Synthesis of hydroxyquinoline derivatives, amino-hydroxychromene, aminocoumarin and their anti-bacterial activities

Article abstract of DOI:10.3987/com-04-10089

Some new diaminochromenes (3a-f, 7a-c, and 10), 7-amino-4-aryl-coumarins (8a,b), 7-hydroxy-4-aryl-1,2-dihydroquinolines (9a-c) and 2-amino-7-hydroxy-4- (4-chlorophenyl)-4H-chromenes (16a-d) were synthesized via Michael addition of different substituted am

Full text of DOI:10.3987/com-04-10089

HETEROCYCLES, Vol. 63, No. 8, 2004, pp. 1793 - 1812
Received, 29th March, 2004, Accepted, 24th June, 2004, Published online, 25th June, 2004
SYNTHESIS OF HYDROXYQUINOLINE DERIVATIVES, AMINO-
HYDROXYCHROMENE, AMINOCOUMARIN AND THEIR ANTI-
BACTERIAL ACTIVITIES
Alaa S. Abd-El-Aziz,*Ahmed M. El-Agrody, Ahmed H. Bedair, T.
Christopher Corkery, and Athar Ata
Department of Chemistry, The University of Winnipeg, Winnipeg, Manitoba,
R3B 2E9, Canada
E-mail: a.abdelaziz@uwinnipeg.ca
Abstract- Some new diaminochromenes (3a-f, 7a-c, and 10), 7-amino-4-
aryl-coumarins (8a,b), 7-hydroxy-4-aryl-1,2-dihydroquinolines (9a-c) and 2-
amino-7-hydroxy-4-(4-chlorophenyl)-4H-chromenes
(16a-d)
were
synthesized via Michael addition of different substituted aminonaphthol (1),
aminophenol (6), resorcinol derivatives (15a-d), chloronaphthol (17) and 4-
hydroxycoumarin (19) with α-cyanocinnamonitriles (2a-c) and ethyl α-
cyanocinnamate (2d-f). 2-Acetylamino-7-amino-4-(4-chlorophenyl)-4H-
chromene-2-carbonitrile (14) was obtained as a unique product via
hydrazinolysis of ethoxymethyleneamino derivative (13). The formation of
coumarins (8a,b) and quinolines (9a-c) were anomalous case. Structures of
the titled compounds cited in this article were elucidated by spectrometric
data (IR, 1H NMR, 13C NMR (APT) and EMS). All of the newly synthesized
compounds were evaluated for antimicrobial activities, where 16b and 16c
exhibited activity against staphylococcus aureus (ATCC 25923).
INTRODUCTION
Naturally occurring coumarins have exhibited several biomedical applications including platelet
aggregation, cytotoxic activity, enzyme inhibition, antiviral, antibacterial, antifungal activities, etc.1-10
Coumarin and chromene derivatives are widely found in plants belonging to the families, Belliferae,
Rutaceae, and Compositae. 1 New derivatives of coumarins have been isolated from plants with an ever-
increasing variety of uses.11-20
More recently, specific studies looking at the effects of coumarins as a cytochrome P-450 inhibitor, which
is a carcinogen metabolizing enzyme.21,22 The ability of some coumarins to inhibit acetylcholinesterase

and monoamine oxidase may decrease the β-amyliod depositions, which indicate that these compounds
may have some therapeutic values to treat the Alzheimer’s disease.23 Acting as selective dopamine
antagonists, chromen-2-ones have been synthesized to reduce the negative effects of schizophrenia.24
Coumarins have also been found to have beneficial effects on lymphedema and malaria.25-26 In addition,
there is evidence that coumarins prevent or slow tumor growth, by acting as antioxidants and inhibiting
superoxide and nitric oxide production.19,27-29 Based on the biological importance of several coumarins;
new coumarins, chromenes, and other benzo- and napthopyrans have been synthesized.30-33
Coumarins and their derivatives may also possess valuable optical properties, especially the 3-
heterarylcoumarins.34-36 By binding coumarins to biological effectors molecules, the path of the molecule
through a biological system may be traced.37 In addition, the removal of a coumarin unit through
photolysis has been used to selectively release compounds in living systems.38
In this paper, we report the synthesis of fused chromenes and coumarins which involves the addition of a
variety of phenols and naphthols to substituted α-cyanocinnamonitriles and ethyl α-cyanocinnamates.
RESULTS AND DISCUSSION
Our compounds (3a-f) (yield 72-84%) were produced through condensation of 5-amino-1-naphthol (1)
with substituted α-cyanocinnamonitriles (2a-c) and ethyl α-cyanocinnamates (2d-f) in ethanolic piperdine
(Scheme 1). The formation of 3a-f indicated that the naphtholate anion attacked at the carbon adjacent to
the aryl ring of 2 to yield the products.
Compounds (3a-f) were isolated as stable gray or red solids and their structures were confirmed with the
aid of spectroscopic data. In the IR spectra, the sharp absorptions at 3463-3167 cm-1 indicated the
presence of amino functionality. The absorptions at 2201-2186 cm-1 were assigned to ν (CN) vibration for
compounds (3a-c), while at 1667-1677 cm-1 were assigned to the ν (C=O) vibration of the chelated
1
carbonyl group for compounds (3d-f). In the H NMR spectra (Table 1), characteristic signals for H-1
appeared as singlets at δ 5.00-4.77 ppm. In the 13C NMR spectra (Table 2), we assigned the signals on the
basis of the observed chemical shifts using an attached proton test (APT) and by comparison with the
known and standard chemical shifts for 1H-chromenes.39,40
As opposed to the anticipated formation of the 8-amino-3-ethoxymethyleneamino-1-(4-methoxyphenyl)-
1H-benzo[h]chromene-2-carbonitrile (4), the reaction of 3c with neat triethyl orthoformate produced the
3-amino-8-ethoxymethyleneamino-1-(4-methoxyphenyl)-1H-benzo[h]chromene-2-carbonitrile (5), in
which the triethyl orthoformate attacked the amino group substituted at C-8 instead of the amino group
present at C-3.3,4,39-41 We believe that formation of 5 from 3c may be due to the steric hindrance between
1
two amino groups and nucleophilic power. Structure (5) was also supported by H NMR spectrum, in
13
which the hydrogens attached to C-8N disappeared, while the C NMR spectrum showed the resonance

of C-2 at δ 56.6 ppm rather than at δ 77.9 ppm for compound (4). Structure (5) was also further confirmed
via a reaction of 5 with hydrazine hydrate in ethanol or benzene with stirring at room temperature. An
addition product formed, which on elimination of ethyl formate hydrazone gave the enaminonitrile (3c)
(Scheme 2).4,43
OH
6
CN
H
NC
7
8
5
OH
Ar
4
O
O
NH
CN
C
C
H2N
4b
CN
H2N
NH2
4a
3
+
H2N
8a
9
CN
2
Ar
10a
CO2Et
1
2a-f
NH2
1
10
Ar
Ar
3a-f
a; Ar = Ph
b; Ar = C6H4Cl-p
c; Ar = C6H4OMe-p
d; Ar = Ph
e; Ar = C6H4Cl-p
f ; Ar = C6H4OMe-p
Scheme 1
Table-1: Selected 1H NMR Chemical Shifts (ppm) of 1H-Chromene Derivatives in DMSO-d6
H-1
NH2-3
H-5
H-7
NH2-8
H-9
H-10
3a
3b
3c
3d
4.83
4.88
4.77
4.98
7.08
7.11
7.00
7.75
7.44
7.42
7.42
7.21-
7.72
7.14-
7.73
7.06-
7.74
6.71
6.70
6.70
6.70
5.77
5.77
5.77
5.75
7.74
7.74
7.71
7.21-
7.72
7.14-
7.73
7.06-
7.74
6.93
6.90
6.87
7.11
3e
3f
5.00
4.91
7.78
7.69
6.72
6.68
5.76
5.74
7.10
6.76
Condensation of 3-aminophenol (6) with α-cyanocinnamonitriles (2a-c) in ethanolic piperdine resulted in
1:1 adducts (7a-c) (yield 77-90%) . Interaction of 6 with ethyl α-cyanocinnamates (2d,e) afforded the
coumarin derivatives (8a,b) (yield 37-42%) in the ratio of 1:1 together with the quinoline derivatives
(9a,b) (yield 38-41%) in the ratio of 1:1, while reaction of 6 with 2f gave the 46% of chromene derivative
(10) and 37% of quinoline derivative (9c) in the ratio of 1:1. Compounds (8a, b; 9a, b; 9c and 10) were
purified by using silica gel flash chromatography. The formation of 7a-c and 10 indicated that the

phenolate anion (C-6) attacked at the β-carbon of 2a-c,f to yield an acyclic Michael adduct which
underwent cyclization (Schemes 3, 4).
Table 2: Selected 13C NMR Shifts (ppm) of 1H-Chromene Derivatives
3 C-1
C-2
C-3 C-4a C-4b
C-8
C-8a C-10a
a
b
c
d
e
f
40.3
55.6 159.7 145.2
123.4 144.2 121.4 120.0
124.1 144.8 122.2 120.6
124.1 142.8 122.0 120.7
124.2 143.1 122.0 120.1
124.6 143.5 122.5 120.3
40.2
40.1
40.1
40.3
39.2
55.9 160.4 144.9
56.5 160.2 144.9
76.5 161.1 148.0
76.5 161.4 147.5
76.7 160.9 144.8 124.1 142.9 121.9 120.8
The formation of 8a,b indicated that the phenolate anion (C-6) attacked at β-carbon of 2d,e to yield an
acyclic Michael adduct which underwent cyclization followed by elimination of EtOH to gives 8a,b. The
formation of 9a-c indicated that phenolate anion (C-4) attacked at β-carbon of 2d-f to yield an acyclic
Michael adduct which underwent cyclization to give 9a-c, with elimination of EtOH and aromatization
(Scheme 4).
O
N
O
O
H2N
H2N ..
O
NH2
CN
N
H
N
CN
H
4
//
Ar
3c
CH(OEt)
+
3
Ar
O
NH2
CN
- H2N-N=CHOEt
O
N
5
Ar
3c
Scheme 2

