CHAPTER-3

SYNTHESIS, CHARACTERIZATION OF SOME NOVEL

CHROMENO OXADIAZOLE DERIVATIVES

36
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 N N N
N N N N
O O O O

a b c d
1,2,4-Oxadiazole 1,2,5-Oxadiazole 1,3,4-Oxadiazole 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].

78
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.

79
 O O
O H O
N N O N OH
S N F O N OH F
N N N
N H H
O N N N
O N
N
O O
162 Zibotentan 163 Ataluren 164 Raltegravir
anticancer agent cystic fibrosis antiretroviral

F F
F O
N O
O N N N N
N N N N
O O O N
O NH NO2
O S
N
N N O
F

165 167
Antiparkinsonic 166
Antiparkinsonic Cannabinoid receptor

N
NH N
N O
N
N
N
O

168 Butalamine 169 Antiglaucoma

vasodilator

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].

N
N
N N
O N N
O

170 171

80
 Fig 3.3: Nonspecific antispasmodic active oxadiazole derivatives

Later in (1969) Breuer prepared a nitro furan containing oxadiazoles and studied the

antimicrobial activity [17].

N NH2
O2N O O N
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].

O N N O
N O O N

R N N R N N
R R
173
174

Where R = Cl, F, 4-F-Ph, CF3, 4-CF3-Ph

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].

NCS

N R1
R Where R, R1= Alkyl, Phenyl
N O

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

81
similar potency to chlordiazepoxide in animal models while demonstrating reduced or negligible

myorelaxant effects [20].

R4 N N N O
N N
R3 R5 Where R1, R2, R3. R4, R5 = Cl, Br, Me, Ethyl, -OCH3
1
R 2 R
176

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
N N

O O
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].

82
 O
H NH2 Where R= CH3, CH2(CH3)2, CH2CO2H, CH2Ph,
N N
N R CH2CH2CO2H, (CHCH3)2
O O
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
X
O N X = C, CH, N.
N
S O
179

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
N O
Cl Cl N N
N O
Cl NH 182
Cl N
Cl
H2N O
180 181
Cl N N

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].

83
 R

N
Where R = CH3, Cl, Ethyl
N O
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].

N O SCN
N O SCN
N
N
Cl
Br
185a
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].

84
 Cl

N O
N O N 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].

H
N
O O
O N N
TFA NH2
187 F

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].

85
 O
H
N N
O
R O N O a: R = -CH2Ph
b: R = -CH2Me
NH
NH2
O

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].

R
H
N N N
CO2H a: R = H,
N O 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].

OR

OR

S S N Where R = H, CH3
N
O
190

86
 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].

CF3
O
NH
N HN NH
N O
O

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].

R2
3
R R1 N

a: R1 = H, R2 = Me, R3 = Me
N N
H N b: R1 = 2-OMe, R2 = H, R3 = H.
N N
O
O
192a-b

87
 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].

N O N
O
O
N
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].

Br
F N N F
F N N
O O
O
O
194 O
195

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

88
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].

Cl NO2 NO2
HO HO
HO
O O
HO HO N
N
HO N N
HO N N
H Cl
Cl
N N
O O
196 198
197

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].

H
O
O
O
H
O Where R= Me, Ph

N O
N
R
199

Fig 3.23: DART oxadiazole derivatives

89
 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].

NC
O N
O
N

N
O Na

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].

F O
O
R1 Where R1= H, CH3
Ar O
N
N OH R2 = Ethyl, Cyclopropyl
N
N N R3
2
R3= H, -OCH3
R
201

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]-

90
oxadiazole derivatives (202) by biophysical, computational characterisation, structural activity

relationship and physiochemical properties for inhibitors of TNKS1and TNKS2 [40].

N N R3
1
N
R S
N
O N R4
Where R1 =Ph. Py, Furan, Thiophene
202
R2, R3, R4 = H, -OMe, Me, F,
R2

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].

O OH
N
H O O
O
N
N N
H OH
N
O O
F N
S H R N
N H
203 H
204

Where R = F, Me, -OMe, CF3

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

91
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].

92
 Ethanol
CHO Triethylamine CN NaBH4/MeOH CN
CN
CN Refux, 2hr O NH2
OH O NH
205 206 207 208

OH
N
NH2OH/MeOH NH2 Where R=
a: 2-Chlorophenyl
Refux, 12hr O NH2 b: 4-Chlorophenyl
209 c: 2-Hydroxyphenyl
d: 3,4-Dimethoxyphenyl
e: 4-Fluorophenyl
R-CHO Microwave f: Cinnamyl
g: 3-Nitrophenyl
h: 5-Bromo-2-fluorophenyl
i: Phenyl
N O j: 2-Thiophenyl
R k: 4-Hydroxy-3-methoxyphenyl
N
l: 4-Bromophenyl
O N m: 2-Thiozolyl
n: 4-Fluoro-3-phenoxy phenyl
(210 a-n) R

Scheme 3.2: Synthetic route for the chromeno-oxadiazoles (210 a-n)

Proposed mechanism for oxadiazole synthesis:

OH O
N OH N
N R
NH2 -H2O N
CHO N R H
R
O NH2 O N
O N
R R

O
N
R
N

O N

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.

93
 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.

94
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

95
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).
1
H 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 %.

96
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,
13
Ar-H), 8.97 (s, 1H, CH). 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). 13C 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)

97
 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),
13
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). 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

98
(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
13
= 7.6 Hz), 7.19-7.29 (m, 5H, Ar-H), 7.47-7.50 (m, 4H, Ar-H), 8.97 (s, 1H, CH). 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). 13C 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). 13C 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,

99
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,
13
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). C 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),
1
1284 (C-O). H 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,
13
Ar-H), 8.92 (s, 1H, CH). 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)

100
 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,
13
4H, Ar-H), 8.94 (s, 1H, CH). C 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). 13C 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,

101
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,
13
1H, Ar-H), 7.34-7.42 (m, 2H, Ar-H), 8.24-8.16 (m, 2H, Ar-H), 9.2 (s, 1H, CH). C 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,
13
Ar-H), 8.92 (s, 1H, CH). 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.

102
3.4.2. Spectral Data

103
 S
O N

N O S
210j

Fig. 3.28: 1H NMR Spectrum of compound 210j

104
 S
O N

N O S
210j
C20H15N3O2S2
Mol. Wt.: 393.48

Fig. 3.29: Mass spectrum of compound 210j

105
 HO

O N
HO
N

N O
210c

Fig. 3.30: 1H NMR Spectrum of compound 210c

HO

O N
HO
N

N O
210c

Fig. 3.31: 1H NMR Spectrum expansion of compound 210c

106
 HO

O N
HO
N

N O
210c

Fig. 3.32: 13C NMR Spectrum of compound 210c

107
 HO

O N
HO
N

N O
210c
C24H19N3O4
Mol. Wt.: 413.43

108
 Fig. 3.33: LCMS of compound 210c

HO

O N
HO
N

N O
210c

Fig. 3.34: IR Spectrum of compound 210c

109
 Cl

O N

N Cl
N O
210b

Fig. 3.35: 1H NMR Spectrum of compound 210b

110
 Cl

O N

N Cl
N O
210b

Fig. 3.36: 13C NMR Spectrum of compound 210b

111
 Cl

O N

N Cl
N O
210b Mol. Wt.: 450.32

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, 13

C-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-

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112
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