Efficient Synthesis of N-(Difluoropropenyl)amides/Amines from Fluorinated Olefins under Base Promotion

Abstract

N-(Difluoropropenyl)amides/amines are an important class of fluorinated compounds. Here, we report an efficient method for synthesizing these compounds without the use of transition metals. Under simple base-promoted conditions, 3-bromo-3,3-difluoroprop-1-ene reacts with N-methylanilines or N-arylacrylamides, with the elimination of one molecule of HBr, to give the target compound. Another efficient method for synthesizing difluoroalkenes is the reaction of 2-bromo-3,3,3-trifluoroprop-1-ene with indole or its analogues.

Key words

difluoropropenylamides - base catalysis - fluoroalkenes - dehydrohalogenation - transition-metal-free synthesis - indoles

• References and Notes

• 1a Kirsch P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications 2004
• 1b Mikami K, Itoh Y, Yamanaka M. Chem. Rev. 2004; 104: 1
• 1c Shimizu M, Hiyama T. Angew. Chem. Int. Ed. 2005; 44: 214
• 1d Schlosser M. Angew. Chem. Int. Ed. 2006; 45: 5432
• 1e Begue J.-P, Bonnet-Delpon D. Bioorganic and Medicinal Chemistry of Fluorine . Wiley; Hoboken: 2008
• 1f Hagmann WK. J. Med. Chem. 2008; 51: 4359
• 1g Ojima I. Fluorine in Medicinal Chemistry and Chemical Biology. Wiley-Blackwell; Chichester: 2009
• 1h Salwiczek M, Nyakatura EK, Gerling UI. M, Ye S, Koksch B. Chem. Soc. Rev. 2012; 41: 2135
• 1i Han W.-Y, Wang J.-S, Zhao J, Long L, Cui B.-D, Wan N.-W, Chen Y.-Z. J. Org. Chem. 2018; 83: 6556
• 1j Zhao W.-W, Shao Y.-C, Wang A.-N, Huang J.-L, He C.-Y, Cui BD, Wan N.-W, Chen Y.-ZHan W.-Y. Org. Lett. 2021; 23: 9256
• 2a McDonald IA, Lacoste JM, Bey P, Palfreyman MG, Zreika M. J. Med. Chem. 1985; 28: 186
• 2b Moore WR, Schatzman GL, Jarvi ET, Gross RS, McCarthy JR. J. Am. Chem. Soc. 1992; 114: 360
• 2c Pan Y, Qiu J, Silverman RB. J. Med. Chem. 2003; 46: 5292
• 2d Weintraub PM, Holland AK, Gates CA, Moore WR, Resvick RJ, Bey P, Peet NP. Bioorg. Med. Chem. 2003; 11: 427
• 2e Altenburger J.-M, Lassalle GY, Matrougui M, Galtier D, Jetha J.-C, Bocskei Z, Berry CN, Lunven C, Lorrain J, Herault J.-P, Schaeffer P, O’Connor SE, Herbert J.-M. Bioorg. Med. Chem. 2004; 12: 1713
• 2f Rogawski MA. Epilepsy Res. 2006; 69: 273
• 3 Motherwell WB, Tozer MJ, Ross BC. J. Chem. Soc., Chem. Commun. 1989; 1437
• 4a Reynolds DW, Cassidy PE, Johnson CG, Cameron ML. J. Org. Chem. 1990; 55: 4448
• 4b Asandei AD, Adebolu OI, Simpson CP. J. Am. Chem. Soc. 2012; 134, 6080
• 4c Patil Y, Alaaeddine A, Ono T, Ameduri B. Macromolecules 2013; 46: 3092
• 5 Liu Y, Zhou Y, Zhao Y, Qu J. Org. Lett. 2017; 19: 946
• 6 Lan Y, Yang F, Wang C. ACS Catal. 2018; 8: 9245
• 7 Li Y, Sun G, He X, Lv H, Gao B. J. Fluorine Chem. 2023; 268: 110115
• 8 Xu Y, Wang S, Liu Z, Guo M, Lei A. Chem. Commun. 2023; 59: 3707
