Sodium Bromide-Catalyzed Oxidation of Secondary Benzylic Alcohols Using Aqueous Hydrogen Peroxide as Terminal Oxidant

Abstract

A halide salt, hydroperoxide and AcOH catalyst system was applied to the oxidation of secondary benzylic alcohols. This simple system can be applied to a variety of secondary benzylic alcohols and scaled up for gram-scale preparation. High secondary benzylic alcohol selectivity of the present method is demonstrated in hydroxyketone synthesis. Based on several experimental results, a catalytic cycle for our oxidation is proposed.

Key words

sodium bromide - bromine - oxidation - hydrogen peroxide - alcohol

• References and Notes

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• 15 In our previous study on α-acetoxylation H₂O₂ was not effective; see ref. 3. Use of other organic solvents (EtOAc, MeCN, DMF) instead of AcOH resulted in no reaction.
• 16 In our previous study, stepwise addition of oxidant was found to be effective; see ref 3. Ishihara and co-workers have also reported stepwise or slow addition of oxidant in their iodide salt catalyzed oxidation, see: Uyanik M, Suzuki D, Watanabe M, Tanaka H, Furukawa K, Ishihara K. Chem. Lett. 2015; 44: 387
• 17 Reaction of 1g with 0.5 equiv of H₂O₂ in AcOH for 1 h at 60 °C in the absence of NaBr gave 3 and 4 in 59% and 20% yields, respectively.
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• 19 We did not perform the reaction in more than 15-mmol scale.
• 20 We have tried the oxidation of 1-hexadecanol (aliphatic primary alcohol) under optimized condition. However no oxidation took place, resulting in recovery of the starting material. Oxidation of 3-undecanol (aliphatic secondary alcohol) under optimized conditions proceeded sluggishly to afford the corresponding ketone in 38% yield. Furthermore, oxidation of substrates possessing alkenyl moiety such as 1-phenyl-5-hexen-1-ol and cinnamyl alcohol did not proceed well probably due to the rapid consumption of catalytically active [Br⁺] species by olefin.
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• 22 For a detail, see the Supporting Information.
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• 25 The amount of [Br⁺] was determined by titration using cyclohexene in hexane (three independent experiments). After titration, usual aqueous work up was performed, and major product from the reaction with cyclohexene was found to be trans-1,2-dibromocyclohexane, indicating the formation of Br₂ instead of other [Br⁺] species, see the Supporting Information.
• 26 Because we observed vigorous evolution of gas immediately after mixing NaBr, AcOH, TEMPO, and H₂O₂, TEMPO might promote the decomposition of H₂O₂.
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• 28 NaOAc-assisted dehydrobromination like E2-elimination is an alternative possibility for step C.
• 29 General Procedure for NaBr-Catalyzed Oxidation: Under a nitrogen atmosphere, to a solution of substrate alcohol (0.5 mmol) in AcOH (1.0 mL) or AcOH–EtOAc (3:7, 2.0 mL) was added a stock solution of aq NaBr solution (1.94 M, 25 μL) and 30% aq H₂O₂ (50 μL, 0.5 mmol). After stirring the mixture for 1 h at 60 °C, additional 30% aq H₂O₂ (50 μL, 0.5 mmol) was added, and stirring was continued for another 1 h. After cooling, the mixture was poured into a sat. aq NaHCO₃ solution (ca. 30 mL) with the aid of CH₂Cl₂, and the resulting mixture was extracted with CH₂Cl₂. The combined organic layers were dried over anhyd MgSO₄, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (flash column or preparative TLC) to afford the corresponding ketone. Caution: When the reaction is carried out on a large scale, treatment of the combined organic layers with aq Na₂S₂O₃ solution is recommended to avoid unexpected explosion. 1-Phenylnonan-1-one (2a): Compound 2a was obtained according to the general procedure and purified by preparative TLC (hexane–EtOAc, 20:1) as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 7.96 (d, J = 7.5 Hz, 2 H), 7.54–7.57 (m, 1 H), 7.45–7.48 (m, 2 H), 2.96 (t, J = 7.5 Hz, 2 H), 1.74 (m, 2 H), 1.27–1.44 (m, 10 H), 0.88 (t, J = 6.9 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 200.6, 137.0, 132.8, 128.5, 128.0, 38.6, 31.8, 29.4, 29.3, 29.1, 24.3, 22.6, 14.1. The NMR data are in agreement with those previously reported in literature (see ref. 30).
• 30 Vautravers NR, Regent DD, Breit B. Chem. Commun. 2011; 47: 6635