Organic Syntheses, CV 9, 9
Submitted by Reuben D. Rieke, Tse-Chong Wu, and Loretta I. Rieke
1.
Checked by Katsutaka Yasue and Hisashi Yamamoto.
1. Procedure
A.
Active calcium. Freshly cut
lithium (41.7 mg, 6.01 mmol) and
biphenyl (1.020 g, 6.61 mmol) in freshly distilled
tetrahydrofuran (THF, 15 mL) (Note
1) are vigorously stirred at room temperature under
argon (Note
2) until the
lithium is completely consumed (approx. 2 hr). The preformed
lithium biphenylide is transferred via a
cannula at room temperature to a well-dispersed suspension of
calcium bromide (CaBr2, 1.213 g, 6.07 mmol) (Note
3) in freshly distilled
THF (15 mL). The reaction mixture is stirred for 1 hr at room temperature prior to use (Note
4).
B.
1-(1-Adamantyl)cyclohexanol. Activated
calcium prepared from preformed
lithium biphenylide and excess CaBr
2 in THF is cooled to −78°C (Note
5).
1-Bromoadamantane (543 mg, 2.52 mmol) (Note
6) in
THF (10 mL) is added via a cannula at −78°C and the mixture is stirred at −78°C for 20 min (Note
7). Excess
cyclohexanone (520 mg, 5.30 mmol) is added via a disposable syringe at −78°C. The resulting mixture is gradually warmed to −20°C and stirred at −20°C for 30 min. The reaction mixture is then quenched with water at −20°C (20 mL) and warmed to room temperature. At this temperature it is filtered through a small
pad of Celite which is washed with
diethyl ether (Et2O, 100 mL). The aqueous layer is extracted with Et
2O (3 × 50 mL). The combined organic phases are washed with water (15 mL) and dried over anhydrous
magnesium sulfate (MgSO
4). Removal of the solvent and flash-column chromatography on
silica gel (150 g, 230–400 mesh, eluted sequentially with hexane/EtOAc [0% to 15%]) affords reasonably pure
1-(1-adamantyl)cyclohexanol as a white solid.
1-(1-Adamantyl)cyclohexanol is recrystallized from hexanes as follows: The white crystals are dissolved in a limited amount of
dichloromethane (CH
2Cl
2),
hexane (15 mL) is added, the solvent is evaporated to 8 mL, more
hexane (15 mL) is added, the solvent is evaporated to about 15 mL, and the solution is gradually cooled and allowed to stand for 24 hr to afford
469–476 mg (
80–82% yield) of product as colorless needles, mp
169–171°C (Note
8),(Note
9).
2. Notes
1.
Lithium was weighed out and charged into reaction
flasks under
argon in a Vacuum Atmospheres Company dry box. (The checkers did not use a dry box:
Lithium was freshly cut in air, rinsed in
hexane, and charged into reaction flasks under
argon.)
Biphenyl was purchased from Aldrich Chemical Company, Inc. Tetrahydrofuran anhydrous, 99.9% purity, was purchased from Aldrich Chemical Company, Inc. It was freshly distilled over Na/K alloy under
argon before use.
2. All glassware, syringes, needles, and cannulas were kept in a 120°C
oven overnight prior to use. All manipulations were carried out on a dual manifold vacuum/argon system. The Linde prepurified grade
argon was further purified by passing it through a 150°C catalyst
column (BASF R3-11), a
phosphorus pentoxide column, and a
column of granular potassium hydroxide. (The checkers used
argon as received.)
3.
Anhydrous calcium(II) bromide was purchased from Cerac, Inc. Commercially available reagents were used as received unless specially noted.
4. Good stirring is important for the preparation of highly reactive
calcium. A
Schlenk tube is better than a flask for the reactor. Excess
calcium salt was present during the oxidative addition reaction with
1-bromoadamantane.
5. Low-temperature reactions were performed using a
Neslab endocal ULT-80 refrigerated circulating bath or a
dry ice/acetone bath.
7. The reaction was checked by GC; all the starting material was consumed.
8. Melting points were determined on a
Thomas Hoover melting point apparatus or an
Electrothermal melting point apparatus and are corrected.
IR spectra were taken on an
Analect RFX-30 FTIR spectrophotometer neat between NaCl or KBr plates or as KBr disks.
