chapter-3 synthesis, characterization of some...
TRANSCRIPT
36
CHAPTER-3
SYNTHESIS, CHARACTERIZATION OF SOME NOVEL
CHROMENO OXADIAZOLE DERIVATIVES
78
3.1. Introduction
Oxadiazole, a heterocyclic nucleus has attracted a wide attention for the chemist in search for the
new therapeutic molecules. Oxadiazoles and their derivatives are considered as simple five membered
heterocycles possessing one oxygen and two nitrogen atoms. The first synthesis of 1,2,4-oxadiazoles,
initially named furo [ab-1]diazoles, was achieved by Tiemann and Kruger in 1884 [[1a, b,c]. Oxadiazole
exists in different isomeric forms such as 1,2,4-, 1,2,5-, 1,3,4- and 1,2,3-oxadiazole (161 a-d).
Oxadiazole is a very weak base due to the inductive effect of the extra heteroatom. The replacement of
two -CH= groups in furan by two pyridine type nitrogen (-N=) reduces aromaticity of resulting
oxadiazole ring to such an extent that the oxadiazole ring exhibit character of conjugated diene.
N
ON N
ON
N
O
N
ON
N
a1,2,4-Oxadiazole
b 1,2,5-Oxadiazole
c 1,3,4-Oxadiazole
d 1,2,3-Oxadiazole
(161 a-d)
Fig 3.1: Different isomeric forms of Oxadiazole
Electrophilic substitutions in oxadiazole ring are extremely difficult at the carbon atom because
of the relatively low electron density on the carbon atom which can be attributed to electron withdrawal
effect of the pyridine type nitrogen atom. However the attack of electrophiles occurs at nitrogen, if
oxadiazole ring is substituted with electron-releasing groups. Oxadiazole ring is generally resistant to
nucleophilic attack. Halogen-substituted oxadiazole, however, undergo nucleophilic substitution with
replacement of halogen atom by nucleophiles. Oxadiazole undergo nucleophilic substitution similarly as
occurring at an aliphatic sp2 carbon atom.
Nitrogen-oxygen containing heterocycles are of synthetic interest because they constitute an
important class of natural and synthetic products, many of which exhibit useful biological activities [2].
79
The interest in five-membered systems containing one oxygen and two nitrogen atoms (positions 1, 2,
and 4) stems from the occurrence of saturated and partially saturated 1,2,4-oxadiazoles in biologically
active compounds and natural products [3,4].
Oxadiazole rings have been introduced into drug discovery programs for several different
purposes. In some cases, they have been used as an essential part of the pharmacophore, favorably
contributing to ligand binding [5]. In other cases, oxadiazole moieties have been shown to act as a flat,
aromatic linker to place substituents in the appropriate orientation [6] as well as modulating molecular
properties by positioning them in the periphery of the molecule [4]. It has also recently been shown that
significant differences in thermodynamic properties can be achieved by influencing the water
architecture within the aldose reductase active site by using two structurally related oxadiazole
regioisomers [7]. Also, oxadiazoles have been used as replacements for carbonyl containing compounds
such as esters, amides, carbamates, and hydroxamic esters [8].
In drug discovery and development, a number of compounds containing an oxadiazole moiety
are in late stage clinical trials, including Zibotentan (162) as an anticancer agent [9] and Ataluren (163)
for the treatment of cystic fibrosis [10]. So far, one oxadiazole containing compound, Raltegravir (164)
[11], an antiretroviral drug for the treatment of HIV infection, has been launched onto the marketplace.
It is clear that oxadiazoles are having a large impact on multiple drug discovery programs across a
variety of disease areas, including diabetes, obesity [12], inflammation [13] cancer [14] and infection
[15]. Aside from being biologically active themselves, 1,2,4- oxadiazoles also present an important
linking site, for instance, for terminal amino groups of biologically important molecules. There are
many drugs containing 1,2,4-oxadiazoles also many molecules are under development stages. Few
drugs containing oxadiazole unit are mentioned below.
80
N
S
HNO
O
NN
ON
N
O
162 Zibotentan anticancer agent
F
N
NO
O
OH
163 Ataluren cystic fibrosis
N
O
NHN
O
N
N
O
OH
HN
O
F
164 Raltegravir antiretroviral
O
NO
N
NN
FF F
165 Antiparkinsonic
N
N
O
N
O
N
O
O
166 Antiparkinsonic
S
F
NH
N
N
NO2
N
O N
N
O
O
167 Cannabinoid receptor
N O
NNH
N
168 Butalamine vasodilator
N
NO
N
169 Antiglaucoma
Fig 3.2: Drugs containing oxadiazole moiety
Palazzo et al, (1961) are the first to report the synthesis and pharmacological screening of 1,2,4-
oxadiazole derivatives. They synthesised a series of 1,2,4-oxadiazole derivatives (170, 171) and studied
their Nonspecific antispasmodic activity in guinea pig intestine oxygenated thyroid liquid. Also the
synthesised compounds were screened for their local anaesthetic action [16].
NO
N
NNO
N
N
O
170 171
81
Fig 3.3: Nonspecific antispasmodic active oxadiazole derivatives
Later in (1969) Breuer prepared a nitro furan containing oxadiazoles and studied the
antimicrobial activity [17].
OO2NO N
N NH2
172
Fig 3.4: Nitro furan containing oxadiazole
Johan et al, (1972) have reported the synthesis of bis 1,2,4-oxadiazole derivatives and their
antimalarial activity [18].
N
ONNO
N RR N
NOON
N RR
Where R = Cl, F, 4-F-Ph, CF3, 4-CF3-Ph
173174
Fig 3.5: Bis-1,2,4-oxadiazole derivatives
Synthesis of isothiocyanatophenyl-1,2,4-oxadiazole derivatives and its antiparasitic propeties
were reported by Haugwitz and co-workers (1985) [19].
R
NCS
N O
N R1Where R, R1= Alkyl, Phenyl
175
Fig 3.6: Isothiocyanatophenyl-1,2,4-oxadiazole derivatives
Tully et al, (1991) have reported the synthesis and antagonist properties of 2-
(0xadiazolyl)imidazo[ 1,2-a] pyrimidines (176). These are a class of compounds which bind to
benzodiazepine receptors with moderate to weak affinity, and yet display antianxiety properties of
82
similar potency to chlordiazepoxide in animal models while demonstrating reduced or negligible
myorelaxant effects [20].
N
N N
N
ONR4
R3
R2 R1R5
176
Where R1, R2, R3. R4, R5 = Cl, Br, Me, Ethyl, -OCH3
Fig 3.7: 2-(Oxadiazolyl)imidazo[ 1,2-a] pyrimidine derivatives
A series of novel 3-(coumarin-4-yl) - 1,2,4-oxadiazoles were synthesized from coumarin-4-
carboxaldehyde via the intermediate coumarin-4-nitriloxide by Nicolaides and co-workers (1998).
These coumarin derivatives were isolated and characterized, and evaluated for their ability to inhibit
trypsin, glucuronidase, and soybean lipoxygenase. The compounds were also tested for antioxidant
activity, and as antiiflammatory agents in the rat carrageenin paw edema assay. Compound (177) found
to be most active compound among all synthesised molecules [21].
O O
N
O
N
177
Fig 3.8: 4-(5-Methyl-1,2,4-oxadiazol-3-yl)-3,4-dihydrochromen-2-one
Oxadiazoles containing terminal amino acid moiety (178) was synthesized and studied their
antimicrobial activity by Leite and co-workers (2000). Compounds with leucine, isoleucine or aspartic
acid residues were the most active against different Gram positive and negative bacteria although their
activity was lower than Ciprofloxacin. Interestingly, after intravenous administration, compounds with
phenylalanine, valine, aspartic acid or glutamic acid residues were the most active in inhibiting the rat
paw oedema induced by carragenin [22].
83
NO
N
O
HN
R
NH2
O
Where R= CH3, CH2(CH3)2, CH2CO2H, CH2Ph,
CH2CH2CO2H, (CHCH3)2
178
Fig 3.9: Oxadiazoles containing terminal amino acid moiety
Gezginci et al, (2001) have synthesised 1,2,4-Oxadiazoles (179) isosteres of pyridine- and
pyrazine-carboxylic acids and tested for their anti-mycobacterial activity and found potency from 2 to 8
times higher than that of reference compound pyrazinamide [23].
N
ON
XN
S
O
179
X = C, CH, N.
Fig 3.10: Oxadiazoles derivatives of Pyridine and Pyrazine
Jager et al, (2002) have reported the ring fission of oxadiazole system to form substituted
guanidines (183) in the presence of base and long reaction times [24].
