Regioselective Chlorination and Suzuki-Miyaura Cross-Coupling of 4-Alkoxy-2-Coumarins, 2-Pyrones and Related Heterocycles

Abstract: Chlorination of the 2-coumarin framework is achieved using trichloroisocyanuric acid in ethyl acetate, which offers several advantages over N-chlorosuccinimide, particularly with respect to cost-effectiveness and toxicity. The Suzuki-Miyaura cross-coupling of the chlorinated 4-alkoxy-2-coumarins with a range of aryl and heteroaryl boronic acids using Pd(OAc)2 and SPhos in an environmentally benign solvent was developed, with yields up to 99%. Sensitive functional groups such as aldehydes and nitriles are tolerated, and the conditions were demonstrated on gram scale. Extension of the cross-coupling methodology to the related 2-pyrone, 2-pyridone and 2-quinolone moieties was highly successful and yields of up to 96% were achieved, which is the first time cross-coupling conditions have been demonstrated to be general across this range of heterocyclic substrates. Demethylation of the Suzuki-Miyaura products allows access to 3-aryl-4-hydroxy-2-coumarins.

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