Checked by L. A. Stolz and Robert K. Boeckman, Jr..
1. Procedure
A.
3-Methylcyclohexanone-3-acetic acid. A
2-L, three-necked Morton flask fitted with a
low-temperature thermometer, a
250-mL addition funnel, an exit tube attached to a
calcium chloride drying tube, and a
Teflon-coated magnetic stirring bar is charged with
1.1 L of anhydrous ethanol. The stirred solution is cooled to 0°C and
23 g (1 mol) of sodium cut into small pieces is added through the exit tube. During the addition, the temperature of the reaction mixture increases; therefore, cooling is applied (Note
1). After all of the
sodium has completely reacted,
160.2 g (1 mol) of neat diethyl malonate is slowly added through the addition funnel while the temperature is maintained at 0°C (Note
2). At this point,
110.2 g (1 mol) of 3-methyl-2-cyclohexen-1-one (Note
3) is gradually introduced through the addition funnel at 0°C. A white precipitate eventually appears. After 9 days of stirring, the brown reaction mixture is poured onto ice, brought to neutrality with concentrated
hydrochloric acid while being vigorously stirred, and extracted with one
600-mL portion and four 300-mL portions of ether (Note
4). The combined organic layers are washed with three
250-mL portions of saturated brine and dried over anhydrous
magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the residual oil is distilled through a
20-cm Vigreux column under reduced pressure. The first fraction (bp <60°C at 0.15 mm) consists of a mixture of unreacted starting materials. The second fraction (bp 145–165°C at 1.5 mm), a mixture of diesters (Note
5), is a colorless oil: 202–205 g (74–76%).
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 concentrated 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 × 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-Methylbicyclo[2.2.2]octane-2,6-dione. A 2-L, three-necked, Morton 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 × 100 mL) and
brine (1 × 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 may solidify on standing at room temperature (Note
9).
C.
4-Methyltricyclo[2.2.2.03,5]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 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 × 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.
2. Notes
1. Cooling should be applied to moderate the reaction while maintaining a vigorous evolution of gas or the reaction time is prolonged unduly.
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) cm
−1: 3500–2500, 1730, 1705;
1H NMR (300 MHz, CDCl
3) δ: 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, CDCl
3) δ: 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 P
2O
5 is dissolved (ca. 6 hr).
8. Continuous extraction of the aqueous phase with
toluene can also be applied for 3 days in order to yield
80% of the diketone after Kugelrohr distillation.
9. The pure diketone is a colorless solid, mp
75–76°C; IR (neat) cm
−1: 1735, 1710;
1H NMR (300 MHz, CDCl
3) δ: 1.17 (s, 3 H), 1.67–1.73 (m, 2 H), 2.07–2.13 (m, 2 H), 2.22 (ABq, 4 H,
JAB = 8.0, Δν
AB = 35.05), 3.16 (t, 1 H,
J = 2.9);
13C NMR (75 MHz, CDCl
3) δ: 22.7, 25.7, 31.0, 33.9, 50.4, 63.4, 206.6.
10. The
1.07 M anhydrous ferric chloride solution in
dimethylformamide is prepared as follows:
178.43 g (1.1 mmol) of anhydrous solid ferric chloride is refluxed over
360 mL of thionyl chloride for 4 days at atmospheric pressure. After the solution is cooled,
thionyl chloride is removed by distillation at 20 mm and trapped in a
1-L, round-bottomed flask cooled to −78°C. The sold residue is stirred for 1 hr at room temperature under reduced pressure (ca. 20 mm) and heated at 40°C for 1 hr under high vacuum (ca. 1 mm). Drying without heating is then continued overnight under high vacuum. The flask is filled with
argon and cooled to 0°C. Approximately
600 mL of freshly distilled dimethylformamide is then slowly added (exothermic reaction). The entire dissolution of solid
ferric chloride is achieved in an
ultrasound bath during 24 hr. After decantation, the dark brown solution is transferred under
argon to a
1-L volumetric flask and the required level is adjusted with freshly distilled
dimethylformamide.
11. The checkers found that vigorous mechanical stirring was required because of the viscosity of the
dimethylformamide solution at −78°C; otherwise, diminished yields were observed.
12. The yields obtained range from
40 to 54% depending principally on the rate of the inverse addition and the scale of the reaction.
13. The tricyclic diketone, a colorless oil which slowly solidifies, exhibits mp
34.5–35.0°C; IR (neat) cm
−1: 1760, 1710;
1H NMR (300 MHz, CDCl
3) δ: 1.26 (s, 3 H), 2.00–2.06 (m, 2 H), 2.27–2.30 (m, 2 H), 2.46–2.68 (m, 1 H), 2.68 (d, 2 H,
J = 1.3);
13C NMR (75 MHz, CDCl
3) δ: 23.3, 26.6, 30.9, 47.1, 48.9, 52.6, 203.5.
3. Discussion
The intermolecular dimerization of ketone enolates to give 1,4-diketones has been accomplished earlier with cupric
5 6,7 and ferric salts.
8 These transition-metal salts have also been used to achieve intramolecular carbon–carbon bond formation.
7,9,10 However, Step C represents the only reported example
11 of cyclopropane construction via technology of this type.
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