Base-Promoted Reactions of Hydroxyquinones with Pyrones: A Direct and Sustainable Entry to Anthraquinones and Naphthoquinones

Abstract

Hydroxybenzoquinones and hydroxynaphthoquinones react with methyl coumalate and 5-cyanopyrone to generate anthraquinones and naphthoquinones in good to excellent yields.

Key words

anthraquinone - naphthoquinone - pyrone - base-promoted - synthesis

• References and Notes

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• 8 Diels–Alder Reaction of Methyl Coumalate with Hydroxyquinone; Typical Procedure for Methyl 6-Methoxy-5,8-dioxo-5,8-dihydronaphthalene-2-carboxylate (9a) To a solution of methyl coumalate (555 mg, 3.6 mmol, 0.9 equiv) and hydroxyquinone 8 (552 mg, 4.0 mmol, 1.0 equiv) in acetonitrile (20 mL), triethylamine (405 mg, 4.0 mmol, 1.0 equiv) was added, and the solution turned dark-red immediately. The mixture was stirred under argon at 45 °C for 24 hours (monitored by ¹H NMR) then was cooled to ambient temperature. 0.5 M HCl solution was added, and the mixture was extracted with ethyl acetate three times. The organic phase was washed with brine and was dried over Na₂SO₄. Purification by column chromatography gave the product 9a (45% yield) as a light-brown solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.75 (d, J = 1.6 Hz, 1 H), 8.39 (dd, J = 8.0, 1.5 Hz, 1 H), 8.16 (d, J = 8.1 Hz, 1 H), 6.23 (s, 1 H), 3.98 (s, 3 H), 3.93 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 184.2, 179.5, 165.6, 160.9, 135.2, 134.9, 134.8, 131.3, 128.2, 126.8, 110.4, 56.8, 53.0. HRMS (ESI-QTOF): m/z [M + H]⁺ calcd for C₁₃H₁₀O₅: 247.0601; found: 247.0600. Synthesis of Tomichaedin Methyl Ester Methyl 7-Hydroxy-5,8-dioxo-5,8-dihydronaphthalene-2-carboxylate (12) Under argon, a suspension of methoxy quinone 9a (180 mg, 0.73 mmol, 1.0 equiv) and AlCl₃ (195 mg, 1.46 mmol, 2.0 equiv) in DCE (5 mL) was stirred under reflux for 1 hour. The reaction mixture was allowed to cool, 0.5 M HCl was added, and the mixture was extracted with ethyl acetate three times, and the organic phase was dried over Na₂SO₄. Filtration through a thin silica pad followed by removal of solvent afforded the product 12 as a solid, which was pure enough to use in the next step. ¹H NMR (400 MHz, CDCl₃): δ = 8.75 (d, J = 1.7 Hz, 1 H), 8.44 (dd, J = 8.0, 1.7 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 7.39 (s, 1 H), 6.43 (s, 1 H), 4.00 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 184.3, 181.4, 165.4, 156.9, 136.1, 135.7, 134.7, 129.7, 128.0, 127.3, 111.4, 53.1. HRMS (ESI-QTOF): m/z [M]^– calcd for C₁₂H₈O₅: 232.0370; found: 232.0323. Tomichaedin Methyl Ester (13) To a stainless-steel reactor, hydroxy quinone 12 (68 mg, 0.3 mmol, 1.0 equiv) was dissolved in a mixture of ethanol/water (1:1 ratio, 2 mL), and paraformaldehyde (40 mg, 1.2 mmol, 4.0 equiv) was added. The reactor was sealed under air, and was heated to 200 °C for 3 hours. After cooling, the mixture was diluted with 0.5 M HCl, and extracted with ethyl acetate. Filtration through a thin silica pad (the compound was found to be unstable on silica) afforded tomichaedin methyl ester 13 (40% over two steps) as a light-yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.71 (d, J = 1.7 Hz, 1 H), 8.39 (dd, J = 8.0, 1.8 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 3.99 (s, 3 H), 2.13 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 184.5, 180.6, 165.5, 153.7, 135.8, 135.7, 134.5, 129.7, 127.6, 127.3, 121.5, 53.0, 9.0. HRMS (ESI-QTOF): m/z [M – H]^– calcd for C₁₃H₉O₅: 245.0455; found: 245.0456