Org. Synth. 1972, 52, 122
DOI: 10.15227/orgsyn.052.0122
REDUCTION OF KETONES BY USE OF THE TOSYLHYDRAZONE DERIVATIVES: ANDROSTAN-17 β-OL
[Androstan-17-ol, (5α, 17β)-]
Submitted by L. Caglioti
1
Checked by J. F. Moser and A. Eschenmoser.
1. Procedure
A 100-ml., round-bottomed flask equipped with a reflux condenser is charged with 1.00 g. (0.00345 mole) of 5α-androstan-17β-ol-3-one (Note 1), 0.90 g. (0.0048 mole) of tosylhydrazide (Note 2), and 70 ml. of methanol (Note 3). The mixture is heated under gentle reflux for 3 hours, then cooled to room temperature. To the solution is added 2.5 g. (0.075 mole) of sodium borohydride in small portions over one hour (Note 4) and the resulting mixture is heated under reflux for an additional 8 hours. The reaction mixture is cooled to room temperature before the solvent is removed under reduced pressure. The residue is dissolved in diethyl ether, transferred to a separatory funnel, and washed successively with water, dilute aqueous sodium carbonate, 2 M hydrochloric acid, and water. The ethereal solution is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue, 0.95 g. of white crystals (Note 5), is dissolved in about 20 ml. of a 7:3 (v/v) mixture of cyclohexane-ethyl acetate and applied to a column packed with 60 g. of silica gel (Merck, 0.05–0.2 mm.). The column is eluted with the 7:3 (v/v) cyclohexane-ethyl acetate mixture and a 200-ml. fraction is collected. Evaporation of this fraction under reduced pressure affords 0.70–0.73 g. (73–76%) of pure 5α-androstan-17β-ol. Recrystallization from aqueous methanol provides 0.64 g. of analytically pure product, m.p. 161–163°.
2. Notes
1.
5α-Androstan-17β-ol-3-one was supplied by Aldrich Chemical Co., Inc.3.
Tetrahydrofuran serves equally well as a solvent. However, the quantity of
sodium borohydride should be reduced to 1.0 g. and the isolation procedure modified in the following way. After the solution has been refluxed for 8 hours, the reaction mixture is cooled and the excess
sodium borohydride is decomposed by the slow addition of dilute
hydrochloric acid. The resulting mixture is extracted with
ether and the ethereal solution is washed as described.
4.
Because of the ready decomposition of
sodium borohydride in
methanol, the solution is maintained at room temperature during the addition of the metal hydride.
5.
The crude product is contaminated with a small amount of a more polar substance which is subsequently removed by chromatography.
3. Discussion
The preparation of 5α-androstan-17β-ol from 5α-androstan-17β-ol-3-one may be realized by classical methods such as the Wolff-Kishner or Clemmensen reduction.
This procedure illustrates a general method for the reduction of aldehyde and ketone functions to methylene groups under very mild conditions. Since strong acids and bases are not employed, this procedure is of particular importance for the reduction of ketones possessing an adjacent chiral center.
2,3 Moreover, the use of deuterated metal hydrides permits the preparation of labeled compounds.
4The reduction of the preformed tosylhydrazones with
sodium borohydride may be effected in aprotic solvents, such as
tetrahydrofuran or
dioxane.
5 The use of
lithium aluminium hydride in nonhydroxylic solvents permits the reduction of aromatic aldehydes and ketones.
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
tosylhydrazone of (+)(S)-4-methyl-3-hexanone
hydrochloric acid (7647-01-0)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether,
diethyl ether (60-29-7)
sodium carbonate (497-19-8)
sodium sulfate (7757-82-6)
cyclohexane (110-82-7)
dioxane (123-91-1)
Tetrahydrofuran (109-99-9)
lithium aluminium hydride (16853-85-3)
sodium borohydride (16940-66-2)
tosylhydrazide
ANDROSTAN-17 β-OL
Androstan-17-ol, (5α, 17β)-,
5α-androstan-17β-ol (1225-43-0)
5α-androstan-17β-ol-3-one
(+)(S)-3-methylhexane
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