One-step synthesis of chromene-3-carboxamide, bis-chromene, chromeno[3,4-c]pyridine and bischromeno[3,4-c]pyridine derivatives for antimicrobial evaluation

Article abstract of DOI:10.3184/030823410X12812852410870

Cyanoacetamide derivatives were reacted with salicylaldehyde under different conditions afforded chromenes and coumarin derivatives respectively. A number of chromeno[3,4-c]pyridine derivatives were prepared from the reaction of N-cyclohexyl-2-imino-2H-chromene-3-carboxamide with malononitrile and/or cynaothiocatemaide. Bischromeno[3,4-c]pyridine derivatives were prepared from the reaction of N,N'-(ethane-1,2-diyl)bis(2-imino-2Hchromene-3-carboxamide) with malononitrile and/or N-alkyl-2-cyanoacetamide derivative with 2-iminochroemen derivative, respectively. Some of these compounds were screened for their antimicrobial activities.

Full text of DOI:10.3184/030823410X12812852410870

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 465
AUGUST, 465–469
One-step synthesis of chromene-3-carboxamide, bis-chromene,
chromeno[3,4-c]pyridine and bischromeno[3,4-c]pyridine derivatives for
antimicrobial evaluation
Mohamed H. Helal*, Gameel A. M. El-Hag Ali, Ahmed A. Ali and Yousry A. Ammar
Chemistry Department, Faculty of Science, Al-Azhar University, 11284 Nasr City, Cairo, Egypt
Cyanoacetamide derivatives were reacted with salicylaldehyde under different conditions afforded chromenes
and coumarin derivatives respectively. A number of chromeno[3,4-c]pyridine derivatives were prepared from the
reaction of N-cyclohexyl-2-imino-2H-chromene-3-carboxamide with malononitrile and/or cynaothiocatemaide.
Bischromeno[3,4-c]pyridine derivatives were prepared from the reaction of N,N’-(ethane-1,2-diyl)bis(2-imino-2H-
chromene-3-carboxamide) with malononitrile and/or N-alkyl-2-cyanoacetamide derivative with 2-iminochroemen
derivative, respectively. Some of these compounds were screened for their antimicrobial activities.
Keywords: chromenes, bischromene, chromeno[3,4-c]pyridines, bischromeno-[3,4-c]pyridines, antimicrobial activity
Antibacterial, coronary dilatory and hypothermal agents as
well as potential laser dyes have been reported for many
chromene derivatives.1–4 Moreover, coumarin derivatives have
anticoagulant and antibacterial activities.5–9 Furthermore, ben-
zocoumarins have analgesic and antihypertensive activities.10
The present study is part of our program aimed at developing
easy routes for the synthesis of fused heterocyclic compounds
starting with cyanoacetanilides as simple organic compounds.
We now report the synthesis of chromene carboxamide and
bischromene derivatives and their use as building blocks in the
synthesis of novel pyridochromene derivatives to evaluate their
antimicrobial activity.
in complete accordance with compound 4. Furthermore, the
structure of 4 was showed the identity (m.p, and mixed m.p) of
an authentic sample synthesised upon hydrolysis of 3 with
EtOH/HCl.
Moreover, the resulting chromene derivatives have latent
functional substituents which have the potential for their
chemical transformations giving new routes for the prepara-
tion of condensed chromene with possible biological activity.
Thus, the dihydrochromenopyridine derivative 7 was obtained
up on treatment of chromene derivative 3 with malononitrile in
presence of piperidine as a catalyst, Scheme 2. The structure
of 7 was confirmed on the basis of elemental analysis and
spectral data. Both elemental and spectral data supported the
proposed structure 11 the other possible structures 9, 10 were
ruled out due to the odour of H2S not observed during the
reaction (lead acetate test). The formation of 7 may be assumed
to proceed via the addition of an active methylene group to the
double bond of chromene to give the Michael adduct 5 which
underwent cyclisation to give dihydropyridine 7.
From the literature, attention has increasingly been paid to
the synthesis of bisheterocyclic compounds which exhibit
various biological activities including antibacterial, fungicidal,
tuberculostatic, and plant growth regulative properties.12−15
Earlier work revealed that bisheterocyclic compounds dis-
played much better antibacterial activity than heterocyclic
compounds.16 Thus, bis 2-imino chromene derivative 12 was
obtained via the reaction of cyanoacetamide 1b with salicylal-
dehyde 2 (1:2 molar ratio) under reflux. Elemental analysis
Results and discussion
N-Alkyl-2-cyanoacetamide derivatives 1a,b were prepared in
high yield from the reaction of aliphatic amines with ethyl cya-
noacetate.11 Cyclocondensation of cyanoacetamide derivative
1a with salicylaldehdye 2 in refluxing ethanol containing a
catalytic amount of ammonium acetate furnished 3, Scheme 1.
The structure of 3 was established on the basis of elemental
analysis and spectral data. The reaction probably takes place
through condensation of the aldehydic group with the active
methylene function in compound 1a followed by nucleophilic
attack of the hydroxyl group on the neighbouring nitrile resi-
due eventually giving the corresponding 3. On the other hand,
cyclocondensation of 1b with salicylaldehdye 2 in refluxing
acetic anhydride containing a catalytic amount of sodium
acetate furnished 4. Elemental analysis and spectral data were
Scheme 1
* Correspondent. E-mail: m_h_helal_chem@yahoo.com

