Synthesis of Some Novel Heteroannelated Chromones by Basic Rearrangement of 6-Methylchromone-3-Carbonitrile

Article abstract of DOI:10.1007/s10593-014-1632-y

A new series of chromeno[2,3-b]pyridines was efficiently synthesized via chemical transformations of 6-methylchromone-3-carbonitrile with some methylene-active compounds bearing -CH₂-CN and -CH₂-CO- moieties. Some heteroannelated chr

Full text of DOI:10.1007/s10593-014-1632-y

DOI 10.1007/s10593-014-1632-y
Chemistry of Heterocyclic Compounds, Vol. 50, No. 11, February, 2015 (Russian Original Vol. 50, No. 11, November, 2014)
SYNTHESIS OF SOME NOVEL HETEROANNELATED
CHROMONES BY BASIC REARRANGEMENT OF
6-METHYLCHROMONE-3-CARBONITRILE
1
1
1
1
*
M. A. Ibrahim , N. M. El-Gohary , S. S. Ibrahim , and S. Said
A new series of chromeno[2,3-b]pyridines was efficiently synthesized via chemical transformations of
6-methylchromone-3-carbonitrile with some methylene-active compounds bearing –CH2–CN and
–CH2–CO– moieties. Some heteroannelated chromeno[2,3-b]pyridines were also synthesized. The
structures of the new synthesized products were deduced on the basis of their analytical and spectral
data.
Keywords: chromeno[2,3-b]pyridines, heteroannelated chromones, 6-methylchromone-3-carbonitrile, basic
rearrangement, cyclocondensation.
Chromones are well-known natural and synthetic products that possess diverse biological activities [1],
including anticancer [2-4], antitumor [5], antiproliferative [6], neuroprotective [7], HIV-inhibitory [8, 9],
antimicrobial [10, 11], antioxidant [12], anti-inflammatory [13], and antibiotic [14]. Heteroannelated chromones
showed significant biological activities including pharmacological [15], antiplatelet [16], antiallergic [17],
antiangiogenic [18], antirheumatic [19], antibacterial [20], anti-inflammatory, and analgesic [21]. 3-Substituted
chromones have been reported to be used as a very good building blocks for the synthesis of various
heterocycles [22-26]. Introduction of an electron-withdrawing cyano group at position 3 of the chromone
system changes crucially the reactivity of the pyrone ring with respect to nucleophiles and provides a broad
synthetic potential of 3-cyanochromones [27-31]. The present work was aiming at studying the chemical
reactivity of 6-methylchromone-3-carbonitrile (1) towards some carbon nucleophiles under basic conditions
using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a basic catalyst, with the hope of constructing a novel
series of heteroannelated chromeno[2,3-b]pyridines.
In our previous work [23], 6-methylchromone-3-carbonitrile (1) showed a different behavior than
chromone-3-carbonitrile in reactions with benzimidazol-2-ylacetonitrile, as methylene-active nitrile. Thus, the
present work was aimed at studying the chemical transformations of 6-methylchromone-3-carbonitrile (1) with
a variety of methylene-active compounds bearing –CH2–CN and –CH2–CO– groups. The reaction of 6-methyl-
chromone-3-carbonitrile (1) with malononitrile in absolute ethanol containing DBU as a basic catalyst afforded
2-amino-7-methyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile (2) as yellow crystals. Compound 2 may
be synthesized via deprotonation of malononitrile followed by Michael addition at the C-2 position of the
_______
*To whom correspondence should be addressed, e-mail: magdy_ahmed1977@yahoo.com.
1Department of Chemistry, Faculty of Education, Ain Shams University, Roxy 11711, Cairo, Egypt.
_________________________________________________________________________________________
Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1766-1776, November, 2014.
Original article submitted July 27, 2014.
1624
0009-3122/15/5011-1624©2015 Springer Science+Business Media New York

γ-pyrone moiety, leading to intermediate A, which underwent retro-Michael reaction with concomitant ring
opening to give open-chained intermediate B. Intermediate B underwent two consecutive cycloaddition
reactions, giving the final product 2 as shown in Scheme 1. The chemical transformation of nitrile 1 into
chromenopyridine 2 can be regarded as a domino reaction "Michael – retro-Michael – nitrile addition –
heterocyclization". The structure of compound 2 was deduced from its correct element analysis and spectral
data. The IR spectrum showed characteristic absorption bands at 3371, 3314, 3158 (NH2), 2224 (C≡N), 1654
1
(C=Opyrone), and 1605 cm-1 (C=N). The H NMR spectrum of compound 2 consists of two doublets at 7.51 and
7.64 ppm assigned to H-9 and H-8 protons and three singlets at 2.43, 7.88, and 8.63 ppm attributed to the CH3
group and protons H-6 and H-4, respectively, in addition to a D2O-exchangeable signal at 8.10 ppm attributed
to NH2 protons.
