Copper-Mediated Synthesis of Monofluoro Aryl Acetates via Decarboxylative Cross-Coupling

Dedicated to Victor Snieckus on the occasion of his 80th birthday.

Abstract

We report the Cu-promoted oxidative cross-coupling of α-fluoromalonate half-esters and aryl boron reagents to deliver mono­fluoro α-aryl acetates under mild conditions (in air at room temperature). The reaction uses a simple, readily available monofluorinated building block to generate arylated compounds with functional groups that are not easily tolerated by existing methods, such as aryl bromides, iodides, pyridines, and pyrimidines.

Key words

arylation - cross-coupling - copper - aerobic catalysis - fluorine

• References and Notes

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• 20 General Procedure for the Copper-Mediated Synthesis of Monofluoro Aryl Acetates via Decarboxylative Cross-Coupling; Procedure A (0.50 mmol scale): In an atmosphere controlled glovebox, Cu(OTf)₂ (90.4 mg, 0.250 mmol, 0.50 equiv) and aryl boronic ester (1.25 mmol, 2.5 equiv) or aryl boroxine (0.42 mmol, 2.5 equiv Ar-B) were added sequentially to a 1 dram screw-top vial containing a stir bar. The fluoromalonic half ester (0.50 mmol, 1.0 equiv) was added as a solution in anhydrous DMA (1.0 mL). Additional DMA (2 × 0.6 mL) was used to quantitatively transfer the solution to the reaction mixture. The solution was stirred until the majority of the solid had dissolved, followed by the addition of NEt₃ (0.2 mL, 1.5 mmol, 3.0 equiv). The vial was sealed with a PTFE-lined cap, removed from the glovebox, and the PTFE septum was pierced with an 18 gauge needle. The reaction mixture was gently stirred at room temperature. Upon reaction completion (24 to 72 h), the reaction mixture was diluted with EtOAc (60 mL), and washed sequentially with NH₄Cl (60 mL), 0.5 M NaOH (2 × 60 mL), and brine (60 mL). The organic layer was dried with Na₂SO₄, concentrated in vacuo, and purified by silica gel chromatography. Note, the needle gauge and vial size can influence the reaction rates and overall efficiency, see the Supporting Information for more detail. Reactions conducted without the use of a glovebox gave similar results. Cu(OTf)₂ and aryl boroxines are hydroscopic and should be stored under inert gas. Synthesis of 2b: Prepared according to Procedure A from the corresponding aryl boroxine (229 mg, 0.42 mmol, 2.5 equiv Ar–B) and fluoromalonic half ester (75 mg, 0.50 mmol, 1.0 equiv), 49 h. Isolated in 73% yield after purification by column chromatography (10:1, Hex/EtOAc) as a light-yellow oil. ¹H NMR (CDCl₃, 700 MHz): δ = 7.63–7.61 (m, 1 H), 7.54–7.51 (m, 1 H), 7.41–7.38 (m, 1 H), 7.29–7.26 (m, 1 H), 5.72 (d, J = 47.4 Hz, 1 H), 4.30–4.20 (m, 2 H), 1.26 (t, J = 7.2 Hz, 3 H); ¹³C NMR (CDCl₃, 176 MHz): δ = 167.9 (d, J = 27.1 Hz), 136.3 (d, J = 21.3 Hz), 132.6, 130.3, 129.5 (d, J = 6.7 Hz), 125.0 (d, J = 6.2 Hz), 122.8, 88.4 (d, J = 187.6 Hz), 62.1, 14.0; ¹⁹F NMR (CDCl₃, 377 MHz): δ = –182.3 (d, J = 47.4 Hz); HRMS (EI): m/z [M]⁺ calcd for C₁₀H₁₀BrFO₄: 259.9848; found: 259.9846