Org. Synth. 1968, 48, 56
Submitted by R. D. Burpitt and J. G. Thweatt1
Checked by William G. Dauben, Michael H. McGann, and Noel Vietmeyer.
To a 500-ml. round-bottomed flask
fitted with a 25- to 30-cm. column
packed with glass helices to which is attached a water separator2
filled with hexane (Note 1)
are added 126 g. (1.00 mole) of cyclooctanone (Note 2)
, 100 g. (1.4 moles) of pyrrolidine
, 100 ml. of xylene
, and 0.5 g. of p-toluenesulfonic acid
. The solution is heated under reflux until the separation of water ceases (Note 3)
. The water separator is replaced by a distillation head, and the reaction mixture is distilled through the column under reduced pressure to remove solvent and unreacted starting materials. When the head temperature reaches 50° (1 mm.), distillation is stopped, and the residue of almost pure N-(1-cycloocten-1-yl)pyrrolidine
) is used in the next step without further purification (Note 4)
The crude enamine is dissolved in 450 ml. of ether, and the solution is transferred to a 1-l. three-necked flask equipped with a sealed stirrer, a 250-ml. dropping funnel, and a two-necked adapter fitted with a calcium chloride tube and a thermometer immersed in the solution. A solution of 71–76 g. (0.85–0.90 mole) (Note 5) of methyl propiolate
(Caution! Methyl propiolate is a severe lachrymator and should be handled only in the hood.) in 150 ml. of ether is added dropwise. During the addition the temperature of the mixture is maintained at 25–30° by periodic cooling of the reaction flask in a dry ice-acetone bath. When the addition is almost complete, a white solid begins to separate. The mixture is stirred at 25–30° for an additional hour, cooled to 0°, and filtered to remove the solid. This is dissolved in 700 ml. of 6% hydrochloric acid (Note 6), the acidic solution is warmed at 55–60° for 1 hour, and the mixture is cooled and extracted with two 100-ml. portions of ether. The ether is removed on a steam bath, and the residue of crude methyl 10-oxocyclodec-2-ene-1-carboxylate is dissolved in 300 ml. of methanol and hydrogenated over 5 g. of 5% palladium-on-alumina catalyst at 40 p.s.i. pressure and room temperature.
The catalyst is filtered, 200 g. (155 ml.) of 25% aqueous sodium hydroxide is added to the filtrate, and the mixture is heated under reflux for 1 hour. The condenser is replaced by a short Vigreux column and distillation head, and the heating is continued until most of the methanol has distilled. The two-phase residue is cooled and extracted with two 100-ml. portions of ether. The ether is removed on a steam bath, and the residue is distilled through a 20-cm. Vigreux column to yield 68–77 g. (44–50%) of cyclodecanone, b.p. 94–98° (10 mm.), m.p. 20–22° (Note 7).
is not used in the trap
, an excessive amount of pyrrolidine
is lost in the aqueous layer.
Cyclooctanone from Aldrich Chemical Co.
, methyl propiolate from Farchan Research Laboratories
, and pyrrolidine from Eastman Organic Chemicals
were used as received.
The reaction is usually complete after 3–6 hours at reflux. Owing to dissolved pyrrolidine
, the aqueous layer amounts to 35–45 ml., and thus its volume is not a good measure of the extent of reaction.
, b.p. 76–78° (1 mm.)
, may be isolated by distillation through a Vigreux column.
The amount used should be adjusted to be equimolar with the amount of crude enamine.
This solid intermediate is reasonably stable to storage under nitrogen
; however, the yield in the acid hydrolysis step is better when freshly prepared material is hydrolyzed immediately.
The same reaction sequence may be used to convert cyclododecanone
. Preparation of the pyrrolidine enamine
requires 2–3 days at reflux, and reaction of the enamine with methyl propiolate
is best carried out in refluxing hexane
. The enamine-propiolate
reaction may also be used to convert cycloheptanone
. In this case the procedure must be modified to provide for partial hydrogenation of the intermediate amino ester without prior hydrolysis.3
The reduced intermediate is saponified as described in the present procedure.
has been obtained together with other products in the pyrolysis of the thorium or yttrium salts of nonanedioic acid
It has also been prepared by reduction of sebacoin
and hydrochloric acid
by dehydration of sebacoin
followed by catalytic hydrogenation,7
by ring enlargement of cyclononanone
and of cyclooctanone
in the presence of a Lewis acid catalyst,9
by hydroboration of 1,2-cyclodecadiene
followed by oxidation of the organoborane,10
and by the present procedure.3
4. Merits of the Preparation
The chief merits of this preparation are its simplicity and the high purity of the product. Although the synthesis involves several steps, each step is a simple operation, and all intermediates may be used in the subsequent steps without purification. The purity of even the crude product is high, and any impurities which may be present are readily removed by a simple distillation.
The overall yield of cyclodecanone
is comparable to the overall yield obtained by conversion of dimethyl sebacate
and subsequent reduction to cyclodecanone
In addition, the present procedure does not require the use of a high-speed stirrer, the rigorous exclusion of air, and the high dilution that are necessary in preparing sebacoin
Chemical Abstracts Nomenclature (Collective Index Number);
thorium or yttrium salts of nonanedioic acid
hydrochloric acid (7647-01-0)
sodium hydroxide (1310-73-2)
dimethyl sebacate (106-79-6)
methyl propiolate (922-67-8)
p-toluenesulfonic acid (104-15-4)
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