1.3.4- Oxadiazol-2 -one 1- oxides

Although benzofuroxan (Bfx) and furoxan (Fx) were first synthesized over 100 years ago, it was not until the middle of the 20th century that its relevant bioactivities were identified. Bfx s and Fx s relevant biological behaviors convert these systems in one of the most current study heterocycles in medicinal chemistry. Formally, these compounds are 1,2,5-oxadiazole hf-oxide derivatives, specifically Bfx should be named as benzo[l,2-c][l,2,5]oxadiazole 1-oxide and Fx as 1,2,5-oxadiazole 2-oxide, however, the common trivial... 

One of the best-known common approaches to generate the 1,2,5-oxadiazole AT-oxide system involves cychzation of a nitro group unto a nitrene, arising... 

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>. 

Several compounds of interest have had their crystal and molecular structures elucidated using x-ray analysis. 7-Methylbenzothieno[3,2-c][l,2,5]oxadiazole 1-oxide (3) was found to align itself in the crystal lattice so that the benzene ring of one molecule faces the 1,2,5-oxadiazole oxide moiety of another, thus superposing the least number of atoms <75CSC13>. 

Dimerization of nitrile oxides is one of the most important methods of synthesis of 1,2,5-oxadiazole iV-oxides (furoxans). However, this process can also lead to formation of symmetrical 1,4,2,5-dioxadiazines. The dipyridyl dioxadiazine 20 was obtained in 59% yield by treatment of 2-pyridyl hydroximinoyl chloride hydrochloride with triethylamine and pyridine in ethanol <2003EJI405>. The coumarin nitrile oxide 196 was dimerized with pyridine in ethanol to give the dioxadiazine 197 in 66% yield (Scheme 34). When a chloroform solution of the nitrile oxide 196 was heated at reflux in the absence of base, the furoxan 198 was produced in 70% yield (Scheme 34). Attempted purification of 196 by recrystallization caused dimerization into furoxan 198 <1998JHC619>. 

CeH5BrN202, N (p-Bromophenyl)sydnone, 28, 494 C8H5NO3, 2H-1,3-Benzoxazine-2,4(3H)-dione, 44B, 335 C8H5NO3, 2H-3,l-Benzoxazine-2,4(lH)-dione, 44B, 335 C8H6N2O3, 3-(p-Hydroxyphenyl)-l,2,5-oxadiazole 2-oxide, 46B, 374 C8H7BrN202, 5-Bromo-4,6-dimethylisoxazolo[3,4-b]pyridin-3(lH)-one, 45B, 397... 

The cycloaddition of nitrile oxide 235 to the 4-iminobenzopyran-2-one 236 gave the fully conjugated 1,2,4-oxadiazole 238 directly, a reaction that most likely proceeds via loss of methanol from the intermediate 237 (Scheme 36) <1996JHC967>. Similarly, nitrile oxide 239 reacted with imine 240 to give the 1,2,4-oxadiazole 242 via the nonisolable intermediate 241 <2002PJC1137>. 

Since arylazoamidoximes release nitric oxide when incubated in rat liver microso-mial fraction [172], 3-arylazo-l,2,4-oxadiazol-5-ones 136 have been prepared from the corresponding arylazoamidoximes 134 as their potential pro-drugs [172]. Reaction with chloroformate afforded compounds 135 which underwent cyclisation to 136 in alkaline medium (Scheme 6.26). 

Substituted-l,3,4-oxadiazolin-2-ones 178 are synthesized by the oxidation of carbo-/-butoxyhydrazones 177 of aromatic aldehydes with IBD. In some cases, in addition to 178, 5-acetoxy-l,3,4-oxadiazoIes 179 are also obtained. The oxidation of ethoxycarbonyl hydrazones 180 affords 2-ethoxy-l,3,4-oxadiazoles 181 (86JHC945) (Scheme 48). 

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). 

The reaction can be performed in one step by adding the nitrile to a mixture of benzhydroxamyl chloride and triethylamine. Unless activated by an electron withdrawing group, aliphatic nitriles do not react with benzonitrile oxide 33e). For example, acetylcyanide gives 3-phenyl-5-acetyl-oxadiazole in 60% yields [32a). 

The action of bromine, ferricyanide,89 and other mild oxidizing agents90 directly on benzamidoxime has been reported to give diphenyl-oxadiazole (16), While it is clear that one nitrogen has been oxidized, no intermediate was isolated. 

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