Preparation of Trifluoromethyl Radical Precursors via Photoredox Catalysis

Trifluoromethylation is an important reaction in organic chemistry, where a trifluoromethyl group (-CF3) is introduced into a molecule. Trifluoromethylation agents are the compounds used to facilitate this process. These agents can be used in various trifluoromethylation reactions, such as nucleophilic, electrophilic, and radical trifluoromethylation, to introduce the trifluoromethyl group into organic molecules. The choice of the appropriate trifluoromethylation agent depends on the specific reaction conditions, the substrate, and the desired product.

Fig.1 The trifluoromethyl group (CF3•) in red and the heptafluoroisopropyl group (C3F7•) in green.^[1]

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CAS NO.	Product Name
1046786-08-6	[(Oxido)phenyl(trifluoromethyl)-λ4-sulfanylidene]dimethylammonium Tetrafluoroborate
112359-25-8	5-Methyl-5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate
120120-26-5	Triethyl(trifluoromethyl)silane
129922-33-4	Se-(trifluoromethyl)dibenzoselenopheniumtrifluoromethanesulfonate
129946-88-9	5-(Trifluoromethyl)-5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate
1300746-79-5	(1,10-Phenanthroline)(trifluoromethyl)copper(I)
130433-68-0	2,6-Dichloro-1-fluoropyridin-1-ium trifluoromethanesulfonate
13171-18-1	Hexafluoroisopropylmethylether	INQUIRY
131880-16-5	5-(Trifluoromethyl)-5H-dibenzo[b,d]thiophen-5-ium tetrafluoroborate
1334890-93-5	(1,10-Phenanthroline)(trifluoromethyl)(triphenylphosphine)copper(I)
1400691-55-5	Colby trifluoromethylation reagent
14353-88-9	[Bis(trifluoroacetoxy)iodo]pentafluorobenzene
14533-84-7	Pentafluorophenyl trifluoroacetate
154093-57-9	(4-Fluorophenyl)diphenylsulfonium trifluoromethanesulfonate
15458-53-4	Trifluoromethanesulfonyl Bromide
1546-79-8	2,2,2-Trifluoro-1-(1H-imidazol-1-yl)ethanone
1547-87-1	2,2,2-Trifluoro-N,N-dimethylacetamide
156241-41-7	Hexafluoroisopropyltrifluoromethanesulfonate

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CF3 Group

The CF3 group has become an important motif in organic chemistry and medicinal chemistry due to its unique electronic and lipophilic properties and is playing an increasingly important role in the pharmaceutical and agrochemical fields. It has a direct impact on product properties such as permeability, lipophilicity, and metabolic stability. The incorporation of CF3 groups into organic molecules, especially the C-trifluoromethylation reaction, has been a hot topic for researchers.

Depending on the type of reactive intermediate derived from the substrate, the methods used to form C-CF3 bonds are generally categorized into the following four groups.

1) Trifluoromethylation where the carbon center is electrophilic (nucleophilic trifluoromethylation)

2) Trifluoromethylation where the carbon center is a nucleophile (electrophilic trifluoromethylation)

3) Trifluoromethylation where the carbon center is a radical (radical trifluoromethylation)

4) Addition of trifluoromethyl radicals to unsaturated groups such as alkenes, alkynes, or isonitriles.

Although this last conversion is sometimes referred to as radical trifluoromethylation, it is different from trifluoromethylation of common carbon-centered radicals and consists mainly of alkyl radicals, alkenyl radicals, and aryl radicals.

This protocol describes a general method for the preparation of trifluoromethyl radical precursors by visible light-mediated photoredox catalysis.

Fig.2 A facile vicinal difunctionalization of alkenes, oxytrifluoromethylation, was established by visible-light-driven photoredox catalysis.^[2]

Materials

• Photoredox catalyst (e.g. Ir(ppy)₃, Ru(bpy)₃Cl₂).
• Trifluoroacetic acid (CF₃CO₂H).
• Amine or alcohol starting materials.
• Organic solvents (e.g. DMF, MeCN).
• Reaction vessels (e.g. round-bottom flasks, vials).
• Stir plates, lights, and other common laboratory equipment.

Procedure

1) In a reaction vessel, combine the amine or alcohol starting material (1.0 equiv), trifluoroacetic acid (2.0 equiv), and photoredox catalyst (2-5 mol%) in the appropriate organic solvent.

2) Seal the reaction vessel and degas the solution by sparging with N₂ or Ar for 10-15 minutes to remove dissolved oxygen.

3) Place the reaction vessel in front of a blue LED light source (compact fluorescent lamp or LED array) and stir the reaction mixture at room temperature for 12-24 hours.

4) Monitor the reaction progress by TLC or NMR spectroscopy.

5) Upon completion, quench the reaction and concentrate the crude mixture under reduced pressure.

6) Purify the desired trifluoromethyl radical precursor by column chromatography or recrystallization as needed.

Representative Result

Using this protocol, a variety of trifluoromethyl radical precursors can be prepared in moderate to excellent yields. For example, the reaction of benzyl alcohol with trifluoroacetic acid under the optimized photoredox conditions affords the corresponding benzyl trifluoromethyl ether in 82% isolated yield.

Discussion

This method provides a practical and versatile approach for the synthesis of trifluoromethyl radical precursors. The use of visible light-mediated photoredox catalysis allows the reaction to proceed under mild conditions and tolerates a range of functional groups. The trifluoromethyl radical precursors generated can then be further elaborated in various trifluoromethylation reactions.

References

1. Lei Z, et al. (2019). "Conformation Analysis of Environmentally Friendly Insulating Gas C5-PFK." IEEE Access, PP(99), 1-1.
2. Yasu Y, et al. (2012). "Three-component Oxytrifluoromethylation of Alkenes: Highly Efficient and Regioselective Difunctionalization of C=C Bonds Mediated by Photoredox Catalysts." Angew. Chem. Int. Ed, 51, 9567-9571.
3. Nagib, D. A., et al. (2011). "Trifluoromethylation of Arenes and Heteroarenes by Means of Photoredox Catalysis." Nature, 480, 224-228.