Synthesis and antimicrobial evaluation of novel urea derivatives from chromene based oxadiazole amines

Article abstract of DOI:10.1007/s00044-016-1651-6

A series of novel aryl ureides were synthesized based on oxadiazoles and different substituted aromatic amines. The intermediate amine, (3-(2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)methanamines (6a) was reacted with aromatic amines in presence of triphosgene

Full text of DOI:10.1007/s00044-016-1651-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1651-6
ORIGINAL RESEARCH
Synthesis and antimicrobial evaluation of novel urea derivatives from
chromene based oxadiazole amines
K. Santosh Kumar1 V. Daniel1 Shiva Shanker Kaki2 Ch. Prasad Rao1
G.L. David Krupadanam1
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Received: 23 April 2015 / Accepted: 4 July 2016
© Springer Science+Business Media New York 2016
Abstract A series of novel aryl ureides were synthesized
based on oxadiazoles and different substituted aromatic
amines. The intermediate amine, (3-(2H-chromen-3-yl)-
1,2,4-oxadiazol-5-yl)methanamines (6a) was reacted with
aromatic amines in presence of triphosgene to obtain the
urea derivatives 7a–d and 7e–i in high yields. The struc-
tures of all the intermediates and the final urea derivatives
were established by IR, NMR and mass spectrometry data.
The antibacterial activity of synthesized compounds was
evaluated against two gram-negative bacteria namely
Escherichia coli and Pseudomonas aeroginosa and it was
observed that the urea derivatives 7a and 7i were promising
antibacterial agents.
fields of biology, agriculture, petrochemicals and pharma-
ceuticals (Deepak et al., 2012). The ureide compounds
structurally contain urea as substructure unit either in the
open or cyclic form. The urea derivatives were reported to
be used as dyes for cellulosic fibers, antioxidants in gaso-
line, plant growth regulators, pesticides and herbicides apart
from pharmacological applications (Isabelle, 2007). These
compounds are reported to posses many biological activities
such as antibacterial, antifungal and antiviral activities. In
addition, they are also reported to exhibit some important
pharmacological activities like antiinfectives, antitumor,
anticancer and in diabetes and hyperlipidemia (Sanjay et al.,
2006). Various types of aryl ureas have been reported to
inhibit expression of enzymes like cyclooxygenase COX-2
(Zarghi et al., 2008), β-secretase (Huang et al., 2005), acyl-
CoA:cholesterol O-acyltransferase (Asano et al., 2009), p38
mitogen-activated protein kinase (Davidson et al., 2004),
and cyclophilin A (Guichou et al., 2006) which make them
interesting molecules with pharmacological activity for
drug designing.
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Keywords Ureides Oxadiazoles Anilines Antibacterial
activity
Introduction
Literature studies report that modified aryl ureas were
found to be potential target specific anti-cancer agents based
on the in vitro inhibition of translation initiation (Séverine
et al., 2012). Among the very diverse range of counterparts
for the synthesis of ureides, the molecules that particularly
contain oxadiazole moiety are preferred due to their broad
spectrum of biological activities. It is well documented that
oxadiazoles exhibit antimicrobial (Mishra et al., 2005),
antimalarial (Zareef et al., 2007) and several other inter-
esting biological activities. It is reported that oxadiazoles
have influence on a wide range of drug discovery areas such
as diabetes, obesity, inflammation, cancer and pesticide
chemistry (Jonas et al., 2012). With the increasing number
of new infections and development of new microbes resis-
tant to antibiotics, several new bioactive molecules are
Aryl ureas or ureides are known to be one of the basic
chemicals which are used as antibacterial agents in hospitals
(Somnath et al., 2006). The biaryl or unsymmetrical urea
derivatives are reported to have extensive applications in the
* K. Santosh Kumar
kondasantosh2015@gmail.com
G.L. David Krupadanam
davidkrupa@hotmail.com
1
Department of Chemistry, Osmania University, Hyderabad
500007, India
2
Centre for Lipid Research, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007, India

Med Chem Res
being prepared and screened for antimicrobial activity.
Molecules containg oxadiazole moiety and urea function-
ality have been reported to exhibit activity against HIV and
hence further research for preparing this type of compounds
could be interesting in view of the novel therapeutic agents
(Summa et al., 2008; Isabelle, 2007).
Based on the above observations and the wide biological
activities exhibited by the ureides, several research groups
focussed on the preparation and biological evaluation of the
urea derivatives. Therefore, the present study was aimed to
design and preare novel urea derivatives containing oxadiazole
and study their antibacterial potential on two microorganisms.
reflux temperature yields 2H-chromene-3-carbonitrile (2a–b).
It was treated with hydroxylamine hydrochloride under
heating conditions to obtain the corresponding amido oxime
(3a–b) in 87 % yield. This amidoxime was treated with a
solution of chloroacetyl chloride in tetrahydrofuran to
obtain the basic oxadiazole moiety with chloromethyl (4a–b)
substituent in 82 % yield. The chloro substituent was con-
verted to corresponding azide (5a–b) with over 90 % yield
on treatment with sodium azide and finally the azide com-
pound was reduced to amine with triphenylphosphine
reagent in a mixture of tetrahydrofuran and water at room
temperature which resulted in the oxadiazole methyl a
amine in 6a–b with overall 58 % yield (Scheme 1). The
oxadiazole methyl amine 6a and methoxy oxadiazole
methyl amine 6b showed the molecular ion peaks at m/z
230 and 260 respectively which confirmed the structures of
the intermediates. The final compounds were obtained by
treating the anilines with triphosgene and intermediate
amine compounds (6a-b) to produce the title urea com-
pounds (7a–i) in 90 yields.
