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

• References and Notes

• 1a Fluorine in Medicinal Chemistry and Chemical Biology. Ojima I. Wiley; Chichester: 2009
• 1b Preshlock S, Tredwell M, Gouverneur V. Chem. Rev. 2016; 116: 719
• 1c Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Acena JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
• 1d Purser SP, Moore R, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 1e Meanwell NA. J. Med. Chem. 2011; 54: 2529

Selected reviews:
• 2a Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
• 2b Lemos A, Lemaire C, Luxen A. Adv. Synth. Catal. 2019; 361: 1500
• 2c Dong D.-Q, Yang H, Shi J.-L, Si W.-J, Wang Z.-L, Xu X.-M. Org. Chem. Front. 2020; 7: 2538
• 2d Wang X, Lei J, Liu Y, Ye Y, Li J, Sun K. Org. Chem. Front. 2021; 8: 2079
• 3a Feng Z, Xiao Y.-L, Zhang X. Acc. Chem. Res. 2018; 51: 2264
• 3b Belhomme M.-C, Besset T, Poisson T, Pannecoucke X. Chem. Eur. J. 2015; 21: 12836
• 4 Wu Y, Zhang H.-R, Cao Y.-Y, Lan Q, Wang X.-S. Org. Lett. 2016; 18: 5564
• 5a Feng Z, Min Q.-Q, Xiao Y.-L, Zhang B, Zhang X. Angew. Chem. Int. Ed. 2014; 53: 1669
• 5b Feng Z, Min Q.-Q, Zhang X. Org. Lett. 2016; 18: 44
• 5c Lee GM, Loechtefeld R, Menssen R, Bierer DE, Riedl B, Baker RT. Tetrahedron Lett. 2016; 57: 5464
• 5d Feng Z, Min Q.-Q, Fu X.-P, An L, Zhang X. Nat. Chem. 2017; 9: 918
• 5e Fu X.-P, Xue X.-S, Zhang X.-Y, Xiao Y.-L, Zhang S, Guo Y.-L, Leng X, Houk KN, Zhang X. Nat. Chem. 2019; 11: 948
• 6 Xiao Y.-L, Guo W.-H, He G.-Z, Pan Q, Zhang X. Angew. Chem. Int. Ed. 2014; 53: 9909
• 7a Tarui A, Shinohara S, Sato K, Omote M, Ando A. Org. Lett. 2016; 18: 1128
• 7b An L, Xu C, Zhang X. Nat Commun. 2017; 8: 1460
• 7c Xu C, Cheng R, Luo Y.-C, Wang M.-K, Zhang X. Angew. Chem. Int. Ed. 2020; 59: 18741
• 8a Lorion MM, Koch V, Nieger M, Chen H.-Y, Lei A, Bräse S, Cossy J. Chem. Eur. J. 2020; 26: 13163
• 8b Araki K, Inoue M. Tetrahedron 2013; 19: 3913
• 9 Li C, Cao Y.-X, Wang R, Wang Y.-N, Lan Q, Wang X.-S. Nat. Commun. 2018; 9: 4951
• 10a Sonogashira K, Tohda Y, Hagihara NA. Tetrahedron Lett. 1975; 16: 4467
• 10b Dieck HA, Heck FR. J. Organomet. Chem. 1975; 93: 259
• 10c Negishi E, Anastasia L. Chem. Rev. 2003; 103: 1979
• 10d Plenio H. Angew. Chem. Int. Ed. 2008; 47: 6954

Selected examples:
• 11a Zhu L, Guo H, Feng X, Yamamoto Y, Bao M. J. Org. Chem. 2020; 85: 8740
• 11b Yamane Y, Miwa N, Nishikata T. ACS Catal. 2017; 7: 6872
• 11c Cao Y.-X, Dong X.-Y, Yang J, Jiang S.-P, Zhou S, Li Z.-L, Chen G.-Q, Liu X.-Y. Adv. Synth. Catal. 2020; 362: 2280
• 11d Dong X.-Y, Zhang Y.-F, Ma C.-L, Gu Q.-S, Wang F.-L, Li Z.-L, Jiang S.-P, Liu X.-Y. Nat. Chem. 2019; 11: 1158
• 11e Mo X, Chen B, Zhang G. Angew. Chem. Int. Ed. 2020; 59: 13998
• 11f Zhang H, Sun N, Hu B, Shen Z, Hu X, Jin L. Org. Chem. Front. 2019; 6: 1983
• 11g Feng Y.-S, Xie C.-Q, Qiao W.-L, Xu H.-J. Org. Lett. 2013; 15: 936

