Organic Syntheses, Coll. Vol. 5, p.245 (1973); Vol. 41, p.9 (1961).
To a solution of 0.200 g. (0.515 mmole) of dry dihydrocholesterol (Note 1)
in 10 ml. of methylene chloride
contained in a 50-ml. Erlenmeyer flask
is added 0.3 ml. of a catalyst stock solution containing 0.0016 ml. (0.018 mmole) of concentrated fluoboric acid (Note 2)
in 3:1 anhydrous diethyl ether-methylene chloride (Note 3)
. The solution is swirled, and a 0.45M solution of diazomethane (Note 4)
in dry methylene chloride
is added from a buret (Note 5)
at a rate of about 2 ml. per minute. The yellow color of diazomethane
disappears rapidly on contact with the reaction mixture and nitrogen
is vigorously evolved. When about 3 ml. of diazomethane
solution has been added, the reaction becomes sluggish. The yellow color persists for several minutes after the total amount of 3.9 ml. of diazomethane solution (1.76 mmoles)
has been added (Note 6)
. After 1 hour the reaction mixture is filtered to remove a small amount of amorphous polymethylene
, which is washed with methylene chloride
. The washings are combined with the methylene chloride
solution, washed with 5 ml. of saturated aqueous sodium bicarbonate
, with three 5-ml. portions of water, and dried over anhydrous sodium sulfate
. The solvent is removed on a steam bath
in a stream of nitrogen
and finally at reduced pressure. The crystalline residue of 0.207 g. (Note 7)
is recrystallized in a 10-ml. conical flask
from 1 ml. of acetone
. When the flask has cooled to room temperature, 0.5 ml. of methanol
is added, and the flask is chilled to +2° for 2 hours. The crystals are collected on a tared Hirsch funnel of 40-mm. diameter
, washed on the funnel with two 0.5-ml. portions of ice-cold methanol
, and dried for 2 hours at 40°/2 mm. The first crop of cholestanyl methyl ether
thus obtained forms large colorless glistening plates, m.p. 85.5–86° (Note 8)
. An additional 0.002 g.
of pure methyl ether adheres to the flask and spatula
and is collected by washing with acetone
. The total first crop material (0.197 g.
) represents a 95%
yield of methyl ether (Note 9)
Satisfactory material of melting point 143–143.5°
is prepared as already described,3
and dried for 2 hours at 110°/2 mm.
Commercial 50% fluoboric acid
is evaporated at 50–60°/5 mm. to afford a residue of about 11N
total acidity, which is satisfactory for use as a catalyst.
The catalyst stock solution should be freshly prepared by placing 19 ml. of anhydrous diethyl ether
in a 25-ml. volumetric flask
cooled to 0° and adding 0.133 ml. of concentrated fluoboric acid (Note 2)
. The volume is made up to 25 ml. with methylene chloride
Rigorous drying and exclusion of moisture are not necessary. The concentration of diazomethane
solutions is determined by analysis,6
using about 0.12 g. of benzoic acid
per milliliter of solution and assuming a concentration of about 0.8M
as in McKay's method.5
Solutions approximately 0.45M
are obtained by appropriate dilution.
Burets with ground-glass stopcocks
should not be used, as leaking is caused by polymethylene
formed preferentially on the ground surfaces. A buret such as "Ultramax F and P," having a stopcock of plastic material
, is satisfactory. The buret should be filled immediately before commencement of the reaction to keep the diazomethane
solution cool and thus to minimize polymerization. The technique used is very similar to that of a titration, and a number of methylations of prepared batches can be quickly performed with one filling of the buret.
Addition of a drop of catalyst stock solution after addition of diazomethane
solution is complete causes rapid disappearance of the yellow color. The yield is not affected.
The crude reaction product is slightly yellow and has a very faint ammoniacal odor. It may be dissolved in acetone
; on slow evaporation to dryness, the solution leaves large glistening transparent plates of good-quality cholestanyl methyl ether
, m.p. 83–85°
All melting points are corrected for stem exposure. Reported7
melting point 83°
The mother liquor may be evaporated to dryness and the slightly colored residue recrystallized in a 3-ml. conical flask
from 6 drops of 1:1 acetone-methanol
. The resulting large plates are easily transferred to a small Hirsch funnel and washed with 5 drops of methanol
. This second crop of colorless methyl ether amounts to 0.010 g.
, m.p. 78.5–79.5°
4. Merits of Preparation
The present procedure is illustrative of the utility of the general method for preparation of methyl ethers from diazomethane
and alcohols with fluoboric acid
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