Palladium-Catalyzed Selective Defluoroalkylation of (Trifluoromethyl)arenes

Abstract

The selective functionalization of C–F bonds in trifluoromethylated arenes (ArCF₃) is essential due to the extensive use of fluorinated compounds in pharmaceuticals, agrochemicals, and materials science, alongside emerging regulatory restrictions on trifluoromethyl groups. Here, we report a hybrid palladium-catalyzed strategy for the selective defluorination and functionalization of ArCF₃, featuring intermolecular carboamination of linear conjugated dienes or defluorinative cross-coupling with nonactivated alkenes. This methodology enables the 1,4-addition of dienes with exclusive E-selectivity or the defluoroalkylation of (trifluoromethyl)arenes, providing efficient routes to difluoromethylated compounds and addressing key challenges in synthetic fluorine chemistry.

Key word

defluorination - palladium catalysis - photocatalysis - alkenes - dienes - stereoselectivity

Publikationsverlauf

Eingereicht: 30. September 2024

Angenommen nach Revision: 04. November 2024

Accepted Manuscript online:
04. November 2024

Artikel online veröffentlicht:
05. Dezember 2024

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• 14 Pd-Catalyzed 1,4-Difluoroalkylamination of 1,3-Dienes: General Procedure In a glovebox, a 10 mL Schlenk tube containing a stirrer bar was sequentially charged with Pd(PPh₃)₄ (11.4 mg, 0.01 mmol), K₂HPO₄ (64.0 mg, 0.3 mmol), anhyd DMSO (4 mL), and the appropriate reactants 1 (0.3 mmol), 2 (0.2 mmol), and 3 (0.3 mmol). The tube was then sealed and the mixture was degassed by three cycles of a freeze–pump–thaw procedure. The mixture was then irradiated with 10 W blue LEDs (λ = 455–460 nm, fan) at r.t. (~25 °C) for 30 h. When the reaction was complete, the mixture was extracted with EtOAc (2 × 2 mL), and the combined organic layers were washed with brine (2 × 2 mL), dried (Na₂SO₄), and concentrated in vacuo. The crude product was purified by column chromatography (silica gel).
• 15 4-{(2E)-5,5-Difluoro-1-(4-fluorophenyl)-5-[3-(trifluoromethyl)phenyl]pent-2-en-1-yl}morpholine (4b) yellow oil; yield: 81%. ¹H NMR (400 MHz, CDCl₃): δ = 7.68–7.63 (m, 2 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.23–7.13 (m, 2 H), 7.03–6.90 (m, 2 H), 5.62–5.45 (m, 2 H), 3.61 (t, J = 4.7 Hz, 4 H), 3.54 (d, J = 7.5 Hz, 1 H), 2.87 (td, J = 15.4, 5.8 Hz, 2 H), 2.21 (ddd, J = 16.4, 11.4, 3.6 Hz, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 138.59, 137.90 (t, J = 27.3 Hz), 137.12 (d, J = 3.9 Hz), 131.15 (q, J = 32.8 Hz), 129.35 (d, J = 7.8 Hz), 129.21, 128.66 (t, J = 5.4 Hz), 126.84–126.60 (m), 123.80 (q, J = 272.0 Hz), 122.43–122.27 (m), 122.17 (dt, J = 9.9, 3.1 Hz), 121.37 (t, J = 243.9 Hz), 115.70, 115.48, 73.37, 67.13, 51.87, 42.45 (t, J = 28.4 Hz). HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₂F₆NO: 430.1600; found: 430.1605.
• 16 Pd-Catalyzed Difluoroalkylhydrogenation of Alkenes: General Procedure In a glovebox, a 10 mL Schlenk tube containing a stirrer bar was sequentially charged with Pd(PPh₃)₄ (11.4 mg, 0.01 mmol), PPh₃ (158.0 mg, 0.6 mmol), NaH₂PO₄ (64.0 mg, 0.3 mmol), H₂O(54 μL, 3.0 mmol), 4:1 anhyd DMF–DMSO (4 mL), and the appropriate reactants 3 (0.6 mmol) and 5 (0.2 mmol). The tube was then sealed and the mixture was degassed by three cycles of a freeze–pump–thaw procedure The mixture was then irradiated with 10 W blue LEDs (λ = 455–460 nm, fan) at 80 °C for 15 h. When the reaction was complete, the mixture was extracted with EtOAc (2 × 2 mL), and the combined organic layer was washed with brine (2 × 2 mL), dried (Na₂SO₄), and concentrated in vacuo. The crude product was purified by column chromatography (silica gel).
• 17 9-{7,7-Difluoro-7-[3-(trifluoromethyl)phenyl]heptyl}-9H-carbazole (6a) yellow oil; yield: 64%. ¹H NMR (400 MHz, CDCl₃): δ = 8.13 (d, J = 7.8 Hz, 2 H), 7.71 (d, J = 11.3 Hz, 2 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 7.7 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.41 (d, J = 8.2 Hz, 2 H), 7.26 (dd, J = 12.2, 4.5 Hz, 2 H), 4.32 (t, J = 7.1 Hz, 2 H), 2.09 (qd, J = 15.8, 7.5 Hz, 2 H), 1.88 (dd, J = 13.6, 6.7 Hz, 2 H), 1.49–1.34 (m, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 140.51, 138.61 (t, J = 27.6 Hz), 131.11 (q, J = 32.8 Hz), 129.21, 128.52 (t, J = 5.6 Hz), 126.62 (d, J = 3.5 Hz), 125.73, 123.93 (q, J = 272.4 Hz), 122.96, 122.41 (t, J = 242.8 Hz), 122.08 (tq, J = 7.9, 4.1 Hz), 120.24 (d, J = 49.5 Hz), 118.91, 108.72, 42.97, 38.94 (t, J = 27.1 Hz), 29.07, 28.89, 27.09, 22.30 (t, J = 3.8 Hz). HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₅F₅N: 446.1902; found: 446.1900.