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Palladium-Catalyzed Electrooxidative Hydrofluorination of Aryl-Substituted Alkenes with a Nucleophilic Fluorine Source

Anup Mandal, Jieun Jang, Baeho Yang, Hyunwoo Kim* and Kwangmin Shin*

*Pohang University of Science and Technology (POSTECH), Pohang 37673; Sungkyunkwan University, Suwon 16419, Republic of Korea, Email: khw7373postech.ac.kr, kmshinskku.edu

A. Mandal, J. Jang, B. Yang, H. Kim, K. Shin, Org. Lett., 2023, 25, 195-199.

DOI: 10.1021/acs.orglett.2c04045



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Abstract

The merger of palladium catalysis with electrooxidation enables the hydrofluorination of aryl-substituted alkenes ranging from styrenes to more challenging α,β-unsaturated carbonyl derivatives to the corresponding benzylic fluorides. This method can also be applied to the late-stage modification of pharmaceutical derivatives.


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proposed mechanism



General Procedure for Hydrofluorination of Aryl Alkenes with Et3N3HF

Inside an argon-filled glovebox, an oven-dried screw-cap reaction tube (Kimble chase, 13100 mm, catalog no. 45066A-13100) equipped with a magnetic stir bar was charged with Pd(OAc)2 (2.8 mg, 12.5 μmol, 5.0 mol%), DPPF (10.4 mg, 18.8 μmol, 7.5 mol%), MeCN (52 μL, 1.0 mmol, 4.0 equiv), and 1,4-dioxane (0.5 mL). The resulting heterogeneous, yellow-colored mixture was allowed to stir for 30 min at room temperature (Fig. S1A). Alkene substrate (styrenyl derivative or α,β-unsaturated ester/amide, 0.25 mmol, 1.0 equiv) was added and 0.3 mL of 1,4-dioxane was used to rinse the sides of the reaction tube. After 3 min stirring, iPr3SiH (154 μL, 0.75 mmol, 3.0 equiv) and additional 0.2 mL of 1,4-dioxane were subsequently added. Once the resulting mixture had stirred for 3 min at room temperature, Et3N3HF (164 μL, 1.0 mmol, 4.0 equiv) and HFIP (1.0 mL) were added. Then, the reaction tube was equipped with a carbon felt anode (1.0 x 0.5 cm2) and a Pt wire cathode (13.0 cm length by 0.1 cm diameter, coiled to a diameter of 0.4 cm) connected to graphite rods (2B pencil lead, 2 mm in diameter, see Fig. S1B-D for details). The tube was tightly sealed and taken out of the glovebox. Electrolysis was initiated at a constant cell voltage of 2.7 V (Ea,i = ~0.6 V vs Fc/Fc+) at room temperature for 12 h (Fig. S1D). After this time, the mixture was filtered through a short pad of silica (rinsed with ca. 50 mL of CH2Cl2) and concentrated under reduced pressure with the aid of a rotary evaporator. The crude residue was purified by flash column chromatography or preparative TLC on silica gel (eluent: hexane/ethyl acetate).


Figure S1. Reaction setup for hydrofluorination.

Hydrofluorination of styrenyl derivatives - Note on purification: In all cases, trace amount (<5%) of the corresponding HFIP adduct (determined by 1H and/or 19F NMR of the crude reaction mixture), which was found to be challenging to separate by conventional flash column chromatography. Therefore, isolation of the title compound was conducted primarily by preparative TLC on silica gel to obtain a pure hydrofluorination product. For selected examples, the products were isolated by column chromatography on silica gel as a mixture with HFIP adduct. Isolation yields and spectral data obtained from column chromatography purification were also reported.

Note on purification of β-fluorinated esters and amides: The β-fluorinated carbonyl compounds, obtained from the hydrofluorination of α,β-unsaturated esters or amides, were found to be unstable over silica. As a result, isolation of these compounds was conducted by preparative TLC on silica gel in a short period of time (in general, less than 30 min to prevent undesired decomposition).

Additional Note: The present hydrofluorination gave no detectable or less than trace amount of side product derived from Ritter type reaction (addition of acetonitrile, determined by 1H NMR analysis).


Key Words

benzylic fluorides, electrochemistry, silanes


ID: J54-Y2023