Scheme 1
O
O
O
6
9
4
CN
CN
Me
Me
8
NH2
O
O
N
1
2
65%
:B
O
O
H
H
CN
CN
Me
NC
CN
H+
–BH+
CN
abs. EtOH
DBU, 
10 min
OH
N
N
CN
A
B
Compound 2 was used as a good precursor to synthesize a novel series of heteroannelated chromones
identified as chromeno[3',2':5,6]pyrido[2,3-d]pyrimidines. Consequently, condensation of compound 2 with
formamide under fusion condition afforded 4-amino-8-methyl-6H-chromeno[3',2':5,6]pyrido[2,3-d]pyrimidin-
6-one (3) (Scheme 2). The IR spectrum of compound 3 showed characteristic absorption bands at 3326, 3222
1
(NH2), 1652 (C=Opyrone), and 1604 cm-1 (C=N). Its H NMR spectrum showed three singlets at 7.96, 8.59, and
9.69 ppm assigned to H-7, H-5, and H-2 protons, respectively, in addition to an exchangeable signal at 6.69
ppm attributed to NH2 protons. The mass spectrum of compound 3 showed the molecular ion peak (m/z 278, Irel
100%) corresponding to the formula weight (278.27), which also confirms the structure.
Moreover, the reaction of compound 2 with formic acid under fusion condition afforded 8-methyl-
6H-chromeno[3',2':5,6]pyrido[2,3-d]pyrimidine-4,6(3H)-dione (4) (Scheme 2). The IR spectrum of compound 4
showed characteristic absorption bands at 3423 (NH), 1685 (C=Opyrimidinone), 1656 (C=Opyrone), and 1628 cm-1
Scheme 2
NH2
O
N
O
O
O
O
7
5
7
5
HCOOH
HCONH2
Me
Me
, 4 h
N
, 4 h
NH
2
61%
52%
2
9
9
2
N
N
N
10
10
Ac2O
, 4 h
3
4
56%
O
N
O
5
7
Me
NH
Me
9
O
N
10
5
1625

1
(C=N). Its H NMR spectrum showed three characteristic singlets at 8.12, 8.59, and 8.79 ppm assigned to H-7,
H-5, and H-2 protons, respectively, in addition to an exchangeable signal at 12.80 ppm attributed to NH proton.
The mass spectrum of compound 4 showed the molecular ion peak at m/z 279, which agrees well with the
proposed molecular weight (279.25).
Further, refluxing compound 1 with acetic anhydride produced 2,8-dimethyl-6H-chromeno[3',2':5,6]-
pyrido[2,3-d]pyrimidine-4,6(3H)-dione (5) (Scheme 2). The IR spectrum of compound 5 showed characteristic
1
absorption bands at 1705 (C=Opyrimidinone), 1669 (C=Opyrone), and 1617 cm-1 (C=N). Its H NMR spectrum
showed two characteristic singlets at 7.93 and 8.76 ppm assigned to H-7 and H-5 protons, respectively, in
addition to the D2O-exchangeable signal attributed to NH proton at 11.30 ppm. The structure of compound 5 was
further deduced from its mass spectrum, which revealed the molecular ion peak, as the base peak, at m/z 293.
On the other hand, reaction of nitrile 1 with ethyl cyanoacetate in boiling ethanol containing DBU
afforded ethyl 2-amino-7-methyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylate (6) (Scheme 3). The IR
spectrum of compound 6 showed characteristic absorption bands at 3407, 3276, 3165 (NH2), 1698 (C=Oester),
1670 (C=Opyrone), and 1626 cm-1 (C=N). Its 1H NMR spectrum showed triplet and quartet signals attributed to
the ethoxy group protons at 1.36 and 4.35 ppm, in addition to characteristic singlet assigned to the H-4 proton at
8.79 ppm. The 1H NMR spectrum also revealed exchangeable signals at 8.07 and 8.29 corresponding to the NH2
protons.
Scheme 3
O
Ph
Ph
O
O
4
6
NC
Me
Me
Me
N
N
H
H
70%
57%
8
8
8
O
O
N
NH2
9
6
7
6
8
abs. EtOH
, 2 h
PhCH2NH2
O
O
4
NC
abs. EtOH
OEt
OEt
1
61%
DBU, 
30 min
O
O
N
NH2
O
9
6
abs. EtOH
, 2 h
PhNH2
O
4
NC
Ph
Ph
N
N
H
H
65%
60%
O
N
NH2
9
In the same manner, treatment of nitrile 1 with N-benzyl-2-cyanoacetamide and N-phenyl-2-cyano-
acetamide afforded 2-aminochromeno[2,3-b]pyridine-3-carboxamide derivatives 7 and 8, respectively (Scheme 3).
Compounds 7 and 8 were authentically prepared by the reaction of ethyl ester 6 with benzylamine and aniline,
respectively. The 1H NMR spectra of compounds 7 and 8 showed characteristic singlet signals at 8.84 and 8.90
1
ppm attributed to H-4 proton. The H NMR spectrum of compound 7 showed the characteristic doublet
exchanged to a singlet at 4.47 ppm assigned to CH2 protons, in addition to the downfield triplet exchangeable
with D2O at 9.44 ppm attributed to NH proton. The 13C NMR spectrum of compound 7 showed two upfield
signals assigned to aliphatic carbons at 20.2 (CH3) and 42.5 ppm (CH2), as well two downfield signals
attributed to carbonyl groups at 166.1 (CONH) and 174.8 ppm (C=Opyrone). The mass spectrum of compound 8
showed the molecular ion peak at m/z 345, corresponding to the proposed formula weight (345.35), which also
supports the structure.
