Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
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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, antiallergic 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: [email protected]
INTRODUCTION
Oxadiazole is a five-membered heterocycle having two
carbon atoms, two nitrogen atoms, one oxygen atom, and
two double bonds1.
N
O
C
C
Oxadiazole is an important heterocyclic ring present in
variety of biologically active molecules inclusive of
fungicidal, bactericidal, anticancer, antitubercular
activities, etc2.
4
5
3
N
N
O
1
2
4
5
N
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.
3
N
N
O
1
2
4
5
N
N
O
1
3
2
4
5
3
N
N
O
2
1
Isomers Of Oxadiazole
Basic Information
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,
furamizole as nitrofuran antibacterial, antihypertensive
agents nesapidil, anti-microbial, anticancer activity etc.
are based on 1,3,4-oxadiazole moiety. The 1, 3, 4oxadiazole 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
OH
N
O
O
NESAPIDIL
there must be association of electron-releasing groups in
oxadiazole ring.
Whereas for Nucleophilic substitution like in Halogensubstituted 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.
Chemical Features of Oxadiazole Moiety
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
R
N
N
N
+
X-
N
substitution of nucleophile or cleavage of ring. The
halogen or sulfonyl group substituted 1, 3, 4-oxadiazole
moiety at 2nd position can easily endure nucleophilic
substitution reaction3.
N
Nu X
R
N
N
O
CH 3
O
C6H 5
B). Reactions with Nucleophile
Now, in case of Nucleophiles the carbon atoms in 1, 3, 4oxadiazole ring have low п electron density which gain
access to the attack of nucleophiles on this carbon atom
and reveals that the reaction progress either with
N
N
RX
CH 3
O
C6H 5
R
N
NH
X
O
R
+
Nu
X
R
O-
Nu
O
Nu
N
N
-
N
N
HN
X
X
Nu
R
Nu
N
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
One-pot synthesis of 1, 2, 4-oxadiazoles using carboxylic
acid esters with amidoxime implementing potassium
carbonate and eventually reflux for 6-12 hrs4.
Literature review for various synthetic approaches
Scheme-1
OH
O
R1
O
N
O
R2
K2CO3, toluene
reflux, 6-12 hrs
N
R1
R2
N
NH 2
R
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
ClCH2CO2C2H5
O 2N
N
Dry acetone
O 2N
K2CO3, D
N
2
CH 3
CH 3
3
1
EtOH, D
N2H4.H2O
CH 2CONHNH 2
N
O 2N
N
CH 3
4
Step: 2
O
CH 2CONHNH 2
N
O 2N
N
5
N
RCO2H
CH 3
R
POCl 3, MW
POCl 3, D
O 2N
N
N
CH 3
N
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.
O
R
O
H 2N
C
HN
NH 2
R
CHO
OC 2H 5
CH3 COCH2 COOC2 H5
CH 3
N
H
O
1
NH2NH2 H2O
R
O
HN
NHNH 2
O
CH 3
N
H
2
2.POCl 3
3.CH2CH2 Cl 2
1.C6 H5COCl
R
O
C 6H5
HN
O
N
CH 3
N
H
N
Where R =
H 3C
; MeO
; O 2N
;
N
H 3C
Scheme-5
Swift Synthesis of 1, 2, 4-Oxadiazoles employing
Polymer-Supported Reagents in Microwave Heating. 1,
2, 4-Oxadiazoles swiftly be synthesized from a range of
carboxylic acids & amidoxime by implementing either of
two method A & B given below, which results in
elevated yields7.
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
O
NOH
R
R
OH
R
R = Aryl or Alkyl
NH2
1). PS-PPh3, CCl 3CN
MW, 100° C, 5 min
N
R'
N
77%-99% yield
2). DIEA, THF
MW, 150°C, 15 min
Method B:
Scheme-6
An upgraded oxadiazole synthesis implementing peptide
coupling reagents:
Synthesis of substituted 1,2,4-oxadiazoles in elevated
yields in one pot method by condensing analogous
HO
N
amidoxime with carboxylic acids in the occurrence of
peptide coupling reagent in diglyme & to heat the
reaction mixture at about 100°C for numerous hours8.
R
O
N
N
O
O
NH 2
R-CO 2H
NH 2
N
R
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
NH 2
C
H
O
+
CH3COCH2COOC2H5
[a-d]
conc. HCl
ethanol
3 hr reflux
Ar
COOC 2H 5
HN
O
CH 3
N
H
conc. H2SO4
ethanol
NH2NH2
Ar
CONHNH 2
HN
O
N
H
Step: 2
CH 3
Ar
CONHNH 2
HN
O
N
H
CH 3
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
O
HN
N
H
O
Isatin
Ar
O
CH 3
Glacial acetic acid
N
HN
N
O
N
H
CH 3
NH 2
N
O
N
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
RC O C l or A c 2 O
reflux 2-4 hrs
NHNH2
NHNH
XH
XH
1
1
O
N
O
NHNH
2
R
NH
OH
O
NHR
R
XH
XH
2''
Ph 3 P/CC l 4 /E t 3 N
CH 2 Cl 2
reflux 1-2 hrs
NH
-H 2 O
N
N
N
N -R
O
R
O
XH
XH
2'''
3
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.
R
CONHNH2
N
CS2 / KOH
R
(1)
N
O
SH
(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
110-20°C, 6hr
CS 2, KOH
80°C, 6hr
N
HS
N
Cl
O
N
N
O
O
2
R
N
O
N
Cl
O
N
O
O
SH
3a-f
N
O
R
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
N
CONHNH-CNHAr
N
R
O
N
N
N
N
CH 3
Hg(OAC) 2
CH 3
N
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
CNBr
CONHNH 2
S
N
CH3OH
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
HN
N
HN
N
N
H
R
N
Ph
FeCl 3
AcOH
C 6H 5
C 6H 5
O
R
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, 4oxadiazoles from 4-substituted benzoic acids).
O
O
CH
C
OH
N
X
N
PPh3
(2)
(1)
Ph3P
O
r o o m te m p
X
N
N
O
N
PPh3
(3)
N
O
N
H
N
O
(4)
H
(5)
PPh 3O
(6)
where X = I; CN; CO2Me; OAc; Et
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International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468