1H NMR spectra were recorded on a
Nicolet NT-360 (360 MHz) or on a
Varian VXR-200 (200 MHz) spectrometer. All chemical shifts are reported in parts per million (δ) downfield from internal
tetramethylsilane. Fully decoupled
13C NMR spectra and DEPT experiments were recorded on a
Varian VXR-200 (50 MHz) spectrometer. The center peak of CDCl
3 (77.0 ppm) was used as the internal reference.
9. The physical properties are as follows: IR (KBr) cm
−1: 3465, 2931, 2902, 2844, 1448, 1344, 980, 955, 935;
1H NMR (200 MHz, CDCl
3) δ: 0.95–2.05 (m, 26 H);
13C NMR (50 MHz, CDCl
3) δ: 21.9, 26.0, 28.7, 29.8, 35.8, 37.3, 39.1, 74.6; MS (EI) m/e (relative intensity) 234 (M
+, 0.2), 135 (26.0), 98 (100.0); HRMS calcd for C
16H
26O m/e 234.1984, found m/e 234.1982. Anal. Calcd: C, 81.99; H, 11.18. Found: C, 82.13; H, 11.41.
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The development of organocalcium chemistry has been slow compared with the extensive studies of organometallic reagents of other light metals,
2 due in part to the lack of a facile method of preparing organocalcium compounds. Direct oxidative addition to
calcium has been limited by the reduced reactivity of
calcium metal with organic substrates, presumably because of surface poisoning. The organocalcium derivatives RCaX were formed most readily when X = I; the preparation of RCaX (X = Br, Cl) usually required activated
calcium. Few examples have been reported and overall yields tend to be low.
2 Although simple primary and secondary alkyl iodides react with
calcium in reasonable yields,
3 4 tertiary alkyliodocalcium compounds are very difficult to prepare and most workers have reported only trace amounts.
5 6 In contrast, the highly reactive
calcium complexes reported here react readily with all these substrates to generate excellent yields of the corresponding organocalcium compounds.
Highly reactive
calcium can be readily prepared by the reduction of
calcium halides in
tetrahydrofuran solution with preformed
lithium biphenylide under an
argon atmosphere at room temperature.
7 This colored
calcium species seems to be reasonably soluble in THF. However, the reactive
calcium complex prepared from preformed
lithium naphthalenide was insoluble in THF solution and precipitated out of solution to give a highly reactive black solid. The exact nature of this black
calcium complex has not been determined. Acid hydrolysis of the black material releases
naphthalene as well as THF. Accordingly, the most likely structure of the black material is a Ca-naphthalene-THF complex similar in nature to the soluble magnesium-anthracene complex recently reported.
8 9 10 11
Highly reactive
calcium was prepared by the
lithium biphenylide reduction of
calcium salts in THF. Both CaBr
2 and CaI
2 generate the reactive
calcium species. The organocalcium compounds, prepared directly from this
calcium complex and organic halides, were found to undergo Grignard-type reactions efficiently. Alkyl bromides and alkyl chlorides reacted rapidly with the calcium complex at temperatures as low as −78°C.
1-Chlorooctane gave
1-octylcyclohexanol in
83% yield.
7 Similar results were noted for secondary halides.
Bromocyclohexane reacted readily with the calcium species at −78°C and the resulting organocalcium reagent underwent carbonyl addition to give the alcohol in 75% yield. Significantly, the highly reactive
calcium complex reacted rapidly with tertiary bromides at −78°C. For example, the Grignard-type reaction of
1-bromoadamantane with the reactive
calcium afforded
1-(1-adamantyl)cyclohexanol in
80% yield. The direct reaction of
1-bromoadamantane with metals is known to yield mainly reductive cleavage or dimerization.
12 Accordingly, this method represents a significant new approach to the
1-metalloadamantane.
Reactions of aryl halides with the reactive
calcium required slightly higher temperatures, up to −30°C for aryl bromides and up to −20°C for aryl chlorides.
7 Surprisingly, the active
calcium reacted readily with
fluorobenzene at room temperature to form the corresponding organocalcium reagent in near quantitative yield.
Addition of copper(I) salts to the organocalcium reagents form novel organocalcium
copper reagents that cross-couple with acid chlorides to yield ketones, and undergo conjugate addition to α,β-unsaturated ketones. The highly reactive
calcium also reacts readily with 1,3-dienes to form bisorganocalcium complexes. Reaction of these
calcium reagents with biselectrophiles generates a wide variety of complex cyclic hydrocarbons.
7
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