466 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 2
and spectral data were in complete agreement with compound
12 (see Figs 1 and 2).
good activities against the reference chemotherapeutics. On
the other hand, most of the prepared compounds exhibited
good antifungal activities against the reference drugs.
We report here a simple and convenient route for the synthe-
sis of some heterocyclic bases on chromene, bischromene,
chromeno[3,4-c]-pyridine, and bischromeno[3,4-c]pyridines
derivatives for antimicrobial evaluation.
The tested compounds were evaluated by the agar diffusion
technique using a 1 mg mL−1 solution in DMSO.18 The test
organisms were four bacterial strains: Bacillius theringiensis,
Serratia marcescens, Klebsiella pneumoniae, and Proteus
mirabilis and two fungi: Fusarium oxysporum, and Aspergillus
ochraceus. A control using DMSO without the test compound
was included for each organism. Ampicillin was purchased
from the Egyptian market and used in a concentration
2 mg mL−1 as reference drugs. The bacterial and fungi were
tested on nutrient agar and potato dextrose agar media, respec-
tively. Three plates were used for each compound as replicates.
The plates were incubated for 24 h, and seven days for bacteria
and fungi, respectively. After the incubation period, the
diameter of inhibition zone was measured as an indicator of
the activity of the compounds.
Treatment of 2-iminochromene derivative 1317 with cyano-
acetamide derivative 1b afforded bischromeno[3,4-c]pyridine
derivative 14 and the other possible structure 15 was excluded
on the basis of elemental and spectral data. Also, bischromeno-
pyridine derivative 16 was obtained via the reaction of 12 with
malononitrile in ethanol in the presence of a catalytic amount
of piperidine. Infrared spectrum of compound 16 displayed
absorption bands at 3436, 3344, 3186 (NH and NH2), 2206
1
(C≡N) and 1660 (C=O). The H NMR spectrum revealed
three singlets at δ 4.01, 6.57, and 9.21 for CH2, NH2, and NH,
respectively, Scheme 3.
Antimicrobial activity
Most synthesised compounds were screened for their antimi-
crobial activity. The diameter of inhibition zone was measured
as an indicator for the activity of the compounds; ampicillin is
used as reference drug.
The results for antibacterial activities depicted in Table 1
revealed that compounds 3, 4, 7, 11, 12, 14 and 16 exhibited