Cl
Cl NH
N
N
O
Cl
Cl
Cl N
N
N
O
Cl
Cl N
H2N
N
O180 181
182
183
Scheme-3.1: Oxadiazole ring fission reaction
Srivastava and co-workers (2003) synthesised a series 3-aryl-5-(n-propyl)-4, 5- dihydro-1,2,4-
oxadiazole derivatives (184) and studied their preliminary antimicrobial activity against Staphylococcus
aureus, Mycobacterium smegmatis, and Candida albicans, few of the oxadiazole derivatives shown
good antimicrobial activity [25].
84
R
N O
NWhere R = CH3, Cl, Ethyl
184
Fig 3.11: 3-Aryl-5-(n-propyl)-4, 5- dihydro-1,2,4-oxadiazole derivatives
Cottrell and co-workers (2004) synthesized oxadiazole derivatives and evaluated for their
activity against kinetoplastid parasites. Compound (185a) displayed modest selectivity for Leshmania
donovani axenic amastigote-like parasites over J774 macrophages, PC3 prostate cancer cells, and Vero
cells (6.4-fold, 3.8-fold, and 9.1-fold, respectively). In a murine model of visceral leishmaniasis,
compound (185a) decreased liver parasitemia caused by Leshmania donovani by 48% when given in
five daily i.v. doses at 5 mg/kg and by 61% when administered orally for 5 days at 50 mg/kg, while
compound (185b) showed 30-fold selectivity against Vero cells but was not selective against PC3 cells
[26].
Cl
N
ON SCN
185aBr
N
ON SCN
185b
Fig 3.12: 3-Phenyl-5-(thiocyanatomethyl)-1,2,4-oxadiazole derivatives
The IL-8 receptor is a seven trans membrane domain G-protein coupled receptor (GPCR) that is
found in abundant quantities on neutrophils. Inhibition of the actions of IL-8 on neutrophils should limit
their migration to the sites of inflammation, prevent activation, and thus inhibit the subsequent release
of lysosomal enzymes. Wells et al, (2004) synthesized oxdiazole derivative (186) as interleukin-8 (IL-8)
antagonists these compounds exhibit activity in an IL-8 binding assay as well as in a functional assay of
IL-8 induced elastase release from neutrophils [27].
85
N O
NO
N
Cl
N
186
Fig 3.13: 1-(3-(4-(3-(4-Chlorophenyl)-1,2,4-oxadiazol-5-yl)phenoxy)propyl)-4-methylpiperazine
The common approach used in diabetes treatment is the inhibition of the dipeptidyl peptidase IV
enzyme (DPP-IV). Xu et al, (2005) have synthesized a novel amino acid pyrrolidide analogs as DPP-IV
inhibitors, the introduction of the polar acidic heterocycle 5-oxo-1,2,4-oxadiazole at the 3rd
position of
the terminal phenyl group of compound (187) improved both potency and selectivity [28].
N
O
F
NH2TFA
HN
O NO
187
Fig 3.14: Amino acid pyrrolidide derivative
Sun et al, (2006) synthesized 1,2,4-oxadiazoles (188a-b) as human tryptase inhibitors for
evaluation as a new class of anti-asthematic agent. The inhibitor design is focused on using a prime-side
hydrophobic pocket and the S2 pocket of β-tryptase to achieve inhibition potency and selectivity over
other serine proteases [29].
86
O
R
HN
O
O
N O
N
O
NHNH2
a: R = -CH2Ph
b: R = -CH2Me
188a-b
Fig 3.15: Human tryptase inhibitor oxadiazole derivatives
Boys et al, (2006) reported a series of β-substituted 1,2,4-oxadiazolyl butanoic acids (189a-c) as
potent and selective αvβ3 receptor antagonist [30].
HN N
N O
N
R
CO2H a: R = H, b: R = Me, c: R = Ph,
189 a-c
Fig 3.16: β-Substituted 1,2,4-oxadiazolyl butanoic acids
Koufaki et al, (2007) have synthesised a series of 1,2- dithiolane-3-pentanoic acid (a-lipoic acid)
and its derivatives and evaluated their neuroprotective activity. This study showed that it is possible to
obtain strong neuroprotective compounds by inserting a heterocyclic ring, whose nature has a strong
effect on the activity, in the alkyl- 1,2-dithiolane moiety in conjunction with another antioxidant entity
such as a free or protected catechol moiety. Compound (190) containing the 1,2,4-oxadiazole linker as
amide bioisostere, was among the most potent in the series [31].
N
ON
OR
OR
SS
190
Where R = H, CH3
87
Fig 3.17: 1,2- Dithiolane-3-pentanoic acid oxadiazole derivatives
Sirtuins are a class of seven proteins (SIRT1–7) which play a major role in age-related diseases.
Based on a virtual database screening, a series of 1,2,4-oxadiazole-carbonylaminourea derivatives (191)
have been synthesized and tested for their SIRT1 and SIRT2 activity by Huhtiniemi et al, (2008).
Compound (191) was the most potent SIRT1 inhibitor in the series [32].
N O
N
O
HN NH
NH
O
CF3
191
Fig 3.18: 1-(3-(Naphthalen-1-yl)-1,2,4-oxadiazole-5-carbonyl)-4-(3-
(trifluoromethyl)phenyl)semicarbazide
Koryakova et al, (2008) reported the synthesis and biological evaluation of heteroaryl substituted
N-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamide inhibitors (192a-b) of GSK-3β
kinase. They found out that the inhibitory activity of the synthesized compounds is highly dependent on
the character of substituents in the phenyl ring and the nature of terminal heterocyclic fragment of the
core molecular scaffold. The most potent compounds from this series contain 3,4-di-methyl (192a) or 2-
metoxy substituents (192b) within the phenyl ring and 3-pyridine fragment connected to the 1,2,4-
oxadiazole heterocycle. These compounds selectively inhibit GSK-3β kinase with IC50 value of 0.35 and
0.41 µM, respectively [33].
N
NHN
O
ON
N
N
R2
R3 R1
192a-b
a: R1 = H, R2 = Me, R3 = Me
b: R1 = 2-OMe, R2 = H, R3 = H.
88
Fig 3.19: N-[3-(4-Phenylpiperazin-1-yl)propyl]-1,2,4-oxadiazole-5-carboxamide derivatives
Rakesh et al, (2009) have developed and studied series of oxadiazole derivatives throughout the
course of development of anti-tuberculosis drugs, substitution of the benzyl-piperazine ring of the lead
compound with a 5-phenyl-1,2,4-oxadiazol-3-yl moiety lead to compound (193) with improved activity
[34].
ON
N
ON
O
O
193
Fig 3.20: Ethyl 5-(4-(5-phenyl-1,2,4-oxadiazol-3-yl)phenyl)-4,5-dihydroisoxazole-3-carboxylate
Chandrakantha et al, (2009) have reported a series of new 1,3,4-oxadiazole derivatives
containing 2-fluoro-4-methoxy moiety and their antibacterial and antifungal studies. Few oxadiazole
derivatives compounds showed significant antibacterial activity against Escherichia coli and
Pseudomonas aeruginosa and antifungal activity against Candida albicans [35].
O
F
O
NNBr
O
F
O
NN
F
O
194195
Fig 3.21: Antibacterial and antifungal active oxadiazoles
Novel nitrocatechol-substituted heterocycles were designed and evaluated by Kiss and co-
workers (2010) for their ability to inhibit catechol-O-methyltransferase (COMT). They found that
replacement of the pyrazole core of the initial hit (196) with a 1,2,4-oxadiazole ring resulted in a series
of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide
residue at position 3 of the 1,2,4-oxadiazole ring led to analogue (197) which was found to possess
89
activity comparable to entacapone and lower toxicity in comparison to Tolcapone. Lead structure (197)
was systematically modified in order to improve selectivity and duration of COMT inhibition as well as
to minimize toxicity. Oxadiazole (198) (2,5-dichloro- 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-
oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely
peripheral inhibitor, which was taken for clinical evaluation as an adjunct to L-Dopa therapy of
Parkinson’s disease [36].
N NH
Cl
HO
HO
HO
NN
O
N
NO2
HO
HO
O
NN
O
N
NO2
HO
HO
O
ClCl
196197
198
Fig 3.22: COMT inhibitor oxadiazole derivatives
Hencken et al, (2010) have reported the oxadiazole derivatives (199) of Dehydroartemisinin
(DART) and its in vitro activity in the toxoplasma cycle. Few of the 1,2,4-oxadiazole derivatives shown
less toxicity and 100 times more inhibitory activity than the frontline drug Trimethoprim [37].
