Reduction of tosylhydrazones

Three different methods have been discussed previously (sections III-C,III-D and IV-A) for the replacement of a carbonyl oxygen by two deuteriums. However, in the conversion of a 3-keto steroid into the corresponding 3,3-d2 labeled analog, two of the three methods, electrochemical reduction (section ni-C) and Raney nickel desulfurization of mercaptal derivatives (section IV-A), lead to extensive deuterium scrambling and the third method, Clemmensen reduction (section III-D), yields a 2,2,3,3,4,4-dg derivative. 

Reduction of tosylhydrazone derivatives to the corresponding methylene analogs with metal hydride complexes provides an excellent solution to this problem. Soon after the discovery of this reaction it was recognized 

According to a detailed mechanistic study, the first step is the abstraction of the relatively acidic hydrazone proton (93- 97). This is followed by hydride attack on the trigonal carbon of the C=N bond, mainly from the a-side at C-3, together with the concomitant loss of the tosylate anion (97 - 98). Expulsion of nitrogen from the resulting intermediate (98) yields a fairly insoluble anion-metal complex (99) which upon decomposition with water provides the methylene derivative (100). 

During the course of these mechanistic studies a wide range of possible applications of this reaction have been revealed. When the reduction is carried out with lithium aluminum deuteride and the anion complex decomposed with water, a monodeuterio compound (95) is obtained in which 70% of the deuterium is in the 3a-position. Reduction with lithium aluminum hydride followed by hydrolysis with deuterium oxide yields mainly (70 %) the 3j5-di-epimer (96), while for the preparation of dideuterio compounds (94) both steps have to be carried out with deuterated reagents.  

One of the inconveniences of this method is the formation of olefinic side products, (see below) but the desired saturated compounds can be readily isolated by chromatography on silver nitrate impregnated silica gel 

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Two techniques, electrochemical reduction (section IIl-C) and Clem-mensen reduction (section ITI-D), have previously been recommended for the direct reduction of isolated ketones to hydrocarbons. Since the applicability of these methods is limited to compounds which can withstand strongly acidic reaction conditions or to cases where isotope scrambling is not a problem, it is desirable to provide milder alternative procedures. Two of the methods discussed in this section, desulfurization of mercaptal derivatives with deuterated Raney nickel (section IV-A) and metal deuteride reduction of tosylhydrazone derivatives (section IV-B), permit the replacement of a carbonyl oxygen by deuterium under neutral or alkaline conditions. 

Thus, the reduction of tosylhydrazones with sodium borodeuteride in dioxane provides only monodeuterated analogs. For the insertion of two deuteriums it is necessary to first exchange the hydrazone proton and to carry out the reduction in aprotic or deuterated solvents. Under these conditions the reduction of the tosylhydrazone derivatives of 7- and 20-keto... 

The reduction of tosylhydrazones by complex metal hydrides has been used very effectively to prepare saturated steroid hydrocarbons in high yields. ... 

The reduction of tosylhydrazones by LiAlH4 or NaBH4 also converts carbonyl groups to methylene.277 It is believed that a diimide is involved, as in the Wolff-Kishner reaction. 

Reduction of tosylhydrazones of a, (3-unsaturated ketones by NaBH3CN gives alkenes with the double bond located between the former carbonyl carbon and the a-carbon.280 This reaction is believed to proceed by an initial conjugate reduction, followed by decomposition of the resulting vinylhydrazine to a vinyldiimide. 

In keto steroids the reductions were also achieved by electrolysis in 10% sulfuric acid and dioxane using a divided cell with lead electrodes (yields 85-97%) [862], hy specially activated zinc dust in anhydrous solvent (ether or acetic anhydride saturated with hydrogen chloride) (yields 50-87%) [155, 86J], and by the above mentioned reduction of tosylhydrazones with sodium borohydride (yields 60-75%) [811]. 

An indirect method of accomplishing the reaction is reduction of tosylhydrazones (R2C=N—NHTs) to R2CH2 with NaBH4, BH3, catecholborane, bis(benzyloxy)borane. 

