Hydrazine halo ketones

It is difficult to determine how general the reaction of a-halo ketones with hydrazines is but one such example has been reported (Scheme 65) (31RTC669). 

Dihalides and 1,5-ditosylates have been used for the preparation of fully-saturated monocyclic 1,2-diazepines 165 (Scheme 83). 5-Halo-aldehydes and 5-halo-ketones react with a wide range of substituted hydrazines to give 4,5,6,7-tetrahydro-l,2-diazepines 166 <1976H(4)1509>. The reaction of 1,5-diketones with hydrazine has been much used as a source of 5,6-dihydro-4/7- 1,2-diazepines 167 . 

Scheme 4 One-pot synthesis of l-amino-l,3-dihyclro-2H-imiclazole-2-thiones 26 starting from a-substituted a-halo ketones 21, potassium thiocyanate, and monosubstituted hydrazines 3.

When 2,5-diamino-l,3,4-thiadiazole is treated with an a-halo ketone in ethanol, the product is a 2-imino-3-(2-oxoalkyl)-5-amino-l,3,4-thiadiazoline hydrohalide (173). Direct treatment with excess hydrazine hydrate, or such treatment subsequent to reaction with aqueous ammonia, gives l-aminoimidazoline-2-thiones (Scheme 102) (70AHC(12)103). 

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. 

Treatment of oc-halo ketones 1392 (X = Br, Cl) with potassium thiocyanate and monosubstituted hydrazines 1393 provides Ar-aminoimidazoline-2-thiones [1397, R R = Me, Ph R R = (042)4 R = Ph, 4-O2NC6H4, PhCH2, etc.]. The reaction is considered to proceed via the formation of azo-alkenes 1394 and thiocyanic acid 1395. The intermediates, in turn, undergo a [34-2] cycloaddition reaction to give azomethine imine cycloadducts 1396, which proceed to the final products 1397 (Scheme 361) <199714(45)691, 2003JME1546>. 

An alternate approach, which also uses enzyme-catalyzed ring-opening of a lactone to generate a mechanism-activated inhibitor, was developed by Katzenellenbogen and his co-workers [183], who found enol lactones, exemplified by (13-8) and (13-9), to be potent, selective inhibitors of HLE. The haloenol lactone (13-9) was an irreversible inactivator of HLE and chymotrypsin, and after exposure to (13-9), active enzyme could not be regenerated even upon treatment with hydrazine. Enol lactone (13-8), on the other hand, was an alternate-substrate inhibitor, which produced only transient inhibition of HLE and chymotrypsin. These results have been interpreted to mean that, with the halo-substituted compounds, ring opening results in formation of an acyl-enzyme that contains a reactive halomethyl ketone, which then alkylates His-57. That these compounds... 

The reaction of gcnt-dihalocyclopropyl acetates with hydrazine and substituted hydrazines provides a synthetic route to pyrazoles. It proceeds via aminolysis of the ester, followed by ring opening of the gcw-dihalocyclopropanoxide to give an a-halo-a,iS-unsaturated ketone. The latter condenses with the hydrazine to form the pyrazole (see Houben-Weyl, Vol. 4/3, p 656). " For example gew-dichlorocyclopropane 26 gave pyrazole 11 ... 

Aldehydes reducing sugars lactates some polyhydric phenols aminophenols some esters of aliphatic acids halo-forms -hydroxy-ketones reducing bases such as the hydrazines. 

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