Synthesis of 4H-chromene, coumarin, 12H-chromeno[2,3-d]pyrimidine derivatives and some of their antimicrobial and cytotoxicity activities

Article abstract of DOI:10.1016/j.ejmech.2010.12.015

Condensation of 3-N,N-diethylaminophenol (1) with α- cyanocinnamonitriles (2a-c) and ethyl α-cyanocinnamates (2d-f) provided compounds 3a-f and 4a-c. 12H-Chromeno[2,3-d]pyrimidine derivatives 6, 11-13 and 16 were obtained by treatment of 4H-chromene compo

Full text of DOI:10.1016/j.ejmech.2010.12.015

European Journal of Medicinal Chemistry 46 (2011) 765e772
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of 4H-chromene, coumarin, 12H-chromeno[2,3-d]pyrimidine
derivatives and some of their antimicrobial and cytotoxicity activities
Nermien M. Sabry b, Hany M. Mohamed c, Essam Shawky A.E.H. Khattab a, Shymaa S. Motlaq b,
,
Ahmed M. El-Agrody a
*
a Chemistry Department, Faculty of Science, King Khalid University, 9004 Abha, Saudi Arabia
b Chemistry Department, Girls College of Education, King Khalid University, Abha, Saudi Arabia
c Chemistry Department, Faculty of Medicine (Boys Branch), Jazan University, Jazan, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Condensation of 3-N,N-diethylaminophenol (1) with
a-cyanocinnamonitriles (2aec) and ethyl a-cya-
Received 23 August 2010
Received in revised form
2 December 2010
Accepted 12 December 2010
Available online 21 December 2010
nocinnamates (2def) provided compounds 3aef and 4aec. 12H-Chromeno[2,3-d]pyrimidine derivatives
6, 11e13 and 16 were obtained by treatment of 4H-chromene compounds (3) with different electrophiles
followed by nucleophilic reagents. Structures of these compounds were established on the basis of IR,
UV, 1H NMR, 13C NMR and MS data. Some of the new compounds were evaluated for antimicrobial and
cytotoxicity activities.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
a-Cyanocinnamonitriles
Ethyl -cyanocinnamates
a
3-N,N-Diethylaminophenol
4H-Chromene
Coumarin
12H-Chromeno[2,3-d]pyrimidine
Antimicrobial
Cytotoxicity
1. Introduction
fused chromenes and evaluation of their antimicrobial and anti-
tumor activities.
4H-Chromene and its derivatives are biologically interesting
compounds known for their antimicrobial and antifungal [1],
antioxidant [2], antileishmanial [3], antitumor [4], hypotensive
[5], antiproliferation [6], local anesthetic [7], antiallergenic [8,9],
central nervous system (CNS) activities and effects [10], as well as
treatment of Alzheimer’s disease [11] and Schizophrenia disorder
[12]. Fused chromene ring systems have platelet antiaggregating,
local anesthetic [13e15] and antihistaminic activities [16]. They
also exhibit antidepressant effects [17], inhibitory effect on influ-
enza virus sialidases [18,19], DNA breaking activities and mutage-
nicity [20], antiviral activities [21] and act as sex pheromone
homologes [22].
2. Chemistry
Treatment of 3-N,N-diethylaminophenol (1) with various
substituted
afforded 3aec, while treatment of 3-N,N-diethylaminophenol (1)
with ethyl -cyanocinnamate (2def) in ethanol and piperidine
a-cyanocinnamonitriles (2aec) in ethanol and piperidine
a
afforded ethyl 2-amino-4-(4-halophenyl)-7-(diethylamino)-4H-
chromene-3-carboxylate (3def) and 4-(4-halophenyl)-7-(dieth-
ylamino)-coumarin-3-carbonitrile (4aec) (Scheme 1).
The formation of 3 indicates that the phenolate anion (C-6) of 1
The present study is a part of our research program [1c,23e34]
directed toward the synthesis of novel 4H-chromene and coumarin
attack at the b-carbon of 2 to yield an acyclic Michael adduct [33],
which underwent cyclization as shown in Scheme 2. The formation
compounds using
b
-enaminonitriles and
b
-enaminocarboxylic
of 4indicates that the phenolate anion (C-6) of 1 attack at the
esters and their use as building blocks in the synthesis of novel
b-carbon of 2 to yield an acyclic Michael adduct which underwent
cyclization via the elimination of ethanol and aromatization [33]
(Scheme 2).
NMR spectra of 3aef showed characteristic signals for
* Corresponding author. Tel.: þ966 530175825.
E-mail address: elagrody_am@yahoo.com (A.M. El-Agrody).
4H-chromene: singlets at d
4.51e4.75 ppm in the 1H NMR and
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.12.015

766
N.M. Sabry et al. / European Journal of Medicinal Chemistry 46 (2011) 765e772
Ar
O
CN
r-CH=C
X
CN
X
A
+
Et2N
OH
2
1
Et2N
Ar
5
30 min.
6 hrs.
a, Ar = p-Cl-C6H4 X= CN
b, Ar = p-Br-C6H4 X= CN
a, X = NHCOCH3
CN
b
, X = N(COCH3)2
Ac2O
EtOH
Ar
O
c, Ar = p-F-C6H4
X= CN
ine
piperid
6
5
4
d, Ar = p-Cl-C6H4 X= CO2Et
e, Ar = p-Br-C6H4 X= CO2Et
Et2N
O
NH2
3
NH
reflux
3a
7
8
f,,Ar = p-F-C6H4
X= CO2Et
Ar
PhCHO
Ar
2
Et2N
O
N
1
CH3
9
6
Ar
CN
5
4
CH3CN
HCl gas
X
3
2
CN
4a
6
7
Et2N
O
N=CHPh
+
3d
7
8a
RNHNH2
Ar
Et2N
O
1
NH2
Et2N
O
O
8
3a
R
H
N
3a-f
4a-c
N
=
CN
H
C
h
P
-
Ar
NH
N
Scheme 1. Synthesis of 2-amino-4-(4-halophenyl)-7-(diethylamino)-4H-chromene
derivatives (3a-f) and 4-(4-halophenyl)-7-(diethylamino)-coumarin-3-carbonitrile
derivatives (4a-c).
Et2N
O
NH
NNHR
Ph
8
CHPh
38.91e39.81 ppm in the 13C NMR. The IR spectra showed NH2
R = H or Ph
Et2N
O
9
y
3471-3401, 3334-3304 and 3216-3196 cmꢀ1; CN stretch
N-NHR
H
stretch at
at
y
2194-2191 cmꢀ1 for 3aec; CO stretch at
y
1675e1676 cmꢀ1 for
R = H or Ph
3def. The UV spectra of 3aef revealed a weak shoulder charac-
teristic for 4H-chromene [23e25,27,35] at lmax (CH3COCH3)
Scheme 3. Synthetic protocol of the compounds (5b-7).
396e430 nm (log e 1.47e3.54). The structure of 4 was established in
the same way. 1H NMR and 13C NMR spectra showed the absence of
heating of 3a with acetic anhydride for 6 h afforded 5-(4-chlor-
ophenyl)-8-(diethylamino)-2-methyl-3,4-dihydro-5H-chromeno[2,3-
d]pyrimidin-4-one (6) (Scheme 3). Attempts to obtain the N-acetyl
derivative were unsuccessful: 2-acetylamino-4-(4-chlorophenyl)-7-
(diethylamino)-4H-chromene-3-carbonitrile (5a) was not formed.
Structure of 6 was also supported by an independent synthesis of the
same compound from ethyl 2-amino-4-(4-chlorophenyl)-7-(dieth-
ylamino)-4H-chromene-3-carboxylate (3d) and acetonitrile in the
presence of HCl gas [36] (m.p. and mixed m.p.) (Scheme 3). Structures
of 5b and 6 were established by spectral data and in conjunction with
our previous work [1c,23e34].