Heterocyclization of compound 7 with acetic anhydride afforded 3-benzyl-2,8-dimethyl-4H,6H-chro-
meno[3',2':5,6]pyrido[2,3-d]pyrimidine-4,6-dione (9) (Scheme 4). The IR spectrum of compound 9 showed
1626

1
characteristic absorption bands at 1684 (C=Opyrimidinone), 1665 (C=Opyrone), and 1615 cm-1 (C=N). Its H NMR
spectrum showed characteristic singlets at 5.51 (CH2) and 8.99 ppm (H-5). The structure of compound 9 was
further deduced from its mass spectrum, which revealed the molecular ion peak at m/z 383.
Scheme 4
O
O
7
5
Me
Ac2O, , 4 h
N
Ph
7
83%
9
Me
N
O
N
10
9
On the other hand, reaction of nitrile 1 with N'-[(4-chlorophenyl)methylidene]-2-cyanoacetohydrazide
(10) in boiling ethanol containing DBU yielded the unexpected 2-amino-N'-[(4-chlorophenyl)methylidene]-
5-cyano-8-methyl-6-oxo-6H-1-benzoxocine-3-carbohydrazide (11) [31]. The expected product of the reaction,
2-amino-N'-[(4-chlorophenyl)methylidene]-7-methyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbohydrazide (12),
was excluded based on the spectral data (Scheme 5). Formation of benzoxocine derivative 11 may occur via the
formation of intermediate C followed by intramolecular nucleophilic addition of the hydroxyl group to the
Scheme 5
O
O
O
O
O
N
Ar
Me
N
Ar
Me
N
N
H
H
CN CN
N
NH2
OH
12
D
O
O
CN
N
Me
O
abs. EtOH
N
Ar
1
+
N
N
Ar
DBU, 
45 min
H
N
OH
CN
H
10
C
O
CN
7
Me
4
H
N
Ar
53%
9
N
O
10
O
Ar = 4-ClC6H4
NH2
11
nitrile function, leading to the final product 11, as shown in Scheme 5 [31]. Another reaction pathway leading
to compound 12, via intermediate D, was ruled out. The IR spectrum of compound 11 showed characteristic
absorption bands at 3444, 3275, 3222 (NH2, NH), 2221 (C≡N), 1670 (C=Oamide), 1651 (C=Ooxocine), and
1
1617 cm-1 (C=N). Its H NMR spectrum showed characteristic singlets at 8.44 and 8.88 ppm attributed to
CH=N and H-4 protons, respectively. The mass spectrum of compound 11 showed the molecular ion peak at
m/z 406, which agrees well with the suggested structure.
Alternative routes were used to synthesize chromeno[2,3-b]pyridine derivative 12. The reaction of ester
6 with hydrazine hydrate in boiling DMF afforded the corresponding carbohydrazide derivative 13, which upon
condensation with p-chlorobenzaldehyde in acetic acid produced the target compound 12 (Scheme 6).
Moreover, compound 12 was prepared directly from the Friedländer condensation reaction of 2-amino-
1627

6-methylchromone-3-carbaldehyde (14) with cyanoacetohydrazide derivative 10 (Scheme 6). The IR spectrum
of compound 12 showed characteristic absorption bands at 3400, 3290 (NH2, NH), 1670 (C=Oamide), 1653
1
(C=Opyrone), and 1607 cm-1 (C=N). Its H NMR spectrum showed characteristic singlets at 8.93 and 8.97 ppm
attributed to CH=N and H-4 protons, respectively.
Scheme 6
O
O
O
N2H4·H2O
NH2
Me
ArCHO
DMF, , 2 h
N
H
6
AcOH
71%
63%
N
NH2
, 2 h
13
O
O
6
9
4
N
Ar
Me
N
H
Ar = 4-ClC6H4
8
O
N
NH2
12
O
O
O
CHO
Me
84%
abs. EtOH
N
Ar
+
N
H
DBU, 
30 min
NH2
CN
10
14
Next, nitrile 1 was allowed to react with some unsymmetrical methylene-active ketones bearing the
–CH2–CO– group. Therefore, reaction of nitrile 1 with acetoacetanilide in boiling ethanol containing DBU
afforded 2,7-dimethyl-5-oxo-N-phenyl-5H-chromeno[2,3-b]pyridine-3-carboxamide (15) (Scheme 7). Another
expected product 16 was ruled out on the basis of the spectral data. Compound 15 was authentically obtained
from condensation of nitrile 1 with ethyl acetoacetate, producing ester 17 which upon condensation with aniline
yielded the target compound 15 (Scheme 7). The IR spectrum of compound 15 showed characteristic absorption
1
bands at 3269 (NH), 1662 (C=Oamide), 1651 (C=Opyrone), and 1618 cm-1 (C=N). Its H NMR spectrum showed
characteristic singlets at 2.73 (2-CH3) and 8.68 ppm (H-4), in addition to the D2O-exchangeable signal at 10.65
ppm assigned to NH proton. 13C NMR spectrum of compound 15 showed signals assigned to two methyl
carbons at 20.1 (7-CH3) and 23.4 ppm (2-CH3), in addition to characteristic signals at 164.8 (C=Oamide) and
176.2 ppm (C=Opyrone). The IR spectrum of compound 17 showed characteristic absorption bands at 1723
Scheme 7
O
O
O
O
O
Ph
Me
Me
N
Me
Ph
H
1
abs. EtOH, DBU
N
N
H
, 30 min
16
O
O
abs. EtOH, DBU
66%
, 30 min
Me
OEt
69%
O
O
O
O
O
4
4
6
9
PhNH2
abs. EtOH
6
9
Ph
Me
Me
OEt
N
H
, 4 h
8
8
O
N
Me
N
Me
84%
15
17
1628

1
(C=Oester), 1668 (C=Opyrone), and 1610 cm-1 (C=N). Its H NMR spectrum showed the characteristic singlet at
8.83 ppm attributed to the H-4 proton.