Results and discussion
Chemistry
Initially the intermediate, oxadiazole methyl amine, (3-(2H-
chromen-3-yl)-1,2,4-oxadiazol-5-yl)methanamines (6a) was
prepared by a four step procedure. Further the intermediate
was converted to phenyl ureas employing substituted ani-
lines as substrates. For the preparation of intermediate,
Salicylaldehydes (1a–b) on reaction with acrylonitrile in the
presence of 1,4-Diazabicyclo[2.2.2]octane (DABCO) at
Structures of all the compounds were confirmed by
NMR, IR and mass spectral analysis and were found to be
in agreement with the proposed structures. IR spectra of
each step in the synthesis showed characteristic absorption
bands corresponding to the functional group transformation.
Scheme 1 Synthetic route for the preparation of novel ureides

Med Chem Res
IR spectrum of compound 3a showed absorptions at 3400
and 3340 cm−1 which are due to the hydroxyl and amine
functional groups and a characteristic absorption at 1515 cm−1
for the oxime C=N functionality. The azide derivative 5a
showed characteristic absorption at 2114 cm−1 which dis-
appeared in the next step to form the amine intermediate 6a.
IR spectra of the compound 6a showed 3375 cm−1 which is
due to amine functional group. IR spectra of the final
compound 7a showed absorption at 1639 cm−1 which is due
to the carbonyl group and the absorption at 3309 cm−1 is
exhibiting activity against both E. coli and P. aeruginosa
with a minimum inhibitory concentration (MIC) value of
9.8 and 10.25 µg/ml respectively. In addition to compound
7h, it was found that compounds 7a, 7c, 7d, 7f and 7g were
more effective against E. coli than the reference drug,
ciprofloxacin as observed by their MIC values. However,
compounds 7b and 7i were found to be less effective against
E. coli than ciprofloxacin with MIC values of 22 and 33.8
µg/ml respectively compared to MIC of ciprofloxacin (20.5
µg/ml). For antimicrobial evaluation against Pseudomonas
aeruginosa, it was found that compounds 7a, 7c, 7f, 7g, 7h
and 7i were more effective than ciprofloxacin. However,
compounds 7b and 7e were found to be showing lower
activity compared to the reference drug, ciprofloxacin.
Compound 7d was observed to be equipotent to cipro-
floxacin as observed by its MIC value (19.5 µg/ml)
Based on the structure-activity relationship data in the
present study, it was found that substitution on the chro-
mene ring by methoxy group led to some interesting results.
Structurally compounds 7a–d are the compounds which
were derived from (3-(2H-chromen-3-yl)-1,2,4-oxadiazol-
5-yl)methanamines and respective anilines (viz., 4-chlor-
ophenyl, 4-bromophenyl, 4-methoxyphenyl and p-tolyl)
whereas compounds 7e–i are the compounds derived from
methoxy substituted chromene intermediate (3-(8-methoxy-
2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)methanamine and
respective anilines. The main difference between these two
groups of compounds is the additional methoxy substituent
over the chromene moiety. The urea derivatives compounds
7b–d were found to be less active when compared to their
counterparts 7g–i as observed by their MIC values on both
the organisms tested. However, compound 7a was more
active than its counterpart compound 7f against E. coli
where as against P. aeroginosa, compound 7f was more
active than 7a. To determine the effect of fluorine as sub-
stituent, compound 7e was prepared from methoxy sub-
stituted chromene and 4-fluoro aniline as substrates where it
exhibited moderate activity which was more or less
equivalent to standard drug ciprofloxacin.
1
due to the –NH functional group. H-NMR spectral data of
one of the final compound 7a showed a peak at δ 9.12
which is due to the –NH proton of the substituted phenyl
moiety. Protons attached to oxygen in chromene ring as
O–CH2– appeared as a doublet at δ 5.1 and the protons
attached to secondary amine of phenyl moiety as –CH2–NH
appeared as a doublet at δ 4.63. The aromatic protons
attached to chromene moiety appeared in the range of δ 6.8
to 7.5 whereas the aromatic protons of the substituted ani-
lines appeared at δ 7.2–7.4. In the 13C–NMR the carbonyl
carbon appeared at δ 153.9 ppm. The mass spectral data
showed m/z about 383 which is the molecular ion for the
compound and also a peak corresponding to [M+2] at 385
in the ratio of 1:3 which further confirmed the structure of
the compound.
Biological activity
All of the synthesized compounds were tested for anti-
bacterial activity against the two Gram negative bacteria
namely Escherichia coli and Pseudomonas aeruginosa
(Table 1).
It can be observed from the above table that all the
compounds prepared were found to exhibit antibacterial
activity against the tested strains. It is interesting to note that
compound 7h was the most potent urea derivative
Table 1 Results of antibacterial activity screening of the synthesized
compounds
Compound
MIC value (µg/ml)
Escherichia coli
Pseudomonas aeruginosa
Conclusion
7a
10.5
22
15.6
25.6
17.2
19.5
22.8
11.6
13
7b
Novel urea derivatives comprising oxadiazole moiety were
synthesized and characterized. All the compounds showed
excellent activity against the two bacterial strains tested.
Among all the urea derivatives, compound 7h was the most
potent compound exhibiting activities better than the stan-
dard drug ciprofloxacin. The results of the present study
suggest that the novel urea derivatives can find possible
applications in pharmaceutical formulations for a wide
range of diseases based on further screening studies against
7c
15.8
11.8
20
7d
7e
7f
14.6
16
7g
7h
9.8
10.25
14.5
19.5
7i
33.8
20.5
Ciprofloxacin

Med Chem Res
additional bacterial, fungal strains along with cytotoxicity
evaluation.
