C(sp3)-H Fluorination with a Copper(II)/(III) Redox Couple

Abstract

<p>Despite the growing interest in the synthesis of fluorinated organic compounds, few methods are able to incorporate fluoride ion directly into alkyl C-H bonds. Here, we report the C(sp<sup>3</sup>)-H fluorination reactivity of a formally copper(III) fluoride complex. The C-H fluorination intermediate, <b>L</b>CuF, along with its chloride and bromide analogs, <b>L</b>CuCl and <b>L</b>CuBr, were prepared directly from halide sources with a chemical oxidant and fully characterized. While all three copper(III) halide complexes capture carbon radicals efficiently to afford C(sp<sup>3</sup>)-halogen bonds, <b>L</b>CuF is two orders of magnitude more efficient at hydrogen atom abstraction (HAA) than <b>L</b>CuCl and <b>L</b>CuBr. Alongside reported kinetic data for other <b>L</b>Cu(III) species, we established a positive correlation between ligand basicity and the rate of HAA. The capability of <b>L</b>CuF to perform both hydrogen atom abstraction and radical capture was leveraged to enable fluorination of allylic and benzylic C-H bonds and α-C-H bonds of ethers at room temperature.</p>

Hydroxyl Transfer to Carbon Radicals by Mn(OH) vs Fe(OH) Corrole Complexes

“…15 Related studies in nonheme chemistry have been carried out recently by us and others for Fe, Cu, and Ni. [16][17][18][19][20][21][22][23] Synthetic, heme-based catalysts are also known to proceed through a mechanism similar to that shown in Scheme 1. In the synthetic systems, metals other than iron can be employed, and manganese porphyrins were employed successfully to carry out challenging C-H hydroxylation and halogenation reactions.…”

A General Strategy for C(sp3)–H Functionalization with Nucleophiles Using Methyl Radical as a Hydrogen Atom Abstractor

“…53 The development of allylic C(sp 3 )-H fluorination methods has proven challenging, as most electrophilic reagents and stoichiometric oxidants utilized in fluorination methodologies favor olefin oxidation over C(sp 3 )-H functionalization; alternatively most sources of fluoride facilitate competitive elimination. 29,37,54,55 As an illustration of the mildness of a HAT-ORPC strategy, the fluorination of cyclohexene proceeded in 55% yield (39), a significant improvement to our prior efforts in the allylic C(sp 3 )-H fluorination of this substrate using a Pd/Cr cocatalyst system. 37 Furthermore, the fluorination of 4-methyl-2-pentenoic acid and the pesticide rotenone occurred in 14% and 33% yield, respectively (40 and 41).…”

“…34,35 Few reports detailing C(sp 3 )-H fluorination with fluoride have been disclosed, due not only to the broad challenges posed by C(sp 3 )-H activation, but also the attenuated nucleophilicity of fluoride. 18,25,29,[36][37][38] Despite these challenges, the development of nucleophilic C(sp 3 )-H fluorination methods is desirable given the low cost of fluoride sources and their application to radiofluorination for positron emission tomography (PET) imaging. 35 To evaluate the feasibility of the HAT-ORPC strategy for C(sp 3 )-H fluorination, we investigated the conversion of diphenylmethane to fluorodiphenylmethane 2 using a variety of phthalimide-derived HAT precursors (Table 1).…”

“…[25][26][27][28] Zhang and coworkers have also developed a fluorination of C(sp 3 )-H bonds using a Cu III fluoride complex generated in situ from fluoride. 29 While highly enabling, the requirement for strong or super-stoichiometric oxidants in these methods limits their application in synthesis and generality across diverse nucleophile coupling A. C(sp 3 )-H bond-breaking strategies…”

Contemporary synthetic strategies in organofluorine chemistry

“…65 Recently, a novel method has been reported for generating carbon-centred radicals for C-H fluorination using formal Cu III fluorides. 66 A further advance in the field is a bioinspired manganese-porphyrin 67 and later benzylic C-H bonds. 68 The nucleophilic fluorine source used in the above method can be used for 18 F-radiolabeling.…”