Similarly, treatment of nitrile 1 with ethyl benzoylacetate in boiling ethanol containing DBU gave ethyl
7-methyl-5-oxo-2-phenyl-5H-chromeno[2,3-b]pyridine-3-carboxylate (18) (Scheme 8). The IR spectrum of
compound 18 showed characteristic absorption bands at 1733 (C=Oester), 1682 (C=Opyrone), and 1618 cm-1
(C=N). Its 1H NMR spectrum showed the characteristic singlet at 8.86 ppm attributed to the H-4 proton.
Scheme 8
O
O
O
O
O
4
6
ArNH2
abs. EtOH
Me
Ph
OEt
OEt
1
abs. EtOH, DBU
, 2 h
8
N
Ph
72%
, 30 min
9
18
75%
O
O
O
O
4
6
9
Ar
Ar
Me
Ph
N
N
H
H
abs. EtOH, DBU
8
O
N
Ph
, 30 min
19
61%
Ar = 4-MeC6H4
Condensation of ester 18 with p-toluidine in boiling ethanol produced 7-methyl-N-(4-methylphenyl)-
5-oxo-2-phenyl-5H-chromeno[2,3-b]pyridine-3-carboxamide (19). The latter compound was also obtained
authentically by the reaction of nitrile 1 with N-(4-methylphenyl)-3-oxo-3-phenylpropanamide (Scheme 8). The IR
spectrum of compound 19 showed characteristic absorption bands at 1663 (C=Oamide), 1650 (C=Opyrone), and
1
1621 cm-1 (C=N). Its H NMR spectrum showed the characteristic singlet at 8.67 ppm attributed to the H-4
proton, in addition to the D2O-exchangeable signal assigned to NH proton at 10.58 ppm. The mass spectrum of
compound 19 showed the molecular ion peak at m/z 420 and the base peak at m/z 314 assigned to [M-
NHC6H4CH3]+ ion.
In conclusion, a new series of chromeno[2,3-b]pyridines was conveniently prepared by reaction of
6-methylchromone-3-carbonitrile and some methylene-active compounds under basic conditions via ring
rearrangement during the course of the reaction. A variety of chromeno[3',2':5,6]pyrido[2,3-d]pyrimidines was
also synthesized.
EXPERIMENTAL
1
IR spectra were recorded on a FTIR Nicolet IS10 spectrophotometer in KBr disks. H and 13C NMR
spectra were recorded on a Mercury-300BB spectrometer (300 and 75 MHz, respectively) in DMSO-d6, internal
standard – TMS. Mass spectra were obtained using a GC-2010 Shimadzu gas chromatography instrument mass
spectrometer (EI, 70 eV). Elemental microanalyses were performed on a Perkin–Elmer CHN-2400 analyzer.
Melting points were determined on a digital Stuart SMP3 apparatus.
2-Amino-7-methyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile (2). A mixture of nitrile 1
(0.55 g, 3.0 mmol) and malononitrile (0.20 g, 3.0 mmol) in abs. EtOH (20 ml) containing DBU (0.1 ml,
0.7 mmol) was refluxed for 10 min. The yellow crystals obtained during heating were filtered off and
recrystallized from DMF–H2O. Yield 0.49 g (65%), yellow crystals, mp >300°C. IR spectrum, ν, cm-1: 3371,
3314, 3158 (NH2), 3019 (CHarom), 2919 (CHaliph), 2224 (C≡N), 1654 (C=Opyrone), 1605 (C=N), 1586 (C=C).
1H NMR spectrum, δ, ppm (J, Hz): 2.43 (3H, s, CH3); 7.51 (1H, d, J = 8.4, H-9); 7.64 (1H, d, J = 8.4, H-8); 7.88
1629

(1H, s, H-6); 8.10 (2H, br. s, NH2 exchangeable with D2O); 8.63 (1H, s, H-4). Found, %: C 66.85; H 3.56; N 16.54.
C14H9N3O2. Calculated, %: C 66.93; H 3.61; N 16.72.
4-Amino-8-methyl-6H-chromeno[3',2':5,6]pyrido[2,3-d]pyrimidin-6-one (3). A mixture of compound 2
(0.50 g, 2 mmol) and formamide (10 ml) was refluxed for 4 h. The solid obtained after cooling was filtered off,
washed with cooled EtOH, and recrystallized from DMF. Yield 0.51 g (61%), yellow crystals, mp >300°C.
IR spectrum, ν, cm-1: 3326, 3222 (NH2), 3045 (CHarom), 2926, 2864 (CHaliph), 1652 (C=Opyrone), 1604 (C=N), 1583
1
(C=C). H NMR spectrum, δ, ppm (J, Hz): 2.39 (3H, s, CH3); 6.69 (2H, br. s, NH2 exchangeable with D2O); 7.32
(1H, d, J = 8.7, H-10); 7.48 (1H, d, J = 8.7, H-9); 7.96 (1H, s, H-7); 8.59 (1H, s, H-5); 9.69 (1H, s, H-2). Mass
spectrum, m/z (Irel, %): 278 (100), 262 (9), 250 (5), 235 (15), 207 (3), 179 (5), 154 (3), 135 (9), 106 (6), 91 (13), 77
(17), 64 (29). Found, %: C 64.45; H 3.39; N 19.82. C15H10N4O2. Calculated, %: C 64.74; H 3.62; N 20.13.
