Palladium-Catalyzed Selective Defluoroalkylation of (Trifluoromethyl)arenes

Abstract

The selective functionalization of C–F bonds in trifluoromethylated arenes (ArCF₃) is essential due to the extensive use of fluorinated compounds in pharmaceuticals, agrochemicals, and materials science, alongside emerging regulatory restrictions on trifluoromethyl groups. Here, we report a hybrid palladium-catalyzed strategy for the selective defluorination and functionalization of ArCF₃, featuring intermolecular carboamination of linear conjugated dienes or defluorinative cross-coupling with nonactivated alkenes. This methodology enables the 1,4-addition of dienes with exclusive E-selectivity or the defluoroalkylation of (trifluoromethyl)arenes, providing efficient routes to difluoromethylated compounds and addressing key challenges in synthetic fluorine chemistry.

Key word

defluorination - palladium catalysis - photocatalysis - alkenes - dienes - stereoselectivity

Publication History

Received: 30 September 2024

Accepted after revision: 04 November 2024

Accepted Manuscript online:
04 November 2024

Article published online:
05 December 2024

• References and Notes

• 1a Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
• 1b Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 1c Hagmann WK. J. Med. Chem. 2008; 51: 4359
• 1d Wang J, Sánchez-Roselló M, José Luis A, Del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
• 1e Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
• 2 For a review, see: O’Hagan D, Wang Y, Skibinski M, Slawin AM. Z. Pure Appl. Chem. 2012; 84: 1587
• 3a O’Hagan D. Chem. Soc. Rev. 2008; 37: 308
• 3b Meanwell NA. J. Med. Chem. 2011; 54: 2529
• 4a Furuya T, Kamlet AS, Ritter T. Nature 2011; 473: 470
• 4b Tomashenko OA, Grushin VV. Chem. Rev. 2011; 111: 4475
• 4c Yang X, Wu T, Phipps RJ, Toste FD. Chem. Rev. 2015; 115: 826
• 4d Feng Z, Xiao Y.-L, Zhang X. Acc. Chem. Res. 2018; 51: 2264
• 5a Tozer MJ, Herpin TF. Tetrahedron 1996; 52: 8619
• 5b Bunnelle WH, McKinnis BR, Narayanan BA. J. Org. Chem. 1990; 55: 768
• 5c Middleton WJ. J. Org. Chem. 1975; 40: 574
• 6a Zemtsov AA, Kondratyev NS, Levin VV, Struchkova MI, Dilman AD. J. Org. Chem. 2014; 79: 818
• 6b An L, Xu C, Zhang X. Nat. Commun. 2017; 8: 1460
• 7 Dang H, Whittaker AM, Lalic G. Chem. Sci. 2016; 7: 505
• 8a Lund H, Jensen NJ. Acta Chem. Scand., Ser. B 1974; 28: 263
• 8b Yamauchi Y, Fukuhara T, Hara S, Senboku H. Synlett 2008; 438
• 9a Munoz SB, Ni C, Zhang Z, Wang F, Shao N, Mathew T, Olah GA, Prakash GK. S. Eur. J. Org. Chem. 2017; 2322
• 9b Fuchibe K, Ohshima Y, Mitomi K, Alkiyama T. Org. Lett. 2007; 9: 1497
• 9c Amii H, Hatamoto Y, Seo M, Uneyama K. J. Org. Chem. 2001; 66: 7216
• 10a Stahl T, Klare HF. T, Oestreich M. ACS Catal. 2013; 3: 1578
• 10b Forster F, Metsänen TT, Irran E, Hrobarik P, Oestreich M. J. Am. Chem. Soc. 2017; 139: 16334
• 11a Chen K, Berg N, Gschwind R, König B. J. Am. Chem. Soc. 2017; 139: 18444
• 11b Wang H, Jui NT. J. Am. Chem. Soc. 2018; 140: 163
• 11c Vogt DB, Seath CP, Wang H, Jui NT. J. Am. Chem. Soc. 2019; 141: 13203
• 11d Sap JB. I, Straathof NJ. W, Knauber T, Meyer CF, Médebielle M, Buglioni L, Genicot C, Trabanco AA, Noël T, am Ende CW, Gouverneur V. J. Am. Chem. Soc. 2020; 142: 9181
• 11e Campbell MW, Polites VC, Patel S, Lipson JE, Majhi J, Molander GA. J. Am. Chem. Soc. 2021; 143: 19648
• 11f Shreiber ST, Granados A, Matsuo B, Majhi J, Campbell MW, Patel S, Molander GA. Org. Lett. 2022; 24: 8542
• 11g Ye J, Bellotti P, Heusel C, Glorius F. Angew. Chem. Int. Ed. 2022; 61: e202115456
• 11h Sugihara N, Suzuki K, Nishimoto Y, Yasuda M. J. Am. Chem. Soc. 2021; 143: 9308
• 11i Liu C, Shen N, Shang R. Nat. Commun. 2022; 13: 354
• 11j Yan S.-S, Liu S.-H, Chen L, Bo Z.-Y, Jing K, Gao T.-Y, Yu B, Lan Y, Luo S.-P, Yu D.-G. Chem 2021; 7: 3099
