Tetrabutylammonium Iodide (TBAI) Catalyzed Electrochemical C–H Bond Activation of 2-Arylated N-Methoxyamides for the Synthesis of Phenanthridinones

Abstract

An electrochemical method for the synthesis of phenanthridinones through constant-potential electrolysis (CPE) mediated by Bu₄NI (TBAI) is reported. The protocol is metal and oxidant free, and proceeds with 100% current efficiency. TBAI plays a dual role as both a redox catalyst and a supporting electrolyte. The intramolecular C–H activation proceeds under mild reaction conditions and with a short reaction time through electrochemically generated amidyl radicals. The reaction has been scaled up to a gram level, showing its practicability, and the synthetic utility and applicability of the protocol have been demonstrated by a direct one-step synthesis of the bioactive compound phenaglaydon.

Key words

tetrabutylammonium iodide - phenanthridinones - amidyl radicals - electrochemistry - C–H bond activation - constant-potential electrolysis

• References and Notes

• 1a Nishiyama Y, Fujii S, Makishima M, Hashimoto Y, Ishikawa M. Int. J. Mol. Sci. 2018; 19: 2090
• 1b Qin S.-Q, Li L.-C, Song J.-R, Li H.-Y, Li D.-P. Molecules 2019; 24: 437
• 1c Matveenko M, Banwell MG, Joffe M, Wan S, Fantino E. Chem. Biodivers. 2009; 6: 685
• 1d Holl V, Coelho D, Weltin D, Dufour P, Bischoff P. Anticancer Res. 2000; 20: 3233
• 2a Wang G.-W, Yuan T.-T, Li D.-D. Angew. Chem. Int. Ed. 2011; 50: 1380
• 2b Karthikeyan J, Cheng C.-H. Angew. Chem. Int. Ed. 2011; 50: 9880
• 2c Senthilkumar N, Parthasarathy K, Gandeepan P, Cheng C.-H. Chem. Asian J. 2013; 8: 2175
• 2d Yedage SL, Bhanage BM. J. Org. Chem. 2016; 81: 4103
• 2e Pimparkar S, Jeganmohan M. Chem. Commun. 2014; 50: 12116
• 2f Sivakumar G, Vijeta A, Jeganmohan M. Chem. Eur. J. 2016; 22: 5899
• 3 Karthikeyan J, Haridharan R, Cheng C.-H. Angew. Chem. Int. Ed. 2012; 51: 12343
• 4a Liang D, Yu W, Nguyen N, Deschamps JR, Imler GH, Li Y, MacKerell AD. Jr, Jiang C, Xue F. J. Org. Chem. 2017; 82: 3589
• 4b Liang D, Sersen D, Yang C, Deschamps JR, Imler GH, Jiang C, Xue F. Org. Biomol. Chem. 2017; 15: 4390
• 5 Moon Y, Jang E, Choi S, Hong S. Org. Lett. 2018; 20: 240
• 6a Kärkäs MD. Chem. Soc. Rev. 2018; 47: 5786
• 6b Liang S, Xu K, Zeng C.-C, Tian H.-Y, Sun B.-G. Adv. Synth. Catal. 2018; 360: 4266
• 6c Zhang P, Chen J, Gao W, Xiao Y, Liu C, Xu S, Yan X, Qin D. Molecules 2019; 24: 696
• 6d Liu K, Tang S, Wu T, Wang S, Zou M, Cong H, Lei A. Nat. Commun. 2019; 10: 639
• 7 Zhang S, Li L, Xue M, Zhang R, Xu K, Zeng C. Org. Lett. 2018; 20: 3443
• 8 Kehl A, Breising VM, Schollmeyer D, Waldvogel SR. Chem. Eur. J. 2018; 24: 17230
• 9a Wu X.-F, Gong J.-L, Qi X. Org. Biomol. Chem. 2014; 12: 5807
• 9b Uyanik M, Okamoto H, Yasui T, Ishihara K. Science 2010; 328: 1376
• 9c Finkbeiner P, Nachtsheim BJ. Synthesis 2013; 45: 979
• 9d Gao W.-J, Li W.-C, Zeng C.-C, Tian H.-Y, Hu L.-M, Little RD. J. Org. Chem. 2014; 79: 9613
• 9e Liang S, Zeng CC, Luo XG, Ren FZ, Tian HY, Sun BG, Little RD. Green Chem. 2016; 18: 2222
• 10a Bard AJ, Faulkner LR. Electrochemical Methods: Fundamentals and Applications, 2nd ed. Wiley; New York: 2001
• 10b Moeller KD. Tetrahedron 2000; 56: 9527
• 11 Tu Z, Chu W, Zhang J, Dence CS, Welch MJ, Mach RH. Nucl. Med. Biol. 2005; 32: 437
• 12 Syroeshkin MA, Krylov IB, Hughes AM, Alabugin IV, Nasybullina DV, Sharipov MY, Gultyai VP, Terent’ev AO. J. Phys. Org. Chem. 2017; 30: e3744
• 13 5-Methoxyphenanthridin-6(5H)-one^2d (2a); Typical Procedure A 25 mL pear-shaped three-necked undivided cell equipped with Pt plate anode (30 × 15 mm) and a Cu plate cathode (30 × 15 mm) was charged with a solution of N-methoxybiphenyl-2-carboxamide (1a; 0.5 mmol, 113.6 mg) and TBAI (0.1 mmol, 36.9 mg) in DMF (15 mL). The cell was then connected to a regulated DC power supply, and constant-potential electrolysis was carried at 2.5 V and 70 °C until 2 F mol^–1 electric charge was consumed (~5 h). The mixture was constantly stirred during the electrolysis. The resulting mixture was diluted with EtOAc and washed twice with H₂O. The organic layers were collected, dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was purified by column chromatography [silica gel, PE–EtOAc (9.5:0.5)] to give a white solid; yield: 101.4 mg (90%); mp 102–104 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.57 (d, J = 8.1 Hz, 1 H), 8.28 (dd, J = 8.3, 4.0 Hz, 2 H), 7.79 (t, J = 7.8 Hz, 1 H), 7.69 (d, J = 8.3 Hz, 1 H), 7.60 (q, J = 7.9, 7.4 Hz, 2 H), 7.41–7.32 (m, 1 H), 4.14 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 157.3, 135.8, 133.0, 132.6, 130.0, 128.5, 128.1, 126.3, 123.2, 121.9, 118.6, 112.6, 62.7. GC/MS (EI, 70 eV): m/z (%) = 225.0 (39.0), 195.0 (100), 180.0 (28.7), 166.05 (58.2), 152.05 (16.0), 140.05 (28.6), 83.4 (13.7), 76.0 (13.2), 40.0 (13.9).