JOURNAL OF CHEMICAL RESEARCH 2010 467
Fig. 1 13C NMR spectrum of compound 12.
Fig. 2 Fragmentation pattern of compound 12.
N-Cyclohexyl-2-imino-2H-chromene-3-carboxamide (3): A mix-
ture of cyanoacetamide derivative (1a) (0.01 mol), salicylaldehyde
(0.01 mol) and ammonium acetate (0.01 mol) was refluxed in ethanol
(30 mL) for 2 h. The solid product which produced on heating was
collected and recrystallised from dioxane as white yellow crystals;
70% yield, m.p. 172–174 °C. IR (KBr): ν = 3180 (NH), 2924 (stretch-
Experimental
All melting points are uncorrected. IR spectra (KBr) were measured
on a Shimadzu 440 spectrometer, H NMR spectra were obtained in
1
DMSO on a Varian Gemini 200 MHz spectrometer using TMS as
internal standard; chemical shifts are reported as (ppm). Mass spectra
were obtained on a GCMS\QP 1000 Ex mass spectrometer at 70 eV.
Elemental analyses were carried out at the Microanalytical Centre,
Faculty of Science (Cairo University, Egypt). Microbiology screening
carried out in Botany Department, Faculty of Science, Al-Azhar
University.
1
ing CH) and 1654 cm−1 (C=O). H NMR (DMSO-d6): δ = 1.32–1.36
(m, 6H, cyclohexyl protons), 1.66–1.86 (m, 4H, cyclohexyl protons),
3.80 (hump, 1H, cyclohexyl proton), 7.40–8.01 (m, 4H, ArH), 8.26 (s,
1H, chromene-H), 8.85, 10.49 (2s, 2H, 2NH; exchangeable with D2O).

468 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 3
Table 1 Zone (mean diameter of inhibition in mm) as a criterion of antibacetrial and antifungal activities of the newly synthesised
compounds
Compound
Bacteria
Fungi
Bacillius
theringiensis
Serratia
marcescens
Klebsiella
pneumoniae
Proteus
mirabilis
Fusarium
oxysporum
Aspergillus
ochraceus
3
12
11
15
14.5
13
14
15
17
30
32
29
31
32
33
34
40
18
17
19
16
17
16
15
20
34
35
30
29
30
34
32
40
12
11
10
11
11
12
14
15
8
7
4
7
8
11
6
6
6.5
7
10
12
14
16
Ampicillin

