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8. This filtration was done in order to remove remaining palladium species and phosphine oxide. A column (4x8 cm) packed with Alfa Silica Gel (58 microns) was used.
9. Acetonitrile was stirred overnight with calcium hydride and then distilled onto freshly activated 4 A molecular sieves.
10. All GLC analyses were performed on a 2.4-m x 6-mm glass column packed with 5% SE-30 on Chromosorb W or crosslinked 50% phenylmethylsilicone.
This procedure for stereoselective 1,4-functionalization of 1,3-dienes is based on 1,4-acetoxychlorination,2 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 procedures3'4 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 the 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.23 Control of the 1,4-relative stereochemistry and preparation of compounds analogous to the title compounds also work for acyclic dienes,2a>5 This process was used to obtain remote stereocontrol in acyclic systems and applied to the synthesis of a pheromone.5
1. Department of Organic Chemistry, Royal Institute of Technology, 100 44 Stockholm, Sweden. Present address of J.E.B.: Department of Organic Chemistry, University of Uppsala, Box 531, 751 21 Uppsala, Sweden.
2 (a) Backvall, J.-E.; Nystrom, J.-E.; Nordberg, R. E. J. Am. Chem. Soc. 1985, 707, 3676; (b) Backvall, J.-E.; Nordberg, R. E.; Nystrom, J.-E. Tetrahedron Lett. 1982,
3. Trost, B. M.; Molander, G. A. J. Am. Chem. Soc. 1981, 103, 5969.
4. Marino, J. P.; Floyd, D. M. Tetrahedron Lett. 1979, 675; Marino, J. P.; Hatanaka, N. J. Org. Chem. 1979, 44, 4467.
5. Backvall, J. E.; Bystrfim, S. E.; Nystrom, J. E. Tetrahedron 1985, 24, 5761.
Chemical Abstracts Nomenclature (Collective Index Number); (Registry Number)
cis-1 -Acetoxy-4-(dicarbomethoxymethyl)-2-cyclohexene: Propanedioic acid, [4-(acetyloxy)-2-cyclohexen-1-yl],- dimethyl ester, cis- (11); (82736-52-5) trans-1 -Acetoxy-4-(dicarbomethoxymethyl)-2-cyclohexene: Propanedioic acid, [4-(acetyloxy)-2-cyclohexen-1-yl]-, dimethyl ester, trans- (11); (82736-53-6) cis-1 -Acetoxy-4-chloro-2-cyclohexene: 2-Cyclohexen-1-ol, 4-chloro-, acetate, cis- (11); (82736-39-8)
Lithium acetate dihydrate: Acetic acid, lithium salt, dihydrate (8,9); (6108-17-4) Palladium acetate: Acetic acid, palladium(2+) salt (8,0); (3375-31-3) p-Benzoquinone (8); 2,5-Cyclohexadiene-1,4-dione (9); (106-51-4)
1,3-Cyclohexadiene (8,9); (592-57-4)
Manganese dioxide: Manganese oxide (8,9); (1313-13-9)
Triphenylphosphine: Phosphine, triphenyl- (8,9); (603-35-0)
Dimethyl malonate: Malonic acid, dimethyl ester (8); Propanedioic acid, dimethyl ester (9); (108-59-8)
ERYTHRO-DIRECTED REDUCTION OF A P-KETO AMIDE: ERYTHRO-1-(3-HYDROXY-2-METHYL-3-PHENYLPROPANOYL)PIPERIDINE (Plperidine, 1-(3-hydroxy-2-methyl-1-oxo-3-phenylpropyl)-, (R*,R*)-(±)-)
O O O
Submitted by M. Fujita and T. Hiyama.1 Checked by Gregory P. Roth and Albert I. Meyers.
A. 1-(2-Benzoylpropanoyl)piperidine. A dry, 300-mL, two-necked, round-bottomed flask is equipped with a magnetic stirrer and charged with nitrogen. One neck is connected to a three-way stopcock equipped with a balloon filled with nitrogen, and the other neck is capped with a rubber septum. The flask is charged with 100 mL of anhydrous tetrahydrofuran (THF) (Note 1) and 10.1 g (14.1 mL, 0.100 mol) of diisopropylamine (Note 2) and immersed in an acetone-dry ice bath. A 1.68-M hexane solution of butyllithium (60 mL, 0.10 mol) (Note 3) is added dropwise with stirring over a 10-min period, and the stirring is continued for 1 hr at -78°C. To the resulting lithium diisopropylamide (LDA) solution is added dropwise 14.1 g (0.100 mol) of propanoylpiperidine (Note 4) with stirring over a 10-min period, and the stirring is continued for 2 hr at -78°C (Note 5). The rubber septum is replaced with a polyvinyl chloride (or Teflon) tube connected to another 300-mL, two-necked, round-bottomed
flask, which is equipped with a magnetic stirrer and a three-way stopcock, charged with 100 mL of anhydrous THF and 13.5 g (16.3 mL, 0.110 mol) of benzoyl chloride (Note 6), and immersed in an acetone-dry ice bath. The balloon is taken off and nitrogen is passed through the two stopcocks so that the reaction mixture does not come in contact with air (see the apparatus shown in Figure 1). By inclining the first flask, the THF solution of the lithium enolate of 1-propanoylpiperidine is added to the THF solution of benzoyl chloride in the second flask through the polyvinyl chloride tube over a 5-min period. After the solution is stirred for 0.5 hr at -78°C, it is allowed to warm to room temperature, diluted with 200 mL of dichloromethane, and washed with 200 mL of water. The organic layer is separated, and the aqueous layer is extracted with two 50-mL portions of diethyl ether. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated with a rotary evaporator. Recrystallization from diethyl ether-hexane affords 12.5 g (51%) of 1-(2-benzoylpropanoyl)piperidine, mp 100-101 °C (Note 7).