4.5- Dihydro-1,2,4-oxadiazoles, oxidation

A new approach to functionally substituted 4,5-dihydro-l,2,3-oxadiazole 2-oxides 134 has been described (Scheme 9) <2005RJ0120>. The method allows access to new derivatives and better access to the known derivatives that relied on difficult-to-prepare starting materials such as A -nitrosulfamides and A -nitro-2-cyanoethylalkylamines. 

Thus nitration of readily accessible hydroxysulfamates followed by conversion to their ammonium salts gave 4,5-dihydro-l,2,3-oxadiazole 2-oxides 134 on cyclization using methanolic alkali. The structure of one derivative (R = CH2N(N02)Me) (Scheme 9) was further confirmed by two-dimensional H—1SN correlation NMR <2005RJ0120>. 

The reaction of the ( -configured Schiff base 315 with benzonitrile oxide gave the 4,5-dihydro-l,2,4-oxadiazole 316 as a single diastereomer (Equation 59) <1999AXC650>. 

Dipolar cycloaddition of nitrile oxide at the C=N bond of indole imino esters 130, followed by elimination of the alcohol moity gives oxadiazole derivatives 131 (Scheme 1.26) (298). Reaction of N-arylbenzamidines with arenenitrile N-oxides (generated in situ from oximoyl chlorides) produce unstable 5-amino-4,5-dihydro-1,2,4-oxadiazoles which, on aqueous acidic treatment hydrolyze to open-chain N-benzoyloxy-N -arylareneamidines (299). 

I.3.4.2.4. Heterocumulenes The 1,3-dipolar cycloaddition of substituted ben-zonitrile oxides to the C=N group of chlorocarbonyl isocyanate C1C(0)N=C=0 gives 3-aryl-4-chlorocarbonyl-5-oxo-4,5-dihydro-l,2,4-oxadiazoles 172 in 75%-80% yield (340). A similar reaction with chlorosulfonyl isocyanate, C1S02N=C=0, affords 4-unsubstituted oxadiazolinones 173 (341). 

Dihydro-1,2,4-oxadiazol-5-ones (74) cannot be 7V-acylated by either chlorocarbonyl isocyanate or trichloroacetyl chloride. However, preparation of 4-chlorocarbonyl compounds (73) can be achieved by cycloaddition of stable nitrile oxides to the C=N double bond of chlorocarbonyl isocyanate <888994, 90ZOR339). Compounds (73) decompose with ammonia, primary amines, or primary amides to isocyanates and (74) (Scheme 26). 

Dihydro-l,2,4-oxadiazoles with hydrogen atoms in the 4- and 5-positions are readily oxidized to 1,2,4-oxadiazoles with air or potassium permanganate <87JHClOl>, chlorine <75JOC248l>, or N-bromosuccinimide <86MI 404-02>. This has been used, for example, for the preparation of oxadiazoles substituted with a carbohydrate moiety (Scheme 71) <86MI 404-02). 

Cycloaddition of nitrile oxides to the double bond of aldoximes under BF3 catalysis affords 4,5-dihydro-4-hydroxy-l, 2,4-oxadiazoles, from which water can be eliminated. Oxadiazoles are obtained in low yields <86izv2i5i, 90IZV625>. 

Xanthines substituted at the 8-position with an oxygen or nitrogen atom are oxidized with peracids to 4,5-dihydro-1,2,4-oxadiazoles (200) (Scheme 87) <940PP353>. 

Another method used to prepare dialkyl-substituted diazomethanes involves the photolysis of 2-alkoxy-2,5-dihydro-1,3,4-oxadiazoles (209), which can be prepared by the oxidative cyclization of A(-acetyUiydrazones. The diazoalkanes are trapped in situ by cycloaddition with dimethyl acetylenedicarboxylate (54) (Scheme 8.49). The resulting pyrazoles 210 are converted into cyclopropenes 211 by continued irradiation. 

The mass spectrometry of 1,2,4-oxadiazoles is dominated by stepwise 1,3-dipolar cycloreversion, i.e., fragmentation 191. This fragmentation is particularly useful for 1,2,4-oxadiazole characterization and a wide selection of derivatives undergo cleavage to a nitrile oxide fragment <2003H(60)2287, CHEC-III(5.04.3.3)249>. Mass spectrometric analysis of 1,2,4-oxadiazoles and dihydro-1,2,4-oxadiazoles has been reviewed <2005MI328>. 

