Modular three-component radical fluoroalkyl-sulfuration of unactivated alkenes

doi:10.1016/S1872-2067(24)60190-7

Abstract

Abstract:

The accompanied forge of C(sp³)-S and C(sp³)-C(sp³) bonds across alkene frameworks serves as a potent strategy to construct biologically important compounds. Here, we report a metal-free, photochemically mediated fluoroalkyl-mono/disulfuration of unactivated alkenes with high efficiency and high selectivity. A wide range of terminal and internal alkenes are good coupling partners, affording the expected products in moderate to good yields (>90 examples). The exceedingly mild reaction conditions, exceptional functional group tolerance, broad substrate scope, and the potential for late-stage modifications of pharmaceutical molecules highlight the utility of this method in the preparation of privileged motifs from readily available disulfides, tetrasulfides, and diselenides. Mechanistic studies suggest that a secondary alkyl radical intermediate undergoes efficient homolytic substitution with disulfides, facilitating the modular synthesis of a diverse array of unsymmetrical thioethers.

Key words: C(sp³)-S bond, Unactivated alkenes, Photoredox catalysis, Fluoroalkylation, Unsymmetrical thioethers

Gao-feng Yang, Zhi Liu, Kai Liu, Xiaopeng Wu, Chengjian Zhu, Weipeng Li, Jin Xie. Modular three-component radical fluoroalkyl-sulfuration of unactivated alkenes[J]. Chinese Journal of Catalysis, 2025, 69: 249-258.

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URL: https://www.cjcatal.com/EN/10.1016/S1872-2067(24)60190-7

https://www.cjcatal.com/EN/Y2025/V69/I2/249

Figures/Tables 7

Fig. 1. Challenges and strategies in C(sp3)-S bond construction. (a) State of art methods for the C(sp3)-S bond preparation. (b) Common strategies used for the introduction of fluorine-containing groups in alkenes. (c) Containing of thioether motifs and fluoroalkyl groups in pharmaceuticals. (d) This work: Modular radical fluoroalkyl-sulfuration of unactivated alkenes. LG, leaving group; X, leaving group; FG, functional group; PC, photocatalyst.

Table 1 Optimization of the reaction conditions a.

Entry	Variation of standard conditions	Yield^b (%)
1	none	81(75) ^c
2	PC1 instead of 4CzIPN	78
3	PC2 instead of 4CzIPN	ND
4	TMG instead of BTMG	70
5	440 nm LEDs	72
6	390 nm LEDs	25
7	without BTMG	trace
8	without 4CzIPN	ND
9	without light	ND

Fig. 2. Scope of alkenes and fluoroalkylating reagents. The reactions were carried out in 0.1 mmol scale. a The diastereomeric ratio (d.r.) was determined by crude 1H NMR spectroscopy. b TMG (1.0 equiv.) was used as base.

Fig. 3. Substrate scope of disulfides/diselenides/tetrasulfides. The reactions were carried out in 0.1 mmol scale. a The diastereomeric ratio (d.r.) was determined by crude 1H NMR spectroscopy. b The base was DBU (0.8 equiv.). c 3.0 equiv. of BTMG was used.

Fig. 4. Modification of natural products or derivatives. The reactions were carried out in 0.1 mmol scale. a The diastereomeric ratio (d.r.) was determined by crude 1H NMR spectroscopy. b The base was TMG (1.0 equiv.). c 3.0 equiv. of BTMG was used.

Fig. 5. Gram-scale reactions and diversification of products. a 3.0 equiv. of BTMG was used. b The diastereomeric ratio (d.r.) was determined by crude 1H NMR spectroscopy.

Fig. 6. Mechanistic studies. a The E/Z configurations was determined by crude 1H NMR spectroscopy.

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