8-Methyl-6H-chromeno[3',2':5,6]pyrido[2,3-d]pyrimidine-4,6(3H)-dione (4). A mixture of compound 2
(0.50 g, 2 mmol) and HCOOH (10 ml) was refluxed for 4 h. The solid obtained after cooling was filtered off,
washed with cooled EtOH, and recrystallized from DMF. Yield 0.44 g (52%), yellow crystals, mp >300°C.
1
IR spectrum, ν, cm-1: 3423 (NH), 1685 (C=Opyrimidinone), 1656 (C=Opyrone), 1628 (C=N), 1602 (C=C). H NMR
spectrum, δ, ppm (J, Hz): 2.42 (3H, s, CH3); 7.47 (1H, d, J = 8.4, H-10); 7.87 (1H, d, J = 8.1, H-9); 8.12 (1H, s,
H-7); 8.59 (1H, s, H-5); 8.79 (1H, s, H-2); 12.80 (1H, br. s, NH exchangeable with D2O). Mass spectrum, m/z
(Irel, %): 279 (11), 269 (100), 251 (90), 224 (59), 195 (16), 135 (27), 105 (19), 89 (22), 80 (35), 77 (45), 64
(43). Found, %: C 64.28; H 3.08; N 14.75. C15H9N3O3. Calculated, %: C 64.52; H 3.25; N 15.05.
2,8-Dimethyl-6H-chromeno[3',2':5,6]pyrido[2,3-d]pyrimidine-4,6(3H)-dione (5). A mixture of
compound 2 (0.50 g, 3 mmol) and Ac2O (10 ml) was refluxed for 4 h. After cooling, the reaction mixture was
poured onto crushed ice. The solid formed was filtered off, washed with H2O, and recrystallized from
DMF–EtOH. Yield 0.49 g (56%), yellow crystals, mp >300°C. IR spectrum, ν, cm-1: 3446 (NH), 3052 (CHarom),
1
2921, 2843 (CHaliph), 1705 (C=Opyrimidinone), 1669 (C=Opyrone), 1617 (C=N), 1559 (C=C). H NMR spectrum,
δ, ppm (J, Hz): 1.90 (3H, s, 2-CH3); 2.45 (3H, s, 8-CH3); 7.61 (1H, d, J = 6.9, H-10); 7.69-7.74 (1H, m, H-9);
7.93 (1H, s, H-7); 8.76 (1H, s, H-5); 11.30 (1H, br. s, NHexchangeable with D2O). Mass spectrum m/z, (Irel, %):
293 (100), 279 (61), 251 (59), 224 (44), 209 (9), 135 (44), 134 (36), 105 (33), 91 (18), 77 (54), 63 (33). Found,
%: C 65.30; H 3.55; N 14.15. C16H11N3O3. Calculated, %: C 65.53; H 3.78; N 14.33.
Ethyl 2-Amino-7-methyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylate (6). A mixture of nitrile
1 (0.55 g, 3.0 mmol) and ethyl cyanoacetate (0.40 ml, 3.0 mmol) in abs. EtOH (20 ml) containing DBU (0.1 ml,
0.7 mmol) was refluxed for 30 min. The white crystals obtained during heating were filtered off and
recrystallized from DMF–EtOH. Yield 0.54 g (61%), white crystals, mp 276-277°C. IR spectrum, ν, cm-1: 3407,
3276, 3165 (NH2), 3049 (CHarom), 2969, 2935 (CHaliph), 1698 (C=Oester), 1670 (C=Opyrone), 1626 (C=N), 1585 (C=C).
1H NMR spectrum, δ, ppm (J, Hz): 1.36 (3H, t, J = 7.2, OCH2CH3); 2.42 (3H, s, 7-CH3); 4.35 (2H, q, J = 7.2,
OCH2CH3); 7.49 (1H, d, J = 8.7, H-9); 7.62 (1H, d, J = 8.4, H-8); 7.88 (1H, s, H-6); 8.07 (1H, br. s) and 8.29 (1H,
br. s, NH2 exchangeable with D2O); 8.79 (1H, s, H-4). Found, %: C 64.40; H 4.66; N 9.11. C16H14N2O4. Calculated,
%: C 64.42; H 4.73; N 9.39.
2-Amino-N-benzyl-7-methyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxamide (7). A. A mixture of
nitrile 1 (0.55 g, 3.0 mmol) and N-benzyl-2-cyanoacetamide (0.52 g, 3.0 mmol) in abs. EtOH (20 ml)
containing DBU (0.1 ml, 0.7 mmol) was refluxed for 30 min. The white crystals obtained during heating were
filtered off and recrystallized from DMF–EtOH. Yield 0.63 g (57%).
B. A mixture of ester 6 (0.60 g, 2 mmol) and benzylamine (0.22 g, 2 mmol) in abs. EtOH (20 ml) was
refluxed for 2 h. The white crystals obtained during heating were filtered off and recrystallized from DMF–EtOH.
