Organic Syntheses, CV 8, 5
[Propanedioic acid, [4-(Acetyloxy)-2-cyclohexen-1-yl]-, dimethyl ester, cis- and trans-]
Submitted by Jan-E. Bäckvall and Jan O. Vågberg
1.
Checked by Michael R. Sestrick and Albert I. Meyers.
1. Procedure
A.
cis-1-Acetoxy-4-chloro-2-cyclohexene. A
1-L, one-necked, round-bottomed flask equipped with a
magnetic stirring bar is charged with
200 mL of acetic acid, 5.1 g (0.12 mol) of lithium chloride,
12.2 g (0.12 mol) of lithium acetate dihydrate,
0.67 g (3 mmol) of palladium acetate, and
12.9 g (0.12 mol) of p-benzoquinone. The contents of the flask are stirred at room temperature until all components are dissolved, and
300 mL of pentane is added. To the
pentane phase of the biphasic system formed is added
4.82 g (60 mmol) of 1,3-cyclohexadiene (Note
1). The reaction mixture is stirred at a moderate rate (Note
2) at room temperature and after 4 hr,
2.87 g (33 mmol) of manganese dioxide (Note
3) is added. After the flask is stirred for another 4 hr at room temperature, the organic phase is separated and saved, and
2.87 g (33 mmol) of manganese dioxide and
20 mL of acetic acid are added to the remaining
acetic acid, which is vigorously stirred for 30 min. To the mixture are added
2.6 g (60 mmol) of lithium chloride and
300 mL of pentane. A new portion of
4.82 g (60 mmol) of 1,3-cyclohexadiene is added and the reaction mixture is stirred at a moderate rate (Note
1) at room temperature overnight (12–15 hr). To the reaction mixture is added
70 mL of saturated sodium chloride solution and the organic phase is separated and saved. The aqueous phase is filtered and extracted with
pentane (2 × 300 mL). The combined organic phases are washed with water (2 × 120 mL),
120 mL of saturated aqueous sodium carbonate,
120 mL of 2 M sodium hydroxide, 120 mL of water, and
120 mL of saturated sodium chloride solution. The organic phase is dried over
magnesium sulfate and the solvent is removed by rotary evaporation at reduced pressure, giving
16.5–17.5 g (
79–84%) of a yellow oil. Kugelrohr distillation (95–105°C, 1 mm) of the crude product affords
14.6–15.6 g (
71–75%) of pure
cis-1-acetoxy-4-chloro-2-cyclohexene (>98%
cis). Analysis by HPLC and GLC [high-performance (pressure) liquid and gas chromatograph] shows about 1% contamination of diacetate as the only impurity. No dichloride can be detected (<0.5%).
B.
cis-1-Acetoxy-4-(dicarbomethoxymethyl)-2-cyclohexene. A
2-L, two-necked, round-bottomed flask equipped with a
magnetic stirrer, a
nitrogen-vacuum inlet, and a
rubber septum is charged with
17.5 g (0.1 mol) of cis-1-acetoxy-4-chloro-2-cyclohexene,
0.49 g (2.2 mol) of palladium acetate and
2.4 g (9.0 mmol) of triphenylphosphine (Note
4). The flask is flushed with
nitrogen (Note
5). To the flask is added
550 mL of a 0.2 M solution (0.11 mol) of sodium dimethyl malonate in
tetrahydrofuran (THF) by syringe (Note
6). The flask is again flushed with
nitrogen and the reaction mixture, which now has turned yellow, is stirred at room temperature for 2 hr (Note
7). The flask is opened and
200 mL of saturated aqueous sodium bicarbonate is added. The stirring is continued for 20 min, and then 100 mL of water and
200 mL of ether are added. The contents of the flask are transferred into a
2-L separatory funnel and the organic phase is separated. The remaining aqueous phase is extracted with
ether (3 × 300 mL). The combined organic phases are washed with
200 mL of saturated brine, dried over anhydrous
magnesium sulfate, concentrated on a
rotary evaporator to approximately 400 mL, and then filtered through a
short silica gel column (Note
8). Removal of the rest of the solvent by rotary evaporation at reduced pressure gives
30.4–31.3 g of a light-brown oil. Excess
dimethyl malonate is removed by Kugelrohr distillation at 100°C (1 mm). Kugelrohr distillation (140°C, 0.2 mm) of the remaining crude product affords
25.9–26.7 g (
91%) of
cis-1-acetoxy-4-(dicarbomethoxymethyl)-2-cyclohexene as a light-brown oil. Analysis by GLC indicates a chemical purity of 95–98%.
2. Notes
2. A stirring rate 5–10 revolutions per second (rps) was used (only a small vortex was present).
5. A manifold system connected to a vacuum line and a
nitrogen line was used.
7. The reaction is usually over after 30 min. The reaction was checked by GLC or TLC to confirm completion.
8. This filtration was done in order to remove remaining
palladium species and
phosphine oxide. A
column (4 × 8 cm) packed with Alfa silica gel (58 μm) was used.
10. All GLC analyses were performed on a
2.4-m × 6-mm glass column packed with 5% SE-30 on Chromosorb W or crosslinked 50% phenylmethylsilicone.
3. Discussion
This procedure for stereoselective 1,4-functionalization of 1,3-dienes is based on 1,4-acetoxychlorination
2 3 and allows the preparation of 1,4-disubstituted 2-cyclohexenes with full stereocontrol of the carbon–carbon bond formation in the 4-position. It is also highly regioselective. Other procedures
4,5 for obtaining 4-alkyl-substituted 3-cyclohexenol derivatives use
1,3-cyclohexadiene monoepoxide as starting material. None of the previous methods allow the selective preparation of both stereoisomers as shown here.
The present procedure uses
palladium catalysis in the first step and in one of the second steps. These reactions occur under very mild conditions (room temperature), and the catalyst used is commercial
palladium acetate.
Since the title compounds can be stereoselectively functionalized in the 1-position by metal-catalyzed nucleophilic substitutions of the acetoxy group, a great number of 1,4-disubstituted 2-cyclohexenes with defined 1,4-relative stereochemistry are available.
While this process works for a great number of conjugated dienes, a few, such as
1,3-cyclopentadiene and those acyclic dienes that have an oxygen substituent in an allylic position, did not give a chloroacetoxylation product.
2 Control of the 1,4-relative stereochemistry and preparation of compounds analogous to the title compounds also work for acyclic dienes,
2,6 This process was used to obtain remote stereocontrol in acyclic systems and applied to the synthesis of a pheromone.
6
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