Srivastav Sanchit et al / IJAP 20, 2 (2) 459-468 eview Article Available online through www.ijrap.net ISS 2229-3566 VAIUS APPACES F SYTESIS F ADIAZLE DEIVATIVES Srivastav Sanchit*, Pandeya S.. Department of pharmacy, Saroj Institute of Technology & Management, Lucknow, India eceived on: /0/20 evised on: 23/02/20 Accepted on: 08/03/20 ABSTACT xadiazole, 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. KEYWDS: (xadiazole, ucleophilic & Electrophilic reactions in xadiazole, Parallel Synthesis, ne-pot synthesis,, 3, 4-xadiazolylphenylene 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 ITDUCTI xadiazole is a five-membered heterocycle having two carbon atoms, two nitrogen atoms, one oxygen atom, and two double bonds. C C xadiazole is an important heterocyclic ring present in variety of biologically active molecules inclusive of fungicidal, bactericidal, anticancer, antitubercular activities, etc 2. xadiazole moiety is derived from furan by replacing two -C= group with 2 pyridine typed nitrogen (-=). So there should be possibility of 4 oxadiazole isomers reliant on the nitrogen atom position in the ring as follows 3. 4 3 4 3 4 3 4 3 5 2 5 2 5 2 5 Isomers f xadiazole 2 Basic Information xadiazole 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, 3, 4-oxadiazole have enormous importance. Variety of therapeutically active agents e.g. raltagravir as IV-integrase inhibitor, furamizole as nitrofuran antibacterial, antihypertensive agents nesapidil, anti-microbial, anticancer activity etc. are based on,3,4-oxadiazole moiety. The, 3, 4- oxadiazole exhibit variety of reactions such as electrophillic substitution, nucleophilic substitution, thermal and photochemical reactions 3. International Journal of esearch in Ayurveda & Pharmacy, 2(2), 20 459-468
Srivastav Sanchit et al / IJAP 20, 2 (2) 459-468 ESAPIDIL Chemical Features of xadiazole Moiety xadiazole is a very weak base because there is an inductive effect of extra heteroatom 3. As we know, xadiazole consists of the 2 pyridine type nitrogen (- =), 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. ather, electrophillic attack can occurs at nitrogen, but again there must be association of electron-releasing groups in oxadiazole ring. Whereas for ucleophilic substitution like in alogensubstituted oxadiazole there is replacement of halogen atom by nucleophiles 3 Brief Descriptions on eactions of xadiazole A). eactions 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 3 rd position and results in,3,4 - oxadiazolium salts as follows 3. + - C 6 5 C C 3 6 5 B). eactions with ucleophile ow, in case of ucleophiles the carbon atoms in, 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, 3, 4-oxadiazole moiety at 2 nd position can easily endure nucleophilic substitution reaction 3. u - + u - u u - u u + u International Journal of esearch in Ayurveda & Pharmacy, 2(2), 20 459-468
