Phase-transfer catalyzed asymmetric Darzens reaction of cyclic α-chloro ketones

Abstract

Catalytic asymmetric Darzens reaction using cyclic α-chloro ketones promoted by chiral quaternary ammonium salts as a phase-transfer catalyst proceeded smoothly under mild reaction conditions to afford the desired products with reasonable enantioselectivities at room temperature.

References

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6. Easily prepared PTCs substituted at the 4-position on the phenyl ring with other electron-withdrawing groups such as NO₂ or CN, and electron-donating groups such as MeO or alkyl groups, gave 3aa with lower ee (4-NO₂, 5% ee; 4-CN, 6% ee; 4-OMe, 0% ee; 4-Bu^t, 5% ee). The PTC involving both a methyl-protected hydroxy group and a 4-trifluoromethylbenzyl unit afforded 3aa as racemate. Other types of PTC including 2- or 3-substituted benzyl moieties also gave 3aa with lower ee [3-CF₃, 3% ee; 2,4-(CF₃)₂, 17% ee].
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8. A typical procedure for the catalytic asymmetric Darzens reaction is as follows: To a suspension of 1a(53.0 mg, 0.3 mmol), PTC A(16.0 mg, 0.03 mmol) and aldehyde 2a(0.06 ml, 0.6 mmol) in Bu₂O (1.5 ml) was added LiOH (28.4 mg, 1.2 mmol) at room temperature. After the mixture had been stirred for 45 h, more 2a(0.06 ml, 0.6 mmol) was added, the mixture was stirred for an additional 16 h and the reaction mixture was quenched with 1 M HCl (3.0 ml), extracted with Et₂O (15 ml × 3), washed with brine and dried over Na₂SO₄. Removal of the solvent followed by flash column chromatography (silica gel, hexane–Et₂O, 5:1) gave the desired coupling adduct 3aa as a colorless oil (64.2 mg, 99%, 69% ee): [α]_D²⁵+55 (c 2.1, CHCl₃). Ees were determined by HPLC analysis by use of DAICEL CHIRALCEL OD+OD, hexane–PrⁱOH, 20:1, retention time, 16.9 (major) and 18.6 min (minor).
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