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DOI:10.15227/orgsyn.067.0076

Organic Syntheses, Coll. Vol. 8, p.141 (1993); Vol. 67, p.76 (1989).

CONDENSATION OF (−)-DIMENTHYL SUCCINATE DIANIONWITH 1,ω-DIHALIDES: (+)-(1S,2S)-CYCLOPROPANE-1,2DICARBOXYLIC ACID
[1,2-Cyclopropanedicarboxylic acid, (1S,2S)-(+)-]

Submitted by Kyoji Furuta, Kiyoshi Iwanaga, and Hisashi Yamamoto1.
Checked by Ichiro Mori and Clayton H. Heathcock.

1. Procedure
A. (−)-Dimenthyl succinate. A 300-mL. one-necked, round-bottomed flask is equipped with amagnetic stirrer, a Dean–Stark trap, and a reflux condenser. The flask is charged with 20 g (0.2 mol) of
succinic anhydride, 62.5 g (0.4 mol) of l-menthol, 250 mg (1.3 mmol) of p-toluenesulfonic acidmonohydrate, and 150 mL of toluene (Note 1). The mixture is heated under reflux in an oil bath (about140°C) for 24 hr. During this period the theoretical amount of water (3.6 mL) is collected. The mixtureis allowed to cool to ambient temperature, diluted with 200 mL of hexane, and poured into a mixture of
250 mL of aqueous saturated sodium bicarbonate, 100 mL of methanol, and 200 mL of water. The
organic phase is separated and the aqueous phase is extracted twice with 100 mL of hexane. The organic
phases are combined, washed once with 200 mL of saturated brine, and dried over sodium sulfate. The
solvent is removed with a rotary evaporator, and the resulting crude product is dissolved in 100 mL ofmethanol. After the solution stands in a refrigerator overnight, colorless crystals appear in the mixture
and are collected by filtration with suction (Note 2). This material (ca. 70 g in two crops) is purified byrecrystallization from methanol to afford 66 g (84%) of pure (−)-dimenthyl succinate, mp 63–64°C(Note 3).

B. (−)-Dimenthyl (1S,2S)-cyclopropane-1,2-dicarboxylate. A dry, 500-mL, three-necked, roundbottomed flask containing a magnetic stirring bar is equipped with a 100-mL pressure-equalizing
dropping funnel, a rubber septum, and a three-way stopcock with a nitrogen inlet. The air in the system
is replaced with dry nitrogen. The flask is charged with 180 mL of dry tetrahydrofuran and cooled with
an ice bath; 74.1 mL of a 1.7 M hexane solution of butyllithium (126 mmol) (Note 4) is added. Thissolution is stirred while 21.3 mL (126 mmol) of 2,2,6,6-tetramethylpiperidine (Note 5) is added
dropwise with a syringe through the septum over a 10-min period. The resulting solution of lithium
2,2,6,6-tetramethylpiperidide (LTMP) is cooled to −78°C with a dry ice–methanol bath (Note 6) andstirred. A solution of 23.7 g (60 mmol) of (−)-dimenthyl succinate in 50 mL of dry tetrahydrofuran isthen added dropwise through the addition funnel over a 1-hr period. The wall of the funnel is rinsed
with 10 mL of dry tetrahydrofuran and the rinse is added to the solution. The resulting yellow solutionof succinate dianion is stirred for 1 hr. To the solution is added dropwise 3.9 mL (60 mmol) of
bromochloromethane (Note 7) with a syringe through the septum over a 10-min period. After thereaction mixture is stirred for 2 hr (Note 8), 2.2 mL (24 mmol) of isobutyraldehyde (Note 9) is added
dropwise to quench any unreacted anions (Note 10). After being stirred for an additional 30 min, thereaction mixture is poured into 250 mL of ice-cooled 1 N hydrochloric acid and the product is extracted
3 times with 150 mL of ether. The combined organic phases are washed with 250 mL of brine, driedover sodium sulfate, filtered, and concentrated with a rotary evaporator. The residue is chromatographedon 700 g of silica gel (Note 11) packed in a 9.5-cm-diameter column using a mixture of ether andhexane (1 : 18) as eluant. The appropriate fractions are collected and concentrated to give 11.5 g (47%)
of (−)-dimenthyl (1S,2S)-cyclopropane-1,2-dicarboxylate as colorless crystals. Analysis by GC indicatesa diastereomeric ratio of 96 : 4 (Note 12). Recrystallization of this material from 25 mL of methanol
affords 9–10 g (38–40%) (Note 13) of optically pure product, mp 95–96°C (Note 14).
C. (+)-(1S,2S)-Cyclopropane-1,2-dicarboxylic acid. (−)-Dimenthyl (1S,2S)-cyclopropane-1,2dicarboxylate (4.06 g, 10 mmol, [α]D25 + 17.8°) is dissolved in 20 mL of a 10% potassium hydroxidesolution in 9 : 1 methanol/water in a 50-mL, one-necked, round-bottomed flask equipped with amagnetic stirring bar. The solution is heated at 60°C with an oil bath. Progress of the reaction ismonitored by TLC on silica gel, using 1 : 1 hexane/ethyl acetate as eluant (Note 15). After about 4 hr
the resulting two-phase mixture is diluted with 20 mL of water and extracted with three 40-mL portionsof ether (Note 16). The aqueous layer is acidified by the addition of 20 mL of ice-cold 6 N hydrochloricacid, saturated with ca. 5 g of sodium chloride, and extracted with five 40-mL portions of ether. The
combined organic layers are dried over sodium sulfate, diluted with 5 mL of hexane, and concentrated
with a rotary evaporator. Filtration provides 1.17 g (90%) of (+)-(1S,2S)-cyclopropane-1,2-dicarboxylicacid, mp 172–173°C, [α]D25 +228° (ethanol, c 1.01) [lit.2 mp 169.5–170°C, [α]D25 +227.9° (ethanol, c2.342)] (Note 17).

