Org. Synth. 1993, 71, 167
DOI: 10.15227/orgsyn.071.0167
DIASTEREOSELECTIVE FORMATION OF trans-1,2-DISUBSTITUTED CYCLOHEXANES FROM ALKYLIDENEMALONATES BY AN INTRAMOLECULAR ENE REACTION: DIMETHYL (1'R,2'R,5'R)-2-(2'-ISOPROPENYL-5'-METHYLCYCLOHEX-1'-YL)-PROPANE-1,3-DIOATE
[Propanedioic acid, [5-methyl-2-(1-methylethenyl)cyclohexyl]-, dimethyl ester, [1R-(1α,2β,5α)]-]
Submitted by L. F. Tietze and U. Beifuss
1.
Checked by David Rawson and Albert I. Meyers.
1. Procedure
A.
Methyl (5R)-2-(methoxycarbonyl)-5,9-dimethyldeca-2,8-dienoate, 3.
2 A
dry, 250-mL, two-necked, round-bottomed flask, equipped with a magnetic stirring bar, calcium chloride drying tube, and rubber septum, is charged with
50 mL of dry dichloromethane (Note 1),
R-citronellal 1 ((Note 2), 15.4 g, 18.0 mL, 100 mmol),
dimethyl malonate, 2 ((Note 3), 14.5 g, 12.5 mL, 110 mmol) and 3 Å molecular sieves (
(Note 4), 9.0 g). To the vigorously stirred mixture,
piperidine ((Note 5), 0.86 g, 1.00 mL, 10.0 mmol) and
acetic acid ((Note 6), 0.63 g, 0.6 mL, 10.0 mmol) are added simultaneously by syringes within a few seconds at room temperature. The reaction mixture is stirred for 30 min, another portion of molecular sieves (
(Note 4), 9.0 g) is added, and stirring is continued for another 2 hr
(Note 7). After the solvent is removed on a
rotary evaporator at 25°C, the resulting slurry is diluted with
30 mL of diethyl ether and the resulting mixture is filtered with suction using a
Büchner funnel.
The residue is washed with
diethyl ether (4 × 30 mL), and the combined organic layers are washed with water (3 × 30 mL),
1 N hydrochloric acid (3 × 30 mL),
saturated sodium bicarbonate solution (3 × 30 mL), water (30 mL), and
brine (3 × 30 ml), and finally dried over
anhydrous sodium sulfate. Filtration and removal of the solvent on a rotary evaporator at 25°C yields
24.1–25.5 g (
90–95%) of the Knoevenagel product as a colorless oil. The crude product is pure enough to be used in the ene reaction. An analytically pure sample of
3 (Note 8) is obtained by column chromatography (SiO
2)
(Note 9) with
petroleum ether/acetone, 98:2. Compound
3 is acid- and base-sensitive and should be stored under
argon in a freezer.
B.
Dimethyl (1'R,2'R,5'R)-2-(2'-isopropenyl-5'-methylcyclohex-1'-yl)propane-1,3-dioate, 4a.
2 A
dry, 500-mL, three-necked, round-bottomed flask, equipped with a circular magnetic stirring bar, two rubber septa, and a three-way stopcock connected to an argon line and a vacuum line, respectively, is charged with
ferric chloride on alumina ((Note 10), 9.25 g, 9.50 mmol of ferric chloride). An argon atmosphere is established in the reaction flask by repeated cycles of evacuation and refilling with
argon. Through use of a syringe,
210 mL of dry dichloromethane is added to the reaction flask. Under a positive
argon stream, one rubber septum is replaced by a thermometer (−110°C to +30°C) and the other rubber septum is replaced by an
argon-flushed, pressure-equalizing dropping funnel sealed with a rubber septum and charged with a solution of
3 (25.5 g, 95.0 mmol) in
40 mL of dry dichloromethane (Note 1). The reaction flask is cooled to −78°C and the solution of
3 in
dichloromethane is added dropwise over a period of 30–45 min with stirring at this temperature. Stirring is continued for 2 hr at −78°C and the mixture is allowed to warm to room temperature during 2 hr by taking away the dry ice-acetone bath. The solvent is removed on a rotary evaporator and the remaining brown slurry is treated with
diethyl ether (50 mL); the resulting suspension is then filtered with suction using a
Büchner funnel. The residue is washed with four
50-mL portions of diethyl ether and the combined organic layers are washed with water (50 mL),
saturated sodium bicarbonate solution (50 mL),
1 N hydrochloric acid (50 mL), water (50 mL), and
brine (50 mL). The ethereal phase is dried over
anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to give
24.9 g (
98%) of crude
4a/4b as a yellowish oil in a 98.8:1.2 ratio. (The checkers determined the composition of
4a/4b to be 97.4–97.8/2.6–2.2 by GC/MS.) The oil is purified by short path distillation under reduced pressure to yield
17.1–19.7 g 71–77%) of
4a/4b as a clear, colorless, analytically pure liquid
(Note 11). Analytically pure samples of
4a/4b can also be obtained by flash column chromatography of the crude material on SiO
2 (Note 12) with
diethyl ether/petroleum ether, 1:4) in
87% yield.
