5- -l,2,4-oxadiazole

The retro-1,3-dipolar cycloaddition of imidazo[l,5- ][l,2,4]oxadiazoles 40, promoted by reaction with triphenylphos-phine at reflux in THF, gives the cyclic nitrones 187 (unreported yields) (Equation 15) <1997T13873>. The ring opening of compounds 40 leading to heterocycles 187 (Equation 15) can also be achieved thermally in the condensed phase under vacuum <1997TL2299>. 

Imidazoline 3-oxides 187 undergo regio- and diastereoselective 1,3-dipolar cyloaddidon with aryl isocyanates to give X-5,6,7,7a-tetrahydroimidazo[l,5- ][l,2,4]oxadiazoles 40 in good yields (Equation 80) <1997TL2299, 1997T13873>. 

Tab.40 5(4)-Amino-4(5)-l,2,4-oxadiazole aus N-Cyan-S-methyl-isothioharnstoffen mit Hydroxylamin... 

One-pot three-component cyclocondensation of l-(3-aryl-l,2,4-oxadia-zol-5-yl)acetone 229, thiourea, and aromatic aldehydes formed 5-(l,2,4-oxadiazol-5-yl) DHPM 230 (Scheme 88) (09MI8). 

Some relevant substituents are displayed in Table XV. Hydrolysis of esters or nitriles followed by thermal decarboxylation of 2-, 5-, 6-, and 7-carboxylic acids is often used for degradation reactions (6ICPB883, 61JCS3046 64UP1). 5-Amino-1,2,4-triazole-3-carboxylic acid isdecarbox-ylated in situ by condensation to TP (83S44) TP-5-amideoxime is cyclized to the 5-(l,2,4-oxadiazol-3-yl) derivative (90EGP282009). 

Dibenzoylpyridazine-4,5-dione 1,2-dioxide is transformed into 3,5-dibenzoyl-l,2,4-oxadiazole in the presence of an alcohol. 

Oxazoles are easily cleaved. 2,5-Dialkyl-l,3,4-oxadiazoles (159) in aqueous solution with acid or base give hydrazides (if suitable substituents are present, further reaction can occur see Section 4.02.3.5.1). 3-Methyl-l,2,4-oxadiazole (160) is easily hydrolyzed to acetamidoxime (61CKL)292). 

Substituents cannot directly conjugate with /3-pyridine-like nitrogen atoms. Azole substituents which are not a or y to a pyridine-like nitrogen react as they would on a benzene ring. Conjugation with an a-pyridine-like nitrogen is much more effective across a formal double bond thus the 5-methyl group in 3,5-dimethyl-l,2,4-oxadiazole (323) is by far the more reactive. 

A different type of rearrangement occurs when suitable side chains are a to a pyridine-like nitrogen atom. In the monocyclic series this can be generalized by Scheme 43. For a given side chain the rate of rearrangement is l,2,4-oxadiazoles>isoxazoles> 1,2,5-oxadiazoles. Typical side chains include hydrazone, oxime and amidine. Some examples are shown in Table 9 (79AHC(25)147). Similar rearrangements for benzazoles are discussed in Section 4.02.3.2.4. 

Additional nitrogen atoms facilitate such reactions, particularly if they are a or y to the alkyl group, and, if a, act across a formal double bond. Thus, the 5-methyl group in 3,5-dimethyl-l,2,4-oxadiazole is much more reactive than the 3-methyl group in this compound or the methyl groups in 2,5-dimethyl-l,3,4-oxadiazole (76AHC(20)65). 

A similar intramolecular trapping of the intermediate (511) from the photolysis of the corresponding methyl tetrazole-l,5-dicarboxylate (510) gave methyl 5-methoxy-l,2,4-oxadiazole-3-carboxylate (512). 

I-Cyano-3-phenylurea, first obtained by the alkaline hydrolysis of 5-anilino-3- -toluyl-l,2,4-oxadiazole, has been prepared by tlic condensation of phenyl isocyanate and the sodium salt of cyanamide. However, in these publications an incorrect structural assignment for the product was made. 1-Cyano-3-phenyl-urea is obtained also, together with other products, by warming gently l-cyano-3-phenylthiourea with caustic soda in the presence of ethylene chlorohydrin, or by gradually adding caustic )otash to a boiling solution of 1-phenyldithiobiuret and ethylene clilorohydrin in ethanol. ... 

For 5-hydroxy-l,2,4-oxadiazoles, equilibria with dominant oxo forms 145b prone to type 146 dimerization were observed (Scheme 54) [76AHC(S1), p. 378 76BSB35 84CHEC-I(6)365 96CHEC-II(4)179]. 