4H, while the IR spectra showed the absence of NH2 and the
appearance of the CN stretch at
y
2193e2221 cmꢀ1 and CO stretch
at
y
1725e1726 cmꢀ1 for 4aec. The mass spectra of compounds
3aef and 4aec gave additional evidences for the proposed
structures.
Treatment of 2-amino-4-(4-chlorophenyl)-7-(diethylamino)-4H-
chromene-3-carbonitrile (3a) with acetic anhydride for 30 min affor-
ded the N,N-diacetylamino derivative 2-diacetylamino-4-(4-chlor-
ophenyl)-7-(diethylamino)-4H-chromene-3-carbonitrile (5b), while
CN
Condensation of 2-amino-4-(4-chlorophenyl)-7-(diethylamino)-
4H-chromene-3-carbonitrile (3a) with benzaldehyde in ethanol
and piperidine under reflux gave the corresponding 2-benzylide-
neamino-4-(4-chlorophenyl)-7-(diethylamino)-4H-chromene-3-car-
bonitrile (7) (Scheme 3). Structure of 7 was confirmed on the basis of
IR, 1H NMR, 13C NMR and MS data [31].
When 2-benzylideneamino-4-(4-chlorophenyl)-7-(diethylamino)-
4H-chromene-3-carbonitrile (7) was treated with hydrazine hydrate or
phenyl hydrazine in ethanol at room temperature or under reflux, the
addition product 8 was formed (R ¼ H or Ph, respectively). From the
intermediate 8, benzaldehyde hydrazone or benzaldehyde phenyl-
Ar-CH=C
+
..
X
Et2N
Ar
OH
2a-f
1
Ar
X
X
CN
O
H
N
C
..
OH
..
Et2N
Et2N
OH
OEt
- EtOH
Ar
Ar
hydrazone were eliminated to give
b-enaminonitrile (3a) [31,37]
CN
instead of the pyrimidine derivative (9) (Scheme 3).
H
Treatment of 3a with triethyl orthoformate in acetic anhydride
at reflux gave the corresponding 4-(4-chlorophenyl)-7-(dieth-
ylamino)-2-ethoxymethyleneamino-4H-chromene-3-carbonitrile
(10a) together with the quaternary ammonium salt 5-(4-chlor-
ophenyl)-N,N-diethyl-2-methyl-4-oxo-4,5-dihydro-3H-chromeno-
[2,3-d]pyrimidin-8-aminium acetate (11), which can be separated
from the reaction (See experimental part). The same treatment
with 3b afforded 4-(4-bromophenyl)-7-(diethylamino)-2-ethox-
ymethyleneamino-4H-chromene-3-carbonitrile (10b) (Scheme 4).
Structures of 10 and 11 were established on the basis of IR, 1H NMR,
13C NMR and MS data [1c,23e34].
NH
Et2N
O
O
Et2N
O
-[H2]
Ar
Ar
CN
X
O
Et2N
O
4a-c
Et2N
O
NH2
3a-f
Scheme 2. Mechanism formation of compounds (3a-f) and (4a-c).

N.M. Sabry et al. / European Journal of Medicinal Chemistry 46 (2011) 765e772
767
Ar
O
Ar
3a
(EtO)3CH, Ac2O
Ar
+
CN
N
CN
NH3 (g)
MeOH
1h
CN
Et2N
NH2
Et2N
O
N=CHOEt
15A
10a
10a
3a
HCONH2
Et2N
O
N=CHOEt
10a
NH3 (g)
MeOH
2h
Ar = p-Cl-C6H4
Ar
Ar
NH2
+
Ar
O
CN
N
Dioxan
piperidine
NH
Et2N
O
N
H
a
b
NH
Et2N
O
N
c
15B
-OCOCH3
16
Et2NH
O
N
CH3
11
Scheme 6. Synthetic protocol of the compounds (15) and (16).
Ar = p-Cl-C6H4
Ar
chromeno[2,3-d]pyrimidine(16). Structure of16 wassupported by its
independent synthesis from 3a and formamide [26,29] and also by
cyclization of 15 in dioxan and piperdine under reflux [31] (m.p. and
mixed m.p.) (Scheme 6).
CN
3b
+
(EtO)3CH, Ac2O
Et2N
O
N=CHOEt
10b
The structure of 15 was supported by IR spectroscopy, which
Ar = p-Br-C6H4
showed the presence of a CN stretch at
NH2 stretch at
3370 & 3163 cmꢀ1. The 1H NMR spectrum for 15
showed signals at
y 2196 and NH stretch or
y
Scheme 4. Formation of 2-ethoxymethyleneamino-4H-chromene derivatives (10a,b)
and ammonium salt (11).
d
8.83 ppm [d, J ¼ 10.0 Hz, 1H, NH(a)], 8.39,
8.38 ppm [dd, J ¼ 10.0 Hz, 1H, CH(b)] and 5.76 ppm [d, J ¼ 10.0 Hz,
1H, NH(c)], while the 13C NMR spectrum showed signals at
Hydrazinolysis of 10a,b in ethanol at room temperature afforded
the aminoimino derivatives 3-amino-5-(4-chloro/bromophenyl)-8-
(diethylamino)-4-imino-3,4-dihydro-5H-chromeno[2,3-d]pyrimi-
dine (12a,b) (Scheme 5). Reaction of 10a with methylamine in
ethanol at room temperature yielded the chromeno[2,3-d]pyrimi-
dine derivative 13, while reaction with dimethylamine in ethanol at
room temperature yielded the open chain product 14 (Scheme 5).
Treatment of 10a with NH3 gas in methanol at room temperature
for 1h yielded the open chain product (E) N0-(4-(4-chlorophenyl)-
3-cyano-7-(diethylamino)-4H-chromen-2-yl)formimidamide (15A)
which is in equilibrium with its tautomer N-(4-(4-chlorophenyl)-
3-cyano-7-(diethylamino)-4H-chromen-2-yl)formimidamide (15B)
(Scheme 6). Similar ammonolysis of 10a for 2 h afforded the cyclic
additionproduct 4-amino-5-(4-chlorophenyl)-8-(diethylamino)-5H-
d
160.20 ppm (C-2) and 154.64 ppm (N]CH). In compound 16, IR
showed the presence of NH2 stretches at
3467, 3317 cmꢀ1. The 1H
NMR spectrum for 16 showed signals at 8.20 ppm (s, 1H, H-2) and
4.87 ppm (bs, 2H, NH2), while the 13C NMR showed signals at
162.62 ppm (C-4) and 157.26 ppm (C-2). A compound that
y
d
d
contains one chlorine atom will have an M þ 2 peak approximately
one-third the intensity of the molecular ion peak because of the
presence of a molecular ion containing the 37Cl isotope, thereby the
mass spectrum of 15 showed m/z (%) peaks at 382 (Mþþ2, 21.38)
and 380 (Mþ, 57.35) with the base peak at 269 (100), while the mass
spectrum of 16 showed m/z (%) peaks at 382 (Mþþ2, 17.75) and 380
(Mþ, 50.76) with the base peak at 269 (100).
