Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468

Review Article Available online through

www.ijrap.net ISSN 2229-3566

VARIOUS APPROACHES FOR SYNTHESIS OF OXADIAZOLE DERIVATIVES

Srivastav Sanchit*, Pandeya S.N.
Department of pharmacy, Saroj Institute of Technology & Management, Lucknow, India

Received on: 11/01/2011 Revised on: 23/02/2011 Accepted on: 08/03/2011

ABSTARCT
Oxadiazole, a five-membered heterocycle having two carbon atoms, two nitrogen atoms, one oxygen atom, and two
double bonds, inclusive of inductive effect & having efficient anticancer, antifungal, antimicrobial, insecticidal, anti-
allergic activity etc... The presence of heterocyclic structures exerts various physiologic effects on the body. In the
present study we have reviewed several newer approches of synthesizing the substituted oxadiazole derivatives via
catalytic reaction & by the application of various suitable reagents.
KEYWORDS: (Oxadiazole, Nucleophilic & Electrophilic reactions in Oxadiazole, Parallel Synthesis, One-pot
synthesis, 1, 3, 4-Oxadiazolylphenylene derivatives, Anti-cancer activity)

*Corresponding author
Sanchit Srivastav, M.Pharm student, Department of pharmacy, Saroj Institute of Technology & Management,
Sultanpur road, Lucknow, 226002 Email: srivastavsanchit@gmail.com

INTRODUCTION
Oxadiazole is a five-membered heterocycle having two N
carbon atoms, two nitrogen atoms, one oxygen atom, and C O
two double bonds1.
C N

Oxadiazole is an important heterocyclic ring present in
variety of biologically active molecules inclusive of
fungicidal, bactericidal, anticancer, antitubercular
activities, etc2.
Oxadiazole moiety is derived from furan by replacing
two -CH= group with 2 pyridine typed nitrogen (-N=).
So there should be possibility of 4 oxadiazole isomers
reliant on the nitrogen atom position in the ring as
follows3.

4 3 4 3 4 3 4
N N N N 3

N N
5 2 5 2 5 2 5
N N
O O
2
O O
1 1 1 1
Isomers Of Oxadiazole

Basic Information furamizole as nitrofuran antibacterial, antihypertensive

Oxadiazole is a heterocyclic nucleus which gains heavy
interest by many research scholars regarding inventions
of novel remedial molecules. There are possibly 4
isomers of oxadiazoles in which 1, 3, 4-oxadiazole have
enormous importance. Variety of therapeutically active
agents e.g. raltagravir as HIV-integrase inhibitor,
agents nesapidil, anti-microbial, anticancer activity etc.
are based on 1,3,4-oxadiazole moiety. The 1, 3, 4-
oxadiazole exhibit variety of reactions such as
electrophillic substitution, nucleophilic substitution,
thermal and photochemical reactions3.

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468

 Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468

N
N O
N

N OH O

O
NESAPIDIL

Chemical Features of Oxadiazole Moiety there must be association of electron-releasing groups in

Oxadiazole is a very weak base because there is an
inductive effect of extra heteroatom3. As we know,
Oxadiazole consists of the 2 pyridine type nitrogen (-
N=), hence reduction in aromaticity of oxadiazole ring
and which in turn leads the oxadiazole ring to exhibit the
conjugated diene character.
There is no or very less scope of electrophillic
substitutions at the carbon atom in oxadiazole ring due to
less electron density on the same carbon atom. Rather,
electrophillic attack can occurs at nitrogen, but again
oxadiazole ring.
Whereas for Nucleophilic substitution like in Halogen-
substituted oxadiazole there is replacement of halogen
atom by nucleophiles3
Brief Descriptions on Reactions of Oxadiazole
A). Reactions with electrophile
If we see the reaction below it proves that, because of
low π-electron density on the carbon atom, electrophile
attacks favorably at 3rd position and results in 1,3,4 -
oxadiazolium salts as follows3.
R

N N
N N
+ RX X-

C6H 5 O CH 3
C6H 5 O CH 3

B). Reactions with Nucleophile substitution of nucleophile or cleavage of ring. The

Now, in case of Nucleophiles the carbon atoms in 1, 3, 4- halogen or sulfonyl group substituted 1, 3, 4-oxadiazole
oxadiazole ring have low п electron density which gain moiety at 2nd position can easily endure nucleophilic
access to the attack of nucleophiles on this carbon atom substitution reaction3.
and reveals that the reaction progress either with
N N N NH N N
Nu -

R X X R Nu
O O
Nu
N N N N HN N
+ - X
Nu X

R X R Nu
O R Nu O
O-

H+

O
X

R NH N

Nu

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468

 Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468

Literature review for various synthetic approaches One-pot synthesis of 1, 2, 4-oxadiazoles using carboxylic
Scheme-1 acid esters with amidoxime implementing potassium
carbonate and eventually reflux for 6-12 hrs4.