2. Notes
1. Succinic anhydride and p-toluenesulfonic acid monohydrate were purchased from Wako Pure
Chemical Industries, Ltd. (Japan). Guaranteed-grade l-(−)-menthol was purchased from Tokyo Kasei
Kogyo Company, Ltd. (Japan). Reagent-grade toluene was dried and stored over sodium metal. Thecheckers obtained p-toluenesulfonic acid from Eastman Kodak and succinic anhydride and l-(−)menthol from the Aldrich Chemical Company, Inc.
2. In the first trial the checkers experiences difficulty in crystallization at this point, even after keeping
the solution in a 5°C refrigerator for 4 days. Crystallization was induced by cooling the crude product(ca. 80 g of oil) to −78°C in a methanol–dry ice bath. Ether (5 mL) was added to the resulting glass, thecooling bath was removed, and the surface of the solid material was scratched continuously with aspatula. At about 0°C the glass began to melt and small white spots appeared. Continued stirring of theviscous material as it warmed resulted in crystallization of the entire mass. The crystalline mass wasdried under vacuum and a small portion kept as seed crystals. The remainder was dissolved in 100 mLof warm methanol. After the solution was cooled to room temperature, a small quantity of the seedmaterial was added and the solution was placed in a 5°C refrigerator overnight. Approximately 68 g ofcrystalline (−)-dimenthyl succinate was obtained. The filtrate was condensed with a rotary evaporator
and cooled again to give another 2.6 g. In subsequent trials, the foregoing procedure was not necessary
as the crude diester crystallized spontaneously, giving a similar yield in two crops.
3. The submitters report mp 65–66°C. The physical properties are as follows: 1H NMR (CDCl3, 250

