reflux for 5–6 h in the presence
of catalytic amount of pyridine, the reaction mixture
produced compound 10 in good yields via the Knoeve-
nagel condensate 9 (Scheme 3) (Table 1, entries 11–13).
Suitably placed NHR2 group in 9 reacted intramolecu-
larly on the carbonyl function with a lesser decrease in
entropy compared to the Michael addition of second
molecule of 8, which is the common feature for the
reaction of an aldehyde with 8 [25].
With an endeavor to synthesize 1(G ¼ CO2Et), com-
pound 3 (R2 ¼ aryl) was stirred at room temperature
with diethyl malonate in pyridine, but no change in 3
was observed (Table 2, entry 1). Ethyl acetoacetate also
failed to cause any change in 3 on stirring at room tem-
perature in pyridine (entry 2), even on heating 3 with
ethyl acetoacetate in ethanol for 25 h in the presence of
pyridine showed no considerable change (entry 3). On
stirring an ethanolic solution of 3 (R2 ¼ aryl) with
diethyl malonate at room temperature in the presence of
piperidine for 40 h resulted in the formation of 1-benzo-
pyrano[2,3-b]-12-quinolone (A) [15,18,19] (Scheme 1)
(Table 2, entry 4). No pure compound could be isolated
from the reaction mixture obtained by heating a mixture
of 3, diethyl malonate, fused NaOAc in Ac2O on a
water bath for 5 h (entry 5). Surprisingly, compound 3
reacted with diethyl malonate in CHCl3 under reflux in
the presence of piperidine to produce 1k,l (entries 6, 7)
(Scheme 4). It was observed that more than stoichiomet-
ric amounts of diethyl malonate (1.5 equiv) and piperi-
dine (1.5 equiv) were required for complete consump-
tion of 3. This methodology was then applied for the
synthesis of 1 having various substituents at its 3-posi-
tion. On heating 3 (R2 ¼ aryl) with ethyl acetoacetate
and piperidine in equimolar amounts in CHCl3 for 4 h
produced 1o (entry 8). Similarly, ethyl benzoylacetate
reacted stoichiometrically with 3 (R2 ¼ aryl) within 2 h
to produce 1q,r (entries 9, 10).
compounds were established on the basis of IR, 1H
NMR, and mass spectral analysis. It is to be mentioned
here that the carboxylic acid protons for compounds 1a
and 1b were not observed in their H NMR spectra. The
presence of carboxylic acid group in 1a and 1b was
confirmed from their mass spectral analyses and the sin-
1
glet appearance of C4-H in the H NMR spectra of 1a,b.
1
In connection to our earlier studies [24] on the reac-
tions of different nitrogenous nucleophiles on 4-[(4-oxo-
4H-1-benzopyran-3-yl)methylene]-2-phenyl-5-oxazolone
7 (R1 ¼ NHR2 ¼ H)(Scheme 2), derived from 3-for-
mylchromone, it has been observed that nitrogenous
nucleophiles are prone to interact on the carbonyl func-
tion of oxazolone moiety. Compound 3 can be consid-
ered as 3-formylchromone moiety having an inbuilt
amino function in appropriate position. To utilize this
special structural feature of 3, an equimolar mixture of
3 (R2 ¼ aryl) and hippuric acid (6) was heated in the
presence of excess amount of fused sodium acetate in
acetic anhydride on water bath for 6–7 h and after usual
work-up, compounds 1f–h were obtained as white solids
in moderate yields (Table 1, entries 6–8). On similar
treatment of 3 (R2 ¼ alkyl), the reaction mixture
yielded 1i and 1j (entries 9, 10) after chromatographic
separation on silica gel using 10% ethyl acetate in ben-
zene as eluent. Formation of 1f–j from 3 may be ration-
alized by the initial formation of azlactone 7, followed
by intramolecular attack of the amino function to the
carbonyl carbon of oxazolone moiety (Scheme 2, path-
b).
Scheme 3
This reaction was further extended by using 4-hydrox-
ycoumarin (8). On heating an equimolar mixture of 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

976
S. Maiti, S. K. Panja, and C. Bandyopadhyay
Vol 47
Table 2
Results of the reactions of 3 with active methylene compounds (EtO2C-CH2-G) under different conditions.
Entry
R1
R2
G
Reaction condition
Time (h)
Product
Yield (%)
Mps (ꢀC)
1
2
H
Me
Me
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Et
CO2Et
COCH3
COCH3
CO2Et
CO2Et
CO2Et
CO2Et
COCH3
COPh
Py/RT
Py/RT
40
20
25
40
5
N. R.
N. R.
–
–
–
–
3
4
Py/EtOH/Reflux
Pip/EtOH/RT
N. R.a
–
70
–
–
A
Not isolated
236–238
–
5
H
NaOAc/Ac2O/heat
Pip/CHCl3/reflux
Pip/CHCl3/reflux
Pip/CHCl3/reflux
Pip/CHCl3/reflux
Pip/CHCl3/reflux
Pip/CHCl3/reflux
Pip/CHCl3/reflux
Pip/CHCl3/reflux
Pip/CHCl3/reflux
Pip/CHCl3/reflux
Pip/EtOH/reflux
Pip/EtOH/reflux
Pip/EtOH/reflux
Morpholine/
6
7
H
18
12
4
1k
1l
1o
1q
1r
1s
55
74
68
72
74
60
62
43
42
40
70
20b
62
60
278–280
208–210
278–280
264–266
278–280
256–258
224–226
218–220
178–180
192–194
224–226
278–280
218–220
264–266
Me
Me
H
8
9
2
10
11
12
13
14
15
16
17
18
19
Me
H
COPh
COPh
COPh
2
2
H
2
1t
H
H
Et
Et
COCH3
CO2Et
CO2Et
COPh
4
1p
1m
1n
1t
1o
1p
1q
28
25
6
Me
H
Et
Et
Me
H
Ph
Et
COCH3
COCH3
COPh
2
7
H
Ph
5
CHCl3/reflux
Et2NH/CHCl3/
reflux
20
H
Ph
COPh
13
1q
56
264–266
‘‘Py’’ stands for Pyridine; ‘‘Pip’’ stands for piperidine; ‘‘RT’’ stands for room temperature.
‘‘N. R.’’ stands for No Reaction.
a 80% 3 was recovered.
b 40% of compound A was isolated.
The reaction was extended with 3 (R2 ¼ alkyl). Ethyl
benzoylacetate (entries 11,12), ethyl acetoacetate (entry
13), and diethyl malonate (entries 14, 15) produced cor-
responding 1 but in lower yields. On changing the sol-
vent from CHCl3 to ethanol, the yield of 1 (R2 ¼ alkyl)
was found to improve, but a little longer reaction time
was required (entries 12,16 and 13, 18). Similar reaction
with 3 (R2 ¼ aryl) in ethanol always produced some 1-
benzopyrano quinolone (A) along with 1 (entry 17). Use
of triethylamine or pyridine as a base in the reaction
between 3 and PhCOCH2CO2Et either in CHCl3 or in
EtOH failed to show the formation of 1 even after heat-
ing under reflux for 30 h. Piperidine was found to be a
better reagent than morpholine or diethylamine for this
transformation (entries 9, 19, 20).
change in 12 was observed and finally the new compound
was assigned to be 11 (G0 ¼ CN). This observation led us
to check the silica-induced conversion of 12 (G0 ¼ CN) to
11 (G0 ¼ CN). A chloroform solution of 12 (G0 ¼ CN)
containing some silica gel was heated under reflux for 5 h
with stirring. Indeed, complete conversion of 12 (G0 ¼
CN) to 11 (G0 ¼ CN) was observed. Use of benzene in
place of chloroform also accomplished this transformation
under identical condition. However, on heating under
reflux in ordinary CHCl3 or benzene in the absence of
silica gel, compound 12 failed to show any change. In an
earlier report [17], b–allylamino-2-nitroacrolein was
made to react with malononitrile and was supposed to
Scheme 4
Compound 3 reacted differently when ethyl cyanoace-
tate or malononitrile were used as active methylene com-
ponent. On stirring an equimolar mixture of 3 and ethyl
cyanoacetate in ethanol in the presence of piperidine at
room temperature, followed by usual work-up [vide exper-
imental Section ‘‘General procedure for the reaction of
ethyl cyanoacetate on 2-alkyl/arylaminochromone-3-car-
baldehyde (3)’’]and chromatographic purification pro-
duced 11 (G’ ¼ CO2Et) (Scheme 5, path a). But malononi-
trile yielded 12 when reacted with 3 under similar reaction
condition (Scheme 5, path b). In an attempt to purify com-
pound 12 (G’ ¼ CN) by column chromatography, a partial
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010 A One-Pot Synthesis of the 1-Benzopyrano[2,3-b]pyridine Moiety from 2-(Alkyl/arylamino)-
4-oxo-4H-1-benzopyran-3-carbaldehyde
977
Scheme 5
2,5-dione moiety bearing various functionalities at its 3-
position. The differential behavior of the active methyl-
ene compounds bearing cyano group toward 3 has also
been reported.
