News Release

Four-component, and asymmetric radical 1,4-oxy-trifluoromethylation to olefins

Peer-Reviewed Publication

Ibaraki University

Prof. Chen group at NTHU

image: from the left, Shiang-Fu Hung, Prof. Chien-Tien Chen, Chia-Hao Lu and Pin-Xuan Tseng view more 


Vanadium oxo (VO) species were often used to oxidise sulfide/amine compounds and alkenes when combined with peroxide oxidants. VO species are well known as important vitamin supplements for potential diabetic prevention. They are highly prevalent as metalloenzyme like haloperoxidase. The current catalyst class comprises VO species, substituted-salicylaldehyde, and alpha-amino acids that are nontoxic and highly enriched in ascidian sea animals and plants. Professor Chien-Tien Chen of NTHU pioneered aerobic asymmetric couplings of 2-naphthol with VO species to form optically active binaphols in 2001 (reported in C&EN News, 79(20), 45-57(2001)), which was believed to proceed in a VO-bound, single/dual-mode activation or free radical-radical/free radical-anion pathway as suggested by groups of Prof. Kyungsoo Oh (Chung-Ang University, South Korea) and Prof. Shinobu Takizawa (Osaka University, Japan) (Org. Lett. 19, 14, 3867-3870 (2017)), and Prof. Kozlowski (University of Pennsylvania, USA) (J. Org. Chem. 83, 14362-14384 (2018)), respectively. Recently, Prof. Chen and his co-workers have successfully identified VO-stabilised acyl and trifluoromethyl radicals, allowing for effective transposition of oxy/acyl radical and oxy/CF3 units across olefin double bonds.

The team of NTHU in Taiwan used chiral VO species as catalysts and Togni reagents to perform trifluoromethylation of olefins under aerobic conditions at ambient temperature. Professor Seiji Mori's team at IU in Japan performed high-level quantum mechanical calculations to identify the working mechanism of guiding the CF3 (trifluoromethyl) radical to olefins with concomitant ketone formation of the incipient vanadium peroxide intermediates under aerobic conditions, leading to various gamma-trifluoromethylated ketones of biomedical significance. Quantum mechanical computations of the formation of the incipient CF3-olefin-vanadyl peroxide adducts and deuterium-labelling experiments indicated a potential 1,4-proton shift to peroxy VO and facile 1,5-proton transfer to vanadium oxo in the (S)-isomer was preferred with high diastereo-/enantio-controls. These hydrogen transfers were specific to vanadyl species and had never been observed in another oxometallic-type catalysis. Furthermore, the computations by IU team suggested a preferential vanadyl (S)-peroxide formation during the benzylic trapping by O2 and vanadyl (IV)-species based on 3,5-dibromo-N-salicylidene-t-leucinate. The 1,5-proton transfer to VO in the (S)-isomer ultimately led to the ketone product (ACS Catalysis, 10, 3676 (2020)).

The NTHU team in Taiwan recently developed a novel strategy of directly introducing both trifluoromethyl and hydroxyl/amino hydroxyl synthon groups across alkenes with high enantioselectivities by redox-active, chiral VO catalysts in alcohol solvents at room temperature. Trifluoromethyl-containing compounds serve as better alternatives as drugs and drug candidates because of the strong intrinsic bonds between carbon and fluorine atoms to improve their medicinal properties and easier metabolic degradation/modification. Unprecedented, four-component couplings (two molecules of olefin, CF3 radical, and NOPI (N-oxyphthalimide)) can be achieved. Some important drugs (anti-convulsant and anti-tumour) and pesticide candidates can also be readily accessed. The IU team's quantum mechanical calculations confirmed unusual hydrogen bonding and non-classical weak interactions, including VO and electron-rich fluorine atoms, pi/pi-interactions between phenyl groups. They found that the substituent on the salicylidene ligand controls the enantioselectivity fashion. The current VO species-mediated catalysis significantly opens a new entry for applying olefins (asymmetric) cross-coupling applications to olefins with unique niches over copper and iron catalysis because of their conceptually different operating mechanisms.

"This work represented the first successful example of intermolecular asymmetric oxytrifluoromethylation of styrene derivatives using chiral vanadyl complex. Furthermore, unique four-component assembly to establish two stereogenic centers in 1,4-relationship would pave a new entry towards similar tactics in intramolecular fashions," says Dr. Tamio Hayashi, NTHU Professor. He also says to the authors, "Congratulations for the publication of your new results on the catalytic asymmetric radical reactions! This is a great achievement in the field of catalytic asymmetric reactions. The reported new asymmetric reaction was realized by the authors' new ideas including design and use of chiral vanadium catalysts and their deep understanding of the reaction mechanism for the radical trifluoromethylation. Most importantly, this research is based on a perfect collaboration between experimental chemistry and computational chemistry, DFT calculations clearly showing the reaction pathways in the catalytic cycle."


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