Ketones, reaction with hydroxylamines

Since an electron-withdrawing group such as ethoxycarbonyl at the a-carbon atom enhanced the electrophilicity of the )3-carbon atom, the reaction of a-ethoxycarbonyl-)3-ethoxyvinyl ketones (298) with hydroxylamine hydrochloride gave solely 5-substituted isoxazole-4-carboxylates (299) (55JOC1342, 59YZ836). 

To synthesize isomeric 3-substituted isoxazoles (301) the reaction of ethylene acetals of )3-ketoaldehydes (300) (readily available from -chlorovinyl ketones (57IZV949)) with hydroxylamine was employed. Owing to the comparative stability of the dioxolane group, this reaction gave exclusively 3-substituted isoxazoles (301) (60ZOB954). The use of noncy-clic, alkyl S-ketoacetals in this reaction resulted in a mixture of 3- and 5-substituted isoxazoles (55AG395). 

The well-known reaction of a-alkyl-/3-ketoaldehydes and hydroxyl-amine has been applied to the elucidation of the structure of formyl-ation products of ketones the conclusions are, however, open to question. Some workers attempted to overcome the ambiguity of the reaction of j8-ketoaldehydes and hydroxylamine, which results in a mixture of 3- and 5-monosubstituted isoxazoles and thus considerably lowers the preparative value of the method, by using various derivatives of yS-ketoaldehydes, especially those of their enolic forms (jS-substituted vinylketones) investigated by Kochetkov et al. The use of readily available /3-chlorovinylketones (12) in the reaction with hydroxylamine represents a rather useful preparative method to synthesize monoalkylisoxazoles but again gives rise to a mixture of 3- (13) and 5-alkylisoxazoles (14). This is due to the attack... 

Axenrod and co-workers reported a synthesis of TNAZ (18) starting from 3-amino-l,2-propanediol (28). Treatment of (28) with two equivalents of p-toluenesulfonyl chloride in the presence of pyridine yields the ditosylate (29), which on further protection as a TBS derivative, followed by treatment with lithium hydride in THF, induces ring closure to the azetidine (31) in excellent yield. Removal of the TBS protecting group from (31) with acetic acid at elevated temperature is followed by oxidation of the alcohol (32) to the ketone (33). Treatment of the ketone (33) with hydroxylamine hydrochloride in aqueous sodium acetate yields the oxime (34). The synthesis of TNAZ (18) is completed on treatment of the oxime (34) with pure nitric acid in methylene chloride, a reaction leading to oxidation-nitration of the oxime group to em-dinitro functionality and nitrolysis of the A-tosyl bond. This synthesis provides TNAZ in yields of 17-21 % over the seven steps. 

General synthesis of pyrroles and 1-vinylpyrroles by the reaction of ketoximes with acetylenes and their synthetic equivalents (vinyl halides and dihaloethanes) in the presence of the strongly basic KOH/DMSO system (Trofimov reaction) has been reviewed ° in recent years. Therefore, in the present work this reaction will be described very shortly. In principle, pyrrole (51) synthesis can be carried out as a one-pot procedure by treating ketones (49) with hydroxylamine and then reacting the ketoximes (50) formed with acetylenes (equation 22). 

The lactam (2) is obtained in 87% yield by treating cycloheptanone with sodium azide and concentrated hydrochloric acid (54JA2317). Beckmann rearrangement of cycloheptanone oxime with concentrated sulfuric acid gives (2) in 88% yield (58JA1510). Alternatively, the ketone gives (2) directly by reaction with hydroxylamine sulfonate in 95% formic acid (79S537). 

Synthesis (Freed and Potoski (American Home), 1971 Freed, 1973 Kleemann et al., 1999,) Dezocine is prepared through the following sequence The condensation of 1-methyl-7-methoxy-2-tetralone with 1,5-di-bromopentane by means of NaH or potassium tertbutylate affords 1 -(5-bromopentyl)-1 -methyl-7-methoxy-2-tetralone this product is cyclized with NaH to give 5-methyl-3-methoxy-5,6,7,8,9,10,11,12-octahydro-5,11 -methano-benzocyclodecen-13-one i. The ketone i, by reaction with hydroxylamine hydrochloride in pyridine, is converted into its oxime ii, which is reduced with H2 over Raney Ni to a mixture of isomeric amines which were separated by crystallization of the HCI salts giving 5-a-methyl-3-methoxy-5,6,7,8,9,11 a, 12-octahydro-5,11 -methanobenzo-cyclodecen-13p-amine, which is finally cleaved with concentrated HBr. 

Reaction of the acetylenic ketone (123) with hydroxylamine gave two isomeric isoxazoles.61 These were probably 124 and the 3-ferro-cenyl isomer. The reaction of A-ferrocenoylglycine with benzaldehyde and sodium acetate in acetic anhydride gave the oxazolone (125)68... 

Reaction of a 1,3-diketone with hydroxylamine gives an isoxazole 50 via the isolable monoxime 48 and 5-hydroxydihydroisoxazole 49 (Scheme 34). Various modifications of this procedure involving other 1,3-dielectrophiles are known the examples can be represented by the reaction of alkynyl ketone 51 with hydroxylamine hydrochloride leading to the 3-substituted isoxazole 52 (Scheme 35) <2000J(P1)2311 >, and the electrophilic cyclization of O-methyl oximes 53 allowing access to a variety of 3,5-disubstituted-4-halo- or -4-selenoisoxazoles 54 under mild reaction conditions (Scheme 36) <20050L5203>. 

Synthesis of 4,5-dihydroisoxazoles. 3-Methyl isoxazolines 506 have been prepared from the ketones 505 by reaction with hydroxylamine hydrochloride and subsequent S-OTi o- ng-cyclization, leading to a single isomer (Equation 81) <2000EJ02079>. 

Now the reaction with hydroxylamine in acid solution. Formation of the oxime of the ketone p. 348) produces one molecule of water - just enough to hydrolyse the acetal - and the pyridine sTTithesis can be completed by cyclization and a double dehydration (p. 1194). 

An aryl cyclopropyl ketone reacted with hydroxylamine followed by a mixture of tosyl chloride and pyridine to give the corresponding 7V-arylcyclopropanecarboxamide as the sole product in fair yield.Alkyl cyclopropyl ketones, on the other hand, afforded mixtures of the corresponding A-alkylcyclopropanecarboxamide and A7-cyclopropylalkanamide in excellent total yield on reaction with hydrazoic acid (Schmidt reaction) in the presence of sulfuric acid or trichloroacetic acid, an example is the formation of 3. When sulfuric acid was used, the amide ratio was sensitive to the acid strength of the reaction mixture. ... 

Isoxazolines and isoxazoles were obtained in good yields by the interaction of acetylenic ketones 114 with hydroxylamine the regioselectivity of the reaction depends on reaction conditions. Thus, when treated with hydroxylamine in alkaline... 

The cyclocondensation proceeds according to the retroanalytical prognosis via the isolable intermediates of a monoxime 5 and a 5-hydroxy-4,5-dihydrooxazole 6. In the case of unsymmetrically substituted y -diketones, it is still possible to control the regioselectivity by using variable carbonyl electro-philicity and observing strict reaction conditions. a-Hydroxymethylene ketones, the corresponding enol ethers and ethynyl ketones also yield isoxazoles by reaction with hydroxylamine. 

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