Ar
O
Ar
O
Ar
CN
CN
NH
CN
CN
CN
ArCH=C
+
CN
H2N
NH2
H2N
OH
H2N
H2N
OH
6
2a-c
7a-c
a; Ar = Ph
b; Ar = C6H4Cl-p
c; Ar = C6H4OMe-p
Scheme 3
6
2f
+
6
2d,e
+
Ar
Ar
Ar
CN
CN
CO2Et
CO2Et
CO2Et
CN
H2N
OH
HO
NH2
H2N
OH
Ar
-EtOH
-EtOH
Ar
O
Ar
CN
CN
CO2Et
NH2
H2N
O HO
N
H
O
H2N
O
10
Ar = C6H4OMe-p
8a,b
9a-c
a; Ar = Ph
a; Ar = Ph
b; Ar = C6H4Cl-p
b; Ar = C6H4Cl-p
c; Ar = C6H4OMe-p
Scheme 4
Again, in contrast to the anticipated formation of the 7-amino-2-ethoxymethyleneamino-4-(4-
chlorophenyl)-4H-chromene-3-carbonitrile (11), the reaction of 7b with neat triethyl orthoformate
without acetic anhydride had the triethyl orthoformate attacked the amino group substituted at C-7 instead
of the amino group present at C-22 to afford (12) similarly to compound (3c).39-41 Compound (12) was
1
supported by H NMR spectrum, in which the C-3/NH2 disappeared, while the 13C NMR spectrum
showed C-3 at δ 55.6 ppm, instead of at δ 77.9 ppm for the expected compound. The reaction of 12 with
hydrazine hydrate in ethanol or benzene with stirring at room temperature produced an addition product,
from which elimination of ethyl formate hydrazone returned to the enaminonitrile (7b) instead of the
cycloaddition product, as in the case of 3c.42,43
The reaction of 7b with triethyl orthoformate in acetic anhydride afforded the 2-acetylamino-7-
ethoxymethyleneamino-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (13), hydrazinolysis of the later
afforded the 2-acetylamino-7-amino-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (14). This reaction

provided a selective acetylation of 7b, in which the C-3/NH2 can be acetylated and the proper amino
group substituted at C-7 remained free (Scheme 5).
Ar
CN
H2N
O
N
O
11
//
Ar
O
CH(OEt)3
Ac2O
7b +
CN
Ar
O
O
N
NH2
CN
12
NH2NH2·2H2O
Ar
NHCOMe
O
N
13
NH2NH2·2H2O
CN
O
Ar
O
H2N
..
CN
N
H
N
H
O
NH2
- H2N-N=CHOEt
7b
H2N
NHCOMe
14
Scheme 5
Ar
R1
R1
CN
CN
CN
ArCH=C
+
CN
HO
OH
HO
OH
Ar
2b
R
15a-d
R
Ar
R1
R1
CN
CN
NH
HO
O
NH2
HO
O
16a-d
R
R
a; R = H ; R1 = H
b; R = Me ; R1 = H
; Ar = C6H4Cl-p
; Ar = C6H4Cl-p
; Ar = C6H4Cl-p
c; R = H
; R1 = Et
d; R = H ; R1= n-hexyl ; Ar = C6H4Cl-p
Scheme 6
Compounds (16a-d) were synthesized through condensation of resorcinol (15a) or resorcinol derivatives
(15b-d) with α-cyanocinnamonitrile (2b) (Scheme 6). Condensation of 4-chloro-1-naphthol (17) and 4-
hydroxycoumarin (19) with substituted α-cyanocinnamonitriles (2g,h) in ethanolic piperdine gave 1:1
adducts (18a,b, 20a,b) (yield 74-85%) as shown in Scheme 7. The formation of 16a-d, 18a,b, 20a,b
indicated that the phenolate and naphtholate anion attacked at the β-carbon of 2 to yield an acyclic
Michael adduct which underwent intramolecular cyclization (Schemes 6, 7).

The reaction of 16a with triethyl orthoformate in acetic anhydride resulted in the 7-acetoxy-2-
ethoxymethyleneamino-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (21) with acetylation of the
hydroxy group at position 7, hydrazinolysis of the later in ethanol at room temperature under stirring
yielded the 3-amino-10-(4-chlorophenyl)-4-imino-3,10-dihydro-4H-9-oxa-1,3-diazaanthracen-7-ol (22)
with the deacetylation of the acetoxy group at position 7. Interaction of 16b with triethyl orthoformate in
acetic anhydride afforded the 7-acetoxy-2-amino-8-methyl-4-(4-chlorophenyl)-4H-chromene-3-
carbonitrile (23) as the only isolable product, while reaction of 16b with neat triethyl orthoformate
produced
carbonitrile (24). The reaction of 23 with hydrazine hydrate returned to 16b, while 24 with hydrazine
hydrate gave 3-amino-8-methyl-10-(4-chlorophenyl)-4-imino-3,10-dihydro-4H-9-oxa-1,3-diaza-
the
2-ethoxymethyleneamino-7-hydroxy-8-methyl-4-(4-chlorophenyl)-4H-chromene-3-
anthracen-7-ol (25). The reaction of 16c,d with triethyl orthoformate in acetic anhydride afforded the 7-
hydroxy-2-acetylamino-6-ethyl/n-hexyl-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (26a,b) as the
only isolable products (Scheme 8).
OH
OH
O
O
19
17
Cl
2g,h
2g,h
9
6
8
7
7
8
10
10a
5
1
O
4
O
4b
NH2
NH2
CN
10b
2
4a
3
6a
8a
9
3
2
O
6
4a
10a
CN
Cl
4
1
10
O
Ar
Ar
18a,b
20 a,b
a; Ar = C6H4OH-p
X = CN
b; Ar = C6H3OMe,OH-3,4 X = CN
Scheme 7
Here, we presented a facile method for the synthesis of chromene, coumarin and quinoline derivatives
containing a proper amino or hydroxy group, which might be the key intermediate for the preparation of
new dyes containing fused chromenes, coumarins and quinolines.
All of the newly synthesized compounds were tested for antibacterial activity against Streptococcus
pyogenes (ATCC 19615), Staphylococcus aureus (ATCC 25923), Enterococcus faecalis (ATCC 19433),
Escherichia coli (ATCC 25933), and Pseudomonas aeruginosa (ATCC 27853) at the concentration of 25

µg/mL, 50 µg/mL and 100 µg/mL by using disc agar diffusion method. We found that only compounds
(16b) and (16c) exhibited antibacterial activity against Staph. aureus at all of the above-mentioned
concentrations. The diameters of zones of inhibition of compounds (16b) and (16c) at the concentration
of 25 µg/ml were measured 15 mm and 12 mm, respectively.
Ar
CN
Ac2O
CH(OEt)3
16a +
AcO
NH
O
N
OEt
21
NH2NH2·2H2O
Ar
O
NH2
16b
N
HO
N
NH2NH2·2H2O
CN
Ar
O
22
Ac2O
CH(OEt)3
16b +
AcO
NH2
Ar
23
Me
NH
N
Ar
NH2
CN
N
NH2NH2·2H2O
HO
N
O
O
OEt
HO
24
25
Me
Me
Ar
R
CN
Ac2O
16c,d
CH(OEt)3
+
HO
O
26a,b
NHCOMe
a; R = Et
b; R = n-hexyl
Scheme 8
EXPERIMENTAL
Melting points were measured in open capillary tubes and are uncorrected. 1H and 13C NMR spectra were
recorded at 200 and 50 MHz respectively, on a Varian Gemini 200 spectrometer, in DMSO-d6, with
chemical shifts being calculated from the solvent signals. NH, NH2 and OH groups were verified by
adding D2O to the solvent and observing which peaks were no longer present. 13C NMR spectra were
obtained by using an attached proton test (APT). MS spectra were reported on Hewlett Packard 5989 B
Mass Spectrometer. IR spectra were recorded on Bomem MB-Series FT-IR spectrophotometer (KBr
pellet).
General Procedure for the synthesis of 3a-f; 7a-c; 8a,b; 9a-c; 10; 16a-d; 18a,b and 20a,b:
A solution of phenolic compounds (1, 6, 15a-d, 17) or 4-hydroxycoumarin (19) (10 mmol) in ethanol (75
ml) was treated with substituted α-cyanocinnamonitriles (2a-c,g,h) (10 mmol) or ethyl α-
cyanocinnamates (2d-f) (10 mmol) and piperdine (0.2 g, 2 mmol). The reaction mixture was heated with

