Sequential Bromination/Dearomatization Reactions of 2-Methoxyphenols en route to Bromo-Substituted ortho-Quinonemonoacetals

Abstract

A novel method involving the sequential dibromination and dearomatization of 2-methoxyphenols with N-bromosuccinimide (NBS) is described, providing rapid access to brominated ortho-quinone monoacetals (o-QMAs). Our method demonstrates two notable aspects: (1) the introduction of a bromo group(s) into the aromatic ring and its subsequent conversion into o-QMAs in a single operation, and (2) the use of NBS as a convenient oxidant in oxidative dearomatization reactions.

Key words

bromination - oxidation - dearomatization - phenols - quinone monoacetals

• References and Notes

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For selected reviews on o-QMAs, see:
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• 6 A related study on NBS-mediated synthesis of 1,2-naphthoquinone from 2-naphthol via bromination followed by oxidative dearomatization has been reported: Sim J, Jo H, Viji M, Choi M, Jung J.-A, Lee H, Jung J.-K. Adv. Synth. Catal. 2018; 360: 852
• 7 The Experimental Procedure To a mixture of 2,3-dimethoxyphenol (55.3 mg, 0.359 mmol) in MeOH (3.6 mL) was added NBS (195 mg, 1.09 mmol) at 0 °C. After stirring for 10 min at this temperature, the mixture was diluted with EtOAc, which was extracted with EtOAc (3×). The combined organic layer was washed with H₂O (2×) and brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EtOAc = 15:1) to afford o-QMA 2a (98.7 mg, 81%) as a yellow amorphous solid. Spectral data of 2a matched the reported data in ref. 4.
• 8 While the precise intricacies of the reaction mechanism for the oxidative dearomatization remain to be elucidated, we propose plausible pathways which may involve the intermediacy of aryl hypobromite G or dienones H, I, and J (Figure 2).
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• 10 It should be noted that the corresponding p-QMAs 11 and 12 could be involved as well as the o-QMAs as intermediates in these reactions: upon treatment of 4-methoxyphenol with NBS (1.05 equiv) in MeOH (0 °C, 40 min), oxidative dearomatization proceeded to afford the corresponding p-QMA in 61% yield (Scheme 5). Note that no aromatic bromination occurred in this reaction, although the reason is not clear.
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• 12 Although the position of the coupling reaction could not be directly confirmed, it could be reasonably assigned from the structure of the byproducts, which were obtained through several attempted second coupling reactions. For details, see the Supporting Information. The observed regioselectivity at the α-position may attribute to favorable frontier molecular orbital interaction between the LUMO of 2a and the HOMO of the Pd(0) catalyst in the transition state. The computed LUMO of 2a (B3LYP/6-31++G(d,p) in vacuum) showed a larger coefficient at the α-position than at the γ-position (Figure 3), which would induce a faster oxidative addition of Pd(0). For the related discussion on 3,5-dibromo-2-pyrone, see: Palani V, Hugelshofer CL, Kevlishvili I, Liu P, Sarpong R. J. Am. Chem. Soc. 2019; 141: 2652 ; and references therein
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