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Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 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: [email protected] INTRODUCTION Oxadiazole is a five-membered heterocycle having two carbon atoms, two nitrogen atoms, one oxygen atom, and two double bonds1.
C N
O
N
C
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.
N
O
N
1
2
34
5
N
O
N
1
2
34
5
NN
O1
2
34
5 N
O
N
1
2
34
5
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, 4-oxadiazole exhibit variety of reactions such as electrophillic substitution, nucleophilic substitution, thermal and photochemical reactions3.
Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468
O
N
N
OH
O
O
N
N
NESAPIDIL
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
there must be association of electron-releasing groups in 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.
N
O
N N
O
N
CH3C6H5 CH3C6H5
R
+ RX X-
B). Reactions with Nucleophile Now, in case of Nucleophiles the carbon atoms in 1, 3, 4-oxadiazole 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
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.
NN NN
O
NHN
OR X
Nu-
X
Nu
R Nu
NN
O
NN
O-
NHN
OXR
+ Nu-
R Nu
X
Nu
X
R
H+
R NH
O
N
X
Nu
Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468
Literature review for various synthetic approaches Scheme-1
One-pot synthesis of 1, 2, 4-oxadiazoles using carboxylic acid esters with amidoxime implementing potassium carbonate and eventually reflux for 6-12 hrs4.
R1
O
O
N
NH2R2
OH
N
NO
R2R1
R
K2CO3, toluenereflux, 6-12 hrs
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.
N
NH
O2NCH3
ClCH2CO2C2H5
Dry acetone
K2CO3, DN
N
O2NCH3
N
N
O2NCH3
1
2 3
4
CH2CONHNH2
CH2CO2C2H5
N2H4.H2OEtOH, D
Step: 2
N
NO2N
CH2CONHNH2
CH3
RCO2H
POCl3, MW
POCl3, D
N
NO2N CH3
N
O
N
R
5 6
Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 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.
C
O
NH2H2N R CHO CH3COCH2COOC2H5
HN
NH
O
R
OC2H5
O
CH3
1
NH2NH2H2O
HN
NH
O
R
NHNH2
O
CH3
HN
NH
O
R
CH3
2
1.C6H5COCl 2.POCl33.CH2CH2Cl2
N
O
N
C6H5
MeO N
H3C
H3C
O2N
Where R =
; ; ;
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.
Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468
R = Aryl or Alkyl
R OH
O
R NH2
NOH
M e t h o d A :
M e t h o d B :
HBTU, PS-BEMP, CH3CN
MW, 160°C, 15 min
1). PS-PPh3, CCl3CN MW, 100 C, 5 min°
2). DIEA, THF MW, 150 C, 15 min°
NO
NR R'
77%-99% yield
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
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.
NH2
NHO
Reagent
N
NH2
O R
O
HEAT
N
N
O
RR-CO2H
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.
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
Where:
Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468
Step: 1
O C
NH2
NH2
+ Ar CH
O
[a-d]
+ CH3COCH2COOC2H5
3 hr refluxconc. HCl ethanol
HN
NH
COOC2H5
CH3O
Ar
conc. H2SO4
ethanolNH2NH2
HN
NH
Ar
CONHNH2
CH3O
Step: 2
HN
NH
Ar
CONHNH2
CH3O
Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468
HN
NH
Ar
CH3O
CNBrethanol
N
O
N
NH2
Isatin Glacial acetic acid
HN
NH
O
Ar
CH3
N
O
N
N
NH
O
Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468
Scheme-8 Synthesis of 1, 3, 4-Oxadiazoles Having Phenol or Thiophenol Group10.
XH
NHNH2
O
MeSO3H / tolueneRCOCl or Ac2Oreflux 2-4 hrs
1XH
NHNH
O
1
O
R
XH
NHNH
O
2
O
NHR
XH2''
NHN
OOH
R
Ph3P/CCl4/Et3NCH2Cl2reflux 1-2 hrs
-H2O
XH
O
NH N
N-R
XH
NN
OR
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.
CONHNH2RCS2 / KOH NN
OR SH
(1) (2)
Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468
Scheme-10 Synthesis of 1, 3, 4-Oxadiazolylphenylene derivatives having Anti-cancer activity11.
O O
NHNH2
H2NHN
O
O
Cl
1
CS2, KOH80 C, 6hr°
RCO2H, POCl3110-20 C, 6hr°
O O
ClNN
O NN
O
HS
SH
O O
ClNN
O NN
O
R
R2 3a-f
4-ClC6H4 4-NO2C6H4 4-ClC6H4OCH2 2,4-ClC6H3OCH2 C6H5NHCH2 4-ClC6H4NHCH2
Where R =
; ; ; ; ; Scheme-11 Preparation of 1, 3, 4-oxadiazole implementing mercuric acetate3.
N
NN
Cl
CH3
CONHNH-CNHAr
S
Hg(OAC)2
acetic acid
N
NN
Cl
CH3
N
O
N
HN R
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.
S SCONHNH2
CNBrCH3OH
N
O
N
NH2
Srivastav Sanchit et al / IJRAP 2011, 2 (2) 459-468
International Journal of Research in Ayurveda & Pharmacy, 2(2), 2011 459-468
Scheme-13 Synthesis of 1, 3, 4-oxadiazole correspondence from Schiff’s Bases using FeCl33.
R
NH
C6H5
HNNH
N
PhO
R
NH
C6H5
HNFeCl3AcOH
NN
OC6H5
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).
X
O
OH
(1)
C
N N PPh3
r o o m t e m p
X
O
O
(3)
CH
N N PPh3
(2)
O
O
N
H
NPh3P
(4) (5)
NN
OH PPh3O
(6)
where X = I; CN; CO2Me; OAc; Et REFERENCES 1. http://en.wiktionary.org/wiki/oxadiazole, 17 Jan. 2011. 2. Mishra MK, Gupta AK, Negi S, Bhatt Meenakshi; International
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