Gold-Catalyzed Direct Arylation

Abstract

Biaryls (two directly connected aromatic rings, Ar(1)-Ar(2)) are common motifs in pharmaceuticals, agrochemicals, and organic materials. Current methods for establishing the Ar(1)-Ar(2) bond are dominated by the cross-coupling of aryl halides (Ar(1)-X) with aryl metallics (Ar(2)-M). We report that, in the presence of 1 to 2 mole percent of a gold catalyst and a mild oxidant, a wide range of arenes (Ar(1)-H) undergo site-selective arylation by arylsilanes (Ar(2)-SiMe(3)) to generate biaryls (Ar(1)-Ar(2)), with little or no homocoupling (Ar(1)-Ar(1)/Ar(2)-Ar(2)). Catalysis proceeds at room temperature and tolerates a broad range of functional groups, including those incompatible with cross-coupling. These features expedite biaryl preparation, as demonstrated by synthesis of the nonsteroidal anti-inflammatory diflunisal.

Formal Synthesis of (±)-Allocolchicine Via Gold-Catalysed Direct Arylation: Implication of Aryl Iodine(III) Oxidant in Catalyst Deactivation Pathways

“…In conclusion, we have developed a synthetic route to a number of allocolchinoid analogues, including a formal synthesis of (±)-allocolchicine (±)-5 using a gold-catalysed direct arylation [1][2][3][4][5][6] in the key bond-forming step. The reaction is vulnerable to severe catalyst deactivation, with the likely cause identified as in situ inhibitor generation, involving a direct (uncatalysed) reaction of the substrate with the iodine(III) oxidant.…”

“…It is thus clear from this study that moving away from hypervalent iodine oxidants to other species will be essential in expanding the generality and utility of the Au-catalysed arylation reaction [1][2][3][4][5]. Despite this, the methodology in its current state provides a number of advantages over other processes, e.g.…”

“…Thus, beyond the simple substrates that are frequently employed for initial reaction discovery, complex Abstract A concise formal synthesis of racemic allocolchicine has been developed, centred on three principal transformations: a retro-Brook alkylation reaction to generate an arylsilane, a gold-catalysed arylative cyclisation to generate the B-ring via biaryl linkage, and a palladiumcatalysed carbonylation of an aryl chloride to generate an ester. 1 H NMR monitoring of the key gold-catalysed cyclisation step reveals that a powerful catalyst deactivation process progressively attenuates the rate of catalyst turnover. The origins of the catalyst deactivation have been investigated, with an uncatalysed side-reaction, involving the substrate and the iodine(III) oxidant, identified as the source of a potent catalyst poison.…”

“…In 2012 we reported a new C-C bond-forming reaction involving the coupling of arylsilanes with arenes, using a gold(III) catalyst in the presence of a stoichiometric ArIX 2 oxidant, Scheme 1 [1]. The methodology was initially established as an intermolecular process, and the mechanism shown to involve sequential auration of the silane then arene, followed by reductive elimination from a diaryl gold intermediate [2].…”

“…A mixture of iodobenzene diacetate and camphorsulfonic acid can be used where HCIB is formed in-situ Scheme 2 Cyclisation to generate an allocolchinoid skeleton (4) ∆ Scheme 3 Formal synthesis of allocolchicine, (±)-5. dcpp = 1,3-Bis(dicyclohexylphosphino)propane the intermolecular arylation of a broad range of heteroarenes at room temperature [5], and developed intramolecular arylations to generate 5-9 membered rings [6]. Of the more than 140 examples of the Au-arylation reaction studied to date [1][2][3][4][5][6], the majority proceed efficiently with low catalyst loadings (typically 1-2 mol% Au) under mild conditions, and quite frequently at ambient (20-25 °C) temperature.…”