Electrochemical Synthesis of Fused Indole Alkaloids By Controlling Radical Cation Reactivities

Abstract

Pyrrolophenanthridone alkaloids are isolated from Amaryllidaceae and it has fused N-benzoyl indole as core structure. Many researchers targeted this simple alkaloids to demonstrate various synthetic method1), such as palladium- or hypervalent iodine-mediated intramolecular cross-coupling, tetrazine-promoted inverse electron-demand Diels-Alder reaction. All examples required DDQ oxidation to convert indoline to indole.We established metal- and oxidant-free electrochemical intramolecular C(sp2)-H cross-coupling and indole synthesis reaction. These reactions were initiated by same anodic oxidation for electron-rich indoline ring, but different electron-transfer pathway was occurred in both cyclization and indole forming reaction. Moreover, non-coordinative medium has crucial role to control reactivity of radical cation. Increasing electrophilicity of radical cation is key strategy to accomplish intramolecular cross-coupling. MeNO2-LiClO4 and HFIP (1,1,1,3,3,3,-hexafluoro-2-propanol), which known as suitable medium for radical cation-mediated reaction2), had not worked well for this reaction. However, MeNO2-HFIP (9:1) mixed solvent strongly enhanced the reactivity of radical cations. This phenomenon was occurred by synergetic stabilization effect of MeNO2 and HFIP3). The low donor number of MeNO2 and anion trapping ability of HFIP made non-coordinative environment and resulting electrophilic radical cation was maintained in this medium. Dehydrogenative indole forming reaction was accomplished in Lewis-basic condition (MeCN-Bu4NClO4), and collidine additive enhanced benzylic deprotonation from radical cation.Finally, we applied both reactions for the synthesis of seven naturally occurred pyrrolophenanthridone alkaloids4). References (1) (a) Black, DC.; Keller, PA.; Kumar, N. Tetrahedron Lett. 1989, 30, 5807-5808; (b) Ganton, MD.; Kerr, MA. Org. Lett. 2005, 21, 4777-4779; (c) Boger, DL.; Wolkenberg, SE. J. Org. Chem. 2000, 65, 9120-9124.(2) (a) Okada, Y.; Chiba, K. Chem. Rev. 2018, 118, 4592-4630; (b) Kirste, A.; Nieger, M.; Malkowsky, IM.; Stecker, F.; Fisher, A.; Waldvogel, SR. Chem. Eur. J. 2009, 15, 2273-2277.(3) (a) Shida, N.; Imada, Y.; Nagahara, S.; Okada, Y.; Chiba, K. Commun. Chem. 2019, 2, 24; (b) Shida, N.; Imada, Y.; Okada, Y.; Chiba, K. Eur. J. Org. Chem. 2020, 2020, 570-574.(4) Okamoto, K.; Chiba, K. Org. Lett. 2020, accepted (DOI: 10.1021/acs.orglett.0c01082). Figure 1