3. Antibacterial activities
Compounds 3aef, 4aec, 5b, 7, 10a,b, 11, 12a,b and 13e16 were
tested in vitro for their antimicrobial activities [38,39] by agar
diffusion method using MuellereHinton agar medium for bacteria
and Sabouraud’s agar medium for fungi. The tested microorganisms
were obtained from the culture collection at the Microbiology
laboratory, National Organization for Drug Control and Research
(NODCAR). The assayed collection included 2 g-negative (Bordetella
bronchiseptica ATCC 4617 and Escherichia coli ATCC 14169) and 4 g-
positive (Bacillus pumilus ATCC 14884, Bacillus subtilis ATCC 6633,
Staphylococcus aureus ATCC 29737 and Staphylococcus epidermidis
Ar
NH
Ar
O
6
5
4
NH2
CN
5a
9a
4a
3
N
7
8
.H O
H NH
N
2
2
2
2
10a
Et2N
O
12a,b
N
1
Et2N
N=CHOEt
9
10a,b
Ar
NH
Me
N
ATCC 12228) pathogenic bacteria using ampicillin 25
a reference compound and two fungi (Candida albicans ATCC 10231
and Saccharomyces cervesia ATCC 9080) using mycostatine 25 g/ml
mg/ml as
10a
Et2N
O
N
m
13
Ar
as a reference compound. The inhibition zone diameters were read
and rounded up to the nearest whole number (mm) for analysis.
The inhibitory effects of the synthetic compounds against these
organisms are given in (Table 1).
CN
N
e NH
M
2
N(Me)2
CH
Et2N
O
4. Cytotoxicity assays
14
Compounds 3aee were evaluated for their human tumor cell
growth inhibitory activity against two cell lines: MCF-7 (breast
Scheme 5. Synthesis of 5H-chromeno[2,3-d]pyrimidine derivatives (12a,b & 13) and
2-dimethylaminomethyleneamino-4H-chromene derivative (14).

768
N.M. Sabry et al. / European Journal of Medicinal Chemistry 46 (2011) 765e772
Table 1
Antibacterial screening data for some of the synthetic compounds.
Compounds (25
m
g/ml) Bo. bronchiseptica (eve) E. coli (eve) Ba. pumilus (þve) Ba. subtilis (þve) St. aureus (þve) St. epidermidis (þve) Ca. albicans Sa. cerevisa
3a
3b
3c
3d
3e
3f
4a
4b
4c
5b
7
10a
10b
11
12a
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
22
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
17
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
27
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
17
14
15
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
16
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
24
NA
NA
NA
NA
14
NA
NA
13
NA
NA
NA
NA
NA
26
NA
NA
NA
NA
14
NA
NA
14
NA
NA
NA
NA
NA
24
12b
21
16
25
15
24
22
15
22
13
20
21
25
21
24
25
14
20
14
15
16
NA
NA
21
NA
NA
20
NA
NA
25
NA
NA
21
NA
NA
25
NA
NA
24
NA
NA
15
NA
NA
20
Ampicillin
Mycostatine
24
e
25
e
20
e
25
e
26
e
25
e
e
e
22
24
NA ¼ not active Diameter of the hole ¼ 10 mm.
5. Result and discussion
The 4H-chromene and coumarin derivatives were chosen for
study because it is known that 4H-chromene and coumarin
derivatives are an important families of active compounds with
a wide range of pharmacological properties [1,41,42]. Twenty-one
compounds of both 4H-chromene and coumarin derivatives were
prepared. Structures of the synthesized compounds were eluci-
dated on the basis of IR, 1H NMR, 13C NMR and MS data.
Compounds 3aef, 4aec, 5b, 7, 10a,b, 11, 12a,b and 13e16 were
screened in vitro for their antibacterial and antifungal activity
against various gram-negative, gram-positive bacteria and fungal
strains using the agar diffusion method. The investigation of
antibacterial and antifungal screening data revealed that some of
the compounds tested have demonstrated congruent activity
against all tested microorganisms as compared with the standards
ampicillin and mycostatine. Compounds 3bee, 4a,b, 5b, 7, 10a,b,
11, 14 and 15 did not show any antimicrobial activity against all the
tested bacteria and fungi. Compounds 3a,f and 4c showed activity
against Staphylococcus aureus and Staphylococcus epidermidis,
while compounds 12a,b 13 and 16 showed high activity against all
Fig. 1. Evaluation of cytotoxicity against MCF-7 cell line.
adenocarcinoma) and HCT (lung carcinoma). The measurement of
cell growth and viability were determined as described in the
literature [40].
Cytotoxicity evaluation using viability assays were performed by
a Regional Center for Mycology & Biotechnology (RCMP), Al-Azhar
University. The inhibitory activity of the synthetic compounds 3aee
against two different human tumor cell lines MCF-7 (breast adeno-
carcinoma) and HCT (lung carcinoma) are given in Figs. 1 and 2.
tested microorganisms at a concentration of 25 mg/ml. These data
indicate that the activity is considerably affected by the presence
of the pyrimidine moiety in the structure, and not of the chromene
or coumarin moieties.
Compounds 3aee were tested against two different human
tumor cell lines MCF-7 (breast adenocarcinoma) and HCT (lung
carcinoma) and the cytotoxicity evaluation using viability assays
and the inhibitory activities are given in Figs. 1 and 2. IC50 values
were in the low concentration in microgram range. Compound 3a
had the most prominent activity against the human breast tumor
cells (MCF-7) (IC50 ¼ 15
mg/ml) and human lung cancer cells (HCT)
(IC50 ¼ 19.7 g/ml).
m
The structure activity relationship (SAR) of 4-aryl-4H-chromenes
demonstrates that substitution of the chlorine atom at the 4-posi-
tion of the phenyl ring and the cyano group at the 3-position in the
4H-chromene generally increased the activity profile. The type and
position of the halogen atom at the phenyl ring and the cyano or
ester group attached to the 4H-chromene seemed to have a variable
influence on the cytotoxic activity against various cell lines.
Fig. 2. Evaluation of cytotoxicity against HCT cell line.

N.M. Sabry et al. / European Journal of Medicinal Chemistry 46 (2011) 765e772
769
6. Conclusion
109.13 (C-4a), 108.31 (C-6), 98.20 (C-8), 60.17 (C-3), 44.42 (CH2),
39.81 (C-4), 12.50 (CH3) 144.53, 131.76, 129.86, 120.81(aromatic); MS
m/z (%): 399 (Mþ þ2, 35.82), 397 (Mþ, 31.37), 383 (100), 381 (87.67),
229 (7.03), 189 (91.94), 162 (24.08), 112 (8.99), 74 (10.06); Anal. Calcd
for C20H20BrN3O: C, 60.31; H, 5.06; N, 10.55. Found: C, 60.32; H, 5.16;
N, 10.46.
In this paper we report the synthesis of some 4H-chromene,
coumarin and chromeno-[2,3-d]pyrimidine derivatives and the
antimicrobial
& antitumor evaluation of some of the novel
compounds. The preliminary in vitro antimicrobial data demon-
strated that the chromeno[2,3-d]pyrimidine derivatives are more
active than 4H-chromene and coumarin derivatives.
Compound 3a has the most potent activity against the human
breast tumor cells (MCF-7) and human lung cancer cells (HCT). This
potency could be attributed to the presence of the chloro atom in
the 4-position of the phenyl ring in combination with the cyano
group in the 3-position in 4H-chromene.
7.1.1.4. 2-Amino-4-(4-fluorophenyl)-7-(diethylamino)-4H-chromene-
3-carbonitrile (3c). Red needles from ethanol; m.p. 165e166 ꢁC;
82%; IR (cmꢀ1) in KBr: 3470, 3302, 3203 (NH2), 2971, 2909, 2886,
2868 (CH), 2193 (CN); 1H NMR (500 MHz, CDCl3)
d: 7.11e6.16 (m,
7H, aromatic), 4.55 (s, 1H, H-4), 4.49 (bs, 2H, NH2), 3.23 (q,
J ¼ 7.5 Hz, 4H, 2CH2), 1.07 (t, J ¼ 7.5 Hz, 6H, 2CH3); 13C NMR
(125 MHz, CDCl3) d: 162.82 (C-2), 159.34 (C-8a), 149.55 (C-7),
7. Experimental
129.48 (C-5), 120.16 (CN), 115.41 (C-4a), 109.14 (C-6), 98.16 (C-8),
61.14 (C-3), 44.41 (CH2), 39.56 (C-4), 12.50 (CH3), 160.87, 141.17,
129.92, 115.58(aromatic); m/z (%) 337 (Mþ, 21.10), 242 (100), 207
(32.20), 170 (7.35), 133 (10.50), 75 (12.30); Anal. Calcd for
C20H20FN3O: C, 71.20; H, 5.97; N, 12.45. Found: C, 71.42; H, 6.11;
N, 12.63.