stirring until complete precipitation (reaction time: approx. 15 min for 2a-c,g,h; 120 min for 2d-f). The
solid product, which formed, was collected by filtration and recrystallized from a suitable solvent to give
3a-f; 7a-c; 8a,b; 9a-c; 10; 16a-d; 18g,h and 20g,h.
3,8-Diamino-1-phenyl-1H-benzo[h]chromene-2-carbonitrile (3a):
o
1
Gray crystals from ethanol/benzene; mp 267-268 C; yield 83 %; H NMR (200 MHz) δ 7.74 (d,
aromatic, J = 8.6 Hz, 1H), 7.44 (d, aromatic, J = 7.8 Hz, 1H), 7.34-7.16 (m, aromatic, 6H), 7.08 (br s,
NH2-3, 2H), 6.93 (d, aromatic, J = 8.6 Hz, 1H), 6.71 (d, aromatic, J = 7.4, 1.2 Hz, 1H), 5.77 (br s, NH2-8,
2H), 4.83 (s, 1H, H-1); 13C NMR (50 MHz) δ 159.7 (C-3), 145.2 (C-4a), 144.2 (C-8), 123.4 (C-4b), 121.4
(C-8a), 120.0 (C- 10a), 55.6 (C-2), 40.3 (C-1), 116.8 (CN), 142.3, 128.0, 126.9, 126.8, 126.2, 122.7,
118.0, 107.8, 107.4 (aromatic); IR cm-1 (KBr) 3428, 3401, 3338, 3299, 3179 (2 NH2), 2201 (CN); MS
m/z (%): 313 (M+, 36), 276 (14), 236 (100), 208 (3), 181 (4), 149 (3), 118 (7), 97 (10), 57 (24); Anal.
Calcd for C20H15N3O: C, 76.66; H, 4.82; N, 13.41. Found: C, 76.78; H, 4.89; N, 13.57.
3,8-Diamino-1-(4-chlorophenyl)-1H-benzo[h]chromene-2-carbonitrile (3b):
o
1
Gray crystals from ethanol/benzene; mp 235-236 C; yield 75 %; H NMR (200 MHz) δ 7.74 (d,
aromatic, J = 7.4 Hz, 1H), 7.42 (d, aromatic, J = 7.8 Hz,1H), 7.36-7.23 (m, aromatic, 5H), 7.11 (br s,
NH2-3, 2H), 6.90 (d, aromatic, J = 9.0 Hz, 1H), 6.70 (d, aromatic, J = 5.6 Hz, 1H), 5.77 (br s, NH2 -8,
2H), 4.88 (s, 1H, H-1); 13C NMR (50 MHz) δ 160.4 (C-3), 144.9 (C-4a), 144.8 (C-8), 124.1 (C-4b), 122.2
(C-8a), 120.6 (C-10a), 55.9 (C-2), 40.2 (C-1), 117.0 (CN), 143.0, 131.5, 129.6, 128.7, 127.6, 123.3,
118.8, 108.6, 108.2 (aromatic); IR cm-1 (KBr) 3463, 3445, 3415, 3342, 3287 (2 NH2), 2187 (CN); MS
m/z (%):349 (M++ 2, 9), 347 (M+, 25), 276 (36), 236 (100), 208 (3), 181 (4), 101 (3), 77 (4); Anal. Calcd
for C20H14N3OCl: C, 69.07; H, 4.06; N, 12.08. Found: C, 69.01; H, 4.07; N, 12.01.
3,8-Diamino-1-(4-methoxyphenyl)-1H-benzo[h]chromene-2-carbonitrile (3c):
o
1
Grey crystals from ethanol/benzene; mp 209-210 C; yield 84 %; H NMR (200 MHz) δ 7.71 (d,
aromatic, J = 8.6 Hz, 1H), 7.42 (d, aromatic, J = 7.4 Hz,1H), 7.30-7.11 (m, aromatic, 5H), 7.00 (br s,
NH2-3, 2H), 6.87 (d, aromatic, J = 8.2 Hz, 1H), 6.70 (d, aromatic, J = 7.0 Hz, 1H), 5.77 (br s, NH2- 8,
2H), 4.77 (s, 1H, H-1), 3.70 (s, 3H, MeO); 13C NMR (50 MHz) δ 160.2 (C-3), 144.9 (C-4a), 142.8 (C-8),
124.1 (C-4b), 122.0 (C-8a), 120.7 (C-10a), 56.5 (C-2), 40.1 (C-1), 117.8 (CN),
158.1,138.0,128.7,127.5,123.5,118.6,114.0, 108.4, 108.1 (aromatic); IR cm-1 (KBr) 3421, 3378, 3330,
3202 (2 NH2), 2186 (CN); MS m/z (%): 343 (M+, 23), 276 (100), 236 (46), 220 (4), 184 (4), 164 (4), 130
(4), 101 (2), 77 (3) .
Ethyl 3,8-Diamino-1-phenyl-1H-benzo[h]chromene-2-carboxylate (3d):
Gray crystals from ethanol/benzene; mp 203-204 oC; yield 75 %; 1H NMR (200 MHz) δ 7.75 (br s, NH2 -
3, 2H), 7.72-7.21 (m, aromatic, 8H), 7.11 (d, aromatic, J = 8.6 Hz, 1H), 6.70 (d, aromatic, J = 7.0 Hz,
1H), 5.75 (br s, NH2 –8, 2H), 4.98 (s, 1H, H-1), 3.98 (q, CH2 , 2H, J = 7.0 Hz), 1.07 (t, 3H, J = 7.0 Hz);

13C NMR (50 MHz) δ 168.7 (CO), 161.1 (C-3), 148.0 (C-4a), 143.1 (C-8), 124.2 (C-4b), 122.0 (C-8a),
120.1 (C-10a), 76.5(C-2), 40.1(C-1), 144.9, 128.2, 127.3, 126.0, 123.8, 118.5, 108.2, 108.1 (aromatic),
58.6 (CH2), 14.3 (Me); IR cm-1 (KBr) 3433, 3397, 3354, 3281 (2 NH2), 1677 (CO); MS m/z (%): 360
(M+, 28), 283 (100), 237 (40), 209 (6), 181 (5), 143 (5), 118 (6), 105 (3), 77 (5); Anal. Calcd for
C22H20N2O3: C, 73.32; H, 5.59; N, 7.77. Found: C, 73.19; H, 5.51; N, 7.81.
Ethyl 3,8-Diamino-1-(4-chlorophenyl)-1H-benzo[h]chromene-2-carboxylate (3e):
o
1
Red crystals from ethanol; mp 185-186 C; yield 72 %; H NMR (200 MHz) δ 7.78 (br s, NH2 -3, 2H),
7.73-7.14 (m, aromatic, 7H), 7.10 (d, aromatic, J = 8.6 Hz, 1H), 6.72 (d, aromatic, J = 8.0 Hz, 1H), 5.76
13
(br s, NH2 –8, 2H), 5.00 (s, 1H, H-1), 4.00 (q, CH2, J = 7.0 Hz, 2H), 1.11 (t, J = 7.0 Hz, 3H); C NMR
(50 MHz) δ 168.7 (CO), 161.4 (C-3), 147.5 (C-4a), 143.5 (C-8), 124.6 (C-4b), 122.5 (C-8a), 120.3 (C-
10a), 76.5(C-2), 40.3(C-1), 145.3, 130.9, 129.6, 128.5, 127.8, 124.1, 119.1, 108.8, 108.6 (aromatic), 56.1
(CH2), 14.7 (Me); IR cm-1 (KBr) 3463, 3420, 3397, 3323, 3251 (2 NH2), 1668 (CO); MS m/z (%):396
(M++ 2, 9), 394 (M+, 27), 283 (100), 237 (36), 209 (6), 181 (5), 154 (4), 118 (5), 101 (3), 77 (3); Anal.
Calcd for C22H19N2O3Cl: C, 66.92; H, 4.85; N, 7.09. Found: C, 67.03; H, 4.91; N, 7.14.
Ethyl 3,8-Diamino-1-(4-methoxyphenyl)-1H-benzo[h]chromene-2-carboxylate (3f):
o
1
Red crystals from ethanol; mp 192-193 C; yield 75 %; H NMR (200 MHz) δ 7.69 (br s, NH2 -3, 2H),
7.74-7.06 (m, aromatic, 7H), 6.76 (d, aromatic, J = 8.6 Hz, 1H), 6.68 (d, aromatic, J = 6.7 Hz, 1H), 5.74
(br s, NH2 –8, 2H ), 4.91 (s, 1H, H-1), 3.98 (q, CH2, J = 7.0 Hz, 2H), 3.64 (s, MeO, 3H,), 1.09 (t, Me, 3H,
13
J = 7.0 Hz); C NMR (50 MHz) δ 168.4 (CO), 160.9 (C-3), 144.8 (C-4a), 142.9 (C-8), 124.1 (C-4b),
121.9 (C-8a), 120.8 (C- 10a), 76.7(C-2), 39.2(C-1), 157.5, 140.2, 128.2, 127.3, 123.9, 118.4, 113.5,
108.8, 108.1 (aromatic), 58.6 (CH2), 54.9 (MeO), 14.32 (Me); IR cm-1 (KBr) 3463, 3366, 3342, 3257 (2
NH2), 1667 (CO); MS m/z (%): 390 (M+, 32), 361 (10), 317 (18), 283 (100), 237 (37), 209 (6), 181 (5),
172 (7), 123 (3), 109 (2), 77 (3); Anal. Calcd for C23H22N2O4: C, 70.75; H, 5.68; N, 7.17. Found: C,
70.75; H, 5.70; N, 7.15.
2,7-Diamino-4-phenyl-4H-chromene-3-carbonitrile (7a):
o
1
Pale yellow crystals from ethanol; mp 236-237 C; yield 81%; H NMR (200 MHz) δ 7.33-7.14 (m,
aromatic, 5H), 6.80 (br s, NH2-2, 2H), 6.64 (d, aromatic, J = 8.2 Hz, 1H), 6.29 (dd, aromatic, J = 8.2, 2.4
Hz, 1H), 6.24 (d, aromatic, J = 1.8 Hz,1H), 5.24 (br s, NH2-7, 2H), 4.53 (s, 1H, H-4); 13C NMR (50 MHz)
δ 160.4 (C-2), 148.9 (C-8a), 148.8 (C-7), 129.4 (C-5), 120.2 (C-4a), 111.2 (C-6), 100.0 (C-8), 56.5 (C-3),
40.1 (C-4), 110.2 (CN), 146.8, 128.5, 127.4, 126.5 (aromatic); IR cm-1 (KBr) 3429, 3353, 3305, 3163 (2
NH2), 2198 (CN); MS m/z (%): 263 (M+, 13), 226 (42), 186 (100), 170 (3), 104 (3) 106 (3), 58 (7); Anal.
Calcd for C16H13N3O: C, 72.99; H, 4.98; N, 15.96. Found: C, 73.10; H, 4.99; N, 15.97.
2,7-Diamino-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (7b):