Srivastav Sanchit et al / IJAP 20, 2 (2) 459-468 Literature review for various synthetic approaches Scheme- ne-pot synthesis of, 2, 4-oxadiazoles using carboxylic acid esters with amidoxime implementing potassium carbonate and eventually reflux for 6-2 hrs 4. 2 2 K 2 C 3, toluene reflux, 6-2 hrs 2 = Me, Et Scheme-2 Parallel synthetic approach of, 2, 4-oxadiazoles implementing CDI activation 5 Scheme-3 Step: Solvent-free microwave-assisted synthesis of oxadiazole containing imidazole moiety 6. C 2 C 2 C 2 5 2 Dry acetone ClC 2 C 2 C 2 5 K 2 C 3, 2 2 3 Et, 2 4. 2 C 2 C 2 2 Step: 2 C 2 C 2 PCl 3, MW 4 C 2 2 PCl 3, 2 5 6 International Journal of esearch in Ayurveda & Pharmacy, 2(2), 20 459-468
Srivastav Sanchit et al / IJAP 20, 2 (2) 459-468 where = a: C 6 5 ; b: 4- C 6 5 ; c: 4- C 6 4 ; d: 4-ClC 6 4 ; e: 2- C 6 4 ; f: C 5 4 ; g: 2-C 4 3 ; h: C 6 5 -C 2, i: 4- -C 6 4 -C 2 ; j: 2- -C 6 4 -C 2 ; k: 4-Cl-C 6 4 -C 2. Scheme-4 Synthesis of 6 Methyl 4 aryl 5-(5-phenyl-,3,4 oxadiazol-2-yl)-,2,3,4-tetrahydropyrimidine-2()-one having efficient antibacterial activity 2. C 2 5 2 C 2 C CC 2 CC 2 5 2 2 2 2 2.C 6 5 CCl 2.PCl 3 3.C 2 C 2 Cl 2 C 6 5 Where = 3 C ; Me ; 2 ; 3 C Scheme-5 Swift Synthesis of, 2, 4-xadiazoles employing Polymer-Supported eagents in Microwave eating., 2, 4-xadiazoles swiftly be synthesized from a range of carboxylic acids & amidoxime by implementing either of two method A & B given below, which results in elevated yields 7. International Journal of esearch in Ayurveda & Pharmacy, 2(2), 20 459-468
Srivastav Sanchit et al / IJAP 20, 2 (2) 459-468 M e t h o d A : BTU, PS-BEMP, C MW, 60 C, 5 min 2 ). PS-PPh 3, CCl 3 C MW, 00 C, 5 min 77%-99% yield ' = Aryl or Alkyl 2). DIEA, TF MW, 50 C, 5 min M e t h o d B : Scheme-6 An upgraded oxadiazole synthesis implementing peptide coupling reagents: Synthesis of substituted,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 00 C for numerous hours 8. 2 -C 2 2 EAT eagent Scheme-7 Synthesis of some 3- [5-(6-methyl-4-aryl-2-oxo-, 2, 3, 4-tetrahydropyrimidin-5-yl)--, 3, 4-oxadiazol-2-yl]-imino -, 3-dihydro-2-indol-2-one derivatives 9. Where: Ar = a:c 6 5, b: 2-ClC 6 4, c: 2,4-(Cl) 2 -C 6 3, d: 3,4,5-( ) 3 -C 6 2, e: 4-C( ) 2 -C 6 4, f: 4-F-C 6 4, h: 3--4- -C 6 3, i: 4-( )-C 6 4 International Journal of esearch in Ayurveda & Pharmacy, 2(2), 20 459-468
Srivastav Sanchit et al / IJAP 20, 2 (2) 459-468 Step: C 2 + Ar C + CC 2 CC 2 5 2 [a-d] conc. Cl ethanol 3 hr reflux Ar CC 2 5 conc. 2 S 4 ethanol 2 2 Ar C 2 Step: 2 Ar C 2 International Journal of esearch in Ayurveda & Pharmacy, 2(2), 20 459-468
Srivastav Sanchit et al / IJAP 20, 2 (2) 459-468 ethanol CBr Ar 2 Isatin Glacial acetic acid Ar International Journal of esearch in Ayurveda & Pharmacy, 2(2), 20 459-468