7.1. Chemistry
Melting points were determined with a Stuart Scientific Co. Ltd
apparatus. UV spectra were measured on a Shimadzu UV-160 1 PC
UVevisible spectrophotometer. IR spectra were determined as KBr
pellets on a Jasco FT/IR 460 plus spectrophotometer. 1H NMR and
13C NMR spectra were recorded using a Bruker AV 500 MHz spec-
trometer. 13C NMR spectra were obtained using distortionless
enhancement by polarization transfer (DEPT), with this technique,
the signals of CH & CH3 carbon atoms appears normal (up) and the
signal of carbon atoms in CH2 environments appears negative
(down). The MS were measured on a Shimadzu GC/MS-QP5050A
spectrometer. Elemental analyses were performed on a Per-
kineElmer 240 microanalyser in the Faculty of Science Cairo
University.
7.1.1.5. Ethyl 2-amino-4-(4-chlorophenyl)-7-(diethylamino)-4H-chro-
mene-3-carboxylate (3d). Colorless needles from ethanol; m.p.
143e144 ꢁC; 45%; IR (cmꢀ1) in KBr: 3410, 3308, 3200 (NH2), 2969,
2926, 2902 (CH), 1676 (CO); 1H NMR (500 MHz, CDCl3)
d: 7.12e6.17
(m, 9H, aromatic and NH2), 4.72 (s, 1H, H-4), 3.95 (q, J ¼ 5.9 Hz, 2H,
CH2), 3.21 (q, J ¼ 7.0 Hz, 4H, 2CH2), 1.10 (t, J ¼ 7.0 Hz, 6H, 2CH3), 1.02
(t, J ¼ 5.9 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3)
d: 169.54 (CO),
160.51 (C-2), 149.65 (C-8a), 147. 52 (C-7), 129.77 (C-5), 112.15 (C-4a),
108.81(C-6), 98.25 (C-8), 78.97 (C-3), 59.37 (CH2 ester) 44.40 (CH2),
39.07 (C-4), 14.36 (CH3 ester), 12.55 (CH3), 147.39, 131.25, 129.00,
128.14 (aromatic); MS m/z (%): 402 (Mþ þ2, 5.67), 400 (Mþ, 12.02),
289 (100), 243 (76.61), 199 (9.64), 151 (16.59), 111 (6.81), 76 (5.39);
Anal. Calcd for C22H25ClN2O3: C, 65.91; H, 6.29; N, 6.99. Found: C,
66.09; H, 6.46; N, 6.95.
7.1.1. Reaction of 3-N,N-diethylaminophenol (1) with 2aef
7.1.1.1. General procedure. A solution of 3-N,N-diethylaminophenol
(1) (0.01 mmol) in EtOH (30 ml) was treated with
a-cyanocinna-
monitriles (2aec) or ethyl -cyanocinnamates (2def) (0.01 mmol)
a
and piperidine (0.5 ml). The reaction mixture was heated until
complete precipitation occurred (reaction times: 60 min for 2aec;
120 min for 2def). The solid product which formed was collected
by filtration and crystallized from ethanol for compounds 3aef.
Compounds 4aec where separated from the fíltrate of the reaction
and crystallized from benzene. The physical and spectral data of
compounds 3aef and 4aec are as follows.
7.1.1.6. Ethyl 2-amino-4-(4-bromophenyl)-7-(diethylamino)-4H-chro-
mene-3-carboxylate (3e). Colorless needles from ethanol; m.p.
145e146 ꢁC; 42%; IR (cmꢀ1) in KBr: 3401, 3304, 3216 (NH2), 2974,
2925, 2892, 2874 (CH), 1676 (CO); 1H NMR (500 MHz, CDCl3)
d:
7.34e6.28 (m, 9H, aromatic and NH2), 4.81 (s, 1H, H-4), 4.07 (q,
J ¼ 7.5 Hz, 2H, CH2 ), 3.32 (q, J ¼ 7.5 Hz, 4H, 2CH2), 1.17 (t, J ¼ 7.5 Hz,
6H, 2CH3), 1.13 (t, J ¼ 7.5 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3)
d:
169.51(CO), 160.49 (C-2), 149.64 (C-8a), 147. 89(C-7), 129.76 (C-5),
112.04 (C-8), 108.81 (C-4a), 98.25 (C-6), 78.90 (C-3), 59.38 (CH2
ester), 44.40 (CH2), 39.14 (C-4), 14.35 (CH3 ester), 12.54 (CH3), 147.53,
131.08,129.42,119.36 (aromatic); MS m/z (%): 446 (Mþ þ2, 9.24), 444
(Mþ, 8.00), 289 (100), 243 (61.18), 199 (19.11), 151 (11.01), 76 (10.39);
Anal. Calcd for C22H25BrN2O3: C, 59.33; H, 5.66; N, 6.29. Found: C,
60.64; H, 6.04; N, 6.23.
7.1.1.2. 2-Amino-4-(4-chlorophenyl)-7-(diethylamino)-4H-chromene-
3-carbonitrile (3a). Yellow needles from ethanol; m.p. 152e153 ꢁC;
81%; IR (cmꢀ1) in KBr: 3471, 3334, 3196 (NH2), 2972, 2932, 2870
(CH), 2192 (CN); 1H NMR (500 MHz, CDCl3)
d: 7.17e6.15 (m, 7H,
aromatic), 4.57 (bs, 2H, NH2), 4.51(s, 1H, H-4), 3.21 (q, J ¼ 7.0 Hz, 4H,
2CH2), 1.05 (t, J ¼ 7.0 Hz, 6H, 2CH3); 13C NMR (125 MHz, CDCl3)
d:
159.58 (C-2), 149.57 (C-8a), 147.95 (C-7), 129.88 (C-5), 120.25 (CN),
109.13 (C-4a), 108.39 (C-6), 98.19 (C-8), 60.50 (C-3), 44.42 (CH2),
39.74 (C-4),12.52 (CH3) 143.98,132.69,129.33,129.07 (aromatic); MS
m/z (%): 355 (Mþ þ2, 0.94), 353 (Mþ, 2.80), 242 (3.27), 198 (23.89),
170 (2.80), 125 (2.03), 111 (34.45), 74 (100); Anal. Calcd for
C20H20ClN3O: C, 67.89; H, 5.70; N, 11.88. Found: C, 67.97; H, 5.79; N,
11.81.
7.1.1.7. Ethyl 2-amino-4-(4-fluorophenyl)-7-(diethylamino)-4H-chro-
mene-3-carboxylate (3f). Colorless needles from ethanol; m.p.
