Diversity-Oriented Synthesis of Fluoromethylated Arenes via Palladium-Catalyzed C–H Fluoromethylation of Aryl Iodides

Abstract

Herein we report the first versatile and expeditious method for the site-selective C−H fluoromethylation of aryl iodides via Pd/norbornene cooperative catalysis, which could work as a robust toolbox for the diversity-oriented synthesis (DOS) of fluoromethylated arenes. This methodology features the use of the low-cost industrial raw material CH 2 IF as the fluoromethyl source, an excellent functional group tolerance, and a broad ipso termination scope and can be expanded to the late-stage modification of biorelevant molecules.

The synthetic versatility of fluoroiodomethane: recent applications as monofluoromethylation platform

“…Li's research group has recently employed fluoroiodomethane in a Pd-norbornene catalyzed C-H fluoromethylation of aryl iodides. 66 The authors proposed a catalytical cycle consisting of (a) oxidative addition of Pd( 0 The protocol tolerates a wide range of aryl (and heteroaryl) iodides and employs alkenes, arylboronates, and alkyl carbagermatranes as nucleophiles (Scheme 22a). Moreover, a bisfluoromethylation was also accomplished when alkenes acted as nucleophiles (Scheme 22b).…”

“…Li's research group has recently employed fluoroiodomethane in a Pd-norbornene catalyzed C–H fluoromethylation of aryl iodides. 66 The authors proposed a catalytical cycle consisting of (a) oxidative addition of Pd(0) to the aryl iodide, norbornene (NBE) insertion and ortho -C–H-activation leading to an electron-rich arylnorbornylpalladacycle (ANP) intermediate; (b) reaction of ANP with fluoroiodomethane affording a Pd( iv ) intermediate; (c) reductive elimination, NBE extrusion, termination with an appropriate nucleophile and subsequent Pd(0) catalyst regeneration (Scheme 21).…”

Fluoroiodomethane: A CH2F‐Moiety‐Delivering Agent Suitable for Nucleophilic‐, Electrophilic‐, and Radical‐Harnessed Operations

“…[66] Very recently, Li and co-workers reported the synthesis of fluoromethylated arenes via the palladi-um-catalyzed site-selective CÀ H fluoromethylation of aryl iodides, using fluoroiodomethane as the fluoromethylating agent (Scheme 15). [67] The starting aryl iodide undergoes the sequential addition with Pd(0), norbornene (NBE) insertion, and ortho-CÀ H activation to form electron-rich arylnorbornyl-palladacycle (ANP) species, which is susceptible to further reaction with CH 2 FI to give a Pd(IV) species. Subsequent reductive elimination and NBE extrusion, followed by the reaction with a nucleophile affords the desired fluoromethylated arene.…”

Modular Approach for Diversity‐Oriented Synthesis of β‐Fluoroalkylated Arenes via Pd/Norbornene Cooperative Catalysis

“…However, the synthetic potential of Catellani strategy has never been released for the direct C−H β‐fluoroalkylation of arenes, while only Liu disclosed the first ortho C−H trifluoroethylation of (hetero)aromatic iodides and indoles [12] . Inspired by the wonderful progress of Catellani reaction and driven by our interest in fluorine chemistry, [13] we recently designed the first protocol for the direct and site‐selective C−H fluoromethylation of arenes using Catellani strategy with ICH 2 F as fluoromethylation reagent, [13d] which will contribute to the diversity‐oriented synthesis (DOS) of polyfunctionalized fluoromethylated arenes. Based on these progresses, we thus further questioned the possibility of C−H β‐fluoroalkylation of arenes with β‐fluoroalkyl iodides via Catellani strategy.…”