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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.



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



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



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.



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:



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



HN

NH

Ar

CH3O

CNBrethanol

N

O

N

NH2

Isatin Glacial acetic acid

HN

NH

O

Ar

CH3

N

O

N

N

NH

O



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)



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



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

Journal of Pharma Sciences & Research 2010; 1 (3): 172-177. 3. Somani RR., Shirodkar PY, Der Pharma Chemica; 2009; 1 (1):

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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.

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Available online through - IJRAP · Review Article Available online through ... The presence of heterocyclic structures exerts various physiologic effects on the body. ... Swift Synthesis