5-Methyl-2- -1,4-oxadiazole, synthesis

Scheme 9 Synthesis of 5-(bromodifluoro-methyl)oxadiazoles 29 and difluoro alcohols 30...

The original route for the synthesis of potassium 5-methyl-l,3,4-oxadiazole-2-carboxylate (39) via an intramolecular condensation of ethyl (2-acetylhydrazinyl)-(oxo)acetate (37) suffered from moderate yields (Scheme 6.10). 

The reaction of 5-[2-(iV,./V-dimethylamino)ethyl]-l,2,4-oxadiazole with methyl iodide forms the quaternary ammonium salt 170 (Scheme 22), which undergoes elimination in the presence of base (diisopropylethylamine (DIEA), TEA, l,8-diazabicyclo[4.3.0]undec-7-ene, etc.) to form an intermediate 5-vinyl-l,2,4-oxadiazole 171, which undergoes in situ Michael addition with nucleophiles to furnish the Michael adducts 172. As an example, also shown in Scheme 22, 3-hydroxy-pyrrolidine allows the synthesis of compound 172a in 97% yield. Mesylation followed by deprotonation of the 1,2,4-oxadiazole methylene at C-5 enables Sn2 displacement of the mesylate to give the 5-azabicycloheptyl derivative 173, which is a potent muscarinic agonist <1996JOC3228>. 

The synthesis of a chloro-, bromo-, and iodomethylbenzo[l,2-c]l,2,5-oxadiazole iV-oxide was performed from methyl- or oxymethylbenzofurazans 254 (Scheme 66) <2005MI294>. 

Acyl nitroso compounds react with 1, 3-dienes as N-O heterodienophiles to produce cycloadducts, which have found use in the total synthesis of a number of nitrogen-containing natural products [21]. The cycloadducts of acyl nitroso compounds and 9,10-dimethylanthracene (4, Scheme 7.3) undergo thermal decomposition through retro-Diels-Alder reactions to produce acyl nitroso compounds under non-oxidative conditions and at relatively mild temperatures (40-100°C) [11-14]. Decomposition of these compounds provides a particularly clean method for the formation of acyl nitroso compounds. Photolysis or thermolysis of 3, 5-diphenyl-l, 2, 4-oxadiazole-4-oxide (5) generates the aromatic acyl nitroso compound (6) and ben-zonitrile (Scheme 7.3) [22, 23]. Other reactions that generate acyl nitroso compounds include the treatment of 5 with a nitrile oxide [24], the addition of N-methyl morpholine N-oxide to nitrile oxides and the decomposition of N, O-diacylated or alkylated N-hydroxyarylsulfonamides [25-29]. 

Sheridan and co-workers144 took the microwave spectra of oxadiazole after its synthesis in 1962.39 From an analysis of Stark effects for a number of transitions, they concluded that the dipole moment should be 1.2 0.3 D (Table II). Davies and Mackrodt139 calculated the dipole moment to be 1.34 D, within the experimental error of Sheridan s value, by the CNDO/2 method of Pople and Segal. Other calculations133,136,138 indicate that the dipole moment of 1,2,4-oxadiazole should be notably less than that of the 1,2,5- and 1,3,4-isomers. Direct measurements of dipole moments by Milone145 had portended this much earlier. Besides the ones given in Table II, Milone had also found the same range of dipole moments for 3-methyl-5-phenyl, 5-methyl-3-phenyl, and other derivatives of the three sets of isomeric oxadiazoles. 

Kidwai, M., Kumar, P., Goel, Y. and Kumar, K., Microwave assisted synthesis of 5-methyl- 1,3,4-thiadiazol-2-ylthio/tetrazol-l-yl substituted pyrazoles, 2-azetidinones, 4-thiazolidinones, benzopyran-2-ones and 1,3,4-oxadiazoles, Indian. J. Chem., Sect. B, 1997, 36, 281. 

The iron-catalyzed [3 + 2]-cycloaddition (Huisgen reaction) of nitriles and carbonyl compounds as reported by Itoh et al. is one of the rare examples reported where an iron reagent can be utilized for the synthesis of 1,2,4-oxadiazoles (Scheme 9.35) [93]. In this reaction, methyl ketones are nitrated at the a-position by Fe(N03)3 to generate an a-nitro ketone. This intermediate rearranges to an acyl cyanate, which reacts further with the nitrile to give the heterocyclic product 48 in good to excellent yields (R1 = Ph, R2 = CH3 95% yield). 

