2. Green Chemistry Approaches

There are various green chemistry approaches to carry out different chemical reactions that include microwave irradiation (MWI), ultrasonication, photo-catalysis, grinding and milling methods (Figure 1). By applying these technologies, organic reactions become more efficient and economic by enhancing the rate of reaction with reduced reaction time and high product yield. Synthetic approaches like grinding or milling techniques involve the application of mechanochemistry for the rapid, clean, efficient and solvent-free synthesis of various biologically active compounds ^[6].

Figure 1. Green chemistry approaches.

During the year 1991, the Environmental Protection Agency (EPA) and the National Science Foundation (NSF) initiated the Green Chemistry Program. P.T. Anastas and J.C. Warner have formulated twelve major principles of green chemistry to reduce or eliminate the risk of chemical hazards and environmental pollution ^{[7][8][9][10]}.

3. Chemistry of OxadiazoleMoiety

Oxadiazoles are five-membered heterocyclic compounds that possess one oxygen atom and two nitrogen atoms in the ring system ^[11]. Depending on the position of heteroatoms (oxygen or nitrogen), there are different isomeric forms of oxadiazole moiety such as 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole (Figure 2).These chemical compounds are of the azole family with the molecular formula C₂H₂N₂O. Among these isomers, 1,2,3-oxadiazole is unstable and ring-opens to form the diazoketone tautomer. However, 1,3,4-oxadiazole is a thermally stable aromatic molecule and plays a major role in developing new drug candidates with diverse biological activities such as anticancer, antiparasitic, antifungal, antibacterial, antidepressant, antitubercular and antiinflammatory, etc. ^[12].

Figure 2. Chemical structures of oxadiazole isomers.

The electrophilic-substitution reaction is very difficult at the carbon atom in the oxadiazole ring because of the relatively low electron density on the carbon atom. However, the electrophilic attack occurs at nitrogen if the oxadiazole ring is substituted with electron releasing groups. Similarly, the oxadiazole ring is usually resistant to nucleophilic attack. However, the halogen-substituted oxadiazole undergoes nucleophilic substitution with the replacement of halogen atom by nucleophiles ^[13]. Although 1,3,4-oxadiazole ring system was known in 1880, significant studies were carried out regarding its chemistry, structure, physical properties and application of its various derivatives from 1950 (Table 1). 1,3,4-oxadiazole is a liquid with a boiling point of 150 °C. The percentage of C, H, N present in 1,3,4-oxadiazole is 34.29%, 2.88%, 40.00%, respectively ^[14].

Table 1. Bond angle and bond length of 1,3,4-oxadiazole moiety.

Angles	Bond Angle (°)	Bonds	Bond Length (Pm)
A	105.6	a	139.9
B	113.4	b	129.7
C	102.0	c	134.8
D	113.4	d	134.8
E	105.6	e	129.7

 

The first monosubstituted 1,3,4-oxadiazoles were reported in 1955 by two independent laboratories. Since 1955, other research groups have performed the reactions of 1,3,4-oxadiazole and reported that it is a liquid that boils at 150°C. Ainsworth first prepared 1,3,4-oxadiazole (2) in 1965 by the thermolysis of ethylformate formyl hydrazone (1) at atmospheric pressure as depicted in Scheme 1 ^[15].

Scheme 1. Synthesis of 1,3,4-oxadiazole.

The 1,2,4-oxadiazole was synthesized first time in 1884 by Tiemann and Kruger. Most of the oxadiazole synthesis is based on heterocyclization of amidoxime and carboxylic acid derivatives or 1,3-dipolar cycloaddition of nitrile and nitrile oxide ^[16]. Microwave irradiation can also be applied in the heterocyclization of amidoximes and acyl chlorides/carboxylic acid esters in the presence of NH₄F/Al₂O₃ or K₂CO₃ to produce corresponding oxadiazole derivatives ^[17]. Similarly, oxadiazole derivatives are produced by the reaction of aryl-nitrile with hydroxylamine hydrochloride to aryl-amidoxime inthe presence of a catalyst (MgO or CH₃COOH or KF) under a microwave-assisted method. In the year 2017, Baykov et al. reported a study on the first one-pot synthetic procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles (3) at room temperature from corresponding amidoximes (1) and carboxylic acids methyl or ethyl esters (2) in the presence of superbase medium NaOH/DMSOas presented in the Scheme 2 ^[18][19].

Scheme 2. Synthesis of 1,2,4-oxadiazole analogs. R₁ = 4-methylphenyl, R₂ = methyl or phenyl, X = methoxy or ethoxy.

Gorjizadeh et al. reported the efficient synthesis of a series of 1,3,4-oxadiazoles (3) from the cyclization–oxidation reaction of acyl hydrazones (1) with substituted aldehydes (2) by using 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate (BTPPDS) as an oxidant in a solvent-free medium under microwave irradiation (Scheme 3). The reaction was found to proceed smoothly under microwave irradiation within 25 min, whereas 12 h were required to complete the reaction under reflux conditions ^[20].

Scheme 3. Synthesis of a series of 1,3,4-oxadiazoles.