O
O
N
N
O
R
H
H
OO
Where R= Me, Ph
199
Fig 3.23: DART oxadiazole derivatives
90
Demont et al, (2011) reported the discovery of new SIP1 agonist compound (200) which
contains 1,2,4-oxadiazole ring in the moiety. This compound found to be more efficacious and shows
excellent pharmacokinetic properties in the preclinical trials [38].
N
NO
N
O
O Na
NC
O
200
Fig 3.24: Sodium 3-(6-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-
dihydroisoquinolin-2(1H)-yl)propanoate
A series of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl]quinoline (201) derivatives were
synthesized and their antibacterial activity was evaluated by Kumar et al, (2011). Few of the molecules
containing oxadiazole ring shown antibacterial activities comparable to the parent compound against all
selected stains [39].
N N
ONAr N
N
O
OH
O
R2
R1F
R3
201
Where R1= H, CH3
R2 = Ethyl, Cyclopropyl
R3= H, -OCH3
Fig 3.25: 7-[4-(5-Aryl-1,3,4-oxadiazole-2-yl)piperazinyl]quinoline derivatives
The Wnt signaling pathway (is a network of proteins that passes signals from receptors on the
surface of the cell to DNA expression in the nucleus. It controls cell-cell communication in the embryo
and adult) is crucial to the regulation of key cellular process. When deregulated it has been shown to
play important role in the growth and progression of multiple human cancers. Shultz et al, (2012) have
studied an early hit assessment of series of [1,2,4] triazolo-3-(ylsulfonylmethyl)-3-phenyl-[1,2,4]-
91
oxadiazole derivatives (202) by biophysical, computational characterisation, structural activity
relationship and physiochemical properties for inhibitors of TNKS1and TNKS2 [40].
N
N
N
SR1
O N
NR3
R2
R4
Where R1 =Ph. Py, Furan, Thiophene
R2, R3, R4 = H, -OMe, Me, F,202
Fig 3.26: [1,2,4] Triazolo-3-(ylsulfonylmethyl)-3-phenyl-[1,2,4]-oxadiazole derivatives
Obesity is a chronic condition characterised by abnormal or excessive fat accumulation.
Diacetyglycerol acyltransferate, DGAT1 is a promising target enzyme for obesity due to its involvement
in the committed step of triglyceride biosynthesis. Jadhav and co-workers (2012) introduced 1,2,4-
oxadiazole ring in the existing drug (203) to increase the solubility of the compound without affecting
the DGAT1 inhibition [41].
S
N
NH
F
O
NH
OH
O
NH
O
NH OH
O
NH
O
N
ON
R
Where R = F, Me, -OMe, CF3
203204
Fig 3.27: DGAT1 inhibitor oxadiazole derivatives
Compounds comprising a coumarin backbone have a wide range of biological activities as
discussed in detail in Chapter-II. As evident from the above discussions the inclusion of two bioactive
motifs like benzopyran and oxadiazole into a single carbon skeleton gives new class of molecules. Also
combination of chromene and oxadiazoles may further enhance the biological activity. Keeping in view
92
of the biological importance of 1,2,4-oxadiazoles, we synthesized a novel series of 1,2,4-oxadiazoles
containing 3,4-dihydro-2H-chromen-2-amine containing moieties and their pharmacological evaluation.
3.2. Results and discussions
The general strategy used for the synthesis of 210 (a-n), (1,2,4-oxadiazol-3-yl)-3,4-dihydro-2H-
chromen-2-amine is outlined in Scheme-3.2. Compound (207) was prepared by following the reported
procedure [42]. Subsequent reduction of (207) using sodium borohydride in alcohol medium gave
compound (208) in high yield. A Variety of methods are present for the synthesis of various
amidoximes like action of hydroxylamine on nitriles. This is the most used process for the preparation
of amidoximes. The experimental procedure recommended by Tiemann and Krüger consists of
liberating hydroxylamine from its hydrochloride using sodium carbonate, adding an equivalent amount
of nitrile and enough alcohol to obtain a clear solution, and keeping the mixture at 60-80°C for few
hours [1a, b, c]. Amidoxime (209) was prepared by treating compound (208) with hydroxylamine
hydrochloride in the presence of base. Further 1,2,4-oxadiazole derivatives were prepared by treating
amidoxime (209) with different aldehydes in microwave condition for 5 min [43, 44, 45].
93
CHO
OH
CN
CNO
CN
NH O
CN
NH2
O NH2
O N
EthanolTriethylamine
Refux, 2hr
NaBH4/MeOH
Refux, 12hr
NH2OH/MeOH
205 206 207 208
209
N
NH2
OH
R-CHO Microwave
N
ONR
R(210 a-n)
Where R= a: 2-Chlorophenyl b: 4-Chlorophenyl c: 2-Hydroxyphenyl d: 3,4-Dimethoxyphenyl e: 4-Fluorophenyl f: Cinnamyl g: 3-Nitrophenyl h: 5-Bromo-2-fluorophenyl i: Phenyl j: 2-Thiophenyl k: 4-Hydroxy-3-methoxyphenyl l: 4-Bromophenyl m: 2-Thiozolyl n: 4-Fluoro-3-phenoxy phenyl
Scheme 3.2: Synthetic route for the chromeno-oxadiazoles (210 a-n)
Proposed mechanism for oxadiazole synthesis:
O NH2
N
NH2
OH
RCHO
O N
N
N
OH
R
R
O N
N
NH
O
R
R
-H2O
O N
N
N
O
R
R
Scheme-3.2a: Proposed mechanism for the synthesis of chromeno-oxadiazoles (210 a-n)
The structure of (210a) was confirmed based on the elemental analyses and spectral studies. The
efficiency of the first reaction prompted us to extend this procedure to synthesize series of compounds
(210 a-n) using microwave reactor.
94
Melting points were determined by open capillary method and were uncorrected. The IR spectra
(In KBr pellets) were recorded on a Shimadzu FT-IR 157 spectrophotometer. 1H -NMR spectra were
recorded on a Perkin-Elmer EM 300MHz spectrometer using TMS as internal standard. The mass
spectra were recorded on a JEOL JMS-D 300 spectrometer operating at 70 eV. Purity of the compounds
was checked by TLC silica coated plates obtained from Merck.
The 1H NMR spectrum of 2-imino-2H-chromene-3-carbonitrile gave the signals at δ 5.84 due to
olefinic proton. Peaks which appeared at δ 7.16-7.67 were assigned to aromatic protons. A singlet peak
at δ 8.83 is observed due to –NH proton. In IR Spectrum peaks at 3293 cm-1
, 2231 cm-1
represents the
presence of –NH and CN functional groups respectively. Finally, the observance of M+ peak at m/z 171
confirms the structure of 2-imino-2H-chromene-3-carbonitrile (207).
(Z)-2-amino-N'-hydroxy-3,4-dihydro-2H-chromene-3-carboxamidine (209) gave the signals due
to amidoxime at δ 5.9 and δ 9.66 assigned to NH and OH respectively in the 1H NMR spectrum. Peaks
which appeared at δ 7.17-7.67 were assigned to aromatic protons. In IR spectrum two peaks at 3416 cm-
1 and 3386 cm
-1 are indicative of –OH and –NH groups. Finally, the observance of M
+ peak at m/z 208
confirms the structure of 2-amino-N'-hydroxy-3,4-dihydro-2H-chromene-3-carboxamidine (209).
Formation of 3,4-dihydro-2H-chromen-2-amine 1,2,4-oxadiazole derivatives was confirmed by
recording their IR, 1H NMR and mass spectra. IR spectrum of oxadiazole (210a) showed absorption at
3006 cm-1
which is due to the aromatic stretching. An absorption band at 1599 cm-1
is due to the C=N
group, band at 1057 cm-1 is due to stretching of oxadiazole. The 1H NMR spectrum of (210a) showed
multiplet in the region of δ, 7.03- 7.14, δ 7.5 is due to aromatic proton. The mass spectrum of (210a)
showed molecular ion peak at m/z 450 & 452 which is in agreement with the molecular formula
C24H17Cl2N3O2. Similarly the spectral values for all the compounds and C, H, N analyses are given in
the experimental part.
95
3.3. Synthesis
3.3.1. General procedure
3.3.1.1. Preparation of 2-imino-2H-chromene-3-carbonitrile (207)
To a stirred solution of salicylaldehyde (205) (10g, 0.08 mol) and malononitrile (206) (5.41g,
0.081 mol) in ethanol (150 ml) was added triethylamine (1 ml, 0.0081 mol).The resulting mixture was
refluxed for 30 min and the completion of reaction was confirmed by TLC. Reaction mixture was then
allowed to cool to room temperature. The precipitate formed was isolated by filtration and washed with
ethanol to get pure product as yellow solid and was recrystalised from ethanol.
