Regioselective Chlorination and Suzuki–Miyaura Cross-Coupling of 4-Alkoxycoumarins, 4-Alkoxy-2-pyrones, and Related Heterocycles

Chlorination of the coumarin framework was achieved by using trichloroisocyanuric acid, which has several advantages over N-chlorosuccinimide, particularly with respect to cost-effectiveness and toxicity. The Suzuki–Miyaura cross-coupling of the chlorinated 4-alkoxycoumarins with a range of aryl- and heteroarylboronic acids was then carried out in the presence of Pd(OAc)₂ and 2-(dicyclohexylphosphino)-2′,6′-dimethoxybiphenyl (SPhos) in an environmentally benign solvent. This transformation afforded the coupled products in yields up to 99 %. Sensitive functional groups such as aldehydes and nitriles were tolerated under the reaction conditions, and the protocol could be performed on a gram scale. The cross-coupling method was also successfully extended to related 2-pyrone, 2-pyridone, and 2-quinolone derivatives to give yields up to 96 %. This is the first time cross-coupling conditions have been shown to be general across this range of heterocyclic substrates. The demethylation of the Suzuki–Miyaura products allowed for access to 3-aryl-4-hydroxycoumarins.