Ketones with hydrazines

A useful variant of the imine-forming reaction just discussed involves the treatment of an aldehyde or ketone with hydrazine, H2NNH2, in the presence of KOH. Called the Wolff-Kishner reaction, the process is a useful and genera method for converting an aldehyde or ketone into an alkane, r2c=o —> R2CH2. 

Treatment of 5-(dichlorophenylmethyl)-3-phenyl[ 1,2,4]triazin-6( 1H)-one 357 or the respective ketone with hydrazine or phenylhydrazine gave 358, which were cyclized with acetic acid to pyrazolo[4,3-c][ 1,2,4]triazines 359 (84PHA504 85MI2) (Scheme 77). 

The formation of a hydrazone by the reaction of a ketone with hydrazine. 

The synthesis of pyrazolo[3,4-. ]pyridines can be achieved by reaction of 2,6-dichloro-3-lithiopyridine with 5-bromo-2-methoxybenzaldehyde 138 to provide the alcohol, which after Jones oxidation gave ketone 139. Treatment of the ketone with hydrazine furnished the desired pyrazolo[3,4-3]pyridine 140 (Scheme 8) <2006BML262>. 

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). 

Hydrazones are readily prepared from a variety of ketones with hydrazine or one of a number of substituted hydrazines. Some hydrazones may be converted into azo compounds by an isomerization procedure (see below). 

Many of the methods discussed in this section can also be treated as combinations of more than two fragments. For instance, in the cyclization of a-hydrazono oximes with orthocarboxylates described in the next section, the a-hydrazono oximes (635) are treated as a five-atom fragment, but since these compounds are usually prepared from ketones by nitrosation and reaction of the oximino ketones with hydrazine, the entire reaction sequence may be described asa[2 + l+ 2+ l] combination. 

AZTNES. The products of the reaction between an aldehyde nr a ketone with hydrazine are termed azines. A number of dyestuffs and complex members of the pyridine family of compounds also are termed azines. See also Pyridine and Derivatives. 

The regioselectivity of pyrazole 55 formation is completely the reverse of that of pyrazoline 57 in the reaction of ketones 54 with hydrazines without DPPH. In addition, heterocycles 56 cannot be obtained from 57 by the action of DPPH. These facts show that the radical-initiated treatment of a, 3-unsaturated ketones with hydrazines does not occur via the initial pyrazoline 57 formation. 

The Wolff-Kishner reduction is an old and still often used method for the reduction of a ketone to the corresponding alkane. The Huang-Minlon modification of this reduction is commonly employed. It entails the treatment of the ketone with hydrazine hydrate and KOH in diethylene glycol, first at low temperature and then at reflux (200 °C). 

O Reaction of the aldehyde or ketone with hydrazine yields a hydrazone in the normal way. 

Reaction of i6a.i7a-epoxy-2o-ketone with hydrazine S. V. Kessar AND A. L, Rampal, TetYahedron, 24 1968) 887. 

Pyrazolines can also be prepared by the oxidation of pyrazolidines. 2-Pyrazolines, which are readily obtained in the reaction of a,j -unsaturated ketones with hydrazine, also undergo nitrogen extrusion at elevated temperature usually in the presence of a basic catalyst. The reaction is believed to proceed via 1-pyrazolines. Treatment of 3,3,5-trialkyl-2-pyrazolines with lead tetraacetate followed by thermolysis affords cyclopropyl acetates ". Oxidation of certain 2-pyrazolines with manganese dioxide gives 3H-pyrazoles, which in turn produce cyclopropenes in the photolysis (equation 7). ... 

Preparation of hydrazones. It usually is not possible to obtain a hydrazone in good yield by reaction of an aldehyde or ketone with hydrazine because of extensive formation of the azine. This difficulty is circumvented by conversion to the N,N-dimethylhydrazone, followed by exchange with hydrazine. The latter reaction is conducted by refluxing the N,N-dimethylhydrazone with a 2-3 fold excess of anhydrous hydrazine. 

A frequently used method is the cyclocondensation of a-acylamino ketones with hydrazine providing 4,5-dihydro-1,2,4-triazines 27 followed by dehydrogenation to triazines 28 ... 

Reactions of a-acylenaminoketones with hydrazines afforded various substituted-pyrazoles <01JHC109>. Treatment of a-benzotriazolyl-a,P-unsaturated ketones with monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring afforded unsymmetrical l,3,5-triaryl-4-alkylpyrazolines and -pyrazoles <01JOC6787>. Cyclocondensations of diacetylenic ketones with hydrazines afforded alkynyl substituted pyrazoles <01JCS(PI)2906>. 

Another method for reducing a ketone to a methylene group is the Wolff-Kishner reduction, which involves heating the ketone with hydrazine and base. The Wolfi Kishner reduction complements the Clemmensen reduction in that it is conducted under basic conditions, whereas the Clemmensen reduction involves acidic conditions. The Wolff-Kishner reduction proceeds via a hydrazone intermediate (Section 16.8B) that is not isolated during the reaction. Ethyl phenyl ketone can be reduced to propylbenzene by the Wolfi Kishner reduction as follows, for example. 

Based on the Amaryllidaceae alkaloid galanthamine, a biomimetic solid-phase synthesis of 2527 compounds was reported by Shair and coworkers (Figure 11.13) The core scaffold, initially prepared in several steps, was diversified by means of four successive reactions Mitsunobu reaction of the phenolic moiety with five primary alcohols, Michael addition of the a, 3-unsatnrated cyclohexenone with thiols, iV-acylation or A -alkylation of the cyclic secondary amine, and treatment of the ketone with hydrazines and hydroxylamines. Further evaluation of library constituents for their ability to block protein trafficking in the secretory pathway of mammalian cells led to the discovery of sercramine as a potent inhibitor of the VSVG-GFP protein movement from the Golgi apparatus to the plasma m brane. 

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