A General and Efficient Solution to Monofluoroalkylation: Divergent Synthesis of Aliphatic Monofluorides with Modular Synthetic Scaffolds

Abstract

Monofluoroalkanes are important in many pharmaceuticals, agrochemicals and functional materials. However, the lack of easily available and transformable monofluoroalkylating reagents that facilitate a broad array of transformations has hampered the application of monofluoroalkylation. Herein, we report a general and efficient method of preparing diverse aliphatic monofluorides with monofluoroalkyl triflate as the synthetic scaffold. Using both nickel-catalyzed hydromonofluoroalkylation of unactivated alkenes and copper-catalyzed CÀ C bond formation, the general diversification of the monofluoroalkylating scaffold has been exhibited. The broad utility of this monofluoroalkylating reagent is shown by concise conversion into various conventional fluoroalkylating reagents and construction of monofluoro-alkoxy, -alkylamino motifs with commercially available heteroatom-based coupling partners.

Unlocking geminal fluorohaloalkanes in nucleophilic fluoroalkylation chemistry: generation and trapping of lithiumfluorocarbenoids enabled by flow microreactors

“…8 Among the available fluorinated reagents, 1-halo-1-fluoroalkanes are emerging as a powerful platform to access secondary alkyl fluorides. 9,10 First, these reagents can serve as electrophilic partners in nucleophilic substitution to access fluoroalkanes (Scheme 1a). 11 Second, most applications of 1-halo-1-fluoroalkanes rely on transition-metal catalyzed fluoroalkylations, as recently demonstrated by Gandelman, 12 Wang, 13 and Martin (Scheme 1b and c).…”

Photoinduced Copper-Catalyzed Monofluoroalkylation of Terminal Alkynes to Propargylic Fluorides

“…With our continuous interest in transition-metal-catalyzed monofluoroalkylation , and photoinduced metal-catalyzed transformations, herein, a photoinduced copper-catalyzed coupling of terminal alkynes and aliphatic fluorides was reported (Scheme c). With easily synthesized monofluoroalkyl triflate as the fluoroalkylating agent, this photoinduced catalytic system has demonstrated high-catalytic activity, mild conditions, and broad substrate scope, thus enabling the late-stage fluoroalkylation of biological science molecules.…”

“…Recently, a Sonogashira cross-coupling of alkyl iodides and terminal alkynes was established to construct a C­(sp)–C­(sp 3 ) bond via photoexcited Cu­(I) complexes, which obviated the need for palladium or nickel catalysts . Encouraged by this photoinduced copper-catalyzed strategy, other different alkyl radical precursors, including redox-active esters and cycloketoximes, have also been used to couple terminal alkynes to realize the construction of C­(sp)–C­(sp 3 ) bonds under the catalysis of excited copper complexes, thereby furnishing a variety of alkylated alkynes. − Our group recently reported a two-step, one-pot synthetic route for monofluoroalkyl triflate, which served as a versatile and efficient monofluoroalkylation reagent to prepare diverse aliphatic monofluorides . Therefore, we envision that monofluoroalkyl triflate could be used as a modular synthetic scaffold to synthesize propargyl fluoride via a C­(sp)–C­(sp 3 ) coupling strategy instead of the known C–F bond-forming methods (Scheme b).…”

Ni-Catalyzed Site-Selective Hydrofluoroalkylation of Terminal and Internal Olefins

“…Given that an increase of sp 3 character in drug candidates has been shown to contribute to clinical success, chemists have been challenged to design new catalytic fluoroalkylations − that complement classical C–F bond formations requiring expensive and/or nonreadily available reagents. − Driven by the emerging demand for forging sp 3 architectures from abundant olefin feedstocks, a particularly rewarding scenario would consist of a site-selective catalytic monofluoroalkylation of unactivated olefins, raw materials obtained in bulk from petroleum processing. In our continuing interest in Ni-catalyzed reactions and olefin functionalization, we report herein the accomplishment of this goal (Scheme ).…”

“…This result tacitly illustrates the potential of light olefin feedstocks to rapidly and reliably homologate alkyl side chains by incorporating monofluorinated backbones. This observation was further assessed by accessing 25 an intermediate en route to a known Δ desaturase inhibitorfrom the formal coupling of ethyl dec-9-enoate, propene, and CHFBr 2 (bottom).…”