Irradiation of a methanolic solution of 3-acylaminofurazans 185 at X = 310 nm in the presence of ammonia or primary or secondary amines produced excellent yields (70-95%) of 3-(R-amino)-5-R -l,2,4-oxadiazoles 186 (Scheme 117) (95S917). Similar results were obtained by irradiation of 3-aroylaminofurazans in the presence of pyrrolidine at X = 254 nm (92AP151). 

The irradiation of 3-amino-5-phenyl-l,2,4-oxadiazole (98) gave the corresponding 1,3,4-oxadiazole (99) (Scheme 41) [88JCS(P1)1313 88JHC931 95FI(41)2095). The formation of 99 has been explained by assuming a RCRE mechanism. 

Recently, the reaction of 3-methoxy-5-aryl-l,2,4-oxadiazoles in the presence of diphenylacetylene to give the corresponding quinazolinones has been reinvestigated and an electron transfer mechanism was proposed (99JOC7028). 

On irradiation in ether at 254 nm 2,5-diphenyl-l,2,4-oxadiazole (102) did not give any interesting result. On the contrary, the irradiation in an immersion apparatus gave, with low conversion (33%), a mixture of three products (103-105) (Scheme 42) [68TL2417 95H(41)2095]. 

Fig. 21. Relative energy of the exeited states of 3-amino-5-phenyl-l,2,4-oxadiazole and of some reaetive intermediates.

The dione 1 is converted into 2,6-dichloro-4,l-benzoxazepin-5(3i/)-one (2) by the action of phosphoryl chloride in jV.lV-dimethylaniline. The crude product on treatment with 3-isocyano-methyl-5-isopropyl-l,2,4-oxadiazole gives the imidazobenzoxazepinone 3.36... 

Ligand abbreviations (6-Mepy)(py)2tren and (6-Mepy)2(py)tren = tris[4-[(6-/ )-2-pyridyl]-3-aza-6-butenyl]amme, R = H or CH3 HB(pz)3 = hydro-tris(pyrazolyl)borate paptH = 2-(2-pyridylamino)-4-(2-pyridyl)thiazole phenmethoxa = 3-[2-(l,10-phenanthrolyl)]-5-methyl-l,2,4-oxadiazole pyimH = 2-(2 -pyridyl)itnidazole pybimH = 2-(2 -pyridyl)benzimidazole ppa = JV -(2-pyridylmethyl)picolineamidine tpmbn = tetrakis(2-pyridylmcthyl)-meso-2,3-butane-diamine tppn = tetrakis-(2-pyridylmethyl)-l-methyl-l,2-propanediainine tpchxn = tetrakis(2-pyridylmethyl)-tra s-l,2-cyclohexanediamine biz = 2,2 -bi-1,4,5,6-tetrahydropyrimidine. 

Monaca et al. (2003) examined the effect of the SSRI citalopram on REMS in 5-HTia and 5-HTib knockout mice. Citalopram suppressed REMS in wild-type and 5-HTib mice but not in 5-HT,A I mutants. The 5-HTja receptor antagonist WAY 100635 prevented the citalopram-induced inhibition of REMS in wild-type and 5-HTib knockout mice. However, pretreatment with the 5-HTib receptor antagonist GR 127935 [2 -methyl-4 -(5-methyl-(l,2,4)oxadiazol-3-yl)-biphenyl-4-carboxylic acid ((4-methoxy-piperazine-l-yl)-phenyl)amide] was ineffective in this respect. It was concluded that the action of citalopram on REMS in the mouse depends exclusively on the activation of 5-HT,A receptors. Notwithstanding this, there is unequivocal evidence showing that administration of selective 5-HTib receptor agonists suppresses REMS in the rat. 

Other non-traditional preparations of 1,2,3-triazoles have been reported. The rearrangement in dioxane/water of (Z)-arylhydrazones of 5-amino-3-benzoyl-l,2,4-oxadiazole into (2-aryl-5-phenyl-27/-l,2,3-triazol-4-yl)ureas was investigated mechanistically in terms of substituents on different pathways <06JOC5616>. A general and efficient method for the preparation of 2,4-diary 1-1,2,3-triazoles 140 from a-hydroxyacetophenones 139 and arylhydrazines is reported <06SC2461>. 5-Alkylamino-] //-], 2,3-triazoles were obtained by base-mediated cleavage of cycloadducts of azides to cyclic ketene acetals <06S1943>. Oxidation of N-... 

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