2. Notes
1.
Dichloromethane is freshly distilled from
phosphorus pentoxide or
calcium hydride.
2.
(R)-Citronellal purchased from Aldrich Chemical Company, Inc., Dragoco, Holzminden, or Takasago, Perfumery Co., Ltd., Tokyo was used as received.
(R)-Citronellal can also be synthesized from
pulegone with ee >99%.
3 The optical purity of
citronellal can be determined by GLC after conversion to the acetal of (−)-(2R,4R)-pentanediol
4 or by HPLC of the amide of citronellic acid and
(R)-(+)-1-(1-naphthyl)ethylamine.
4 The chemical purity was checked by TLC. We are grateful to Dr. Brunke, Dragoco, Holzminden, Dr. Kumobayashi, Takasago, Tokyo and Dr. Nürrenbach, BASF, Ludwigshafen for gifts of
(+)- and (±)-citronellal.
3.
Dimethyl malonate was purified by distillation.
4.
Molecular sieves (3 Å) were finely ground and dried under reduced pressure at 100°C for 24 hr prior to use.
5.
Piperidine was purified by distillation prior to use.
6.
Acetic acid was purified by distillation.
7.
The final stirring period can be shortened to 1 hr if an additional
0.6 mL of acetic acid and 1 mL of piperidine are added at this point.
8.
The physical properties of
3 are as follows: R
f 0.51 (
ether/
hexane, 1:1); HPLC 3.4 min (Nucleosil CN-10;
ether/
hexane, 1:2; flow 1.5 mL/min); IR (film, cm
−1: 1730, 1645, 1260, 1225, 1060; UV sh 210 (4.13);
1H NMR (100 MHz, C
6D
6) δ: 0.78 (d, 3 H, J = 6.5, 5-CH
3), 0.94–1.46 (m, 3 H, 5-H, 6-H
2), 1.53 (s br, 3 H, 10-H
3), 1.66 (s br, 3 H, 9-CH
3), 1.91 (q m, 2 H, J = 7, 7-H
2), 2.13 (multiplet centered, 2 H, 4-H
2), 3.39 (s, 3 H, OCH
3), 3.51 (s, 3 H, OCH
3), 5.10 (tm, 1 H, J = 7, 8-H), 7.06 (t, 1 H, J = 8, 3-H);
13C NMR (20 MHz, C
6D
6) δ: 17.66 (C-10), 19.59 (5-CH
3), 25.81 (9-CH
3), 25.81 (C-7), 32.68 (C-5), 36.99 and 37.03 (C-4 and C-6), 51.69 and 51.81 (OCH
3), 124.89 (C-8), 129.80 (C-2), 131.25 (C-9), 148.48 (C-3), 164.20 (2-CO), 165.76 (C-1); MS m/z 268 (1, M
+), 237 (2, M-CH
3O), 136 (47, C
10H
16). Anal. Calcd for C
15H
24O
4: C, 67.14; H, 9.01. Found: C, 67.19; H, 9.03.
9.
Compound
3 is isolated in
82% yield by flash chromatography on SiO
2; SiO
2 is Silica Woelm 32–63 active, Fa. Woelm Pharma, Eschwege or Aldrich Grade 951.
10.
Iron(III) chloride on alumina is prepared as follows: A
two-necked, round-bottomed flask is equipped with a circular
magnetic stirring bar, a
rubber septum, and an
argon inlet adapter. The flask is flushed with
argon and an
argon atmosphere is maintained during the reaction. By use of a syringe the reaction flask is charged with dry
dichloromethane (160 mL, (Note 1)).
Iron(III) chloride from Merck AG, Darmstadt or Fluka Chemie AG, Buchs (10.0 g, 61.6 mmol) is added under
argon and the suspension is vigorously stirred. Chromatography-grade neutral or basic
alumina from Woelm Pharma, Eschwege (50.0 g) is added in small portions under
argon. Stirring is continued for 1 hr to achieve homogeneous adsorption and the solvent is then removed on a rotary evaporator under reduced pressure at room temperature. The rotary evaporator is carefully flushed with
argon. After drying under reduced pressure (0.01 atm) for 12 hr,
60 g of alumina-supported iron(III) chloride is obtained that can be stored under
argon for several months without substantial loss of catalytic activity.
11.
