Iron-Catalyzed C(sp³)–H Alkylation through Ligand-to-Metal Charge Transfer

Abstract

We report the FeCl₃-catalyzed alkylation of nonactivated C(sp³)–H bonds. Photoinduced ligand-to-metal charge transfer at the iron center generates chlorine radicals that then preferentially abstract hydrogen atoms from electron-rich C(sp³)–H bonds distal to electron-withdrawing functional groups. The resultant alkyl radicals are trapped by electron-deficient olefins, and the catalytic cycle is closed by Fe(II) recombination and protodemetalation.

Key words

C(sp³)–H bond activation - photocatalysis - charge transfer - iron catalysis - alkylation - alkenes

Publication History

Received: 17 June 2021

Accepted after revision: 19 July 2021

Article published online:
09 August 2021

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• 40 Benzyl 6-Oxooctanoate (3); Typical Procedure An oven-dried 1.5 dram vial was charged with FeCl₃ (25 mol%). (Any solid reactants were also added at this stage.) A magnetic stirrer bar was added, and the vial was transferred to a glovebox. Anhyd MeCN (1 mL, 0.3 M) was then added, followed by pentan-3-one (5 equiv) and benzyl acrylate (1 equiv, 0.3 mmol). The vial was sealed and then placed on a stirrer plate 2 in. (5 cm) from a 390 nm Kessil lamp. Ambient temperature was maintained by the use of a fan above the setup. After 36 h, the mixture was concentrated in vacuo and purified by flash column chromatography [silica gel, EtOAc–hexanes (1:5)]. to give a colorless oil; yield: 40.4 mg (54%). IR (film): 2939, 1732, 1712, 1497, 1455, 1414, 1377, 1211, 1113, 1084, 976, 739, 697 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.62–7.12 (m, 5 H), 5.11 (s, 2 H), 2.54–2.25 (m, 6 H), 1.72–1.51 (m, 4 H), 1.04 (t, J =7.4 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 211.12, 173.26, 136.14, 128.63, 128.38, 128.28, 66.24, 41.92, 35.95, 34.13, 24.56, 23.34, 7.90. LRMS (EI): m/z [M⁺] calcd for C₁₅H₂₀O₃; 248.14; found: 248.1.
• 41 Ethyl 3-(3-Oxocyclobutyl)propanoate (10) Prepared by following the typical procedure from cyclobutanone and ethyl acrylate as a yellow oil; yield: 20.1 mg (39%). IR (film): 2979, 1780, 1728, 1448, 1374, 1342, 1251, 1179, 1099, 1028 cm^–1. ¹H NMR (500 MHz, CDCl3) δ = 4.13 (q, J = 7.1 Hz, 2 H), 3.23–3.02 (m, 2 H), 2.79–2.61 (m, 2 H), 2.47–2.35 (m, 1 H), 2.34 (t, J = 7.5 Hz, 2 H), 1.92 (q, J = 7.6 Hz, 2 H), 1.26 (t, J = 7.1 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 207.51, 173.06, 60.64, 52.48, 33.18, 31.45, 23.58, 14.34. HRMS (ASAP): m/z [M + H]⁺calcd for C₉H₁₅O₃: 171.1021; found: 171.1012. Benzyl 3-(1,1-Dioxidotetrahydro-3-thienyl)propanoate (16) Prepared by following the typical procedure from sulfolane and benzyl acrylate as a viscous colorless oil; yield: 49.3 mg (58%). IR (film): 2940, 1728, 1497, 1454, 1414, 1388, 1354, 1301, 1268, 1168, 1117, 749, 698, 570, 460 cm^–1. ¹H NMR (500 MHz, CDCl3) δ = 7.41–7.30 (m, 5 H), 5.12 (s, 2 H), 3.19 (tdd, J = 13.2, 7.8, 2.1 Hz, 2 H), 2.99 (ddd, J = 13.2, 11.3, 7.7 Hz, 1 H), 2.64 (dd, J = 13.0, 10.8 Hz, 1 H), 2.47–2.35 (m, 3 H), 2.31 (dddd, J = 14.9, 7.7, 3.5, 1.6 Hz, 1 H), 1.92–1.72 (m, 3 H). ¹³C NMR (126 MHz, CDCl3) δ = 172.31, 135.67, 128.73, 128.54, 128.46, 66.69, 56.61, 52.26, 36.16, 31.99, 29.50, 28.94. LRMS (EI): m/z [M⁺] calculated for C₁₄H₁₈O₄S; 282.09; found: 282.1. 1-Methyl-3-(3-Oxopentyl)pyrrolidine-2,5-dione (22) Prepared by following the typical procedure from pentan-3-one and N-methylmaleimide as a yellow oil; yield: 33.9 mg (57%). IR (film): 2938, 1774, 1691, 1434, 1379, 1278, 1117, 954, 698 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 2.94 (s, 3 H), 2.89–2.75 (m, 2 H), 2.71–2.55 (m, 2 H), 2.43 (q, J =7.3 Hz, 2 H), 2.33 (dd, J =17.3, 3.7 Hz, 1 H), 2.05–1.95 (m, 1 H), 1.93–1.83 (m, 1 H), 1.04 (t, J =7.3 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 210.16, 179.70, 176.39, 39.04, 38.84, 36.11, 34.86, 25.64, 24.85, 7.84. HRMS (ASAP): m/z [M + H]⁺ calcd for C₁₀H₁₆NO₃: 198.1130; found: 198.1127.