Metal-Free Catalyzed Defluorinative O-Arylation of Pyrazolones with Polyfluoroarenes

Abstract

An efficient and general method for defluorinative O-arylation of pyrazolones has been successfully developed under metal-free conditions. This methodology allows for the synthesis of desired products by using a wide range of pyrazolones and polyfluoroarenes as starting materials. The compatibility of various substrates was demonstrated, ensuring the applicability of this method. Furthermore, the synthesis of the target compounds at a gram scale and the ability to perform late-stage modifications highlight the potential of this approach in preparative pharmaceutical synthesis and organofluorine chemistry.

Key words

defluorinative - O-arylation - pyrazolones - polyfluoroarenes - metal-free

Publication History

Received: 24 July 2023

Accepted after revision: 22 August 2023

Accepted Manuscript online:
22 August 2023

Article published online:
27 September 2023

• References and Notes

• 1 Xiao JJ, Liao M, Chu MJ, Ren ZL, Zhang X, Lv XH, Cao HQ. Molecules 2015; 20: 807
• 2a Meanwell NA. J. Med. Chem. 2018; 61: 5822
• 2b Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 3 He J, Li Z, Dhawan G, Zhang W, Sorochinsky AE, Butler G, Soloshonok VA, Han J. Chin. Chem. Lett. 2023; 34: 107578
• 4a Tang ML, Bao Z. Chem. Mater. 2011; 23: 446
• 4b Kirsch P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, 2nd ed.. Wiley-VCH; Weinheim: 2013: 1
• 5a Braun T, Perutz RN, Sladek MI. Chem. Commun. 2001; 21: 2254
• 5b Baron A, Sandford G, Slater R, Yufit DS, Howard JA, Vong A. J. Org. Chem. 2005; 70: 9377
• 5c Liu C, Wang H, Xing X, Xu Y, Ma JA, Zhang B. Tetrahedron Lett. 2013; 54: 4649
• 5d Ahrens T, Kohlmann J, Ahrens M, Braun T. Chem. Rev. 2015; 115: 931
• 6a Brooke GM. J. Fluorine Chem. 1997; 86: 1
• 6b Ahrens T, Kohlmann J, Ahrens M, Braun T. Chem. Rev. 2015; 115: 931
• 6c Arora A, Weaver JD. Acc. Chem. Res. 2016; 49: 2273
• 6d Vaidyanathaswamy R, Radha K, Dharani M, Raguraman TS, Anand R. J. Fluorine Chem. 2012; 144: 33
• 6e Lu W, Gao J, Yang JK, Liu L, Zhao Y, Wu HC. Chem. Sci. 2014; 5: 1934
• 6f Teegardin KA, Weaver JD. Chem. Commun. 2017; 53: 4771
• 6g Qin J, Zhu S, Chu L. Organometallics 2021; 40: 2246
• 6h Chen YJ, Deng WH, Guo JD, Ci RN, Zhou C, Chen B, Li XB, Guo XN, Liao RZ, Tung CH, Wu LZ. J. Am. Chem. Soc. 2022; 144: 17261
• 6i Braun T, Izundu J, Steffen A, Neumann B, Stammler HG. Dalton Trans. 2006; 43: 5118
• 6j Schaub T, Backes M, Radius U. J. Am. Chem. Soc. 2006; 128: 15964
• 6k Nakamura Y, Yoshikai N, Ilies L, Nakamura E. Org. Lett. 2012; 14: 3316
• 6l Li X, Fu B, Zhang Q, Yuan X, Zhang Q, Xiong T, Zhang Q. Angew. Chem. Int. Ed. 2020; 59: 23056
• 6m Zhao Y, Fu B, Wang S, Li Y, Yuan X, Yin J, Xiong T, Zhang Q. Org. Lett. 2023; 25: 2492
