Copper-Promoted Intramolecular Aminotrifluoromethylation of Alkenes with Langlois Reagent as the Trifluoromethyl Source

Abstract

A novel approach for copper-promoted intramolecular aminotrifluoromethylation of alkenes using inexpensive CF₃SO₂Na as the trifluoromethyl source is described. The feature of this method is the concurrent construction of a five-membered ring and a C–CF₃ bond in the simple copper salt/TBHP system. A gram-scale reaction was tested with a slight decrease in the yield. This protocol provides an operationally simple, step-economical and synthetically useful access to a variety of trifluoromethyl indolines, pyrrolidines and lactams.

Key words

Langlois reagent - aminotrifluoromethylation - azaheterocycles - copper-promoted - alkenes

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• 15 General Procedures for the Copper-Promoted Intramolecular Aminotrifluoromethylation of Alkenes: To a Schlenk tube were added 1a (0.2 mmol), CF₃SO₂Na (0.4 mmol), Cu(TFA)₂·xH₂O (0.2 mmol) and charged with argon three times. Anhydrous MeCN (1.5 mL) and TBHP (0.6 mmol) were added via a syringe and the mixture was stirred at 60 °C under Ar. When the substrate was consumed (monitored by TLC), the reaction mixture was cooled to r.t. The solvent was removed by rotary evaporation and the resulting residue was purified by column chromatography on silica gel to afford the product 2a in 73% yield. Characterization of Typical Products: 2e: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.42–7.45 (m, 1 H), 7.22–7.25 (m, 2 H), 7.09–7.13 (m, 1 H), 4.59–4.66 (m, 1 H), 3.60–3.67 (m, 2 H), 3.50–3.56 (m, 1 H), 3.13–3.17 (m, 2 H), 3.04–3.09 (m, 1 H), 2.85–2.92 (m, 1 H), 2.41–2.55 (m, 1 H), 2.24–2.30 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 140.32, 129.61, 128.48, 125.72, 124.96, 115.40, 125.36 (q, J = 256.1 Hz), 57.33 (d, J = 4.0 Hz), 46.82, 42.64, 40.78 (q, J = 27.3 Hz), 34.34, 26.18. ¹⁹F NMR (376 MHz, CDCl₃): δ = –62.90 (s, 3 F). HRMS (ESI): m/z [M + NH₄]⁺ calcd for C₁₃H₁₉ClF₃N₂O₂S: 359.0808; found: 359.0802. 2l: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.62–7.65 (m, 1 H), 7.53 (d, J = 8.3 Hz, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 6.92–6.97 (m, 1 H), 6.75–6.78 (m, 1 H), 4.42–4.48 (m, 1 H), 2.83–2.94 (m, 2 H), 2.70–2.75 (m, 1 H), 2.40–2.49 (m, 1 H), 2.38 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 160.55 (d, J = 245.1 Hz), 144.57, 136.79 (d, J = 2.1 Hz), 133.84, 132.95 (d, J = 8.8 Hz), 129.84, 127.17, 125.53 (q, 278.8 Hz), 118.57 (d, J = 8.8 Hz), 114.83 (d, J = 23.6 Hz), 112.42 (d, J = 24.3 Hz), 57.29 (q, J = 3.1 Hz), 40.46 (q, J = 27.0 Hz), 34.09, 21.54. ¹⁹F NMR (376 MHz, CDCl₃): δ = –63.09 (s, 3 F), –117.49 (s, 1 F). HRMS (ESI): m/z [M + NH₄]⁺ calcd for C₁₇H₁₉F₄N₂O₂S: 391.1103; found: 391.1098. 2o: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.19–7.39 (m, 10 H), 4.24 (d, J = 11.2 Hz, 1 H), 4.13–4.16 (m, 1 H), 3.98–4.05 (m, 1 H), 3.33–3.38 (m, 1 H), 3.01–3.15 (m, 1 H), 2.39–2.44 (m, 1 H), 2.22 (s, 3 H), 2.04–2.17 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 144.48, 143.81, 129.13, 128.85, 127.38, 126.99, 126.76, 126.40, 125.72 (q, J = 278.4 Hz), 59.29, 54.28, 53.37, 43.25, 40.45 (q, J = 26.26 Hz), 35.06. ¹⁹F NMR (376 MHz, CDCl₃): δ = –63.43 (s, 3 F). HRMS (ESI): m/z [M + NH₄]⁺ calcd for C₁₉H₂₄F₃N₂O₂S: 401.1511; found: 401.1505. 2q: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.21–7.45 (m, 10 H), 4.46–4.53 (m, 1 H), 3.86 (s, 3 H), 3.07 (dd, J = 12.7, 4.6 Hz, 1 H), 2.76–2.90 (m, 1 H), 2.65–2.71 (m, 1 H), 2.37–2.51 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 158.96, 142.20, 141.21, 128.77, 128.13, 128.07, 127.62, 127.59, 127.13, 125.10 (q, J = 278.0 Hz), 73.87 (d, J = 3.0 Hz), 62.74, 57.41, 45.44, 38.84 (q, J = 28.3 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –63.70 (s, 3 F). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₉F₃NO₂: 350.1368; found: 350.1362. 2r: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.24–7.40 (m, 10 H), 4.56–4.63 (m, 1 H), 3.19 (dd, J = 13.1, 3.2 Hz, 1 H), 2.65–2.78 (m, 2 H), 2.39–2.52 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 176.01, 141.33, 138.94, 129.15, 128.56, 128.06, 127.58, 127.52, 127.21, 125.02 (q, J = 278.3 Hz), 70.47 (d, J = 3.0 Hz), 57.52, 43.44, 39.17 (q, J = 29.3 Hz). ¹⁹F NMR (376 MHz, CDCl₃): δ = –63.76 (s, 3 F). HRMS (ESI): m/z [M + NH₄]⁺ calcd for C₁₈H₁₉F₃NO₂: 338.1368; found: 338.1362.
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