various approaches for synthesis of oxadiazole derivatives

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 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): 130-140. 4. Kande KD. Amarasinghe Matthew B Maier, Srivastava Anil, Jeffrey L Gray, Tetrahedron Letters 2006; 47 (22, 29): 36293631. 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.

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