Pale yellow crystals from ethanol; mp 226-227 oC; yield 77 %; 1H NMR (200 MHz) δ 7.34 and 7.17 (2 d,
aromatic, J = 8.2 Hz, 4H), 6.83 (br s, NH2-2, 2H), 6.60 (d, aromatic, J = 8.2 Hz, 1H), 6.27 (dd, aromatic, J
13
= 8.2, 2.4 Hz, 1H), 6.21 (d, aromatic, J = 2.0 Hz, 1H), 5.25 (br s, NH2 -7, 2H), 4.56 (s, 1H, H-4); C
NMR (50 MHz) δ 160.4 (C-2), 155.6 (C-8a), 148.9 (C-7), 129.4 (C-5), 120.7 (C-4a), 111.2 (C-6), 99.9
(C-8), 56.0 (C-3), 39.4 (C-4), 109.5 (CN), 145.7, 131.1, 129.2, 128.5 (aromatic); IR cm-1 (KBr) 3443,
3367, 3317, 3240, 3221 (2 NH2), 2190 (CN); MS m/z (%):299 (M++ 2, 3), 297 (M+, 10), 226 (37), 186
(100), 170 (3), 131 (3), 114 (1), 58 (6); Anal. Calcd for C16H12N3OCl: C, 64.54; H, 4.06; N, 14.11.
Found: C, 64.72; H, 4.12; N, 14.19.
2,7-Diamino-4-(4-methoxyphenyl)-4H-chromene-3-carbonitrile (7c):
o
1
Pale yellow crystals from ethanol; mp 218-219 C; yield 90 %; H NMR (200 MHz) δ 7.05, 6.84 (d,
aromatic, J = 8.6 Hz, 4H), 6.73 (br s, NH2-2, 2H), 6.59 (d, aromatic, J = 8.2 Hz, 1H), 6.25 (dd, aromatic, J
= 8.2, 2.4, Hz, 1H), 6.19 (d, aromatic, J = 2.0 Hz,1H), 5.21 (br s, NH2- 7, 2H), 4.46 (s, 1H, H-4), 3.70 (s,
3H, MeO); 13C NMR (50 MHz) δ 160.3 (C-2), 148.9 (C-8a), 148.7 (C-7), 129.5 (C-5), 121.0 (C-4a),
111.2 (C-6), 100.0 (C-8), 56.8 (C-3), 39.3 (C-4), 110.5 (CN), 158.0, 138.9, 128.4, 113.9 (aromatic), 55.0
(MeO); IR cm-1 (KBr) 3444, 3372, 3311, 3226, 3226 (2 NH2), 2958, 2897, 2837, (CH aliphatic), 2188
(CN); MS m/z (%): 293 (M+, 23), 226 (56), 186 (100), 170 (5), 141 (3), 114 (4), 77 (4); Anal. Calcd for
C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C, 69.50; H, 5.14 N, 14.22.
7-Amino-4-phenylcoumarin-3-carbonitrile (8a):
Yellow crystals from ethanol/benzene; mp 285-286 oC; yield 42 %; 1H NMR (200 MHz) δ 7.60-7.49 (m,
aromatic, 5H), 7.03 (br s, NH2-7, 2H), 6.90 (d, aromatic, J = 8.6 Hz, 1H), 6.58 (dd, aromatic, J = 8.2, 2.4
Hz, 1H), 6.50 (d, aromatic, J = 1.6 Hz, 1H); 13C NMR (50 MHz) δ 163.1 (CO), 156.8 (C-4), 156.6 (C-8a),
152.0 (C-7), 128.3 (C-5), 115.7 (C-4a), 112.9 (C-6), 98.3 (C-8), 97.7 (C-3), 107.3 (CN), 132.9, 130.3,
130.2, 128.7 (aromatic); IR cm-1 (KBr) 3457, 3366, 3250 (NH2), 2217 (CN), 1693 (CO); MS m/z (%):
262 (M+, 100), 234 (57), 205 (41), 178 (7), 151 (10), 117 (6), 103 (10), 76 (16), 44 (9); Anal. Calcd for
C16H10N2O2: C, 73.27; H, 3.84; N, 10.68. Found: C, 73.15; H, 3.83; N, 10.74.
7-Amino-4-(4-chlorophenyl)coumarin-3-carbonitrile (8b):
Yellow crystals from ethanol/benzene; mp 335-336 oC; yield 37 %; 1H NMR (200 MHz) δ 7.67, 7.52 (2d,
aromatic, J = 8.6 Hz, 4H), 7.07 (br s, NH2 -7, 2H), 6.90 (d, aromatic, J = 9.0 Hz, 1H), 6.58 (dd, aromatic,
J = 8.6, 2.4 Hz, 1H), 6.49 (d, aromatic, J = 1.8 Hz, 1H); 13C NMR (50 MHz) δ 161.8 (CO), 158.3 (C-4),
156.8 (C-8a), 156.7 (C-7), 128.9 (C-5), 115.6 (C-4a), 113.0 (C-6), 98.3 (C-8), 91.0(C-3), 107.2 (CN),
135.1, 131.8, 130.3, 130.2 (aromatic); IR cm-1 (KBr) 3457, 3359, 3251 ( NH2), 2220 (CN), 1699 (CO);
MS m/z (%):298(M++ 2, 34), 296 (M+, 100), 268 (57), 205 (58), 177 (13), 151 (11), 117 (9), 89 (13), 44
(20); Anal. Calcd for C16H9N2O2Cl: C, 64.77; H, 3.06; N, 9.44. Found: C, 64.82; H, 3.11; N, 9.53.
7-Hydroxy-4-phenyl-2-oxo-1,2-dihydroquinoline-3-carbonitrile (9a):

