Radical Cyclopropanol Ring Opening Initiated Tandem Cyclizations for Efficient Synthesis of Phenanthridines and Oxindoles

Abstract

β-Keto radicals can be readily generated from single-electron oxidation and ring opening of cyclopropanols. Herein, we report new ways of trapping β-keto radicals derived from Mn(III)-mediated oxidative cyclopropanol ring opening with biaryl isonitriles and N-aryl acrylamides derived from anilines. Through tandem radical cyclization processes, substituted phenanthridines and oxindoles can be synthesized in one step and good to excellent yield. These new synthetic methods feature broad substrate scope and mild reaction conditions, efficiently form two carbon–carbon bonds, and use cheap and commercially available manganese salts as oxidants. Concomitant installation of ketone functionality in the final products provides a handle for further functionalization of these important and biologically relevant scaffolds.

Key words

cyclopropanol - radical - phenanthridine - oxindole - manganese

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• 13 Representative Procedure for the Phenanthridine Synthesis An argon-degassed solution of cyclopropanol 1 (1 equiv) in t-BuOH (0.02 M) was added dropwise over 2 h to an argon-degassed, stirred solution of 2-isocyano biphenyl 2 (2 equiv) and manganese(III) acetylacetonate (2.2 equiv) in t-BuOH (0.042 M) at 26 °C. The resulting solution (0.01 M with respect to the cyclopropanol) was stirred for an additional 5 min before the solvent was removed under reduced pressure, and the resulting residue purified by flash chromatography to yield the desired 2-substituted phenanthradine 3. Compound 3aa was prepared according to the above procedure using 1a (0.125 mmol, 31 mg) and 2a (0.25 mmol, 45 mg) and isolated as a yellow solid (43 mg, 83%) following flash chromatography (hexanes–EtOAc, 10:1). ¹H NMR (500 MHz, CDCl₃): δ = 8.62 (d, J = 8.3 Hz, 1 H), 8.52 (d, J = 8.0 Hz, 1 H), 8.27 (d, J = 8.2 Hz, 1 H), 8.05 (d, J = 7.5 Hz, 1 H), 7.82 (t, J = 7.5 Hz, 1 H), 7.69 (t, J = 7.85 Hz, 2 H), 7.61 (t, J = 7.35 Hz, 1 H), 3.69 (t, J = 6.8 Hz, 2 H), 3.64 (t, J = 6.4 Hz, 2 H), 3.16 (t, J = 6.9 Hz, 2 H), 2.70 (t, J = 7.4 Hz, 2 H), 1.73 (quin, J = 7.7 Hz, 2 H), 1.58 (quin, J = 6.9 Hz, 2 H), 0.90 (s, 9 H), 0.06 (s, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 210.9, 159.7, 143.7, 132.8, 130.5, 129.7, 128.7, 127.6, 126.5, 125.9, 125.6, 123.9, 122.6, 122.1, 63.1, 43.3, 39.5, 32.6, 29.2, 26.2, 20.6, 18.5, –5.1. IR (neat): 2964, 2903, 1666, 1578, 1393, 1238, cm^–1. ESI-MS: m/z calcd for C₂₆H₂₅NO₂Si [M + H]⁺: 422.24; found: 422.2.
• 14 Representative Procedure for the 2-Oxindole Synthesis An argon-degassed solution of cyclopropanol 1 (2 equiv) in t-BuOH (0.0625 M) was added dropwise over 3 h to an argon-degassed, stirred solution of acrylamide 4 (1 equiv) and manganese(III) acetylacetonate (2.2 equiv) in t-BuOH (0.114 M) at 26 °C. The resulting solution (0.03 M with respect to the cyclopropanol) was stirred for an additional 5 min before the solvent was removed under reduced pressure and the resulting residue purified by flash chromatography to yield the desired oxindole. Compound 5aa was prepared according to the above procedure using 4a (0.125 mmol, 22 mg) and 1a (0.25 mmol, 62 mg) and isolated as a yellow oil (38 mg, 72%) following flash chromatography (hexanes–EtOAc, 6:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.25 (t, J = 7.7 Hz, 1 H), 7.17 (d, J = 7.3 Hz, 1 H), 7.05 (t, J = 8.2 Hz, 1 H), 6.83 (d, J =7.8 Hz, 1 H), 3.56 (t, J = 6.2 Hz, 2 H), 3.20 (s, 3 H), 2.30 (t, J = 7.5 Hz, 2 H), 2.26 (q, J = 7.2 Hz, 2 H), 1.70–1.86 (m, 2 H), 1.49–1.57 (m, 2 H), 1.40–1.47 (m, 2 H), 1.33 (s, 3 H), 1.14–1.22 (m, 2 H), 0.86 (s, 9 H), 0.02 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 210.3, 180.4, 143.1, 133.6, 127.7, 126.4, 122.5, 107.9, 62.7, 48.2, 42.3, 23.2, 37.6, 32.1, 26.0, 25.8, 23.8, 20.1, 18.7, 18.2, 5.4. IR (neat): 2951, 2928, 2856, 1714, 1613, 1493, 1253, 1100, 835 cm^–1. MS: m/z calcd for C₂₄H₃₉NO₃Si [M + H]⁺: 418.28; found. 418.2.