3.3.1.1. Preparation of 2-amino-3,4-dihydro-2H-chromene-3-carbonitrile (208)
To a mixture of 2-imino-2H-chromene-3-carbonitrile (207) (12g, 0.069 mol) in methanol (150
ml) was added sodium borohydride (0.83g, 0.034 mol) at 0oC. Reaction mixture was stirred for 20
minutes. The completion of reaction was confirmed by TLC. Reaction mixture poured to water,
precipitated solid was filtered, washed with water and dried to get pure product.
3.3.1.3. Preparation of 2-amino-N'-hydroxychroman-3-carboxamidine (209)
To stirred solution of 2-amino-3,4-dihydro-2H-chromene-3-carbonitrile (208) (10g, 0.05 mol) in
methanol (100 ml) was added hydroxylamine hydrochloride (7.8g, 0.1 mol) and triethylamine (6.9g,
0.06 mol) at 0oC. Reaction mixture was heated to reflux for 8 hours; TLC confirmed the completion of
reaction. Reaction mixture was cooled to room temperature, diluted with water (100 ml), solid separated
was filtered, dried to get pure compound as yellow solid.
3.3.1.4. General procedure for the synthesis of Chromeno-oxadiazole derivatives (210a–n)
A mixture of 2-amino-N'-hydroxychroman-3-carboxamidine (209) (2.4 mmol) and aldehyde (6
mmol) was irradiated in microwave synthesis system at 120W power and 100 ºC temperature for 5
96
minutes. The completion of reaction was monitored by TLC. The reaction mixture was diluted with
diethyl ether to get desired compound as a solid, which was recrystalised using ethanol.
3.4. Characterization
3.4.1. Experimental data
3.4.1.1 2-Imino-2H-chromene-3-carbonitrile (207)
Yield 90 %, Yellow solid, IR (KBr, νmax cm-1
): 3293 (NH), 2231 (CN), 1653 (CH), 1256 (C-O).
1H NMR (300 MHz, DMSO-d6) δ (ppm): 5.84 (1H, s, CH=C); 7.18–7.21 (1H, m, Ar-H); 7.24–7.29 (1H,
m, Ar-H); 7.55–7.61 (2H, m, Ar-H); 8.83 (1H, s NH). MS: m/z = 171 (M+). Anal. calcd. for C10H6N2O:
C, 70.58; H, 3.55; N, 16.46. Found: C, 70.31; H, 3.60; N, 16.37%.
3.4.1.2. 2-Amino-3,4-dihydro-2H-chromene-3-carbonitrile (208)
Yield 88 %, Yellow solid, IR (KBr, νmax cm-1
): 3360 (NH), 3041 (CH), 1606 (C=N), 1254 (C-
O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.5 (m, 2H, CH2), 2.6 (bs, 2H, NH2), 3.5 (m, 1H, CH), 4.8
(m, 1H, CH), 7.18-7.21 (m, 1H, Ar-H), 7.24-7.29 (m, 1H, Ar-H), 7.55-7.61 (m, 2H, Ar-H). MS: m/z =
200.2 (M+). Anal. calcd. for C11H9N3O: C, 66.32; H, 4.55; N, 21.09. Found: C, 66.43; H, 6.48; N,
21.06%.
3.4.1.3. 2-Amino-N'-hydroxychroman-3-carboxamidine (209)
Yield, 96 %, Off white solid, M.p. 187-190 oC, IR (KBr, νmax cm
-1): 3416 (O-H), 3386 (N-H),
3003 (C-H), 1699 (C=N), 1284 (C-O). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 2.5 (m, 2H, CH2), 3.5
(m, 1H, CH), 4.18 (m, 1H, CH), 5.9 (bs, 2H, NH2), 7.18–7.21 (m, 1H, Ar-H), 7.24–7.29 (m, 1H, Ar-H),
7.55–7.61 (m, 2H, Ar-H), 9.63(s, 2H, NH2). MS: m/z =208.1 (M+1). Anal. calcd. for C10H13N3O2: C,
57.96; H, 6.32; N, 20.28. Found: C, 57.95; H, 6.38; N, 22.33 %.
97
3.4.1.4. N-(2-Chlorobenzylidene)-3-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2H-
chromen-2-amine (210a)
Yield 85 %, Off white solid, M.p. 150-152 oC, IR (KBr, νmax cm-1): 3006 (C-H), 1699 (C=N),
1284 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.59 (m, 2H, CH2), 3.3 (m, 1H, CH), 3.88 (m,
1H, CH), 6.31 (d, 1H, Ar-H, J = 8 Hz), 6.76-6.80 (m, 1H, Ar-H), 6.88 (d, 1H, Ar-H, J = 8 Hz), 6.96 (m,
1H, Ar-H), 7.03-7.14 (m, 3H, Ar-H), 7.15 (m, 2H, Ar-H), 7.34-7.29 (m, 1H, Ar-H), 7.58-7.61 (m, 2H,
Ar-H), 8.97 (s, 1H, CH). 13
C NMR (75 MHz, DMSO-d6) δ (ppm): 176.2, 173.2, 159.5, 155.6, 141.3,
137.8, 135.0, 134.8, 133.5, 131.2, 129.4, 129.1, 128.8, 128.4, 127.5, 126.7, 124.5, 120.5, 98.2, 47.4,
28.3. MS: m/z = 450 (M+1), 452 (M+2). Anal. calcd. for C24H17Cl2N3O2: C, 64.01; H, 3.81; N, 9.33.
Found: C, 64.11; H, 3.91; N, 9.38.
3.4.1.5. N-(4-Chlorobenzylidene)-3-(5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2H-
chromen-2-amine (210b)
Yield 88 %, Light brown solid, M.p. 145-147 oC, IR (KBr, νmax cm
-1): 3013 (C-H), 1689 (C=N),
1413 (C=C), 1284 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.58 (m, 2H, CH2), 3.3 (m, 1H,
CH), 3.94 (m, 1H, CH), 6.69 (m, 1H, Ar-H), 6.91 (d, 1H, Ar-H, J = 7.6 Hz), 7.0 (t, 1H, Ar-H, J = 7.6
Hz), 7.19 (d, 1H, Ar-H, J = 7.6 Hz), 7.47-7.50 (m, 4H, Ar-H), 7.8 (d, 2H, Ar-H, J = 8.4 Hz), 7.90 (d,
2H, Ar-H, J = 9.2 Hz), 8.97 (s, 1H, CH). 13
C NMR (75 MHz, DMSO-d6) δ (ppm): 192.1, 168.3, 166.6,
165.3, 162.4, 160.8, 135.4, 132.5, 131.9, 129.9, 127.9, 125.0, 120.2, 120.0, 119.6, 119.2, 117.3, 115.3,
105.8, 96.2, 47.0.4, 21.3. MS: m/z = 450 (M+1), 452 (M+2). Anal. calcd. for C24H17Cl2N3O2: C, 64.01;
H, 3.81; N, 9.33. Found: C, 64.08; H, 3.84; N, 9.34.
3.4.1.6 N-(2-Hydroxybenzylidene)-3- (5-(2-hydroxyphenyl) -1,2,4-oxadiazol-3-yl) -3,4 -dihydro-
2H-chromen-2-amine (210c)
98
Yield 90 %, Off white solid, M.p:130-132 oC, IR (KBr, νmax cm
-1): 3387 (O-H), 2992 (C-H),
1597 (C=N), 1495 (C=C), 1366 (C-N), 1271 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.90 (m,
1H, CH2), 3.07 (m, 2H, CH2), 3.90 (m, 1H, CH), 6.73 (t, 1H, Ar-H, J = 7.6 Hz), 6.80 (d, 1H, Ar-H, J = 8
Hz), 6.96-7.05 (m, 5H, Ar-H), 7.15 (d, 1H, Ar-H, J = 7.8 Hz), 7.44-7.53 (m, 2H, Ar-H), 7.54-7.55 (m,
1H, Ar-H), 7.60-7.62 (m, 1H, Ar-H), 9.0 (s, 1H, CH), 9.07 (bs, 1H, -OH). 13C NMR (75 MHz, DMSO-
d6) δ (ppm): 173.2, 166, 161, 160, 136.2, 134.8, 130.8, 130.7, 129.2, 128.9, 128.3, 125.0, 1119.2, 115.2,
107.2, 98.2, 48.0.4, 28.3. MS: m/z = 414.1 (M+1). Anal. calcd. for C24H19N3O4: C, 69.72; H, 4.63; N,
