Green, Smooth and Easy Electrochemical Synthesis of N-Protected Indole Derivatives

Here, we report a simple method for the direct conversion of 6-Nitro-1H-indole into N-substituted indoles via electrochemical dehydrogenative reaction with halogenated reagents under strongly basic conditions through N–R bond formation. The N-protected indoles have been prepared under moderate and scalable electrolytic conditions. The conduct of the reactions was performed in a simple divided cell under constant current without oxidizing reagents or transition-metal catalysts. The synthesized products have been characterized via UV/Vis spectrophotometry, 1H-NMR, and FTIR spectroscopy. A possible reaction mechanism is discussed based on the N-protective products. This methodology could be applied to the synthesis of various biologically active N-substituted indole derivatives.

• Sarah Fahad Alajmi
• Tamer Ezzat Youssef

• Green chemistry
• 1H-indole
• NH-containing heteroaromatic
• organic electrosynthesis.

[1] L. Wang, Y. Chen, and J. Xiao, “Alkylideneindoleninium ions and alkylideneindolenines: key intermediates for the asymmetric synthesis of 3‐indolyl derivatives,” Asian J. Org. Chem., vol. 3, no.10, pp.1036-1052, Oct. 2014.
[2] J. Bergman, and P. Sand, “Synthesis of indoles via ring closure of 2-alkylnitroaniline derivatives,” Tetrahedron, vol. 46, no.17, pp. 6085-6112, Jan. 1990.
[3] S. A. Yamashkin, and M. A. Yurovskaya, “Synthesis of nitro-and aminoindoles,” Chem Heterocycl Compd, vol. 35, no.12, pp. 1426-1432, Dec. 1999.
[4] K. Yamada, F. Yamada, T. Shiraishi, S. Tomioka, and M. Somei,“ Nucleophilic substitution reaction in indole chemistry: 1-methoxy-6-nitroindole-3-carbaldehyde as a versatile building block for 2, 3, 6-trisubstituted indoles,” Heterocycles, vol. 77, no. 2, pp. 971-982, Jan. 2009.
[5] S. Sampaolesi, S. Gabrielli, R. Ballini, and A. Palmieri, “Two‐step synthesis of polysubstituted 6‐nitroindoles under flow chemical and microwave conditions,” Adv. Synth. Catal., vol. 359, no. 19, pp. 3407-3413, Oct. 2017.
[6] I. Marcotte, A. Lemire, and J. Lessard, The Synthesis of Substituted Aminoindoles by Chemical and Electrochemical Reduction of Nitroindoles in Novel Trends in Electroorganic Synthesis. Tokyo: Springer, 1998, (pp. 329-332).
[7] C. C. Zeng, F. J. Liu, D. W. Ping, L. M. Hu, Y. L. Cai, and R. G. Zhong, “One-pot electrochemical synthesis of fused indole derivatives containing active hydroxyl groups in aqueous medium,” J. Org. Chem., vol. 74, no. 16, pp. 6386-6389, Aug. 2009.
[8] J. Wu, Y. Dou, R. Guillot, C. Kouklovsky, and G. Vincent, “Electrochemical dearomative 2, 3-difunctionalization of indoles,” J. Am. Chem. Soc., vol. 141, no. 7, pp. 2832-2837, Jan. 2019.
[9] D. I. Bugaenko, A.V. Karchava, and M. A. Yurovskaya, “Synthesis of indoles: recent advances,” Russ. Chem. Rev., vol. 88, no. 2, pp. 99-159, Feb. 2019.
[10] D. Kumar, N. Kumar, S. Kumar, T. Singh, and C.P. Singh, “Synthesis of pharmacologically active 2-phenyl sulpha/substituted indoles,” Int. J. Eng. Sci. Technol., vol. 2, no. 7, pp. 2553-2557, July 2010.
