Angular methyl group oxidation

The oxidation of alcohols with lead tetraacetate was the first reaction used for oxygenation of an angular methyl group in steroids. It is a simple and efficient method and produces tetrahydrofuran derivatives directly from alcohols. 

The removal of angular methyl groups is important in the transformation of steroids and related compounds. In these reactions, the methyl group is oxidized to the aldehyde before fission in which the carbonyl group oxygen is retained in formate (or acetate), and one oxygen atom from dioxygen... 

Therefore, nine steps or synthetic operations are necessary in the conessine synthesis for isomerising the cir-B/C decalin system to trans-hIC, a transformation that in the cortisone synthesis is accomplished without any extra step, since it takes place spontaneously in the oxidation step, which, in turn, is necessary to introduce the second angular methyl group and build up ring D of cortisone in a stereoselective manner. Better correlation amongst different synthetic operations would be difficult to find in more recent synthesis of similar complexity and magnitude than that of Sarett. 

For the substitution of the angular methyl groups in steroids five methods are known (a) homolysis of N-chloramines [Loffier-Freytag reaction (only C-18)] (b) oxidation of alcohols with lead tetraacetate (c) photolysis of nitrite esters (d) homolysis of hypochlorites (e) the hypoiodite reaction. ... 

Methyl-2-vinylbenzofurans also undergo cycloaddition with acetylenic dienophiles, but ready aromatization of the products is blocked by the angular methyl group. It can, however, be achieved by oxidizing agents, such as selenium dioxide or chromium trioxide, or even by exposure to air (Scheme 35). Mechanisms for these reactions have been postulated. 

II. Functionalization of the Angular Methyl Groups / 237 General principles of substitution / 237 Lead tetraacetate oxidations / 240 Hypohalite reactions / 246 Photolysis of nitrites (Barton reaction) / 253 A-Chloroamine reactions (Hoffmann-Lofller reaction) / 257 Ketone irradiations / 260 Summary / 264... 

Bicyclic alcohols with angular methyl groups (11, 10-11). The reaction of 2,5-dimethylmethylenecyclopentane (1) with acrolein (1 equiv.) and (CH3)2A1C1 involves two sequential ene reactions to give the expected bicyclic alcohol 2 (69%) and in addition the corresponding ketone 3 (12% yield), even in the absence of an oxidant.6 In the presence of 2 equiv. of acrolein, the reaction results in 3 in 60% yield and only 1% of 2. Apparently, the alkoxide precursor to 2 undergoes... 

Steric Effects. Despite the fact that singlet oxygen is small, steric effects can reduce the rate of the singlet oxygen ene reaction and allow competitive reactions to occur. For example, the preferential approach to the bottom face of 8 is a result of the steric interaction with the angular methyl group on the top face of the molecule. A steric effect is also responsible for the reversal of the exojendo hydroperoxide ratio in the photo-oxidations of the norbornene derivative 11 and 12 [38,39]. 

The 16 Da loss corresponds to a methane loss observed, as for the hydrogen loss, when it produces a conjugation or aromaticity gain, especially in cyclic compounds. Thus steroids or bile salts commonly lose methane from an angular methyl group. This 16 Da loss is also observed in N-oxides and sulfoxides, and then results from an oxygen atom loss. 

Mercuric oxide-iodine. This combination has been used as a possibly superior alternative to the lead tetraacetate-iodine reagent for oxidative attack of angular methyl groups. Thus a 6j8-hydroxysteroid (1) reacts with mercuric oxide and iodine in a light-induced reaction to give the 6,19-oxide (2) through an intermediate hypoiodite. ... 

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