Reduction of thioketals

Olefin formation by reduction of keto derivatives via tosylhydrazones, 354 Olefin formation by reduction of thioketals, 356... 

The reduction of carbonyl compounds to hydrocarbons may be achieved under acidic conditions e.g. the Clemmensen reduction with zinc and concentrated hydrochloric acid), basic conditions (e.g. the Wolff-Kishner reduction of a hydrazone with alkali) or neutral conditions (e.g. the catalytic reduction of thioketals with Raney nickel). The carbonyl group may represent the residue from an earlier step in the synthesis of a compound. 

The present preparation Illustrates a general and convenient method for a two-step deoxygenation of carbonyl compounds to olefins. Related procedures comprise the basic decomposition of p-toluenesulfonylhydrazones,2 the hydride reduction of enol ethers,3 enol acetates,9 enamines,3 3 the reduction of enol phosphates (and/or enol phosphorodlamidates) by lithium metal in ethylamine (or liquid ammonia),33 the reduction of enol phosphates by titanium metal under aprotic conditions,32 the reduction of thioketals by Raney nickel,33 and the reduction of vinyl sulfides by Raney nickel in the presence of isopropylmagnesium bromide.3 ... 

AHylestrenol (37) is prepared from (32), an intermediate in the synthesis of norethindrone. Treatment of (32) with ethanedithiol and catalytic boron trifluoride provides a thioketal. Reduction with sodium in Hquid ammonia results in the desired reductive elimination of the thioketal along with reduction of the 17-keto group. Oxidation of this alcohol with chromic acid in acetone followed by addition of aHyl magnesium bromide, completes the synthesis... 

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

However, examples of the failure of thioketals to survive lithium aluminium hydride reduction have been reported (see ref. 134). 

The selective organosilane reduction of ketone functions can be effected in the presence of a number of other functional groups including epoxides,320,366 ketals,86,367 thioketals,368 other ketones,369,370 /1-lactams,371 alkynes,372 esters,79,80,83,84,87,320,373,374 a-bromides,76,80,83 amides80,83,84,86,276,320,375... 

Treatment of a pentacyclic la, I I -(2-oxethano) thioketal steroid with excess Et3SiH/TFA causes reduction of the carbon-carbon double bonds as well as the 17-carbonyl group to give a single reaction product (Eq. 213).368 Other work utilizes trifluoroacetic acid, triethylsilane, and anisole in the presence of a catalytic amount of boron trifluoride etherate to reduce the acetyl carbonyl of a 3-acetyl-2-azetidinone derivative with a dr of 8 1 (Eq. 214).395... 

The enone (137) was allowed to react with MeMgBr—Cu2I2 complex at 0 °C to furnish the keto-ester (138), which was then reduced by NaBH4 to afford the lactone (139). On the other hand, consecutive thioketalization, desulfurization and reduction of the ester (138) gave the alcohol (140), which was allowed to react with pTsCl in pyridine to afford (141) after smooth and concomitant fragmentation. The compound (141) was converted to 5-epi-kessane (142) and dehydrokessane (143) 47). 

Reductions of keto esters to esters are not very frequent. Both Clemmensen and Wolff-Kizhner reductions can hardly be used. The best way is desulfurization of thioketals with Raney nickel (p. 130). Thus ethyl acetoacetate was reduced to ethyl butyrate in 70% yield, methyl benzoylformate (phenylglyoxy-late) to methyl phenylacetate in 79% yield, and other keto esters gave equally high yields (74-77%) [82J]. 

Lithium naphthalenide has been used for reductive lithiation of thioketals (8, 306 9, 284), but has the disadvantage that naphthalene is sometimes difficult to separate from final products of alkylation. In such cases, lithium I -(dimethylamino)-naphthalenide can be used advantageously since dimethylaminonaphlhalene is removed from reaction mixtures by extraction with dilute acid.1... 

When the carbonyl compound is sensitive to both acids and bases, or for other reasons gives poor yields in both the Clemmensen and Wolff-Kishner reductions, a recourse may be reduction of the corresponding thioacetal or thioketal with hydrogen-saturated Raney nickel (Section 11-2B) ... 

The reduction of a carbonyl group to an olefin has been accomplished by the Shapiro modification5 of the Bamford-Stevens reaction and by the hydride reduction of the corresponding enol ether,6 enol acetate,7 or en-amine.8 The nickel reduction of the thioketal has also been used successfully.9... 

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