EXPERIMENTAL
General. The recorded mps are uncorrected. IR spectra
were recorded in KBr on a Beckman IR 20a, 1H NMR/13C
NMR spectra on a bruker 300 MHz/75 MHz spectrometer,
mass spectra on a Qtof micro YA 263 instrument and elemen-
tal analysis on a Perkin Elmer 240c elemental analyzer. Light
petroleum refers to the fraction with 60–80ꢀC. All chemicals
used were of commercial grade and were used as such.
General procedure for the synthesis of 1-alkyl/aryl-
2H,5H-1-benzopyrano[2,3-b]pyridine-3-carboxylic acids
(1a–e). An ethanolic solution (10 mL) of a mixture of 3 (1
mmol), 4 (144 mg, 1 mmol), and catalytic amount of pyridine
(2 drops) was heated under reflux for 2–4 h. The white solid
separated out during the reaction was filtered off and crystal-
lized from benzene to obtain 1a–e as white crystalline solids.
1-Phenyl-2H,5H-2,5-dioxo-1-benzopyrano[2,3-b]pyridine-3-
carboxylic acid (1a). This compound was obtained in 70%
yield as white crystalline solid, mp > 320ꢀC; IR: 3493, 3064,
pass through an amidine like intermediate as in 12, but the
intermediate could not be isolated. Isolation of 12 (G0 ¼
CN) gave us an impetus to take an attempt for the isolation
of 12 (G0 ¼ CO2Et). But careful investigation of the solid
[vide experimental Section ‘‘General procedure for the
reaction of ethyl cyanoacetate on 2-alkyl/arylaminochro-
mone-3-carbaldehyde (3)’’] obtained from the reaction
mixture of 3 (R1 ¼ H, R2 ¼ Ph) and ethyl cyanoacetate
revealed that there was more than one product (TLC).
However, chromatographic separation yielded only 11a in
moderate yield. The other components were separated by
preparative TLC and the bands corresponding to two dif-
ferent spots were extracted separately with CHCl3.
Unfortunately, the isolated compounds were same in both
cases and the compound was 11a. Compound 12 (R2 ¼
aryl, G0 ¼ CO2Et) could not be isolated even after using
neutral Al2O3 as adsorbent in the column chromatography.
The only such compound 12d was obtained by stirring a
pyridine solution of 3 (R1 ¼ Me, R2 ¼ Et) and ethyl cya-
noacetate at room temperature. Compound 12d was read-
ily converted to 11d within 1 h when heated in ordinary
CHCl3 in the presence of silica gel. Formation of 12 can
be rationalized via the Knoevenagel condensate 13
(Scheme 5). It was presumed that the conversion of 12 to
11 took place by silica-induced hydration. The source of
water was supposed to be from silica adsorbent or solvent
or atmosphere. Water molecule attacks 12 and opens the
pyran ring to form 14 and subsequently tautomerizes to
11. To justify this presumption, compound 12 was heated
in dry CHCl3 in the presence of dry silica gel and under ar-
gon atmosphere and indeed compound 12 failed to show
any change.
2784, 1754, 1646, 1533, 1427 cmꢁ1 1H NMR (DMSO-d6):
;
d 7.23 (br d, 1H, 9-H, J ¼ 8.1 Hz), 7.56–7.64(m, 6H, ArH),
7.75–7.80 (m, 1H, 8-H), 8.17 (br d, 1H, 6-H, J ¼ 7.5 Hz),
8.86 (s, 1H, 4-H); ms: m/z 356 (Mþ þNa). Anal. Calcd for
C19H11NO5: C, 68.47; H, 3.33; N, 4.20. Found: C, 68.67; H,
3.37; N, 4.12.
1-p-Tolyl-2H,5H-2,5-dioxo-1-benzopyrano[2,3-b]pyridine-3-
carboxylic acid (1b). This compound was obtained in 68%
yield as white crystalline solid, mp > 320ꢀC; IR: 3453, 2976,
1
2755, 1767, 1652, 1540, 1453 cmꢁ1; H NMR (DMSO-d6): d
2.36 (s, 3H, CH3), 7.27 (br d, 1H, 9-H, J ¼ 8.4 Hz), 7.38–7.50
(m, 4H, ArH), 7.57 (br t, 1H, 7-H, J ¼ 7.5 Hz), 7.75–7.80 (m,
1H, 8-H), 8.17 (br d, 1H, 6-H, J ¼ 7.5 Hz), 8.86 (s, 1H, 4-H);
ms: m/z 370 (Mþ þNa). Anal. Calcd for C20H13NO5: C,
69.16; H, 3.77; N, 4.03. Found: C, 68.98; H, 3.72; N, 3.95.
7-Methyl-1-p-tolyl-2H,5H-2,5-dioxo-1-benzopyrano[2,3-
b]pyridine-3-carboxylic acid (1c). This compound was
obtained in 70% yield as white crystalline solid, mp 298–
300ꢀC; IR: 3460, 3015, 2812, 1743, 1647, 1553, 1437 cmꢁ1
;
1H NMR (CDCl3): d 2.46 (s, 3H, ArCH3), 2.53 (s, 3H,
ArCH3), 7.12–7.47 (m, 6H, ArH), 8.03 (br s, 1H, 6-H), 9.32
(s, 1H, 4-H), 12.94 (s, 1H, COOH, deuterium oxide exchange-
able)). Anal. Calcd for C21H15NO5: C, 69.80; H, 4.18; N, 3.88.
Found: C, 70.01; H, 4.11; N, 3.79.
1,7-Dimethyl-2H,5H-2,5-dioxo-1-benzopyrano[2,3-b]pyridine-
3-carboxylic acid (1d). This compound was obtained in 52%
yield as white crystalline solid, mp 296–298ꢀC; IR: 3456,
1
3045, 2934, 1741, 1634, 1542, 1475 cmꢁ1; H NMR (CDCl3):
d 2.51 (s, 3H, ArCH3), 3.89 (s, 3H, NCH3), 7.47 (d, 1H, 9-H,
J ¼ 8.4 Hz), 7.62 (br d, 1H, 8-H, J ¼ 8.4 Hz), 8.11 (br s, 1H,
6-H), 9.35 (s, 1H, 4-H), 13.20 (s, 1H, COOH, deuterium oxide
exchangeable)). Anal. Calcd for C15H11NO5: C, 63.16; H,
3.89; N, 4.91. Found: C, 62.98; H, 3.82; N, 4.83.