o
1
Yellow crystals from ethanol/benzene; mp > 360 C; yield 38 %; H NMR (200 MHz) δ 12.31 (s, OH,
1H), 10.84 (br s, NH , 1H), 7.60-7.47 (m, aromatic, 5H), 7.00 (d, aromatic, J = 9.0 Hz, 1H), 6.75 (dd,
13
aromatic, J = 8.2, 2.4 Hz, 1H), 6.65 (d, aromatic, J = 2.4 Hz, 1H); C NMR (50 MHz) δ 162.8 (CO),
160.0 (C-4), 159.2 (C-7), 142.3 (C-8a), 128.5 (C-5), 116.0 (C-4a), 113.6 (C-6), 100.2 (C-8), 97.7 (C-3),
111.4 (CN), 134.2, 130.0, 129.6, 128.7 (aromatic); IR cm-1 (KBr) 3461, 3372 (NH), 3245 (OH), 2221
(CN), 1693 (CO); MS m/z (%): 262 (M+, 100), 234 (35), 205 (12), 178 (5), 151 (8), 131 (4), 89 (9), 76
(15), 51 (4); Anal. Calcd for C16H10N2O2: C, 73.27; H, 3.84; N, 10.68. Found: C, 73.40; H, 3.91; N,
10.60.
7-Hydroxy-4-(4-chlorophenyl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile (9b):
Pale yellow crystals from acetic acid; mp > 360 oC; yield 41 %; 1H NMR (200 MHz) δ 12.30 (s, OH, 1H),
10.90 (br s, NH, 1H), 7.58 (2d, aromatic, J = 7.8 Hz, 4H), 7.00 (d, aromatic, J = 7.8 Hz, 1H), 6.79- 6.70
13
(m, aromatic, 2H); C NMR (50 MHz) δ 162.8 (CO), 160.3 (C-4), 159.8 (C-7), 142.3 (C-8a), 128.5 (C-
5), 115.8 (C-4a), 113.7 (C-6), 100.2 (C-8), 98.3 (C-3), 111.2 (CN), 135.1, 130.5, 130.3, 129.9 (aromatic);
IR cm-1 (KBr) 3463, 3368, (NH), 3241 (OH), 2225 (CN), 1693 (CO); MS m/z (%): 296 (M+, 100), 298
(M++ 2, 34), 268 (10), 233 (51), 205 (6), 177 (10), 151 (7), 116 (7), 89 (10), 75 (16), 44 (41); Anal. Calcd
for C16H9N2O2Cl: C, 64.77; H, 3.06; N, 9.44. Found: C, 64.79; H, 3.06; N, 9.43.
7-Hydroxy-4-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile (9c):
o
1
Yellow crystals from dioxane; mp 355-356 C; yield 37 %; H NMR (200 MHz) δ 12.30 (s, OH, 1H),
10.83 (br s, NH, 1H), 7.39 (2d, aromatic, J = 8.6 Hz, 4H), 7.10 (d, aromatic, J = 8.6 Hz, 1H), 6.75-6.70
(dd aromatic, J = 10.2, 2.2 Hz, 1H), 6.65 (d, aromatic, J = 2.2 Hz, 1H); 13C NMR (50 MHz) δ 163.1 (CO)
,162.9 (C-4), 159.8 (C-7), 142.4 (C-8a), 126.2 (C-5), 116.4(C-4a), 113.7 (C-6), 100.4 (C-8), 97.8 (C-3),
111.5 (CN), 156.8, 130.1, 129.5, 124.9 (aromatic), 56.3 (MeO); IR cm-1 (KBr) 3480, 3370 (NH), 3246
(OH), 2971, 2946, 2849 (CH aliphatic), 2225 (CN), 1699 (CO); MS m/z (%): 292 (M+, 100), 264 (25),
249 (15), 221 (12), 192 (6), 146 (5), 121 (6), 97 (6), 57 (14); Anal. Calcd for C17H12N2O3: C, 69.86; H,
4.14; N, 9.58. Found: C, 70.01; H, 4.21; N, 9.70.
Ethyl 2,7-Diamino-4-(4-methoxyphenyl)-4H-chromene-3-carboxylate (10):
o
1
Colorless crystals from ethanol; mp 175-176 C; yield 46 %; H NMR (200 MHz) δ 7.52 (br s, NH2-2,
2H), 7.03, 6.75 (2d, aromatic, J = 8.6, Hz, 4H), 6.76 (d, aromatic, J = 8.2 Hz, 1H), 6.28 (dd, aromatic, J =
7.2, 2.0 Hz, 1H), 6.14 (d, aromatic, J = 2.4 Hz, 1H) 5.14 (br s, NH2-7, 2H), 4.65 (s, 1H, H-4), 3.94 (q,
13
CH2 , J = 7.0 Hz, 2H), 3.65 (s, MeO, 3H,), 1.06 (t, Me, J = 7.0 Hz, 3H); C NMR (50 MHz) δ 168.6
(CO), 161.2 (C-2), 149.2 (C-8a), 148.2 (C-7), 129.4 (C-5), 113.8 (C-4a), 111.0 (C- 6), 100.1 (C-8), 77.2
(C-3), 38.2 (C-4), 157.2, 141.4, 127.9, 113.4 (aromatic), 58.5 (CH2), 54.9 (MeO), 14.3 (Me); IR cm-1
(KBr) 3417, 3372, 3325, 3224 (2 NH2), 2983, 2959, 2899, 2831 (CH aliphatic), 1665 (CO); MS m/z (%):
340 (M+, 11), 293 (9), 273 (55), 233 (100), 187 (65), 159 (6), 131 (6), 104 (5), 58 (9), 43 (12); Anal.

Calcd for C19H20N2O4: C, 67.05; H, 5.92; N, 8.23. Found: C, 67.06; H, 5.94; N, 8.22.
2-Amino-7-hydroxy-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (16a):
o
o
1
Colorless crystals from ethanol; mp 230-231 C ( Literature44 mp 178 C ); yield 85 %; H NMR (200
MHz) δ 9.8 (br, OH, 1H), 7.36, 7.18 (2d, aromatic, J = 8.6 Hz, 4H), 6.91 (br s, NH2-2, 2H), 6.77 (d,
aromatic, J = 8.6 Hz, 1H), 6.49, 6.45 (dd, aromatic, J = 8.2, 2.2 Hz, 1H), 6.39 (d, aromatic, J = 2.4 Hz,
1H), 4.65 (s, 1H, H-4); 13C NMR (50 MHz) δ 160.3 (C-2), 157.4 (C-8a), 148.8 (C-7), 129.8 (C-5), 120.5
(C-4a), 112.5 (C-6), 102.2 (C-8), 55.8 (C-3), 39.3 (C-4), 113.0 (CN), 145.3, 131.2, 129.8, 129.3
(aromatic); IR cm-1 (KBr) 3400, 3336, 3214 (OH, NH2), 2186 (CN); MS m/z (%):300 (M++ 2, 4), 298
(M+, 11), 187 (100), 144 (1), 131 (2), 89 (2), 75 (3), 43 (5); Anal. Calcd for C16H11N2O2Cl: C, 64.33; H,
3.71; N, 9.38. Found: C, 64.44; H, 3.78; N, 9.46.
2-Amino-7-hydroxy-8-methyl-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (16b) :
Beige needles from ethanol; mp 220-221 oC ; yield 89 %; 1H NMR (200 MHz) δ 9.62 (br, OH, 1H), 7.33,
7.16 (2d, aromatic, J = 7.8 Hz, 4H), 6.93 (br s, NH2-2, 2H), 6.63 (d, aromatic, J = 8.2 Hz, 1H), 6.54 (d,
aromatic, J = 8.2 Hz, 1H), 4.64 (s, 1H, H-4), 2.09 (s, Me, 3H); 13C NMR (50 MHz) δ 160.6 (C-2), 155.1
(C-8a), 147.3 (C-7), 129.3 (C-5), 120.8 (C-4a), 111.4 (C- 6), 111.2 (C-8), 55.9 (C-3), 39.5 (C-4), 113.5
(CN), 145.6, 131.3, 128.6, 126.1 (aromatic), 8.5 (Me); IR cm-1 (KBr) 3458, 3380, 3322, 3213 (OH, NH2),
2196 (CN); MS m/z (%):314 (M++ 2, 3), 312 (M+, 10), 201 (100), 156 (1), 128 (3), 103 (2), 75 (4), 51
(1); Anal. Calcd for C17H13N2O2Cl: C, 65.29; H, 4.19; N, 8.96. Found: C, 65.21; H, 4.15; N, 8.99.
2-Amino-6-ethyl-7-hydroxy-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (16c):
o
1
Colorless crystals from ethanol; mp 215-216 C ; yield 92 %; H NMR (200 MHz) δ 9.37 (br, OH, 1H),
7.35, 7.19 (2d, aromatic, J = 7.0 Hz, 4H), 6.78 (br s, NH2-2, 2H), 6.65 (s, aromatic, 1H), 6.47 (s, aromatic,
1H), 4.63 (s, 1H, H-4), 2.41 (q, CH2, J = 7.4 Hz, 2H,), 1.02 (t, Me, J = 7.4 Hz, 3H,); 13C NMR (50 MHz)
δ 160.3 (C-2), 154.7 (C-8a), 146.7 (C-7), 129.2 (C-5), 127.2 (C-4a), 120.6 (C- 6), 101.8 (C-8), 55.9 (C-3),
39.4 (C-4), 112.7 (CN), 145.4, 131.1, 128.7, 128.5, (aromatic), 22.2 (CH2) 14.1 (Me); IR cm-1 (KBr)
3419, 3333, 3221 (OH, NH2), 2966, 2935, 2874 (CH aliphatic), 2180 (CN); MS m/z (%):328 (M++ 2, 3),
326 (M+, 9), 215 (100) 171 (3), 115 (3), 89 (2), 69 (4), 51 (1); Anal. Calcd for C18H15N2O2Cl: C, 66.16;
H, 4.63; N, 8.57. Found: C, 66.23; H, 4.70; N, 8.63.
2-Amino-6-(n-hexyl)-7-hydroxy-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (16d):
o
1
Colorless crystals from ethanol; mp 195-196 C; yield 89 %; H NMR (200 MHz) δ 9.60 (br, OH, 1H),
7.26 (2d, aromatic, J = 7.0 Hz, 4H), 6.86 (br s, NH2-2, 2H), 6.61 (s, aromatic, 1H), 6.47 (s, aromatic, 1H),
4.63 (s, 1H, H-4), 2.30 (t, CH2, 2H, J = 7.2 Hz), 1.36-1.14 (m, 4 CH2, 8H), 0.78 (t, Me, J = 4.6 Hz, 3H);
13C NMR (50 MHz) δ 160.3 (C-2), 154.7 (C-8a), 146.7 (C-7), 129.6 (C-5), 125.6 (C-4a), 120.6 (C-6),
101.8 (C-8), 55.9 (C-3), 39.4 (C-4), 112.5 (CN), 145.4, 131.2, 129.2, 128.5 (aromatic), 31.0 (CH2), 29.1
(CH2), 28.9 (CH2), 28.3 (CH2), 22.1 (CH2) 13.8 (Me); IR cm-1 (KBr) 3468, 3334, 3215 (OH, NH2), 2966,

