Quinolinamide-Enabled Nickel-Catalyzed Regio- and Diastereoselective γ,δ-Arylalkylation of Nonactivated Alkenes

Abstract

A quinolinamide-enabled nickel-catalyzed γ,δ-arylalkylation of homoallylic amines with aryl iodides and organozinc compounds has been developed. The cleavable quinolinamide directing group facilitates the stabilization of a five-membered nickelacycle, and enables the dicarbofunctionalization of nonactivated alkenes with excellently regio-, chemo-, and diastereoselectivity. The reaction with internal alkenes proceeds stereospecifically to provide valuable γ-alkyl-δ-aryl-substituted amines with two vicinal stereocenters. The scope of substrates and the utility of the protocol have been thoroughly studied.

Key words

alkenes - directing group - aryalkylation - nickel catalysis - diastereoselectivity

Publication History

Received: 15 September 2023

Accepted after revision: 16 October 2023

Accepted Manuscript online:
16 October 2023

Article published online:
04 December 2023

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• 19 Amides 2b–ah; General Procedure In an argon-filled glovebox, NiCl₂·DME (0.02 mmol, 10 mol%) and the appropriate alkene substrate (0.2 mmol, 1.0 equiv), aryl iodide (0.44 mmol, 2.2 equiv), and alkylzinc reagent (0.4 mmol, 2 equiv), together with DMA (1 mL), were added to a 4 mL tube, and the mixture was stirred at 50 °C for 24 h. The vessel was then allowed to cool to r.t., and the mixture was diluted with 1 M aq HCl (15 mL) and extracted with EtOAc (5 × 10 mL). The organic layers were combined and concentrated under vacuum to afford a residue that was purified by flash chromatography (silica gel, EtOAc–hexane). N-[4-(2-Methoxyphenyl)-3-methylbutyl]quinoline-2-carboxamide (2b) Isolated by column chromatography [silica gel, EtOAc–hexane (1:6)] as a colorless oil; yield: 75%. ¹H NMR (400 MHz, CDCl₃): δ = 8.32 (s, 2 H), 8.27 (s, 1 H), 8.12 (d, J = 8.5 Hz, 1 H), 7.92–7.84 (m, 1 H), 7.78–7.74 (m, 1 H), 7.67–7.58 (m, 1 H), 7.09 (d, J = 8.6 Hz, 2 H), 6.85–6.80 (m, 2 H), 3.78 (s, 3 H), 3.68–3.49 (m, 2 H), 2.65 (dd, J = 13.6, 6.4 Hz, 1 H), 2.44 (dd, J = 13.6, 7.8 Hz, 1 H), 1.88 (dt, J = 13.2, 6.7 Hz, 1 H), 1.82–1.72 (m, 1 H), 1.66–1.54 (m, 1 H), 0.98 (d, J = 6.6 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 164.4, 157.7, 150.0, 146.5, 137.5, 131.0, 130.1, 129.6, 129.5, 129.3, 127.8, 127.1, 120.2, 118.9, 110.3, 55.2, 37.8, 37.7, 36.6, 31.4, 19.8. GC/MS (EI): m/z [M⁺] calcd for C₂₂H₂₄N₂O₂: 348.18; found: 348.11. N-[4-(3-Methoxyphenyl)-3-methylbutyl]quinoline-2-carboxamide (2c) Isolated by column chromatography [silica gel, EtOAc–hexane (1:6)] as a yellow oil; yield: 81%. ¹H NMR (400 MHz, CDCl₃): δ = 8.35–8.27 (m, 2 H), 8.23 (s, 1 H), 8.10 (d, J = 8.5 Hz, 1 H), 7.87 (d, J = 8.1 Hz, 1 H), 7.80–7.72 (m, 1 H), 7.61 (dd, J = 11.1, 3.9 Hz, 1 H), 7.23–7.13 (m, 1 H), 6.76 (dd, J = 14.1, 6.9 Hz, 3 H), 3.77 (s, 3 H), 3.71–3.44 (m, 2 H), 2.68 (dd, J = 13.4, 6.5 Hz, 1 H), 2.47 (dd, J = 13.4, 7.8 Hz, 1 H), 1.92 (m, 1 H), 1.83–1.72 (m, 1 H), 1.62–1.50 (m, 1 H), 0.99 (d, J = 6.6 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 164.5, 159.6, 150.0, 146.6, 142.7, 137.6, 130.1, 129.8, 129.4, 129.2, 127.9, 127.9, 121.8, 119.0, 115.0, 111.2, 55.2, 55.2, 43.7, 36.4, 33.0, 19.6. GC/MS (EI): m/z [M⁺] calcd for C₂₂H₂₄N₂O₂: 348.18; found: 348.10. N-[4-(4-Methoxyphenyl)-3-methylbutyl]quinoline-2-carboxamide (2d) Isolated by column chromatography [silica gel, EtOAc–hexane (1:6)] as a colorless oil; yield: 75%. ¹H NMR (400 MHz, CDCl₃): δ = 8.32 (s, 2 H), 8.27 (s, 1 H), 8.12 (d, J = 8.5 Hz, 1 H), 7.91–7.86 (m, 1 H), 7.77 (m, 1 H), 7.64–7.60 (m, 1 H), 7.09 (d, J = 8.6 Hz, 2 H), 6.84–6.80 (m, 2 H), 3.78 (s, 3 H), 3.70–3.49 (m, 1 H), 2.65 (dd, J = 13.6, 6.4 Hz, 1 H), 2.44 (dd, J = 13.6, 7.8 Hz, 1 H), 1.88 (m, 1 H), 1.83–1.71 (m, 1 H), 1.54 (m, 2 H), 0.98 (d, J = 6.6 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 164.3, 157.9, 149.9, 146.3, 137.8, 133.1, 130.3, 130.2, 129.6, 129.4, 128.0, 127.9, 119.1, 113.7, 55.3, 42.7, 37.9, 36.3, 33.2, 19.5. GC/MS (EI): m/z [M⁺] calcd for C₂₂H₂₄N₂O₂: 348.18; found: 348.11. N-[4-(1,3-Benzodioxol-5-yl)-3-methylbutyl]quinoline-2-carboxamide (2e) Isolated by column chromatography [silica gel, EtOAc–hexane (1:6)] as a colorless oil; yield: 85%. ¹H NMR (400 MHz, CDCl₃): δ = 8.34–8.26 (m, 2 H), 8.24 (s, 1 H), 8.10 (d, J = 8.5 Hz, 1 H), 7.84 (t, J = 9.6 Hz, 1 H), 7.75 (m, 1 H), 7.63–7.55 (m, 1 H), 6.76–6.57 (m, 3 H), 5.96–5.81 (m, 2 H), 3.72–3.46 (m, 2 H), 2.72–2.55 (m, 1 H), 2.48–2.33 (m, 1 H), 1.95–1.67 (m, 2 H), 1.64–1.44 (m, 1 H), 0.96 (d, J = 7.1 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 164.4, 149.9, 147.5, 146.5, 145.6, 137.5, 134.7, 130.1, 129.7, 129.3, 127.8, 122.0, 118.9, 109.5, 108.0, 100.7, 43.3, 37.7, 36.3, 33.1, 19.4. GC/MS (EI): m/z [M⁺] calcd for C₂₂H₂₂N₂O₃: 362.16; found: 362.22.