135e136 ꢁC; 40%; IR (cmꢀ1) in KBr: 3409, 3306, 3205 (NH2), 2977,
2928, 2903, 2874 (CH), 1675 (CO); 1H NMR (500 MHz, CDCl3)
d:
7.19e6.18 (m, 9H, aromatic and NH2), 4.74 (s, 1H, H-4), 3.99 (q,
J ¼ 7.5 Hz, 2H, CH2), 3.23 (q, J ¼ 7.5 Hz, 4H, 2CH2), 1.08 (t, J ¼ 7.5 Hz,
6H, 2CH3), 1.05 (t, J ¼ 7.5 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3)
d:
7.1.1.3. 2-Amino-4-(4-bromophenyl)-7-(diethylamino)-4H-chromene-
3-carbonitrile (3b). Red needles from ethanol; m.p.150e151 ꢁC; 80%;
IR (cmꢀ1) in KBr: 3430, 3329, 3196 (NH2), 2970, 2929, 2886, 2868
169.57 (CO), 162.08 (C-2), 149.68 (C-8a), 147. 53 (C-7), 129.76 (C-5),
112.62 (C-8), 108.88 (C-4a), 98.35 (C-6), 79.34 (C-3), 59.28 (CH2
ester), 44.40 (CH2), 38.91 (C-4), 14.32 (CH3 ester),12.54 (CH3), 160.47,
144.60, 128.97, 114.77 (aromatic); MS m/z (%): 384 (Mþ, 7.10), 367
(30.00), 271 (32.00), 227 (8.00), 207 (100), 177 (6.20), 133 (10.50), 75
(18.30), Anal. Calcd for C22H25FN2O3: C, 68.73; H, 6.55; N, 7.29.
Found: C, 68.71; H, 6.62; N, 7.33.
(CH), 2194 (CN); 1H NMR (500 MHz, CDCl3)
d: 7.36e6.18 (m, 7H,
aromatic), 4.79 (bs, 2H, NH2), 4.75 (s, 1H, H-4), 3.17 (q, J ¼ 7.0 Hz, 4H,
2CH2), 1.00 (t, J ¼ 7.0 Hz, 6H, 2CH3); 13C NMR (125 MHz, CDCl3)
d:
159.69 (C-2), 149.57 (C-8a), 147.95 (C-7), 129.69 (C-5), 120.36 (CN),

770
N.M. Sabry et al. / European Journal of Medicinal Chemistry 46 (2011) 765e772
7.1.1.8. 4-(4-Chlorophenyl)-7-(diethylamino)-coumarin-3-carbonitrile
CH3), 1.08(t, J ¼ 7.0 Hz, 6H, 2CH3); 13C NMR (125 MHz, CDCl3)
d:
(4a). Yellow needles from benzene; m.p. 175e176 ꢁC; 35%; IR (cmꢀ1
)
165.35 (C-2), 162.59 (C-10a), 157.98 (C-4), 150.59 (C-9a), 147.29
(C-8), 130.01(C-6), 109.26 (C-5a), 109.03 (C-7), 100.87 (C-9), 99.13
(C-4a), 44.49 (CH2), 37.67 (C-5), 21.23 (CH3), 12.49 (CH3), 144.43,
132.11, 129.63, 128.30 (aromatic); MS m/z (%): 397 (Mþ þ2, 32.88),
395 (Mþ, 100), 282 (24.41), 380 (79.84), 270 (35.08), 240 (94.75),
198 (26.08), 150 (25.26), 114 (24.01), 74 (11.91); Anal. Calcd for
C22H22ClN3O2: C, 66.75; H, 5.60; N, 10.61. Found: C, 66.64; H, 5.55;
N, 10.56.
in KBr: 3085, 2977, 2931, (CH), 2221 (CN), 1725 (CO); 1H NMR
(500 MHz, CDCl3)
d
: 7.48e6.45 (m, 7H, aromatic), 3.40 (q, J ¼ 7.5 Hz,
4H, 2CH2), 1.17 (t, J ¼ 7.5 Hz, 6H, 2CH3); 13C NMR (125 MHz, CDCl3)
d:
161.79 (C-4), 158.79 (CO), 157.24 (C-8a), 153.19 (C-7), 129.99 (C-5),
115.17 (CN),110.07 (C-4a),107.21 (C-6), 97.49 (C-8), 92.26 (C-3), 45.26
(CH2), 12.43 (CH3) 136.77, 131.26, 129.27, 128.34 (aromatic); MS m/z
(%): 354 (Mþ þ2, 11.24), 352 (Mþ, 37.36), 339 (32.60), 337 (100), 311
(10.42), 309 (33.01), 198 (4.34), 151 (20.89), 69 (86.45), 55 (95.37);
Anal. Calcd for C20H17ClN2O2: C, 68.09; H, 4.86; N, 7.94. Found: C,
68.02; H, 4.91; N, 8.00.
7.1.3.2. Method (b). A stream of dry HCl gas was passed through
a solution of 3d (0.01 mmol) in MeCN (30 ml) for 4e6 h. The
reaction mixture was poured into ice water and basified with 10%
ammonium hydroxide solution to give 6 with a yield of (62%) (m.p.
and mixed m.p. 238e239 ꢁC).
7.1.1.9. 4-(4-Bromophenyl)-7-(diethylamino)-coumarin-3-carbonitrile
(4b). Orange needles from benzene; m.p. 187e188 ꢁC; 34%; IR
(cmꢀ1) in KBr: 3080, 2977, 2931, (CH), 2222 (CN), 1726 (CO); 1H NMR
(500 MHz, CDCl3)
d
: 7.71e6.54 (m, 7H, aromatic), 3.49 (q, J ¼ 7.5 Hz,
7.1.4. 2-Benzylideneamino-4-(4-chlorophenyl)-7-(diethylamino)-
4H-chromene-3-carbonitrile (7)
4H, 2CH2), 1.27 (t, J ¼ 7.5 Hz, 6H, 2CH3); 13C NMR (125 MHz, CDCl3)
d:
161.78 (C-4), 158.17 (CO), 157.24 (C-8a), 153. 19 (C-7), 129.99 (C-5),
115.15 (CN),110.06 (C-4a),107.13 (C-6), 97.49 (C-8), 92.20 (C-3), 45.26
(CH2), 12.43 (CH3), 132.22, 131.73, 130.16, 125.06 (aromatic); MS m/z
(%): 398 (Mþ þ2, 46.39), 396 (Mþ, 43.33), 383 (100), 381 (96.34), 227
(1.00), 189 (66.89), 151 (13.34), 75 (10.14); Anal. Calcd for
C20H17BrN2O2: C, 60.47; H, 4.31; N, 7.05. Found: C, 59.72; H, 5.44; N,
6.29.
A mixture of 3a (0.01 mmol), benzaldehyde (0.01 mmol),
ethanol (20 ml) and piperidine (0.5 ml) was refluxed for 2 h. The
solid product, was collected by filtration and crystallized from
ethanol give 7 as yellow crystals; m.p. 185e186 ꢁC; 85%; IR (cmꢀ1
)
in KBr: 3083, 3061, 3034, 2969, 2927, 2891 (CH), 2207 (CN), 1638
(C]N); 1H NMR (500 MHz, CDCl3)
d: 8.92 (s, 1H, N]CH), 7.94e6.30
(m,12H, aromatic), 4.75 (s, 1H, H-4), 3.27 (q, J ¼ 7.0 Hz, 4H, 2CH2),
1.09 (t, J ¼ 7.0 Hz, 6H, 2CH3); 13C NMR (125 MHz, CDCl3)
d: 162.21
7.1.1.10. 4-(4-Fluoromophenyl)-7-(diethylamino)-coumarin-3-car-
bonitrile (4c). Orange needles from benzene; m.p. 208e209 ꢁC;
36%; IR (cmꢀ1) in KBr: 3060, 2979, 2934, (CH), 2217 (CN), 1725 (CO);
