Checked by Naoki Hirayama and Hisashi Yamamoto.
1. Procedure
A.
3-Chloro-5,5-dimethylcyclohex-2-en-1-one (
1)
3,4 (Note
1). An
oven-dried, 250-mL, one-necked, round-bottomed flask is equipped with a
magnetic stirring bar and graduated
addition funnel topped with a
nitrogen inlet. The flask is charged with
dimedone (28.1 g, 200 mmol) and
toluene (100 mL) (Note
2). The suspension is stirred while
oxalyl chloride (35 mL, 400 mmol) is slowly added via the addition funnel over a 10-min period (Note
3). After the addition is complete and gas evolution has subsided, the addition funnel is quickly exchanged for a
reflux condenser topped with a nitrogen inlet. The mixture is then heated at 60–70°C for 30 min, or until no more suspended
dimedone remains and gas evolution has ceased. (Additional
oxalyl chloride may be added until
dimedone has completely reacted.) The reaction is allowed to cool and concentrated by rotary evaporation at reduced pressure. The crude red oil is distilled through a short path apparatus to give
3-chloro-5,5-dimethylcyclohex-2-en-1-one (
1) (
29.3 g,
93% yield) as a colorless oil, bp
68–71°C (6.0 mm) (Note
4).
B.
1,4-Dilithiobutane (
2).
5,6,7 (All transfers are conducted under dry
nitrogen; reagents are introduced into reaction vessels through rubber septa using a
cannula or
syringe.) An
oven-dried, 1-L, three-necked, round-bottomed flask is equipped with a large magnetic stirring bar and glass beads (ca. 3-mm diameter), graduated addition funnel, stopper, and large diameter
nitrogen inlet (at least 2 mm in diameter). The flask is purged with
nitrogen, charged with anhydrous
diethyl ether (250 mL) (Note
2), and cooled to 0°C. The stopper is removed from the flask and replaced with a conical funnel while a rapid flow of dry
nitrogen is passed through the flask.
Lithium wire, 1% Na (9.48 g, 1.36 mol, 4.5 eq.) (Note
5), prewashed with hexanes, is held with forceps over the funnel and cut with clean scissors into pieces no larger than 2 mm in length (Note
6) so that the freshly cut
lithium pieces drop directly into the anhydrous
ether.
1,4-Dichlorobutane (33.5 mL, 300 mmol) (Note
2) is then dissolved in anhydrous
diethyl ether (85 mL) and introduced into the addition funnel; approximately 10% of this solution is introduced into the
lithium/
ether suspension, and the reaction is initiated by vigorous stirring. A white precipitate (LiCl) signaling initiation of the reaction should be apparent within 5 to 15 min, at which time the remainder of the solution is added dropwise over a 1 to 2-hr period (Note
7). The white suspension is rapidly stirred for 20 hr at 0°C.
The mixture is most conveniently filtered by gravity filtration through an
oven-dried coarse (15 μM) sintered glass frit (Note
8), (Note
9). The concentration of
1,4-dilithiobutane (
2) in ether is determined by titration with
sec-butyl alcohol using
1,10-phenanthroline as indicator. The molarity of the solution obtained under these optimized conditions is approximately 1.7 M in "RLi", i.e., 0.9 M in
1,4-dilithiobutane (
2) (Note
10). This solution is stable for several months when stored at −10°C under
nitrogen.
C.
9,9-Dimethylspiro[4.5]decan-7-one (
3).
6,7 (All transfers are conducted under dry
nitrogen; reagents are introduced into reaction vessels through rubber septa using a cannula or syringe.) An
oven-dried, 2-L, three-necked, round-bottomed flask is equipped with a graduated addition funnel, overhead
mechanical stirrer, and a
nitrogen inlet. The flask is purged with
nitrogen and charged with
copper(I) thiophenoxide (36.7 g, 212 mmol) and anhydrous
tetrahydrofuran (400 mL) (Note
2), and the heterogeneous suspension is mechanically stirred while cooling in a −78°C cold
bath (dry ice-acetone).
1,4-Dilithiobutane (
2), 0.87 (± 0.02) M in
diethyl ether (122 mL, 106 mmol) is added via the addition funnel over 5 min, and then the reaction mixture is allowed to slowly warm to −15°C (Note
11) over a 20 to 45-min period, during which time the initial yellow color changes to brown-red with concomitant dissolution of
copper thiophenoxide. The addition funnel is washed with a few milliliters of anhydrous
tetrahydrofuran, and a solution of
3-chloro-5,5-dimethylcyclohex-2-en-1-one (1) (15.85 g, 100 mmol) in anhydrous
tetrahydrofuran (250 mL) is added dropwise over a 1 to 2-hr period, while the temperature of the cold bath is maintained at −15°C to −20°C. The reaction turns olive-green and then black as the
chloroenone is added. After the addition is complete, the cold bath is removed and the reaction flask is allowed to warm to room temperature.
After 30 to 45 min, the reaction mixture is opened to the air and poured into approximately
500 mL of saturated aqueous ammonium chloride solution, diluted with approximately
500 mL of diethyl ether washings, and allowed to stir for 10 to 15 min. The resulting mixture is filtered through a
Büchner funnel, washing with small portions of
diethyl ether (Note
12). The layers are separated in a
separatory funnel, the aqueous layer is extracted with
diethyl ether, and the combined organic layers are washed with water, saturated aqueous
sodium bicarbonate, and saturated aqueous
sodium chloride, dried over approximately
100 g of sodium sulfate, filtered through a Büchner funnel, and concentrated by rotary evaporation. The concentrated product may still contain solid
diphenyl disulfide that can now be efficiently removed by chromatography of the neat crude product mixture through a
5-cm diameter × 10-cm height silica gel column and elution with
hexane-
diethyl ether (7:1) (Note
13). Evaporation of solvent by rotary evaporation at reduced pressure gives
13.28 g (
74% yield) of
9,9-dimethylspiro[4.5]decan-7-one (
3) as a pale yellow to colorless oil (Note
14).