8-Methoxy-2H-chromene-3-carbonitrile (2b)
Yellow solid; yield 70 %; m.p.: 105 °C, Rf 0.5 (40 % EtoAc/
hexane); IR (KBr): λmax 2260(CN) cm−1; 1H-NMR (CDCl3,
400 MHz): δ 7.17 (1H, m, H-5), 6.91-6.94(2H, m, H-4,7),
6.73–6.75 (1H, m, H-6), 4.86 (2H, d, J = 1.2 Hz, 2H), 3.88
(3H, s, OCH3); 13C-NMR (CDCl3, 100.6 MHz): δ 148.3 (C,
C-8), 143.6 (C, C-8a), 138.7 (CH, C-4), 122.2 (CH, C-6),
120.4 (CH, C-7), 120.2 (CH, C-5), 116.2 (C, C-4a), 115.8
(CN), 103.7 (C, C-3), 64.7 (CH2, C-2), 56.3 (OCH3); EIMS
m/z 188 [M+].
Experimental
Silica gel (60–120 mesh) for column chromatography was
purchased from M/s Acme Synthetic Chemicals (Mumbai,
India) and pre-coated TLC plates (Silica gel 60F254) were
purchased from Merck (Darmstadt, Germany). All the
chemicals, reagents and solvents were purchased from M/s
SD Fine Chemicals (Mumbai, India) and were of the highest
grade of purity. The H-NMR and 13C-NMR spectra were
Synthesis of N′-hydroxy-2H-chromene-3-
carboximidamide (3a–b)
1
recorded on bruker 400 and 100 MHz, respectively, and
TMS was used as an internal standard. Chemical shifts
relative to TMS as internal standards were given as δ values
in ppm. Mass spectra were recorded using electron spray
ionization on Waters e2695 Seperators module (Waters,
Milford, MA, USA) mass spectrometer. IR spectra were
recorded on a Fourier transform (FT-IR), USA (Perkin-
Elmer model 337) instrument. The melting points were
Synthesis of N′-hydroxy-2H-chromene-3-carboximidamide
(3a)
A mixture of 2H-chromene-3-carbonitrile (intermediate 2a)
(4 g, 25.4 mmol), hydroxylamine hydrochloride (3.2 g, 46.0
mmol) and 10 ml of triethylamine were refluxed for 2 h in
ethanol. After the reaction, ethanol and excesses of trie-
thylamine was removed under reduced pressure. A light
yellow solid was obtained to which water (20 ml) was
added and the solid precipitate was collected by filtration,
washed with water and dried at 50 °C to furnish amidoxime
(3a) as a white solid (4.2 g, 87 % yield).
determined on
Instrument.
a Barnstead Electro Thermal 9200
Synthesis of 2H-chromene-3-carbonitrile (2a–b)
Synthesis of 2H-chromene-3-carbonitrile (2a)
To a solution of salicylaldehyde (1a) (10.0 g, 82 mmol) in
acrylonitrile (100 ml) DABCO (1 g, 8.92 mmol) was added
and refluxed for 8 h. After completion of the reaction, the
excess of acrylonitrile was removed under reduced pressure.
The resultant crude product was dissolved in ethyl acetate
(200 ml) and the resultant solution was washed with 5 % dil
HCl. The organic layer was washed with water (30 ml),
brine solution (30 ml) and dried over anhydrous sodium
sulphate. The crude product was purified by column chro-
matography over 60–120 mesh silica gel and eluted with
EtOAc:hexane 1:10 to give 2H-chromene-3-carbonitrile
(2a) as white solid (7.2 g, 56 % yield).
N′-hydroxy-2H-chromene-3-carboximidamide (3a)
White solid; m.p.: 200 °C, Rf 0.1 (20 % EtoAc/hexane); IR
(KBr): λmax 3400 (OH), 3340 (NH2), 1515 (C=N) cm−1;
1H-NMR (CDCl3, 400 MHz): δ 9.96 (1H, s, -OH),
7.10–7.17 (2H, m, H-5,7), 7.00 (1H, s, H-4), 6.90 (1H, ddd,
J = 1.0, 7.2, 8.5 Hz, H-6), 6.80 (1H, d, J = 8.0 Hz, H-8),
5.66 (2H, s, NH2), 4.89 (2H, d, J = 1.2 Hz, OCH2); 13C-
NMR (CDCl3, 100.6 MHz): δ 153.6 (CN), 148.7 (C, C-8a),
129.3 (CH, C-7), 127.2 (CH, C-5), 125.1 (C, C-3), 122.0
(C, C-4a), 121.5 (CH, C-6), 120.4 (CH, C-4), 115.6 (CH, C-
8), 63.7 (CH2, C-2); ESIMS m/z 191[M+].
2H-chromene-3-carbonitrile (2a)
N′-hydroxy-8-methoxy-2H-chromene-3-carboximidamide (3b)
White solid; m.p.: 51 °C, Rf 0.5 (20 % EtoAc/hexane); IR
White solid; m.p.: 160 °C, Rf 0.1 (40 % EtoAc/hexane);
yield: 92 %; IR (KBr): λmax 3470(OH), 3350(NH2), 1515
1
(KBr): λmax 2270(CN) cm−1; H-NMR (CDCl3, 400 MHz):
1
δ 7.23 (1H, ddd, J = 1.5, 8.0, 9.0 Hz, H-7), 7.13 (1H, s, H-
4), 7.07 (1H, dd, J = 1.7, 7.7 Hz, H-5), 6.93 (1H, ddd, J =
1.0, 7.5, 8.5 Hz, H-6), 6.84 (1H, d, J = 8.2 Hz, H-8), 4.77
(2H, d, J = 1.2 Hz, -OCH2); 13C-NMR (CDCl3, 100.6
MHz): δ 154.2 (C, C-8a), 138.7 (CH, C-4), 132.7 (CH, C-
7), 128.5 (CH, C-5), 122.4 (CH, C-6), 120.0 (C, C-4a),
116.5 (CH, C-8), 116.4 (CN), 103.3 (C, C-3), 64.2 (CH2,
C-2); EIMS m/z 158[M+].