(C-2), 158.23 (N]CH), 150.01 (C-8a), 148.30 (C-7), 130.23 (C-5),
117.96 (CN), 109.53 (C-4a), 107.29 (C-6), 98.38 (C-8), 88.16 (C-3),
44.47 (CH2), 42.35 (C-4), 12.58 (CH3), 142.54, 134. 98, 133.24, 133.18,
129.96, 129.69, 129.05, 128.96 (aromatic); MS m/z (%): 443 (Mþ þ2,
21.64), 441 (Mþ, 61.98), 243 (32.65), 198 (27.49), 148 (25.89), 104
(68.23), 88 (100). Anal. Calcd for C27H24ClN3O: C, 73.38; H, 5.47; N,
9.51. Found: C, 73.41; H, 5.34; N, 8.91.
1H NMR (500 MHz, CDCl3)
d: 7.48e6.53 (m, 7H, aromatic), 3.49 (q,
J ¼ 5.0 Hz, 4H, 2CH2), 1.25 (t, J ¼ 5.0 Hz, 6H, 2CH3); 13C NMR
(125 MHz, CDCl3) d: 164.85 (C-4), 162.02 (CO), 158.90 (C-8a), 157.12
(C-7), 128.89 (C-5), 116.26 (CN), 110.34 (C-4a), 107.35 (C-6), 97.43
(C-8), 92.23 (C-3), 45.25 (CH2), 12.42 (CH3), 162.85, 153.20, 130.80,
115.31(aromatic); m/z % 336 (Mþ, 39.33), 321 (100), 293 (26.10), 199
(3.15), 170 (7.80), 133 (8.50), 75 (5.60); Anal. Calcd for C20H17FN2O2:
C, 71.42; H, 5.09; N, 8.33. Found: C, 71.33; H, 5.04; N, 8.28.
7.1.5. Reaction of 7 with hydrazine derivatives
A mixture of 7 (0.01 mmol), hydrazine hydrate or phenyl
hydrazine (0.01 mmol) in EtOH was stirring at room temperature or
reflux for 2 h to give 3a (m.p. and mixed m.p. 152e153 ꢁC) yield
(80%).
7.1.2. 2-Diacetylamino-4-(4-chlorophenyl)-7-(diethylamino)-4H-
chromene-3-carbonitrile (5b)
A solution of 3a (0.01 mmol) in Ac2O (20 ml) was heated under
reflux for 30 min. The solid product that formed was filtered,
washed with cooled EtOH, dried and crystallized from ethanol to
give 5b as pale yellow crystals; m.p. 137e138 ꢁC; 75%; IR (cmꢀ1) in
KBr: 3065, 2964, 2924, 2894 (CH), 2224 (CN), 1742 (CO); 1H NMR
7.1.6. Reaction of 3a,b with triethyl orthoformate
7.1.6.1. General procedure. A mixture of
b-enaminonitrile 3a
(0.01 mmol), triethyl orthoformate (0.01 mmol) and Ac2O (30 ml)
was refluxed for 3 h. The solvent was removed under reduced
pressure and the resulting solid was crystallized from benzene to
give 10a, while the remaining solid was crystallized from ethanol to
give 11. The same treatment with 3b afforded 10b which was
crystallized from benzene. The physical and spectra data of the
compounds are as follows.
(500 MHz, CDCl3)
3.40 (q, J ¼ 7.0 Hz, 4H, 2CH2), 2.44 (s, 6H, 2COCH3), 1.05 (t, J ¼ 7.0 Hz,
6H, 2CH3); 13C NMR (125 MHz, CDCl3)
: 170.51 (CO), 152.13 (C-2),
d: 7.48e6.36 (m, 7H, aromatic), 5.13 (s, 1H, H-4),
d
149.28 (C-8a), 147.86 (C-7), 129.88 (C-5), 115 (CN), 110.07 (C-4a),
108.18 (C-6), 97.92 (C-8), 92.18 (C-3), 43.64 (CH2), 40.38 (C-4), 24.00
(CH3), 12.22 (CH3), 142.13, 132.25, 129.67, 128.73 (aromatic); m/z (%)
439 (Mþ þ2, 0.32), 437 (Mþ, 1.10), 356 (3.67), 354 (14.33), 316
(39.69), 314 (100), 290 (16.75), 288 (49.80), 176 (13.28), 151 (89.89),
89 (18.51), 54 (42.87); Anal. Calcd for C24H24ClN3O3: C, 65.82; H,
5.52; N, 9.60. Found: C, 65.61; H, 5.34; N, 9.41.
7.1.6.2. 4-(4-Chlorophenyl)-7-(diethylamino)-2-ethoxymethylenea-
mino-4H-chromene-3-carbonitrile (10a). Pale yellow crystals from
benzene; m.p. 144e145 ꢁC; 61%; IR (cmꢀ1) in KBr: 2967, 2925, 2868
(CH), 2203 (CN), 1644 (C]N); 1H NMR (500 MHz, CDCl3)
d: 8.43 (s,
1H, N]CH), 7.31e6.31 (m,7H, aromatic), 4.75 (s, 1H, H-4), 4.44 (q,
J ¼ 7.2 Hz, 2H, CH2), 3.34 (q, J ¼ 7.2 Hz, 4H, 2CH2), 1.40 (t, J ¼ 7.2 Hz,
7.1.3. 5-(4-Chlorophenyl)-8-(diethylamino)-2-methyl-3,4-dihydro-
5H-chromeno-[2,3-d]-pyrimidin-4-one (6)
3H, CH3), 1.83 (t, J ¼ 7.2 Hz, 6H, 2CH3); 13C NMR (125 MHz, CDCl3)
d:
159.44 (C-2), 157.68 (N]CH), 150.01 (C-8a), 148.14 (C-7), 129.93 (C-
5), 118.47 (CN), 109.14 (C-4a), 107.47 (C-6), 98.27 (C-8), 80.87 (C-3),
64.08 (CH2 ethoxy), 44.42 (CH2), 41.68 (C-4), 13.96 (CH3 ethoxy),
12.54 (CH3), 142.97, 133.01, 129.59, 128.64 (aromatic); MS m/z (%):
411 (Mþ þ2, 17.18), 409 (Mþ, 40,29), 298 (100), 270 (18.86), 242
(52.75), 169 (13.86), 113 (15.08), 75 (12.16); Anal. Calcd for
C23H24ClN3O2: C, 67.39; H, 5.90; N,10.25. Found: C, 67.47; H, 6.01; N,
10.32.
7.1.3.1. Method (a). A solution of 3a (0.01 mmol) in Ac2O (20 ml)
was heated under reflux for 15 min, 30 min or 6h. The solid product
was filtered, washed with cooled EtOH, dried and crystallized from
ethanol to give 6 as colorless crystals; m.p. 238e239 ꢁC; 75%; IR
(cmꢀ1) in KBr: 3300 (NH), 2966, 2929, 2868 (CH), 1647 (CO); 1H
NMR (500 MHz, CDCl3)
d: 13.00 (br, 1H, NH) 7.23e6.31(m, 7H,
aromatic), 5.02 (s, 1H, H-4), 3.24 (q, J ¼ 7.0 Hz, 2H, CH2), 2.34(s, 3H,

N.M. Sabry et al. / European Journal of Medicinal Chemistry 46 (2011) 765e772
771
7.1.6.3. 4-(4-Bromophenyl)-7-(diethylamino)-2-ethoxymethylenea-
mino-4H-chromene-3-carbonitrile (10b). Pale red crystals from
benzene; m.p. 143e144 ꢁC; 83%; IR (cmꢀ1) in KBr: 2966, 2925, 2868
(40.13), 157 (11.49), 114 (14.53), 76 (9.97). Anal. Calcd for
21H22BrN5O: C, 57.28; H, 5.04; N, 15.90. Found: C, 57.15; H, 5.06; N,
15.82.
