Nitriles reaction with hydroxylamines

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). 

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). 

The pharmacological versatility of this general substitution strategy is further illustrated by diazonium coupling of 14 with 2-nitrobenzenediazonium chloride to produce biarylal-dehyde 18. Formation of the oxime with hydroxylamine is followed by dehydration to the nitrile. Reaction with anhydrous methanolic hydrogen chloride leads to imino ether and addition-elimination of ammonia leads to the antidepressant amid-ine, nitrafudam (20). ... 

The nitrile can be prepared from citral by reaction with hydroxylamine and subsequent dehydration with acetic anhydride. 

The product (15-2) from aldol condensation of meto-nitrobenzaldehyde with the dimethyl acetal from ethyl 4-formylacetoacetate (15-1) provides the starting material for a dihydropyridine in which one of the methyl groups is replaced by a nitrile. Reaction of (15-2) with the eneamine from isopropyl acetoacetate gives the corresponding dihydropyridine hydrolysis of the acetal function with aqueous acid affords the aldehyde (15-3). That function is then converted to its oxime (15-4) by reaction with hydroxylamine. Treatment of that intermediate with hot acetic acid leads the oxime to dehydrate to a nitrile. There is this obtained nilvadipine (15-5) [16]. 

Nitriles. Aldehydes can be converted directly in satisfactory yield into nitriles by reaction with hydroxylamine hydrochloride at 90-140° when N-methylpyrrolidone is used as solvent. 

Hydroxylamine supported on magnesia reacted, under microwave irradiation, with nitriles and benzoyl chlorides to afford in a one-pot reaction 1,2,4-oxadiazoles <07TL2829>. In a stepwise procedure, amino acids and dicarboxylic acids were transformed into the corresponding 3,5-disubstituted 1,2,4-oxadiazoles, useful as peptidomimetic building blocks <07TL1465>. 

The Vilsmeier-Haack reaction of electron-rich carbocyclic aromatic compounds (Ar—H) with chloromethyleneiminium salt (1) gives aldehyde derivatives (Ar—CHO), generally in good yield. The intermediate iminium salt (cf. salt 5 Scheme 1) can be treated with hydroxylamine to obtain nitrile derivatives (Ar—CN). Benzene and naphthalene are not sufTiciently electron rich to participate in the Vilsmeier-Haack reaction, but polycyclic hydrocarbons, such as anthracene, do react. Benzene and naphthalene derivatives that possess an electron-releasing substituent (—OMe,—SMe,—NMe2, etc.) af-... 

The nitrile can be prepared from citral by reaction with hydroxylamine and subsequent dehydration with acetic anhydride or by reaction with ammonia and hydrogen peroxide in the presence of copper salts [75a]. 

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