(C=N) cm−1; H-NMR (CDCl3, 400 MHz): δ 9.93 (1H, s,
-OH), 6.99 (1H, s, H-4), 6.84-6.91 (2H, m, H-5,6), 6.72 (1H,
ddd, J = 2.0, 7.2, 9.0 Hz, H-7), 5.63 (2H, brs, NH2), 4.84
(2H, d, J = 1.0 Hz, OCH2), 3.74 (3H, s, OCH3); 13C-NMR
(CDCl3, 100.6 MHz): δ 148.3 (C=N-OH), 147.0 (C, C-8),
142.4 (C, C-8a), 124.7 (C, C-3), 122.2 (CH, C-4), 120.4
(CH, C-6), 120.0 (C, C-4a), 118.8 (CH, C-7), 113.2 (CH, C-
5), 64.6 (CH2, C-2), 57.2 (-OCH3); ESIMS m/z 221[M+].

Med Chem Res
Synthesis of 5-(chloromethyl)-3-(2H-chromen-3-yl)-
1,2,4-oxadiazole (4a–b)
mmol) were dissolved in a 1:1 mixture of water and tetra-
hydrofuran (10 ml) and refluxed for about 5 h After com-
pletion of the reaction (monitored by TLC), the reaction
mixture was extracted with ethyl acetate (3×30 ml), the
combined organic layers were washed with water and brine
solution. The organic layer was dried over sodium sulphate
and concentrated under reduced pressure to afford light
yellow crude solid (5a) which was used as such for the next
step. (0.92 g, 90 % yield).
Synthesis of 5-(chloromethyl)-3-(2H-chromen-3-yl)-1,2,4-
oxadiazole (4a)
N′-hydroxy-2H-chromene-3-carboximidamide (3a) (3.0 g,
15.8 mmol) was dissolved in 30 ml of tetrahydrofuran and
the reaction mixture was cooled to 10 °C. To this cooled
mixture, a solution of chloroacetyl chloride (1.5 ml, 18.8
mmol) was added drop wise. After completion of the
addition, the resulting mixture was refluxed for 4 h. Tetra-
hydrofuran and excess chloroacetyl chloride was removed
under reduced pressure. A light yellow solid was obtained
to which water (20 ml) was added. The solid precipitate was
collected by filtration and washed with water and dried at
reduced pressure to obtain white amorphous solid (3.2 g,
82 % yield).
5-(Azidomethyl)-3-(2H-chromen-3-yl)-1,2,4-oxadiazole
(5a)
Yellow solid; m.p.:108–110 °C, Rf 0.6 (20 % EtoAc/hex-
ane); IR (KBr): λmax 2114(N3) cm−1; 1H-NMR (CDCl3, 400
MHz): δ 7.47 (1H, s, H-4), 7.18 (1H, ddd, J = 1.5, 8.0, 9.0
Hz, H-7), 7.13 (1H, dd, J = 1.5, 7.5 Hz, H-5), 6.90 (1H,
ddd, J = 1.0, 7.5, 8.5 Hz, H-6), 6.85 (1H, d, J = 8.0 Hz, H-
8), 5.17 (2H, d, J = 1.5 Hz, OCH2), 4.55 (2H, s, -CH2N3);
13C-NMR (CDCl3, 100.6 MHz): δ 173.5 (C, C-3′), 165.9
(C, C-5′), 154.6 (C, C-8a), 131.2 (CH, C-7), 129.0 (CH, C-
4), 128.4 (CH, C-5), 121.8 (CH, C-6), 121.1 (C, C-3), 118.5
(C, C-4a), 116.0 (C, C-8), 64.2 (CH2, C-2), 44.9 (CH2N3);
ESIMS m/z: 256[M+].
5-(Chloromethyl)-3-(2H-chromen-3-yl)-1,2,4-oxadiazole (4a)
1
White solid; m.p.:108 °C, Rf 0.7 (20 % EtoAc/hexane); H-
NMR (CDCl3, 400 MHz): δ 7.46 (1H, s, H-4), 7.19 (1H,
ddd, J = 1.7, 8.0, 9.2 Hz, H-7), 7.13 (1H, dd, J = 1.5, 7.5
Hz, H-5), 6.91 (1H, ddd, J = 1.0, 7.2, 8.5 Hz, H-6), 6.86
(1H, d, J = 8.0 Hz, H-8), 5.18 (2H, d, J = 1.2 Hz, OCH2),
4.69 (2H, s, -CH2Cl); 13C-NMR (CDCl3, 100.6 MHz): δ
173.8 (C, C-3′), 166.1 (C, C-5′), 154.6 (C, C-8a), 131.2
(CH, C-7), 128.9 (CH, C-4), 128.3 (CH, C-5), 121.8 (CH,
C-6), 121.1 (C, C-3), 118.5 (C, C-4a), 116.1 (CH, C-8),
64.2 (CH2, C-2), 33.2 (CH2Cl); ESIMS m/z: 249, 251[M+].
