Birch reduction of estradiol 3-methyl ether at

Birch reduction of estradiol 3-methyl ether at 0.12M concentration, 50... 

Birch Reduction of Estradiol 3-Methyl Ether at 0.12 M Concentration32... 

A remarkable feature of the Birch reduction of estradiol 3-methyl ether derivatives, as well as of other metal-ammonia reductions, is the extreme rapidity of reaction. Sodium and -butyl alcohol, a metal-alcohol combination having a comparatively slow rate of reduction, effects the reduction of estradiol 3-methyl ether to the extent of 96% in 5 minutes at —33° lithium also effects complete reduction under the same conditions as is to be expected. Shorter reaction times were not studied. At —70°, reduction with sodium occurs to the extent of 56 % in 5 minutes, although reduction with lithium is virtually complete (96%) in the same time. (The slow rates of reduction of compounds of the 5-methoxytetralin type is exemplified by 5-methoxy-tetralin itself with sodium and f-butyl alcohol reduction occurs to the extent of only 50% in 6 hours vs. 99+% with lithium.) The iron catalyzed reaction of sodium with alcohols must be very fast since it competes so well with the rapid Birch reduction. One cannot compensate for the presence of iron in a Birch reduction mixture containing sodium by adding additional metal to extend the reaction time. The iron catalyzed sodium-alcohol reaction is sufficiently rapid that the aromatic steroid still remains largely unreduced. 

The product from Birch reduction of estradiol 3-methyl ether, nandrolone, 1-5, comprises one of the simplest androgens in the gonane series. This compound suffers extremely fast metabolic inactivation by attack at C17 most androgens consequently incorporate an additional substituent at that position. 

The sequence for preparing the first oral contraceptives thus starts by Birch reduction of estradiol 3-methyl ether (14-1) to afford the 1,4-dihydro derivative 14-2 (Scheme 4.14). The enol ether in this product is sensitive to acid, mandating that the succeeding reactions be carried out under neutral or slightly basic conditions. The hydroxyl at C17 in... 

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