C–H activation has emerged as a viable alternative to traditional C–C bond forming reactions such as the Suzuki–Miyaura, Stille, Negishi and others. However, C–H activation is rarely employed in total synthesis or fine chemical manufacture, particularly as an end‐game strategy. This may be due to the harsh conditions typically required. For C–H activation to become a truly useful and versatile methodology, conditions must emerge which are applicable to compounds with multiple functionalities. In this review, we hope to inspire the chemistry community to focus their efforts on milder conditions for C–H activation and cross‐dehydrogenative coupling. To this end, we have focused on describing C–H activation as it has been applied to several classes of biologically interesting, but chemically sensitive motifs: the 2‐pyrones, 2‐pyridones, 2‐coumarins and 2‐quinolones.
Aryl-heteroaryl coupling via double C-H activation is a powerful transformation that avoids the installation of activating groups. A double C-H activation of privileged biological scaffolds, 2-coumarins and 2-pyrones, is reported. Despite the rich chemistry of these molecular frameworks, the yields are very good. Excellent regioselectivity was achieved on the pyrones. This methodology was applied to the synthesis of flemichapparin C in three steps. Isotope effect experiments were carried out, and a mechanism is proposed.
Direct arylation represents a favourable alternative to traditional cross‐coupling reactions and has found widespread use with simple aryls and robust heterocycles. Herein a direct arylation protocol has been optimised and applied to more delicate, privileged biological motifs. The intramolecular direct arylation of 2‐pyrones, 2‐coumarins, 2‐pyridones and 2‐quinolones occurs in very good to excellent yields using a Pd0 source and pivalic acid as a crucial additive. Preliminary mechanistic investigations were also carried out.
Direct arylation represents a favorable alternative to traditional cross-coupling and has found widespread use with simple aryls and robust heterocycles. Herein a direct arylation protocol has been optimized and applied to 2-pyrones, which are delicate and privileged biological motifs. Regioselective halogenation at the 3-position allows intramolecular coupling by activation of a pyrone C-Br or C-Cl bond and a phenoxy C-H bond. Importantly, electron-poor phenoxy substrates also worked well. The methodology was extended to 2-coumarins and applied to the synthesis of flemichapparin C and a novel analogue. Deuterium isotope effects, typical of a concerted metalation-deprotonation (CMD) mechanism, were observed in the case of a bromopyrone, but a highly unusual, inverse kinetic isotope effect was evident using a chlorocoumarin, implying that a different mechanism is operating.
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.
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