Palladium-Catalyzed Stereoselective Allylic Alkylation of Lithium Enolates

Abstract

The lithium enolates, generated from cyclohexanone, cyclopentanone, and 1-tetralone, react with allyl acetate 1b or carbonate 1c enantioselectively, when catalyzed by (R)- or (S)-BINAP-derived palladium complexes. The presence of lithium chloride is crucial to stereoselectivity. Diastereoselective and enantioselective allylation occurs between cyclohexanone and carbonate 1d. It is shown in the case of the acyclic substrates (Z)-12 and (E)-17 that π-allyl palladium complexes are attacked by lithium enolates from the face opposite to the noble metal.

Key words

asymmetric synthesis - stereoselectivity - ketones - ­nucleophilic additions - allyl complexes

References

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15

The opposite diastereomer was predominantly obtained in the rearrangement of allyl β-ketoesters: cf. ref. 14a. The product 10 was isolated in 35% yield aside from recovered carbonate 1d (40%). The fact that the latter is non-racemic indicates an at least partial kinetic resolution.

22

Procedure for the Synthesis of ( R )-4a.
A 100-mL two-necked flask is equipped with a magnetic stirrer and charged with [Pd₂(dba)₃]·CHCl₃ (25.9 mg; 25 µmol), (R)-8 (63.0 mg, 101 µmol), and LiCl (0.49 g, 12 mmol). The flask is closed with a septum, connected to a combined N₂/vacuum line, evacuated for 4 h at 25 °C and filled with N₂. A solution of 1c (0.562 g, 4.84 mmol) in anhyd THF (13 mL) is added by syringe. The deep purple mixture is stirred at 25 °C until the color changes to yellow (approximately 1 min). A 500-mL two-necked flask is equipped with a magnetic stirrer, a resistance thermometer, a connection to the combined N₂/vacuum line and a septum. The air in the flask is replaced by N₂, and diisopropylamine (17.0 mL, 120.3 mmol) and THF (80 mL) are injected. After cooling to -78 °C, a 1.6 M solution of n-BuLi in hexane (75 mL, 120.0 mmol) is added, whereby the temperature is kept below -70 °C. After stirring at 0 °C for 30 min, it is cooled again to -78 °C and treated with distilled, degassed cyclohexanone (12.5 mL, 120.5 mmol) in 70 mL of THF. After stirring at 0 °C for 30 min, the solution is stored at - 78 °C. At -78 °C, 11 mL (5.09 mmol) of the enolate solution are added to the 100-mL flask by syringe. After stirring at -78 °C for 40 h, the mixture is poured into 100 mL of phosphate buffer (pH = 7) and extracted four times with CH₂Cl₂ (50 mL each). The combined organic layers are dried with MgSO₄ and evaporated at 40 °C at a pressure that does not fall below 200 mbar. The flask is connected by glass tubes with two subsequent traps that are cooled to 0 °C and -196 °C, respectively. When the flask containing the crude product is heated to 50 °C at 0.07 mbar, pure product is collected in the 0 °C trap. Yield of (R)-4a: 0.422 g (63%); t _R = 24.8 min for (R)-4a; t _R = 26.6 min for (S)-4a; 90% ee.