Caution! Since hydrogen is liberated in the first step of this reaction, it should be conducted in a hood. A dry
2-l. three-necked flask is fitted with a
Trubore mechanical stirrer, an
Allihn condenser, and a
1-l. pressure-equalizing dropping funnel, the top of which is fitted with a
gas inlet tube. After
40.0 g. (1.64 g. atoms) of clean, dry magnesium ribbon (Note
1) has been placed in the flask, the system is flushed with
nitrogen and
600 ml. of anhydrous methanol (Note
2) is added. As soon as the vigorous reaction begins, the
nitrogen flow is stopped; if necessary, the reaction may be moderated by external cooling with wet towels. When the
hydrogen evolution has ceased, a slow stream of
nitrogen is passed through the reaction system and the condenser is replaced by a total condensation-partial take-off distillation head. The
nitrogen flow is stopped, and the bulk of the
methanol is distilled from the solution under reduced pressure (Note
3) with stirring while the reaction flask is heated to 50–55° with a
water bath. This distillation is stopped when stirring of the pasty suspension of
magnesium methoxide is no longer practical.
Nitrogen is readmitted to the system, and the outlet from the distillation head is attached to a small
trap containing mineral oil so that the volume of gas escaping from the reaction system can be estimated. Anhydrous
dimethylformamide (700 ml.; (Note 4)) is added to the reaction flask, and the resulting suspension is stirred vigorously while a stream of anhydrous
carbon dioxide (Note
5) is passed into the reaction vessel through the gas inlet tube attached to the dropping funnel. The dissolution of the
carbon dioxide is accompanied by an exothermic reaction with the suspended
magnesium methoxide to form a solution. When the absorption of
carbon dioxide has stopped (Note
6), the colorless solution is heated with a mantle under a slow stream of anhydrous
carbon dioxide gas until the temperature of the liquid distilling from the flask reaches 140°, indicating that the residual
methanol has been removed from the reaction mixture. The flow of
carbon dioxide is stopped, and a slow stream of
nitrogen is passed through the system while the resulting solution (Note
7) is cooled below 100° with a water bath.
Cyclohexanone (20.0 g., 0.204 mole) (Note
8) is added to the reaction mixture, and the solution is heated under reflux for 2 hours while a slow stream of
nitrogen (2–3 bubbles per second) is passed over the reaction mixture. The resulting solution is cooled first to room temperature with a water bath and then to −5° with a
dry ice-acetone bath (Note
9).
Meanwhile,
700 ml. of anhydrous methanol is placed in a
2-l. flask fitted with a gas inlet tube extending approximately 5 mm. below the surface of the
methanol and a
calcium chloride tube to protect the contents of the flask from atmospheric moisture. The
methanol is cooled with an external cooling bath prepared from ice and
calcium chloride (Note
10) and saturated with anhydrous
hydrogen chloride (Note
10) (
290–300 g. of hydrogen chloride is required). This solution is transferred to the dropping funnel by means of a gooseneck adapter and the methanolic
hydrogen chloride solution is then added, dropwise and with stirring, to the reaction flask, the temperature of the reaction being maintained at 0° ± 5° by means of a cooling bath. This addition is accompanied by the vigorous evolution of
carbon dioxide and the separation of a white solid. After the addition is complete, the reaction mixture is allowed to stand overnight at room temperature and then the bulk of the
methanol is removed from the solution by distillation under reduced pressure with stirring. During the distillation the temperature of the reaction mixture is kept below 55°. The remaining suspension is poured into a
4-l. beaker containing 1 kg. of crushed ice. The crude product separates as shiny white flakes which are collected on a filter and washed with water. A small second crop of the crude material may be obtained by cooling the aqueous filtrates to 0° overnight. The total crude product (
25–26 g.) is dissolved in
250 ml. of boiling methanol, and this solution is concentrated to 125–150 ml. and allowed to cool. The keto diester separates as flat white needles, m.p.
128–132° (Note
11), yield
19.3–19.7 g. (
44–45%). Concentration of the mother liquors affords an additional
2.2– 2.5 g. of crude product, m.p.
122–128° (Note
11).