• 9 Qin T, Xu C, Zhang G, Zhang Q. Org. Chem. Front. 2023; 10: 1981
• 10 Xiong B, Chen X, Liu J, Zhang X, Xia Y, Lian Z. ACS Catal. 2021; 11: 11960
• 11 Yang Z, Pei C, Koenigs RM. Org. Lett. 2020; 22: 7234
• 12 Patra K, Reddy MK, Mallik S, Baidya M. Org. Lett. 2022; 24: 4014
• 13 Kim H, Jung Y, Cho SH. Org. Lett. 2022; 24: 2705
• 14 Zhao Y, Empel C, Liang W, Koenigs RM, Patureau FW. Org. Lett. 2022; 24: 8753
• 15 Yang Z, Möller M, Koenigs RM. Angew. Chem. Int. Ed. 2020; 59: 5572
• 16 Aelterman M, Biremond T, Jubault P, Poisson T. Chem. Eur. J. 2022; 28: e202202194
• 17 Cai S.-H, Ye L, Wang D.-X, Wang Y.-Q, Lai L.-J, Zhu C, Feng C, Loh T.-P. Chem. Commun. 2017; 53: 8731
• 18 Lin Z, Lan Y, Wang C. ACS Catal. 2019; 9: 775
• 19 Ni Y.-Q, Li D.-J, Mei Y, Jiang Y, Zhang J.-L, He K.-H, Pan F. Org. Lett. 2023; 25: 6784
• 20 Akiyama S, Nomura S, Kubota K, Ito H. J. Org. Chem. 2020; 85: 4172
• 21 Tang W, Fan P. Org. Lett. 2023; 25: 5756
• 22 Li Y, Hao M, Xia M, Sun N, Zhang C.-L, Zhu W.-Q. React. Chem. Eng. 2020; 5: 961
• 23 Li Y, Hao M, Chang Y.-C, Liu Y, Wang W.-F, Sun N, Zhu W.-QGao Z. Chin. J. Chem. 2021; 39: 2962
• 24 Li Y, Sun N, Zhang C.-L, Hao M. Chin. J. Chem. 2021; 39: 1477
• 25 Li Y, Zhang C.-L, Huang W.-H, Sun N, Hao M, Neumann H, Beller M. Chem. Sci. 2021; 12: 10467
• 26 Li Y, Sun N, Hao M, Zhang C.-L, Li H, Zhu W.-Q. Catal. Lett. 2021; 151: 764
• 27 Wen X.-R, Zhu W.-Q, Zhang C.-L, Li H, Zhang J, Yang M.-G, Kou Y.-L, Liu Y.-X, Li Y. ACS Omega 2023; 8: 7128
• 28 Li Y, Shi L.-T, Zhu W.-Q, Li H, Zhang Q. Synlett 2018; 29: 1847
• 29 CCDC 2323785 contains the supplementary crystallographic data for compound 7e. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
• 30 N-(3,3-Difluoroprop-2-en-1-yl)-N-(4-methoxyphenyl)acrylamide; Typical Procedure A 35.0 mL glass reaction tube was charged with N-(4-methoxyphenyl)acrylamide (1a; 1.0 mmol), 3-bromo-3,3-difluoropropene (2; 2.0 mmol) t-BuOK (2.0 mmol), and MeCN (2.0 mL), and the tube was placed in an autoclave. The autoclave was sealed, purged three times with N₂, and heated in an oil bath at 100 °C for 8 h. The autoclave was then cooled to r.t. and the crude product was purified by column chromatography [silica gel, PE–EtOAc (30:1 to 10:1)] to give a yellow liquid; yield: 39.2 mg (55%). ¹H NMR (400 MHz, CDCl₃): δ = 7.05–6.70 (m, 4 H), 6.28 (d, J = 16.8 Hz, 1 H), 6.02–5.80 (m, 1 H), 5.44 (d, J = 10.3 Hz, 1 H), 4.48–4.30 (m, 1 H), 4.25 (d, J = 7.9 Hz, 2 H), 3.76 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 165.7, 159.2, 157.7 (t, J = 289.0 Hz), 133.9, 129.2, 128.4, 127.8, 114.8, 74.9 (dd, J = 18.8, 23.2 Hz), 55.5, 42.7 (d, J = 7.4 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –85.75 (d, J = 38.09 Hz, 1 F), –88.17 (dd, J = 24.52, 37.41 Hz). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₃F₂NNaO₂: 276.0812; found: 276.0810.