You are hereCHEMISTRY AND COMMON SYNTHETIC ROUTE OF 1, 3, 4-OXADIAZOLE: AN IMPORTANT HETEROCYCLIC MOIETY IN MEDICINAL CHEMISTRY

CHEMISTRY AND COMMON SYNTHETIC ROUTE OF 1, 3, 4-OXADIAZOLE: AN IMPORTANT HETEROCYCLIC MOIETY IN MEDICINAL CHEMISTRY


About Authors:
Sukhbir L.Khokara1*, Naveen2, Jitendra2, Balram2, Dhirender2, Rajender Kumar1

1Department of Pharmacy, Manav Bharti University, Solan (H.P.) 173229
2Institute of pharmaceutical sciences, Kurukshetra University, Kurukshetra, Harayana-136119
rajkaushal13@gmail.com

ABSTRACT
These heterocyclic moiety are prepared by different method and  have different biological and physiological properties. The widespread use of 1,3, 4 –oxadiazole as a scaffold in medicinal chemistry establishes this moiety as an important bioactive class of heterocyclic compounds. These compound have biological properties like anticonvulsant, analgesic, antipyretic, antimitotic,antitubercular and antimicrobial etc.

REFERENCE ID: PHARMATUTOR-ART-1315

INTRODUCTION:
Oxadiazole ring is considered to be derived from furan ring by replacement of two methane (-CH=) group by two pyridine type nitrogen (-N=) [1]. There are four possible isomers of oxadiazole (I, II, III and IV)depending on the position of nitrogen atom in the ring and are numbered as shown in.

Heterocyclic compounds bearing 1, 3, 4-oxadiazole moiety has been used as a pi-conjugation relay to prepare a number of donor-acceptor molecules carrying a pi-electron rich aromatic ring. Therefore the compounds bearing 1 ,3, 4-oxadiazole moiety may be a good candidate for optical material or biologically active chemicals [2].

1, 3, 4-oxadiazoles have attracted an interest in medicinal chemistry as ester and amide bioisosteres for a number of biological targets [3, 4].

As such their peptidomimetic ability has been explored and reported in the development of Phe-Gly mimetics of dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) and substance P(Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2) [5].

The widespread use of 1, 3, 4-oxadiazoles as a scaffold in medicinal chemistry establishes this moiety as an important bioactive class of heterocycles. These molecules are also used as pharmacophores due to their favourable metabolic profile and ability to engage in hydrogen bonding [6]. 1, 3, 4-oxadiazoles have proved to be useful in material science as probe for their fluorescence and scintillation properties [7].

In addition oxadiazole derivatives have been widely used as electron conducting and hole blocking material in molecules based as well as polymeric light emitting devices [8].

Oxadiazole, a heterocyclic nucleus has attracted a wide attention of the chemist in search for the new therapeutics. Out of its four possible isomers 1, 3, 4-oxadiazole is widely exploited for various applications. A number of therapeutic agents such as HIV-integrase inhibitor raltegravir [9], a nitrofuran antibacterial furamizole [10], antihypertensive agents tiodazosin [11], and nesapidil [12] are based on 1,3, 4-oxadiazole moiety.

Drugs containing 1, 3, 4-oxadiazole moiety

1. Chemistry of oxadiazole:-As 1,3 ,4-oxadiazoles have a relatively low electron density at carbon (position 2 & 5) and a relatively high electron density at nitrogen (position 3 & 4), the major reactions are nucleophilic attack at carbon, generally followed by ring cleavage, and electrophilic attack at nitrogen. This

reactivity towards nucleophiles, also catalysed by acid, causes difficulties when carrying out reactions which involves basic or acidic conditions. The ring is more stable when substituted by one or more aryl groups [13].          


Tautomeric oxadiazoles (a&b) react with electrophiles at ring nitrogen, at the exocyclic heteroatom or at both centres. Reactions in the subsstituent group of alkyl or aryl-1, 3,4-oxadiazoles are possible but they are limited by sensitivity of the ring to the reagent used.

1.1. Fully conjugated Rings; Reactivity at Ring Atoms:-

1.1.1.Thermal and photochemical rections, formally involving no other species:-
1,3,4-oxadiazoles are thermally stable compounds and this stability is increased on substitutions, particularly by aryl and perfluoroalkyl groups. Oxadiazolin-5-ones and 5-thiones are somewhat less stable and undergo selective pyrolysis at high temperatures.