2923, 2875, 2850 (CH aliphatic), 2198 (CN); MS m/z (%): 382 (M+, 7), 384 (M++ 2, 3), 271 (100), 200
(12), 171 (3), 128 (1), 89 (1), 69 (6), 43(9); Anal. Calcd for C22H23N2O2Cl: C, 69.01; H, 6.05; N, 7.32.
Found: C, 68.94; H, 6.04; N, 7.30.
3-Amino-9-chloro-1-(4-hydroxyphenyl)-1H-benzo[h]chromene-2-carbonitrile (18a):
Pale yellow crystals from ethanol; mp 241-242 oC; yield 81 %; 1H NMR (200 MHz) δ 9.37 (br, OH, 1H),
8.19 (2d, aromatic, J = 7.4 Hz, 4H), 7.74 (d, aromatic, J = 7.8 Hz, 1H), 7.25 (s, aromatic, 1H), 7.15 (br s,
NH2-3, 2H), 7.07-6.68 (m, aromatic, 3H), 4.78 (s, 1H, H-1); 13C NMR (50 MHz) δ 159.8 (C-3), 141.9 (C-
4a), 129.2 (C-8a), 128.3 (C-6), 127.8 (C-10), 126.1 (C-7), 125.5 (C-4b), 124.0 (C-9), 123.9 (C-8), 121.5
(C-5), 120.4 (C-10a), 56.6 (C-2), 39.9 (C-1), 119.2 (CN), 156.5, 135.7, 128.8, 115.6 (aromatic); IR cm-1
(KBr) 3427, 3384, 3348 (OH,NH2), 2196 (CN); MS m/z (%): 348 (M+, 24), 350 (M++ 2, 8), 255 (100),
200 (2), 128 (2), 100 (3), 65 (2), 43 (2); Anal. Calcd for C20H13ClN2O2: C, 68.87; H, 3.76; N, 8.03.
Found: C, 68.96; H, 3.79; N, 8.12.
3-Amino-9-chloro-1-(4-hydroxy-3-methoxyphenyl)-1H-benzo[h]chromene-2-carbonitrile (18b):
o
1
Colorless needles from ethanol; mp 248-249 C; yield 84 %; H NMR (200 MHz) δ 8.94 (s, OH, 1H),
8.32-8.27 (m, aromatic, 6H), 7.31 (s, aromatic, 1H), 7.16 (br s, NH2-3, 2H), 6.88 (d, aromatic, J = 2.0,
1H), 4.78 (s, 1H, H-1), 3.72 (s, MeO, 3H); 13C NMR (50 MHz) δ 159.8 (C-3), 141.8 (C-4a), 129.2 (C-8a),
128.2 (C-6), 127.6 (C-10), 126.0 (C-7), 125.4 (C-4b), 124.0 (C-9), 123.8 (C-8), 121.5 (C-5), 120.4 (C-
10a), 56.4 (C-2), 40.2 (C-1), 119.1 (CN), 147.6,141.8,136.2,120.2,115.0,111.9 (aromatic); IR cm-1 (KBr)
3474, 3323, 3251, 3202 (OH,NH2), 2983, 2928, 2837 (CH aliphatic), 2199 (CN); MS m/z (%):380 (M++
2, 8), 378 (M+, 23), 255 (100), 220 (4), 193, (10), 164 (5), 124 (6), 94 (2), 75 (1), 43 (2); Anal. Calcd for
C21H15N2O3Cl: C, 66.58; H, 3.99; N, 7.40. Found: C, 66.65; H, 4.10; N, 7.48.
2-Amino-3-cyano-4-(4-hydroxyphenyl)-4H,5H-pyrano[3,2-c]benzopyran-5-one (20a):
o
1
Colorless crystals from dioxane; mp 265-266 C; yield 85 %; H NMR (200 MHz) δ 9.34 (s, OH, 1H),
7.87, 7.65 (2d, aromatic, J = 8.2 Hz, 4H), 7.56 to 7.41 (m, aromatic, 2H), 7.32 (br s, NH2-2, 2H), 7.05,
13
7.02 (dd aromatic, J = 8.2, 1.6 Hz, 1H), 6.68 (dd aromatic, J = 8.2, 1.6 Hz, 1H), 4.32 (s, 1H, H-4); C
NMR (50 MHz) δ 159.6 (CO), 158.0 (C-2), 156.6 (C-10b), 152.1 (C-6a), 128.8 (C-8), 124.6 (C-10),
122.4 (C-9), 119.5 (C-10a), 116.5 (C-7), 104.5 (C-4a), 58.6 (C-3), 36.3 (C-4), 113.0 (CN), 153.0, 133.8,
132.7, 115.3 (aromatic); IR cm-1 (KBr) 3514, 3417, 3295, 3186 (OH, NH2), 2197 (CN), 1708 (CO); MS
m/z (%): 332 (M+, 39), 265 (44), 239 (100), 211 (5), 184 (4), 145 (5), 121 (43), 92 (12), 66 (19), 55 (1);
Anal. Calcd for C19H12N2O4: C, 68.67; H, 3.64; N, 8.43. Found: C, 68.82; H, 3.74; N, 8.40.
2-Amino-3-cyano-4-(4-hydroxy-3-methoxyphenyl)-4H,5H-pyrano[3,2-c]benzopyran-5-one (20b):
o
1
Colorless crystals from dioxane; mp 252-253 C; yield 74 %; H NMR (200 MHz) δ 8.92 (s, OH, 1H),
7.89-7.41 (m, aromatic, 4H), 7.32 (br s, NH2-2, 2H), 6.81-6.75 (m, aromatic, 3H), 4.35 (s, 1H, H-4) 3.72
(s, MeO, 3H); 13C NMR (50 MHz) δ 159.6 (CO), 158.0 (C-2), 153.0 (C-10b), 152.1 (C-6a), 132.8 (C-8),

