3- -l ,2,4-oxadiazol

Thiazolo[4,3-/)][l,2,4]oxadiazoles 110 react with hydrazine hydrate to give thiazolo[3,4-/)][l,2,4]triazoles 114 (Equation 113) <2001IJC(B)440>. 

The reaction of pyrido[2,3-c/]pyrimidine-3-oxide (415) and diethyl malonate in the presence of sodium ethylate in ethanol at 0°C for 10 min led to the formation of Af-[3-(l,2,4-oxadiazol-3-yl)-2-pyridyl]aminomethylene-malonate (416) in 73% yield, but at ambient temperature for 1.5 hr, the product was diethyl N-(3-cyano-2-pyridyl)aminomethylenemaIonate in 61% yield (83JOC4132). 

Like the foregoing isomeric substrates (Section 2.2.7), these isoxazolopyrazines were frequently made from pyrazines. Thus 3-(/V-hydroxyamidino)-2(l//)-pyrazi-none (102) was converted in two stages into isoxazolo[4,5-b]pyrazin-3-aminc (103), which on vigorous treatment with acetic anhydride afforded 2-acetoxy-3-(5-methyl-l,2,4-oxadiazol-3-yl)pyrazine (104) in 78% yield the same substrate (103) in hot formic acid for 5 min gave mainly 3-(l,2,4-oxadiazol-3-yl)-2(l/7)-pyrazi-none (105) (50%) but if heating was prolonged for 3 h only 3-oxo-3,4-dihydro-2-pyrazinecarbonitrile (106) was obtained, presumably via the oxadiazolopyrazine (105).1115... 

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). 

Phenylisothiazole is nitrated predominantly in the meta position of the phenyl group, whereas 4-phenylisothiazole is nitrated ortho and para in the phenyl group <72AHC(14)1). Nitration of 3-phenyl-l,2,4-oxadiazole gives a mixture of m- and p-nitrophenyl derivatives <6301196). 

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). 

Several 3-acylamino-l,2-benzisoxazoles such as (278) underwent rearrangement to 3-(o-hydroxyphenyl)-l,2,4-oxadiazoles (279) on heating with base. It has been questioned whether the same mechanism is operative in these last rearrangements (8lAHC(29)l4l, p. 150). 

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. ... 

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). 

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. 

Imidazopyridothiazines (and imidazopyridopyrazines) can be prepared from the corresponding aminochloropyr-idines in a one-pot reaction, as shown in Scheme 69. Products in which R= l,2,4-oxadiazol-3-yl are of interest as possible 7-aminobutyric acid (GABA) receptor ligands <2002M653, 2002M1205>. 

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-... 

Microwave irradiation induces 1,3-dipolar cycloadditions of nitrones, such as 152, with aliphatic and aromatic nitriles in the absence of solvent. The products of these reactions are the corresponding 2,3-dihydro-l,2,4-oxadiazoles 156 (Scheme 9.48). The use of microwaves led to yields that were always higher than those obtained with classical heating, with the differences being more significant with the less reactive nitriles [99]. 

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