• 11k Huang J, Gao Q, Zhong T, Chen S, Lin W, Han J, Xie J. Nat. Commun. 2023; 14: 8292
• 12 Luo Y.-C, Tong F.-F, Zhang Y.-X, He C.-Y, Zhang X. J. Am. Chem. Soc. 2021; 143: 13971
• 13a Liang Y, Bian T, Yadav K, Zhou Q, Zhou L, Sun R, Zhang Z. ACS Cent. Sci. 2024; 10:  1191
• 13b Zhang F, Zhang G, Zhou Q, Bian T, Zhou L, Zhang Z. J. Org. Chem. 2024; 89: 7790
• 13c Zhou Q, Wang J, Bian T, Liang Y, Yan W, Zhou L, Zhang Z. Org. Lett. 2024; 26: 9091
• 14 Pd-Catalyzed 1,4-Difluoroalkylamination of 1,3-Dienes: General Procedure In a glovebox, a 10 mL Schlenk tube containing a stirrer bar was sequentially charged with Pd(PPh₃)₄ (11.4 mg, 0.01 mmol), K₂HPO₄ (64.0 mg, 0.3 mmol), anhyd DMSO (4 mL), and the appropriate reactants 1 (0.3 mmol), 2 (0.2 mmol), and 3 (0.3 mmol). The tube was then sealed and the mixture was degassed by three cycles of a freeze–pump–thaw procedure. The mixture was then irradiated with 10 W blue LEDs (λ = 455–460 nm, fan) at r.t. (~25 °C) for 30 h. When the reaction was complete, the mixture was extracted with EtOAc (2 × 2 mL), and the combined organic layers were washed with brine (2 × 2 mL), dried (Na₂SO₄), and concentrated in vacuo. The crude product was purified by column chromatography (silica gel).
• 15 4-{(2E)-5,5-Difluoro-1-(4-fluorophenyl)-5-[3-(trifluoromethyl)phenyl]pent-2-en-1-yl}morpholine (4b) yellow oil; yield: 81%. ¹H NMR (400 MHz, CDCl₃): δ = 7.68–7.63 (m, 2 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.23–7.13 (m, 2 H), 7.03–6.90 (m, 2 H), 5.62–5.45 (m, 2 H), 3.61 (t, J = 4.7 Hz, 4 H), 3.54 (d, J = 7.5 Hz, 1 H), 2.87 (td, J = 15.4, 5.8 Hz, 2 H), 2.21 (ddd, J = 16.4, 11.4, 3.6 Hz, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 138.59, 137.90 (t, J = 27.3 Hz), 137.12 (d, J = 3.9 Hz), 131.15 (q, J = 32.8 Hz), 129.35 (d, J = 7.8 Hz), 129.21, 128.66 (t, J = 5.4 Hz), 126.84–126.60 (m), 123.80 (q, J = 272.0 Hz), 122.43–122.27 (m), 122.17 (dt, J = 9.9, 3.1 Hz), 121.37 (t, J = 243.9 Hz), 115.70, 115.48, 73.37, 67.13, 51.87, 42.45 (t, J = 28.4 Hz). HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₂F₆NO: 430.1600; found: 430.1605.
• 16 Pd-Catalyzed Difluoroalkylhydrogenation of Alkenes: General Procedure In a glovebox, a 10 mL Schlenk tube containing a stirrer bar was sequentially charged with Pd(PPh₃)₄ (11.4 mg, 0.01 mmol), PPh₃ (158.0 mg, 0.6 mmol), NaH₂PO₄ (64.0 mg, 0.3 mmol), H₂O(54 μL, 3.0 mmol), 4:1 anhyd DMF–DMSO (4 mL), and the appropriate reactants 3 (0.6 mmol) and 5 (0.2 mmol). The tube was then sealed and the mixture was degassed by three cycles of a freeze–pump–thaw procedure The mixture was then irradiated with 10 W blue LEDs (λ = 455–460 nm, fan) at 80 °C for 15 h. When the reaction was complete, the mixture was extracted with EtOAc (2 × 2 mL), and the combined organic layer was washed with brine (2 × 2 mL), dried (Na₂SO₄), and concentrated in vacuo. The crude product was purified by column chromatography (silica gel).
• 17 9-{7,7-Difluoro-7-[3-(trifluoromethyl)phenyl]heptyl}-9H-carbazole (6a) yellow oil; yield: 64%. ¹H NMR (400 MHz, CDCl₃): δ = 8.13 (d, J = 7.8 Hz, 2 H), 7.71 (d, J = 11.3 Hz, 2 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 7.7 Hz, 1 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.41 (d, J = 8.2 Hz, 2 H), 7.26 (dd, J = 12.2, 4.5 Hz, 2 H), 4.32 (t, J = 7.1 Hz, 2 H), 2.09 (qd, J = 15.8, 7.5 Hz, 2 H), 1.88 (dd, J = 13.6, 6.7 Hz, 2 H), 1.49–1.34 (m, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 140.51, 138.61 (t, J = 27.6 Hz), 131.11 (q, J = 32.8 Hz), 129.21, 128.52 (t, J = 5.6 Hz), 126.62 (d, J = 3.5 Hz), 125.73, 123.93 (q, J = 272.4 Hz), 122.96, 122.41 (t, J = 242.8 Hz), 122.08 (tq, J = 7.9, 4.1 Hz), 120.24 (d, J = 49.5 Hz), 118.91, 108.72, 42.97, 38.94 (t, J = 27.1 Hz), 29.07, 28.89, 27.09, 22.30 (t, J = 3.8 Hz). HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₅F₅N: 446.1902; found: 446.1900.