CONCLUSION
1-Ethyl-7-methyl-2H,5H-2,5-dioxo-1-benzopyrano[2,3-b]pyri-
dine-3-carboxylic acid (1e). This compound was obtained in
50% yield as white crystalline solid, mp 276–278ꢀC; IR: 3420,
We have reported a few new efficient one-pot meth-
ods for the synthesis of 1-benzopyrano [2,3-b]pyridine-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

978
S. Maiti, S. K. Panja, and C. Bandyopadhyay
Vol 47
1
3050, 2945, 1750, 1634, 1530, 1466 cmꢁ1; H NMR (CDCl3):
d 1.51 (t, 3H, CH2CH3, J ¼ 6.9 Hz ), 2.51 (s, 3H, ArCH3),
4.52 (q, 2H, CH2CH3, J ¼ 6.9 Hz), 7.47 (d, 1H, 9-H, J ¼ 8.1
Hz), 7.62 (br d, 1H, 8-H, J ¼ 8.1 Hz), 8.10 (br s, 1H, 6-H),
9.32 (s, 1H, 4-H), 13.27 (s, 1H, COOH, deuterium oxide
exchangeable)). Anal. Calcd for C16H13NO5: C, 64.21; H,
4.38; N, 4.68. Found: C, 64.32; H, 4.43; N, 4.59.
3-Benzoylamino-1-ethyl-7-methyl-2H,5H-1-benzopyrano[2,3-
b]pyridine-2,5-dione (1j). This compound was obtained in 30%
yield as white crystalline solid, mp 286–288ꢀC; IR: 3390,
3100, 2968, 1670, 1651, 1626, 1500, 1468 cmꢁ1 1H NMR
;
(CDCl3): d 1.48 (t, 3H, CH2CH3, J ¼ 6.6 Hz), 2.46 (s, 3H,
ArCH3), 4.50 (q, 2H, CH2CH3, J ¼ 6.6 Hz), 7.39 (d, 1H, 9-H,
J ¼ 8.4 Hz), 7.47–7.56 (m, 4H, ArH), 7.93 (brd, 2H, ArH,
J ¼ 7.2 Hz), 8.07 (br s, 1H, 6-H ), 8.96 (br s, 1 H, NH, deute-
rium oxide exchangeable), 9.19 (s, 1H, 4-H). Anal. Calcd for
C22H18N2O4: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.41; H,
4.78; N, 7.39.
General procedure for the synthesis of 1-alkyl/aryl-3-sali-
cyloyl-2H,5H-1-benzopyrano[2,3-b]pyridine-2,5-diones (10a–
c). An ethanolic solution of a mixture of 3 (1 mmol), 8 (162
mg, 1 mmol), and pyridine (2 drops) was heated under reflux
for 5–6 h. A white solid, separated out during the reaction,
was filtered off and crystallized from benzene-light petroleum
(80:20) to obtain 10a–c as white crystalline solid.
General procedure for the synthesis of 3-benzoylamino-
1-alkyl/aryl-2H,5H-1-benzopyrano[2,3-b]pyridine-2,5-diones
(1f–j). A mixture of 3 (1 mmol), 6 (180 mg, 1 mmol), NaOAc
(250 mg, 3 mmol), and acetic anhydride (5 mL) was heated on
water bath for 6–7 h. Crushed ice (50 g) was then added to
the cold reaction mixture. A solid mass was separated when
the reaction was carried out with 3 (R2 ¼ aryl). The solid was
filtered off, washed with water, dried in air, and recrystallized
from CHCl3 to afford 1f–h. But the reaction mixture obtained
from 3 (R2 ¼ alkyl) afforded a semisolid mass when ice-water
was added. The semisolid mass was extracted with CHCl3.
The organic layer was washed with water, dried over Na2SO4,
and chromatographed over silica gel (100–200) using 10%
EtOAc in benzene as eluent to get 1i–j as white crystalline
solid.
7-Methyl-1-phenyl-3-salicyloyl-2H,5H-1-benzopyrano[2,3-
b]pyridine-2,5-dione (10a). This compound was obtained in
85% yield as white crystalline solid, mp 284–286ꢀC; IR: 3448,
;
2925, 1681, 1648, 1623, 1544 cmꢁ1 1H NMR (CDCl3): d
3-Benzoylamino-1-phenyl-2H,5H-1-benzopyrano[2,3-b]pyri-
dine-2,5-dione (1f). This compound was obtained in 41% yield
as white crystalline solid, mp > 320ꢀC; IR: 3379, 3050, 1655,
2.46 (s, 3H, ArCH3), 6.87 (br t, 1H, ArH, J ¼ 7.8 Hz), 7.05
(br t, 2H, ArH, J ¼ 7.8 Hz), 7.36–7.59 (m, 8H, ArH), 8.06 (br
s, 1H, 6-H), 8.52 (s, 1H, 4-H), 11.90 (s, 1H, OH, deuterium
oxide exchangeable); 13C NMR (CDCl3): d 20.8, 101.7, 117.4,
118.4, 118.9, 119.5, 121.6, 126.1, 126.2, 128.2, 128.3, 129.7,
132.7, 133.3, 135.6, 136.6, 136.9, 137.8, 151.9, 156.9, 159.1,
163.2, 173.4, 197.2; ms: m/z 424 (MþþH), 446 (MþþNa).
Anal. Calcd for C26H17NO5: C, 73.75; H, 4.05; N, 3.31.
Found: C, 73.61; H, 4.12; N, 3.22.
1-Phenyl-3-salicyloyl-2H,5H-1-benzopyrano[2,3-b]pyridine-
2,5-dione (10b). This compound was obtained in 79% yield as
white crystalline solid, mp 268–270ꢀC; IR: 3400, 2940, 1692,
1660, 1630, 1524 cmꢁ1 1H NMR (CDCl3): d 6.87 (br t, 1H,
;
ArH, J ¼ 7.5 Hz), 7.03 (br d, 1H, 9-H, J ¼ 8.4 Hz), 7.16 (br
d, 1H, ArH, J ¼ 8.4 Hz), 7.36–7.41 (m, 3H, ArH), 7.44–7.52
(m, 2H, ArH), 7.58–7.67 (m, 4H, ArH), 8.27 (br d, 1H, 6-H, J
¼ 7.5 Hz), 8.51 (s, 1H, 4-H), 11.88 (s, 1 H, OH, deuterium
oxide exchangeable). Anal. Calcd for C25H15NO5: C, 73.35; H,
3.69; N, 3.42. Found: C, 73.52; H, 3.63; N, 3.35.
1520, 1459 cmꢁ1 1H NMR (CDCl3): d 7.13 (br d, 1H, 9-H,
;
J ¼ 8.1 Hz), 7.36–7.66 (m, 10H, ArH), 7.93 (dd, 2H, ArH, J
¼ 8.1, 1.2 Hz), 8.32 (dd, 1H, 6-H, J ¼ 7.8, 1.5 Hz), 8.99 (br
s, 1H, NH, deuterium oxide exchangeable), 9.35 (s, 1 H, 4-H);
ms: m/z 409 (Mþ þ H), 431 (Mþ þNa). Anal. Calcd for
C25H16N2O4: C, 73.52; H, 3.95; N, 6.86. Found: C, 73.67; H,
3.86; N, 6.75.
3-Benzoylamino-7-methyl-1-phenyl-2H,5H-1-benzopyrano[2,3-
b]pyridine-2,5-dione (1g). This compound was obtained in 40%
yield as white crystalline solid, mp > 320ꢀC; IR: 3360, 3120,
1640, 1545, 1422 cmꢁ1 1H NMR (CDCl3): d 2.44 (s, 3H,
;
ArCH3), 7.03 (d, 1H, 9-H, J ¼ 8.1 Hz), 7.40-7.63 (m, 9H,
ArH), 7.92 (dd, 2H, ArH, J ¼ 8.0, 1.2 Hz), 8.10 (brs, 1H, 6-
H), 8.97 (br s, 1H, NH, deuterium oxide exchangeable), 9.34
(s, 1H, 4-H). Anal. Calcd for C26H18N2O4: C, 73.92; H, 4.29;
N, 6.63. Found: C, 73.80; H, 4.26; N, 6.58.
