Brønsted Acid Catalyzed Friedel–Crafts Alkylation Reactions of Trifluoro­methyl-α,β-ynones with Indoles

Abstract

The successful development of a Brønsted acid catalyzed Friedel–Crafts alkylation reaction between trifluoromethyl-α,β-ynones and indoles has been described. The reaction is catalyzed by benzoic acid (5 mol%), with the indoles adding to the carbonyl carbon of the trifluoromethyl-α,β-ynones producing the corresponding 1,2-addition products as trifluoromethyl propargyl alcohols in high yields. Furthermore, treatment of the product with indoles in the presence of trifluoroacetic acid (10 mol%) afforded trifluoro­methyl-functionalized unsymmetrical bis(indolyl)propynes in high yields.

Key words

Brønsted acid - trifluoromethyl-α,β-ynones - indoles - trifluoromethyl propargyl alcohols - bis(indolyl)propynes

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• 12 General Procedure for the Synthesis of Propargyl Alcohols The reaction was performed in a 3 mL V-vial equipped with Teflon-coated magnetic stirrer bar and screw cap. The V-vial was charged with indole (0.5 mmol), trifluoromethyl-α,β-ynone (1.05 equiv, 0.525 mmol), and CH₂Cl₂ (0.5 mL; as needed), then was stirred for 10 min. Then benzoic acid (5 mol%, 25 μmol, 3 mg) was added in one portion. After completion of reaction as indicated by TLC, the mixture was purified by silica gel chromatography directly. 1,1,1-Trifluoro-2-(1H-indol-3-yl)-4-phenylbut-3-yn-2-ol (5) Purification by silica gel chromatography (CHCl₃–MeOH, 29:1) gave white solid (mp 134–136 °C). ¹H NMR (400 MHz, CDCl₃): δ = 3.11 (s, 1 H), 7.20 (ddd, J = 7.5, 7.0, 1.2 Hz, 1 H), 7.25 (ddd, J = 7.5, 7.0, 1.2 Hz, 1 H), 7.23–7.24 (m, 4 H), 7.52–7.56 (m, 3 H), 8.02 (d, J = 8.0 Hz, 1 H), 8.29 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 71.01 (q, J = 34.3 Hz), 84.50, 87.12, 111.41, 111.51, 120.54, 121.04, 121.13, 122.66, 123.94 (q, J = 285.5 Hz), 124.80, 128.20, 129.39, 132.03, 136.53. ¹⁹F NMR (376.5 MHz, CDCl₃): δ = –71.6. IR (KBr): 3425, 3360, 2240 cm^–1. HRMS (EI): m/z calcd for C₁₈H₁₂F₃NO: 319.1184; found: 319.1208. Anal. Calcd for C₁₈H₁₂F₃NO: C, 68.57; H, 3.84; N, 4.44. Found: C, 68.87; H, 3.91; N, 4.50.
• 13 General Procedure for the Synthesis of Unsymmetrical Bis(indolyl) Propynes To a solution of trifluoromethyl propargyl alcohol derivative 5 (0.5 mmol) in CHCl₃ (2 mL) were added indoles (1.5 equiv, 0.75 mmol) and TFA (10 mol%, 50 μmol, 6 mg) at r.t. The reaction mixture was stirred until the disappearance of trifluoromethyl propargyl alcohol derivatives as observed by TLC. The reaction mixture was quenched with an aq sat. NaHCO₃ solution (2 mL), and the organic layer was separated. The aqueous layer was extracted 3 times with CHCl₃. The combined organic layer was dried with anhyd Na₂SO₄ and then evaporated. The residue was purified by column chromatography. 5-Methyl-3-[1,1,1-trifluoro-2-(1H-indol-3-yl)-4-phenylbut-3-yn-2-yl]-1H-indole (10) Purification by silica gel chromatography (CHCl₃) gave a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 2.33 (s, 1 H), 6.97–7.04 (m, 2 H), 7.13–7.19 (m, 1 H), 7.19–7.21 (m, 1 H), 7.21–7.24 (m, 2 H), 7.26–7.31 (m, 3 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.45–7.49 (m, 2 H), 7.56 (s, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 8.00 (s, 1 H), 8.09 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.56, 46.52 (q, J = 31.0 Hz), 85.14, 86.23, 110.91, 111.14, 111.24, 111.85, 119.70, 120.85, 121.29, 122.09, 122.53, 123.82, 124.33, 124.46, 125.87, 126.07, 126.15 (q, J = 284.6 Hz), 128.22, 128.47, 128.88, 131.74, 134.77, 136.45. ¹⁹F NMR (376.5 MHz, CDCl₃): δ = –71.54. IR (KBr): 3413, 2235 cm^–1. ESI-HRMS: m/z calcd for C₂₇H₁₈F₃N₂: 427.1422; found: 427.1419.