C
(CH), 2204 (CN), 1644 (C]N); 1H NMR (500 MHz, CDCl3)
d: 8.43 (s,
1H, N]CH), 7.47e6.30 (m,7H, aromatic), 4.74 (s, 1H, H-4), 4.44 (q,
J ¼ 7.2 Hz, 2H, CH2), 3.34 (q, J ¼ 7.0 Hz, 4H, 2CH2), 1.40 (t, J ¼ 7.2 Hz,
7.1.9. 5-(4-Chlorophenyl)-8-(diethylamino)-4-imino-3-methyl-3,4-
dihydro-5H-chromeno-[2,3-d]pyrimidine (13)
3H, CH3), 1.83 (t, J ¼ 7.0 Hz, 6H, 2CH3); 13C NMR (125 MHz, CDCl3)
d:
A mixture of 10a (0.01 mmol) and methylamine (0.01 mmol) in
ethanol was stirred at room temperature for 1h. The solid product
was collected and crystallized from ethanol to give 13 as colorless
needles, m.p. 160e161 ꢁC; 83%; IR (cmꢀ1) in KBr: 3334 (NH), 2971,
159.43 (C-2), 157.69 (N]CH), 150.01 (C-8a), 148.14 (C-7), 129.94 (C-
5), 118.45 (CN), 109.37 (C-4a), 107.38 (C-6), 98.25 (C-8), 80.76 (C-3),
64.09 (CH2 ethoxy), 44.41 (CH2), 41.75 (C-4), 13.95 (CH3 ethoxy),
12.54 (CH3), 143.45, 131.89, 131.68, 121.19 (aromatic); MS m/z (%):
455 (Mþ þ2, 30.46), 453 (Mþ, 27.52), 298 (100), 242 (38.41), 198
(21.59),151 (8.33), 74 (3.07); Anal. Calcd for C23H24BrN3O2: C, 60.80;
H, 5.32; N, 9.25. Found: C, 60.93; H, 5.42; N, 9.34.
2930, 2880 (CH), 1638 (C]N); 1H NMR (500 MHz, CDCl3)
d: 7.71 (s,
1H, H-2), 7.17e6.27 (m,8H, aromatic and NH), 4.73 (s, 1H, H-5), 3.33
(s, 3H, CH3), 3.22 (q, J ¼ 7.5 Hz, 4H, 2CH2), 1.06 (t, J ¼ 7.5 Hz, 6H,
2CH3); 13C NMR (125 MHz, CDCl3)
d: 158.32 (C-4), 157.51(C-10a),
150.01 (C-9a),149.59 (C-2), 147.88 (C-8), 129.65 (C-6), 109.28 (C-5a),
108.94 (C-7), 99.01 (C-9), 98.30 (C-4a), 44.42 (CH2), 39.52 (C-5),
35.12 (CH3), 12.49 (CH3), 143.22, 132. 83, 129.19, 128.84 (aromatic);
MS m/z (%): 396 (Mþ þ2, 17.42), 394 (Mþ, 44.42) 379(100), 242
(26.25), 198 (42.89), 141 (26.15), 113 (10.43), 77 (6.96). Anal. Calcd
for C22H23ClN4O: C, 66.91; H, 5.87; N,14.19. Found: C, 67.02; H, 6.03;
N, 14.21.
7.1.7. 5-(4-Chlorophenyl)-N,N-diethyl-2-methyl-4-oxo-4,5-dihydro-
3H-chromeno[2,3-d]-pyrimidin-8-aminium acetate (11)
Pale red crystals; m.p. 234e235 ꢁC; 35%; IR (cmꢀ1) in KBr: 3389
(NH), 2972, 2934, 2871 (CH), 1652, 1663 (CO); 1H NMR (500 MHz,
CDCl3)
H-4), 3.33 (q, J ¼ 7.0 Hz, 2H, CH2), 2.37 (s, 3H, CH3), 1.21 (t, J ¼ 7.0 Hz,
6H); 13C NMR (125 MHz, CDCl3)
: 165.53 (C-2), 162.62 (C-10a),
d: 13.37 (br,1H, NH), 7.38e6.41 (m, 7H, aromatic), 5.08 (s,1H,
d
158.11 (C-4), 150.60 (C-9a), 147.89 (C-8), 130.03 (C-6), 109.47 (C-5a),
104.30 (C-7), 99.16 (C-4a), 97.11 (C-9), 44.69 (CH2), 39.07 (C-5), 21.17
(CH3), 12.60 (CH3), 144.47, 132.24, 129.67, 128.35 (aromatic); MS m/z
(%): 457 (Mþþ2, 0.89), 455 (Mþ, 2.70), 284 (100), 270 (13.68), 240
(25.00), 198 (10.15), 143 (3.29), 111 (9.73), 77 (32.91); Anal. Calcd for
C24H26ClN3O4: C, 63.22; H, 5.75; N, 9.22. Found: C, 63.30; H, 5.82; N,
9.33.
7.1.10. 2-Dimethylaminomethyleneamino-4-(4-Chlorophenyl)-8-
(diethylamino)-4H-chromene-3-carbonitrile (14)
A mixture of 10a (0.01 mmol) and dimethylamine (0.01 mmol)
in ethanol was stirred at room temperature for 1h. The solid
product was collected and crystallized from ethanol to give 14 as
colorless needles, m.p. 159e160 ꢁC; 81%; IR (cmꢀ1) in KBr: 2974,
2910, 2895, 2875 (CH), 2193 (CN), 1670 (C]N); 1H NMR (500 MHz,
CDCl3) d: 8.24 (s, 1H, N]CH), 7.28e6.31 (m,7H, aromatic), 4.72 (s,
7.1.8. Reaction of 10 with hydrazine hydrate
1H, H-4), 3.35 (q, J ¼ 7.5 Hz, 4H, 2CH2), 3.14, 3,12 (s, 6H, 2CH3), 1.18
7.1.8.1. General procedure. A solution of (10a,b) (0.01 nmol) and
hydrazine hydrate (99%, 5 ml) in EtOH (50 ml) was stirred at room
temperature for 1h. The solid product, was collected by filtration
and crystallized from benzene to give 12a,b. The physical and
spectra data of the compounds 12a,b are as follows.
(t, J ¼ 7.5 Hz, 6H, 2CH3); 13C NMR (125 MHz, CDCl3)
