Radical α-C–H Cyclobutylation of Aniline Derivatives

Published as part of the Cluster 9th Pacific Symposium on Radical Chemistry

This paper is dedicated to Jürgen Klopp (manager of Liverpool F.C.) for his inspirational leadership.

Abstract

A catalytic system has been developed for the direct alkylation of α-C–H bonds of aniline derivatives with strained C–C σ-bonds. This method operates through a photoredox mechanism in which oxidative formation of aminoalkyl radical intermediates enables addition to a bicyclobutane derivative, giving rise to α-cyclobutyl N-alkylaniline products. This mild system proceeds through a redox- and proton-neutral mechanism and is operational for a range of substituted arylamine derivatives.

Key words

photoredox reaction - catalysis - C–C bond activation - anilines - alkylation - iridium catalysis

• References and Notes

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• 24 α-Cyclobutylanilines 2–14; General Procedure A screw-top test tube equipped with a stirrer bar was charged with [Ir{dF(CF₃)ppy}₂(dtbbpy)]·PF₆ (1 mol%), 1C (1 equiv), and, if solid, the appropriate aniline (5 equiv). The tube was sealed with a PTFE/silicon septum and connected to a Schlenck line. The atmosphere was exchanged by applying a vacuum and backfilling with N₂ (this process was conducted a total of three times). Under a N₂ atmosphere, the tube was charged by syringe with previously degassed solvent (DMA; 2 mL/mmol 1C) and, if liquid, the appropriate aniline. The resulting solution was stirred at 700 rpm and irradiated with blue LEDs (4 cm from the lamp) for 16 h. The reaction was then quenched with sat. aq NaHCO₃ (10 mL), and the mixture was extracted with EtOAc (3 × 15 mL). The combined extracts were washed sequentially with 5% aq LiCl (3 × 15 mL) and brine (2 × 15 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by chromatography (silica gel) to give the desired product. See the Supporting Information for full details, along with physical and spectroscopic data for the products.
• 25 2-{3-[(3,5-Difluorophenyl)sulfonyl]cyclobutyl}-1-phenylazepane (cis-7) By following general procedure, the reaction of 1C (116.6 mg, 0.5 mmol, 1 equiv), 1-phenylazepane (450 μl, 2.5 mmol, 5 equiv), and [Ir{dF(CF₃)ppy}₂(dtbbpy)]·PF₆ (6.4 mg, 0.005 mmol, 0.01 equiv), followed by purification by flash column chromatography [silica gel, EtOAc–hexanes (0–20%)], gave a clear oil; yield: 128.8 mg (64%). ¹H NMR (600 MHz, CDCl₃): δ = 7.38–7.32 (m, 2 H), 7.19 (dd, J = 8.5, 7.0 Hz, 2 H), 7.07–6.97 (m, 1 H), 6.72 (d, J = 8.3 Hz, 2 H), 6.61 (t, J = 7.2 Hz, 1 H), 3.86 (dt, J = 10.4, 6.9 Hz, 1 H), 3.63–3.52 (m, 2 H), 3.06 (dd, J = 15.6, 11.4 Hz, 1 H), 2.52–2.43 (m, 1 H), 2.41–2.30 (m, 2 H), 2.23 (dp, J = 11.9, 4.1 Hz, 1 H), 2.15 (dtd, J = 12.0, 7.9, 4.1 Hz, 1 H), 2.08 (dt, J = 14.4, 7.2 Hz, 1 H), 1.77–1.66 (m, 3 H), 1.60–1.52 (m, 1 H), 1.37–1.22 (m, 2 H), 1.22–1.13 (m, 1 H). ¹³C NMR (151 MHz, CDCl₃): δ =162.8 (dd, J = 255.8, 11.4 Hz), 148.5, 141.3 (t, J = 7.8 Hz), 129.4, 115.1, 112.1–111.7 (m), 110.8, 109.4 (t, J = 24.9 Hz), 58.6, 53.2, 43.2, 34.3, 31.9, 29.8, 26.9, 26.3, 25.9, 24.8. ¹⁹F (376 MHz, CDCl₃): δ = –104.95 to –104.96 (m). X-ray-quality crystals of cis-7 were obtained by Et₂O and hexane vapor diffusion. C₂₂H₂₅F₂NO₂S, M_r = 405.49, monoclinic, P2₁/n (No. 14), a = 9.56610(10), b = 21.4256(3), c = 19.3969(2) Å, β = 96.1240(10)^°, V = 3952.89(8) Å³, T = 102(4) K, Z = 8, Z′ = 2, μ(MoK_α) = 0.200; 135731 reflections measured, 20640 unique (R_int  = 0.0684), which were used in all calculations. The final wR₂ was 0.1495 (all data) and R₁ was 0.0566 [I > 2σ(I)]. Cambridge Crystallographic Data Centre (CCDC) contains the supplementary crystallographic data for compound cis-7. The data can be obtained free of charge from The CCDC via www.ccdc.cam.ac.uk/getstructures. 2-{3-[(3,5-Difluorophenyl)sulfonyl]cyclobutyl}-1-phenylazepane (trans-7) By following general procedure, the reaction of 1C (116.6 mg, 0.5 mmol, 1 equiv), 1-phenylazepane (450 μl, 2.5 mmol, 5 equiv), and [Ir{dF(CF₃)ppy}₂(dtbbpy)]·PF₆ (6.4 mg, 0.005 mmol, 0.01 equiv), followed by purification by flash column chromatography [silica gel, EtOAc–hexanes (0–20%)], gave a clear oil; yield: 64 mg (32%). ¹H NMR (600 MHz, CDCl₃): δ = 7.40–7.35 (m, 2 H), 7.15 (dd, J = 8.9, 7.1 Hz, 2 H), 7.04 (tt, J = 8.4, 2.3 Hz, 1 H), 6.70 (d, J = 8.4 Hz, 2 H), 6.57 (t, J = 7.2 Hz, 1 H), 3.84 (td, J = 9.1, 6.4 Hz, 1 H), 3.69–3.58 (m, 2 H), 3.07 (ddd, J = 15.7, 11.5, 2.0 Hz, 1 H), 2.90–2.82 (m, 1 H), 2.66–2.58 (m, 1 H), 2.50–2.42 (m, 1 H), 2.24–2.13 (m, 2 H), 2.13–2.04 (m, 1 H), 1.74–1.65 (m, 3 H), 1.53–1.51 (m, 1 H), 1.37–1.22 (m, 2 H), 1.20–1.13 (m, 1 H).¹³C NMR (151 MHz, CDCl₃): δ =162.9 (dd, J = 255.9, 11.4 Hz), 148.8, 141.3 (t, J = 8.0 Hz), 129.4, 115.1, 111.9 (dd, J = 21.7, 6.5 Hz), 110.9, 109.4 (t, J = 24.9 Hz), 58.6, 54.7, 43.0, 36.2, 32.2, 29.6, 26.0, 25.7, 25.7, 24.7.¹⁹F NMR (376 MHz, CDCl₃): δ = –105.01 to –105.04 (m).