10.16. Found: C, 69.75; H, 4.53; N, 10.14.
3.4.1.7. N-(3,4-Dimethoxybenzylidene) -3,4-dihydro- 3-(5- (3,4 -dimethoxyphenyl)-1,2,4-
oxadiazol-3-yl)-2H-chromen-2-amine (210d)
Yield 93 %, Off white solid, M.p. 141-143 oC, IR (KBr, νmax cm
-1): 3012 (C-H), 1658 (C=N),
1440 (C=C), 1346 (C-N), 1293 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.59 (m, 1H, CH2),
2.79 (m, 1H, CH2), 3.5 (m, 1H, CH), 3.84 (s, 6H, 2-OCH3), 3.94 (s, 6H, 2-OCH3) 4.09 (m, 1H, CH),
6.65-6.75 (m, 3H, Ar-H), 6.98-7.11 (m, 4H, Ar-H), 7.47-7.56 (m, 3H, Ar-H), 9.02 (s, 1H, CH). 13
C
NMR (75 MHz, DMSO-d6) δ (ppm): 176.1, 172.7, 161.8, 156.2, 154.5, 153.8, 153.5, 153.1, 133.8,
131.0, 128.2, 126.3, 124.1, 122.0, 121.5, 121.8, 120.8, 118.2,117.8,116.2,115.3, 97.1, 57.3, 47.8, 27.3.
MS: m/z = 502.2 (M+1). Anal. calcd. for C28H27N3O6: C, 67.05; H, 5.43; N, 8.38. Found: C, 67.12; H,
5.38; N, 8.38.
3.3.1.8 N-(4-Fluorobenzylidene)-3-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2H-
chromen-2-amine (210e)
Yield 93 %, Off white solid, M.p. 154-157 oC, IR (KBr, νmax cm
-1): 3010 (C-H), 1654 (C=N),
1432 (C=C), 1340 (C-F), 1284 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.58 (m, 2H, CH2), 3.3
99
(m, 1H, CH), 3.88 (m, 1H, CH), 6.69 (m, 1H, Ar-H), 6.91 (d, 1H, Ar-H, J = 7.6 Hz), 7.0 (t, 1H, Ar-H, J
= 7.6 Hz), 7.19-7.29 (m, 5H, Ar-H), 7.47-7.50 (m, 4H, Ar-H), 8.97 (s, 1H, CH). 13
C NMR (75 MHz,
DMSO-d6) δ (ppm): 175.9,172.8, 166.2, 162.9, 161.4, 156.6, 136.5, 131.1, 130.2, 129.3, 128.0, 126.7,
122,6, 117.3, 116.0, 115.5, 97.6, 47.7, 27.9. MS: m/z = 418 (M+1). Anal. calcd. for C24H17F2N3O2: C,
69.06; H, 4.11; N, 10.07. Found: C, 69.02; H, 4.13; N, 9.97.
3.4.1.9. 3,4-Dihydro-N- (3-phenylallylidene) -3- (5-styryl-1,2,4-oxadiazol-3-yl)-2H-chromen-2-
amine (210f)
Yield 78 %, Brown solid, M.p.160-162 oC, IR (KBr, νmax cm-1): 2996 (C-H), 1656 (C=N), 1478
(C=C), 1352 (C-N), 1281 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.88 (m, 1H, CH2), 3.01 (m,
1H, CH2), 3.68 (m, 1H, CH), 4.12 (m, 1H, CH), 5.8 (m, 1H, CH), 6.70 (m, 2H, Ar-H, CH), 6.84-6.99
(m, 3H, Ar-H,CH), 7.15-7.30 (m, 10H, Ar-H), 8.5 (s, 1H, CH). 13
C NMR (75 MHz, DMSO-d6) δ (ppm):
166.9, 166.0, 166.1, 162.8, 161.3, 156.1, 136.4, 131.0, 130.1, 130.5, 129.3, 128.0, 126.4, 124.3, 122,5,
117.1, 116.1, 115.4, 97.5, 47.1, 27.2. MS: m/z = 434.2 (M+1). Anal. calcd. for C28H23N3O2: C, 77.58;
H, 5.35; N, 9.69. Found: C, 77.55; H, 5.36; N, 9.59.
3.4.1.10. N-(3-Nitrobenzylidene) -3,4- dihydro-3- (5-(3-nitrophenyl) -1,2,4-oxadiazol-3-yl)-2H-
chromen-2-amine (210g)
Yield 87 %, Yellow solid, M.p. 168-170 oC, IR (KBr, νmax cm
-1): 3012 (C-H), 1648 (C=N),
1537(N-O), 1358(N-O), 1490 (C=C), 1330 (C-N), 1274 (C-O). 1H NMR (300 MHz, DMSO-d6) δ
(ppm): 2.60 (m, 1H, CH2), 3.17 (m, 1H, CH2), 3.58 (m, 1H, CH), 4.06 (m, 1H, CH), 6.76 (t, 1H, Ar-H,
J = 7.6 Hz), 6.85 (d, 1H, Ar-H, J = 8 Hz), 6.96-7.25 (m, 5H, Ar-H), 7.35 (d, 1H, Ar-H, J = 7.8 Hz),
7.44-7.53 (m, 2H, Ar-H), 7.54-7.55 (m, 1H, Ar-H), 7.60-7.62 (m, 1H, Ar-H), 9.1 (s, 1H, CH). 13
C NMR
(75 MHz, DMSO-d6) δ (ppm):175.1,172.2, 166.4, 163.0, 161.1, 155.6, 131.5, 131.1, 130.2, 129.3,
100
127.0, 126.7, 122,6, 118.3, 115.0, 117.5, 97.6, 47.7, 27.9. MS: m/z = 472.2 (M+1). Anal. calcd. for
C24H17N5O6: C, 61.15; H, 3.63; N, 14.86. Found: C, 61.08; H, 3.65; N, 14.81.
3.4.1.11. N-(5-Bromo-2-fluorobenzylidene)-3-(5-(5-bromo-2-fluorophenyl)-1,2,4 oxadiazol-3-yl)-
3,4-dihydro-2H-chromen-2-amine (210h)
Yield 93 %, Off white solid, M.p. 134-136 oC, IR (KBr, νmax cm
-1): 2996 (C-H), 1664 (C=N),
1419 (C=C), 1328 (C-F), 1276 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.52 (m, 1H, CH2), 3.2
(m, 1H, CH), 3.8 (m, 1H, CH), 3.84 (m, 1H, CH), 6.34 (m, 1H, Ar-H), 6.47 (m, 1H, Ar-H), 6.80 (t, 1H,
Ar-H, J = 7.2 Hz), 6.88-6.96 (m, 2H, Ar-H), 7.02-7.15 (m, 5H, Ar-H), 8.91 (s, 1H, CH). 13C NMR
(75 MHz, DMSO-d6) δ (ppm): 176.5, 173.8, 160.9, 159.7, 158.4, 155.6, 136.2, 135.0, 134.9, 133.7,
129.9, 128.1, 127.3, 126.8, 126.5, 122.6, 122.0, 121.5, 121.2, 117.1, 97.9, 47.5, 27.3. MS: m/z = 476
(M+1). Anal. calcd. for C24H15Br2F2N3O2: C, 50.11; H, 2.63; N, 7.3. Found: C, 50.17; H, 2.55; N, 7.28.
3.4.1.12. N-Benzylidene-3,4-dihydro-3-(5-phenyl-1,2,4-oxadiazol-3-yl)-2H-chromen-2-amine
(210i)
Yield 95 %, Off white solid, M.p. 140-142 oC, IR (KBr, νmax cm
-1): 3000 (C-H), 1699 (C=N),
1284 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.59 (m, 2H, CH2), 3.2 (m, 1H, CH), 3.89 (m,
1H, CH), 6.31 (d, 1H, Ar-H, J = 8 Hz), 6.76-6.80 (m, 1H, Ar-H), 6.88 (d, 1H, Ar-H, J = 8 Hz), 6.96 (m,
1H, Ar-H), 7.03-7.14 (m, 5H, Ar-H), 7.15 (m, 2H, Ar-H), 7.34-7.39 (m, 1H, Ar-H), 7.58-7.61 (m, 2H,
Ar-H), 8.92 (s, 1H, CH). 13
C NMR (75 MHz, DMSO-d6) δ (ppm): 176.2, 172.8, 150.9, 140.3, 132.8,
131.3, 131.0,130.6, 129.1, 127.1,126.0, 121.5,116.2, 98.0, 47.4, 27.2. MS: m/z = 382.2 (M+1). Anal.
calcd. for C24H19N3O2: C, 75.57; H, 5.02; N, 11.02. Found: C, 75.59; H, 5.02; N, 11.12.