d: 160.32 (C-2),
153.91 (N]CH), 150.45 (C-8a), 147.97 (C-7), 129.84 (C-5), 120.64
(CN), 108.88 (C-4a), 108.58 (C-6), 98.30 (C-8), 74.07 (C-3), 44.38
(CH2), 41.80 (CH3), 40.87 (CH3), 34.76 (C-4), 12.54 (CH3), 144.09,
132.53, 129.49, 128.96 (aromatic); MS m/z (%): 410 (Mþ þ2, 11.84),
408 (Mþ, 32.06), 297 (100), 253 (14.45), 204 (12.06), 150 (1.51), 127
(6.33), 74 (1.34); Anal. Calcd for C22H25ClN4O: C, 67.55; H, 6.16; N,
13.70. Found: C, 67.60; H, 6.24; N, 13.83.
7.1.8.2. 3-Amino-5-(4-chlorophenyl)-8-(diethylamino)-4-imino-3,4-
dihydro-5H-chromeno-[2,3-d]pyrimidine (12a). Colorless needles;
m.p. 178e179 ꢁC; 81%; IR (cmꢀ1) in KBr: 3322, 3315, 3300, 3266
(NH2 and NH), 3060, 2969, 2880 (CH), 1636 (C]N); 1H NMR
7.1.11. (E) N0-(4-(4-chlorophenyl)-3-cyano-7-(diethylamino)-4H-
chromen-2-yl)formimidamide (15)
(500 MHz, CDCl3) d: 8.00 (s, 1H, H-2), 7.19e6.26 (m,7H, aromatic),
6.00 (br,1H, NH), 4.71 (brs, 2H, NH2), 4.67 (s, 1H, H-5), 3.22 (q,
A mixture of 10a (0.01 mmol) and NH3 gas in methanol was
stirred for 1 h, then the mixture was left overnight. The solid
product was collected and crystallized from ethanol to give 15 as
colorless needles; m.p. 170e171 ꢁC; 80%; IR (cmꢀ1) in KBr: 3370,
3164 (NH2), 2975, 2933, 2880 (CH), 2196 (CN),1677 (C]N); 1H NMR
J ¼ 7.5 Hz, 4H, 2CH2), 1.05(t, J ¼ 7.5 Hz, 6H, 2CH3); 13C NMR
(125 MHz, CDCl3) d: 158.62 (C-4), 157.06 (C-10a), 150.46 (C-9a),
149.55 (C-8), 143.09 (C-2), 129.62 (C-6), 109.17 (C-5a), 108.94 (C-7),
98.97 (C-4a), 98.03 (C-9), 44.43 (CH2), 39.85 (C-5), 12.51 (CH3),
147.88, 132.93, 129.46, 128.87 (aromatic); MS m/z (%): 397 (Mþ þ2,
5.65), 395 (Mþ, 13.16), 381 (37.05), 379 (100), 354 (4.80), 352
(14.81), 242 (19.70), 197 (32.49), 151 (21.09), 113 (9.06), 74 (5.57).
Anal. Calcd for C21H22ClN5O: C, 63.71; H, 5.60; N, 17.69. Found: C,
63.59; H, 5.48; N, 17.58.
(500 MHz, CDCl3)
d
: 8.83 [d, J ¼ 10 Hz, 1H, NH(a)], 8.39, 8.38 [dd,
J ¼ 10 Hz, 1H, CH(b)], 7.29e6.18 (m, 7H, aromatic), 5.76 [d, J ¼ 10 Hz,
1H, NH(c)], 4.58 (s, 1H, H-4), 3.24 (q, J ¼ 7.5 Hz, 4H, 2CH2), 1.07 (t,
J ¼ 7.5 Hz, 6H, 2CH3); 13C NMR (125 MHz, CDCl3)
d: 160.20 (C-2),
154.64 (N]CH), 150.09 (C-8a), 148.06 (C-7), 129.77 (C-5), 120.91
(CN), 109.10 (C-4a), 106.22 (C-6), 98.24 (C-8), 74.59 (C-3), 44.39
(CH2), 41.58 (C-4), 12.55 (CH3), 143.68, 132.77, 129.54, 128.85
(aromatic); MS m/z (%): 382 (Mþþ2, 21.38), 380 (Mþ, 57.35), 269
(100), 242 (8.26), 225 (13.91), 198 (16.50), 149 (4.72), 95 (11.67), 69
(20.88); Anal. Calcd for C21H21ClN4O: C, 66.22; H, 5.56; N, 14.71.
Found: C, 66.13; H, 5.44; N, 14.65.
7.1.8.3. 3-Amino-5-(4-bromophenyl)-8-(diethylamino)-4-imino-3,4-
dihydro-5H-chromeno-[2,3-d]pyrimidine (12b). Colorless needles;
m.p. 175e176 ꢁC; 80%; IR (cmꢀ1) in KBr: 3345, 3315, 3299, 3266
(NH2 and NH), 3061, 2970, 2927, 2890 (CH), 1636 (C]N); 1H NMR
(500 MHz, CDCl3) d: 8.05 (s, 1H, H-2), 7.29e6.35 (m,7H, aromatic),
6.09 (br,1H, NH), 4.84 (brs, 2H, NH2), 4.80 (s, 1H, H-5), 3.31 (q,
J ¼ 6.2 Hz, 4H, 2CH2), 1.14(t, J ¼ 6.2 Hz, 6H, 2CH3); 13C NMR
7.1.12. 4-Amino-5-(4-chlorophenyl)-8-(diethylamino)-5H-
chromeno[2,3-d]pyrimidine (16)
(125 MHz, CDCl3) d: 158.62 (C-4), 157.06 (C-10a), 150.48 (C-9a),
149.56 (C-8), 143.10 (C-2), 129.86 (C-6), 109.17 (C-5a), 108.95 (C-7),
99.26 (C-4a), 98.97 (C-9), 44.42 (CH2), 39.82 (C-5), 12.52 (CH3),
147.88, 132.90, 129.86, 128.87 (aromatic); MS m/z (%): 439 (Mþ,
3.34), 423 (4.48), 398 (Mþ þ2,10.10), 396 (Mþ,10.46), 242 (100),198
7.1.12.1. Method (a). A mixture of 10a (0.01 mmol) and NH3 gas in
methanol was stirred for 2h, then the mixture was left overnight.
The solid product was collected and crystallized from benzene to
give 16 as colorless needles; m.p. 240e241 ꢁC; 81%; IR (cmꢀ1) in

772
N.M. Sabry et al. / European Journal of Medicinal Chemistry 46 (2011) 765e772
KBr: 3467, 3317, 3148 (NH2), 2972, 2931, 2895 (CH), 1649 (C]N); 1H
NMR (500 MHz, CDCl3) : 8.20 (s, 1H, H-2), 7.21e6.25 (m, 7H,
[19] R.N. Taylor, A. Cleasby, O. Singh, T. Sharzynski, J.A. Wonacott, W.P. Smith,
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[26] A.H. Bedair, N.A. El-Hady, M.S. Abd El-Latif, A.H. Fakery, A.M. El-Agrody, IL
Farmaco 55 (2000) 708.
[27] A.Z. Sayed, N.A. El-Hady, A.M. El-Agrody, J. Chem. Res. (S) (2000) 146.
[28] A.M. El-Agrody, M.S. Abd El-Latif, N.A. El-Hady, A.H. Fakery, A.H. Bedair,
Molecules 6 (2000) 519.
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Farmaco 56 (2001) 965.
d
aromatic), 4.87 (bs, 2H, NH2), 4.79 (s, 1H, H-5), 3.22 (q, J ¼ 7.5 Hz,
4H, 2CH2), 1.04 (t, J ¼ 7.5 Hz, 6H, 2CH3); 13C NMR (125 MHz, CDCl3)
d: 163.20 (C-10a), 162.62 (C-4), 157.26 (C-2), 149.85 (C-8), 148.03 (C-
9a), 129.65 (C-6), 108.90 (C-5a), 108.65 (C-7), 99.24 (C-4a), 96.46 (C-
9), 44.43 (CH2), 39.10 (C-5), 12.49 (CH3), 142.81, 133. 34, 129.61,
128.95 (aromatic); MS m/z (%): 382 (Mþþ2, 17.75), 380 (Mþ, 50.76),
369 (100), 242 (13.02), 225 (15.84), 198 (25.26), 168 (6.88), 112
(5.70), 94 (5.176), 68 (5.72); Anal. Calcd for C21H21ClN4O: C, 66.22;
H, 5.56; N, 14.71. Found: C, 66.33; H, 5.61; N, 14.83.
7.1.12.2. Method (b). A mixture of 3a (0.01 mmol) and formamide
(0.01 mmol) was stirred at reflux for 3 h. The solvent was removed
under vacuum. The solid obtained was recrystallized from benzene
to give 16 with a (61%) yield (m.p. and mixed m.p. 240e241 ꢁC).
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Heterocycles 63 (2004) 1793.
7.1.12.3. Method (c). Compound 15 (0.01 mmol) was heated under
reflux in dioxan (20 ml) and piperidine (0.5 ml) for 3 h to give 16
with a (58%) yield (m.p. and mixed m.p. 240e241 ꢁC).
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Determination of minimum inhibitory concentrations (MICs) of antibacterial
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