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

Publication History

Received: 20 November 2023

Accepted after revision: 22 January 2024

Article published online:
04 March 2024

• References and Notes

• 1a Barreiro EJ, Kümmerle AE, Fraga CA. M. Chem. Rev. 2011; 111: 5215
• 1b Schönherr H, Cernak T. Angew. Chem. Int. Ed. 2013; 52: 12256
• 1c Leung CS, Leung SS. F, Tirado-Rives J, Jorgensen WL. J. Med. Chem. 2012; 55: 4489
• 2a Atzrodt J, Derdau V, Kerr WJ, Reid M. Angew. Chem. Int. Ed. 2018; 57: 3022
• 2b Atzrodt J, Derdau V, Fey T, Zimmermann J. Angew. Chem. Int. Ed. 2007; 46: 7744
• 2c Tung RD. Future Med. Chem. 2016; 8: 491
• 2d Pang X, Peng L, Chen Y. J. Labelled Compd. Radiopharm. 2017; 60: 401
• 2e Russak EM, Bednarczyk EM. Ann. Pharmacother. 2019; 53: 211
• 2f Cargnin S, Serafini M, Pirali T. Future Med. Chem. 2019; 11: 2039
• 2g Schmidt C. Nat. Biotechnol. 2017; 35: 493
• 2h Kopf S, Bourriquen F, Li W, Neumann H, Junge K, Beller M. Chem. Rev. 2022; 122: 6634
• 3a Mullard A. Nat. Rev. Drug Discovery 2022; 21: 623
• 3b Roskoski RJr. Pharmacol. Res. 2023; 189: 106642
• 3c Chen X, Sun Y, Zhang T, Shu L, Roepstorff P, Yang F. Genomics, Proteomics Bioinf. 2021; 19: 689
• 4a Atzrodt J, Derdau V, Kerr WJ, Reid M. Angew. Chem. Int. Ed. 2018; 57: 1758
• 4b Pirali T, Serafini M, Cargnin S, Genazzani AA. J. Med. Chem. 2019; 62: 5276
• 4c Kondo Y, Nonaka H, Takakusagi Y, Sando S. Angew. Chem. Int. Ed. 2021; 60: 14779
• 5a Steverlynck J, Sitdikov R, Rueping M. Chem. Eur. J. 2021; 27: 11751
• 5b Aynetdinova D, Callens MC, Hicks HB, Poh CY. X, Shennan BD. A, Boyd AM, Lim ZH, Leitch JA, Dixon DJ. Chem. Soc. Rev. 2021; 50: 5517
• 5c Sun Q, Soulé J.-F. Chem. Soc. Rev. 2021; 50: 10806
• 6a Liang Z, Xue W, Lin K, Gong H. Org. Lett. 2014; 16: 5620
• 6b Wang J, Zhao J, Gong H. Chem. Commun. 2017; 53: 10180
• 6c Smith RT, Zhang X, Rincón JA, Agejas J, Mateos C, Barberis M, García-Cerrada S, de Frutos O, MacMillan DW. C. J. Am. Chem. Soc. 2018; 140: 17433
• 6d Chen Y. Chem. Eur. J. 2019; 25: 3405

For examples, see:
• 7a Hu L, Liu X, Liao X. Angew. Chem. Int. Ed. 2016; 55: 9743
• 7b Komeyama K, Yamahata Y, Osaka I. Org. Lett. 2018; 20: 4375
• 7c Jin J, MacMillan DW. C. Nature 2015; 525: 87
• 7d Kariofillis SK, Shields BJ, Tekle-Smith MA, Zacuto MJ, Doyle AG. J. Am. Chem. Soc. 2020; 142: 7683
• 7e Zhang W, Lu L, Zhang W, Wang Y, Ware SD, Mondragon J, Rein J, Strotman N, Lehnherr D, See KA, Lin S. Nature 2022; 604: 292
• 7f Ibrahim MY. S, Cumming GR, Gonzalez de Vega R, Garcia-Losada P, de Frutos O, Kappe CO, Cantillo D. J. Am. Chem. Soc. 2023; 145: 17023
• 8a Yan G, Borah AJ, Wang L, Yang M. Adv. Synth. Catal. 2015; 357: 1333
• 8b Everson DA, Weix DJ. J. Org. Chem. 2014; 79: 4793

For examples, see:
• 9a Weix DJ. Acc. Chem. Res. 2015; 48: 1767
• 9b Zhang P, Le C, MacMillan DW. C. J. Am. Chem. Soc. 2016; 138: 8084
• 9c Gu J, Wang X, Xue W, Gong H. Org. Chem. Front. 2015; 2: 1411
• 9d Wang X, Dai Y, Gong H. Top. Curr. Chem. 2016; 374: 61
• 9e Liu J, Ye Y, Sessler JL, Gong H. Acc. Chem. Res. 2020; 53: 1833
• 9f Charboneau DJ, Hazari N, Huang H, Uehling MR, Zultanski SL. J. Org. Chem. 2022; 87: 7589

For examples, see:
• 10a Perkins RJ, Hughes AJ, Weix DJ, Hansen EC. Org. Process Res. Dev. 2019; 23: 1746
• 10b Durandetti M, Nédélec J.-Y, Périchon J. J. Org. Chem. 1996; 61: 1748
• 10c Perkins RJ, Pedro DJ, Hansen EC. Org. Lett. 2017; 19: 3755
• 10d Li H, Breen CP, Seo H, Jamison TF, Fang Y.-Q, Bio MM. Org. Lett. 2018; 20: 1338
• 10e Koyanagi T, Herath A, Chong A, Ratnikov M, Valiere A, Chang J, Molteni V, Loren J. Org. Lett. 2019; 21: 816
• 10f Jiao K.-J, Liu D, Ma H.-X, Qiu H, Fang P, Mei T.-S. Angew. Chem. Int. Ed. 2020; 59: 6520
• 10g Truesdell BL, Hamby TB, Sevov CS. J. Am. Chem. Soc. 2020; 142: 5884
• 10h Watanabe E, Chen Y, May O, Ley SV. Chem. Eur. J. 2020; 26: 186
• 11a Sklyaruk J, Borghs JC, El-Sepelgy O, Rueping M. Angew. Chem. Int. Ed. 2019; 58: 775
• 11b Pipal RW, Stout KT, Musacchio P, Ren ZS, Graham TJ. A, Verhoog S, Gantert L, Lohith TG. Schmitz A, Lee HS, Hesk D, Hostetler ED, Davies IW, MacMillan DW. C. Nature 2021; 589: 542
• 12 Kumar GS, Zhu C, Kancherla R, Shinde PS, Rueping M. ACS Catal. 2023; 13: 8813
• 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).