5-(azidomethyl)-3-(8-methoxy-2H-chromen-3-yl)-1,2,4-
oxadiazole (5b)
Off white solid; m.p.: 113-117 °C, Rf 0.6 (40 % EtoAc/
1
hexane); yield 93 %; IR(KBr): λmax 2096(N3) cm−1; H-
NMR (CDCl3, 400 MHz): δ 7.53 (1H, s, H-4), 6.98–7.03
(2H, m, H-5,7), 6.93 (1H, m, H-6), 5.12 (2H, d, J = 1.2 Hz,
OCH2), 4.96 (2H, s, CH2N3), 3.82 (3H, s, OCH3); 13C-
NMR (CDCl3, 100.6 MHz): δ 174.9 (C, C-3′), 165.1 (C, C-
5′), 147.5 (C, C-8), 143.0 (C, C-8a), 128.2 (CH, C-4), 121.6
(C, C-3), 121.5 (C, C-, 4a), 120.4 (CH, C-6), 118.5 (CH, C-
7), 114.6 (CH, C-5), 63.5 (CH2, C-2), 55.6 (OCH3), 44.5
(CH2N3); ESIMS.m/z: 286[M+].
5-(Chloromethyl)-3-(8-methoxy-2H-chromen-3-yl)-1,2,4-
oxadiazole (4b)
White solid; m.p.144 °C, Rf 0.7 (40 % EtoAc/hexane); yield
1
82 %; H-NMR (CDCl3, 400 MHz): δ 7.48 (1H, s, H-4),
6.88–6.91 (2H, m, H-5,7), 6.81 (1H, m, H-6), 5.26 (2H, s,
–OCH2), 4.70 (2H, s, –CH2Cl), 3.80 (3H, s, OCH3); 13C-
NMR (CDCl3, 100.6 MHz): δ 173.8 (C, C-3′), 166.1 (C, C-
5′), 148.1 (C, C-8), 144.0 (C, C-8a), 128.8 (CH, C-4), 122.0
(C, C-3), 121.4 (C, C-4a), 120.6 (CH, C-6), 118.7 (CH, C-
7), 114.9 (CH, C-5), 64.5 (CH2, C-2), 56.0 (OCH3), 33.1
(CH2Cl); ESIMS m/z: 279, 281 [M+].
Synthesis of (3-(2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)
methanamines (6a–b)
Synthesis of (3-(2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)
methanamine (6a)
Synthesis of 5-(azidomethyl)-3-(2H-chromen-3-yl)-1,2,4-
oxadiazole (5a–b)
5-(azidomethyl)-3-(2H-chromen-3-yl)-1,2,4-oxadiazole (inter-
mediate 5a) (0.1 g, 0.393 mmol) was taken in a solution of
tetrahydrofuran (5 ml). To this triphenyl phosphine (0.411
g, 1.572 mmol) and water (1 ml) was added. The reaction
mixture was stirred at room temperature about 24 h. After
starting material has disappeared by checking the TLC, the
solvent was removed under reduced pressure to yield the
crude amine. The mixture was dissolved in toluene and
Synthesis of 5-(azidomethyl)-3-(2H-chromen-3-yl)-1,2,4-
oxadiazole (5a)
5-(chloromethyl)-3-(2H-chromen-3-yl)-1,2,4-oxadiazole
(4a) (1.0 g, 4.03 mmol) and sodium azide (0.288 g. 4.43

Med Chem Res
concentrated HCl was dropped to get solid amine hydro-
chloride. Which was purified by recyrstallisation from
CHCl3–petether yields light yellow solid.
1-((3-(2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-3-(4-
chlorophenyl)urea (7a)
White solid; m.p.: 238–243 °C; yield 86 %; IR (KBr): λmax
3309 (N–H amide), 1639 (C=O), 1566 (–N–C=O) cm−1;
(3-(2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)methanamine (6a)
m.p.: 140–144 °C, Rf 0.5 (1 % CHCl3/MeOH); yield 90 %;
1H–NMR (DMSO–d6, 400 MHz):
δ
9.12 (1H, s,
–CO–NH–Ar), 7.50 (1H, s, H-4), 7.43 (2H, d, J = 8.7 Hz,
H-2′′,6′′), 7.35 (1H, dd, J = 1.2, 7.5 Hz, H-5), 7.23–7.30
(3H, m, H-7,3′′,5′′), 6.95–6.99 (2H, m, H-6,
–CH2–NH–CO), 6.88 (1H, s, J = 8.0 Hz, H-8), 5.13 (2H, d,
J = 1.2 Hz, OCH2), 4.63 (2H, d, J = 5.7 Hz, -CH2–NH);
13C-NMR (DMSO-d6,100.6 MHz): δ 178.0 (C, C-3′), 165.0
(C, C-5′), 154.8 (C, C-8a), 153.9 (C=O), 138.9 (C, C-1′′),
131.7 (CH, C-7), 128.5 (CH, C-4), 128.6 (CH, C-3′′,5′′),
127.6 (CH, C-5), 125.0 (C, C-4′′), 121.8 (CH, C-6), 120.9
(C, C-3), 119.3 (CH, C-2′′,6′′), 118.9 (C, C-4a), 115.6 (CH,
C-8), 63.7 (CH2, C-2), 36.1 (-CH2NH); ESIMS m/z: 383,
385[M+].
