Ag(I)–C–H Activation Enables Near-Room-Temperature Direct α-Arylation of Benzo[b]thiophenes

Abstract

The first example of near-room-temperature α-arylation of benzo[ b]thiophenes is reported. The discovery rests on the observation of a switch in α-/β-regioselectivity at different loadings of Pd(dba)·CHCl in the coupling between benzo[ b]thiophene and 4-iodotoluene. We show that this unprecedented regioselectivity switch is driven by a Ag(I)-mediated C-H activation at the α-C-H position, which becomes the dominant mode of reactivity at low concentrations of Pd. Competition experiments, kinetic studies, KIE, and D/H scrambling experiments have been carried out supporting this mechanism.

Nickel-catalyzed and Li-mediated regiospecific C–H arylation of benzothiophenes

“…11,12 Among heterobiaryls, benzothiophenes are widely used as API 13,14 and optoelectronics building blocks. [15][16][17][18] In contrast to 30 years of literature on Pd [19][20][21][22][23][24] or Ir-catalyzed reactions, 25,26 the direct C-H arylation of benzothiophene using earth-abundant metal systems remains scarcely studied. For example, Daugulis and co-workers reported the C-H phenylation of benzothiophene catalyzed by the combination of 10 mol% CuI/phenanthroline and lithium 3-ethyl-3-pentanolate in N,N'dimethylpropyleneurea.…”

Is silver a mere terminal oxidant in palladium catalyzed C–H bond activation reactions?

“…While a whole range of oxidants such as copper acetate, molecular oxygen, benzoquinone, etc., are in use, [13][14][15] silver salts like silver acetate or silver triate seem to remain one of the most prominent choices. [16][17][18][19] It is inherently interesting to inquire whether the customary choice of silver salts in a gamut of different palladium-catalyzed reactions has more to do with practice or whether it could have an underlying molecular origin. A recent effort involving multiple roles of silver salt additives in the mechanism of a palladium-catalyzed meta C-H activation reaction is particularly impressive toward this end.…”

Visual kinetic analysis

“…VTNA has already been used successfully by academic and industrial research groups in metal-catalysed [25][26][27][28][29][30][31][32][33][34][35][36][37][38] and organocatalytic reactions. [39][40][41][42][43]…”