Uses of 1,3,4-Oxadiazoles

A group of l,3,4-oxadiazolin-5-ones and l,3,4-oxadiazoline-5-thiones show antitubercular activity.18,43a 76,84 86,181, 132,157 160 They have been investigated with regard to their mode of action. 2-(4 -Pyridyl)-l,3,4-oxadiazolin-5-one (S 57) has shown itself active against Mycobacterium tuberculosis and Mycobacterium leprae.86-158 It possesses some advantages compared with isonicotinic acid hydrazide. Derivatives of S 57 also have some tuberculostatic activity.159, lfl1,162 Further tuberculostatic compounds are derived from p-aminosalicylic acid, for example WS 127 [2-(4 -amino-2 -hydroxyphenyl)-l,3,4-oxadiazoline-5-thione] and WS 174 [2-(4 -acetamido-2 -hydroxyphenyl)-l,3,4-oxadiazolin-5-one].85 2-Cyano-methyl-l,3,4-oxadiazolin-5-one shows a tuberculostatic activity comparable with that of Reazid. 18 Oxadiazolin-5-ones and oxa- 

Wilder Smith, Swiss Patent 322,065 (1957) see Chem. Abatr. 52, 1560 

4-Oxadiazoles are acquiring greater significance in the stabilizing167 and preparation of macromolecular materials.38,168 Thus poly-1,3,4-oxadiazoles with aliphatic substituents are used as films, although aryl derivatives can be used neither as fibres nor films. The high thermal stability of these compounds is worthy of note. 

5-perfluoroalkyl-l,3,4-oxadiazoles show an extraordinarily high thermal stability. Among other possible applications, they can be used as bath liquids and solvents for highly fluorinated polymers.38 In the last few years numerous 1,3,4-oxadiazole derivatives 

Wilder Smith, E. Frommel, and S. Radouco-Thomas, Arzneimittel-Forsch. 13, 338 (1963). 

---

The following pages will be devoted mainly to the syntheses, the reactivity, the physical properties, and the uses of 1,3,4-oxadiazoles. 

As mentioned above, the cycloaddition reaction with 1,3,4-oxadiazole is predicted to be LUMO diene (heterocycle) controlled. That definitely suggests that with electron-withdrawing substituents in the two and five positions of the heterocycle ring, the heterocycle should become more reactive as a diene for Diels-Alder reactions. To study the usefulness of 1,3,4-oxadiazole and its derivatives as dienes for the Diels-Alder reaction, we are presenting the results of our theoretical study of the cyclopropene addition to 2,5-di(trifluoromethyl)-l,3,4-oxadiazole. The AMI computed FMO energy gap for this reaction pair was only 8.00266 eV in comparison to 9.64149 eV FMO energy gap between LUMO of 1,3,4-oxadiazole and HOMO of cyclopropene. Therefore, the computed activation barrier for the cyclopropene addition to 2,5-bis(trifluoromethyl)-1,3,4-oxadiazole should be very... 

Schemes Synthesis of 1,3,4-oxadiazoles using PEG-bound Burgess reagent...

Various theoretical methods (self-consistent field molecular orbital (SCF-MO) modified neglect of diatomic overlap (MNDO), complete neglect of differential overlap (CNDO/2), intermediate neglect of differential overlap/screened approximation (INDO/S), and STO-3G ab initio) have been used to calculate the electron distribution, structural parameters, dipole moments, ionization potentials, and data relating to ultraviolet (UV), nuclear magnetic resonance (NMR), nuclear quadrupole resonance (NQR), photoelectron (PE), and microwave spectra of 1,3,4-oxadiazole and its derivatives <1984CHEC(6)427, 1996CHEC-II(4)268>. 

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

Microwaves were used to support S-arylation of 5-substituted oxadiazoline-2-thiones <2000BMC69> and <2000M1207>. 5-(4-Pyridyl)oxadiazoline-2-thiones treated with 2-haloesters also afforded A-alkyl derivatives <2000CHE851>. A similar reaction occurred in the case of 5-pyrazolyloxadiazoline-2-thiones <2000JFA5312>. Organophosphorus derivatives of 1,3,4-oxadiazole were obtained by the reaction of bis(oxadiazolinethiones) with 0,0-diethylchlorophosphate (Scheme 21) <1998JFA1609>. 

