Oximes, cyclization

Attempts have been made to cyclize oxime 336 into isoxazolo[4,3-c]pyridones (equation 125). However, only the expected Beckmann rearrangement product 337 was observed in relatively good yields . 

Formylbenzeneboronic acid reacts with hydroxylamine to give a cyclized oxime (200), and the thiophene analogue (201) was prepared in a similar way. These fused 3//-1,2,3-azoxaborines are analogs of the above-mentioned 2,3-dihydro-l,2,3-diazaborines. Compound (200) is resistant to hydrolysis and air, but cannot be converted to its 5-methyl derivative. 

Af-Oxides, e.g. (125), were similarly prepared using hydroxylamine to give intermediates such as (124) (79JOC1695, 78H(9)1327), and an alternative synthesis of Af-oxides involves cyclization of 3-acylamino-2-aroylpyridine oximes (126) —> (127) (69MIP21500). 

Ring closures based upon electrophilic processes are uncommon. The cationic cyclization in Scheme 29a proceeds via transformation of the commencing oxime into a nitrilium ion (81CC568). Schemes 29b (82CB706) and 29c (82CB714) exemplify the application of intramolecular acylation. 

Oximes with a displaceable group in the /S-position cyclize in the presence of base to produce 2-isoxazolines as exemplified in the conversion of (480) into (481) (62HC(l7)l, 78JOC2020, 66JAP6616384, 70JOC2065). 

In a number of cases the intermediate oxime has been isolated in the reaction of hydroxylamine and /3-keto esters. The reaction of ethyl acetoacetate with hydroxylamine generated an oxime which cyclized on base treatment (Scheme 144) (70MI41600). Likewise, treatment of an analogous amide with hydroxylamine generated a ring opened material which cyclized on treatment with HCl (Scheme 144) (67T831). The presence of a minor contaminant in the standard reaction of ethyl acetoacetate with hydroxylamine was discovered and identified as an isomeric isoxazolin-3-one. The mechanism of product formation has been discussed (70BSF2685). 

The course of the reaction is dependent on the configuration of the oxime. The (Z)-oxime gave 1,2-benzisoxazoles as the primary product while the (E)-oxime generally produced a Beckmann rearrangement product with or without subsequent cyclization to a benzisoxazole (Scheme 167) (67AHC(8)277). Bunnett conducted a kinetic study on the reaction shown in Scheme 167 and determined that cyclization to intermediate (551) was the rate determining step (61JA3805). 

The importance of the configuration of the oxime is again demonstrated in the oxidative cyclization of o-aminobenzophenone oximes. The (Z)-oxime with nitrous acid produced 3-phenyl-l,2-benzisoxazole, while the (E)-oxime with similar treatment yielded ben-zotriazine N-oxides (27CB1736). 

The sulfonate ester of o-hydroxyacetophenone oximes, when treated with pyridine, are similarly converted into a benzoxazole, but cyclize to a 1,2-benzisoxazole when treated with aqueous KOH <73JCS(P1)2220, 71T711). 

The treatment of 2-hydroxyacetophenone with hydroxylamine-O-sulfonic acid in dilute aqueous base produced 3-methyl-1,2-benzisoxazole. The mechanism was reported to be a C(2)—C(3) ring closure via intermediate (560) (Scheme 171). Salicylaldehyde failed to cyclize with dilute base, but with 20% KOH and hydroxylamine-O-sulfonic acid the transformation to 1,2-benzisoxazole succeeded (76MI41600). Kemp and Woodward isolated an oxime sulfonate (561) from salicylaldehyde and hydroxylamine-O-sulfonic acid and the subsequent decomposition gave 1,2-benzisoxazole in 95% yield (65T3019). 

The electrochemical reduction of 3-nitrophthalic acid at controlled potentials gave 2,1-benzisoxazole-3-carboxylic acid. Cyclization is presumed to proceed via an intermediate oxime (67AHC(8)277). Treating 5-iodoanthranilic acid with acetic anhydride gave 3-acetoxy-5-iodo-2,l-benzisoxazole (596) (65JMC550). 

The mechanism of the original Knorr pyrrole synthesis entails in situ reduction of the oxime moiety to an amine, condensation with the second carbonyl compound, and cyclization with loss of a second molecule of water to give a pyrrole for example, 10 + 11 to 12. Several studies have demonstrated that different pathways and pyrrole products obtain depending on the substrates. 

Stop-flow conditions that carbinolamine intermediate 4 dehydrates to form syn and anti oximes. The syn isomer 5 cyclized within several minutes to 3, while conversion of the anti form required several hours. 

To date, only the parent benzoisotellurazole 9 has been obtained. For its synthesis, methods similar to those used for the preparation of benzoisothiazole andben-zoisoselenazole were employed. The reaction of 2-bromotellurenylbenzaldehyde with ammonia affords 9 in 74% yield, whereas cyclization of the oxime of o-butyltellurobenzaldehyde catalyzed by PPA gives 9 in 40% yield (78JHC865). In contrast to the reaction of 2-bromoselenenylacetophenone with ammonia, which leads to 3-methylbenzoisoselenazole (73JHC267), 2-bromotellurenylacetophe-none reacts with ammonia to give telluroindoxyl (78JHC865). 

Evidently, analogously to the mentioned cyclization of similar oximes to ben-zisoxazole derivatives (See Section II.A), reaction can take place only in compounds with suitable configuration. However, in case of hydrazones, due to the tautomeric equilibrium of both possible configurations, the reaction usually achieves complete conversion. The usual setup involves heating with the respective hydroxide if an ester group is present, it is partially or completely hydrolyzed to the corresponding acids, which, in addition, can also undergo decarboxylation. 

This presumably forms oxime, 120, on reaction with hydroxylamine that intermediate is not isolated as it cyclizes spontaneously to the isoxazole, 121. Acylation of the isoxazole with the sulfonyl chloride, 88, affords sulfisoxazole (98) after removal of the acetyl group. 

A variant on this structure, dioxyline, has much the same activity as the natural product but shows a better therapeutic ratio. Reduction of the oxime (113) from 3,4-dimethoxyphenyl-acetone (112) affords the veratrylamine homolog bearing a methyl group on the amine carbon atom (114). Acylation of this with 4-ethoxy-3-methoxyphenyl acetyl chloride gives the corresponding amide (115). Cyclization by means of phosphorus oxychloride followed by dehydrogenation over palladium yields dioxyline (116). ... 

During hydrogenation, intermediate aromatic hydroxylamines may undergo various cyclization reactions in molecules containing a suitably disposed carbonyl group, or carbonyl derivative, such as an oxime (13). The cyclized product may or may not maintain the N—OH bond, depending on the solvent, the catalyst, and the electrophilicity of the carbonyl (27,28,29,32,67,68). 

Dibenz[c 1c ]azepine (32 a) is obtained by acid-mediated cyclization of 2 -(aminomethyl)bi-phenyl-2-carbaldehyde (31 a), which is generated in situ by reduction of the oxime acetal 30a.85 The acetyl 30 a and benzoyl 30c oximes behave similarly and give the dimethyl and diphenyl derivative 32 b and 32 c, respectively. 

Acylamino)benzaldehyde oximes 2 cyclize under the influence of sulfuric acid to afford high yields of benzoxadiazepines 3. Selected examples arc given yields were generally not reported.314... 

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