Oxadiazolinones (1) lose carbon dioxide at high temperature to give nitrilimines (2) which react further. Recrystallization in the nitrilimine, formed at 210-230?C from oxadiazolinone (1a), yields a 2-alkoxy-1,3,4-oxadiazole which at the reaction temperature, undergo a further rearrangements to oxadiazolinone (1c). A similar rearrangement occurs on thermolysis of oxadiazolinone (1b). 2,5-diphenyl-1,3,4-oxadiazole is produced on heating oxadiazolinone (1d) at 250?C. Oxadiazolinones (1e) & (1f) are more stable but undergo flash vacuum pyrolysis at 500?C to give indazoles. At higher temperature, loss of nitrogen also occurs, and styrene or fluorine respectively is produced in high yield. A variety of hydrocarbons are formed on flash vacuum pyrolysis of oxadiazolinones (1; R2= alkenyl).



a

R1

R2

b

Ph

COOR

c

Ph

COSEt

d

Ph

R

e

Ph

COPh

f

Me

Ph

g

Ph

Ph

Carbon dioxide is lost on thermolysis of 4-ethoxycarbonyl-2-phenyl-Δ2-1, 3, 4-oxadiazoline-5-thione. Migration of the ethyl group from oxygen to sulfur leads to the product, 5-ethylthio-2-phenyl-1,3,4-oxadiazole.Photolysis of oxadiazolinone (1f) yields a nitrilimine (2f) which, in the presence of alkenes, undergoes cycloaddition to give pyrazoles. Azobenzene is produced on irradiation of 3,4-diphenyl-1,3,4-oxadiazolidine-2,5-dione.

1.1.2. Electrophilic attack at nitrogen:-
Alkyl and aryl-1,3,4-oxadiazoles are neutral compounds and 2-amino derivatives are weak bases. Protonation is believed to occur at ring nitrogen in position 3 which facilitates ring cleavage in aqueous acid. The pka (water) value of 2-amino-5-methyl-1, 3, 4-oxadiazole is 2.37 and values in the range 2.3-2.7 have been recorded for 2-amino-5-phenyl- and 2-N-methylamino-5-phenyl-1,3,4-oxadiazole in 50% aqueous ethanol. In the same solvent pka values of the more basic imines, 4-methyl-2-phenyl- and 4 N-dimethyl-2-phenyl- Δ2-1,3,4-oxadiazolin-5-imine, are 6.3 and 6.38 respectively.

Alkylation of oxadiazolines (3) and aminooxadiazole (4) generally result in substitution at ring nitrogen in position 4 or 3 respectively, particularly under neutral conditions. In alkaline medium, alkylation at the exocyclic heteroatom may occur                           


Oxadiazolinones (3a) and thiones (3b) acylate, for example, with acetic anhydride, benzoyl chloride or alkyl chloroformates at ring nitrogen in position 4.

2,5-disubstituted 1,3,4-oxadiazoles form double salts with mercuric chloride or with silver nitrate, which in the latter case, are used to purify or characterize the oxadiazole.

1.1.3. Electrophilic substitution at carbon:-
The relatively low electron density at carbon, coupled with the possibility of Protonation at nitrogen, makes electrophilic substitution at carbon difficult. A further problem is acid catalyzed ring cleavage, particularly with alkyl-oxadiazoles. No example of nitration or sulfonation has been reported.

1.1.4. Reaction of nucleophiles at carbon:-
The attack of a nucleophiles at carbon leads either to nucleophilic displacement (path a) or ring cleavage (path b), the latter being the most common result. Treatment of 2-chloro     (4) or 2-Methyl sulfonyl-oxadiazoles with amines, theorem or azide ion to yields the corresponding 2-substituted oxadiazoles (5).

The most frequently encountered result of the reaction of a 1,3,4-oxadiazoles with a nucleophiles is ring opening to a hydrazine derivative (6). This may undergo further reaction such as hydrolysis, or recrystallization to a 1,2,4-triazole (7) where x or nu is an amino group.


Alkyl and aryl-1,3,4-oxadiazoles undergo acid or base catalysed ring opening in water. Susceptibility of hydrolysis increase with solubility. Hence alkyl-oxadiazoles ring opening is more readily than aryl-oxadiazole and 2,4-diaryl-1,3,4-oxadiazoles are fairly stable in dilute acid or alkali at 100?C

Oxadiazolinones undergo ring opening in hot water to form hydrazine carboxylic acids (8) which decarboxylate to acylhydrazines. These acyl hydrazines may subsequently attack the ring of the starting oxadiazole causing cleavage to 1,5-diacylcarbonohydrazides. Oxadiazolinethiones are more resistant to nucleophilic attack and thiones is stable in hot water.

1.1.5. Nucleophilic attack at hydrogen; Acidity:-
Deprotonation at C-2 or C-5 has not been reported. Oxadiazolin-5-ones (9) and -5-thiones (10) are weak acids and formally undergo deprotonation at the NH group. pKa values in the range 6.6-6.7 have been quoted for oxadiazolinones and a slightly higher pKa of 7.93 has been quoted for 2-methyl- Δ2-1,3,4-oxadiazolin-5-one. Oxadiazolinethiones are stronger acids, having pKa values of 3.85, 4.45 and 4.27 respectively.

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