Synlett 2012; 23(18): 2699-2703
DOI: 10.1055/s-0032-1317485
letter
© Georg Thieme Verlag Stuttgart · New York

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

Shigeru Sasaki*
Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan   Fax: +81(3)54985768   Email: s-sasaki@hoshi.ac.jp
,
Yuta Ikekame
Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan   Fax: +81(3)54985768   Email: s-sasaki@hoshi.ac.jp
,
Manabu Tanayama
Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan   Fax: +81(3)54985768   Email: s-sasaki@hoshi.ac.jp
,
Takayasu Yamauchi
Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan   Fax: +81(3)54985768   Email: s-sasaki@hoshi.ac.jp
,
Kimio Higashiyama
Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa, Tokyo 142-8501, Japan   Fax: +81(3)54985768   Email: s-sasaki@hoshi.ac.jp
› Author Affiliations
Further Information

Publication History

Received: 18 August 2012

Accepted after revision: 25 September 2012

Publication Date:
18 October 2012 (online)


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.

Supporting Information

 
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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.