Trideuteromethylation of Alkyl and Aryl Bromides by Nickel-Catalyzed Electrochemical Reductive Cross-Electrophile Coupling

Abstract

A new nickel-catalyzed electrochemical, reductive cross-coupling for the trideuteromethylation of alkyl and aryl bromides is reported in which CD₃ arenesulfonate derivatives were used as effective and readily available CD₃ sources. The CD₃-labeled products were obtained with good yields. It was demonstrated that this methodology is scalable and can be efficiently used for various methylations, including ¹³CH₃ and ¹³CD₃ labeling.

Key words

electrosynthesis - nickel catalysis - isotopic labeling - methylation - aryl halides - cross-coupling

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• 13 Trideuteromethylation of Alkyl Bromides; General Procedure A 6 mL electrochemical cell equipped with a stirrer bar, a stainless-steel (SS) anode, and a Cu foam cathode (20 × 10 × 1 mm) was charged with the appropriate alkyl bromide (0.4 mmol, 1.0 equiv), NiCl₂(DME) (8.8 mg, 4 μmol, 0.1 equiv), 4,4′,4″-tri-tert-butyl-2,2′:6′,2″-terpyridine (60.6 mg, 6 μmol, 0.15 equiv), TBAB (64.4 mg, 0.2 mmol, 0.5 equiv), and TsOCD₃ [149 mg, 0.8 mmol, 2.0 equiv (447 mg, 1.2 mmol, 3.0 equiv for primary halides)]. The mixture was stirred for 10 min and then an electrical current (10 mA) was applied for 5 h. The mixture was then dissolved in 50:50 EtOAc–PE (50 mL) and washed with H₂O (×3). The organic layer was separated, dried (MgSO₄), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel). tert-Butyl 4-(²H₃)Methylpiperidine-1-carboxylate (3) Viscous colourless liquid; yield: 76 mg (94%). ¹H NMR (500 MHz, CDCl₃): δ = 4.21–3.88 (m, 2 H), 2.75–2.51 (m, 2 H), 1.60–1.51 (m, 2 H), 1.43 (bs, 1 H), 1.41 (s, 9 H), 1.11–0.95 (m, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 155.1, 79.3, 44.2 (br), 34.1, 30.9, 28.6, 21.06 (hept, J = 19.5). Trideuteromethylation of Aryl Bromides; General Procedure A 6 mL electrochemical cell equipped with a stirrer bar, a stainless-steel (SS) anode, and a Cu foam cathode (20 × 10 × 1 mm) was charged with the appropriate aryl halide (0.4 mmol, 1.0 equiv), NiCl₂(DME) (8.8 mg, 4 μmol, 0.1 equiv), 6,6′-dimethyl-2,2′-bipyridine (10.6 mg, 6 μmol, 0.15 equiv), TBAB (64.4 mg, 0.2 mmol, 0.5 equiv), and 4-F₃CC₆H₄SO₃CD₃ (74.5 mg, 0.4 mmol, 2 equiv). The mixture was stirred for 10 min and then an electrical current (10 mA) was applied for 5 h. The mixture was then dissolved in 50:50 EtOAc–PE (50 mL) and washed with H₂O (×3). The organic layer was separated, dried (MgSO₄), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel). [4-(²H₃)Methylphenyl](pyrrolidin-1-yl)methanone (22) White solid; yield: 56 mg (73%). ¹H NMR (500 MHz, CDCl₃): δ = 7.44–7.38 (m, 2 H), 7.25–7.09 (m, 2 H), 3.64–3.40 (m, 4 H), 1.96–1.83 (m, 4 H). ¹³C NMR (126 MHz, CDCl₃): δ = 169.9, 139.9, 134.4, 129.8, 128.9, 127.29, 127.2, 49.7, 46.3, 26.5, 24.6, 20.65 (hept, J = 19.3).