Unexpected One-Pot Synthesis of 3-Cinnamoyl-3-hydroxyphthalide Derivatives

Intouch Rakchaya; Phanida Thongaram; Sengchan Saiyalard; Kredmanee Yimnoi; Worawat Wattanathana; Nutthawat Chuanopparat; Paiboon Ngernmeesri

doi:10.1055/a-2312-0444

Synlett, Inhaltsverzeichnis

Synlett 2025; 36(01): 59-64
DOI: 10.1055/a-2312-0444

letter

Unexpected One-Pot Synthesis of 3-Cinnamoyl-3-hydroxyphthalide Derivatives

Intouch Rakchaya

^aDepartment of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand

,

Phanida Thongaram

^aDepartment of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand

,

Sengchan Saiyalard

^aDepartment of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand

,

Kredmanee Yimnoi

^aDepartment of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand

,

Worawat Wattanathana

^bDepartment of Materials Engineering, Faculty of Engineering, Kasetsart University, Bangkok 10900, Thailand

,

Nutthawat Chuanopparat

^aDepartment of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand

,

Paiboon Ngernmeesri ∗

^aDepartment of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand

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Abstract

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Abstract

A new and simple method to prepare 3-cinnamoyl-3-hydroxyphthalide derivatives from 2-hydroxy-3-methyl-1,4-naphthoquinone and substituted benzaldehydes was unexpectedly uncovered. The reaction was conveniently performed in DMSO at 100 °C with K₃PO₄ as a base and AlCl₃ as a catalyst. We propose that the reaction proceeds by a cascade process involving nucleophilic addition followed by demethylation and rearrangement. The products were typically obtained in moderate to good yields. The highest yield (95%) was obtained when the reaction of 2-bromobenzaldehyde was performed for 24 hours. X-ray crystallography of the product derived from 2-fluorobenzaldehyde unequivocally confirmed the structure of the hydroxyphthalide derivatives.

Key words

hydroxyphthalides - one-pot synthesis - cascade reaction - natural product - benzaldehydes

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Referenzen

References and Notes

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14 3-Hydroxy-3-[(2E)-3-(2-iodophenyl)prop-2-enoyl]-2-benzofuran-1(3H)-one (11a):Typical Procedure Compound 9 (50 mg, 0.27 mmol), AlCl₃ (7 mg, 0.05 mmol), 2-iodobenzaldehyde (6a) (0.43 mmol), and K₃PO₄ (169 mg, 0.80 mmol) were dissolved in DMSO (3 mL), and the mixture was stirred at 100 °C for 48 h. The resulting mixture was allowed to cool to r.t., diluted with H₂O (50 mL), and extracted with EtOAc (3 × 50 mL). The organic extracts were combined, washed with sat. aq NH₄Cl, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel EtOAc–hexanes (1:3 and 1:2)] to give a yellow-brown solid; yield: 46 mg (43%); mp 134–136 °C. IR (neat): 3376, 1776, 1743, 1689 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.13 (d, J = 15.5 Hz, 1 H), 8.02 (dt, J = 7.5, 1.0 Hz, 1 H), 7.87 (dd, J = 8.0, 1.2 Hz, 1 H), 7.77 (td, J = 7.5, 1.2 Hz, 1 H), 7.70 (td, J = 7.5, 1.1 Hz, 1 H), 7.52 (dt, J = 7.5, 1.0 Hz, 1 H), 7.35 (dd, J = 7.9, 1.7 Hz, 1 H), 7.29 (ddd, J = 7.3, 1.2, 0.6 Hz, 1 H), 7.06 (ddd, J = 8.0, 7.3, 1.7 Hz, 1 H), 6.30 (d, J = 15.5 Hz, 1 H), 5.88 (br s, 1 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 189.7, 168.3, 152.0, 145.1, 140.5, 136.8, 135.6, 132.7, 131.9, 128.8, 128.0, 127.5, 126.3, 123.6, 119.2, 102.6, 102.4. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₁INaO₄: 428.9594; found: 428.9590.

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16 CCDC 2311144 contains the supplementary crystallographic data for compound 6c. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures. See also the Supporting Information for more details.

Zusatzmaterial

Supporting Information