Srivastav Sanchit et al / IJAP 20, 2 (2) 459-468 Scheme-8 Synthesis of, 3, 4-xadiazoles aving Phenol or Thiophenol Group 0. 2 MeS 3 / toluene CCl or Ac 2 reflux 2-4 hrs 2 Ph 3 P/CCl 4 /Et 3 C 2 Cl 2 reflux -2 hrs 2'' - 2-2''' 3 Where; = a: ; b: S Scheme-9 The synthesis of 2-mercapto-5-aryl-, 3, 4-oxadiazole (2) from well substituted acid hydrazide () in presence of CS 2 /K in alkaline media 3. C 2 CS 2 / K S () (2) International Journal of esearch in Ayurveda & Pharmacy, 2(2), 20 459-468
Srivastav Sanchit et al / IJAP 20, 2 (2) 459-468 Scheme-0 Synthesis of, 3, 4-xadiazolylphenylene derivatives having Anti-cancer activity. Cl 2 2 CS 2, K 80 C, 6hr C 2, PCl 3 0-20 C, 6hr Cl Cl S 2 S 3a-f Where = 4-ClC 6 4 ; 4-2 C 6 4 ; 4-ClC 6 4 C 2 ; 2,4-ClC 6 3 C 2 ; C 6 5 C 2 ; 4-ClC 6 4 C 2 Scheme- Preparation of, 3, 4-oxadiazole implementing mercuric acetate 3. S C-CAr g(ac) 2 acetic acid Cl Cl Scheme-2 Preparation of, 3, 4-oxadiazole amine using cyanogen bromide, which is very easy to apply, takes lesser time & also having better yields 3. CBr S C 2 S 2 International Journal of esearch in Ayurveda & Pharmacy, 2(2), 20 459-468
Srivastav Sanchit et al / IJAP 20, 2 (2) 459-468 Scheme-3 Synthesis of, 3, 4-oxadiazole correspondence from Schiff s Bases using FeCl 3 3. Ph C 6 5 FeCl 3 Ac C 6 5 C 6 5 Scheme-5 Iminophosphorane-facilitated one-pot synthesis of, 3, 4-oxadiazole derivatives 2 (Preparation of 2-aryl-, 3, 4- oxadiazoles from 4-substituted benzoic acids). C C r o o m t e m p PPh 3 () PPh 3 (2) (3) Ph 3 P (4) (5) PPh 3 (6) where = I; C; C 2 Me; Ac; Et EFEECES. http://en.wiktionary.org/wiki/oxadiazole, 7 Jan. 20. 2. Mishra MK, Gupta AK, egi S, Bhatt Meenakshi; International Journal of Pharma Sciences & esearch 200; (3): 72-77. 3. Somani., Shirodkar PY, Der Pharma Chemica; 2009; (): 30-40. 4. Kande KD. Amarasinghe Matthew B Maier, Srivastava Anil, Jeffrey L Gray, Tetrahedron Letters 2006; 47 (22, 29): 3629-363. 5. Deegan TL, Theodore J, Diane Cebzanov, Denise E Pufko and John A Porco, Bioorganic & Medicinal Chemistry Letters, 999; 9 (2): 209-22. 6. Priya V Frank, Girish KS, Kalluraya Balakrishna, J. Chem. Sci., 2007; 9 (): 4 46. 7. Ying Wang, eagan L Miller, Daryl Sauer, Stevan W Djuric, rg. Lett., 2005; 7 (5): 925 928. 8. Gui-Bai Liang, Danqing D. Feng, Tetrahedron Letters, 996; 37 (37): 6627-6630. 9. George Sonia, Parameswaran MK, Chakraborty A, Thengungal K, Synthesis and evaluation of the biological activities of some 3- [5-(6-methyl-4-aryl-2-oxo-,2,3,4-tetrahydropyrimidin-5-yl)-,3,4-oxadiazol-2-yl]-imino -,3-dihydro-2-indol-2-one derivatives, Acta Pharm., 2008; 58: 9 29. 0. Chang oon Lee, yun In Cho, Kee-Jung Lee, Bull. Korean Chem., Soc. 200; 22: 0.. olla BS, Poojary K, Bhat KS, Mithun Ashok, Poojary Boja, Synthesis & Anticancer activity of, 3, 4-xadiazolylphenylene derivatives, Ind. Journal of chemistry, 2005; 44 (B): 669-673. 2. amazani Ali, Souldozi Ali, General papers AKIVC 2008; 6: 235-242 International Journal of esearch in Ayurveda & Pharmacy, 2(2), 20 459-468