Facile Access to Fluoromethylated Arenes by Nickel‐Catalyzed Cross‐Coupling between Arylboronic Acids and Fluoromethyl Bromide

Abstract

The nickel-catalyzed fluoromethylation of arylboronic acids was achieved with the industrial raw material fluoromethyl bromide (CH2 FBr) as the coupling partner. The reaction proceeded under mild reaction conditions with high efficiency; it features the use of a low-cost nickel catalyst, synthetic simplicity, and excellent functional-group compatibility, and provides facile access to fluoromethylated biologically relevant molecules. Preliminary mechanistic studies showed that a single-electron-transfer (SET) pathway is involved in the catalytic cycle.

Nickel‐Catalyzed Methylation of Aryl Halides with Deuterated Methyl Iodide

“…We started our investigations with amodel reaction using 4-butyl-iodobenzene (1a)a nd CH 3 I. When the reaction was conducted with several bidentate nitrogen-containing ligands, which were commonly employed in nickel-catalyzed crosscoupling reactions, [16] no desired product was obtained (see entries 1-4 of Table S1 in the Supporting Information). We suspected that nitrogen-containing ligands might be involved in N-methylation side reactions and not suitable for methyl iodide substrate.T hus,w eswitched our focus on phosphorus ligands.T oo ur delight, the desired methylation product 2a was obtained in 7% yield by using dppp as aligand ( Table 1, entry 1).…”

Nickel‐Catalyzed Reductive Cross‐Coupling of Aryl Halides with Monofluoroalkyl Halides for Late‐Stage Monofluoroalkylation

“…This method has demonstrated high catalytic reactivity and broad scope, thus enabling the late‐stage fluoroalkylation of different drugs. The key to success is the combination of diverse readily available bidentate and monodentate pyridine‐type ligands for nickel, which generated a number of highly active catalysts to promote the cross‐coupling of a broad range of both electrophiles. This strategy based on combinatorial catalysis offers a new solution to nickel‐catalyzed reductive cross‐coupling reactions and provides a new method for the facile synthesis of α‐fluoroalkylated arenes.…”

Reagenzien für die selektive Fluormethylierung: Herausforderungen der Organofluorchemie

“…So können Arylboronsäureester oder Arylboronsäuren durch Kupplung mit CH 2 FI, CH 2 FBr oder CHRFBr (R=CO 2 Et, SO 2 Ph) in Pd 0 ‐ (Suzuki, Hu, Qing), Cu I ‐ (Qing) bzw. Ni II ‐katalysierten (Zhang, X.‐S. Wang) Reaktionen in die entsprechenden Fluormethylderivate überführt werden.…”