JOURNAL OF CHEMICAL RESEARCH 2010 469
MS: m/z = 269 (M-1, 25%), 76 (100%). Anal. Calcd for C16H18N2O2
(270.33): C, 71.09; H, 6.71; N, 10.36. Found: C, 71.00; H, 6.60; N,
10.30%.
2,2p-(Ethane-1,2-diylbis(azanediyl))bis(4,5-dioxo-4,5-dihydro-3H-
chromeno-[3,4-c]pyridine-1-carbonitrile) (14): A mixture of com-
pound (1b) (0.01 mol), 2-imino-chromene derivative (13) (0.02 mol)
and piperidine (0.01 mol) was refluxed in dioxane (30 mL) for 3 h.
The solid product which produced on heating was collected and
recrystallised from acetic acid as white yellow crystals; 62% yield as
brown crystals, m.p. 296–298 °C. IR (KBr): ν = 3312 (NH), 2196
(C≡N), and 1664 cm−1 (C=O). 1H NMR (DMSO-d6): δ = 4.00 (s, 4H,
2CH2), 6.56–8.22 (m, 8H, ArH), 8.83, 10.32 (2s, 4H, 4NH). MS:
m/z = 530 (M+-2, 7%), 497 (20%), 304 (18%), 218 (15%), 173 (75%),
89 (100%). Anal. Calcd for C28H16N6O6 (532.46): C, 63.16; H, 3.03;
N, 15.78. Found: C, 62.98; H, 2.82; N, 15.54%.
3,3p-(Ethane-1,2-diyl)bis(2-amino-5-imino-4-oxo-4,5-dihydro-3H-
chromeno-[3,4-c]pyridine-1-carbonitrile) (16): A mixture of com-
pound (12) (0.01 mol), malononitrile (0.02 mol) and piperidine
(0.01 mol) in dioxane (30 mL) was heated under reflux for 3h. The
solid product which produced on heating was collected by filtration
and recrystallised from acetic acid as brown crystals; 60% yield, m.p.
>300 °C. IR (KBr): ν = 3436, 3344, 3184 (NH and NH2), 2206 (C≡N),
and 1660 cm−1 (C=O). 1H NMR (DMSO-d6): δ = 4.01 (s, 4H, 2CH2),
6.57 (s, 4H, 2NH2; exchangeable with D2O), 7.11–7.63 (m, 8H, ArH),
9.21 (s, 2H, 2NH; exchangeable with D2O).Anal. Calcd for C28H18N8O4
(530.49): C, 63.39; H, 3.42; N, 21.12. Found: C, 63.30; H, 3.45; N,
21.16%.
N-Cyclohexyl-2-oxo-2H-chromene-3-carboxamide (4)
Method A: A mixture of cyanoacetamide derivative (1a) (0.01 mol),
salicyl-aldehyde (0.01 mol) and sodium acetate (0.01 mol) was
refluxed in acetic anhydride (30 mL) for 1hr. The solid product which
produced on heating was collected and recrystallised from dioxane as
white yellow crystals; 65% yield, m.p. 194–196 °C. IR (KBr):
ν = 3260 (NH), 3057 (CH-arom.), 2970, 2924 (stretching CH) and
1695, 1640 cm−1 (C=O). 1H NMR (DMSO-d6): δ = 1.21–1.39 (m, 6H,
cyclohexyl protons), 1.54–1.87 (m, 4H, cyclohexyl protons), 3.80–
3.82 (m, 1H, cyclohexyl proton), 7.41–8.00 (m, 4H, ArH), 8.84 (s, 1H,
chromene-H), 8.60 (d, 1H, NH; exchangeable with D2O). Anal. Calcd
for C16H17NO3 (271.31): C, 70.83; H, 6.32; N, 5.16. Found: C, 70.80;
H, 6.20; N, 5.10%.
Method B: A solution of the corresponding iminochromene deriva-
tives (3) (0.01 mol) in ethanol (30 mL), hydrochloric acid (5 mL) was
refluxed for 1h. The solid product which produced on heating was
collected and worked up as above.
2-Amino-3-cyclohexyl-5-imino-4-oxo-4,4a,5,10b-tetrahydro-3H-
chromeno[3,4-c]pyridine-1-carbonitrile (7): A mixture of compound
(4) (0.01 mol), malononitrile (0.01 mol) and piperidine (0.01 mol)
was refluxed in dioxane (30 mL) for 3h. The solid product which
produced on heating was collected and recrystallised from acetic acid
as white yellow crystals; 70% yield, m.p. 211–212 °C. IR (KBr):
ν = 3440, 3348, 3164 (NH&NH2), 2984 (stretching CH), 2208 (C≡N),
Received 9 May 2010; accepted 12 July 2010
Paper 1000112 doi: 10.3184/030823410X12812852410870
Published online: 30 August 2010
1
and 1650 cm−1 (C=O). H NMR (DMSO-d6): δ = 1.21–1.39 (m, 6H,
cyclohexyl protons), 1.56–1.87 (m, 4H, cyclohexyl protons), 3.68 (d,
1H, chromene H-3), 3.73 (hump, 1H, cyclohexyl proton), 4.67 (d, 1H,
chromene H-4), 6.95 (s, 2H, NH2; exchangeable with D2O), 7.08–8.50
(m, 4H, ArH), 10.80 (s, 1H, NH; exchangeable with D2O). MS:
m/z = 320 (M-NH2, 20%), 60 (100%). Anal. Calcd for C19H20N4O2
(336.39): C, 67.84; H, 5.99; N, 16.66. Found: C, 67.80; H, 5.85; N,
16.70%.
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ν = 3432, 3360, 3170 (NH&NH2), and 1656 cm−1 (C=O). H NMR
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1647 cm−1 (C=O). 1H NMR (DMSO-d6): δ = 4.21 (s, 4H, 2CH2),
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(402.40): C, 65.66; H, 4.51; N, 13.92. Found: C, 65.60; H, 4.40; N,
13.80%.
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