Nucleophilic attack at substituted ring carbon is probably the most common reaction of 1,3,4-oxadiazoles. However, few examples have been reported of nucleophilic attack at unsubstituted carbon since such compounds (19a) are relatively uncommon. The mechanism of the well-known conversion of 2-amino-oxadiazoles (in aqueous alkali) into triazoles has been studied in the case of the reaction where (19a R = NHPh) is converted to (20). This proceeds via the anion of semi-carbazide PhNHCONHNHCHO and is initiated by hydroxide attack at C-5 <84JCS(P2)537>. A similar nucleophilic attack by hydroxide on oxadiazole (19a R = 5-pyrazolyl) was followed by cyclization to the pyrazolo-triazine (21). Hydrolytic cleavage of 2-ary 1-1,3,4-oxadiazoles to aroyl-hydrazides allows use of the former as protected hydrazides. Oxadiazole (19a R = 4-... 

A new and convenient synthesis of 1,3,4-thiadiazoles was reported and involved the direct conversion of 1,3,4-oxadiazoles using thiourea as the thionating agent <98SC4611>. Courtois et al. have described an efficient monohydroxyarylation (or alkylation) and symmetrical bis-hydroxyarylation (or alkylation) of 2,5-dimethyl-1,3,4-thiadiazole using LDA and the appropriate carbonyl compound <99SC145>. 

Brain, C.T. and Brunton, S.A., Synthesis of 1,3,4-oxadiazoles using polymer-supported reagents, Synlett, 2001, 382-384. 

Brain, C.T., Paul, J.M., Loong, Y. and Oakley, P.J., Novel procedure for the synthesis of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using polymer-supported Burgess reagent under microwave conditions, Tetrahedron Lett., 1999, 40, 3275. 

An example of the use of DAIB for intermolecular N-N bond formation is provided by the synthesis of 1,3,4-oxadiazoles 66 from acylhydrazides by the two-step sequence shown in Scheme 20 (97JCR(S)468). The intermediate diacylhydrazides 65 can be isolated or simply generated in situ prior to treatment with thionyl chloride. 

Sangshetti et al. [18] synthesized a novel series of 1,3,4-oxadiazoles (vii) by a one pot reaction of hydrazide (vi), aromatic aldehyde in ethanol water using sodium bisulfate as the catalyst. All the compounds showed good antifungal activities. 

Wang et al. [34] gave the single step, rapid and efficient synthesis of 1,3,4-oxadiazoles (xxxii) from carboxylic acids and acid hydrazides by using commercially available PS-PPhs resin combined with microwave heating. 

Polshettiwar et al. [38] gave a novel, one-pot, solvent free, green protocol for the synthesis of 1,3,4-oxadiazoles (xLii) by the condensation of acid hydrazide and triethyl orthoalkanates (xLi) using solid supported Nafion NR50 and phosphorus pentasulphide in alumina as a catalyst. 

Li Z, Yu J et al (2004) Microwave accelerated solvent-free synthesis of 1,3,4-oxadiazoles using polymer supported dehydration reagent. Synth Commun 34 2981-2986... 

Scheme 93 summarizes the overall reaction much used for the conversion of 1,3,4-oxadiazoles (196 X = O) and thiadiazoles (196 X = S) to triazoles (197) and (198). Intermediates such as (199) and (200) have been isolated in some cases and have been reasonably assumed in others, especially when such amidrazones could be converted either into (197) or (198) according to the reaction conditions (see also 70KGS991). 

Computational studies concerning theoretical approaches to the intrinsic basicity of neutral nitrogen bases have been reported, including those of phos-phoranimines. The non-ionic phosphazene bases BEMP (112), BTPP (113) and (114, R = Ph) appear to be excellent catalysts for the Michael addition reactions. Thus the yield of the coupling reaction of ethyl isocyanoacetate with l,2-bis(4-bromomethylphenyl)ethane is increased by the addition of the phosphazene base BEMP. Polymer-supported BEMP (P-BEMP) has been applied for the allylation of 2H-benzo[d]l,3-dioxolan-5-ol by allyl bromide. " Cyclodehydration of 1,2 diacylhydrazines by tosyl chloride in the presence of P-BEMP leads to excellent yields of 1,3,4,-oxadiazoles. Addition of P-BEMP also improves the yield of the Hofmann elimination step in the synthesis of tertiary mines using REM resin (polymer-bound acrylate ester). ... 

---