The physical properties of
4a/
4b are as follows: R
f 0.56 (
diethyl ether/
hexane, 1:1); GLC t
(4a) 16.88 min, t
(4b) 17.11 min (Chrompack 0.13 μm CpSil 5, 0.32 mm × 25 m; 100°C, 5°C/min),
4a/
4b = 98.82: 1.18 ± 0.043, bp
128–129°C/0.5 mbar;
[α]D20 −34.6° (CH
3CN,
c 1,2); IR (film, cm
−1) 3065, 1750, 1735, 1645, 1155, 1035, 1020, 895;
1H NMR (200 MHz, CDCl
3) δ: 0.91 (d, 3 H, J = 6.5, 5'-CH
3), 0.95 (dq, 1 H, J = 3.5, 12, 4'-H ax), 1.11 (q, 1 H, J = 11.5, 6'-H ax), 1.24–1.57 (m, 2 H, 3'-H ax, 5'-H ax), 1.65 (multiplet centered, 3 H, 2"-CH
3), 1.57–1.94 (m, 3 H, 3'-H eq, 4'-H eq, 6'-H eq), 2.05 (dt, 1 H, J = 3.0, 11.5, 2'-H), 2.13 (tt, 1 H, J = 3.5, 11.5, 1'-H), 3.56 (d, 1 H, J = 3.5, 2-H), 3.73 (s, 6 H, OCH
3), 4.74 (multiplet centered, 1 H, 1"-H), 4.79 (m, 1 H, 1"-H); double resonance experiment, irradiation at δ 2.13 (1'-H), 3.56 (2-H), 4.79 (1"-H); significant change at δ 3.56 (s, 2-H) and 1.11 (t, 6'-H ax) 2.13 (1'-H), 1.65 (d, 2"-CH
3);
13C NMR (50 MHz, CDCl
3) of
4a/
4b, δ 18.96/19.36 (C-3"), 22.54/17.89 (5'-CH
3), 32.35/26.27 (C-3'), 32.73/27.32 (C-5'), 34.68/31.09 (C-4'), 36.59/33.47 (C-6'), 39.88/34.33 (C-1'), 48.68 (C-2'), 51.80 and 52.22 (OCH
3), 53.22/53.14 (C-2), 112.43/112.22 (C-1"), 147.52 (C-2"), 169.03 and 170.11/169.95 (C-1 and C-3); MS m/z 268 (4, M
+), 136 (100, C
10H
16). Anal. Calcd for C
15H
24O
4: C, 67.14, H, 9.01. Found: C, 67.22; H, 9.07.
12.
A mixture of
4a/4b is isolated in
87% yield by flash chromatography on SiO
2; SiO
2 is Silica Woelm 32–63 active, Woelm Pharma, Eschwege or Aldrich Grade 951. Diastereomers
4a and 4b can be separated by chromatography, (
diethyl ether/
petroleum ether, 1:9) which, however, causes loss of material; it is also possible to separate the corresponding diols, that can be obtained by reduction with
lithium aluminum hydride (LiAlH4), by crystallization from
diethyl ether.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
The domino-Knoevenagel-ene reaction is a powerful tool to synthesize five- and six-membered carbocycles.
2,5 The process is exemplified by the diastereoselective synthesis of
4a. Compound
4a has been obtained in both enantiomeric forms and as a racemate according to the procedure described here. The sequence includes the Knoevenagel reaction of
citronellal,
1, and
dimethyl malonate, 2, followed by the intramolecular ene cyclization of the chiral 1,7-diene
3 to yield the trans 1,2-disubstituted products
4a and 4b. Whereas the thermal cyclization of
3 at 180°C provides
4a and 4b in a ratio of only 89.7 : 10.3, the Lewis acid promoted reaction can be performed at a lower temperature and shows a much higher diastereoselectivity.
2 If
ferric chloride adsorbed on
aluminum oxide is used, the reaction can be carried out at −78°C to give
4a and 4b in a ratio of 98:2 in
87% yield.
2 It should be stressed that FeCl
3/Al
2O
3 is employed as a catalyst using about 0.1 equiv. In the ene reaction other Lewis acids such as
diethylaluminum chloride (Et2AlCl) and
zinc bromide (ZnBr2) may be used; however, they have to be added in at least equimolar amounts.
2 Compound
4a has been used in the synthesis of terpenoid natural products.
6
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
alumina
petroleum ether
brine
(+)- and (±)-citronellal
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
ether,
diethyl ether (60-29-7)
sodium bicarbonate (144-55-8)
sodium sulfate (7757-82-6)
acetone (67-64-1)
piperidine (110-89-4)
ferric chloride,
iron(III) chloride (7705-08-0)
dichloromethane (75-09-2)
aluminum oxide (1344-28-1)
lithium aluminum hydride (16853-85-3)
zinc bromide (7699-45-8)
hexane (110-54-3)
argon (7440-37-1)
calcium hydride (7789-78-8)
diethylaluminum chloride
citronellal (106-23-0)
dimethyl malonate (108-59-8)
phosphorus pentoxide (1314-56-3)
pulegone (89-82-7)
(R)-(+)-1-(1-Naphthyl)ethylamine (42882-31-5)
Methyl (5R)-2-(methoxycarbonyl)-5,9-dimethyldeca-2,8-dienoate (106431-76-9)
R-citronellal,
(R)-Citronellal (2385-77-5)
Dimethyl (1'R,2'R,5'R)-2-(2'-isopropenyl-5'-methylcyclohex-1'-yl)propane-1,3-dioate,
DIMETHYL (1'R,2'R,5'R)-2-(2'-ISOPROPENYL-5'-METHYLCYCLOHEX-1'-YL)-PROPANE-1,3-DIOATE
dimethyl malonate, 2
Propanedioic acid, [5-methyl-2-(1-methylethenyl)cyclohexyl]-, dimethyl ester, [1R-(1α,2β,5α)]- (106431-81-6)
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