Selected examples:
• 12a Eckhardt M, Fu GC. J. Am. Chem. Soc. 2003; 125: 13642
• 12b Altenhoff G, Wurtz S, Glorius F. Tetrahedron Lett. 2006; 47: 2925
• 12c Yi J, Sun Y.-Y, Xiao B, Liu L. Angew. Chem. Int. Ed. 2013; 52: 12409
• 12d Hazra A, Lee MT, Chiu JF, Lalic G. Angew. Chem. Int. Ed. 2018; 57: 5492
• 12e Fan Q, Sun H, Xie S, Dong Y, Li X, Fuhr O, Fenske D. Organometallics 2021; 40: 2240
• 12f Pérez García PM, Ren P, Scopelliti R, Hu X. ACS Catal. 2015; 5: 1164
• 12g Vechorkin O, Barmaz D, Proust V, Hu X. J. Am. Chem. Soc. 2009; 131: 12078
• 13a Hu J, Zhang W, Wang F. Chem. Commun. 2009; 48: 7465
• 13b Yokomatsu T, Suemune K, Murano T, Shibuya S. J. Org. Chem. 1996; 61: 7207

Selected examples:
• 14a Belhomme M.-C, Dru D, Xiong H.-Y, Cahard D, Besset T, Poisson T, Pannecoucke X. Synthesis 2014; 46: 1859
• 14b Feng X, Wang X, Chen H, Tang X, Guo M, Zhao W, Wang G. Org. Biomol. Chem. 2018; 16: 2841
• 14c Ma J.-J, Yi W.-B. Org. Biomol. Chem. 2017; 15: 4295
• 15 Besset T, Poisson T, Pannecoucke X. Eur. J. Org. Chem. 2014; 7220

Selected examples:
• 16a Taguchi T, Kitagawa O, Morikawa T, Nishiwaki T, Uehara H, Endo H, Kobayashi Y. Tetrahedron Lett. 1986; 27: 6103
• 16b Iqbal N, Iqbal N, Han SS, Cho EJ. Org. Biomol. Chem. 2019; 17: 1758
• 16c Fan S, Zheng C, Zheng K, Li J, Liu Y, Yan F, Xiao H, Feng Y.-S, Zhu Y.-Y. Org. Lett. 2021; 23: 3190

Selected examples:
• 17a Ivanova MV, Bayle A, Besset T, Poisson T, Pannecoucke X. Angew. Chem. Int. Ed. 2015; 54: 13406
• 17b Li X, Li S, Sun S, Yang F, Zhu W, Zhu Y, Wu Y, Wu Y. Adv. Synth. Catal. 2016; 358: 1699
• 18a Guo W.-H, Luo Z.-J, Zeng W, Zhang X. ACS Catal. 2017; 7: 896
• 18b Zhang X.-Y, Fu X.-P, Zhang S, Zhang X. CCS Chem. 2020; 2: 293
• 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
• 19b Kumar S, Misra N, Raj K, Srivastava K, Puri SK. Nat. Prod. Res. 2008; 22: 305
• 19c Shen S, Picci C, Ustinova K, Benoy V, Kutil Z, Zhang G, Tavares MT, Pavlicek J, Zimprich CA, Robers MB, Van Den Bosch L, Barinka C, Langley B, Kozikowski AP. J. Med. Chem. 2021; 64: 4810
• 20 Ge S, Arlow SI, Mormino MG, Hartwig JF. J. Am. Chem. Soc. 2014; 136: 14401
• 21a Li Y, Liu J, Zhao S, Du X, Guo M, Zhao W, Tang X, Wang G. Org. Lett. 2018; 20: 917
• 21b Sun K, Wang S, Feng R, Zhang Y, Wang X, Zhang Z, Zhang B. Org. Lett. 2019; 21: 2052
• 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.