Manufacturing technologies
Drug development, Organic electronic materials

Carbon–fluorine bond scission & reconstruction: new synthetic method for organofluorinecompounds by insertion reaction of C1 unit into C–F bondDepartment of Applied Chemistry, Graduate School of Engineering / Innovative Catalysis Science Division, Institute for Open and Transdisciplinary Research Initiatives (ICS-OTRI)Associate Professor Yoshihiro Nishimoto

https://researchmap.jp/nishimoto123

Professor Makoto Yasuda

https://researchmap.jp/read0185253

Abstract
We have established the first synthetic method for fluorine compounds by insertion reaction of a C1 unit into a carbon–fluorinebond. This reaction is a new synthetic method for fluorine compounds, in which the innovative concept of carbon-fluorine bondscission & reconstruction is the key. Quantum chemical calculations revealed that the two functions of boron trifluoride, scission &reconstruction carbon-fluorine bond, are important. Boron trifluoride
abstracts fluoride ions from alkyl fluorides (scission of C-F bond)and then returns fluoride ions to the intermediate (reconstruction ofC-F bond) to complete the insertion reaction.

agrochemicals, functional resins, organic electronic materials, etc.
Therefore, this research will have a great impact on the development of next-generation pharmaceuticals and functional materials.

Manufacturing technologies▍ Background & Results
Fluorine is an important substituent in high value products that
support modern society, such as pharmaceuticals, agrochemicals,lubricants, surfactants, and organic electronic materials. In pharmaceuticals and agrochemicals, the introduction of fluorine atom
dramatically increases drug activity, including metabolic stability
and the mimic effect for recognition by enzymes. For this reason,
the development of new synthetic methods for organofluorinecompounds is of great significance in modern society. However,conventional methods are limited to the introduction of fluorine
substituents into organic compounds, which is problematic because it requires expensive, corrosive, and highly toxic fluorinating
reagents. Therefore, the establishment of a new methodology forthe synthesis of fluorinated compounds is an urgent issue. In thiscontext, this research established the first method for the synthesisof fluorine compounds by insertion reaction of a C1 unit into a carbon–fluorine bond. This reaction is a new synthetic method for fluorine compounds, in which the innovative concept of carbon-fluorinebond scission & reconstruction is the key. The reaction of alkyl
fluorides with diazo compounds in the presence of boron trifluoride
catalyst yielded a product in which a C1 unit from the diazo compound was inserted into the carbon–fluorine bond of the alkyl fluoride. Quantum chemical calculations for the reaction mechanism
revealed that the two functions of boron trifluoride, carbon-fluorinebond scission & reconstruction, are important. Boron trifluoride
abstracts fluoride ions from alkyl fluorides (scission of C-F bond)and then returns fluoride ions to the intermediate (reconstruction ofC-F bond) to complete the insertion reaction. By utilizing this reaction, we have also succeeded in synthesizing fluorine analogues of
TRPC channel inhibitors.

▍ Significance of the research and Future perspective
This innovative scission & reconstruction of carbon-fluorinebond method developed enables the construction of libraries forcomplex fluorine compounds, which is expected to create novel
chemical spaces. Fluorine compounds are an important group ofcompounds that have practical applications in pharmaceuticals,

P a t e n tWang, Fei; Nishimoto, Yoshihiro; Yasuda, Makoto. Insertion of Diazo Esters into C–F Bonds toward Diastereoselective One-Carbon Elongation of Benzylic
T r e a t i s e Fluorides: Unprecedented BF3 Catalysis with C–F Bond Cleavage and Re-formation. Journal of the American Chemical Society. 2021, 143 (49),p. 20616–20621, doi: 10.1021/jacs.1c10517
URL
K e y w o r d lewis acid, fluorine compound, C–F bond activation, insertion reaction