Pd-Catalyzed C(sp³)–H Biarylation via Transient Directing Group Strategy

Abstract

Here, we describe a highly selective Pd-catalyzed C­(sp3)–H biarylation of 2-methylbenzaldehydes using cyclic diaryliodonium salts as arylation reagents. The key strategy is the employment of tert-leucine as a bidentate transient directing group for the proximity-driven metalation to achieve reactivity and selectivity in C–H activation. Various functionalized biaryls bearing both aldehyde and iodine functional groups were prepared successfully, which could be further transformed into a wide range of compounds with potential applications in pharmaceutical chemistry and materials science.

HFIP in Organic Synthesis

“…A Pd-catalyzed C–H biarylation of 2-methylbenzaldehydes utilized a transient tert -leucine bidentate DG and diaryliodinium salts for an effective transformation (Scheme ). Optimization with AcOH led to product in lower yield when compared to 9:1 HFIP/AcOH (31% vs 65%). Electron-poor or -rich 2-methylbenzaldehydes and substituted diaryliodinium salts were amenable to this method with yields ranging from 39–84%.…”

Hexafluoroisopropanol: the magical solvent for Pd-catalyzed C–H activation

“… 71 This result was the outcome of the cooperative effect between the transient directing group and external pyridone ligands in HFIP solvent medium. In addition, other research groups like Jin, 72 Ge and Li, 73 and Chen in collaboration with He, 74 Wei, 75 and Zhang 76 also contributed with their valuable results to enrich this area. However, the exact role of HFIP in the aforementioned reactions is still unknown, presumably due to the lack of computational and mechanistic studies.…”

Transient Directing Groups in Metal−Organic Cooperative Catalysis

“…Indeed, while the groups of Li, and Liu and Lou could demonstrate the ability of semicarbazide [101] and 2-dimethylaminoethylamine, [102] respectively, to act as efficient transient directing mediators (Scheme 60, c and d), the group of Bao extended the use of acetyl hydrazine as a transient directing mediator to aluminasupported nanoparticles of palladium(0) (Scheme 60, e). [103] Eventually, the groups of Bhat, Li and Zhang could extend the method to the arylation of 3-methylheteroarene-2-carbaldehydes with L-valine (Scheme 60, f), [104] to the use of glycinamide hydrochloride as a transient directing mediator (Scheme 60, g) [105] and to the biarylation of ortho-methylbenzaldehydes with cyclic diaryliodonium salt reactants using L-tert-leucine (Scheme 60, h), [106] respectively.…”