3-Benzoylamino-7-methyl-1-p-tolyl-2H,5H-1-benzopyrano[2,3-
b]pyridine-2,5-dione (1h). This compound was obtained in 45%
yield as white crystalline solid, mp > 320ꢀC; IR: 3350, 3074,
1-Ethyl-3-salicyloyl-2H,5H-1-benzopyrano[2,3-b]pyridine-2,5-
dione (10c). This compound was obtained in 79% yield as
white crystalline solid, mp 238–240ꢀC; IR: 3425, 2920, 1690,
;
1640, 1620, 1500 cmꢁ1 1H NMR (CDCl3): d 1.48 (t, 3H,
1635, 1533, 1428 cmꢁ1 1H NMR (CDCl3): d 2.45 (s, 3H,
;
ArCH3), 2.51 (s, 3H, ArCH3), 6.90 (d, 1H, 9-H, J ¼ 8.4 Hz),
7.39–7.56 (m, 8H, ArH), 7.93 (br d, 2H, ArH, J ¼ 7.2 Hz),
8.11 (brs, 1H, 6-H), 8.99 (br s, 1H, NH, deuterium oxide
exchangeable), 9.34 (s, 1H, 4-H). Anal. Calcd for
C27H20N2O4: C, 74.30; H, 4.62; N, 6.42. Found: C, 74.15; H,
4.55; N, 6.34.
3-Benzoylamino-1-ethyl-2H,5H-1-benzopyrano[2,3-b]pyridine-
2,5-dione (1i). This compound was obtained in 32% yield as
white crystalline solid, mp 256–258ꢀC; IR: 3385, 3096, 1680,
1651, 1628, 1518, 1482 cmꢁ1 1H NMR (CDCl3): d 1.50 (t,
;
3H, CH2CH3, J ¼ 6.5 Hz), 4.52 (q, 2H, CH2CH3, J ¼ 6.5
Hz), 7.49–7.53 (m, 5H, ArH), 7.68–7.70 (m, 1H, 8-H), 7.93
(br d, 2H, ArH, J ¼ 7.2 Hz), 8.31 (br d, 1H, 6-H, J ¼ 7.2
Hz), 8.97 (br s, 1H, NH, deuterium oxide exchangeable), 9.21
(s, 1H, 4-H). Anal. Calcd for C21H16N2O4: C, 69.99; H, 4.48;
N, 7.77. Found: C, 70.18; H, 4.43; N, 7.84.
CH2CH3, J ¼ 6.9 Hz), 4.47 (q, 2H, CH2CH3, J ¼ 6.9 Hz),
6.86 (br t, 1H, ArH, J ¼ 7.5 Hz), 7.04 (br d, 1H, 9-H, J ¼ 8.4
Hz), 7.48–7.59 (m, 4H, ArH), 7.79 (br t, 1H, 8-H, J ¼ 8.4
Hz), 8.30 (br d, 1H, 6-H, J ¼ 7.8 Hz), 8.39 (s, 1H, 4-H),
11.92 (s, 1 H, OH, deuterium oxide exchangeable). Anal.
Calcd for C21H15NO5: C, 69.80; H, 4.18; N, 3.88. Found: C,
69.62; H, 4.12; N, 3.95.
General procedure for the synthesis of ethyl 1-alkyl/aryl-
2H,5H-2,5-dioxo-1-benzopyrano[2,3-b]pyridine-3-carbox-
ylates (1k-n) and 3-acetyl/benzoyl-1-alkyl/aryl-2H,5H-1-
benzopyrano[2,3-b]pyridine-2,5-diones (1o-t). A mixture
of 3 (1 mmol), diethyl malonate (240 mg, 1.5 mmol) and pi-
peridine (130 mg, 1.5 mmol) or 3 (1 mmol), ethyl acetoacetate
(130 mg, 1 mmol) and piperidine (85 mg, 1 mmol) or 3 (1
mmol), ethyl benzoylacetate (190 mg, 1 mmol) and piperidine
(85 mg, 1 mmol) in CHCl3 (10 mL) was heated under reflux
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010 A One-Pot Synthesis of the 1-Benzopyrano[2,3-b]pyridine Moiety from 2-(Alkyl/arylamino)-
4-oxo-4H-1-benzopyran-3-carbaldehyde
979
for several hours (Table 2) till the completion of reaction
(TLC). Solvent was removed from the reaction mixture under
reduced pressure and resulted residue was stirred with water
(10 mL) for 10 min. The separated solid was filtered off, dried,
and purified by column chromatography over silica gel (100–
200) using 10% EtOAc in benzene as eluent to obtain 1k–t.
Ethyl 1-phenyl-2H,5H-2,5-dioxo-1-benzopyrano[2,3-b]pyri-
dine-3-carboxylate (1k). This compound was obtained in 55%
yield as white crystalline solid, mp 278–280ꢀC; IR: 2927,
3-Acetyl-1-ethyl-2H,5H-1-benzopyrano[2,3-b]pyridine-2,5-
dione (1p). This compound was obtained in 43% yield as
white crystalline solid, mp 218–220ꢀC; IR: 2940, 1700, 1660,
1
1540, 1480 cmꢁ1; H NMR (CDCl3): d 1.47 (t, 3H, CH2CH3,
J ¼ 6.9 Hz), 2.70 (s, 3H, COCH3), 4.45 (q, 2H, CH2CH3, J ¼
6.9 Hz), 7.49–7.56 (m, 2H, ArH), 7.75–7.80 (m, 1H, 8-H),
8.27 (br d, 1H, 6-H, J ¼ 7.8 Hz), 8.92 (s, 1H, 4-H). Anal.
Calcd for C16H13NO4: C, 67.84; H, 4.63; N, 4.94. Found: C,
67.70; H, 4.56; N, 4.87.
1752, 1717, 1657, 1542 cmꢁ1 1H NMR (CDCl3): d 1.40 (t,
;
3-Benzoyl-1-phenyl-2H,5H-1-benzopyrano[2,3-b]pyridine-2,
5-dione (1q). This compound was obtained in 72% yield as
white crystalline solid, mp 264–266ꢀC; IR: 2930, 1671, 1643,
3H, CH2CH3, J ¼ 7.2 Hz), 4.39 (q, 2H, CH2CH3, J ¼ 7.2
Hz), 7.13 (br d, 1H, 9-H, J ¼ 8.4 Hz), 7.34 (br d, 2H, ArH,
J ¼ 7.5 Hz), 7.46 (br t, 1H, ArH, J ¼ 7.2 Hz), 7.59–7.66 (m,
4H, ArH), 8.28 (br d, 1H, 6-H, J ¼ 7.2 Hz), 9.08 (s, 1H, 4-H);
13C NMR (CDCl3): d 14.2, 61.4, 101.4, 117.6, 117.8, 121.7,
126.3, 126.5, 128.1, 129.6, 129.7, 133.2, 134.5, 141.7, 153.4,
157.5, 158.4, 163.5, 173.3; ms: m/z 362 (MþþH), 384
(MþþNa). Anal. Calcd for C21H15NO5: C, 69.80; H, 4.18; N,
3.88. Found: C, 69.67; H, 4.09; N, 3.81.
Ethyl 7-methyl-1-phenyl-2H,5H-2,5-dioxo-1-benzopyrano[2,
3-b]pyridine-3-carboxylate (1l). This compound was obtained
in 74% yield as white crystalline solid, mp 208–210ꢀC; IR:
2940, 1740, 1710, 1648, 1535 cmꢁ1 1H NMR (CDCl3): d
;
1.39 (t, 3H, CH2CH3, J ¼ 7.2 Hz), 2.44 (s, 3H, ArCH3), 4.39
(q, 2H, CH2CH3, J ¼ 7.2 Hz), 7.01 (d, 1H, 9-H, J ¼ 8.4 Hz),
7.41 (br d, 1H, 8-H, J ¼ 8.4 Hz), 7.40–7.43 (m, 2H, ArH,),
7.50–7.58 (m, 3H, ArH), 8.10 (br s, 1H, 6-H), 9.06 (s, 1H, 4-
H). Anal. Calcd for C22H17NO5: C, 70.39; H, 4.56; N, 3.73.