3.4.1.13. 3,4-Dihydro-3-(5-(thiophen-2-yl)-1,2,4-oxadiazol-3-yl)-N-((thiophen-2-yl)methylene)-
2H-chromen-2-amine (210j)
101
Yield 73 %, Dark solid, M.p, 126-128 oC, IR (KBr, νmax cm
-1): 2990 (C-H), 1675 (C=N),
1286(C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.58 (m, 2H, CH2), 2.89 (m, 1H, CH), 3.90 (m,
1H, CH), 6.82-6.86 (m, 1H, Ar-H), 6.96-6.98 (m, 1H, Ar-H,), 7.12-7.28 (m, 4H, Ar-H), 7.13-7.24 (m,
4H, Ar-H), 8.94 (s, 1H, CH). 13C NMR (75 MHz, DMSO-d6) δ (ppm): 171.2, 170.1, 153.9, 151.3,
132.8, 131.7, 131.3, 130.9, 129.8, 127.1, 126.0, 121.5, 116.2, 98.0, 47.2, 27.1. MS: m/z = 394.2 (M+1).
Anal. calcd. for C20H15N3O2S2: C, 61.05; H, 3.84; N, 10.68. Found: C, 61.25; H, 3.80; N, 10.69.
3.4.1.14. N-(4-Hydroxy-3-methoxybenzylidene)-3-(5-(4-hydroxy-3-methoxyphenyl)-1,2,4-
oxadiazol-3-yl)-3,4-dihydro-2H-chromen-2-amine (210k)
Yield 85 %, Off-White solid, M.p. 172-174 oC, IR (KBr, νmax cm-1): 2994 (C-H), 1660 (C=N),
1420 (C=C), 1328 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.48 (m, 1H, CH2), 2.96 (m, 1H,
CH), 3.88 (m, 1H, CH), 3.93 (s, 6H, -OCH3), 4.04 (m, 1H, CH), 6.65 (m, 1H, Ar-H), 6.77 (m, 2H, Ar-
H), 6.80-6.90 (m, 3H, Ar-H), 6.98-7.06 (m, 2H, Ar-H), 7.15-7.24 (m, 2H, Ar-H), 8.91 (s, 1H, CH), 9.6
(bs, 1H, -OH). 13
C NMR (75 MHz, DMSO-d6) δ (ppm): 176.2, 173.2, 161.5, 156.1, 153.4, 149.7, 148.8,
129.4, 128.1, 126.0, 124.1, 123,2, 123.0, 120.5, 118.4, 117.8, 116.1, 115.5, 98.1, 47.9, 27.3. MS: m/z =
474.1 (M+1). Anal. calcd. for C26H23N3O6: C, 65.95; H, 4.90; N, 8.87. Found: C, 65.99; H, 4.80; N,
8.97.
3.4.1.15. N-(4-Bromobenzylidene)-3-(5-(4-bromophenyl)-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2H-
chromen-2-amine (210l)
Yield 94 %, Off-White solid, M.p. 151-154 oC, IR (KBr, νmax cm
-1): 3015 (C-H), 1689 (C=N),
1412 (C=C), 1290 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.56 (m, 2H, CH2), 3.32 (m, 1H,
CH), 3.97 (m, 1H, CH), 6.71 (m, 1H, Ar-H), 6.91 (d, 1H, Ar-H, J = 7.6 Hz), 7.0 (t, 1H, Ar-H, J = 7.6
Hz), 7.19 (d, 1H, Ar-H, J = 7.6 Hz), 7.47-7.50 (m, 4H, Ar-H), 7.8 (d, 2H, Ar-H, J = 8.4 Hz), 7.90 (d,
102
2H, Ar-H, J = 9.2 Hz), 8.93 (s, 1H, CH). 175.3,172.5, 166.2, 162.9, 161.3, 156.7, 136.8, 131.0, 130.1,
129.1, 128.4, 126.3, 122.5, 117.1, 116.0, 115.6, 97.5, 47.7, 27.6. MS: m/z = 540 (M+1), 542 (M+2).
Anal. calcd. for C24H17Br2N3O2: C, 53.46; H, 3.18; N, 7.79. Found: C, 53.41; H, 3.12; N, 7.84.
3.4.1.16. 3,4-Dihydro-3-(5-(thiazol-2-yl)-1,2,4-oxadiazol-3-yl)-N-((thiazol-2-yl) methylene)-2H-
chromen-2-amine (210m)
Yield 70 %, Brown solid, M.p. 136-138 oC, IR (KBr, νmax cm
-1): 2994 (C-H), 1680 (C=N),
1283(C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.56 (m, 2H, CH2), 3.15 (m, 1H, CH), 4.12 (m,
1H, CH), 6.61 (d, 1H, Ar-H, J = 8 Hz), 6.76-6.80 (m, 1H, Ar-H), 6.88 (d, 1H, Ar-H, J = 8 Hz), 6.96 (m,
1H, Ar-H), 7.34-7.42 (m, 2H, Ar-H), 8.24-8.16 (m, 2H, Ar-H), 9.2 (s, 1H, CH). 13C NMR (75 MHz,
DMSO-d6) (ppm): 173.2, 165.7, 158.9,157.6, 155.6, 143.8, 131.2, 127.4, 126.0, 121.5, 119.8, 115.5,
97.8, 47.6, 27.3. MS: m/z = 394.2 (M+1). Anal. Calcd. For C18H13N5O2S2: C, 54.67; H, 3.31; N, 17.71.
Found: C, 54.66; H, 3.38; N, 17.63.
3.4.1.17. N-(4-Fluoro-3-phenoxybenzylidene) -3- (5-(4-fluoro-3-phenoxyphenyl) -1,2,4-oxadiazol-
3-yl)-3,4-dihydro-2H-chromen-2-amine (210n)
Yield 91 %, Off-White solid, M.p. 158-161 oC, IR (KBr, νmax cm
-1): 3010 (C-H), 1688 (C=N),
1289 (C-O). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 2.59 (m, 2H, CH2), 3.2 (m, 1H, CH), 3.89 (m,
1H, CH), 6.31 (d, 1H, Ar-H, J = 8 Hz), 6.76-6.80 (m, 1H, Ar-H), 6.88 (d, 1H, Ar-H, J = 8 Hz), 6.96 (m,
1H, Ar-H), 7.03-7.14 (m, 5H, Ar-H), 7.15 (m, 3H, Ar-H), 7.34-7.39 (m, 4H, Ar-H), 7.58-7.61 (m, 4H,
Ar-H), 8.92 (s, 1H, CH). 13
C NMR (75 MHz, DMSO-d6) δ (ppm): 172.0, 165.7, 158.1, 157.1, 156.1,
154.6, 143.2, 142.8, 138.9, 131.2, 128.5, 127.4, 126.0, 121.9, 121.5, 119.8, 117.2, 115.5, 97.8, 47.6,
27.3. MS: m/z = 602.2 (M+1). Anal. calcd. for C36H25F2N3O4: C, 71.87; H, 4.19; N, 6.98. Found: C,
71.80; H, 4.23; N, 6.70.
103
3.4.2. Spectral Data
104
Fig. 3.28: 1H NMR Spectrum of compound 210j
O N
ON
N
S
S
210j
105
Fig. 3.29: Mass spectrum of compound 210j
O N
ON
N
S
S
210j
C20H15N3O2S2Mol. Wt.: 393.48
106
Fig. 3.30: 1H NMR Spectrum of compound 210c
Fig. 3.31: 1H NMR Spectrum expansion of compound 210c
O N
ON
N
HO
HO
210c
O N
ON
N
HO
HO
210c
107
Fig. 3.32: 13
C NMR Spectrum of compound 210c
O N
ON
N
HO
HO
210c
108
O N
ON
N
HO
HO
210c
C24H19N3O4Mol. Wt.: 413.43
109
Fig. 3.33: LCMS of compound 210c
Fig. 3.34: IR Spectrum of compound 210c
O N
ON
N
HO
HO
210c
110
Fig. 3.35: 1H NMR Spectrum of compound 210b
O N
ON
N
Cl
Cl
210b
111
Fig. 3.36: 13C NMR Spectrum of compound 210b
O N
ON
N
Cl
Cl
210b
112
Fig. 3.37: Mass spectrum of compound 210b
3.5. Conclusion
A series of novel chromeno oxadiazoles were synthesized by microwave reaction in reasonably
good yield. They were characterized by 1H-NMR,
13C-NMR, mass spectrometry, IR studies and
elemental analyses. All the newly synthesized compounds were screened for antibacterial activity by
MIC method. The structural activity relationship (SAR) and antimicrobial activity of all the compound
are discussed in CHAPTER 6.