Yield 0.52 g (70%), white crystals, mp 284-285°C. IR spectrum, ν, cm-1: 3434, 3281, 3154 (NH2, NH), 3061
1
(CHarom), 2923, 2885 (CHaliph), 1669 (C=Opyrone and C=Oamide), 1624 (C=N), 1585 (C=C). H NMR spectrum, δ,
ppm (J, Hz): 2.43 (3H, s, CH3); 4.47 (2H, d, J = 5.7, CH2 exchanged to singlet in D2O); 7.23-7.25 (1H, m, H-4
Ph); 7.34-7.36 (4H, m, H Ph); 7.49 (1H, d, J = 8.4, H-9); 7.63 (1H, d, J = 8.7, H-8); 7.91 (1H, s, H-6); 8.10 (2H,
br. s, NH2 exchangeable with D2O); 8.84 (1H, s, H-4); 9.44 (1H, t, J = 5.4, NH exchangeable with D2O).
13C NMR spectrum, δ, ppm: 20.2 (CH3); 42.5 (CH2); 105.6 (C-3); 109.3 (C-4a); 120.9 (C-5a); 125.1; 125.2;
1630

127.2; 127.4; 128.4; 131.2; 134.1; 137.3; 139.7; 152.7; 161.2; 161.4; 166.1 (CONH); 174.8 (C-5). Found, %:
C 70.01; H 4.54; N 11.52. C21H17N3O3. Calculated, %: C 70.18; H 4.77; N 11.69.
2-Amino-7-methyl-5-oxo-N-phenyl-5H-chromeno[2,3-b]pyridine-3-carboxamide (8). A. A mixture of
nitrile 1 (0.55 g, 3.0 mmol) and 2-cyano-N-phenylacetamide (0.49 g, 3.0 mmol) in abs. EtOH (20 ml)
containing DBU (0.1 ml, 0.7 mmol) was refluxed for 30 min. The white crystals obtained during heating were
filtered off and recrystallized from DMF. Yield 0.67 g (65%).
B. A mixture of ester 6 (0.60 g, 2 mmol) and aniline (0.19 g, 2 mmol) in abs. EtOH (20 ml) was
refluxed for 2 h. The white crystals obtained during heating were filtered off and recrystallized from DMF. Yield
0.62 g (60%), white crystals, mp >300°C. IR spectrum, ν, cm-1: 3373, 3302, 3150 (NH2, NH), 1666 (C=Oamide), 1632
(C=Opyrone), 1616 (C=N), 1599 (C=C). 1H NMR spectrum, δ, ppm (J, Hz): 2.44 (3H, s, CH3); 7.13 (1H, t, J = 7.2,
H Ph); 7.34-7.39 (2H, m, H Ph); 7.51 (1H, d, J = 8.1, H-9); 7.63-7.67 (2H, m, H Ph); 7.73 (1H, d, J = 8.4, H-8); 7.94
(1H, s, H-6); 8.15 (2H, br. s, NH2 exchangeable with D2O); 8.90 (1H, s, H-4); 10.55 (1H, br. s, NH exchangeable
with D2O). Mass spectrum, m/z (Irel, %): 345 (30), 253 (100), 225 (8), 198 (21), 134 (12), 106 (4), 93 (15), 77 (10),
65 (10). Found, %: C 69.28; H 4.15; N 12.00. C20H15N3O3. Calculated, %: C 69.56; H 4.38; N 12.17.
3-Benzyl-2,8-dimethyl-4H,6H-chromeno[3',2':5,6]pyrido[2,3-d]pyrimidine-4,6-dione
(9).
A
mixture of compound 7 (0.72 g, 2 mmol) and Ac2O (15 ml) was refluxed for 4 h. The yellow crystals obtained
during heating were filtered off and recrystallized from AcOH. Yield 0.64 g (83%), yellow crystals,
mp >300°C. IR spectrum, ν, cm-1: 2911, 2870 (CHaliph), 1684 (C=Opyrimidinone), 1665 (C=Opyrone), 1615 (C=N),
1580 (C=C). 1H NMR spectrum, δ, ppm: 1.90 (3H, s, 2-CH3); 2.42 (3H, s, 8-CH3); 5.51 (2H, s, CH2); 7.29-7.71
(7H, m, H-9,10, H Ph); 7.93 (1H, s, H-7); 8.99 (1H, s, H-5). Mass spectrum, m/z (Irel, %): 383 (30), 368 (10),
294 (38), 279 (61), 251 (7), 223 (11), 210 (6), 195 (10), 134 (7), 105 (23), 91 (77), 80 (57), 64 (100). Found, %:
C 71.78; H 4.16; N 10.75. C23H17N3O3. Calculated, %: C 72.05; H 4.47; N 10.96.
2-Amino-N'-[(4-chlorophenyl)methylidene]-5-cyano-8-methyl-6-oxo-6H-1-benzoxocine-3-carbo-
hydrazide (11). A mixture of nitrile 1 (0.55 g, 3.0 mmol) and N'-[(4-chlorophenyl)methylidene]-
2-cyanoacetohydrazide (10) (0.65 g, 3.0 mmol) in abs. EtOH (20 ml) containing DBU (0.1 ml, 0.7 mmol) was
refluxed for 45 min. The yellow crystals obtained during heating were filtered off and recrystallized from
DMF–EtOH. Yield 0.65 g (53%), yellow crystals, mp >300°C. IR spectrum, ν, cm-1: 3444, 3275, 3222 (NH2,
NH), 3065 (CHarom), 2947, 2880 (CHaliph), 2221 (C≡N), 1670 (C=Oamide), 1651 (C=Ooxocine), 1617 (C=N), 1583
1
(C=C). H NMR spectrum, δ, ppm (J, Hz): 2.44 (3H, s, CH3); 7.09 (2H, br. s, NH2 exchangeable with D2O);
7.29–7.55 (4H, m, H Ar); 7.64 (1H, H-10)*; 7.76 (1H, d, J = 6.3, H-9); 7.93 (1H, s, H-7); 8.44 (1H, s, CH=N);
8.88 (1H, s, H-4); 10.07 (1H, br. s, NH exchangeable with D2O). Mass spectrum, m/z (Irel, %): 408 [M (37Cl)]+ (3),
406 [M (35Cl)]+ (10), 269 (19), 253 (100), 225 (9), 198 (25), 170 (4), 135 (18), 107 (7), 89 (28), 77 (17), 64 (18).