MHz) δ: 0.70–2.02 (complex, 18 H), 0.75 (d, 6 H, J = 6.9), 0.89 (d, 12 H, J = 6.4), 2.60 (s, 4 H), 4.70
(dt, 2 H, J = 4.4, 10.8); [α]D25 −88.7° (CHCl3, c 1.02).
4. Tetrahydrofuran was freshly distilled from sodium–benzophenone. Butyllithium was obtained from
Wako Pure Chemical Industries, Ltd. or Foote Mineral Company. It was titrated with anhydrous 2butanol using 1,10-phenanthroline as an indicator.
5. 2,2,6,6-Tetramethylpiperidine, purchased from Tokyo Kasei Kogyo Company, Ltd. or Aldrich
Chemical Company, Inc., was used. The use of this sterically hindered lithium amide is crucial for highdiastereoselectivity. If lithium diisopropylamide is used, the diastereoselectivity of the reaction isreduced significantly.3
6. The flask was cooled with a dry ice–methanol bath for 30 min before subsequent addition.
7. Bromochloromethane was purchased from Tokyo Kasei Kogyo Company, Ltd. or from Aldrich
Chemical Company, Inc. and was used without purification.
8. TLC (ether–hexane) showed residual starting material.
9. Isobutyraldehyde was obtained from Wako Pure Chemical Industries, Ltd. or from Aldrich ChemicalCompany, Inc. and was used without purification.
10. This procedure was not essential but facilitated the subsequent chromatographic separation ofdesirable product from residue.
11. Silica gel (70–200 mesh) purchased from Fuji Davison Chemical (BW-820 MH) was used. The
checkers used silica gel (230–400 mesh) purchased from Merck (Kieselgel 60).
12. GC analysis was performed with a capillary column (PEG, 0.25 mm × 25 m) purchased fromGaskuro Kogyo Company, Ltd. (Japan). The checkers used a 0.2-mm × 25-m Carbowax 20 M capillarycolumn. The diastereomeric excess ranged from about 80–92%. In all cases, however, essentially purematerial could be obtained by a subsequent single recrystallization. The diastereomeric ratio can befurther improved by reducing the amount of added bromochloromethane. This may be due to thestereochemical purity of the enolates. On treatment with lithium 2,2,6,6-tetramethylpiperidide, thesuccinate affords mainly the E,E-enolate and only a slight amount of Z,Z-enolate; the latter may induce
the opposite stereochemistry in the product. Fortunately, the E,E-enolate is more reactive, and therefore,
the undesirable reaction with Z,Z-enolate can be suppressed, kinetically by reducing the amount ofhalide. Thus the use of 0.5 equivalent of bromochloromethane compared to starting ester results in over
99% diastereoselectivity with comparable chemical yield, based on the halide. The procedure describedin the text is, however, recommended from a practical point of view.
13. This yield ranges from 38 to 57% in several experiments. Recrystallization was accomplished bydissolving the crude diester in warm methanol and then allowing this solution to cool to room
temperature. The checkers found that, if crystallization was induced by cooling the methanol solution ina refrigerator, the crystalline diester was accompanied by an oily by-product. A second recrystallization
was then necessary to purify the material.
14. The submitters report mp 99–100°C. The physical properties are as follows: 1H NMR (CDCl3, 250
MHz) δ: 0.70–2.02 (complex, 20 H), 0.76 (d, 6 H, J = 7.0), 0.90 (d, 12 H, J = 6.8), 2.12. (dd, 2 H, J =7.4, 7.2), 4.68 (dt, 2 H, J = 5.4, 10.9); [α]D25.5 + 17.8° (CHCl3, c 1.0).
15. During the course of the saponification, a spot with Rf intermediate between that of the reactant andproduct (presumably the monoester) was observed.
16. The combined organic layer may be washed with 50 mL of brine, dried over sodium sulfate, andevaporated to recover 3.45 g of crude menthol.
17. The checkers note that in the paper by Inouye et al.2 the diacid was prepared by ozonolysis of (+)trans-2-phenylcyclopropanecarboxylic acid having 96.3% optical purity. The product diacid was
purified by sublimination and recrystallization from water to obtain material giving the cited physicalproperties. Although the original publication2 claims an optical purity of 96.3% for this diacid, it isprobably optically pure because of the recrystallization step.

3. Discussion
The procedure described here provides a simple and general method for the construction of optically
active trans-cycloalkane-1,2-dicarboxylic acids.3 The reaction has been applied successfully to a seriesof dihalides and ditosylates (Table I).

