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In a 2-L, one-necked, round-bottomed flask fitted with a magnetic stirring bar is placed 99 g (0.366 mol) of the diesters. A 1.0-M solution of potassium hydroxide (750 mL, 0.75 mol) is added to the flask with stirring. The mixture is stirred overnight and subsequently heated to reflux for 1 hr. After the mixture is cooled, it is acidified with 100 mL of concd hydrochloric acid and gently boiled for 20 min. Following return to room temperature, the mixture is transferred to a 2-L separatory funnel and extracted with dichloromethane (6 x 100 mL). The combined organic layers are washed with saturated brine (100 mL) and dried over sodium sulfate. The solvent is removed in a rotary evaporator and the residue is distilled in a Kugelrohr apparatus (140-160°C and
0.3-0.5 mm) to provide 49.3 g (79%) of the keto acid (Note 6).
B. 4-Methylbicydo[2.2.2]octane-2,6-dione. A 2-L, three-necked, Morion flask fitted with a mechanical stirrer, a thermometer, and a reflux condenser, is charged with
245.0 g of polyphosphoric acid (PPA, Note 7), 26.8 g (158 mmol) of the keto acid, and 427 mL of glacial acetic acid. The vigorously stirred mixture is heated at 100°C for 7 hr. After being cooled, the reaction mixture is diluted with 500 mL of saturated brine and extracted with four 200-mL portions of benzene (Note 8). The combined organic layers are washed with saturated sodium bicarbonate (4 x 100 mL) and brine (1 x 100 mL) solutions, and dried over anhydrous magnesium sulfate. After removal of the solvents on a rotary evaporator, the viscous residue is distilled under reduced pressure in a Kugelrohr apparatus, affording 11.0-13.3 g (46-55%) of cyclized diketone as a colorless liquid, bp 100°C at 0.1 mm, which on standing at room temperature may solidify (Note 9).
C. 4-Methyltricydo[2.2.2.03-s]octane-3,5-dione. A 500-mL, one-necked, round-bottomed flask fitted with a Teflon-coated magnetic stirring bar and a rubber septum is charged under nitrogen with a solution of 30.8 mL (220 mmol) of dry diisopropylamine in 170 mL of anhydrous tetrahydrofuran. The solution is cooled to 0°C (acetone-dry ice bath) and 137.5 mL (220 mmol) of a 1.6 M solution of n-butyllithium in hexanes is introduced over a 35-min period. The resulting colorless solution is stirred for 15 min at 0°C and then cooled to -78°C.
The diketone (15.20 g, 100 mmol) is dissolved in 27 mL of dry tetrahydrofuran in a 50-mL, round-bottomed flask and added dropwise through a 16-gauge cannula (nitrogen pressure) during 35 min to the lithium diisopropylamide solution. This mixture is stirred for 30 min at -78°C and is added in turn to 280.4 mL (300 mmol) of a
1.07 M solution of anhydrous ferric chloride (Note 10) in dry dimethylformamide diluted with 39 mL of dry dimethylformamide and contained in a 1-L, three-necked, round-bottomed flask equipped with an efficient mechanical stirrer and cooled to -78°C (Note 11). This addition is accomplished as rapidly as possible through an 8-gauge cannula
(nitrogen pressure). After the reaction mixture is stirred for 2 hr at -78°C, it is quenched by the dropwise addition of 24 mL of dry methanol and allowed to reach room temperature. Saturated brine (300 mL) is added and the entire mixture is filtered through Celite. The aqueous phase is extracted with four 250-mL portions of ether. The combined organic layers are washed with saturated brine (3 x 150 mL) and dried over anhydrous magnesium sulfate. After solvent evaporation under reduced pressure, the residue is chromatographed (100 g of TLC grade silica gel; eluant is 15% ethyl acetate in petroleum ether). There is isolated 6.4-6.5 g (43%, Note 12) of the cyclized diketone as a colorless oil (Note 13) and 1.11 g (7.3%) of starting material.
1. Cooling should be applied to moderate the reaction while maintaining a vigorous evolution of gas or the reaction time is prolonged unduly.
2. Cooling below 0°C will induce precipitation of the sodium diethyl malonate.
3. 3-Methyl-2-cyclohexen-1-one can be purchased from the Aldrich Chemical Company, Inc. or prepared according to a known procedure.2 Checkers obtained material from Aldrich Chemical Company, Inc. and Lancaster Synthesis, Inc.
4. The checkers employed 600 mL of ether in the first extraction to ensure separation of the phases.
5. According to the literature,3 these esters consist of the product of Michael addition to 3-methylcyclohexenone and of an isomer arising from rearrangement of this primary adduct.
6. The keto acid exhibits the following spectral properties: IR (neat) cnri: 3500-2500, 1730, 1705; 1H NMR (300 MHz, CDCI3) 8: 1.07 (s, 3 H), 1.61-1.77 (m, 2 H), 1.77-1.97 (m, 3 H), 2.14-2.44 (m, 5 H), 8.4-10 (br s, 1 H); 13C NMR (75 MHz, CDCI3) 8: 21.8, 25.3, 35.7, 38.0, 40.7, 45.4, 53.0, 176.9, 179.7.
7. Polyphosphoric acid can be prepared by the addition of 200 g of phosphorus pentoxide (P2O5) to 100 mL of an 85% solution of phosphoric acid and heating to 170°C with vigorous stirring until all of the P2O5 is dissolved (ca. 6 hr).