1
IR (KBr): λmax 3375(NH2) cm−1; H-NMR (CDCl3, 400
MHz): δ 7.47 (1H, s, H-4), 7.20 (1H, ddd, J = 1.7, 8.0, 9.2
Hz, H-7), 7.14 (1H, dd, J = 1.5, 7.5 Hz, H-5), 6.92 (1H, ddd,
J = 1.2, 7.5, 8.5 Hz, H-6), 6,87 (1H, d, J = 8.0 Hz, H-8),
5.19 (2H, d, J = 1.2 Hz, OCH2), 4.13 (2H, s, –CH2–NH2),
1.69 ( 2H, brs, NH2); 13C-NMR (CDCl3, 100.6 MHz): δ
179.5 (C, C-3′), 165.5 (C, C-5′), 154.6 (C, C-8a), 131.0
(CH, C-7), 128.3 (CH, C-4), 128.2 (CH, C-5), 121.8 (CH,
C-6), 121.2 (C, C-3), 119.0 (C, C-4a), 116.0 (CH, C-8), 64.4
(CH2, C-2), 38.3 (CH2NH2); ESIMS m/z: 230[M+].
(3-(8-Methoxy-2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)
methanamine (6b)
1-((3-(2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-3-(4-
bromophenyl)urea (7b)
Yellow solid; m.p.: 122–126 °C, Rf 0.5 (4 % CHCl3/
1
MeOH); yield 88 %; IR (KBr): λmax 3336(NH2) cm−1; H-
White solid; m.p.: 236–241 °C; yield 88 %; IR (KBr): λmax
3309 (N–H amide), 1639 (C=O), 1562 (–N–C=O) cm−1;
NMR (CDCl3, 400 MHz): δ 7.40 (1H, s, H-4), 6.89–7.02
(3H, m, H-5,6,7), 5.11 (2H, d, J = 1.2 Hz, OCH2), 3.99 (2H,
s, -CH2–NH2), 3.78 (3H, s, OCH3), 2.14 (2H, brs, NH2);
13C-NMR (CDCl3,100.6 MHz): δ 180.8 (C, C-3′), 164.8 (C,
C-5′), 147.4 (C, C-8), 142.8 (C, C-8a), 127.5 (CH, C-4),
121.6 (C, C-3), 121.5 (C, C-4a), 120.2 (CH, C-6), 119.1
(CH, C-7), 114.4 (CH, C-5), 63.6 (CH2, C-2), 55.6 (OCH3),
37.8 (CH2NH2); ESIMS m/z: 260[M+].
1H-NMR (DMSO-d6, 400 MHz):
δ
9.12 (1H, s,
–CO–NH–Ar), 7.50 (1H, brs, H–4), 7.35 (1H, dd, J = 1.2,
7.5 Hz, H-5), 7.23 (1H, ddd, J = 1.5, 7.7, 8.7 Hz, H–7),
6.95–6.98 (2H, m, H–6, –CH2–NH–CO), 6.87 (1H, d, J =
8.0 Hz, H-8), 5.13 (2H, d, J = 1.0 Hz, OCH2), 4.63 (2H, d,
J = 5.7 Hz, –CH2–NH); 13C–NMR (DMSO-d6, 100.6
MHz): δ 178.0 (C, C-3′), 165.0 (C, C-5′), 154.8 (C, C-8a),
153.9 (C=O), 139.4 (C, C-1′′), 131.3 (CH, C-3′′,5′′), 131.1
(CH, C-7), 128.6 (CH, C-4), 127.6 (CH, C-5), 121.8 (CH,
C-6), 120.9 (C, C-3), 119.7 (CH, C-2′′,6′′), 118.9 (C, C-4a),
115.6 (CH, C-8), 112.8 (C, C-4′′), 63.7 (CH2, C-2), 36.1
(CH2NH); ESIMS m/z: 427, 429[M+].
Synthesis of 1-((3-(2H-chromen-3-yl)−1,2,4-oxadiazol-5-
yl)methyl)-3-phenylureas (7a–i)
Synthesis of 1-((3-(2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)
methyl)-3-(4-chlorophenyl)urea (7a)
1-((3-(2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-3-(p-
To the solution of triphosgene (1.48 g, 5 mmol) in toluene
(10 ml) chloro aniline (10 mmol) in toluene (10 ml) was
added drop wise followed by the drop wise addition of
triethylamine (1 ml) in toluene (5 ml). The reaction mixture
was refluxed for about 3 h. After dissappearance of starting
material based on TLC, the solvent was removed on a rotary
evaporator. The resulting residue was dissolved in DCM
(20 ml), and (3-(2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)
methanamine (6a) (10 mmol) in DCM (20 ml) was added.
After the reaction mixture was stirred at room temperature
for about 3–4 h, a white solid precipitated in the reaction
tolyl)urea (7c)
White solid; m.p.: 223–230 °C; yield 85 %;IR (KBr): λmax
3309 (N–H amide), 1639 (C=O), 1566 (–N–C=O) cm−1;
1H-NMR (DMSO-d6, 400 MHz): δ 8.90 (1H, s, –NH–CO-
Ar), 7.50 (1H, s, H–4), 7.35 (1H, dd, J = 1.2, 7.5 Hz, H-5),
7.28 (2H, d, J = 8.5 Hz, H-2′′,6′′), 7.23 (1H, ddd, J = 1.5,
7.7, 9.0 Hz, H-7), 7.02 (2H, d, J = 8.2 Hz, H-3′′,5′′), 6.94
(1H, ddd, J = 1.0, 7.5, 8.5 Hz, H-6), 6.87 (2H, m, H-8,
CH2NHCO), 5.13 (2H, d, J = 1.2 Hz, OCH2), 4.66 (2H, d,
J = 5.7 Hz, –CH2NH), 2.21 (3H, s, –CH3); 13C-NMR
(DMSO-d6, 100.6 MHz): δ 178.2 (C, C-3′), 164.9 (C, C-5′),
155.0 (C, C-8a), 153.9 (C=O), 137.4 (C, C-4′′), 131.1 (CH,
C-7), 130.2 (C, C-1′′), 128.6 (CH, C-3′′,5′′,4), 127.5 (CH,
C-5), 121.8 (CH, C-6), 120.9 (C, C-3), 118.9 (C, C-4a),
mixture. The precipitate was collected on
a
funnel by vacuum filtration and washed with chilled DCM
(5 ml) to afford the final compounds (7a–i) (Dazhi Liu,
et al., 2013).

