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

• Published in: European journal of organic chemistry Vol. 2017; no. 32; pp. 4827 - 4835
• Main Authors: Prendergast, Aisling M., McGlacken, Gerard P.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.09.2017; Wiley Subscription Services, Inc
• Subjects: Aldehydes; Aromatic compounds; Chemistry; Chemistry, Organic; Chlorination; Coumarin; Cross coupling; Functional groups; Green chemistry; Halogenation; Heterocycles; Nitriles; Physical Sciences; Protecting groups; Regioselectivity; Science & Technology; Substrates; Toxicity; Heterocycles; ROUTE; DIRECT ARYLATION; ACID; 3-ARYL-4-HYDROXYCOUMARINS; COUMARINS; Cross-coupling; Protecting groups; 2-PYRONES; Halogenation; CHEMISTRY; Green chemistry; DERIVATIVES; CYCLIZATION
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201700837

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. The chlorination of biologically important 4‐alkoxycoumarins was achieved by using trichloroisocyanuric acid, a favorable alternative to N‐chlorosuccinimide. The Suzuki–Miyaura cross‐coupling of chlorinated coumarins with various boronic acids afforded the products in up to 99 % yield. This protocol was successfully applied to related 2‐pyrone, 2‐pyridone, and 2‐quinolone derivatives.