Nickel-Catalyzed Enantioselective Friedel–Crafts Alkylation of Indoles with β,β-Disubstituted Nitroalkenes

Abstract

An enantioselective Friedel–Crafts alkylation of indoles with β,β-disubstituted nitroalkenes was developed by using a nickel(II) perchlorate–bisoxazoline complex as a catalyst. A range of nitroalkenes and indoles participated in this reaction, affording chiral indole compounds bearing all-carbon quaternary stereocenters in excellent yields and with moderate to good enantioselectivities (up to 80% ee).

Key words

Friedel–Crafts reactions - nitroalkenes - indoles - asymmetric catalysis - nickel

• References and Notes


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• 12 Indoles 3; General Procedure A dried Schlenk tube was charged with Ni(ClO₄)₂·6H₂O (7.3 mg, 0.02 mmol) and ligand L5 (11.7 mg, 0.024 mmol) under N₂. Toluene (2.0 mL) was then added from a syringe and the mixture was stirred at 50 °C for 1 h. The appropriate nitroalkene 2 (0.2 mmol) and indole 1 (0.3 mmol) were added, and the mixture was stirred at 50 °C until the reaction was complete (TLC). The solvent was removed under vacuum, and the residue was purified by chromatography [silica gel, EtOAc–PE (1:4)].
• 13 3-[(1S)-1-Methyl-2-nitro-1-phenylethyl]-1H-indole (3aa) White solid; 90% yield, 77% ee; mp 145–146 °C; [α]_D ²⁰ +47.6 (c 0.5, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 2.03 (s, 3 H), 5.16 (d, J = 10.5 Hz, 1 H), 5.26 (d, J = 10.5 Hz, 1 H), 6.62–6.97 (m, 2 H), 7.15–7.18 (m, 2 H), 7.26–7.34 (m, 5 H), 7.38 (d, J = 8.0 Hz, 1 H), 8.11 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 26.8, 43.8, 84.6, 111.5, 119.2, 119.5, 120.5, 122.2, 125.2, 126.5, 127.0, 128.5, 136.9, 143.9. HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₈H₁₅F₃N₂NaO₂: 371.0983; found: 371.099. HPLC [Daicel Chiralpak AD-H column (25 × 0.46 cm), hexane–i-PrOH (90:10), 1.0 mL/min, λ = 254 nm]: t_minor  = 18.5 min, t_major  = 17.1 min.
• 14 The absolute configuration of product 3aa was assigned as S; for details see the Supporting Information.