Copper-Catalyzed Cross-Coupling of Arylacetylenes with Bromodifluoroacetamides

Abstract

A copper-catalyzed radical difluoroalkylation of arylacetylenes with bromodifluoroamides has been developed. The reaction exhibits good functional group tolerance and allows access to a variety of substituted α-alkynyl-α,α-difluoroacetamides in moderate to good yields. The potential for scale-up reaction and products derivatization also makes this method attractive for practical applications. Preliminary mechanistic studies suggest that a radical reaction pathway might be involved in the catalytic system.

Key words

copper catalysis - arylacetylenes - bromodifluoroacetamides - cross-coupling - difluoroalkylation

Publication History

Received: 17 December 2021

Accepted after revision: 25 January 2022

Accepted Manuscript online:
26 January 2022

Article published online:
15 February 2022

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• 22a General Procedure To a 15 mL Schlenk tube CuCl (20 mol%), L7 (20 mol%), Cs₂CO₃ (1.5 equiv), and a stir bar were added. The vessel was then evacuated and filled with Ar (three cycles). 1 (0.3 mmol), 2 (0.2 mmol), and solvent (1 mL) were then added in turns under Ar. The reaction mixture was stirred at 90 °C for 24 h. Next, the reaction was diluted with EtOAc and washed with saturated sodium chloride solution (20 mL). The aqueous phase was further extracted with EtOAc (3 × 20 mL). The organic phase was combined, dried over Na₂SO₄, and concentrated and purified by column chromatography through silica gel (EtOAc/hexane = 1:10 to 1:5, v/v) to afford the desired product 3. 2,2-Difluoro-1-morpholino-4-phenylbut-3-yn-1-one (3aa) Prepared by following the general procedure as a yellow liquid; yield 79%. ¹H NMR (400 MHz, CDCl₃): δ = 7.52 (d, J = 7.1 Hz, 2 H), 7.49–7.44 (m, 1 H), 7.42–7.37 (m, 2 H), 3.83–3.78 (m, 2 H), 3.78–3.71 (m, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 159.65 (t, J = 30.6 Hz), 132.23 (t, J = 2.3 Hz), 130.70 (s), 128.70 (s), 119.13 (s), 106.27 (t, J = 241.5 Hz), 90.99 (t, J = 6.4 Hz), 78.78 (t, J = 38.2 Hz), 66.67 (s), 66.43 (s), 46.95 (s), 43.67 (s). ¹⁹F NMR (376 MHz, CDCl₃): δ = –85.72 (s). HRMS (ESI): m/z calcd for C₁₄H₁₄F₂NO₂ [M + H]⁺: 266.0987; found: 266.0982.