Photosensitized direct C-H fluorination and trifluoromethylation in organic synthesis

Abstract

The importance of fluorinated products in pharmaceutical and medicinal chemistry has necessitated the development of synthetic fluorination methods, of which direct C-H fluorination is among the most powerful. Despite the challenges and limitations associated with the direct fluorination of unactivated C-H bonds, appreciable advancements in manipulating the selectivity and reactivity have been made, especially via transition metal catalysis and photochemistry. Where transition metal catalysis provides one strategy for C-H bond activation, transition-metal-free photochemical C-H fluorination can provide a complementary selectivity via a radical mechanism that proceeds under milder conditions than thermal radical activation methods. One exciting development in C-F bond formation is the use of small-molecule photosensitizers, allowing the reactions i) to proceed under mild conditions, ii) to be user-friendly, iii) to be cost-effective and iv) to be more amenable to scalability than typical photoredox-catalyzed methods. In this review, we highlight photosensitized C-H fluorination as a recent strategy for the direct and remote activation of C-H (especially C(sp³)-H) bonds. To guide the readers, we present the developing mechanistic understandings of these reactions and exemplify concepts to assist the future planning of reactions.

Keywords: C–H activation; energy transfer; fluorination; photocatalysis; photosensitization; visible light.

Figure 1

Fluorine-containing drugs.

Figure 2

Fluorinated agrochemicals.

Scheme 1

Selectivity of fluorination reactions.

Scheme 2

Different mechanisms of photocatalytic activation. Sub = substrate.

Figure 3

Jablonski diagram showing visible-light-induced energy transfer pathways: a) absorption, b) IC, c) fluorescence, d) radiationless transitions, e) ISC, f) phosphorescence and g) TTET.

Figure 4

Schematic illustration of TTET.

Figure 5

Organic triplet PSCats.

Figure 6

Additional organic triplet PSCats.

Figure 7

A) Further organic triplet PSCats and B) transition metal triplet PSCats.

Figure 8

Different fluorination reagents grouped by generation.

Scheme 3

Synthesis of Selectfluor^®.

Scheme 4

General mechanism of PS TTET C(sp³)–H fluorination.

Scheme 5

Selective benzylic mono- and difluorination using 9-fluorenone and xanthone PSCats, respectively.

Scheme 6

Chen’s photosensitized monofluorination: reaction scope.

Scheme 7

Chen’s photosensitized benzylic difluorination reaction scope.

Scheme 8

Photosensitized monofluorination of ethylbenzene on a gram scale.

Scheme 9

Substrate scope of Tan’s AQN-photosensitized C(sp³)–H fluorination.

Scheme 10

AQN-photosensitized C–H fluorination reaction on a gram scale.

Scheme 11

Reaction mechanism of the AQN-assisted fluorination.

Figure 9

3D structures of the singlet ground and triplet excited states of Selectfluor^®.

Scheme 12

Associated transitions for the activation of acetophenone by violet light.

Scheme 13

Ethylbenzene C–H fluorination with various PSCats and conditions.

Scheme 14

Effect of different PSCats on the C(sp³)–H fluorination of cyclohexane (39).

Scheme 15

Reaction scope of Chen’s acetophenone-photosensitized C(sp³)–H fluorination reaction.

Figure 10

a) Site-selectivity of Chen’s acetophenone-photosensitized C–H fluorination reaction [201]. b) Site-selectivity of Tan’s AQN-photosensitized C–H fluorination reaction [198].

Scheme 16

Formation of the AQN–Selectfluor^® exciplex Int1.

Scheme 17

Generation of the C3 2° pentane radical and the Selectfluor^® N-radical cation from the exciplex.

Scheme 18

Hydrogen atom abstraction by the Selectfluor^® N-radical cation from pentane to give the C3 2° pentane radical.

Scheme 19

Fluorine atom transfer from Selectfluor^® to the C3 2° pentane radical to yield 3-fluoropentane and the Selectfluor^® N-radical cation.

Scheme 20

Barrierless fluorine atom transfer from Int1 to the C3 2° pentane radical to yield 3-fluoropentane, AQN and the Selectfluor^® N-radical cation.

Scheme 21

Ketone-directed C(sp³)–H fluorination.

Scheme 22

Ketone-directed fluorination through a 5- and a 6-membered transition state, respectively.

Scheme 23

Effect of different PSCats on the photosensitized C(sp³)–H fluorination of 47.

Scheme 24

Substrate scope of benzil-photoassisted C(sp³)–H fluorinations.

Scheme 25

A) Benzil-photoassisted enone-directed C(sp³)–H fluorination. B) Classification of the reaction modes and transition states to rationalize the site-selectivity. C) C–H fluorination site-selectivity.

Scheme 26

A) Xanthone-photoassisted ketal-directed C(sp³)–H fluorination. B) Substrate scope. C) C–H fluorination site-selectivity.

Scheme 27

Rationale for the selective HAT at the C2 C–H bond of galactose acetonide.

Scheme 28

Photosensitized C(sp³)–H benzylic fluorination of a peptide using different PSCats.

Scheme 29

Peptide scope of 5-benzosuberenone-photoassisted C(sp³)–H fluorinations.

Scheme 30

Continuous flow PS TTET monofluorination of 72.

Scheme 31

Photosensitized C–H fluorination of N-butylphthalimide as a PSX.

Scheme 32

Substrate scope and limitations of the PSX C(sp³)–H monofluorination.

Scheme 33

Substrate crossover monofluorination experiment.

Scheme 34

PS TTET mechanism proposed by Hamashima and co-workers.

Scheme 35

Photosensitized TFM of 78 to afford α-trifluoromethylated ketone 80.

Scheme 36

Substrate scope for photosensitized styrene TFM to give α-trifluoromethylated ketones.

Scheme 37

Control reactions for photosensitized TFM of styrenes.

Scheme 38

Reaction mechanism for photosensitized TFM of styrenes to afford α-trifluoromethylated ketones.

Scheme 39

Reaction conditions for TFMs to yield the cis- and the trans-product, respectively.

Scheme 40

Substrate scope of trifluoromethylated (E)-styrenes.

Scheme 41

Strategies toward trifluoromethylated (Z)-styrenes.

Scheme 42

Substrate scope of trifluoromethylated (Z)-styrenes.

Scheme 43

Reaction mechanism for photosensitized TFM of styrenes to afford E- or Z-products.