Practical One-Pot Four-Step Synthesis of Isocoumarin-3-Carboxylic Acids

Abstract We report a facile and versatile, one-pot four-step synthesis of functionalized isocoumarin-3-carboxylic acids on a 70–100 g scale. Commercially available substituted anthranilic acids are converted into the corresponding 2-carboxydiazonium bromides, which subsequently undergo the CuBr-catalyzed Meerwein reaction with methyl-2-fluoroacrylate to afford 2-(2-bromo-2-fluoro-3-methoxy-3-oxopropyl)benzoic acids, whereas o-bromobenzoic acids are formed as minor impurities in the concomitant Sandmeyer reactions. The treatment of the reaction mixture with CH2Cl2 and aqueous NaHCO3 removes the salts of the o-bromobenzoic acids into the aqueous phase while 2-(2-bromo-2-fluoro-3-methoxy-3-oxopropyl)benzoic acids cyclize to give methyl 3-fluoro-isocoumarin-3-carboxylates whose trituration with AcOH/HCl/H3BO3 eliminates HF and hydrolyses the ester groups to afford substituted isocoumarin-3-carboxylic acids in overall 42–53% yield.

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Publication Details

Journal
Synlett
Published
2025-08-12
DOI
https://doi.org/10.1055/a-2681-6047
Primary Topic
Synthesis and Biological Activity
Type
article
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article

Practical One-Pot Four-Step Synthesis of Isocoumarin-3-Carboxylic Acids

V. N. FETYUKHIN, Bohdan A. Demydchuk, Oleg Lukin, V. S. Matiychuk et al.
Synlett
Synthesis and Biological Activity
article

Practical One-Pot Four-Step Synthesis of Isocoumarin-3-Carboxylic Acids

V. N. FETYUKHIN, Bohdan A. Demydchuk, Oleg Lukin, V. S. Matiychuk, Yevhen Karpun, Roman Y. Vasylyshyn, Alexander Shivanyuk, Sergiy М. Kovalenko, Svitlana V. Shishkina
article en

Abstract

Abstract We report a facile and versatile, one-pot four-step synthesis of functionalized isocoumarin-3-carboxylic acids on a 70–100 g scale. Commercially available substituted anthranilic acids are converted into the corresponding 2-carboxydiazonium bromides, which subsequently undergo the CuBr-catalyzed Meerwein reaction with methyl-2-fluoroacrylate to afford 2-(2-bromo-2-fluoro-3-methoxy-3-oxopropyl)benzoic acids, whereas o-bromobenzoic acids are formed as minor impurities in the concomitant Sandmeyer reactions. The treatment of the reaction mixture with CH2Cl2 and aqueous NaHCO3 removes the salts of the o-bromobenzoic acids into the aqueous phase while 2-(2-bromo-2-fluoro-3-methoxy-3-oxopropyl)benzoic acids cyclize to give methyl 3-fluoro-isocoumarin-3-carboxylates whose trituration with AcOH/HCl/H3BO3 eliminates HF and hydrolyses the ester groups to afford substituted isocoumarin-3-carboxylic acids in overall 42–53% yield.

SynlettVol. 37(01)
National Academy of Sciences of Ukraine (UA), Lviv University (UA), National University of Life and Environmental Sciences of Ukraine (UA), State Scientific Institution “Institute for Single Crystals” of National Academy of Sciences of Ukraine (UA), Institute of Bioorganic Chemistry and Petrochemistry V.P. Kukhar (UA), Institute of Organic Chemistry (UA), V. N. Karazin Kharkiv National University (UA)
Openalex Percentile: Top 74%
Synthesis and Biological Activity
DOISourceOpenAlex
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Practical One-Pot Four-Step Synthesis of Isocoumarin-3-Carboxylic Acids — V. N. FETYUKHIN, Bohdan A. Demydchuk, et al. · Synlett (2025) | TGRS Research Map | TGRS