OH O
O N
N
K2CO3, toluene
reflux, 6-12 hrs R1
R1 O N R2
R2 NH 2

R = Me, Et
Scheme-2
Parallel synthetic approach of 1, 2, 4-oxadiazoles implementing CDI activation5

Scheme-3
Step: 1 Solvent-free microwave-assisted synthesis of oxadiazole containing imidazole moiety6.
CH 2CO 2C 2H 5

N
NH Dry acetone
ClCH2CO2C2H5 O 2N
O 2N
K2CO3, D
N CH 3
N CH 3
2 3
1
EtOH, D N2H4.H2O

CH 2CONHNH 2

O 2N
N CH 3
4
Step: 2
O R
POCl 3, MW
CH 2CONHNH 2

N N N N
RCO2H

CH 3 CH 3
O 2N POCl 3, D O 2N
N N

5 6

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468

 Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468

where R = a: C6H5; b: 4-CH3C6H5; c: 4-OCH3C6H4; d: 4-ClC6H4; e: 2-CH3C6H4;

f: C5H4N; g: 2-C4H3O; h: C6H5-OCH2, i: 4-CH3-C6H4-OCH2; j: 2-CH3-C6H4-OCH2;
k: 4-Cl-C6H4-OCH2.
Scheme-4
Synthesis of 6–Methyl–4–aryl–5-(5-phenyl-1,3,4–oxadiazol-2-yl)-1,2,3,4-tetrahydropyrimidine-2(1H)-one having
efficient antibacterial activity2.
R O

O
HN OC 2H 5

H 2N C NH 2 R CHO CH3 COCH2 COOC2 H5

CH 3
O N
H
1

NH2NH2 H2O

R O

HN NHNH 2

CH 3
O N
H
2

1.C6 H5COCl 2.POCl 3

3.CH2CH2 Cl 2
R

O C 6H5
HN

N N
CH 3
O N
H

Where R =
H 3C
; MeO ; O 2N ; N
H 3C

Scheme-5 carboxylic acids & amidoxime by implementing either of

Swift Synthesis of 1, 2, 4-Oxadiazoles employing two method A & B given below, which results in
Polymer-Supported Reagents in Microwave Heating. 1, elevated yields7.
2, 4-Oxadiazoles swiftly be synthesized from a range of

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468

 Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
Method A:
HBTU, PS-BEMP, CH3CN
MW, 160°C, 15 min O N
O NOH

R R'
N
R OH R NH2 1). PS-PPh3, CCl 3CN
MW, 100° C, 5 min 77%-99% yield
2). DIEA, THF
R = Aryl or Alkyl MW, 150°C, 15 min
Method B:

Scheme-6 amidoxime with carboxylic acids in the occurrence of

An upgraded oxadiazole synthesis implementing peptide peptide coupling reagent in diglyme & to heat the
coupling reagents: reaction mixture at about 100°C for numerous hours8.
Synthesis of substituted 1,2,4-oxadiazoles in elevated
yields in one pot method by condensing analogous

N O R
HO
N N O
O
NH 2 NH 2 N R
R-CO 2H HEAT
Reagent

Scheme-7
Synthesis of some 3- [5-(6-methyl-4-aryl-2-oxo-1, 2, 3, 4-tetrahydropyrimidin-5-yl)--1, 3, 4-oxadiazol-2-yl]-imino -
1, 3-dihydro-2H-indol-2-one derivatives9.

Where:
Ar = a:C6H5, b: 2-ClC6H4, c: 2,4-(Cl)2-C6H3, d: 3,4,5-(OCH3)3-C6H2,
e: 4-CH(CH3)2-C6H4, f: 4-F-C6H4, h: 3-OH-4-OCH3-C6H3, i: 4-N(CH3)-C6H4

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468

 Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468

Step: 1
NH 2

O C + Ar C O + CH3COCH2COOC2H5
H
NH 2
[a-d]

conc. HCl 3 hr reflux

ethanol

Ar

COOC 2H 5
HN

O N CH 3
H

conc. H2SO4
NH2NH2
ethanol

Ar

CONHNH 2
HN

O N CH 3
H
Step: 2
Ar

CONHNH 2
HN

O N CH 3
H

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468

 Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468

ethanol CNBr

Ar N N

HN O NH 2

O N CH 3
H

Isatin Glacial acetic acid

Ar N N

HN O N

O N CH 3 O N
H H

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468

 Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468

Scheme-8
Synthesis of 1, 3, 4-Oxadiazoles Having Phenol or Thiophenol Group10.
O O
O
M eSO 3 H / toluene
NHNH2 RC O C l or A c 2 O NHNH
reflux 2-4 hrs R

XH XH
1 1

O N NH
O

NHNH OH
NHR O
R

XH XH
2 2''
Ph 3 P/CC l 4 /E t 3 N
-H 2 O
CH 2 Cl 2
reflux 1-2 hrs

NH N
N N

N -R
O R
O

XH
XH 3
2'''

Where; X = a: O; b: S
Scheme-9
The synthesis of 2-mercapto-5-aryl-1, 3, 4-oxadiazole (2) from well substituted acid hydrazide (1) in presence of
CS2/KOH in alkaline media3.

