Reduction to ethers

The application of the Birch reduction to ethers of estradiol by A. J. Birch opened up the area of 19-norsteroids to intensive research. The major Birch reduction product is an enol ether which affords either a 3-keto-A -or a 3-keto-A -19-norsteroid depending upon the hydrolysis conditions. Various 19-norsteroids have been found to have useful clinical activity compounds (30), (31), and (32) are oral contraceptive agents and compound (33) has been used as an oral anabolic agent. Several of these compounds were prepared on an industrial scale for a number of years by the Birch reduction of estradiol derivatives. 

Reduction to ether 16 To iodoalkene 87 To methylene 87 Kulinkovich cyclization 197... 

The reductions are exothermic and are generally completed within a few hours. In addition to the metal powder, one or more moles of alkali salt are generated. Convenient systems of reducing agents and solvents include potassium and THF, sodium and 1,2-dimethoxyethane (DME), and sodium or potassium with benzene or toluene. For many metal salts, solubility considerations restrict reductions to ethereal solvents. Also, for some metal salts, reductive cleavage of the ethereal solvents requires reductions in hydrocarbon solvents such as benzene or toluene. This is the case for Al, In, and Cr. When reductions... 

With higher alcohols, the formation of the ether becomes negligible, the reaction being limited almost entirely to reduction to the hydrocarbon. 

Reduction to hydroquinone. Dissolve, or suspend, 0-5 g. of the quinone in 5 ml. of ether or benzene and shake vigorously with a solution of 1 0 g. of sodium hydrosulphite (Na2S204) in 10 ml. of N sodium hydroxide until the colour of the quinone has disappeared. Separate the alkaline solution of the hydroquinone, cool it in ice, and acidify with concentrated hydrochloric acid. Collect the product (extract with ether, if necessary) and recrystalhse it from alcohol or water. 

LiAlH —(C2H )2NH. The use of BH or LiAlH —BE 0(C2H )2 as a reducing reagent converts esters to ethers. Thus, reduction of esters can be manipulated by the judicious selection of metal-containing reducing reagents. 

The o-nitrobenzyl and p-nitrobenzyl ethers can b prepared and cleaved by many of the methods described for benzyl ethers. The p-nitrobenzyl ether is also prepared from an alcohol and p-nitrobenzyl alcohol (trifluoroacetic anhydride, 2,6-lutidine, CH2CI2, 67% yield). In addition, the o-nitrobenzyl ether can be cleaved by irradiation (320 nm, 10 min, quant, yield of carbohydrate " 280 nm, 95% yield of nucleotide ). The p-nitrobenzyl ether has been cleaved by electrolytic reduction (—1.1 V, DMF, R4N X, 60% yield) and by reduction with Na2S204 (pH 8-9, 80-95% yield). These ethers can also be cleaved oxidatively (DDQ or electrolysis) after reduction to the aniline derivative. ... 

Capaurine, Ci,Hj2N(OH)(OMe)4. (Items 9, 16, 17, 22 list, p. 170.) M.p. 164°. Yields an 0-methyl ether, m.p. 152°, which on oxidation by iodine to the quaternary iodide, followed by reduction to the tetrahydro-base forms capauridine methyl ether, m.p. 142° capauridine must therefore be dZ-capaurine. Capaurine ethyl ether, C23H29O5N, m.p. 134°, on oxidation furnishes 3-ethoxy-4 5-dimethoxyphthalic acid. The methyl ether on oxidation by potassium permanganate gives hemipinic acid... 

The hydrogenation of 5a-cholestanone (58) in methanolic hydrobromic acid over platinum gives 3j5-methoxycholestane ° (61). This compound is also obtained from the palladium oxide reduction of (58) in methanol in the absence of acid. Hydrogenation of 5 -cholestanone also gives the 3j5-methoxy product under these conditions. Reduced palladium oxides are quite effective for the conversion of ketones to ethers. The use of aqueous ethanol as the solvent reduces the yield of ether. Ketals are formed on attempted homogeneous hydrogenation of a 3-keto group in methanol. ... 

Although crude cyanoamidine (10) can be used for many reactions, reduction to the 2-formyl-A-norsteroid (11) is most satisfactory when purified material is employed. The crude cyanoamidine is stirred for about 15 min with boiling toluene (120 ml/g of steroid) to effect dissolution, the hot solution is filtered quickly through fluted paper, and the filtrate is cooled and diluted with an equal volume of petroleum ether. The mixture is cooled for 0.5 hr in ice, affording from 25 g of crude material about 18 g of colorless 2a-(A-pyrrolidinylcyanoiminomethyl)-A-nor-5a-androstan-17 -ol (10) mp 252-255° (anal, sample mp 262-263°, from benzene-hexane 250 m ... 

Similarly, trimethylsilyl inflate can be used as a catalyst for the alkylation of 2 methoxy 1,3-oxazolidines [104] or 1-acetoxyadamantane [105] with allylsilane and for the reduction of acetals to ethers with trialkylsilanes [106]... 

The ethers (40) are hydrolyzed in high yields, by boiling water (4 hr), to 4-hydroxyquinazoline 1-oxide, and their structures were deduced by methylation followed by reduction to 3-methyl-4(3H)-quinazolinone (Scheme 6). These N-1 oxides show the typical reac-... 

Freshly distilled decahydronaphthalene was used. With the more easily reduced halides, and where the boiling point of the neutral reduction product was close to that of decahydronaptha-lene, an excess of 2-propanol was used as the reaction medium. Other hydrocarbons and secondary or tertiary alcohols may be employed for convenience in particular reductions. Diethyl ether and tetrahydrofuran were not found to be generally suitable media. 

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