Med Chem Res
117.9 (CH, C-2′′,6′′), 115.6 (CH, C-8), 63.7 (CH2, C-2),
36.0 (CH2NH), 20.2 (CH3); ESIMS m/z: 363[M+].
(C=O), 147.4 (C, C-8), 142.9 (C, C-8a), 138.9 (C, C-1′′),
128.4 (CH, C-3′′,5′′), 127.7 (CH, C-4), 124.9 (C, C-4′′),
121.6 (C, C-3), 121.5 (C, C-4a), 120.3 (CH, C-6), 119.3
(CH, C-2′′,6′′), 118.9 (CH, C-7), 114.5 (CH, C-5), 63.6
(CH2, C-2), 55.6 (OCH3), 36.1 (CH2NH); ESIMS m/z: 413,
415[M+].
1-((3-(2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)methyl)-3-(4-
methoxyphenyl)urea (7d)
White solid; m.p.: 227–237 °C; Yield 89 %; IR (KBr): λmax
3309 (N–H amide), 1633 (C=O), 1560 (–N–C=O) cm−1;
1-(4-Bromophenyl)-3-((3-(8-methoxy-2H-chromen-3-yl)-
1,2,4-oxadiazol-5-yl)methyl)urea (7g)
1H-NMR (DMSO-d6, 400 MHz):
δ
8.72 (1H, s,
–CO–N–Ar), 7.50 (1H, s, H-4), 7.35 (1H, dd, J = 1.2, 7.5
Hz, H-5), 7.30 (2H, d, J = 9.0 Hz, H-2′′,6′′), 7.23 (1H, ddd,
J = 1.7, 8.0, 9.2 Hz, H-7), 6.95 (1H, ddd, J = 1.0, 7.5, 8.5
Hz, H-6), 6.87 (1H, d, J = 8.0 Hz, H-8), 6.79 −6.84 (3H, m,
H-3′′,5′′, NHCONHAr), 5.13 (2H, d, J = 1.0 Hz, OCH2),
4.61 (2H, d, J = 5.7 Hz, –CH2–NH), 3.69 (3H, s, –OCH3);
13C-NMR (DMSO-d6,100.6 MHz): δ 178.2 (C, C-3′), 165.0
(C, C-5′), 155.1 (C, C-8a), 154.2 (C, C-4′′), 153.9 (C=O),
133.0 (C, C-1′′), 131.1 (CH, C-7), 128.6 (CH, C-4), 127.5
(CH, C-5), 121.8 (CH, C-6), 120.9 (C, C-3), 119.6 (CH, C-
2′′,6′′), 118.9 (C, C-4a), 115.6 (CH, C-8), 113.8 (CH, C-3′′,
5′′), 63.7 (CH2, C-2), 55.0 (OCH3), 36.1 (CH2NH); ESIMS
m/z: 379[M+].
Wite solid; m.p.: 241–255 °C; yield 90 %; IR (KBr): λmax
3329 (N–H amide), 1641 (C=O), 1587 (–N–C=O) cm−1; 1H-
NMR (DMSO-d6, 400 MHz): δ 9.11 (1H, s, –CO–NH–Ar),
7.47 (1H, s, H-4), 7.40 (4H, s, H-2′′,3′′,5′′,6′′), 6.95–7.02
(3H, m, H-5,6,7), 6.89 (1H, d, J = 7.5 Hz, –CH2–NH–CO),
5.10 (2H, d, J = 1.2 Hz, OCH2), 4.62 (2H, d, J = 5.7 Hz,
–CH2–NH), 3.77 (3H, s, OCH3); 13C–NMR(DMSO-
d6,100.6 MHz): δ 178.0 (C, C-3′), 165.0 (C, C-5′), 154.8
(C=O), 147.5 (C, C-8), 142.9 (C, C-8a), 139.4 (C, C-1′′),
131.3 (CH, C-3′′,5′′), 127.7 (CH, C-4), 121.6 (C, C-3), 121.5
(C, C-4a), 120.3 (CH, C-6), 119.3 (CH, C-2′′,6′′), 118.9
(CH, C-7), 114.5 (CH, C-5), 112.8 (C, C-4′′), 63.5 (CH2, C-
2), 55.6 (OCH3), 36.1 (CH2NH); ESIMS m/z: 457, 459[M+].
