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

Abstract

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.

Palladium‐Catalyzed Selective Carbofunctionalization of Inert γ‐C(sp3)−O Bonds with 4‐Hydroxypyridin‐2(1H)‐ones and 4‐Hydroxy‐2H‐pyran‐2‐ones

“…There has been considerable activity focused on the development of efficient and general methods for the construction of 4‐hydroxypyridin‐2( 1H )‐one and 4‐hydroxy‐ 2H ‐pyran‐2‐one because of their comprehensive pharmacological profiles such as anti‐tumor and antivirus activities. Among these, a strategy that uses 4‐hydroxypyridin‐2( 1H )‐one [2a–j] and 4‐hydroxy‐ 2H ‐pyran‐2‐one [2k] as the starting material has been demonstrated as an important strategy ascribed to its bi‐functional character. Consequently, development of efficient methods for the synthesis and structural modifications of 4‐hydroxypyridin‐2( 1H )‐ones and 4‐hydroxy‐ 2H ‐pyran‐2‐ones is still in urgent need.…”

Access to Some C5‐Cyclised 2‐Pyrones and 2‐Pyridones via Direct Arylation; Retention of Chloride as a Synthetic Handle

“…We therefore tested the conditions reported by Hultin for the Suzuki–Miyaura cross‐coupling of an α‐chloro‐α,β‐unsaturated ester (Table , entry 3) . To our delight, similar conditions gave 60 % conversion to the desired product 15 . Using KOAc as base (Table , entry 4), gave a slightly increased conversion (to 70 %).…”

3-Phenylcoumarins as a Privileged Scaffold in Medicinal Chemistry: The Landmarks of the Past Decade

“…The demethylation of the Suzuki-Miyaura products allowed obtaining 3-aryl-4-hydroxycoumarins. Chlorination of the coumarin framework was achieved by using trichloroisocyanuric acid (C 3 Cl 3 N 3 O 3 ), which has several advantages over N-chlorosuccinimide, particularly regarding cost-effectiveness and toxicity [28].…”