Found: C, 70.25; H, 4.52; N, 3.68.
1
1540, 1458 cmꢁ1; H NMR (CDCl3): d 7.16 (br d, 1H, 9-H, J
¼ 8.4 Hz), 7.37–7.40 (m, 2H, ArH), 7.43–7.48 (m, 3H, ArH),
7.55–7.67 (m, 5H, ArH), 7.87 (br d, 2H, ArH, J ¼ 7.8 Hz),
8.28 (br d, 1H, 6-H, J ¼ 7.8Hz), 8.64 (s, 1H, 4-H); 13C NMR
(CDCl3): d 101.8, 117.7, 121.8, 126.3, 126.4, 126.6, 128.1,
128.4, 129.4, 129.7, 129.8, 133.1, 133.2, 134.5, 137.0, 139.0,
153.5, 157.0, 159.4, 173.4, 192.3; ms: m/z 394 (MþþH), 416
(MþþNa). Anal. Calcd for C25H15NO4: C, 76.33; H, 3.84; N,
3.56. Found: C, 76.20; H, 3.80; N, 3.49.
3-Benzoyl-7-methyl-1-phenyl-2H,5H-1-benzopyrano[2,3-
b]pyridine-2,5-dione (1r). This compound was obtained in
74% yield as white crystalline solid, mp 278–280ꢀC; IR: 2936,
1680, 1650, 1550, 1480 cmꢁ1 1H NMR (CDCl3): d 2.46 (s,
;
3H, ArCH3), 7.05 (d, 1H, 9-H, J ¼ 8.4 Hz), 7.36–7.60 (m, 9H,
ArH), 7.86 (br d, 2H, ArH, J ¼ 7.5 Hz), 8.06 (br s, 1H, 6-H),
8.64 (s, 1H, 4-H). Anal. Calcd for C26H17NO4: C, 76.65; H,
4.21; N, 3.44. Found: C, 76.50; H, 4.16; N, 3.47.
Ethyl 1-ethyl-2H,5H-2,5-dioxo-1-benzopyrano[2,3-b]pyri-
dine-3-carboxylate (1m). This compound was obtained in 42%
yield as white crystalline solid, mp 178–180ꢀC; IR: 2939,
;
1728, 1685, 1610, 1537 cmꢁ1 1H NMR (CDCl3): d 1.41 (t,
3-Benzoyl-1-methyl-2H,5H-1-benzopyrano[2,3-b]pyridine-2,5-
dione (1s). This compound was obtained in 60% yield as white
crystalline solid, mp 256–258ꢀC; IR: 3010, 1675, 1660, 1540,
1
1470 cmꢁ1; H NMR (CDCl3): d 3.80 (s, 3H, CH3), 7.44–7.62
3H, NCH2CH3, J ¼ 7.2 Hz), 1.46 (t, 3H, OCH2CH3, J ¼ 7.2
Hz), 4.38 (q, 2H, NCH2CH3, J ¼ 7.2 Hz), 4.46 (q, 2H,
OCH2CH3, J ¼ 7.2 Hz), 7.49–7.56 (m, 2H, ArH), 7.78 (br t,
1H, 8-H, J ¼ 7.2 Hz), 8.29 (br d, 1H, 6-H, J ¼ 7.8 Hz), 8.95
(s, 1H, 4-H). Anal. Calcd for C17H15NO5: C, 65.17; H, 4.83;
N, 4.47. Found: C, 64.95; H, 4.78; N, 4.49.
Ethyl 1-ethyl-7-methyl-2H,5H-2,5-dioxo-1-benzopyrano[2,
3-b]pyridine-3-carboxylate (1n). This compound was obtained
in 40% yield as white crystalline solid, mp 192–194ꢀC; IR:
2956, 1712, 1690, 1618, 1540 cmꢁ1 1H NMR (CDCl3): d
;
(m, 5H, ArH), 7.79 (br t, 1H, ArH, J ¼ 8.1 Hz), 7.84 (br d,
2H, ArH, J ¼ 8.1 Hz), 8.30 (br d, 1H, 6-H, J ¼ 8.1 Hz), 8.52
(s, 1H, 4-H). Anal. Calcd for C20H13NO4: C, 72.50; H, 3.95;
N, 4.23. Found: C, 72.40; H, 3.88; N, 4.19.
3-Benzoyl-1-ethyl-2H,5H-1-benzopyrano[2,3-b]pyridine-2,5-
dione (1t). This compound was obtained in 62% yield as white
crystalline solid, mp 224–226ꢀC; IR: 2958, 1690, 1662, 1548,
1474 cmꢁ1
;
1H NMR (CDCl3): d 1.47 (t, 3H, CH2CH3, J ¼
6.9 Hz), 4.45 (q, 2H, CH2CH3, J ¼ 6.9 Hz), 7.44–7.61 (m,
5H, ArH), 7.76–7.79 (m, 1H, ArH), 7.84 (br d, 2H, ArH, J ¼
7.5 Hz), 8.30 (br d, 1H, 6-H, J ¼ 7.5 Hz), 8.51 (s, 1H, 4-H).
Anal. Calcd for C21H15NO4: C, 73.04; H, 4.38; N, 4.06.
Found: C, 72.91; H, 4.32; N, 3.98.
1.41 (t, 3H, NCH2CH3, J ¼ 7.2 Hz), 1.44 (t, 3H, OCH2CH3,
J ¼ 7.2 Hz), 2.50 (s, 3H, ArCH3), 4.38 (q, 2H, NCH2CH3, J
¼ 7.2 Hz), 4.44 (q, 2H, OCH2CH3, J ¼ 7.2 Hz), 7.43 (d, 1H,
9-H, J ¼ 8.4 Hz), 7.56 (br d, 1H, 8-H, J ¼ 8.4 Hz), 8.08 (br s,
1H, 6-H,), 8.96 (s, 1H, 4-H). Anal. Calcd for C18H17NO5: C,
66.05; H, 5.23; N, 4.28. Found: C, 65.90; H, 5.17; N, 4.21.
3-Acetyl-7-methyl-1-phenyl-2H,5H-1-benzopyrano[2,3-b]pyri-
dine-2,5-dione (1o). This compound was obtained in 68% yield
as white crystalline solid, mp 278–280ꢀC; IR: 2940, 1696,
General procedure for the reaction of ethyl cyanoacetate
on 2-alkyl/arylaminochromone-3-carbaldehyde (3). An etha-
nolic solution (30 mL) of a mixture of 3 (1 mmol), ethyl cya-
noacetate (115 mg, 1 mmol), and piperidine (85 mg, 1 mmol)
was stirred at room temperature for 3.5 h to afford a solid. The
solid was filtered off, washed with ethanol, and purified by col-
umn chromatography over silica gel (100–200) using 10%
EtOAc in benzene as eluent to afford 11a–e in moderate yields.