1-(4-Fluorophenyl)-3-((3-(8-methoxy-2H-chromen-3-yl)-
1,2,4-oxadiazol-5-yl)methyl)urea (7e)
1-((3-(8-Methoxy-2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)
methyl)-3-(p-tolyl)urea (7h)
White solid; m.p.: 239–243 °C. yield 90 %; IR (KBr): λmax
3325 (N–H amide), 1637 (C=O), 1568 (–N–C=O) cm−1;
White solid; m.p.: 220–224 °C; yield 90 %; IR (KBr): λmax
3327 (N–H amide), 1639 (C=O), 1593 (–N–C=O) cm−1; 1H-
NMR (DMSO-d6, 400 MHz): δ 8.90 (1H, s, –CO–NH–Ar),
7.48 (1H, s, H-4), 7.28 (2H, d, J = 8.2 Hz, H-2′′,6′′), 7.02
(2H, d, J = 8.2 Hz, H-3′′,5′′), 6.89–7.01 (4H, m, H-5,6,7,
CH2NHCO), 5.10 (2H, d, J = 1.0 Hz, OCH2), 4.61 (2H, d,
J = 5.7 Hz, –CH2–NH), 3.77 (3H, s, –OCH3), 2.21(3H, s,
–CH3); 13C-NMR (DMSO-d6, 100.6 MHz): δ 178.4 (C, C-
3′), 164.9 (C, C-5′), 155.0 (C=O), 147.4 (C, C-8), 142.9 (C,
C-8a), 137.4 (C, C-4′′), 130.1 (C, C-1′′), 129.0 (CH, C-3′′,5′
′), 127.7 (CH, C-4), 121.6 (C, C-3), 121.5 (C, C-4a), 120.3
(CH, C-6), 118.9 (CH, C-7), 117.8 (CH, C-2′′,6′′), 114.4
(CH, C-5), 63.6 (CH2, C-2), 55.6 (8–OCH3), 36.0 (CH2NH),
20.2 (4′′–CH3); ESIMS m/z: 393[M+].
1H–NMR (DMSO-d6, 400 MHz):
δ
9.13 (1H, s,
–CO–NH–Ar), 7.48 (1H, s, H-4), 7.40-7.45 (2H, m, H-2′′,
6′′), 7.05–7.09 (2H, m, H-3′′,5′′), 6.89–7.03 (4H, m, H-
5,6,7,-CH2-NHCO), 5.10 (2H, d, J = 1.2 Hz, OCH2), 4.62
(2H, d, J = 5.7 Hz, –CH2–NH), 3.77 (3H, s, OCH3); 13C-
NMR (DMSO-d6,100.6 MHz): δ 178.1 (C, C-3′), 165.0 (C,
C-5′), 155.1 (C, CO, C-4′′), 147.4 (C, C-8), 142.9 (C, C-
8a), 136.3 (C, C-1′′), 127.7 (CH, C-4), 121.6 (C, C-3),
121.5 (C, C-4a), 120.3 (CH, C-6), 119.4 (CH, C-2′′,6′′),
118.9 (CH, C-7), 115.2 (CH, C-3′′,5′′), 114.5 (CH, C-5),
63.6 (CH2, C-2), 55.6 (OCH3), 36.0 (CH2NH); ESIMS m/z:
397[M+].
1-(4-Chlorophenyl)-3-((3-(8-methoxy-2H-chromen-3-yl)-
1,2,4-oxadiazol-5-yl)methyl)urea (7f)
1-((3-(8-Methoxy-2H-chromen-3-yl)-1,2,4-oxadiazol-5-yl)
methyl)-3-(4-methoxyphenyl)urea (7i)
White solid; m.p.: 247–252 °C; yield 88 %; IR (KBr): λmax
3311 (N–H amide), 1637 (C=O), 1589 (–N–C=O) cm−1;
White solid; m.p.: 236–240 °C; yield 92 %; IR (KBr): λmax
3329 (N–H amide), 1647 (C=O), 1568 (–N–C=O) cm−1;
1H-NMR (DMSO-d6, 400 MHz):
δ
9.13 (1H, s,
–CO–NH–Ar), 7.48 (1H, s, H-4), 7.44 (2H, d, J = 9.0 Hz,
H-2′′,6′′), 7.27 (2H, d, J = 8.7 Hz, H-3′′,5′′), 6.95-7.02
(3H, m, H-5,6,7), 6.89 (1H, d, J = 7.5 Hz, –CH2–NH–CO),
5.11 (2H, d, J = 1.2 Hz, OCH2), 4.63 (2H, d, J = 5.7 Hz,
–CH2–NH), 3.78 (3H, s, –OCH3); 13C-NMR(DMSO-d6,
100.6 MHz): δ 178.0 (C, C-3′), 165.0 (C, C-5′), 154.9
1H-NMR (DMSO-d6, 400 MHz):
δ
8.72 (1H, s,
–CO–NH–Ar), 7.48 (1H, s, H-4), 7.29 (2H, d, J = 9.0 Hz,
H-2′′,6)′′), 7.00 (1H, dd, J = 1.7, 8.0 Hz, H-5), 6.95 (1H,
dd, J = 1.5, 7.5 Hz, H-7), 6.89 (1H, d, J = 7.7 Hz,
–CH2–NH–CO), 6.78–6.84 (3H, m, H-3′′,5′′,6), 5.10 (2H,
d, J = 1.0 Hz, OCH2H), 4.60 (2H, d, J = 5.7 Hz,

Med Chem Res
–CH2–NH), 3.77 (3H, s, –OCH3), 3.69 (3H, s, –OCH3);
13C-NMR(DMSO-d6, 100.6 MHz): δ 178.2 (C, C-3′), 165.0
(C, C-5′), 155.1 (C=O), 154.2 (C, C-4′′), 147.5 (C, C-8),
142.9 (C, C-8a), 133.0 (C, C-1′′), 127.7 (CH, C-4), 121.6
(C, C-3), 121.5 (C, C-4a), 120.3 (CH, C-6), 119.6 (CH, C-
2′′,6′′), 119.0 (CH, C-7), 114.4 (CH, C-5), 113.8 (CH, C-3′
′,5′′), 63.6 (CH2, C-2), 55.6 (OCH3), 55.0 (OCH3), 36.1
(CH2NH); ESIMS m/z: 409[M+].
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The minimum inhibitory concentration was determined
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Conflict of interest The authors declare that they have no conflict of
interest.