Facile Synthesis of 4-Perfluoroalkylated 2H-Pyran-2-ones Bearing Indole Skeleton via a Base-Promoted Cascade Process

Abstract

A protocol for the synthesis of 4-perfluoroalkylated 2H-pyran-2-ones bearing indole skeleton is reported. This efficient synthesis involves a Et₃N-promoted Michael addition/enolization/cyclization cascade process at 40 °C in air, using 3-(1-methyl-1H-indol-3-yl)-3-oxopropanenitriles and methyl perfluoroalk-2-ynoates as the easily available starting materials. Various functionalized 6-(1-methyl-1H-indol-3-yl)-2-oxo-4-(perfluoroalkyl)-2H-pyran-5-carbonitrile derivatives were obtained in 44–99% yield.

Key words

2H-pyran-2-one - indole - perfluoroalkylated - heterocyclic synthesis - Michael addition

Publication History

Received: 08 June 2021

Accepted after revision: 09 June 2021

Accepted Manuscript online:
09 June 2021

Article published online:
25 June 2021

• References


For some recent reviews, see:
• 1a Goel A, Ram VJ. Tetrahedron 2009; 65: 7865
• 1b Kranjc K, Kočevar M. ARKIVOC 2013; (i): 333
• 1c Albanese DC, Gaggero N. Eur. J. Org. Chem. 2014; 5631
• 1d Usachev BI. J. Fluorine Chem. 2015; 175: 36
• 1e Pratap R, Ram VJ. Tetrahedron 2017; 73: 2529
• 2a Tressaud A, Haufe G. Fluorine and Health: Molecular Imaging, Biomedical Materials and Pharmaceuticals. Elsevier; Amsterdam: 2008
• 2b Yamazaki T, Taguchi T, Ojima I. Unique Properties of Fluorine and Their Relevance to Medicinal Chemistry and Chemical Biology. John Wiley & Sons; Chichester: 2009
• 2c Wang J, Gakh AA, Kirk KL. Fluorinated Heterocycles . American Chemical Society; Washington DC: 2009
• 2d Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and Applications. Petrov VA. John Wiley & Sons; Hoboken: 2009
• 2e O’Hagan D. J. Fluorine Chem. 2010; 131: 1071
• 2f Wang J, Roselló MS, Aceña JL, Pozo CA, Sorochinsky E, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432

For some recent representative examples, see:
• 3a Clarke SL, McGlacken GP. Tetrahedron 2015; 71: 2906
• 3b Yan W, Wang R, Zhang T, Deng H, Chen J, Wu W, Weng Z. Org. Biomol. Chem. 2018; 16: 9440
• 3c Usachev BI. J. Fluorine Chem. 2015; 172: 80
• 3d Usachev BI. J. Fluorine Chem. 2015; 175: 36
• 3e Babu SM, Pozzo J. J. Heterocycl. Chem. 1991; 28: 819
• 3f Usachev BI, Obydennov DL, Röschenthaler GV, Sosnovskikh VY. Org. Lett. 2008; 10: 2857
• 3g Yeh PP, Daniels DS, Cordes DB, Slawin AM, Smith AD. Org. Lett. 2014; 16: 964
• 3h Marangoni MA, Bencke CE, Bonacorso HG. M, Martins A, Zanatta N. Tetrahedron Lett. 2018; 59: 121
• 4a Sundberg RJ. Indoles 1996
• 4b Horton DA, Bourne GT, Smythe ML. Chem. Rev. 2003; 103: 893
• 4c Humphrey GR, Kuethe JT. Chem. Rev. 2006; 106: 2875

For some representative examples, see:
• 5a Chen I, Safe S, Bjeldanes L. Biochem. Pharmacol. 1996; 51: 1069
• 5b Suzen S, Buyukbingol E. Farmaco 2000; 55: 246
• 5c Buyukbingol E, Suzen S, Klopman G. Farmaco 1994; 49: 443
• 5d Suzen S, Buyukbingol E. Farmaco 1998; 53: 525
• 5e Lieberman PM, Wolfler A, Felsner P, Hofer D, Schauenstien K. Int. Arch. Allergy Immunol. 1997; 112: 203
• 5f Chyan YJ, Poeggler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA. J. Biol. Chem. 1999; 274: 21937
• 6a Brown ED, Wright GD. Nature 2016; 529: 336
• 6b Wright GD. Nat. Prod. Rep. 2017; 34: 694
• 6c Neto LR, Filho JT, Neves BJ, Maidana RL, Guimarães AC, Furnham N, Andrade CH, Silva FP. Front. Chem. 2020; 8: 93
• 7a Cao W, Ding W, Huang T, Huang H, Wei C. J. Fluorine Chem. 1998; 91: 99
• 7b Cao W, Ding W, Liu R, Huang T, Cao J. J. Fluorine Chem. 1999; 95: 135
• 8 For a recent review, see: Sun X, Han J, Chen J, Zhang H, Cao W. Chem. Rec. 2016; 16: 907
• 9 CCDC 1846440 (3c) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures. Unit cell parameters (3c) a = 10.990(2) Å; b = 11.402(3) Å; c = 23.691(5) Å; α = 90°; β = 92.650°; γ = 90°; space group: P2(1)/n.
• 10a Liu W, Jiang H, Qiao C. Tetrahedron 2009; 65: 2110
• 10b Cao H, Zhong H, Lin Y, Yang L. Tetrahedron 2012; 68: 4042
• 11 Hamper BC. Org. Synth. 1992; 70: 246
• 12 General Procedure for the Preparation of Perfluoroalkylated Indolylpyranone Derivatives 3 Under air in a sealed tube, a mixture of 3-(1-methyl-1H-indol-3-yl)-3-oxopropanenitriles 1 (1.0 mmol) and methyl perfluoroalk-2-ynoates 2 (2.0 mmol) in the presence of Et₃N (1.0 mmol) in THF (5 mL) was stirred at 40 °C for 24 h; then after cooled to room temperature, THF was removed under vacuum, and the residue was purified by column chromatography on silica gel by eluting with petroleum ether/ethyl acetate (20:1) to give the purified product 3. 6-(1-Methyl-1H-indol-3-yl)-2-oxo-4-(trifluoromethyl)-2H-pyran-5-carbonitrile (3a) Light yellow solid; yield 97%; mp 239.8–240.9 °C. ¹H NMR (500 MHz, CDCl₃): δ = 3.95 (s, 1 H), 6.40 (s, 1 H), 7.39–7.44 (m, 3 H), 8.38–8.40 (m, 1 H), 8.65 (s, 1 H) ppm. ¹³C NMR (125 MHz, DMSO-d ₆): δ = 34.4, 78.9, 106.5, 106.9 (q, ³ J_C–F = 5.3 Hz), 110.6, 115.1, 120.6 (q, ¹ J_C–F = 274.2 Hz), 123.1, 124.1, 124.8, 125.7, 136.5, 137.2, 144.5 (q, ² J_C–F = 33.2 Hz), 157.5, 168.9 ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –66.8 ppm. IR (KBr): ν = 3127, 2217, 1737, 1515, 1276, 1173, 1141, 882, 753, 670 cm^–1. MS (ESI): m/z (%) = 319.0 [M + H]⁺. HRMS (ESI): m/z calcd for C₁₆H₉F₃N₂O₂ [M + H]⁺: 319.0687; found: 319.0686.