Organic Syntheses, CV 8, 460
[Cyclohexanone, 2-(1-methyl-2-propynyl)-, (R*,R*) and (R*,S*)-]
Submitted by Valsamma Varghese, Manasi Saha, and Kenneth M. Nicholas
1.
Checked by T. V. Rajanbabu, Leslie G. Upchurch, and Bruce E. Smart.
1. Procedure
Caution! Dicobalt octacarbonyl is highly toxic and air sensitive. All operations with this reagent should be carried out in an inert atmosphere and in a well-ventilated hood.
A.
1-Trimethylsiloxycyclohexene.2 A
1-L, three-necked, round-bottomed flask is equipped with a
magnetic stirring bar, a
rubber septum, and a
reflux condenser fitted with a
nitrogen gas inlet tube that is attached to a
mineral oil bubbler. The system is flushed with
nitrogen and flame-dried, and while the system is maintained under a static pressure of
nitrogen, the flask is charged with
300 mL of dry dimethylformamide (Note
1) and
110.3 g (1.1 mol) of triethylamine (Note
2);
58.3 (0.54 mol) of chlorotrimethylsilane (Note
3) is added by syringe.
Cyclohexanone (40.0 g, 0.41 mol) (Note
4) is added and the mixture is refluxed with stirring for 48 hr. After the flask is cooled to room temperature, the contents are poured into
600 mL of pentane. The resulting mixture is transferred to a
separatory funnel and washed with three
500-mL portions of cold aqueous sodium bicarbonate. The organic layer is washed rapidly in succession with
200 mL of cold 1.5N hydrochloric acid and
200 mL of cold aqueous sodium bicarbonate. The
pentane solution is dried over
sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product is distilled through a
short Vigreux column to give
53–54 g (
76–77%) of
1-trimethylsiloxycyclohexene as a colorless liquid, bp
75–80°C (20–21 mm) (Note
5).
B.
Hexacarbonyl(1-methyl-2-propynylium)dicobalt tetrafluoroborate (1). A
2-L, two-necked, round-bottomed flask fitted with a magnetic stirring bar, a stopper, and a gas inlet T-tube that is attached to a mineral oil bubbler is flame-dried under a flow of
nitrogen. The flask is charged with
200 mL of dry dichloromethane (Note
6) and
13.0 g (0.185 mol) of 3-butyn-2-ol (Note
7). After the mixture is stirred for 15 min,
65.0 g (0.19 mol) of dicobalt octacarbonyl (Note
8) is added in portions over a few minutes while maintaining a slow stream of
nitrogen. Vigorous gas evolution (
carbon monoxide!) is observed. The mixture is stirred for 4–5 hr, and the solvent is then removed under reduced pressure (20–25 mm). The residual solid (alkyne)Co
2(CO
6) complex is dissolved in
40 mL of propionic anhydride under
nitrogen and cooled to −45°C in a
dry ice–acetonitrile bath.
Tetrafluoroboric acid–dimethyl etherate (37.3 g, 0.28 mol) (Note
9) is added with stirring. After 30 min,
600–800 mL of anhydrous diethyl ether is added with continuous stirring. The burgundy-red salt that precipitates is isolated by filtration under a flow of
nitrogen (Note
10) and is thoroughly washed with anhydrous
diethyl ether to give
60–61 g (
76–77%) of
hexacarbonyl(1-methyl-2-propynylium)dicobalt tetrafluoroborate. This material is used immediately in the following step.
C.
2-(1-Methyl-2-propynyl)cyclohexanone. A 2-L, two-necked, round-bottomed flask is equipped with a magnetic stirring bar, a stopper, and a
pressure-equalizing dropping funnel fitted with a gas inlet T-tube that is connected to a mineral oil bubbler. The flask is flushed with
nitrogen and charged with
150 mL of dry dichloromethane (Note
6) and
60.0 g (0.141 mol) of the salt from Part B. The mixture is stirred and cooled to −78°C in a
dry ice/2-propanol bath, and
23.9 g (0.141 mol) of 1-trimethylsiloxycyclohexene (Part A) is added dropwise over a few minutes. The mixture is stirred at −78°C for 4 hr. After the solution is warmed to room temperature,
dichloromethane is removed under reduced pressure and replaced with
400 mL of acetone. The dark-red solution of the alkyne complex is cooled to −78°C and
175 g (0.32 mol) of ceric ammonium nitrate (Note
11) is added in portions. The mixture is stirred until the gas evolution (
carbon monoxide!) ceases (ca. 4 hr) (Note
12). The reaction mixture is warmed to room temperature, poured into
1 L of saturated brine solution, and extracted with four
250-mL portions of diethyl ether. The combined
ether extracts are dried over
magnesium sulfate, filtered, and concentrated on a
rotary evaporator. The residual red oil is distilled at reduced pressure to afford
15.0–15.2 g (
71–72%) of
2-(1-methyl-2-propynyl)cyclohexanone as a pale-yellow liquid, bp
57–60°C (10 mm) (Note
13).
