Fluoroalkenes

Fluoroalkenes

Introduction

Fluoroalkenes are very useful fluorinated building blocks in many chemists' synthetic work. They can prepare organic fluorides containing different groups. Fluoroalkenes are also widely used in the synthesis of bioactive molecules, and can prepare target molecules with various pharmacological activities such as anti-cancer, antibacterial, anti-HIV, and anti-diabetes. Therefore, fluoroalkenes have received increasing attention in organic synthesis and medicinal chemistry.

Synthesis

At present, there have been many methods for the synthesis of fluoroalkenes. Among them, the one-pot reaction can conveniently prepare fluoroalkenes. For example, Shimizu et al. reported a one-pot synthesis of trifluoromethyl-substituted alkenes. Specifically, they used an organolithium reagent R²Li to treat 2-substituted 3,3-dichloro-1,1,1-trifluoropropan-2-ol in THF at  -98 ℃, which produced intermediate 2,3-disubstituted 2-lithio-3-trifluoromethyloxirane. And then reacted with an organoborane R³B(OCMe₂)₂ to obtain trifluoromethyl-substituted alkenes with excellent stereoselectivity^[1].

Fig.1 Synthesis of trifluoromethyl-containing fluoroalkenes through one-pot reaction

In addition, Crudden's group developed a method for the synthesis of fluoroalkenes through the Ramberg-Bäcklund reaction. They used alkyl sulfone compounds and organomagnesium compounds to synthesize a series of gem-difluoroalkenes through the Ramberg-Bäcklund reaction. This protocol allows for rapid synthesis of gem-difluoroalkenes in a modular manner^[2].

Fig.2 Synthesis of gem-difluoroalkenes through Ramberg-Bäcklund reaction

Applications

Fluoroalkenes building blocks have potential applications in organic synthesis and medicinal chemistry. They are widely used in transition-metal-catalyzed, photocatalytic, and electrocatalytic selective defluorination functionalization to prepare various fluorinated organic compounds. As an isostere of amides, fluoroalkenes also play an important role in drug development. They can achieve rapid preparation of target drug molecules under mild reaction conditions. Furthermore, fluoroalkenes can be used in medicinal chemistry as peptide bond isoenzymes, which opens up new opportunities for finding new bioactive compounds.

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References

1. Shimizu, M; et al. New, general, and stereoselective synthesis of CF₃-containing tri- and tetrasubstituted oxiranes and tetrasubstituted alkenes. J. Am. Chem. Soc. 2001, 123(28): 6947-6948.
2. Crudden, C. M.; et al. Alkyltriflones in the Ramberg-Bäcklund reaction: an efficient and modular synthesis of gem-difluoroalkenes. J. Am. Chem. Soc. 2020, 142(37): 15667-15672.