A New Synthesis of Hemialdals and Their Stereoselective Tandem Reaction in the Construction of 1,3-Dioxolane Derivatives

Abstract

A new synthesis for hemialdals by directly oxidizing ­acetophenones using dimethyl sulfoxide and a catalytic amount of iodine is reported. A tandem reaction between these hemialdals and α-bromoketones using triethylamine as a base in the presence of lithium bromide, followed by a Williamson/aldol-type condensation has been developed. The reaction proceeds with high stereoselectivity for a wide range of α-bromoketones and hemialdals and leads to various 2,4,5-triacyl-1,3-dioxolanes.

Key words

lithium - stereoselectivity - tandem reactions - iodine - ketones

References and Notes

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7

Crystallographic data for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 281489 (2a). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or email: [e-mail]].

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Typical Procedure for the Preparation of Hemialdals 2 from Acetophenones 1: Synthesis of Bis(α-hydroxy-phenacyl) Ether (2a)
Acetophenone (1a, 6.01 g, 50.0 mmol) and I₂ (3.17 g, 12.5 mmol) were placed in a 250 mL round-bottom flask and dissolved in toluene (100 mL) before the addition of DMSO (25 mL). The flask was fitted with a Dean-Stark trap and the reaction mixture was heated to reflux to remove H₂O. The reaction was followed by TLC (PE-EtOAc, 3:1). When the reaction was completed in 5 h, the mixture was quenched with ice water and extracted with Et₂O (100 mL). The organic layer was washed with 10% aq Na₂SO₄, and evaporated in a rotary evaporator to afford yellow syrup. Bulb-to-bulb distillation afforded 2a (3.58 g), light yellow syrup, yield 53%. Recrystallization from toluene afforded crystals suitable for X-ray diffraction analysis; mp 96 ˚C(toluene); bp 78-82 ˚C (9.33 mbar). ^¹H NMR (500 MHz, CDCl₃): δ = 8.11 (d, J = 8.0 Hz, 4 H), 7.56-7.60 (m, 2 H), 7.43-7.49 (m, 4 H), 6.36 (d, J = 7.6 Hz, 2 H), 5.09 (d, J = 7.6 Hz, 2 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 193.1, 134.8, 132.6, 130.2, 129.0, 88.9. IR (KBr): ν = 3406, 1698, 1597, 1450, 1225, 1112, 1038, 965 cm^-¹. ESI-MS: m/z (%) = 287 (75.0) [M⁺ + 1], 317.3 (93.5 [M⁺ + CH₃OH]. Anal. Calcd for C₁₆H₁₄O₅: C, 67.13, H, 4.93. Found: C, 66.90; H, 4.94.

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Typical Procedure for the Preparation of 2,4,5-Triacyl-1,3-dioxolanes from Hemialdals 2 and α-Bromoketones 3: Synthesis of Compound 4a
To a solution of hemialdal 2a (286 mg, 1 mmol) and
α-bromoacetophenone (3a, 259 mg, 1.3 mmol) in THF (10 mL) was added LiBr (104 mg, 1.2 mmol), followed by Et₃N (181 µL, 1.3 mmol). The reaction mixture was stirred at r.t. for 30 min, quenched with aq H₂SO₄ (10%, 1 mL), and extracted with CH₂Cl₂ (2 × 30 mL), washed with H₂O (10 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and purified by column chromatography (PE-EtOAc). Further purification by recrystallization (PE-EtOAc) affords 251 mg of compound 4a as a white solid in 65% yield. ^¹H NMR (500 MHz, CDCl₃): δ = 8.14 (d, J = 7.0 Hz, 2 H), 8.07 (d, J = 6.5 Hz, 2 H), 8.01 (d, J = 9.0 Hz, 2 H), 7.65-7.61 (m, 1 H), 7.58-7.50 (m, 4 H), 7.46-7.42 (m, 4 H), 6.35 (s, 1 H), 6.17 (d, J = 4.0 Hz, 1 H), 5.81 (d, J = 4.0 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 194.49, 194.15, 191.43, 134.64, 134.29, 134.13, 133.89, 133.79, 133.63, 129.44, 129.42, 129.24, 128.90, 128.60, 128.56, 102.62, 80.11, 79.11. IR (KBr): ν = 1710, 1703, 1674, 1596, 1449, 1231, 1240, 689. ESI-MS: m/z (%) = 403.9 (100) [M⁺ + H₃O]. Anal. Calcd for C₂₄H₁₈O₅: C, 74.60; H, 4.70; Found: C, 74.43; H, 4.81.