3.6. References
1. (a).Tiemann, F., Kruger, P. Chem. Ber., 1884, 17, 1685-1698. (b).Eloy, F., “Preparation of 1,2,4-
oxadiazoles by dipolar addition to aliphatic nitrile oxide” NASA TTF-F-16861. January 1976,
O N
ON
N
Cl
Cl
210b Mol. Wt.: 450.32
113
Unclassified. (c) Pace, A., Pierro, P. “The new era of 1,2,4-oxadiazoles” Org. Biomol. Chem.
2009, 7, 4337−4348.
2. Vu, C. B., Corpuz, E. G., Merry, T. J., Pradeepan, S. G., Bartlett, C., Bohacek, R. S., Botfield, M.
C., Eyermann, C. J., Lynch, B. A., MacNeil, I. A., Ram, M. K., Schravendijk, M. R., Violette, S.,
Sawyer, T. K. “Discovery of Potent and Selective SH2 Inhibitors of the Tyrosine Kinase ZAP-70”
J. Med. Chem. 1999, 42 (20), 4088-4098.
3. Ankersen, M., Peschke, B., Hansen, B. S., Hansen, T. K. “Investigation of bioisosters of the
growth harmone secretagogue L-692,429” Bioorg. Med. Chem. Lett. 1997, 7, 1293-1298.
4. Orlek, B. S., Blaney, F. E., Brown, F., Clark, M. S. G., Hadley, M. S., Hatcher, J., Riley, G. J.,
Rosenberg, H. E., Wadsworth, H. J., Wyman, P. “Comparison of azabicyclic esters and
oxadiazoles as ligands for the muscarinic receptor” J. Med. Chem. 1991, 34 (9), 2726-2735.
5. Ohmoto, K., Yamamoto, T., Horiuchi, T., Imanishi, H., Odagaki, Y., Kawabata, K., Sekioka, T.,
Hirota, Y., Matsuoka, S., Nakai, H., Toda, M., Cheronis, J. C., Spruce, L. W., Gyorkos, A.,
Wieczorek, M. “Design and synthesis of new orally active nonpeptidic inhibitors of human
neutrophil elastase” J. Med. Chem. 2000, 43, 4927-4929.
6. Ono, M., Haratake, M., Saji, H., Nakayama, M. “Development of novel β-amyloid probes based
on 3,5-diphenyl 1,2,4-oxadiazole” Bioorg. Med. Chem. 2008, 16, 6867-6872.
7. Ladbury, J. E., Klebe, G., Freire, E. “Adding calorimetric data to decision making in lead
discovery: a hot tip” Nat. Rev. Drug Discovery, 2010, 9, 23-27.
8. Patani, G. A., LaVoie, E. J. “Bioisosterism: A rational approach in drug design” Chem. Rev. 1996,
96, 3147−3176.
9. James, N. D., Growcott, J. W. “Zibotentan” Drugs of the Fut. 2009, 34 (8), 624-633.
10. Jones, A. M., Helm, J. M. “Emerging treatments in cystic fibrosis” Drugs. 2009, 69, 1903-1910.
114
11. Summa, V., Petrocchi, A., Bonelli, F., Crescenzi, B., Donghi, M., Ferrara, M., Fiore, F., Gardelli,
C., Gonzalez Paz, O., Hazuda, D. J., Jones, P., Kinzel, O., Laufer, R., Monteagudo, E., Muraglia,
E., Nizi, E., Orvieto, F., Pace, P., Pescatore, G., Scarpelli, R., Stillmock, K., Witmer, M. V.,
Rowley, M. “Discovery of raltegravir, a potent, selectiveorally bioavailable HIV-integrase
inhibitor for the treatment of HIVAIDS infection” J. Med. Chem. 2008, 51, 5843-5855.
12. Lee, S. H., Seo, H. J., Jung, M. E., Park, J. H., Park, H. J., Yoo, J., un, H., Na, J., Kang, S. Y.,
Song, K. S. M. A. “Biaryl pyrazolyl oxadiazole as potent, selective, orally bioavailable
cannabinoid-1 receptor antagonists for the treatment of obesity” J. Med. Chem. 2008, 51, 7216-
7233.
13. Unangst, P. C., Shrum, G. P., Connor, D. T., Dyer, R. D., Schrier, D. J. “Novel 1,2,4-oxadiazoles
and 1,2,4-thiadiazoles as dual 5-lipoxygenaseand cyclooxygenase inhibitors” J. Med. Chem. 1992,
35, 3691-3698.
14. Zhang, H.-Z., Kasibhatla, S., Kuemmerle, J., Kemnitzer, W., Ollis- Mason, K., Qiu, L., Crogan-
Grundy, C., Tseng, B., Drewe, J., Cai, S. X. “Discovery and structure-activity relationship of 3-
aryl-5-aryl-1,2,4- oxadiazoles as a new series of apoptosis inducers and potential anticancer
agents” J. Med. Chem. 2005, 48, 5215-5223.
15. Cottrell, D. M., Capers, J., Salem, M. M., DeLuca-Fradley, K., Croft, S. L., Werbovetz, K. A.
“Antikinetoplastid activity of 3-aryl-5- thiocyanatomethyl-1,2,4-oxadiazoles” Bioorg. Med. Chem.
2004, 12, 2815-2824.
16. Palazzo, G., Tavella, M., Strani, G., Silverstrini, B. “1,2,4-Oxadiazoles-IV. Synthesis and
pharmacological properties of a series of substituted aminoalkyl 1,2,4- oxadiazoles” Journal of
Medicinal and Pharmaceutical Chemistry. 1961, 4, 352-366.
115
17. Breuer, H. “Nitroheterocycles. 1. Nitrofuryl- substituted 3-amino-1,2,4- oxadiazoles and 5- amino-
1,2,4- oxadiazoles. J. Med. Chem. 1969, 12 (4), 708-709.
18. Johan, B. H., Roy, F. G. “Hydroxylamine derivatives as potential antimalarial agents. 1,2,4-
Oxadiazoles.” J. Med. Chem. 1972, 15, 1198-1200.
19. Haugwitz, R. D., Martinez, A. J., Venslavsky, J., Angel, R. G., Maurer, B. V., Jacobs, G. A.,
Narayanan, V. L., Cruthers, L. R., Szanto, J. “Antiparasitic agents. Synthesis and Anthelminitic
activities of novel isothiocyanatophenyl-1,2,4-oxadiazoles” J. Med. Chem. 1985, 28, 1234-1241.
20. Tully, W. R., Gardner, C. R., Gillespie, R. J., Westwood. R. “2-(O xadiazoly1)- and 2-
(Thiazolyl)imidazo[1,2-a] pyrimidines as Agonists and Inverse Agonists at Benzodiazepine
Receptors” J. Med. Chem. 1991, 34 (7), 2060-2067.
21. Nicolaides, D. N., Fylaktakidou, K. C., Litinas, K. E., Hadjipavlou-Litina, D. “Synthesis and
biological evaluation of several coumarin-4-carboxamidoxime and 3-(coumarin-4-yl)-1,2,4-
oxadiazole derivatives” Eur. J. Med. Chem. 1998, 33, 715-724.
22. Leite, A. C. L., Vieira, R. F., De Faria, A. R., Wanderley, A. G., Afiatpour, P., Ximenes, E. C.
P. A., Srivastava, R. M., de Oliveira, C. F., Medeiros, M. V., Antunes, E., Brondani, D. J.
“Synthesis, anti-inflammatory and antimicrobial activities of new 1, 2, 4-oxadiazoles
peptidomimetics” Farmaco. 2000, 55, 719-724.
23. Gezginci, M. H., Martin, A. R., Franzblau, S. G. “Antimycobacterial Activity of Substituted
isosteres of Pyridine and Pyrazinecarboxylic Acids” J. Med. Chem. 2001, 44, 1560-1563.
24. Jager, C., Laggner, C., Mereiter, K., Holzer, W. “A ring fission/C-C bond cleavage reaction with
N-alkyl-N-Methyl-N-[(5-phenyl-1,2,4-oxadiazolol-3-yl) methyl]amine” Tetrahydron. 2002, 58,
10417-10422.
116
25. Srivasta, R. M., Analice de, A. L., Osnir, S. V., Marcelo J. da, C. S., Maria, T. J. A .
“Antiinflammatory Property of 3-Aryl-5-(n-propyl)-1,2,4-oxadiazoles and Antimicrobial Property
of 3-Aryl-5- (n-propyl)-4,5-dihydro-1,2,4-oxadiazoles:Their Syntheses and Spectroscopic
Studies.” Bioorg. Med. Chem. 2003, 11, 1821–1827.
