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DOI:10.15227/orgsyn.070.0204

Organic Syntheses, Coll. Vol. 9, p.350 (1998); Vol. 70, p.204 (1992).

SPIROANNELATION VIA ORGANOBIS(CUPRATES): 9,9DIMETHYLSPIRO[4.5]DECAN-7-ONE[Spiro[4.5]decan-7-one, 9,9-dimethyl-]

Submitted by Paul A. Wender12, Alan W. White1, and Frank E. McDonald2.
Checked by Naoki Hirayama and Hisashi Yamamoto.

1. Procedure
Note: All reactions should be conducted in an efficient fume hood.
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 theaddition 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 andgas evolution has ceased. (Additional oxalyl chloride may be added until dimedone has completelyreacted.) 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-en1-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 indiameter). 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 arapid 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 inanhydrous diethyl ether (85 mL) and introduced into the addition funnel; approximately 10% of thissolution 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 whitesuspension 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 determinedby 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 1,4dilithiobutane (2) (Note 10). This solution is stable for several months when stored at −10°C undernitrogen.
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 ovendried, 2-L, three-necked, round-bottomed flask is equipped with a graduated addition funnel, overheadmechanical 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 theheterogeneous 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 concomitantdissolution 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) inanhydrous 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 thechloroenone is added. After the addition is complete, the cold bath is removed and the reaction flask isallowed to warm to room temperature.
After 30 to 45 min, the reaction mixture is opened to the air and poured into approximately 500 mLof 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 washedwith water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried overapproximately 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 ofsolvent 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 thedimedone.3,4
4. The spectral properties of 1 were as follows: 1H NMR (400 MHz, CDCl3) δ: 1.10 (s, 6 H), 2.26 (s, 2H), 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.
6. The lithium wire must be freshly cut and in pieces not exceeding 2 mm in length. The yield dropped
sharply when the average length of lithium wire was increased to 5 mm. The preparation of 1,4dilithiobutane (2) from 1,4-dichlorobutane failed with the use of lithium shot5 or low-sodium (<0.8%Na) lithium wire.
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 tomaximize 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, thestopper was replaced by a reflux condenser open to the atmosphere at the top. Approximately 100 mL ofdiethyl 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 theaddition funnel until all of the lithium wire was consumed. Caution: The quench is exothermic and isaccompanied by the evolution of large amounts of hydrogen gas. The mixture was then transferred to aseparatory 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 accurateindication 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 ofdry 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. Thesubmitters 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 efficiententrainment 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, CDCl3) 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.

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 procedure in Section C is representative of the synthesis of spirobicyclic systems featuring thereaction of bis(nucleophile) reagents with geminal bis(electrophile) acceptors. This strategy provides forformation of both carbon-carbon bonds of the new ring in a single step.
The starting material 3-chloro-5,5-dimethylcyclohex-2-en-1-one (1) is easily synthesized fromdimedone by the general methodology developed by Clark and Heathcock.3,4 The β-chlorine can also bereplaced with a variety of carbon- and heteronucleophiles,8 and β-chloroenones can be easily reduced byzinc/silver couple to the corresponding enone.4The 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 reactivityof metallocyclopentanes.5,10 The methodology described in Section B is general for the synthesis of avariety of 1,4- and 1,5-dilithioalkanes, as evident in the Table below.6,7

TABLE ISPIROANNELATION USING ORGANOBIS(CUPRATES)
Reagent M = CuSPhEquiv.

SubstrateProductTime hr

Yield %

1.1

131(96)

1.1

1(85)

1.1

1(80)

1.1

18(93)

4

1.11(87)4

1.11(76)44

4.051(74)

1.2

51(49)

3.0

5288

239294

3.0
5
10.0

1.1

50.5(66)

4.0

50.5(56)

Yields in parantheses were determined by internal standard gas chromatographic analysis.
The synthesis of 9,9-dimethylspiro[4.5]decan-7-one (3) uses the organobis(cuprate) derived from
1,4-dilithiobutane (2) as a bis(nucleophile) component, which is added to the bis(electrophile) 3-chloro5,5-dimethylcyclohex-2-en-1-one (1).

This methodology provides for spiroannelation at a carbon beta to the ketone, and is acomplementary protocol for the cyclization of α,ω-dihaloalkanes to the kinetic enolates of 1,3cycloalkanedione enol ethers (at the alpha position).11
The methodology has been successfully extended with modifications to both the bis(nucleophile)and the bis(electrophile) components, as shown in the Table.6,7

References and Notes
1.
2.
3.
4.
5.
6.
7.
8.

Department of Chemistry, Harvard University, Cambridge, MA 02138.
Department of Chemistry, Stanford University, Stanford, CA 94305.
Clark, R. D.; Heathcock, C. H. Synthesis 1974, 47;
Clark, R. D.; Heathcock, C. H. J. Org. Chem. 1976, 41, 636.
McDermott, J. X.; White, J. F.; Whitesides, G. M. J. Am. Chem. Soc. 1976, 98, 6521;
Wender, P. A.; White, A. W. J. Am. Chem. Soc. 1988, 110, 2218;
Wender, P. A.; Eck, S. L. Tetrahedron Lett. 1977, 1245.
For example, see (a) Sato, N.; Ishiyama, T.; Miyaura, N.; Suzuki, A. Bull. Soc. Chem. Jpn. 1987,60, 3471; Kienzle, F.; Minder, R. E. Helv. Chim. Acta 1987, 70, 1537.

9. West, R.; Rochow, E. G. J. Org. Chem. 1953, 18, 1739.
10. McDermott, J. X.; Wilson, M. E.; Whitesides, G. M. J. Am. Chem. Soc. 1976, 98, 6529;
11. Stork, G.; Danheiser, R. L.; Ganem, B. J. Am. Chem. Soc. 1973, 95, 3414.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)sodium-benzophenone ketyl
chloroenone
β-chlorine
β-chloroenones
organobis(cuprate)
Benzene (71-43-2)
ether,diethyl ether (60-29-7)
ammonium chloride (12125-02-9)hydrogen (1333-74-0)
chloroform (67-66-3)
sodium bicarbonate (144-55-8)
sodium chloride (7647-14-5)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)acetone (67-64-1)
copper(I) oxide
toluene (108-88-3)
zinc (7440-66-6)
sodium (13966-32-0)
ethylene glycol (107-21-1)

menthol (15356-60-2)
Thiophenol (108-98-5)
silver (7440-22-4)
lithium (7439-93-2)
dimedone (126-81-8)
Tetrahydrofuran (109-99-9)
1,4-dichlorobutane (110-56-5)
oxalyl chloride (79-37-8)
hexane (110-54-3)
t-butyl alcohol (75-65-0)
diphenyl disulfide (882-33-7)
sec-butyl alcohol (78-92-2)
1,10-phenanthroline (66-71-7)
copper(I) thiophenoxide (34012-88-9)
9,9-Dimethylspiro[4.5]decan-7-one,
Spiro[4.5]decan-7-one, 9,9-dimethyl- (63858-64-0)
3-Chloro-5,5-dimethylcyclohex-2-en-1-one (17530-69-7)
1,4-Dilithiobutane
copper thiophenoxide
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