2. Notes
1.
Dimethylformamide, obtained from Aldrich Chemical Company, Inc., was vacuum distilled from
calcium hydride, bp
44°C (25 mm), and stored over Linde 3A molecular sieves.
4.
Cyclohexanone was purchased from the Aldrich Chemical Company, Inc., redistilled, and stored over Linde 4A molecular sieves.
5. The product is over 99.5% pure by GLPC (6 ft × 1/8 in. 3% SP 2100 on 100–120-mesh Supelcoport column) and has the following spectral characteristics:
1H NMR (CDCl
3) δ: 0.21 (s, 9 H), 1.55 (m, 2 H), 1.69 (m, 2 H), 2.05 (br d, 4 H), 4.88 (br s, 1 H).
7.
3-Butyn-2-ol was obtained from the Aldrich Chemical Company, Inc., and used without further purification.
8.
Dicobalt octacarbonyl was obtained from Alfa Products, Morton/Thiokol, Inc. It is best weighed in a
nitrogen-filled polyethylene glove bag or in a dry box.
10. The filtration under
nitrogen is conveniently carried out in a
Schlenk filter flask.
3
12. The disappearance of the dark red (alkyne)Co
2(CO)
6 complex can be monitored by TLC on silica gel with a 1 : 9
diethyl ether :
petroleum ether solvent mixture.
13. The product is obtained as a 2 : 1 diastereomeric mixture and is over 99% pure by GLPC (6 ft × 1/8 in. 3% SP 2100 on 100–120-mesh Supelcoport column). It has the following spectral characteristics: IR (CCl
4) 1710 cm
−1;
1H NMR (CDCl
3) δ: 0.8–2.9 (br envelope, 10 H), 1.05 (d, 3 H,
J = 7, minor diastereomer), 1.10 (d, 3 H,
J = 7, major diastereomer), 2.15 (s, 1 H, both diastereomers);
13C NMR (CDCl
3) δ: 16.3, 19.2, 24.2, 25.6, 24.7, 27.1, 28.4, 30.7, 41.7, 41.9, 54.1, 54.8, 68.2, 69.6, 86.3, 87.5, 209.7, 210.3; MS (70 eV)
m/e 150, 121 (100%).
3. Discussion
In addition to their reactions with trimethylsilyl enol ethers, (propargylium)-Co
2(CO)
6+ complexes react with a variety of other mild
carbon nucleophiles including activated aromatic compounds,
4 β-dicarbonyl compounds,
5 other enol derivatives (enol acetates and ketones directly),
6 allylsilanes,
7 and alkyl- and alkynyl-aluminum reagents.
8,9 These reactions provide a flexible means of introducing the synthetically versatile propargyl function. Key features of propargylations using these complexes are (a) ready introduction and removal of the activating and directing -Co
2(CO)
6 group, (b) regiospecific attack by nucleophiles at the carbon α to the coordinated alkynyl group, giving propargyl products only (no allenic coproducts); and (c) very mild reaction conditions and good overall yields.
The method reported here appears to be the one of choice for the dependable, efficient α-propargylation of ketones. It can be applied to propargylate ketones regioselectively at either the less substituted α-position (via the trimethylsilyl enol ether) or the more substituted α-position (using the enol acetate or even the ketone directly
6). The resulting α-propargylated ketones are very useful synthetic intermediates. They have been converted to chromanols,
10 furans,
11 other heterocycles,
11 and cyclohexenones,
12 and they undergo regiospecific hydration to 1,4-diketones that, in turn, can be converted to cyclopentenones.
13,14,15 More classical indirect ketone propargylations generally give low yields with substantial coproduction of allenic by-products, as with enamine
10,16 or acetoacetic ester propargylations.
11,17 Direct coupling of ketone enolates with propargyl halides or tosylates have rarely been attempted and can be expected to have the same limitations.
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