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TCI Practical Example: The Deoxyfluorination of Alcohol Using a Photoredox Catalyst

We are proud to present the deoxyfluorination of 2-methyl-4-phenyl-2-butanol with [Ir(p-F(Me)ppy)₂-(4,4'-dtbbpy)]PF₆, a photoredox iridium catalyst. The tertiary alcohol activated as an oxalate half-ester is utilized as an efficient radical precursor to conduct C-F coupling.

Used Chemicals

• 2-Methyl-4-phenyl-2-butanol [M0398]
• Oxalyl Chloride (= (COCl)₂) [O0082]
• (4,4'-Di-tert-butyl-2,2'-bipyridine)bis[2-(4-fluorophenyl)-5-methylpyridine]iridium(III) Hexafluorophosphate (= [Ir(p-F(Me)ppy)₂-(4,4'-dtbbpy)]PF₆) [B6258]
• N-Fluoro-N'-(chloromethyl)triethylenediamine Bis(tetrafluoroborate) (= F-TEDA-BF₄) [F0358]
• Disodium Hydrogenphosphate Dodecahydrate (= Na₂HPO₄)
• Diethyl Ether
• Acetone

Procedure

A four-neck round bottom flask was charged with 2-methyl-4-phenyl-2-butanol (5 g, 30 mmol, 1 eq.) and diethyl ether (300 mL). The solution was cooled under 5 ˚C, then oxalyl chloride (7.78 g, 60 mmol, 2 eq.) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 6 h. After the reaction, the reaction mixture was cooled under 5 ˚C and quenched with ion-exchanged water (55 mL). The solution was transferred into a separatory funnel, and the aqueous layer was extracted with diethyl ether (30 mL, twice). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate (50 g) for about 30 minutes and then filtered. The solvent was removed in vacuo to give compound 1 as a light yellow oil (4.91 g, 68% yield), which was used without further purification.
1 (1.3 g, 5.5 mmol, 1.0 eq.), disodium hydrogenphosphate dodecahydrate (3.9 g, 11 mmol, 2.0 eq.), F-TEDA-BF₄ (3.3 g, 9.3 mmol, 1.7 eq.), [Ir(p-F(Me)ppy)₂-(4,4'-dtbbpy)]PF₆ (0.053 g, 0.05 mmol, 0.94 mol%) were dissolved in acetone (44 mL) and of ion-exchanged water (11 mL) at rt under N₂. The reaction mixture was degassed with nitrogen for 15 minutes before irradiation. The mixture was placed at a distance of 2-3 cm from Blue LED lamp with a cooling fan. The reaction mixture was stirred at rt under visible light irradiation until 1 was completely consumed. After 6 h of irradiation, the reaction mixture was diluted with diethyl ether (50 mL) and ion-exchanged water (50 mL). The solution was transferred to a separatory funnel, and the aqueous layer was extracted with diethyl ether (30 mL, twice). The combined organic layers were washed with brine, dried over sodium sulfate (50 g) for about 30 minutes and then filtered. The solvent was removed in vacuo, giving crude as a blown oil (0.96 g). The crude was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1, Rf = 0.75) to give compound 2 as a colorless oil (0.394 g, 43% yield).

Experimenter’s Comments

Irradiation of visible light was performed with Kessil A160WE Tuna Blue 40W×2.
The reaction mixture was cooled to rt with a cooling fan.
The reaction mixture was monitored by ¹H NMR and GCMS.

Analytical Data

Compound 2

¹H NMR (400 MHz, CDCl₃); δ 7.32-7.27 (m, 2H), 7.20 (d, J = 7.8 Hz, 3H), 2.75-2.71 (m, 2H), 1.97-1.88 (m, 2H), 1.41 (d, J = 21.5 Hz, 6H).

¹³C NMR (101 MHz, CDCl₃); δ 142.01, 128.42, 128.28, 125.85, 95.33 (d, J_C,F = 165.0 Hz), 43.32 (d, J_C,F = 22.9 Hz), 30.24 (d, J_C,F = 4.8 Hz), 26.67 (d, J_C,F = 24.8 Hz).

¹⁹F NMR (376 MHz, CDCl₃); δ -139.87 (m, 1F).

Lead Reference

• Photoredox-catalyzed deoxyfluorination of activated alcohols with Selectfluor^🄬
• • M. González-Esguevillas, J. Miró, J. L. Jeffrey, D. W. C. MacMillan, Tetrahedron 2019, 75, 4222.

Other References

• Direct, enantioselective α-alkylation of aldehydes using simple olefins
• • A. G. Capacci, J. T. Malinowski, N. J. McAlpine, J. Kuhne, D. W. C. MacMillan, Nat. Chem. 2017, 9, 1073.
• Decarboxylative sp³ C–N coupling via dual copper and photoredox catalysis
• • Y. Liang, X. Zhang, D. W. C. MacMillan, Nature 2018, 559, 83.