26. Cottrell, D. M., Capers, J., Salem, M. M., DeLuca-Fradley, K., Croft, S. L., Werbovetz, K. A.
“Antikinetoplastid activity of 3-aryl-5-thiocyanatomethyl-1,2,4-oxadiazoles” Bioorg. Med. Chem.
2004, 12, 2815-2824.
27. Wells, M. A. W., Henninger, T. C., Fraga-Spano, Boggs, S. A. C. M., Matheis, M., Ritchie, D. M.,
Argentieri, D. C., Wachter, M. P., Hlasta, D. J. “Synthesis and structure–activity relationships of
3,5-diarylisoxazoles and 3,5-diaryl-1,2,4-oxadiazoles, novel classes of small molecule interleukin-
8 (IL-8) receptor antagonists” Bioorg. Med. Chem Lett. 2004, 14, 4307-4311.
28. Xu, J., Wei, L., Mathvink, R., He, J., Park, Y. J., He, H., Leiting, B., Lyons, K. A., Marsilio, F.,
Patel, R. A., Wu, J. K., Thornberry, N. A., Weber, A. E. “Discovery of potent and selective
phenylalanine based dipeptidyl peptidase IV inhibitors” Bioorg. Med. Chem. Lett. 2005, 15, 2533-
2536.
29. Sun, L. C., Weili, L., Paul, A. S., John, R. S., James, W. J., David, S. J. R., Michael, J. G., Mary,
E. M. “Design of novel, potent, and selective human β-tryptase inhibitors based on α-keto-[1,2,4]-
oxadiazoles” Bioorg. Med. Chem. Lett. 2006, 16, 4036-4040.
30. Boys, M. L., Schretzman, L. A., Chandrakumar, N. S., Tollefson, M. B., Mohler, S. B., Downs, V.
L., Penning, T. D., Russell, M. A., Wendt, J. A., Chen, B. B., Stenmark, H. G., Wu, H.,
Spangler, D. P., Clare, M., Desai, B. N., Khanna, I. K., Nguyen, M. N., Duffin, T., Engleman,
V. W., Finn, M. B., Freeman, S. K., Hanneke, M. L., Keene, J. L., Klover, J. A., Nickols, G. A.,
Nickols, M. A., Steininger, C. N., Westlin, M., Westlin, W., Norring, S. A. “Convergent, parallel
117
synthesis of a series of β-substituted 1,2,4-oxadiazole butanoic acids as potent and selective αvβ3
receptor antagonists” Bioorg. Med. Chem. Lett. 2006, 16, 839-844.
31. Koufaki, M., Kiziridi, C., Nikoloudaki, F., Alexis, M. N. “Design and synthesis of 1,2-dithiolane
derivatives and evaluation of their neuroprotective activity” Bioorg. Med. Chem. Lett. 2007, 17,
4223-4227.
32. Huhtiniemi, T., Suuronen, T., Rinne, V. M., C. Wittekindt, C., Lahtela-Kakkonen, M., Jarho, E.,
Wallen, E. A. A., Salminen, A., Poso, A., Leppanen, J. “Oxadiazole-carbonyl amino thioureas as
SIRT1 and SIRT2 Inhibitors” J. Med. Chem. 2008, 51, 4377–4380.
33. Koryakova, A. G., Ivanenkov, Y. A., Ryzhova, E. A., Bulanova, E. A., Karapetian, R. N., Mikitas,
O. V., Katrukha, E. A., Kazey, V. I., Okun, I., Kravchenko, D. V., Lavrovsky, Y. V., Korzinov,
O. M., Ivachtchenko, A. V. “Novel aryl and heteroaryl substituted N-[3-(4-phenylpiperazin-1-
yl)propyl]-1,2,4-oxadiazole-5-carboxamides as selective GSK-3 inhibitors” Bioorg. Med. Chem.
Lett. 2008, 18, 3661-3661.
34. Rakesh, D. S., Lee, R. B., Tangallapally, R. P. L., Lee, R. E. “Synthesis, optimization and
structure–activity relationships of 3,5-disubstituted isoxazolines as new anti-tuberculosis agents”
Eur. J. Med. Chem. 2009, 44, 460–472.
35. Chandrakantha, B., Shetty, P., Nambiyar, V., Isloor, N., Isloor, A. M. “Synthesis, characterization
and biological activity of some new 1,3,4-oxadiazole bearing 2-flouro-4-methoxy phenyl moiety”
Eur. J. Med. Chem. 2010, 45(3),1206-1210.
36. Kiss, L. E., H Ferreira, H. S., Torrão, L., Bonifacio, L. M., Palma, P. N., Pa-Silva, P. S., an
Learmonth, D. A “Discovery of a Long-Acting, Peripherally Selective Inhibitor of Catechol-O-
methyltransferase” J. Med. Chem. 2010, 53, 3396-3411.
118
37. Hencken, C. P., Jones-Brando, L., Bordón, C., Stohler, R., Mot,t B. T., Yolken, R., Posner, G. H.,
Woodard, L. E. “Thiazole, oxadiazole, and carboxamide derivatives of Artemisinin are higly
selective and potent inhibitors of Toxoplasma gondii” J. Med. Chem. 2010, 53, 3594-3601.
38. Demont, E. H., Andrews, B. I., Bit, R. A., Campbell, C. A., Cooke, J. W. B., Deeks, N., Desai, S.,
Dowel, S. J., Gaskin, G., Gray, J. R. J., Haynes, A., Holmes, D. S., Kumar, U., Morse, M. A.,
Osborne, G. J., Panchal, T., Patel, B., Perboni, A., Taylor, S., Watson, R.,Witherington, J., Willis,
R. “Discovery of new selective SIP1 receptor agonist efficacious at low oral dose and devoid of
effects on heart rate” ACS Med.Chem. Lett. 2011, 2, 444-449.
39. Kumar, R., Kumar, A., Jain, S., Kaushik, D. “Synthesis, antibacterial evaluation and QSAR
studies of 7-[4-(5-aryl-1,3,4-oxadiazole-2-yl)piperazinyl]quinoline derivatives” Eur. J. Med.
Chem. 2011, 46, 3543-3550.
40. Shultz, M. D., Kirby, C. A., Stams, T., Chin, D. N., Blank, J., Charlat, O., Cheng. H., Cheung, A.,
Cong, F., Feng, Y., Fortin, P. D., Hood, T., Tyagi, V., Xu, M., Zhang, B., Shao, W. “[1,2,4]
Triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4] oxadiazoles: Antagonist of the Wnt Pathway that
inhibit tankyrases 1 and 2 via novel adenosine pocket binding” J. Med. Chem. 2012, 55, 1127-
1136.
41. Jadhav, R. D., Kadam, K. S., Kandre, S., Guha, T., Reddy, M. M. K., Brahma, M. K., Deshmukh,
N J., Dixit, A., Doshi, L., Potdar, N., Enose, A. A., Vishwakarma, R. M., Sivaramakrishnan, H.,
Srinivasan, S., Nemmani, K. V. S., Gupte, A., Gangopadhyay, A. K., Sharma, R. “Synthesis and
biological evaluation of isoxazole, oxazole and oxadiazole containing heteroaryl analogues of
biaryl ureas as DGAT1 inhibitors.” Eur. J. Med. Chem. 2012, 54, 324-342.
119
42. Evdokimov, N. M., Kireev, A.,Yakovenko, A. A., Yu, M., Antipin, Igor, V., Magedov, Kornienko,
A. “One-Step Synthesis of Heterocyclic Privileged Medicinal Scaffolds by a Multicomponent
Reaction of Malononitrile with Aldehydes and Thiols” J. Org. Chem. 2007, 72, 3443-3453.
43. Adib, M., Jahromi, A. H., Tavoosi, N., Mahdavi, M., Bijanzadeh, H. R. “Microwave-assisted
efficient, one-pot three-component synthesis of 3,5-disubstituted 1,2,4-oxadiazoles under solvent-
free conditions” Tetrahedron Letts. 2006, 47, 2965-2967.
44. Augustine, J. K., Akabote, V, Hegde, S. G., Alagaswamy, P. “PTAS-ZnCL2: An efficient catalyst
for synthesis of 1,2,4-Oxadiazoles from amidoximes and organic nitriles” J. Org. Chem. 2009, 74,
5640-5640.
45. Kaboudin, B., Malekzadeh, L. “Organic reactions in water: an efficient method for the synthesis of
1,2,4-oxadiazoles in water” Tetrahedron Letts. 2011, 52, 6424-6426.