Found, %: C 61.77; H 3.52; N 13.45. C21H15ClN4O3. Calculated, %: C 62.00; H 3.72; N 13.77.
2-Amino-N'-[(4-chlorophenyl)methylidene]-7-methyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carb-
ohydrazide (12). A. A mixture of 2-amino-6-methylchromone-3-carbaldehyde (14) (0.41 g, 2.0 mmol) and
N'-[(4-chlorophenyl)methylidene]-2-cyanoacetohydrazide (0.65 g, 2.0 mmol) in abs. EtOH (20 ml) containing
DBU (0.1 ml, 0.7 mmol) was refluxed for 30 min. The solid obtained during heating was filtered off and
recrystallized from DMF–H2O. Yield 0.68 g (84%).
B. A mixture of compound 13 (0.57 g, 2 mmol) and 4-chlorobenzaldehyde (0.28 g, 2 mmol) in acetic
acid was refluxed for 2 h. The solid obtained during heating was filtered off and recrystallized from DMF–H2O.
Yield 0.51 g (63%), yellow crystals, mp >300°C. IR spectrum, ν, cm-1: 3400, 3290 (NH2, NH), 2920, 2875
(CHaliph), 1670 (C=Oamide), 1653 (C=Opyrone), 1607 (C=N), 1577 (C=C). 1H NMR spectrum, δ, ppm (J, Hz): 2.45
(3H, s, CH3); 7.36 (1H, d, J = 7.8, H-9); 7.52 (2H, d, J = 8.1, H Ar); 7.65 (1H, H-8)*; 7.84 (2H, H Ar)*; 7.95
(1H, s, H-6); 8.93 (1H, s, CH=N); 8.97 (1H, s, H-4); 9.74 (2H, br. s, NH2 exchangeable with D2O); 12.20 (1H,
br. s, NH exchangeable with D2O). Found, %: C 61.69; H 3.54; N 13.58. C21H15ClN4O3. Calculated, %:
C 62.00; H 3.72; N 13.77.
______
* Unresolved doublet.
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2-Amino-7-methyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbohydrazide (13). A mixture of ester 6
(0.60 g, 2 mmol) and N2H4·H2O (0.1 ml, 2 mmol) in DMF (15 ml) was refluxed for 2 h. The white crystals
obtained after cooling were filtered off and recrystallized from DMF–EtOH. Yield 0.42 g (71%), white crystals,
mp >300°C. IR spectrum, ν, cm-1: 3371, 3335, 3252, 3176 (2NH2, NH), 2920, 2865 (CHaliph), 1669
(C=Ocarbohydrazide), 1653 (C=Opyrone), 1614 (C=N), 1583 (C=C). 1H NMR spectrum, δ, ppm (J, Hz): 2.44 (3H, s, CH3);
4.54 (2H, br. s, NH2 exchangeable with D2O); 7.50 (1H, d, J = 8.7, H-9); 7.63 (1H, d, J = 8.1, H-8); 7.90 (1H, s,
H-6); 8.17 (2H, br. s, NH2 exchangeable with D2O); 8.66 (1H, d, H-4); 10.09 (1H, br. s, NH exchangeable with
D2O). Mass spectrum, m/z (Irel, %): 284 (28), 253 (100), 225 (11), 198 (27), 134 (14), 106 (4), 91 (5), 77 (10), 64 (5).
Found, %: C 58.86; H 4.13; N 19.65. C14H12N4O3. Calculated, %: C 59.15; H 4.25; N 19.71.
2,7-Dimethyl-5-oxo-N-phenyl-5H-chromeno[2,3-b]pyridine-3-carboxamide (15). A. A mixture of
nitrile 1 (0.55 g, 3.0 mmol) and acetoacetanilide (0.50 g, 3.0 mmol) in abs. EtOH (20 ml) containing DBU
(0.1 ml, 0.7 mmol) was refluxed for 30 min. The solid obtained during heating was filtered off and
recrystallized from AcOH. Yield 0.68 g (66%).
