This work was financially supported by Grants-in-Aid from the Japan Society for the Promotion of Science (JSPS, 21H02068 and 21H05211), the Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from the Japan Agency for Medical Research and Development (AMED, 22ama121042j0001 and 22ama121034j0001), and the Tokyo Biochemical Research Foundation.
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.
5 Although not extensively investigated, sequential monoiodination and oxidative dearomatization of 2-methoxyphenol by iodine have been reported:
Andersson G,
Berntsson P.
Acta Chem. Scand., Ser. B 1975; 29: 948
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
7The 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).
9
Urankar D,
Rutar I,
Modec B,
Dolenc D.
Eur. J. Org. Chem. 2005; 2349
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.
11a
Ziegler K,
Späth A,
Schaaf E,
Schumann W,
Winkelmann E.
Justus Liebigs Ann. Chem. 1942; 551: 80
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