N N
CS2 / KOH
R CONHNH2
R SH
O

(1) (2)

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468

 Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468

Scheme-10
Synthesis of 1, 3, 4-Oxadiazolylphenylene derivatives having Anti-cancer activity11.
O Cl

H 2NHN O O O

1
NHNH 2

RCO 2H, POCl 3

CS 2, KOH 110-20°C, 6hr
80°C, 6hr

N N Cl
N N Cl
HS
O N N R
O O O
O O N N

2 SH
O 3a-f R
O

Where R =
4-ClC6H4 ; 4-NO2C6H 4 ; 4-ClC6H4 OCH2 ; 2,4-ClC H OCH
6 3 2 ; C6H5 NHCH2 ; 4-ClC6H4 NHCH2
Scheme-11
Preparation of 1, 3, 4-oxadiazole implementing mercuric acetate3.
S N N

H
CONHNH-CNHAr N R
N N O

N N
N CH 3 N CH 3
Hg(OAC) 2
acetic acid

Cl Cl

Scheme-12
Preparation of 1, 3, 4-oxadiazole amine using cyanogen bromide, which is very easy to apply, takes lesser time &
also having better yields3.

N N
CNBr

CONHNH 2
CH3OH
S S O NH 2

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468

 Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468

Scheme-13
Synthesis of 1, 3, 4-oxadiazole correspondence from Schiff’s Bases using FeCl33.

O N N
Ph
HN
N HN C 6H 5
N
R H FeCl 3 R
O

C 6H 5 AcOH
C 6H 5
N
H N
H

Scheme-15
Iminophosphorane-facilitated one-pot synthesis of 1, 3, 4-oxadiazole derivatives12 (Preparation of 2-aryl-1, 3, 4-
oxadiazoles from 4-substituted benzoic acids).
O
O CH
O
C r o o m te m p N N PPh3
OH

N N PPh3 X
X (2) (3)
(1)

Ph3P
N
N N
O N

H PPh 3O
O H O
(4) (6)
(5)

where X = I; CN; CO2Me; OAc; Et

REFERENCES 8. Gui-Bai Liang, Danqing D. Feng, Tetrahedron Letters, 1996; 37

1. http://en.wiktionary.org/wiki/oxadiazole, 17 Jan. 2011.
2. Mishra MK, Gupta AK, Negi S, Bhatt Meenakshi; International
Journal of Pharma Sciences & Research 2010; 1 (3): 172-177.
3. Somani RR., Shirodkar PY, Der Pharma Chemica; 2009; 1 (1):
130-140.
4. Kande KD. Amarasinghe Matthew B Maier, Srivastava Anil,
Jeffrey L Gray, Tetrahedron Letters 2006; 47 (22, 29): 3629-
3631.
5. Deegan TL, Theodore JN, Diane Cebzanov, Denise E Pufko and
John A Porco, Bioorganic & Medicinal Chemistry Letters, 1999;
9 (2): 209-212.
6. Priya V Frank, Girish KS, Kalluraya Balakrishna, J. Chem. Sci.,
2007; 119 (1): 41–46.
7. Ying Wang, Reagan L Miller, Daryl R Sauer, Stevan W Djuric,
Org. Lett., 2005; 7 (5): 925–928.
(37): 6627-6630.
9. George Sonia, Parameswaran MK, Chakraborty AR, Thengungal
KR, Synthesis and evaluation of the biological activities of some
3- [5-(6-methyl-4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidin-5-yl)-
1,3,4-oxadiazol-2-yl]-imino -1,3-dihydro-2H-indol-2-one
derivatives, Acta Pharm., 2008; 58: 119–129.
10. Chang Hoon Lee, Hyun In Cho, Kee-Jung Lee, Bull. Korean
Chem., Soc. 2001; 22: 10.
11. Holla BS, Poojary KN, Bhat KS, Mithun Ashok, Poojary Boja,
Synthesis & Anticancer activity of 1, 3, 4-Oxadiazolylphenylene
derivatives, Ind. Journal of chemistry, 2005; 44 (B): 1669-1673.
12. Ramazani Ali, Souldozi Ali, General papers ARKIVOC 2008;
16: 235-242

International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468