Formation from 1,2,4-oxadiazoles

An interesting example of oxadiazole ring formation from formally O-C-N-N-C-O component 109 is the synthesis of tricyclic system (pyridooxadiazolpyridine) depicted in Scheme 26 <1998MI655>. 

Substituted acylamidines, such as (119), have been cyclized to oxadiazoles with hydroxylamine-0-sulfonic acid (Scheme 51) <9UMC1086>. Mechanistically related reactions include formations of oxadiazoles from oxazinium salts (120) (Scheme 52) <92KGS540>, and other oxadiazole-forming ring transformations <94H(38)ii3>, such as (121) (122) (Scheme 53) <89CB1107>. 

Sydnones 78 (R1 = Ph, Ar or 3-pyridyl, R3 = H or Me) are obtained from the nitrosoamino acids 77 and acetic anhydride under ultrasound (94MI153). Three examples of the formation of oxadiazoles by microwave irradiation are from O-acyl amide oximes 79 in the presence of aluminium oxide, from amide oximes 80 and isoprop-enyl acetate in the presence of KSF-clay and from N,N -diacylhydrazines 81 and thionyl chloride (95SC1451). 

The formation of oxadiazole (159) or triazole (160) from the thiosemicarbazide (161) under different conditions of methylation in the presence of base (Scheme 67) is less readily explained (71MI41200). Relative rates of methylation on S and O are involved but the different temperatures make a direct comparison impossible. The effect of acidity cannot be neglected as shown in Scheme 68 (63CB1059). 

With suitably constructed oxazapyrrolidinones, new heterocycles can also be formed via the hydrogenolysis of the N—O bond followed by a reclosure sequence. The formation of pyrazinone 75 from isoxazolone indole 77 from oxadiazole and... 

The irradiation of 3-( -aminophenyl)-l,2,4-oxadiazoles 65 allowed the process to be extended to the formation of an internal N-N bond (Scheme 4), leading either to the indazoles 68 directly from photolytic species 66, or to the formation of benzimidazoles 69, which were formed from the carbodiimide 67, the rearrangement product of photolytic species 66 <1996JOC8397>. 

The cyclization of the five-atom component O-acylated amidoximes 204 leads to 1,2,4-oxadiazoles via C-N bond formation as shown in Scheme 30. The requisite O-acylated amidoximes 204 are accessed via the reaction of an amidoxime with an activated carboxylic acid or a carboxylic acid derivative. Often the O-acylated amidoxime 204 is not isolated and the cyclization is either spontaneous or occurs in a one-pot process, and these approaches are dealt with in Section 5.04.9.1.2 as syntheses from a one-atom component and a four-atom component. In this section, only those methods in which the O-acylated amidoxime 204 is isolated and cyclized in a separate step are dealt with. 

A new three-component approach to the highly substituted 2,5-dihydro-l,2,4-oxadiazoles 359 has been reported from the reaction of nitriles 354 under mild conditions with iV-alkylhydroxylamines 355 in the presence of electron-deficient alkynes 356 (Scheme 60) <20050L1391>. This synthesis is proposed to proceed via the initial formation of the alkyl or arylamidoximes 357, which then undergo a sequential double Michael addition to the electron deficient alkyne. The intermediate alkyl or arylamidoximes 357 can be isolated and then reacted with the alkyne to produce the product. The initial Michael adduct 358 is stable in cases where R2 is H. 

Dimerization of nitrile oxides derived from 4-amino- and 4-R-substituted l,2,5-oxadiazole-3-carbohydroximoyl chlorides 201 leads to the formation of tricyclic furoxans 200 or compound 202 (Scheme 45) <2001RJ01355>. 

Two variations of the transformation of 3-acyltetrazoles into oxadiazoles are useful from a synthetic point of view. The first transformation involves the reaction of tetrazole with diketene. In the second, the sodium salt of the tetrazole is treated with oxalyl chloride. UV irradiation of some 3-amino-l,2,4-oxadiazoles leads to the formation of the corresponding 2-amino-l,3,4-oxadiazoles <1996CHEC-II(4)268>. 

The energetic 1,3,4-oxadiazole (22) is synthesized from the reaction of the tetrazole (20) with oxalyl chloride. In this reaction the tetrazole (20) undergoes a reverse cycloaddition with the expulsion of nitrogen and the formation of the 1,3-dipolar diazoalkane (21) which reacts with the carbonyl groups of oxalyl chloride to form the 1,3,4-oxadiazole rings. 

---