Benzylic C(sp3)-H fluorination

Abstract

The selective fluorination of C(sp³)-H bonds is an attractive target, particularly for pharmaceutical and agrochemical applications. Consequently, over recent years much attention has been focused on C(sp³)-H fluorination, and several methods that are selective for benzylic C-H bonds have been reported. These protocols operate via several distinct mechanistic pathways and involve a variety of fluorine sources with distinct reactivity profiles. This review aims to give context to these transformations and strategies, highlighting the different tactics to achieve fluorination of benzylic C-H bonds.

Keywords: C–H functionalization; benzylic; fluorination; photoredox catalysis.

Figure 1

A) Benzylic fluorides in bioactive compounds, with B) the relative BDEs of different benzylic C–H bonds reported in kcal mol⁻¹.

Figure 2

Base-mediated benzylic fluorination with Selectfluor.

Figure 3

Sonochemical base-mediated benzylic fluorination with Selectfluor.

Figure 4

Mono- and difluorination of nitrogen-containing heteroaromatic benzylic substrates.

Figure 5

Palladium-catalysed benzylic C–H fluorination with N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate.

Figure 6

Palladium-catalysed, PIP-directed benzylic C(sp³)–H fluorination of α-amino acids and proposed mechanism.

Figure 7

Palladium-catalysed monodentate-directed benzylic C(sp³)–H fluorination of α-amino acids.

Figure 8

Palladium-catalysed bidentate-directed benzylic C(sp³)–H fluorination.

Figure 9

Palladium-catalysed benzylic fluorination using a transient directing group approach. Ratio refers to fluorination (red) vs oxygenation (blue) product.

Figure 10

Outline for benzylic C(sp³)–H fluorination via radical intermediates.

Figure 11

Iron(II)-catalysed radical benzylic C(sp³)–H fluorination using Selectfluor.

Figure 12

Silver and amino acid-mediated benzylic fluorination.

Figure 13

Copper-catalysed radical benzylic C(sp³)–H fluorination using NFSI.

Figure 14

Copper-catalysed C(sp³)–H fluorination of benzylic substrates with electrochemical catalyst regeneration. Yields are NMR yields quoted vs copper catalyst.

Figure 15

Iron-catalysed intramolecular fluorine-atom-transfer from N–F amides.

Figure 16

Vanadium-catalysed benzylic fluorination with Selectfluor.

Figure 17

NDHPI-catalysed radical benzylic C(sp³)–H fluorination with Selectfluor.

Figure 18

Potassium persulfate-mediated radical benzylic C(sp³)–H fluorination with Selectfluor.

Figure 19

Benzylic fluorination using triethylborane as a radical chain initiator.

Figure 20

Heterobenzylic C(sp³)–H radical fluorination with Selectfluor.

Figure 21

Benzylic fluorination of phenylacetic acids via a charge-transfer complex. NMR yields in parentheses.

Figure 22

Oxidative radical photochemical benzylic C(sp³)–H strategies.

Figure 23

9-Fluorenone-catalysed photochemical radical benzylic fluorination with Selectfluor.

Figure 24

Xanthone-photocatalysed radical benzylic fluorination with Selectfluor II.

Figure 25

1,2,4,5-Tetracyanobenzene-photocatalysed radical benzylic fluorination with Selectfluor.

Figure 26

Xanthone-catalysed benzylic fluorination in continuous flow.

Figure 27

Photochemical phenylalanine fluorination in peptides.

Figure 28

Decatungstate-photocatalyzed versus AIBN-initiated selective benzylic fluorination.

Figure 29

Benzylic fluorination using organic dye Acr⁺-Mes and Selectfluor.

Figure 30

Palladium-catalysed benzylic C(sp³)–H fluorination with nucleophilic fluoride.

Figure 31

Manganese-catalysed benzylic C(sp³)–H fluorination with AgF and Et₃N·3HF and proposed mechanism. ¹⁹F NMR yields in parentheses.

Figure 32

Iridium-catalysed photocatalytic benzylic C(sp³)–H fluorination with nucleophilic fluoride and N-acyloxyphthalamide HAT reagent.

Figure 33

Iridium-catalysed photocatalytic benzylic C(sp³)–H fluorination with TBPB HAT reagent.

Figure 34

Silver-catalysed, amide-promoted benzylic fluorination via a radical-polar crossover pathway.

Figure 35

General mechanism for oxidative electrochemical benzylic C(sp³)–H fluorination.

Figure 36

Electrochemical benzylic C(sp³)–H fluorination with HF·amine reagents.

Figure 37

Electrochemical benzylic C(sp³)–H fluorination with 1-ethyl-3-methylimidazolium trifluoromethanesulfonate ([emim][OTf]) and HF·amine reagents.

Figure 38

Electrochemical benzylic C(sp³)–H fluorination of phenylacetic acid esters with HF·amine reagents.

Figure 39

Electrochemical benzylic C(sp³)–H fluorination of triphenylmethane with PEG and CsF.

Figure 40

Electrochemical benzylic C(sp³)–H fluorination with caesium fluoride and fluorinated alcohol HFIP.

Figure 41

Electrochemical secondary and tertiary benzylic C(sp³)–H fluorination. GF = graphite felt. DCE = 1,2-dichloroethane.

Figure 42

Electrochemical primary benzylic C(sp³)–H fluorination of electron-poor toluene derivatives. Ring fluorination–migration product yields in parentheses.

Figure 43

Electrochemical primary benzylic C(sp³)–H fluorination utilizing pulsed current electrolysis.