Coumarin to Isocoumarin: One-Pot Synthesis of 3-Substituted Isocoumarins from 4-Hydroxycoumarins and Benzyne Precursors

Abstract

A novel transition-metal-free direct synthesis of 3-substituted isocoumarin from 4-hydroxycoumarin and a benzyne precursor is developed. This synthetic strategy proceeds via C-O and C-C bond cleavage as well as C-O and C-C bond formations in a single reaction vessel by simple treatment with CsF in the absence of catalyst. This methodology affords moderate to good yields of 3-substituted isocoumarins and is tolerant of a variety of functional groups including halide.

Discussion Addendum for: The Direct Acyl-Alkylation of Arynes. Preparation of Methyl 2-(2-acetylphenyl)acetate

“…21 Isocoumarins can also be prepared under transition-metal-free conditions. 22 Biju presented methods for the synthesis of oxaphosphacycles (16), 23 phthalimides (17), 24 and indoles (18). 25 The Greaney lab has also synthesized indoles from arynes by means of a Fischer indole-type reaction.…”

Isocoumarins: General Aspects and Recent Advances in their Synthesis

“…The isomerization of coumarins to isocoumarins was achieved by performing the reaction of 4‐hydroxycoumarins with benzynes (Scheme ) …”

Ultrasound Assisted Synthesis of 3, 4-Disubstituted Isocoumarins and their Biological Evaluation

“…Because of the pharmaceutical importance of isocoumarin compounds, there has been growing interest in the development of efficient strategies for their synthesis. In this regard, various synthetic methods have been developed for the synthesis of these molecules [11][12][13][14] . The classical methods for the synthesis of these molecules have involved multiple steps, transition metal as catalyst, costly reagents / catalyst and harsh reaction conditions.…”