Copper-Catalyzed Cross-Coupling of Arylacetylenes with Bromodifluoroacetamides
Guo-Qin Hu
,
Li-Wei Yao
,
Shu-Sheng Gui
,
Chuang Geng
,
Wen-Yan Zhang
,
Jing-Hui Liu∗
,
Bin Zhao∗
Financial support from Henan Provincial Science and Technology Research Project (Grant Number 182102210184), Postdoctoral Science Foundation of He’nan Scientific Committee.
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.
19a
Kent CR,
Bryja M,
Gustafson HA,
Kawarski MY,
Lenti G,
Pierce EN,
Knopp RC,
Ceja V,
Pati B,
Walters DE,
Karver CE.
Bioorg. Med. Chem. Lett. 2016; 26: 5476
22aGeneral 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.
