Flow Electrochemical Cyclizations via Amidyl Radicals: Easy Access to Cyclic Ureas

Abstract

Flow chemistry has advantages over batch processes and can achieve the synthesis of substances in high yield under safe working conditions. The combination of electrochemistry and flow microreactor technology has made chemical transformations possible without the use of oxidants or catalysts. Herein, we report flow electrosynthesis of cyclic ureas via oxyamination of N-allylic ureas. We have found that continuous flow is able to outperform its batch counterpart, producing cyclic ureas in excellent yields.

Key words

alkenes functionalization - microreactor technology - flow electrosynthesis - oxyamination - cyclic ureas

• References and Notes

• 1a Suga S, Okajima M, Fujiwara K, Yoshida J. J. Am. Chem. Soc. 2001; 123: 7941
• 1b Kuhn S, Noël T, Gu L, Heider PL, Jensen KF. Lab Chip 2011; 11: 2488
• 1c Gütz C, Stenglein A, Waldvogel SR. Org. Process Res. Dev. 2017; 21: 771
• 1d Green RA, Brown RC. D, Pletcher D, Harji B. Org. Process Res. Dev. 2015; 19: 1424
• 2 Folgueiras-Amador AA, Philipps K, Guilbaud S, Poelakker J, Wirth T. Angew. Chem. Int. Ed. 2017; 56: 15446; Angew. Chem. 2017, 129, 15648
• 3 Folgueiras-Amador AA, Qian X.-Y, Xu H.-C, Wirth T. Chem. Eur. J. 2018; 24: 487
• 4 Folgueiras-Amador A, Wirth T. J. Flow Chem. 2017; 7: 94
• 5a Martins GM, Shirinfar B, Hardwick T, Ahmed N. ChemElectroChem 2019; 6: 1300
• 5b Ahmed N, Khatoon S, Shirinfar B. ChemElectroChem 2018; 5: 1245
• 6a Atobe M, Tateno H, Matsumura Y. Chem. Rev. 2018; 118: 4541
• 6b Hardwick T, Ahmed N. RSC Adv. 2018; 8: 22233
• 7 Islam M, Kariuki BM, Shafiq Z, Wirth T, Ahmed N. Eur. J. Org. Chem. 2019; 1371
• 8 Ahmed N, Khatoon S. ChemistryOpen 2018; 7: 576
• 9 https://www.vapourtec.com/products/flow-reactors/ion-electrochemical-reactor-videos/
• 10a Muñiz K, Hövelmann CH, Streuff J. J. Am. Chem. Soc. 2008; 130: 763
• 10b Streuff J, Hövelmann CH, Nieger M, Muñiz KJ. J. Am. Chem. Soc. 2005; 127: 14586
• 11a Muñiz K, Iglesias A, Fang Y. Chem. Commun. 2009; 5591
• 11b Li H, Widenhoefer RA. Tetrahedron 2010; 66: 4827
• 12a Cochran BM, Michael FE. Org. Lett. 2008; 10: 5039
• 12b Farid U, Wirth T. Angew. Chem. Int. Ed. 2012; 51: 3462
• 13 Rao W.-H, Yin X.-S, Shi B.-F. Org. Lett. 2015; 17: 3758
• 14 General Procedure for Flow ElectrolysisThe N-allylic urea (0.20 mmol) was dissolved in a mixture of acetonitrile/water (19:1, 8.30 mL), then TEMPO (0.30 mmol, 1.5 equiv) and benzyltrimethylammonium hydroxide solution (Triton B, 40% solution in water, 0.21 mmol, 1.1 equiv) were added to the solution, and the mixture was electrolyzed in the electrochemical reactor, fitted with a graphite anode and a platinum cathode and separated by a FEP (fluorinated ethylene propylene) film spacer of 500 (m (0.40 mL inner volume; 3 F, 1–3 V), by using a syringe pump (0.1 mL min^–1). After attaining steady flow, the solution (8.0 mL) was collected in a vial after 100 min. The resulting reaction mixture was quenched with saturated aqueous NH₄Cl (5 mL), concentrated in vacuo, diluted with water (25 mL), and extracted with ethyl acetate (25 mL). The aqueous phase was extracted with ethyl acetate (3 ( 20 mL), and the extracts were washed with brine. The combined organic layers were dried over anhydrous MgSO₄, filtered, and the filtrate concentrated in vacuo. The residue was purified by column chromatography, eluting with hexane/ethyl acetate, 9:1, giving the pure cyclic urea. Spectroscopic data (NMR, MASS) were in agreement with reported data given in reference 8.