B. A mixture of ester 17 (0.59 g, 2 mmol) and aniline (0.20 g, 2 mmol) in abs. EtOH was refluxed for
4 h. The solid obtained during heating was filtered off and recrystallized from AcOH. Yield 0.58 g (84%),
pale-yellow crystals, mp 301-302°C. IR spectrum, ν, cm-1: 3269 (NH), 3058 (CHarom), 2920, 2880 (CHaliph), 1662
(C=Oamide), 1651 (C=Opyrone), 1618 (C=N), 1598 (C=C). 1H NMR spectrum, δ, ppm (J, Hz): 2.46 (3H, s, 7-CH3);
2.73 (3H, s, 2-CH3); 7.12-7.17 (2H, m, H Ph); 7.36-7.41 (3H, m, H Ph); 7.67 (1H, d, J = 8.7, H-9); 7.75 (1H, d,
J = 7.2, H-8); 7.99 (1H, s, H-6); 8.68 (1H, s, H-4); 10.65 (1H, br. s, NH exchangeable with D2O). 13C NMR
spectrum, δ, ppm: 20.1 (7-CH3); 23.4 (2-CH3); 112.9 (C-4a); 118.3 (C-5a); 119.9; 120.6; 123.9; 125.1; 128.7;
129.6; 134.6; 135.8; 137.1; 138.7; 153.0; 158.9; 162.7; 164.8 (CONH); 176.2 (C-5). Found, %: C 73.05;
H 4.45; N 8.02. C21H16N2O3. Calculated, %: C 73.24; H 4.68; N 8.13.
Ethyl 2,7-dimethyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylate (17). A mixture of nitrile 1
(0.55 g, 3.0 mmol) and ethyl acetoacetate (0.39 g, 3.0 mmol) in abs. EtOH (20 ml) containing DBU (0.1 ml,
0.7 mmol) was refluxed for 30 min. The white crystals obtained after cooling were filtered off and recrystallized
from EtOH. Yield 0.61 g (69%), pale-yellow crystals, mp 177-178°C. IR spectrum, ν, cm-1: 3050 (CHarom),
1
2990, 2899 (CHaliph), 1723 (C=Oester), 1668 (C=Opyrone), 1610 (C=N), 1590 (C=C). H NMR spectrum, δ, ppm
(J, Hz): 1.38 (3H, t, J = 6.9, OCH2CH3); 2.44 (3H, s, 7-CH3); 2.73 (3H, s, 2-CH3); 4.37 (2H, q, J = 6.9,
OCH2CH3); 7.57 (1H, d, J = 8.7, H-9); 7.71 (1H, d, J = 8.4, H-8); 7.90 (1H, s, H-6); 8.83 (1H, s, H-4). Found,
%: C 68.62; H 5.01; N 4.66. C17H15NO4. Calculated, %: C 68.68; H 5.09; N 4.71.
Ethyl 7-methyl-5-oxo-2-phenyl-5H-chromeno[2,3-b]pyridine-3-carboxylate (18). A mixture of
nitrile 1 (0.55 g, 3.0 mmol) and ethyl benzoylacetate (0.58 g, 3.0 mmol) in abs. EtOH (20 ml) containing DBU
(0.1 ml, 0.7 mmol) was refluxed for 30 min. The solid obtained after cooling was filtered off and recrystallized
from EtOH. Yield 0.81 g (75%), pale-yellow crystals, mp 164-165°C. IR spectrum, ν, cm-1: 3056 (CHarom),
1
2977, 2910 (CHaliph), 1733 (C=Oester), 1682 (C=Opyrone), 1618 (C=N), 1602 (C=C). H NMR spectrum, δ, ppm
(J, Hz): 1.15 (3H, t, J = 7.5, OCH2CH3); 2.47 (3H, s, 7-CH3); 4.18 (2H, q, J = 7.2, OCH2CH3); 7.51-7.68 (5H,
m, H Ph); 7.76 (1H, d, J = 8.7, H-9); 7.94-7.97 (1H, m, H-8); 7.99 (1H, s, H-6); 8.86 (1H, s, H-4). Found, %:
C 73.26; H 4.50; N 3.64. C22H17NO4. Calculated, %: C 73.53; H 4.77; N 3.90.
7-Methyl-N-(4-methylphenyl)-5-oxo-2-phenyl-5H-chromeno[2,3-b]pyridine-3-carboxamide (19). A. A
mixture of ester 18 (0.40 g, 2 mmol) and p-toluidine (0.22 g, 2 mmol) in abs. EtOH (20 ml) was refluxed for
2 h. The white crystals obtained during heating were filtered off and recrystallized from DMF–MeOH. Yield
0.42 g (72%).
B. A mixture of nitrile 1 (0.55 g, 3.0 mmol) and N-(4-methylphenyl)-3-oxo-3-phenylpropanamide
(0.76 g, 3.0 mmol) in abs. EtOH (20 ml) containing DBU (0.1 ml, 0.7 mmol) was refluxed for 30 min. The pale-
yellow crystals obtained during heating were filtered off and recrystallized from DMF–MeOH. Yield 0.77 g
(61%), white crystals, mp 309-310°C. IR spectrum, ν, cm-1: 3265 (NH), 3057 (CHarom), 2919, 2880 (CHaliph),
1663 (C=Oamide), 1650 (C=Opyrone), 1621 (C=N), 1599 (C=C). 1H NMR spectrum, δ, ppm: 2.23 (3H, s, ArCH3);
2.44 (3H, s, 7-CH3); 7.09-7.13 (2H, m, H Ar); 7.33-7.36 (2H, m, H Ar); 7.46-7.75 (7H, m, H Ar); 7.97 (1H, s,
1632

H-6); 8.67 (1H, s, H-4); 10.58 (1H, s, NH exchangeable with D2O). Mass spectrum, m/z (Irel, %): 420 (19), 314
(100), 286 (12), 257 (2), 230 (6), 106 (5), 91 (6), 77 (13). Found, %: C 76.87; H 4.59; N 6.37. C27H20N2O3.
Calculated, %: C 77.13; H 4.79; N 6.66.
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