• 6n Wu FP, Gu XW, Geng HQ, Wu XF. Chem. Sci. 2023; 14: 2342
• 7a Yokoyama N, Ritter B, Neubert AD. J. Med. Chem. 1982; 25: 337
• 7b Fryer RI, Zhang P, Rios R, Gu Z.-Q, Basile AS, Skolnick P. J. Med. Chem. 1993; 36: 1669
• 7c Savini L, Massarelli P, Nencini C, Pellerano C, Biggio G, Maciocco A, Tuligi G, Carrieri A, Cinone N, Carotti A. Bioorg. Med. Chem. 1998; 6: 389
• 8a Hamama WS, El-Gohary H, Kuhnert GN, Zoorob HH. Curr. Org. Chem. 2012; 16: 373
• 8b Zea A, Alba A.-NR, Mazzanti A, Moyano A, Rios R. Org. Biomol. Chem. 2011; 9: 6519
• 8c Li Y, Zhang S, Yang J, Jiang S, Li Q. Dyes Pigm. 2008; 76: 508
• 8d Prasad YR, Rao AL, Prasoona L, Murali K, Kumar PR. Bioorg. Med. Chem. Lett. 2005; 15: 5030
• 9a Liao YH, Chen WB, Wu ZJ, Du XL, Cun LF, Zhang XM, Yuan WC. Adv. Synth. Catal. 2010; 352: 827
• 9b Yang Z, Wang Z, Bai S, Liu X, Lin L, Feng X. Org. Lett. 2011; 13: 596
• 9c Wang Z, Yang Z, Chen D, Liu X, Lin L, Feng X. Angew. Chem. Int. Ed. 2011; 21: 5030
• 9d Li JH, Du DM. Org. Biomol. Chem. 2013; 11: 6215
• 10a Mao S, Geng X, Yang Y, Qian X, Wu S, Han J, Wang L. RSC Adv. 2015; 5: 36390
• 10b Huang T, Ji X, Wu W, Liang F, Cao S. RSC Adv. 2015; 5: 66598
• 11 1-Methyl-2-phenyl-1H-indole (3a) – Typical ProcedureAdded 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1a, 34.8 mg, 0.2 mmol, 1.0 equiv), N,N-diethyl-2,3,4,5,6-pentafluorobenzamide (2a, 64.08 mg, 0.24 mmol, 1.2 equiv), and Cs₂CO₃ (130.0 mg, 0.4 mmol, 2.0 equiv) in 2.0 mL of CH₃CN. The solution was warmed up to 80 ℃ and was stirred for 12 h until the reaction was complete as indicated by TLC. The reaction mixture was then quenched with H₂O, extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic layers were concentrated in vacuo. The resulting crude product was purified by flash column chromatography on silica gel to obtain the product. N,N-Diethyl-2,3,5,6-tetrafluoro-4-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)oxy]benzamide (3a)The crude was purified by flash chromatography using petroleum ether/ethyl acetate (15:1) to afford 3a as colorless oil (69.0 mg, 81% yield). TLC: R_f = 0.16 (petroleum ether/ethyl acetate = 15:1; UV). ¹H NMR (400 MHz, CDCl₃): δ = 7.70 (d, J = 7.2 Hz, 2 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 1 H), 5.48 (s, 1 H), 3.60 (q, J = 7.2 Hz, 2 H), 3.24 (q, J = 7.2 Hz, 2 H), 2.27 (s, 3 H), 1.28 (t, J = 6.8 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 157.9, 151.1, 149.0, 142.9 (dm, J = 248.0 Hz), 141.0 (dm, J = 299.0 Hz), 137.9, 134.2 (t, J = 13.0 Hz), 129.2, 127.2, 122.9, 114.1 (t, J = 13.0 Hz), 89.5, 43.4, 40.0, 14.6, 14.2, 12.9. ¹⁹F NMR (376 MHz, CDCl₃): δ = –142.00 to –142.14 (m, 2 F), –152.27 to –152.40 (m, 2 F). HRMS (ESI-TOF): m/z calcd for C₂₁H₂₀F₄N₃O₂ [M + H]⁺: 422.1486; found: 422.1480.