Hydroxy-ketones with hydrazines

In 1913, Kishner observed in one instance that under standard Wolff-Kishner reduction conditions, 2-hydroxy-2,6-dimethyloctan-3-one underwent eliminative reduction upon treatment with hydrazine hydrate and base at elevated temperatures to afford 2,6-dimethyloctan-2-ene (Scheme 7). This same reaction was later found to occur in the case of a-methoxy ketones and has since been referred to as the Kishner eliminative reduction. The reaction entails initial formation of the hydrazone and elimination of the a-substituent to afford the intermediate alkenyldiazene, which subsequently collapses to the desired alkene. Given the facile transformation of ketones into a-halo ketones, these conditions have been used to introduce alkenes regioselectively in the 2a-halocholestan-3-one series as shown in Scheme 8. Yields of 2-cholestene parallel the resistance of the a-halogen to undergo competitive elimination reactions. 

Both the hydroxy aldehydes or aldehyde alcohols and the hydroxy ketones or ketone alcohols undergo the characteristic aldehyde and ketone reactions due to the carbonyl group. They react with hydrogen cyanide, phenyl hydrazine and hydroxyl amine. These reactions have been discussed in connection with the aldehydes (pp. 116, 224) and will be considered again when we study the carbohydrates. The carbohydrates in fact belong here with these hydroxy aldehyde and hydroxy ketone compounds but on account of other relations they are better considered at a later time. 

Hydroxylamine converts a 16a-bromoandrostan-17-one (216) cleanly into the 17-oxime (217) of the 16a-hydroxy-ketone,""" closely paralleling the action of hydrazine."" Reduction of the oxime-acetate (218) with diborane gave the 17/8-acetamido- 16a -acetoxy-derivative (219)."""... 

Another 1,3-dicarbonyl equivalent is keto-enol. Treatment of the ketone with ethyl formate in the presence of NaH afforded the keto-enol as the 2-hydroxy-methylene ketone. Condensation of the keto-enol with hydrazines provided the corresponding pyrazole fused bile acid methyl ester... 

An alternative approach used phthalimido-ketone 4.121, which was converted to an N-phthalimidoyl alcohol under Reformatsky conditions, but removal of the phthalimidoyl group led to formation of lactam 4.J22.55 Treatment with acid led to conjugated lactam 4.123 rather than the amino acid. If 4.121 was reacted with bromo f-butyl acetate and zinc, alcohol 4.124 was obtained after hydrolysis of the ester.55 Removal of the phthalimidoyl group with hydrazine then led to 5-amino-3-hydroxy-3-methylpentanoic acid, 4.125. 2-Aryl-3-hydroxy derivatives such as... 

A different approach converted the ketone moiety in cis-pinononic acid [7.75, derived by permanganate oxidation of (-)-2-hydroxy pinocamphone] to an oxime (7.16). Raney nickel reduction and Beckmann rearrangement of the oxime gave 7.77. Subsequent treatment with hydrazine gave 3-amino-2,2-dimethyl-cyclobutane carboxylic acid (7.75). 

The 1,2,4-triazine 4-oxides 55 were synthesized by the reaction of nitrones 158 (generated from a-hydroxylamino ketones and aldehydes) with an excess of hydrazine, followed by the oxidation of the intermediate 4-hydroxy-2,3,4,5-tetrahydro-l,2,4-triazines 159 with lead(TV) oxide (73KGS134). 

However, in some cases azines can be converted to hydrazones by treatment with excess hydrazine and NaOH. Arylhydrazines, especially phenyl, p-nitrophenyl, and 2,4-dinitrophenyl, are used much more often and give the corresponding hydrazones with most aldehydes and ketones.Since these are usually solids, they make excellent derivatives and are commonly employed for this purpose. Cyclic hydrazones are also known, ° as are conjugated hydrazones. a-Hydroxy aldehydes and ketones and ot-dicarbonyl compounds give osazones, in which two adjacent carbons have carbon-nitrogen double bonds ... 

The carbazate linker 1.12 (69), obtained from hydroxy Argogel resin activated with CDI and reacted with anhydrous hydrazine, was used to support ketone-based protease inhibitors and to release them after SPS using TFA/H2O/CH3CHO/TFE 1/4/4/15 in 4 h at rt. 

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