Late-Stage Sulfoximidation of Electron-Rich Arenes by Photoredox Catalysis

Abstract

The sulfoximine group has been reported as a versatile and beneficial functionality for pharmaceutical or agrochemical entities. Herein, we report the C_sp2–H sulfoximidation of electron-rich arenes ­under the irradiation of blue light using an organic acridinium photocatalyst and molecular oxygen or peroxodisulfates as terminal oxidants. The method allows for the late-stage introduction of various sulfoximines onto complex bioactive compounds showing high functional group compatibility without the need for prefunctionalization.

Key words

photocatalysis - C–H functionalization - sulfoximines - arylation - late-stage functionalization

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• 23 General Procedure A (Oxygen Atmosphere) To a microwave vial equipped with a stir bar was added the substrate (1.0 equiv, 0.4–1.0 mmol), sulfoximine (2.0 equiv), photocatalyst (0.05 equiv), and TEMPO (0.2 equiv), then the vial was closed with a septum cap. DCE or MeCN (0.1 M) was added, and the mixture was sparged with oxygen. The reaction mixture was subsequently irradiated in a Hepatochem PhotoRedOx Duo photoreactor and two Kessil LED lamps (each 40 W, A160WE) or a PennOC photoreactor m1 (450 nm). For the reaction workup, the mixture was either directly evaporated or half-saturated aqueous NaHCO₃ solution was added followed by extraction (5 × EtOAc, Na₂SO₄). Purification was performed using an automated Isolera™ Spektra System or preparative HPLC as described in the Supporting Information. General Procedure B (Stoichiometric Oxidant) To a microwave vial equipped with a stir bar were added the substrate (1.0 equiv, 0.6–0.9 mmol), sulfoximine (2.0 equiv), photocatalyst (0.05 equiv), TEMPO (0.2 equiv), and peroxodisulfate salt (1.1 equiv), then the vial was closed with a septum cap. DCE or MeCN (0.1 M) was added, and the mixture was sparged with argon. The reaction mixture was subsequently irradiated in a Hepatochem PhotoRedOx Duo photoreactor and two Kessil LED lamps (each 40 W, A160WE) or a PennOC photoreactor m1 (450 nm). For the reaction workup, the mixture was either directly evaporated or half-saturated aqueous NaHCO₃ solution was added followed by extraction (5 × EtOAc, Na₂SO₄). Purification was performed using an automated Isolera™ Spektra System or preparative HPLC as described in the Supporting Information.
• 24 Nicewicz and coworkers reported for other nucleophiles that in the case of mesitylene and m-xylene, 1.1 equiv of TEMPO under N₂ atmosphere was necessary to avoid benzylic oxidation (see ref. 16a, 21). We observed minor side products under oxygen atmosphere leading to 41% isolated yield. However, the use of 1.1 or 2.2 equiv of TEMPO under argon atmosphere just led to incomplete conversion and low isolated yield. The use of peroxodisulfates led just to trace amounts of desired product.
• 25 Nitrile 12 Yellow solid; mp 118.4–120.0 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 7.50 (d, J = 7.6 Hz, 2 H), 7.40 (t, J = 7.3 Hz, 2 H), 7.33 (t, J = 7.3 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 1 H), 6.95 (d, J = 2.7 Hz, 1 H), 6.86 (dd, J = 8.4, 2.7 Hz, 1 H), 5.10 (s, 2 H), 3.83 (s, 2 H), 3.16 (s, 6 H) ppm. ¹³C NMR (151 MHz, DMSO-d ₆): δ = 150.4, 139.5, 137.2, 128.4, 127.8, 127.4, 124.1, 122.7, 119.9, 119.0, 113.2, 69.7, 41.3, 18.2 ppm. HRMS (ESI): m/z calcd for C₁₇H₁₉N₂O₂S [M + H]^+∙: 315.1162; found: 315.1167.
• 26 Nitrile 14 Yellow solid; mp 131.8–135.0 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 7.46 (d, J = 7.2 Hz, 2 H), 7.42 (t, J = 7.6 Hz, 2 H), 7.35 (t, J = 7.3 Hz, 1 H), 7.20–7.15 (m, 3 H), 5.20 (s, 2 H), 3.20 (s, 6 H) ppm. ¹³C NMR (151 MHz, DMSO-d ₆): δ = 154.5, 139.9, 136.4, 129.3, 128.6, 128.1, 127.6, 126.0, 116.5, 114.7, 101.1, 70.2, 41.4 ppm. HRMS (ESI): m/z calcd for C₁₆H₁₇N₂O₂S [M + H]^+∙: 301.1005; found: 301.1014.
• 27 Clofibrate derivative 17 (major regioisomer) Slightly pink oil. ¹H NMR (major regioisomer, 500 MHz, DMSO-d ₆): δ = 6.99 (d, J = 2.5 Hz, 1 H), 6.85 (dd, J = 8.6, 2.5 Hz, 1 H), 6.76 (d, J = 8.6 Hz, 1 H), 4.16 (q, J = 7.6 Hz, 2 H), 3.19 (s, 6 H), 1.46 (s, 6 H), 1.20 (t, J = 7.3 Hz, 3 H) ppm. ¹³C NMR (major regioisomer, 101 MHz, DMSO-d ₆): δ = 173.4, 147.7, 140.2, 126.4, 123.2, 121.9, 120.9, 79.9, 60.8, 42.0, 24.7, 14.0 ppm. HRMS (ESI): m/z calcd for C₁₄H₂₁Cl^35/37NO₄S [M + H]^+∙: 334.0874/336.0845; found: 334.0883/336.0856; Clofibrate derivative 17′ (minor regioisomer) Slightly pink oil. ¹H NMR (600 MHz, DMSO-d ₆): δ = 7.21 (d, J = 8.4 Hz, 1 H), 6.67 (d, J = 2.7 Hz, 1 H), 6.34 (dd, J = 8.8, 3.1 Hz, 1 H), 4.16 (q, J = 7.2 Hz, 2 H), 3.23 (s, 6 H), 1.50 (s, 6 H), 1.19 (t, J = 6.5 Hz, 4 H) ppm. ¹³C NMR (151 MHz, DMSO-d ₆): δ = 173.0, 154.0, 143.6, 129.7, 120.5, 112.8, 112.4, 78.9, 61.1, 41.8, 25.0, 13.9 ppm. HRMS (ESI): m/z calcd for C₁₄H₂₁Cl^35/37NO₄S [M + H]^+∙: 334.0874/336.0845; found: 334.0879/336.0852.
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• 29 The regiochemistry of the products 19–22 was assigned based on extensive 2D NMR studies. See the Supporting Information for further details.
• 30 The esfenvalerate derivatives 24 and 25 were isolated as epimeric mixtures of the two stereogenic centers. The facile epimerization of the stereogenic center next to the nitrile group is described in the literature: Aketa K, Suzuki Y, Ohno N, Nakayama I, Kato T. US4312816A, 1982