TABLE IASYMMETRIC SYNTHESIS OF CYCLOALKANE DICARBOXYLATESElectrophileXnYield(%)

Diastereomeric
Excess (%)

Configuration

272—a,b—c

377

65

S,S

363

92

S,S

364

88

R,Rd

357

83a—c461

75

S,S

Br

Br

OTs

OTs

CleOTsReaction first at −100°C, and then warming to −20°C.
dNot determined. [α]25 −51.7° (CHCl , c 1.0).
D3cNot determined.
dd-Menthyl ester was used.
e3-Chloro-2-chloromethyl-1-propene.

aA few methods are described in the literature for the preparation of optically active dialkyl transcyclopropane-1,2-dicarboxylates,2 including a Michael addition–condensation sequence of menthyl
chloroacetate and menthyl acrylate,4 and cobalt(0) or nickel(0) complex-catalyzed cyclopropanation ofdimenthyl fumarate with dibromomethane.5 The present method is characterized by good chemical andhigh optical yields, simple operation, preparation of both enantiomers with equal ease, and the readyavailability of the starting materials.

References and Notes
1. Department of Applied Chemistry, Faculty of Engineering, Nagoya University, Chikusa, Nagoya
464, Japan.
2. Inouye, Y.; Sugita, T.; Walborsky, H. M. Tetrahedron 1964, 20, 1695.
3. Misumi, A.; Iwanaga, K.; Furuta, K.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 3343;

Djerassi, C.; Klyne, W.; Norin, T.; Ohloff, G.; Klein, E. Tetrahedron 1965, 21, 163; Inouye, Y.;
Sawada, S.; Ohno, M.; Walborsky, H. M. Tetrahedron 1967, 23, 3237.
4. Inouye, Y.; Inamasu, S.; Ohno, M.; Sugita, T.; Walborsky, H. M. J. Am. Chem. Soc. 1961, 83,2962; Inouye, Y.; Inamasu, S.; Horiike, M.; Ohno, M.; Walborsky, H. M. Tetrahedron 1968, 24,2907; Inamasu, S.; Horiike, M.; Inouye, Y. Bull. Chem. Soc. Jpn. 1969, 42, 1393.
5. Matsuda, H.; Kanai, H. Chem. Lett. 1981, 395.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)
Lithium 2,2,6,6-tetramethylpiperidide
brine(−)-Dimenthyl succinate(−)-Dimenthyl (1S,2S)-cyclopropane-1,2-dicarboxylate
lithium 2,2,6,6-tetramethylpiperidide (LTMP)l-(−)-mentholtrans-cycloalkane-1,2-dicarboxylic acids
d-Menthyl estertrans-cyclopropane-1,2-dicarboxylates
ethanol (64-17-5)hydrochloric acid (7647-01-0)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether (60-29-7)
sodium bicarbonate (144-55-8)
sodium chloride (7647-14-5)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
nickel(0) (7440-02-0)

potassium hydroxide (1310-58-3)
toluene (108-88-3)
Benzophenone (119-61-9)
sodium (13966-32-0)
menthol,l-menthol (15356-60-2)
dibromomethane (74-95-3)
Succinic anhydride (108-30-5)
isobutyraldehyde (78-84-2)
butyllithium (109-72-8)
Tetrahydrofuran (109-99-9)
SUCCINATE DIANION
lithium amide (7782-89-0)
hexane (110-54-3)
cobalt(0) (7440-48-4)
2-Butanol (78-92-2)
p-toluenesulfonic acid (104-15-4)
lithium diisopropylamide (4111-54-0)
1,10-phenanthroline (66-71-7)
2,2,6,6-tetramethylpiperidine (768-66-1)
bromochloromethane (74-97-5)(+)-(1S,2S)-Cyclopropane-1,2-dicarboxylic acid,
1,2-Cyclopropanedicarboxylic acid, (1S,2S)-(+)- (14590-54-6)
3-Chloro-2-chloromethyl-1-propene (1871-57-4)
menthyl chloroacetate
menthyl acrylate
dimenthyl fumaratep-toluenesulfonic acid monohydrate (6192-52-5)(+)-trans-2-phenylcyclopropanecarboxylic acid (939-90-2)
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