1654, 1527, 1478 cmꢁ1 1H NMR (CDCl3): d 2.45 (s, 3H,
;
ArCH3), 2.68 (s, 3H, COCH3), 7.03 (d, 1H, 9-H, J ¼ 8.4 Hz),
7.36–7.38 (m, 2H, ArH), 7.43 (br d, 1H, 8-H, J ¼ 8.4 Hz),
7.63–7.65 (m, 3H, ArH), 8.05 (br s, 1H, 6-H), 9.08 (s, 1H, 4-
H); 13C NMR (CDCl3): d 20.8, 30.8, 102.0, 117.4, 121.3,
124.1, 126.0, 128.0, 129.7, 129.8, 133.4, 135.6, 136.5, 141.0,
151.7, 157.7, 160.5, 173.5, 195.4; ms: m/z 346 (Mþþ H), 368
(MþþNa). Anal. Calcd for C21H15NO4: C, 73.04; H, 4.38; N,
4.06. Found: C, 72.90; H, 4.34; N, 3.99.
Ethyl
pyridine-3-carboxylate (11a). This compound was obtained in
2-amino-1,6-dihydro-5-(salicyloyl)-6-oxo-1-phenyl-
60% yield as yellow crystalline solid, mp 166–168ꢀC; IR: 3351,
1
3253, 2983, 1694, 1654, 1574 cmꢁ1; H NMR (CDCl3): d 1.36
(t, 3H, CH2CH3, J ¼ 6.9 Hz), 4.30 (q, 2H, CH2CH3, J ¼ 6.9 Hz),
4.93 (br s, 1H, NH2, deuterium oxide exchangeable), 6.83–6.85
(br t, 1H, 5’-H, J ¼ 7.2 Hz), 6.97 (br d, 1H, 3’-H, J ¼ 8.1 Hz),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

980
S. Maiti, S. K. Panja, and C. Bandyopadhyay
Vol 47
7.29–7.31 (m, 2H, ArH), 7.36–7.44 (m, 1H, ArH), 7.54–7.62 (m,
4H, ArH), 8.41 (s, 1H, 4-H), 9.18 (br s, 1H, NH2, deuterium ox-
ide exchangeable), 12.03 (s, 1 H, OH, deuterium oxide
exchangeable); 13C NMR (CDCl3): d 14.3, 60.8, 89.6, 114.9,
117.8, 118.4, 119.7, 128.4, 130.2, 130.7, 132.8, 133.5, 135.8,
145.2, 156.6, 159.5, 162.4, 166.6, 197.7; ms: m/z 379 (Mþ þH),
401 (Mþ þNa). Anal. Calcd for C21H18N2O5: C, 66.66; H, 4.79;
N, 7.40. Found: C, 66.80; H, 4.85; N, 7.45.
Ethyl 2-amino-1,6-dihydro-5-(5-methylsalicyloyl)-6-oxo-1-
phenylpyridine-3-carboxylate (11b). This compound was
obtained in 57% yield as yellow crystalline solid, mp 116–
118ꢀC; IR 3400, 3156, 2985, 1691, 1650, 1554 cmꢁ1 1H
;
(85 mg, 1 mmol) in ethanol (30 mL) was stirred at room tem-
perature for 1 h. The deposited solid was filtered off, washed
with ethanol, and recrystallized from benzene to afford 12f–i.
7-Methyl-1-phenyl-2H,5H-2-imino-5-oxo-1-benzopyrano[2,
3-b]pyridine-3-carbonitrile
obtained in 80% yield as faint yellow crystalline solid, mp
(12f). This
compound was
1
286–288ꢀC; IR 3316, 2210, 1637, 1533, 1475 cmꢁ1; H NMR
(CDCl3): d 2.44 (s, 3H, ArCH3), 6.95 (d, 1H, 9-H, J ¼ 8.4
Hz), 7.27–7.39 (m, 5H, ArH), 7.60–7.67 [m, 2H (1 H, deute-
rium oxide exchangeable), NHþArH)], 7.98 (br s, 1H, 6-H),
8.23 (s, 1H, 4-H); ms: m/z 328 (MþþH), 350 (MþþNa). Anal.
Calcd for C20H13N3O2: C, 73.39; H, 4.00; N, 12.84. Found: C,
73.25; H, 3.92; N, 12.78.
NMR (CDCl3): d 1.35 (t, 3H, CH2CH3, J ¼ 6.9 Hz), 2.25 (s,
3H, ArCH3), 4.30 (q, 2H, CH2CH3, J ¼ 6.9 Hz), 4.94 (br s,
1H, NH2, deuterium oxide exchangeable ), 6.88 (d, 1H, 3’-H, J
¼ 8.4Hz), 7.23–7.31 (m, 3H, ArH), 7.36–7.39 (m, 1H, ArH),
7.54–7.63 (m, 3H, ArH), 8.36 (s, 1H, 4-H), 9.15 (br s, 1H,
NH2, deuterium oxide exchangeable), 11.81 (s, 1H, OH, deute-
rium oxide exchangeable). Anal. Calcd for C22H20N2O5: C,
67.34; H, 5.14; N, 7.14. Found: C, 67.55; H, 5.08; N, 7.08.
Ethyl 2-amino-1,6-dihydro-5-(5-methylsalicyloyl)-6-oxo-1-
p-tolylpyridine-3-carboxylate (11c). This compound was
obtained in 52% yield as yellow crystalline solid, mp 202–
1-Phenyl-2H,5H-2-imino-5-oxo-1-benzopyrano[2,3-b]pyridine-
3-carbonitrile (12g). This compound was obtained in 83% yield
as faint yellow crystalline solid, mp > 320ꢀC; IR 3330, 2230,
1648, 1520, 1460 cmꢁ1; 1H NMR (CDCl3): d 7.05 (br d, 1H, 9-
H, J ¼ 8.1 Hz ), 7.44 (br t, 1H, 7-H, J ¼ 7.2 Hz), 7.58–7.63 (m,
1H, 8-H), 7.64–7.67 (m, 6H, NHþArH), 8.22 (br d, 1H, 6-H, J
¼ 7.2 Hz), 8.30 (s, 1H, 4-H). Anal. Calcd for C19H11N3O2: C,
72.84; H, 3.54; N, 13.41. Found: C, 72.72; H, 3.48; N, 13.48.
1-Ethyl-2H,5H-2-imino-5-oxo-1-benzopyrano[2,3-b]pyri-
dine-3-carbonitrile (12h). This compound was obtained in
86% yield as faint yellow crystalline solid, mp 266–268ꢀC; IR
204ꢀC; IR 3320, 3148, 2976, 1685, 1663, 1562 cmꢁ1 1H
;
NMR (CDCl3): d 1.34 (t, 3H, CH2CH3, J ¼ 6.9 Hz), 2.24 (s,
3H, ArCH3), 2.42 (s, 3H, ArCH3), 4.30 (q, 2H, CH2CH3, J ¼
6.9 Hz), 5.02 (br s, 1H, NH2, deuterium oxide exchangeable),
6.87 (d, 1H, 3’-H, J ¼ 8.4 Hz), 7.16 (d, 2H, ArH, J ¼ 7.8
Hz), 7.23 (br d, 1H, 4’-H, J ¼ 8.4 Hz), 7.36–7.40 (m, 3H,
ArH), 8.35 (s, 1H, 4-H), 9.12 (br s, 1H, NH2, deuterium oxide
exchangeable), 11.82 (s, 1H, OH, deuterium oxide exchange-
able). Anal. Calcd for C23H22N2O5: C, 67.97; H, 5.46; N, 6.89.
Found: C, 67.80; H, 5.41; N, 6.82.
Ethyl 2-amino-1,6-dihydro-1-ethyl-5-(5-methylsalicyloyl)-6-
oxo-pyridine-3-carboxylate (11d). This compound was
obtained in 40% yield as yellow crystalline solid, mp 160–
162ꢀC; IR 3359, 3204, 2977, 1689, 1604, 1542 cmꢁ1 1H
;
3298, 3022, 2222, 1626, 1610 cmꢁ1 1H NMR (CDCl3): d
;
1.45 (t, 3H, CH2CH3, J ¼ 6.9 Hz), 4.49 (q, 2H, CH2CH3, J ¼
6.9 Hz), 7.48–7.52 (m, 2H, ArH), 7.62 (br s, 1H, NH, deute-
rium oxide exchangeable), 7.75 (ddd, 1H, 8-H, J ¼ 8.4, 7.9,
1.8 Hz), 8.19 (s, 1H, 4-H), 8.24 (dd, 1H, 6-H, J ¼ 7.8, 1.8
Hz). Anal. Calcd for C15H11N3O2: C, 67.92; H, 4.18; N, 15.84.
Found: C, 68.10; H, 4.23; N, 15.76.