124.6 (C-10), 122.4 (C-9), 119.4 (C-10a), 116.5 (C-7), 104.3 (C-4a), 58.4 (C-3), 36.5 (C-4), 113.0 (CN),
147.3, 145.8, 134.3, 119.9, 115.5, 112.1 (aromatic), 55.7 (Me); IR cm-1 (KBr) 3417, 3299, 3251, 3190
(OH, NH2), 2191 (CN), 1711 (CO); MS m/z (%): 362 (M+, 40), 331 (23), 295 (23), 279 (19), 239 (100),
161 (5), 121 (43), 92 (12), 66 (18), 51 (6); Anal. Calcd for C20H14N2O5: C, 66.30; H, 3.89; N, 7.73.
Found: C, 66.31; H, 3.94; N, 7.77.
General Procedure for the synthesis of 5; 12; 13; 21; 23; 24 and 26a,b:
Method (a):
A mixture of 3c, 7b, 16b (10 mmol) and triethyl orthoformate (4.99 g, 30 mmol) was refluxed for 3 h.
The solid product that formed on cooling was collected and crystallized from a suitable solvent to give 5,
12 and 24.
Method (b):
A mixture of 7b, 16a-d (10 mmol), triethyl orthoformate (4.99 g, 30 mmol) and acetic anhydride (20 mL)
was refluxed for 3 h. The solid product that formed on cooling was collected and crystallized from a
suitable solvent to give 13, 21, 23 and 26a,b.
3-Amino-8-ethoxymethyleneamino-1-(4-methoxyphenyl)-1H-benzo[h]chromene-2-carbonitrile (5):
Pale gray crystals from benzene; mp 195-196 oC; yield 73 %; 1H NMR (200 MHz) δ 8.06 (s, N=CH, 1H),
7.98 (br s, NH2–3, 2H), 7.76 (d, aromatic, J = 9.4 Hz, 1H), 7.55-7.03 (m, aromatic, 7H), 6.85 (d, aromatic,
J = 8.2 Hz, 1H), 4.82 (s, 1H, H-1), 4.34 (q, CH2, J = 7.0 Hz, 2H,), 3.69 (s, 3H, MeO), 1.33 (t, Me, J = 7.0
13
Hz, 3H,); C NMR (50 MHz) δ 160.1 (C-3), 155.9 (N=CH), 144.4 (C-4a), 142.7 (C-8), 128.0 (C-4b),
123.5 (C-8a), 120.6 (C- 10a), 56.6 (C-2), 40.2 (C-1), 118.5 (CN), 158.2,137.9,
128.7,128.3,127.0,125.7,119.6,116.8(C-),115.4,114.0 (aromatic), 62.3 (CH2), 55.0 (MeO), 14.1 (Me); IR
cm-1 (KBr) 3405, 3326, 3205 ( NH2), 2191 (CN), 1664 (C=N); MS m/z (%): 399 (M+, 38), 370 (4),292
(100), 264 (16), 236 (5), 208 (2), 164 (3), 151 (1), 77 (2); Anal. Calcd for C24H21N3O3: C, 72.16 H, 5.30;
N, 10.52. Found: C, 72.35; H, 5.22; N, 10.60.
2-Amino-7-ethoxymethyleneamino-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (12):
o
1
Pale yellow crystals from benzene; mp 135-136 C; yield 81 %; H NMR (200 MHz) δ 7.96 (s, N=CH,
1H), 7.37, 7.21 (2d, aromatic, J = 8.6 Hz, 4H), 6.98 (br s, NH2-2, 2H), 6.92 (d, aromatic, J = 8.2 Hz, 1H),
6.71 (dd, aromatic, J = 7.8, 2.0 Hz, 1H), 6.64 (d, aromatic, J = 2.0 Hz, 1H), 4.76 (s, 1H, H-4), 4.19 (q,
CH2, J = 7.0 Hz, 2H,), 1.21 (t, Me, J = 7.0, Hz, 3H,); 13C NMR (50 MHz) δ 160.3 (C-2), 156.7 (N=CH),
148.5 (C-8a), 147.9 (C-7), 129.6 (C-5), 120.4 (C-4a), 118.4 (C-6), 108.5 (C-8), 55.6 (C-3), 39.5 (C-4),
118.5 (CN), 144.9, 131.4, 129.3, 128.6 (aromatic), 62.1 (CH2), 14.0 (Me); IR cm-1 (KBr) 3360, 3318,
3161 (NH2), 2977, 2934, 2892, 2861 (CH aliphatic), 2196 (CN); MS m/z (%):355 (M++ 2, 1), 353 (M+,
4), 297 (11), 268 (5), 242 (36), 214 (5), 186 (100), 170 (4), 114 (5), 89 (4), 75 (2); Anal. Calcd for
C19H16N3O2Cl: C, 64.50 H, 4.56; N, 11.88. Found: C, 64.56; H, 4.57; N, 11.92.

2-Ethoxymethyleneamino-7-hydroxy-8-methyl-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile
(24):
Pale yellow crystals from benzene; mp 212-213 oC; yield 82 %; 1H NMR (200 MHz) δ 9.66 (br, OH, 1H),
8.62 (s, N=CH, 1H), 7.32 (2d, aromatic, J = 8.2 Hz, 4H), 6.62 (d, aromatic, J = 8.6 Hz, 1H), 6.56 (d,
aromatic, J = 8.6 Hz, 1H), 4.92 (s, 1H, H-4), 4.33 (q, CH2, J = 7.0 Hz 2H,), 2.07 (s, Me, 3H), 1.31 (t, Me,
J = 7.0 Hz, 3H); 13C NMR (50 MHz) δ 161.1, (N=CH), 160.6 (C-2), 157.6 (C-8a), 155.3 (C-7), 126.3 (C-
5), 131.9 (C-4a), 112.1 (C-6), 111.7 (C-8), 79.6 (C-3), 41.0 (C-4), 118.1 (CN), 147.2, 143.8, 129.7, 128.8
(aromatic), 63.9 (CH2), 13.8 (Me), 8.4 (Me); IR cm-1 (KBr) 3365 (OH), 2983, 2928 (CH aliphatic), 2213
(CN); MS m/z (%):370 (M++ 2, 5), 368 (M+, 15), 257 (100), 229 (16), 201 (72), 165 (2), 128 (4), 103 (3),
77 (5), 43 (6); Anal. Calcd for C20H17N2O3Cl: C, 65.13; H, 4.65; N, 7.60. Found: C, 65.24; H, 4.69; N,
7.69.
2-Acetylamino-7-ethoxymethyleneamino-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (13):
o
1
Colorless crystals from benzene; mp 194-195 C; yield 67 %; H NMR (200 MHz) δ 10.09 (br s, NH,
1H), 8.67 (s, N=CH, 1H), 7.67 (s, aromatic, 1H), 7.34 (2d, aromatic, J = 8.6 Hz, 4H), 7.10 (d, aromatic, J
= 8.2 Hz, 1H), 6.89 (d, aromatic, J = 8.2 Hz, 1H), 5.00 (s, 1H, H-4), 4.32 (q, CH2, J = 7.0 Hz, 2H), 2.02
13
(s, COMe, 3H), 1.30 (t, Me, J = 7.0, Hz, 3H); C NMR (50 MHz) δ 168.6 (CO), 161.9 (N=CH), 157.8
(C-2), 148.2 (C-8a), 143.2 (C-7), 129.9 (C-5), 117.9 (C-4a), 116.0 (C- 6), 106.6 (C-8), 56.5 (C-3), 40.3
(C-1), 115.7 (CN), 139.42, 132.0, 129.4, 128.8 (aromatic), 63.9 (CH2), 24.0 (COMe), 13.8 (Me); IR cm-1
(KBr) 3330, 3287 (NH), 2984, 2958, 2892, (CH aliphatic), 2208 (CN), 1702 (CO); MS m/z (%): 395
(M+, 14), 397 (M++ 2, 5), 284 (100), 256 (12), 228 (33), 186 (40), 158 (6), 114 (3), 103 (1), 75 (2); Anal.
Calcd for C21H18N3O3Cl: C, 63.72; H, 4.58; N, 10.62. Found: C, 63.71; H, 4.62; N, 10.66.
7-Acetoxy-2-ethoxymethyleneamino-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (21):
Colorless crystals from benzene; mp 145-146 oC; yield 81 %; 1H NMR (200 MHz) δ 8.34 (s, N=CH, 1H),
7.36-7.06 (m, aromatic, 7H), 4.81 (s, 1H, H-4), 4.34 (q, CH2, J = 7.2 Hz, 2H), 2.27 (s, COMe, 3H), 1.35
13
(t, Me, J = 7.2 Hz 3H); C NMR (50 MHz) δ 168.9 (CO), 159.6 (N=CH), 157.1 (C-2), 156.6 (C-8a),
150.3 (C-7), 130.2 (C-5), 129.0 (C-4a), 118.8 (C-6), 110.2 (C-8), 80.6 (C-3), 41.9 (C-4), 117.6 (CN),
141.0, 133.5, 129.5, 129.1 (aromatic), 64.3 (CH2), 21.0 (Me), 13.8 (Me); IR cm-1 (KBr) 2966, 2953 (CH
aliphatic), 2212 (CN), 1726 (CO); MS m/z (%):398 (M++ 2, 7), 396 (M+, 21), 285 (87), 243 (100), 215
(18), 187 (1), 158 (7), 114 (3), 103 (2), 69 (2), 43 (3); Anal. Calcd for C21H17N2O4Cl: C, 63.56; H, 4.32;
N, 7.06. Found: C, 63.50; H, 4.31; N, 7.00.
7-Acetoxy-2-Amino-8-methyl-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (23):
o
1
Colorless crystals from ethanol; mp 200-201 C ; yield 76 %; H NMR (200 MHz) δ 7.38, 7.23 (2d,
aromatic, J = 8.2 Hz, 4H), 7.08 (br s, NH2-2, 2H), 6.90 (d, aromatic, J = 8.4 Hz, 1H), 6.70 (d, aromatic, J
13
= 8.4 Hz, 1H), 4.80 (s, 1H, H-4), 2.28 (s, MeCO, 3H), 2.06 (s, Me, 3H); C NMR (50 MHz) δ 168.8

