Oxidation nitrile

Pyrroles from 1,4-dicarbonyl compounds and ammonia isoxazolines from olefins and nitrile oxides. 

Isocyanates are derivatives of isocyanic acid, HN=C=0, ia which alkyl or aryl groups, as weU as a host of other substrates, are direcdy linked to the NCO moiety via the nitrogen atom. StmcturaHy, isocyanates (imides of carbonic acid) are isomeric to cyanates, ROCMSI (nitriles of carbonic acid), and nitrile oxides, RCMSI—>0 (derivatives of carboxyUc acid). 

Dipolar cycloaddition reactions with azides, imines, and nitrile oxides afford synthetic routes to nitrogen-containing heterocycles (25—30). 

Phototransformation of pyridazine 1,2-dioxides sharply contrasts with that of pyridazine 1-oxides. Pyridazine 1,2-dioxide derivatives give 3a,6a-dihydroisoxazolo[5,4- f]isoxazoles (53) through postulated bisiminoxyl radicals. 3,6-Diphenylpyridazine 1,2-dioxide gives, besides the corresponding bicyclic derivative (53), 3-phenylisoxazole (54) and 4,5-diphenyl-furoxan (55). The last two products can be explained by generation of the nitrile oxide from the intermediate (53) with subsequent dimerization to the furoxan (55 Scheme 18) (79T1267). 

Dihydrofuran (376) and 2,5-dihydrofuran (377) react with nitrile oxides to give furo[2,3-6 ]isoxazoles (378) and furo[3,4-rf]isoxazoles (379), respectively, as cycloadducts. The double bonds of furan, pyrrole and thiophene also react when the nitrile oxide is generated in situ. Thus furan and benzonitrile oxide gave (380), and with 2-methyl-2-oxazoline the cycloadduct (381) was obtained (71AG(E)810). These and related cycloadditions are discussed in Chapter 4.36. 

Hi) Preparation of isoxazoles from nitrile N-oxides The reaction between a nitrile //-oxide and an alkyne is so facile that it is usually sufficient to leave an ether solution of the reactants at room temperature to obtain the desired isoxazole in good yield. The reaction is in general sensitive to the size of the substituent on the alkyne but not on the nitrile -oxide. In the case of poorly reactive alkynes, the difficulty may be overcome by generating the nitrile -oxide in situ and keeping its concentration low. 

A -Isoxazolines are readily available from the 1,3-dipolar cycloaddition of nitrile -oxides with alkenes and from the condensation reaction of ehones with hydroxylamine. Therefore, methods of conversion of -isoxazolines into isoxazoles are of particular interest and of synthetic importance. 

The two major methods of preparation are the cycloaddition of nitrile oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamines. Additional methods include reaction of /3-haloketones and hydroxylamine, the reaction of ylides with nitrile oxides by activation of alkyl nitro compounds from isoxazoline AT-oxides (methoxides, etc.) and miscellaneous syntheses (62HC(i7)i). 

Nitrile oxides react with a wide variety of alkenic compounds and this reaction may be complicated by dimerization of the nitrile oxide to furoxan in the presence of unreactive double bonds (Scheme 98). 

The reaction of alkyl nitro compounds with acetyl chloride in the presence of an alkenic compound produced a 2-isoxazoline. The mechanism is believed to proceed via a nitrile oxide and is illustrated in Scheme 112 (B-79MI41613). 

Rahman and Clapp decomposed dinitromethane derivatives in DMF in the presence of alkenes to obtain 2-isoxazolines. Without any alkene present, an acid and KNO2 were obtained. They proposed a mechanism which proceeded via a three-membered ring or a nitrocarbene which rearranged to a nitrile oxide (76JOC122, 75MI41612). 

Generalized methods of preparation include the reaction of /3-keto esters (or amides) with hydroxylamine, a-alkynic and a,/3-unsaturated esters (or amides) with hydroxylamine (real or generated in situ), hydroxylamine and nitrile oxides, and /3-keto and a-alkynic nitriles with hydroxylamine (62HC(l7)l, pp. 3,7). 

Alkynic esters react with nitrile oxides in a pH dependent reaction to product isoxazolin-5-ones (Scheme 145) (71JCS(C)86). Alkynic ethers also react with benzonitrile oxide to produce an isoxazole-ether which on treatment with HCl or HBr gave an isoxazolinone (Scheme 145) (63CB1088,58MI41600). The reaction of benzonitrile oxide with dimethoxyketene yielded a dimethyl acetal which was split with acid into the isoxazolinone (Scheme 145) (59G15H). 

Isoxazolin-5-imines were produced by nitrile oxide addition to cyanoacetates (62HC(17)l,p.7), by the reaction of nitrones with phenylacetonitrile (74CB13), and by base addition of nitrosobenzene to nitriles (Scheme 148) (72LA(762)154). 

The reaction of vinylogous amides, or ketoaldehydes, with hydroxylamine produced 4,5,6,7-tetrahydro-l,2-benzisoxazole. A side product is the 2,1-benzisoxazole (Scheme 173) (67AHC(8)277). The ring system can also be prepared by the reaction of cyclohexanone enamines with nitrile oxides (Scheme 173) (78S43, 74KGS901). Base treatment produced ring fission products and photolysis resulted in isomerization to benzoxazoles (76JOC13). 

A variety of 1-azirines are available (40-90%) from the thermally induced extrusion (>100 °C) of triphenylphosphine oxide from oxazaphospholines (388) (or their acyclic betaine equivalents), which are accessible through 1,3-dipolar cycloaddition of nitrile oxides (389) to alkylidenephosphoranes (390) (66AG(E)1039). Frequently, the isomeric ketenimines (391) are isolated as by-products. The presence of electron withdrawing functionality in either or both of the addition components can influence the course of the reaction. For example, addition of benzonitrile oxide to the phosphorane ester (390 = C02Et) at... 

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