1-Ethyl-7-methyl-2H,5H-2-imino-5-oxo-1-benzopyrano[2,3-
b]pyridine-3-carbonitrile (12i). This compound was obtained
in 64% yield as faint yellow crystalline solid, mp 256–258ꢀC;
1
IR 3300, 2983, 2254, 1645, 1615 cmꢁ1; H NMR (CDCl3): d
1.44 (t, 3H, CH2CH3, J ¼ 6.9 Hz), 2.48 (s, 3H, ArCH3), 4.46
(q, 2H, CH2CH3, J ¼ 6.9 Hz), 7.39 (br d, 1H, 9-H, J ¼ 8.4
Hz), 7.54 (br d, 1H, 8-H, J ¼ 8.4 Hz), 7.58 (br s, 1H, NH,
deuterium oxide exchangeable), 8.01 (br s, 1H, 6-H), 8.17 (s,
1H, 4-H). Anal. Calcd for C16H13N3O2: C, 68.81; H, 4.69; N,
15.04. Found: C, 68.70; H, 4.62; N, 14.96.
NMR (CDCl3): d 1.33 (t, 6H, 2ꢂCH2CH3, J ¼ 6.9 Hz), 2.25
(s, 3H, ArCH3), 4.12 (q, 2H, CH2CH3, J ¼ 6.9 Hz), 4.29 (q,
2H, CH2CH3, J ¼ 6.9 Hz), 5.11 (br s, 1H, NH2, deuterium ox-
ide exchangeable), 6.91 (d, 1H, 30-H, J ¼ 8.4 Hz), 7.25 (br d,
1H, 40-H, J ¼ 8.4 Hz), 7.32 (br s, 1H, 60-H), 8.24 (s, 1H, 4-
H), 8.99 (br s, 1H, NH2, deuterium oxide exchangeable), 11.87
(s, 1H, OH, deuterium oxide exchangeable); ms: m/z 345
(MþþH), 367 (MþþNa). Anal. Calcd for C18H20N2O5: C,
62.78; H, 5.85; N, 8.13. Found: C, 62.62, H, 5.80; N, 8.10.
Ethyl 2-amino-1,6-dihydro-1-methyl-5-(5-methylsalicyloyl)-
6-oxo-pyridine-3-carboxylate (11e). This compound was
obtained in 45% yield as yellow crystalline solid, mp 208–
Silica-induced hydrolysis of 12 to 1-alkyl/aryl-2-amino-
1,6-dihydro-5-(salicyloyl)-6-oxo-pyridine-3-carbonitrile
(11f). Compound 12 (1 mmol) was dissolved in CHCl3 (25
mL). Silica gel (1 g) was added to the CHCl3 solution and the
resultant mixture was heated under reflux with stirring for 5 h.
Silica gel was filtered off and it was eluted with 20% ethyl ac-
etate in benzene. Filtrate (CHCl3 solution) and eluents were
mixed together and was concentrated under reduced pressure.
The residue was crystallized from benzene to afford 11f–i.
2-Amino-1,6-dihydro-1-phenyl-5-(5-methylsalicyloyl)-6-oxo-
pyridine-3-carbonitrile (11f). This compound was obtained in
70% yield as yellow crystalline solid, mp 194–196ꢀC; IR
210ꢀC; IR 3333, 3194, 2970, 1684, 1635, 1574 cmꢁ1 1H
;
NMR (CDCl3): d 1.33 (t, 3H, CH2CH3, J ¼ 6.9 Hz), 2.25 (s,
3H, ArCH3), 3.50 (s, 3H, NCH3), 4.29 (q, 2H, CH2CH3, J ¼
6.9 Hz), 5.12 (br s, 1H, NH2, deuterium oxide exchangeable),
6.91 (d, 1H, 30-H, J ¼ 8.4 Hz), 7.26 (br d, 1H, 40-H, J ¼ 8.4
Hz), 7.32 (br s, 1H, 60-H), 8.23 (s, 1H, 4-H), 8.98 (br s, 1H,
NH2, deuterium oxide exchangeable), 11.86 (s, 1H, OH, deute-
rium oxide exchangeable). Anal. Calcd for C17H18N2O5: C,
61.81; H, 5.49; N, 8.48. Found: C, 61.74; H, 5.45; N, 8.42.
General procedure for the reaction of malononitrile on
2-alkyl/arylaminochromone-3-carbaldehyde (3). A mixture
of 3 (1 mmol), malononitrile (66 mg, 1 mmol), and piperidine
3400, 3388, 3220, 2981, 2255, 1690, 1647, 1540 cmꢁ1 1H
;
NMR (CDCl3): d 2.26 (s, 3H, ArCH3), 5.50 (br s, 2H, NH2,
deuterium oxide exchangeable), 6.89 (d, 1H, 3’-H, J ¼ 8.7
Hz), 7.29–7.31 (m, 4H, ArH), 7.57–7.65 (m, 3H, ArH), 7.74
(s, 1H, 4-H), 11.61 (s, 1H, OH, deuterium oxide exchange-
able); 13C NMR (CDCl3): d 20.6, 72.0, 116.2, 117.1, 118.0,
119.1, 127.7, 128.1, 128.3, 130.8, 131.0, 132.1, 133.2, 137.6,
144.2, 156.5, 160.7, 196.4; ms: m/z 346 (MþþH), 368
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010 A One-Pot Synthesis of the 1-Benzopyrano[2,3-b]pyridine Moiety from 2-(Alkyl/arylamino)-
4-oxo-4H-1-benzopyran-3-carbaldehyde
981
(MþþNa). Anal. Calcd for C20H15N3O3: C, 69.56; H, 4.38; N,
REFERENCES AND NOTES
12.17. Found: C, 69.38; H, 4.40; N, 12.12.
[1] Unangst, P. C.; Capiris, T.; Connor, D. T.; Heffner, T. G.;
Mackenzie, R. G.; Miller, S. R.; Pugsley, T. A.; Wise, L. D. J Med
Chem 1997, 40, 2688.
2-Amino-1,6-dihydro-1-phenyl-5-salicyloyl-6-oxo-pyridine-
3-carbonitrile (11g). This compound was obtained in 72%
yield as yellow crystalline solid, mp 228–230ꢀC; IR 3410,
[2] Edwards, J. D.; Higuchi, R. I.; Winn, D. T.; Pooley, C. F.;
Caferro, T. R.; Hamann, L. G.; Zhi, L.; Marschke, K. B.; Goldman,
M. E.; Jones, T. K. Bioorg Med Chem Lett 1999, 9, 1003.
[3] Siddique, Z. N.; Khuwaja, G.; Asad, M. Indian J Chem
2006, 45B, 2341.
3398, 3213, 2922, 2216, 1681, 1638, 1526 cmꢁ1 1H NMR
;
(CDCl3): d 5.41 (br s, 2H, NH2, deuterium oxide exchange-
able), 6.85 (ddd, 1H, 5’-H, J ¼ 7.5, 7.2, 0.6 Hz), 6.98 (dd, 1H,
3’-H, J ¼ 8.1, 0.6 Hz), 7.28–7.31 (m, 2H, ArH), 7.42–7.48
(m, 1H, ArH), 7.55–7.65 (m, 4H, ArH), 7.81 (s, 1H, 4-H),
11.81 (s, 1H, OH, deuterium oxide exchangeable); Anal. Calcd
for C19H13N3O3: C, 68.88; H, 3.95; N, 12.68. Found: C,
68.75; H, 3.92; N, 12.63.
[4] Weng, L. L.; Ln, G.; Zheng, H. Chin Chem Lett 2002, 13, 13.
[5] Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Tol-
machev, A. A. Synlett 2004, 2287.