The structure of 1,2,4-oxadiazoles has not been in dispute since covalent structures can be drawn from the methods of synthesis. The geometry of the ring was estimated for theoretical calculations years before X-ray measurements were available. Microwave spectra and recently fluorescence spectra have been used to determine the dipole moments of oxadiazoles and oxadiazolines, the latter being high by comparison (Table 7). Electron densities were calculated for 5-methyl-3-phenyl-l,2,4-oxadiazole (88) and its 2,3-dihydro derivative (89) (77JOC1555). 

Cyclization in phosphorus oxychloride of semicarbazides (79 X = NHR) yields aminooxadiazoles (81) whereas thermolysis leads to loss of ammonia (when X = NH2) and formation of an oxadiazolinone (80). Cyclization to aminooxadiazoles (81) occurs when thiosemicarbazides (82) are heated with an oxidizing agent such as lead oxide. This reaction has been widely applied to the synthesis of aminooxadiazoles, sometimes in low yields, and has been used to prepare 2-amino-l,3,4-oxadiazole (81 R1 =R2 = H). 5-Methyl ethers of thiosemicarbazides (82) cyclize, with loss of methanethiol, to aminooxadiazoles (81) on heating, but in PPA cyclization to 2-methylthio-l,3,4-oxadiazoles occurs. 

Examples include the synthesis of 3-amino-l,2,4-oxadiazoles starting from 3-acylamino-5-methyl-l,2,4-oxadiazole <2002H811> and 2-aryl-l,2,3-triazoles from l,2,4-oxadiazole-3-ketone arylhydrazones <1999T12885, 2006JOC5616>. Oximes, hydrazones, formamidines, and thioureas of the furazan series also undergo base-catalyzed mononuclear rearrangements <2004RCB1121>. Nucleophilic attack at N(3) takes place in the benzofuroxan series. For example, reaction with secondary amines leads to o-nitroarylhydrazines (Scheme 55). 

Oxadiazoles can be prepared by acylation of amidoximes. A variation of this method gives a one-pot synthesis from the amidoxime, an organic acid and a peptide coupling agent the method is sufficiently mild that there is no racemisation when mandelic acid is used. 1,2,4-Oxadiazoles can also be prepared from amides via acylamidines, " or via the cycloaddition of nitrile oxides to nitriles, as illustrated, or to 6>-methyl oximes. ... 

Later work from Orach s group resulted in a general synthesis of the previously unknown 2-aryl-4-cyano-5-hydrazinooxazoles 1648 from a 2-(acylamino)-3,3-dichloroacrylonitrile 1647 (Scheme 1.424). Refluxing 1648 in acetic acid afforded the 2-methyl-5-substituted 1,3,4-oxadiazoles 1650. The structure of 1650 (X = CH3O) was confirmed by X-ray crystallography. All attempts to cyclize 1648 to an oxazolopyrazole 1651 failed. 

Synthesis from Acylhydrazines. The condensation of acyl hydrazines and ethyl dithioacetate in boiling ethanol furnishes 5-aryl-2-methyl-l,3,4-thiadiazoles, but 1,3,4-oxadiazoles are formed as main products in some cases. Under suitable conditions, the intermediate thioacetylacylhydrazines may be isolated. ... 

Dipolar cycloadditions of nitrile oxides to the various unsaturated alditol derivatives 92 led to pairs of isoxazolidine regio-isomers, e.g. 93 and 94, each as predominantly one stereoisomer (Scheme 16). The isoxazole 95 was the major product from addition of bromoformonitrile oxide to the nitro-alkene. The nitrile moiety of D-mannononitrile pentabenzoate was transformed into either a 3-substituted 5-methyl-1,2,4-oxadiazole moiety (with NH2OH then AC2O) or a 5-substituted 2-methyl-1,3,4-oxadiazole moiety (with NH4N3 then AC2O, Py) cf. Vol.24, p.l35. The synthesis of 2-(alditol-l-yl) substituted 2-aza-3,7-dioxabicy-clo[3.3.0]octanes by intramolecular dipolar cyclization of 2-0-d y -aldehydo-sugar nitrones is covered in Chapter 24. 

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