Anodic oxidation of azomethine, hydrazone, oxime, formazane, and semicarbazone structures has been used to initiate the intramolecular cyclization [119] under formation of heterocycles like triazoles [126,127], oxadiazoles [128,129], triazolinones [129], benzoxa-zoles [130,131], benzimidazoles [130,131], pyrazoles [132], indazoles [133], furoxanes [134], and tetrazolium salts [135] (see Chapter 18). Some of these reactions can be performed advantageously by indirect electrolysis using tris(4-bromophenyl)amin or 2,3-dihydro-2,2-dimethylphenothiazine-6(l/7)-one as mediators [119,136]. Two examples are given in Eqs. (19) and (20). 

Indirect oxidation with tris-(4-bromophenyl)amine or 2,3-dihydro-2,2-dimethylphe-nothiazine-6(l/7)-one transforms formazane to tetrazolium, semicarbazones to 2-amino-1,3,4-oxadiazoles, benzaldehyde 2-pyridylhydrazones to 5-triazolo[4,3-a]pyridinium compounds, and phenyl 2-pyridyl ketone phenylhydrazone to 1/7-1,2,3-triazolo[3,4-a]-pyridi-nium compounds [123]. 

While 2,5-bis(perfluoroalkyl)-l,3,4-oxadiazoles 3 react with hydrazine to give the N2-(x-hy-drazonoperfluoroalkyl)perfluoroalkylhydrazides 4 (see Section 5.1.1.2.1.), 2,5-bis(trifluoro-methyl)-l,3,4-oxadiazole (3, RF = CF3) reacts with hydrazine to afford the dihydro-1,2,4,5-tetrazine 5 which is oxidized by iron(lll) chloride to give 3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine (6, RF = CF3).164... 

The reaction of imidazole with benzonitrile oxide (in excess) gives little (Z)-l-benzoylimidazole oxime (70) besides (Z)-3-benzoyl-2,3-dihydro-l//-imidazol-2-one oxime (73) and benzonitrile (and in addition some side products). In the solid state only the chain form (70) is observed, but the formation of (72) indicates a chain-ring tautomerism in solution. The latter tautomer (71) is supposed to undergo nucleophilic addition to benzonitrile oxide. The resultant 7-benzoyl-3-phenyl-7, 7a-dihydroimidazo [4,5-a][l,2,4]oxadiazole (72) is considered the key intermediate suffering a [3 + 2]... 

The cycloaddition of 2,2,5,5-tetramethyl-l-oxyl-2,5-dihydro-l//-imidazol-3-oxide (312) with isocyanates yields the 6-oxyl-1 /7-imidazo[ 1,5-6][ 1,2,4]oxadiazol-2-ones (109) (Equation (91)) <85TL4801, 90MI 805-03, 92S1223, 93JCS(P2)2157, 93T10693>. 

Similarly, 2,2,3,4,4-pentamethyl-2,5-dihydro-l/f-imidazol-l-oxide (313) undergoes [3 -I- 2] cycloaddition with isothiocyanates to give 5,5,6,7,7-pentamethyl-l,2,5,6,7,7a-hexahydroimidazo[ 1,5-6][l,2,4]oxadiazole-2-thione (314) (Equation (92)) <91IZV2642>. 

The 2-methyl-4,5-dihydrooxazoles (358 Z = O) or 2-methyl-4,5-dihydrothiazole (358 Z = S) undergo 1,3-dipolar cycloaddition reactions with benzonitrile A -oxide to give the corresponding 7a-methyl-3-phenyl-5,6-dihydro-7a//-oxazolo[3,2- ][l,2,4]oxadiazoles (16) or -thiazolo[3,2-c ]-[l,2,4]oxadiazoles (17) (Equation (121)) <92T7703>. 

A new method for the synthesis of 1,1-dialkyldiazomethanes (2.101) has been developed by Warkentin s group (Majchrzak et al., 1989). A-Acylhydrazones of ketones (2.99) are oxidized with lead tetraacetate to 2,5-dihydro-l,3,4-oxadiazoles (2.100). This intermediate undergoes a photolytic cleavage if irradiated with UV light (300 nm) at room temperature in benzene (2-45). 

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