[6] (a) Nohara, A.; Sugihara, H.; Ukawa, K. Ger. Pat. 2,809,720;
(b) Nohara, A.; Ishiguro, T.; Ukawa, K. Ger. Pat. 2,841,644; (c) Nohara,
A.; Sugihara, H.; Ukawa, K. Jpn. Pat. 7,988,298; (d) Nohara, A.; Sugi-
hara, H.; Ukawa, K. U.S. Pat. 4,255,576;
2-Amino-1-ethyl-1,6-dihydro-5-salicyloyl-6-oxo-pyridine-3-
carbonitrile (11h). This compound was obtained in 69%
yield as yellow crystalline solid, mp 252–254ꢀC; IR 3344,
3314, 3227, 2941, 2212, 1631, 1581 cmꢁ1
;
1H NMR
[7] Connor, D. T.; Strandtmann, V. U.S. Pat. 4,117,134;
[8] Atkinson, P.; Findlay, K. S.; Kielar, F.; Pal, R.; Parker, D.;
Poole, R. A.; Puschmann, H.; Richardson, S. L.; Stenson, P. A.;
Thompson, A. L.; Yu, J. Org Biomol Chem 2006, 4, 1707.
[9] Ghosh, C. K.; Sinha Roy, D. K.; Mukhopadhyay, K. K. J
Chem Soc Perkin Trans1 1979,1964.
(DMSO-d6): d 1.09 (t, 3H, CH2CH3, J ¼ 6.9 Hz), 4.0 (q,
2H, CH2CH3, J ¼ 6.9 Hz), 6.81–6.88 (m, 2H, ArH), 7.34–
7.36 (m, 2H, ArH), 7.78 (s, 1H, 4-H), 8.14 (br s, 2H, NH2,
deuterium oxide exchangeable), 10.61 (s, 1H, OH, deute-
rium oxide exchangeable). Anal. Calcd for C15H13N3O3: C,
63.60; H, 4.63; N, 14.83. Found: C, 63.45; H, 4.56; N,
14.74.
2-Amino-1-ethyl-1,6-dihydro-5-(5-methylsalicyloyl)-6-oxo-
pyridine-3-carbonitrile (11i). This compound was obtained in
67% yield as yellow crystalline solid, mp 248–250ꢀC; IR
3340, 3324, 3220, 2955, 2220, 1640, 1578 cmꢁ1 1H NMR
;
(DMSO-d6): d 1.10 (t, 3H, CH2CH3, J ¼ 6.9 Hz), 2.20 (s, 3H,
ArCH3), 4.00 (q, 2H, CH2CH3, J ¼ 6.9 Hz), 6.77 (d, 1H, 3’-
H, J ¼ 7.5 Hz), 7.16–7.18 (m, 2H, ArH), 7.75 (s, 1H, 4-H),
8.12 (br s, 2H, NH2, deuterium oxide exchangeable), 10.42 (s,
1H, OH, deuterium oxide exchangeable). Anal. Calcd for
C16H15N3O3: C, 64.64; H, 5.03; N, 14.13. Found: C, 64.74;
H, 5.06; N, 14.19.
Synthesis of Ethyl 1-ethyl-7-methyl-2H,5H-2-imino-5-oxo-
1-benzopyrano[2,3-b]pyridine-3-carboxylate (12d) from 3
(R1 ¼ Me, R2 ¼ Et). A mixture of 3 (R1 ¼ Me, R2 ¼ Et)
(230 mg, 1 mmol), ethyl cyanoacetate (115 mg, 1 mmol) in
pyridine (5 mL) was stirred at room temperature for 2 h when
a solid was found to separate. It was filtered off, washed with
water, dried in air, and crystallized from benzene-light petrol
(80:20) to produce 12d.
[10] (a) Langer, P.; Appel, B. Tetrahedron Lett 2003, 44, 5133;
(b) Rashid, M. A.; Rasool, N.; Appel, B.; Adeel, M.; Karapetyan, V.;
Mkrtchyan, S.; Reinke, H.; Fischer, C.; Langer, P. Tetrahedron 2008,
64, 5416.
[11] Ghosh, T.; Bandyopadhyay, C. J Heterocycl Chem 2006,
43, 1431.
[12] Plaskon, A. S.; Ryabukhin, S. V.; Volochnyuk, D. M.; Gav-
rilenko, K. S.; Shivanyuk, A. N.; Tolmachev, A. A. J Org Chem 2008,
73, 6010.
[13] Ghosh, C. K.; Bandyopadhyay, C.; Maiti, J. Heterocycles
1987, 26, 1623.
[14] (a) Sottofattori, E.; Anzaldi, M.; Balbi, A.; Artali, R.;
Bombieri, G. Helv Chim Acta 2002, 85, 1698; (b) Singh, G.; Singh,
L.; Ishar, M. P. S. Tetrahedron 2002, 58, 7883; (c) Maiti, S.; Panja, S.
K.; Bandyopadhyay, C. Indian J Chem 2009, 48B, 1447.
[15] Maiti, S.; Panja, S. K.; Bandyopadhyay, C. Tetrahedron
Lett 2009, 50, 3966.
[16] Esmaeili, A. A.; Gharenghani, O. Helv Chim Acta 2007,
90, 1712.
[17] Nakaike, Y.; Hayashi, D.; Nishiwaki, N.; Tobe, Y.; Ariga,
M. Org Biomol Chem 2009, 7, 325.
[18] Singh, G; Singh, G.; Ishar, M. P. S. Helv Chim Acta 2003,
86, 169.
Ethyl 1-ethyl-7-methyl-2H,5H-2-imino-5-oxo-1-benzopyr-
ano[2,3-b]pyridine-3-carboxylate (12d). This compound was
obtained in 40% yield as faint yellow crystalline solid, mp 256–
[19] (a) Ishar, M. P. S.; Kumar, K.; Singh, R. Tetrahedron Lett
1998, 39, 6547; (b) Ghosh, T.; Bandyopadhyay, C. Tetrahedron Lett
2004, 45, 6169.
1
258ꢀC; IR 3303, 2985, 1702, 1625, 1537, 1478 cmꢁ1; H NMR
[20] (a) Bandyopadhyay, C.; Sur, K. R.; Patra, R.; Banerjee, S. J
Chem Res (S) 2003,459; (b) Bandyopadhyay, C.; Sur, K. R.; Patra, R.;
Banerjee, S. J Chem Res (M) 2003, 847.
(CDCl3): d 1.37–1.44 (m, 6H, 2ꢂCH2CH3), 2.47 (s, 3H, ArCH3),
4.34 (q, 2H, NCH2CH3, J ¼ 6.9 Hz), 4.47 (q, 2H, OCH2CH3, J ¼
6.6 Hz), 7.36 (d, 1H, 9-H, J ¼ 8.4 Hz), 7.48 (br d, 1H, 8-H, J ¼
8.4 Hz), 8.01 (br s, 1H, 6-H), 8.63 (s, 1H, 4-H), 9.57 (br s, 1H,
NH, deuterium oxide exchangeable). Anal. Calcd for
C18H18N2O4: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.40; H,
5.49, N, 8.52.
[21] (a) Song, A.; Wang, X.; Lam, K. S. Tetrahedron Lett 2003,
44, 1755; (b) Gao, S.; Tsai, C. H.; Yao, C.-F. Synlett 2009, 949.
[22] Chopra, D.; Zhurov, V. V.; Zhurova, E. A.; Pinkerton, A.
A. J Org Chem 2009, 74, 2389.
[23] (a) Mc Nab, H. Chem Soc Rev 1978, 7, 345; (b) Ivanor, A.
S. Chem Soc Rev 2008, 37, 789.
[24] Ghosh, C. K.; Bandyopadhyay, C. Indian J Chem 1984,
23B, 1048.
Acknowledgments. Financial assistance from the Department
of Biotechnology (DBT), India (No. BT/PR8217/Med/14/1239/
2006) is gratefully acknowledged. We also gratefully acknowl-
edge IICB and IACS, Jadavpur for spectral analysis and the col-
lege authorities for providing research facilities.
[25] (a) Trivedi, K. N.; Madhava Rao, S. S.; Mistry, S. V.;
Desai, S. M. J Indian Chem Soc 2001, 78, 579; (b) Mitra, A. K.; De,
A.; Karchaudhuri, N.; Misra, S. K.; Mukhopadhyay, A. K. J Indian
Chem Soc 1998, 75, 666.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet