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Accessing Diverse Cross-Benzoin and α-Siloxy Ketone Products via Acyl Substitution Chemistry

Chloe N. Larcombe and Lara R. Malins*

*Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia, Email: lara.malinsanu.edu.au

C. N. Larcombe, L. R. Malins, J. Org. Chem., 2022, 87, 9408-9413.

DOI: 10.1021/acs.joc.2c00801


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Abstract

Acyl substitution of readily accessible α-siloxy Weinreb amides with organolithium compounds provides diverse cross-benzoin and α-siloxy ketone products. Enantiopure benzoins can be accessed via a chiral pool approach.

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General procedure A for the synthesis of α-siloxy ketones

The starting material indicated (e.g. aryl bromide, heterocycle, or other) (1.0 mol equiv) was dissolved in dry tetrahydrofuran (0.16 M) and cooled to 78 C in a dry ice/acetone bath under argon. n-Butyllithium (as a solution at the specified concentration in hexanes, 1.1 mol equiv) was added dropwise and the reaction was stirred at 78 C for 1 hour. A solution of α-siloxy Weinreb amide (1.2 mol equiv) in tetrahydrofuran (0.58 M) was added dropwise and the resulting reaction mixture was stirred at 78 C (except where specified) for 2.53 hours. The reaction was quenched with saturated aqueous NH4Cl and extracted three times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via flash column chromatography using the specified solvent system afforded the pure α-siloxy ketones.

General procedure B for the synthesis of α-siloxy ketones

The α-siloxy Weinreb amide (1.0 mol equiv) was dissolved in dry tetrahydrofuran (0.12 M) and cooled to 78 C in a dry ice/acetone bath under argon. The organometallic reagent (as a solution at the specified concentration in hexanes or tetrahydrofuran, 1.1 mol equiv) was added dropwise and the resulting solution was stirred at 78 C for 2.5 hours. The reaction was quenched with saturated aqueous NH4Cl and extracted three times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via flash column chromatography using the specified solvent system afforded the pure α-siloxy ketones.


Key Words

acylation, benzoins, Weinreb ketone synthesis


ID: J42-Y2022