(CO), 160.4 (C-2), 148.3 (C-8a), 146.9 (C-7), 129.3 (C-5), 120.4 (C-4a), 120.2 (C-6), 118.2 (C-8), 55.3
(C-3), 39.8 (C-4), 118.3 (CN), 144.7, 131.5, 128.7, 126.4 (aromatic), 20. 4 (Me) 8.9 (Me); IR cm-1 (KBr)
3411, 3332, 3220, 3213 (NH2), 2971, 2934 (CH aliphatic), 2195 (CN), 1748 (CO); MS m/z (%): 354 (M+,
11), 356 (M++ 2, 4), 243 (38), 201 (100), 172 (1), 128 (2), 101 (1), 77 (2), 43 (3); Anal. Calcd for
C19H15N2O3Cl: C, 64.32 H, 4.26; N, 7.90. Found: C, 64.20; H, 4.21; N, 7.85.
2-Acetylamino-7-hydroxy-6-ethyl/n-hexyl-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (26a,b):
26a:
Colorless crystals from benzene; mp 160-161 oC; yield 67 %; 1H NMR (200 MHz) δ 11.09 (br, OH, 1H),
8.64 (br s, NH, 1H), 7.77-7.01 (m, aromatic, 6H), 5.09 (s, 1H, H-4), 2.38 (q, CH2, J = 7.4 Hz 2H), 2.36 (s,
MeCO, 3H), 1.00 (t, Me, J = 7.4 Hz, 3H); 13C NMR (50 MHz) δ 169.0 (CO), 163.0 (C-2), 148.0 (C-8a),
146.1 (C-7), 129.7 (C-5), 132.2 (C-4a), 119.6 (C- 6), 111.1 (C-8), 56.5 (C-3), 40.3 (C-4), 116.8 (CN),
142.4, 133.5, 129.6, 129.1 (aromatic), 22.2 (CH2), 20.5 (Me), 14.1 (Me); IR cm-1 (KBr) 3315, 3180 (OH,
NH), 2971, 2934, 2964, 2873 (CH aliphatic), 2209 (CN), 1728 (CO); MS m/z (%):370 (M++ 2, 0), 368
(M+, 1), 243 (100), 215 (96), 165 (3), 115 (3), 89 (2), 69 (14); Anal. Calcd for C20H17N2O3Cl: C, 65.13;
H, 4.65; N, 7.60. Found: C, 65.15; H, 4.67; N, 7.62.
26b: Colorless crystals from ethanol; mp 150-151 oC ; yield 57 %; 1H NMR (200 MHz) δ 11.10 (br, OH,
1H), 8.73 (br , NH, 1H), 7.75, 7.59 (2d, aromatic, J = 8.4 Hz, 4H), 7.02 (s, aromatic, 1H), 6.96 (s,
aromatic, 1H), 5.08 (s, 1H, H-4), 2.50 (t, CH2, 2H, J = 6.6 Hz), 2.37 (s, MeCO, 3H), 1.50-1.10 (m, 4 CH2,
8H), 0.81 (t, Me, J = 4.3 Hz, 3H); IR cm-1 (KBr) 3329 (NH), 2954, 2926, 2855 (CH aliphatic), 2192
(CN), 1708 (CO); MS m/z (%):426 (M++ 2, 1), 424 (M+, 3), 381 (49), 298 (98), 171 (100), 240 (6), 200
(15), 139 (2), 89 (1), 69 (18), 43(91); Anal. Calcd for C24H25N2O3Cl: C, 67.84; H, 5.93; N, 6.59. Found:
C, 67.90; H, 5.99; N, 6.67.
Reaction of 5 and 12 with hydrazine hydrate:
A solution of 5 or 12 (10 mmol) and hydrazine hydrate (0.84 g, 12 mmol) in 30 mL of ethanol or benzene
was stirred at rt for 1 h to give 3c as pale gray crystals; mp 209-210 C; yield 83% and 7b as pale yellow
crystals; mp 226-227 oC; yield 82 % (mp and mixed mp).
2-Acetylamino-7-amino-4-(4-chlorophenyl)-4H-chromene-3-carbonitrile (14):
A mixture of 13 (3.95 g, 10 mmol) and hydrazine hydrate (0.84 g, 12 mmol) in ethanol (30 mL) was
stirred at room temperature for 1 h. The solid product that formed on cooling was collected and
crystallized from (SOLVENT) to give 14 as colorless crystals; mp 210-211 oC; yield 81 %; 1H NMR (200
MHz) δ 10.05 (br s, NH, 1H), 7.58 (s, aromatic, 1H), 7.36, 7.19 (2d, aromatic, J = 8.6 Hz, 4H), 7.08-7.03
(dd, aromatic, J = 8.2, 1.8 Hz, 1H), 6.98 (br s, NH2-7, 2H), 6.90 (d, aromatic, J = 8.2 Hz, 1H), 4.72 (s, 1H,
13
H-4), 2.02 (s, COMe, 3H); C NMR (50 MHz) δ 168.6 (CO), 160.3 (C-2), 148.2 (C-8a), 145.0 (C-7),
129.9 (C-5), 120.4 (C-4a), 115.3 (C-6), 106.1 (C-8), 55.6 (C-3), 39.5 (C-1), 117.1 (CN), 139.2, 131.4,

129.3, 128.6 (aromatic), 24.0 (COMe); IR cm-1 (KBr) 3384, 3330, 3202 (NH2, NH), 2928 (CH aliphatic),
2194 (CN), 1687 (CO); MS m/z (%):341 (M++ 2, 4), 339 (M+,13), 295 (12), 268 (10), 228 (100), 186
(39), 158 (4), 141 (3), 114 (3), 66 (5), 43 (32); Anal. Calcd for C18H14N3O2Cl: C, 63.63; H, 4.15; N,
12.37. Found: C, 63.85; H, 4.24; N, 12.51.
3-Amino-10-(4-chlorophenyl)-4-imino-3,10-dihydro-4H-9-oxa-1,3-diazaanthracen-7-ol (22):
A solution of 21 (3.96 g, 10 mmol) and hydrazine hydrate (0.84 g, 12 mmol) in 30 mL of ethanol or
benzene was stirred at room temperature for 1 h to give 22 as colorless needles; mp 225-226 oC; yield 91
1
%; H NMR (200 MHz) δ 9.72 (br, OH, 1H), 8.05 (s, 1H, H-2), 7.34- 6.50 (m, aromatic, 7H), 6.62 (br ,
NH, 1H), 5.63 (br s, NH2, 2H), 5.09 (s, 1H, H-10); 13C NMR (50 MHz) δ 157.2 (C-4), 156.0 (C-8), 154.9
(C-9a), 150.6 (C-2), 149.6 (C-7), 131.1 (C-5), 114.0 (C-10), 112.6 (C-6), 102.8 (C-8), 98.3 (C-4a), 38.1
(C-10), 144.5, 131.1, 129.4, 128.4 (aromatic); IR cm-1 (KBr) 3349, 3298, 3221, 3182 (OH, NH, NH2),
1660 (C=N); MS m/z (%):342 (M++ 2, 7), 340 (M+, 20), 324 (78), 297 (17), 214 (100), 187 (42), 162 (4),
131 (3), 89 (4), 58 (11); Anal. Calcd for C17H13N4O2Cl: C, 59.92; H, 3.85; N, 16.44. Found: C, 59.90; H,
3.83; N, 16.42.
Reaction of 23 with hydrazine hydrate:
A solution of 23 (3.54 g, 10 mmol) and hydrazine hydrate (0.84 g, 12 mmol) in 30 mL of ethanol or
benzene (30 mL) was stirred at rt for 1 h to give 16b as beige needles; mp 220-221 oC (mp and mixed
mp); yield 83 %.
3-Amino-10-(4-chlorophenyl)-4-imino-8-methyl-3,10-dihydro-4H-9-oxa-1,3-diazaanthracen-7-ol
(25):
A solution of 24 (3.68 g, 10 mmol) and hydrazine hydrate (0.84 g, 12 mmol) in ethanol or benzene (30
mL) was stirred at room temperature for 1 h to give 25 as pale yellow crystals; mp 283-284 oC; yield 88
1
%; H NMR (200 MHz) δ 9.92 (s, OH, 1H), 9.10 (br s, NH, 1H), 8.72 (s, 1H, H-2), 7.35- 6.69 (m,
aromatic, 6H), 6.66 (br , NH2, 2H), 5.57 (s, 1H, H-10), 2.15 (s, Me, 3H); 13C NMR (50 MHz) δ 160.5 (C-
4), 160.4 (C-2), 156.0 (C-8a), 155.6 (C-9a), 147.1 (C-7), 128.3 (C-5), 125.9 (C-6), 113.0 (C-8), 112.0 (C-
10a), 98.0 (C-4a), 36.8 (C-10), 142.3, 131.9, 129.3, 128.7 (aromatic), 8.4 (Me); IR cm-1 (KBr) 3439-2980
( br, OH, NH, NH2), 1647 (C=N); MS m/z (%):356 (M++ 2, 9), 354 (M+, 27), 338 (100), 228 (85), 169
(12), 128 (5), 77 (6), 43 (5); Anal. Calcd for C18H15N4O2Cl: C, 60.94; H, 4.26; N, 15.79. Found: C,
60.99; H, 4.35; N, 15.72.
ACKNOWLEDGEMENT
Financial support for this research provided by the Natural Sciences and Engineering Research Council of
Canada (NSERC) is gratefully acknowledged.

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