2. Notes
1. This procedure is identical to that originally published by Heathcock and Clark,
3,4 except that
toluene has been substituted for
benzene and
chloroform as the solvent, because of the relative health hazards associated with the latter two solvents.
2.
Dimedone, oxalyl chloride, 1,4-dichlorobutane, and copper thiophenoxide were purchased from Fluka Chemical Corporation, and were used without further purification. The checkers purchased
dimedone, oxalyl chloride and 1,4-dichlorobutane from Nacalai Tesque, Inc., Kyoto, Japan and Tokyo Kasei Kogyo Co., LTD, Japan, and prepared
copper thiophenoxide from
thiophenol and
copper(I) oxide.
Toluene,
diethyl ether and
tetrahydrofuran were distilled from
sodium-benzophenone ketyl immediately prior to use.
3. The addition of
oxalyl chloride was accompanied by much gas evolution, but no apparent exothermic reaction. Two equivalents of
oxalyl chloride were required in order to consume completely the
dimedone.
3,4
4. The spectral properties of
1 were as follows:
1H NMR (400 MHz, CDCl
3) δ: 1.10 (s, 6 H), 2.26 (s, 2 H), 2.57 (d, 2 H, J = 1.4), 6.23 (t, 1 H, J = 1.4); IR (film) cm
−1: 2980 (m), 1680 (s), 1616 (m), 1346 (m), 1300 (m), 1276 (m), 1008 (m). The submitters obtained
30.1 g (
95% yield) of
1, bp
79–80°C (7.5 mm).
5.
Lithium wire was obtained from Aldrich Chemical Company, Inc. The use of 4.5 equiv of
lithium represented a 12.5% excess. The use of only 4 equiv of
lithium gave a lower titer of
1,4-dilithiobutane (
2), and a small amount of unreacted
lithium always remained even after prolonged reaction times.
7. We have not yet observed an exothermic reaction in the initiation of this reaction, although maintaining the temperature at 0°C might help to control safely the lithiation reaction as well as to maximize the yield of
1,4-dilithiobutane (
2).
8. Gravity filtration was preferred over vacuum filtration, since the latter method tended to pull LiCl through the frit. Small amounts of LiCl did not interfere with the formation or reaction of the biscuprate generated in Section C. The checkers used this solution without filtration.
9. In order to quench the small amount of unreacted
lithium wire remaining in the reaction flask, the stopper was replaced by a reflux condenser open to the atmosphere at the top. Approximately
100 mL of diethyl ether was added to the reaction flask containing the
lithium and the flask was cooled to 0°C under a stream of
nitrogen. A 4:1 mixture of
t-butyl alcohol : water was then added dropwise via the addition funnel until all of the
lithium wire was consumed.
Caution: The quench is exothermic and is accompanied by the evolution of large amounts of hydrogen gas. The mixture was then transferred to a separatory funnel for separation of the organic and aqueous layers followed by disposal.
10. Significant amounts of
ether solvent are lost presumably by evaporation during the
nitrogen flush and/or filtration steps. Thus, the molarity of the
1,4-dilithiobutane (
2) solution is not an accurate indication of yield. The submitters titrated with
menthol instead of with
sec-butyl alcohol
11. Temperature control of the cold bath at −15°C was accomplished by addition of small amounts of dry ice to
acetone and monitoring with a low-temperature
thermometer. A slurry of dry ice in
ethylene glycol was occasionally used as a −15°C cold bath.
12. The omnipresent solid contaminant was
diphenyl disulfide, which was sparingly soluble in
diethyl ether. Each filtration noted in the text was necessary for a successful workup on this large scale. The submitters used a medium (90 μm) sintered glass frit for these filtrations. The attempted removal of product
3 by distillation from
diphenyl disulfide was largely unsuccessful because of efficient entrainment of
3 in
diphenyl disulfide.
13. Pure
3 is best obtained by chromatography. Product
3 could also be purified by vacuum distillation through a
10-cm Vigreux column, bp
100–103°C (2.2 mm). However, distillation did not efficiently separate
3 from
diphenyl disulfide, and bumping was often a serious problem.
14. The spectral properties of
3 were as follows:
1H NMR (400 MHz, CDCl
3) δ: 1.02 (s, 6 H), 1.42–1.68 (m, 8 H), 1.70 (s, 2 H), 2.18 (s, 2 H); IR (film) cm
−1: 2950 (s), 1710 (s), 1450 (m), 1370 (m), 1280 (m), 1230 (m). The submitters obtained
13.01 g (
72% yield) of
3.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The procedure in Section C is representative of the synthesis of spirobicyclic systems featuring the reaction of bis(nucleophile) reagents with geminal bis(electrophile) acceptors. This strategy provides for formation of both carbon-carbon bonds of the new ring in a single step.
The formation of
1,4-dilithiobutane (2) was first described by West and Rochow.
9 The original procedure was modified by Whitesides, et al., in their pioneering studies on the synthesis and reactivity of metallocyclopentanes.
5,10 The methodology described in Section B is general for the synthesis of a variety of 1,4- and 1,5-dilithioalkanes, as evident in the Table below.
6,7
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