[11] S. Dadashpour, and S. Emami, “Indole in the target-based design of anticancer agents: a versatile scaffold with diverse mechanisms,” Eur. J. Med. Chem., vol. 150, pp. 9-29, Apr. 2018.
[12] J. Dhuguru, and R. Skouta, “Role of indole scaffolds as pharmacophores in the development of anti-lung cancer agents,” Molecules, vol. 25, no. 7, p. 1615, Jan. 2020.
[13] C. N. Marconett, S. N. Sundar, K. M. Poindexter, T. R. Stueve, L. F. Bjeldanes, and G. L. Firestone, “Indole-3-carbinol triggers AhR-dependent ERalpha protein degradation in breast cancer cells disrupting an ERalpha-GATA3 transcriptional cross-regulatory loop,” Mol. Biol. Cell, vol. 21, no. 7, pp. 1166-1177, Feb. 2010.
[14] Y. M. Jeong, H. Li, S. Y. Kim, W. J. Park, H. Y. Yun, K. J. Baek, N. S. Kwon, J. H. Jeong, S. C. Myung, and D. S. Kim, “Photo-activated 5-hydroxyindole-3-acetic acid induces apoptosis of prostate and bladder cancer cells,” J PHOTOCH PHOTOBIO B, vol. 103, no. 1, pp. 50-56, Apr. 2011.
[15] B. Dulla, E. Sailaja, U. R. CH, M. Aeluri, A. M. Kalle, S. Bhavani, D. Rambabu, M. B. Rao, and M. Pal, “Synthesis of indole based novel small molecules and their in vitro anti-proliferative effects on various cancer cell lines,” Tetrahedron Lett., vol. 55, no. 4, pp. 921-926, Jan. 2014.
[16] S. Muralikrishna, P. Raveendrareddy, L. K. Ravindranath, S. Harikrishna, and P. A. Raju, “Synthesis characterization and anti-inflammatory activity of indole derivatives bearing-4-oxazetidinone,” J Chem Pharm Res, vol. 5, no. 10, pp. 280-288, Jan. 2013.
[17] S. Sarva, J. S. Harinath, S. P. Sthanikam, S. Ethiraj, M. Vaithiyalingam, and S. R. Cirandur “Synthesis, antibacterial and anti-inflammatory activity of bis (indolyl) methanes,” Chin. Chem. Lett., vol. 27, no. 1, pp. 16-20, Jan. 2016.
[18] T. MahamadAlli Shaikh, and H. Debebe, “Synthesis and evaluation of antimicrobial activities of novel N-substituted indole derivatives,” J. Chem., vol. 2020, no. 5, pp. 1-159, Apr. 2020.
[19] S. Süzen, Antioxidant Activities of Synthetic Indole Derivatives and Possible Activity Mechanisms in Bioactive Heterocycles V. Berlin: Springer, 2007, pp. 145-178.
[20] M. S. Estevão, L. C. Carvalho, D. Ribeiro, D. Couto, M. Freitas, A. Gomes, L. M. Ferreira, E. Fernandes, and M. M. Marques, “Antioxidant activity of unexplored indole derivatives: synthesis and screening,” Eur. J. Med. Chem., vol. 45, no. 11, pp. 4869-4878, Nov. 2010.
[21] H. Xu, M. Lv, “Developments of indoles as anti-HIV-1 inhibitors,” Curr. Pharm. Des., vol. 15, no. 18, pp. 2120-2148, Jun. 2009.
[22] A. Attia, O. I. Abd El-Salam, T. E. Youssef, “Electron and hydrogen transfer reductions of some 2, 4-disubstituted pyridines,” Indian J Hetero Chem, vol. 8, no. 4, pp. 325-328, Apr. 1999.
[23] S. T. Gadge, A. Mishra, A. L. Gajengi, N. V. Shahi, and B. M. Bhanage, “Magnesium oxide as heterogeneous and recyclable base for the N-methylation of indole and O-methylation of phenol using dimethyl carbonate as a green methylating agent,” RSC Adv., vol. 4, no. 91, pp. 50271-50276, Oct. 2014.