Versatile Synthesis of Isocoumarins and α-Pyrones by Ruthenium-Catalyzed Oxidative C–H/O–H Bond Cleavages

Abstract

An inexpensive cationic ruthenium(II) catalyst enabled the expedient synthesis of isocoumarins through oxidative annulations of alkynes by benzoic acids. This C-H/O-H bond functionalization process also proved applicable to the preparation of α-pyrones and was shown to proceed by rate-limiting C-H bond ruthenation.

A decarboxylative approach for regioselective hydroarylation of alkynes

“…Ruthenium catalysts have been explored rarely as promoters of the decarboxylation of benzoic acids 47 . A major challenge was to achieve high chemoselectivity to promote hydroarylation product 3a over multiple by-products from reported coupling reactions, which include alkyne hydrocarboxylation (4a) 29 , oxidative [4+2] heterocyclization (5a) 48 and oxidative [2+2+2] carbocyclization via decarboxylation (6a) 35 . To this end, we evaluated a wide range of reaction parameters, such as ruthenium catalyst precursor, ligand, salt additive, solvent and reaction temperature.…”

“…Unsymmetrical aryl-alkyl alkynes reacted with exclusive regioselectivity to form 1-alkyl-1-meta-anisyl alkene products (3bb-3bf ). Methyl-, ethyl-and n-butyl-substituted phenylacetylenes were less reactive than diphenylacetylene (2a) and required 20 mol% Cu(OAc) 2 additive to give products 3bb-3bd in 60-77% yields as well as small amounts of the isocoumarin by-product 5 and the naphthalene by-product 6a from oxidative annulation reactions 35,48 . The observed higher overall yields and lower chemoselectivity with added Cu(OAc) 2 probably results from its wellknown role as an oxidizing reagent for ruthenium-catalysed oxidative C-H functionalization processes 26,49 .…”

“…Both Path A and Path A′ feature decarboxylation assisted by coordination of the ortho-alkenyl moiety, which occurs through π-alkene complexation in Path A and σ-alkenyl ligation in Path A′. As a competing process, C−O bond-forming reductive elimination from III would generate an isocoumarin 5 as the by-product of oxidative [4+2] annulation (Path B) 48 . As a third possible reaction of III, the insertion of a second equivalent of alkyne 2 into the Ru-alkenyl bond (Path C) would lead to the formation of an oxidative [2+2+2] by-product 6 via sequential decarboxylation and C−C reductive elimination to close the ring 35 .…”

“…1d). This catalytic process operates by a tandem sequence that involves an initial C-H activation stage during which the carboxyl group causes a specific C-H bond to add to the metal and an alkyne subsequently inserts into the metal-aryl bond to form an ortho-alkenylbenzoic acid intermediate (IIa) 27,48 . This coupling of the arene with the alkyne is followed by a decarboxylation stage in which the newly installed alkenyl moiety coordinates to the metal centre of a carboxylate intermediate to facilitate CO 2 release either as an alkenyl σ-donor ligand (III) or as a π-olefin ligand (III′).…”

Total synthesis of Sparstolonin B, a potent anti-inflammatory agent

“…[29][30][31][32][33][34] Therefore, the rhodium-catalysed oxidative coupling would be used to construct ring C and the oxidation-cyclization reaction would be used to construct ring B, which would complement the core structure of SsnB.…”