Deoxygenation of carbonyl compounds (6, 98 7, 54 8, 79-80). This easily prepared borane is as effective as catechol borane for reduction of tosylhydrazones of carbonyl compounds to the corresponding methylene compounds. 

The reduction of tosylhydrazones can also be performed with sodium borodeuteride in boiling methanol or dioxane, but the mechanism of this reaction (in boiling dioxane at least) is radically different from that of the lithium aluminum deuteride reductions.82 With sodium borohydride the first step is apparently hydride attack on the carbon atom of the C=N bond which is probably concerted with the elimination of the tosylate anion (110 - 111). Migration of the hydrogen from nitrogen to C-3 in (111) concerted with expulsion of nitrogen, provides the corresponding methylene derivative (100).82... 

The reduction of tosylhydrazones by complex metal hydrides has been used very effectively to prepare saturated steroid hydrocarbons in high yields.317 In certain cases this reduction (with lithium aluminum hydride) takes a different course, and olefins are formed.318 The effect is dependent on both the reagent concentration and the steric environment of the hydrazone.319 Dilute reagent and hindered hydrazone favor olefins borohydride gives the saturated hydrocarbon. The hydrogen picked up in olefin formation comes from solvent, and in full reduction one comes from hydride and the other from solvent. This was shown by deuteriation experiments with the hydrazone (150) 319... 

Reduction of tosylhydrazones Tosylhydrazones of benzoin derivatives (1) are reduced by NaBHsCN in the presence of TsOH stereoselectively to eryffcro-dia-stereomers (2) in excellent yield. 

Reduction of tosylhydrazones of conjugated acetylenic ketones with catechol-borane (1) proceeds with migration of the triple bond to give allenes. ... 

This salt is superior to sodium acetate in the reduction of tosylhydrazones with catecholborane (6, 98 7, 54). The efiect results from the increased solubility in organic solvents. ... 

The transition metal complex bis(triphenylphosphine)copper(I) borohydride, (Ph3P)2CuBH4, has also been shown to be effective for the reduction of tosylhydrazones to hydrocarbons under mild conditions (refluxing chloroform). Yields from unhindered aliphatic aldehyde and ketone tosylhydrazones are generally in the range 48-84%. Reductions of hindered ketones (e.g. camphor) and aromatic aldehydes were less successful giving 0-20% of reduced products. ... 

One successful application of cyanoborohydride reductions is the reduction of tosylhydrazones to hydrocarbons which, since its introduction in 1971, has been employed extensively for such conversions. The reductions are most often conducted in 1 1 DMFrsulfolane containing a small amount of acid at... 

In situ reduction of tosylhydrazones by NaBHjCN provides an efficient method for the deoxygenation of carbonyl compounds to furnish the corresponding hydrocarbons (see also Section 3.4). In the case of tosylhydrazones derived from a,P-unsaturated carbonyl compounds, the reduction leads to a stereoselective migration of the double bond to give the corresponding tran -alkene. 

Cleavage of tosylhydrazones, arylhydrazones, and oximes to their parent ketones simply by exchange in acetone is said to offer a mild and convenient method under non-acidic conditions. Hexadeuterioacetone affords a-deuteriated ketones. Although tosylhydrazones of saturated ketones are reduced by borohydride in methanol to give hydrocarbons, similar treatment of the tosylhydrazone of cholest-4-en-3-one gave a mixture of 3a- and 3/S-methoxycholest-4-enes, apparently through a diazonium alkoxide ion pair. The reduction of tosylhydrazones of... 

Yields by this method are higher than those obtained by reduction of tosylhydrazones with NaBH4 (2, 377-378) moreover NaBH, CN is more selective than NaBH4. 

In ether media (diethylether or THF), the nature of the reagent is ill defined. It reduces aldehydes, ketones, and acid chlorides, but leaves esters, anhydrides, and amides unchanged. In methanol, the reduction of enamines and imines to amines may be effected in the same way as the reduction of tosylhydrazones to hydrocarbons (Section 3.3.4). 

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