Organocatalytic Fischer Indolization Using the 2,2′-Biphenol/ B(OH)₃ System

Abstract

An organocatalyzed Fischer indolization is established by combining 2,2′-biphenol (10 mol%) and B(OH)₃ (30 mol%) as weak, readily available, and easy-to-handle acids. The inclusion of MgSO₄, which efficiently scavenges NH₃ (a possible acid catalyst poison), appears to be key to the success of this process. The corresponding indoles are obtained in yields of up to 91% using this method.y

Key words

Fischer indolization - 2,2′-biphenol - boric acid - organocatalyst - indoles

• References and Notes

• 1 Present address: Faculty of Science and Technology, Kyoto Prefectural University, 1-5 Hangi-cho, Shimogamo, Sakyo-ku, Kyoto 606-8522, Japan; [e-mail]
• 2a Horton DA, Bourne GT, Smythe ML. Chem. Rev. 2003; 893
• 2b de Sa Alves F, Barreiro EJ, Manssour Fraga C. Mini-Rev. Med. Chem. 2009; 9: 782
• 2c Heterocyclic Scaffolds II: Reactions and Applications of Indoles. In Topics in Heterocyclic Chemistry, Vol. 26. Gribble GW. Springer; Berlin/Heidelberg: 2010
• 2d Biswal S, Sahoo U, Sethy S, Kumar HK. S, Banerjee M. Asian J. Pharm. Clin. Res. 2012; 5: 1
• 2e Gribble GW. In Indole Ring Synthesis: From Natural Products to Drug Discovery. John Wiley & Sons; Chichester: 2016
• 3a Gribble GW. J. Chem. Soc., Perkin Trans. 1 2000; 1045
• 3b Humphrey GR, Kuethe JT. Chem. Rev. 2006; 106: 2875
• 3c Taber DF, Tirunahari PK. Tetrahedron 2011; 67: 7195
• 3d Inman M, Moody CJ. Chem. Sci. 2013; 4: 29
• 4a Robinson B. The Fischer Indole Synthesis . John Wiley & Sons; Chichester: 1982
• 4b Heravi MM, Rohani S, Zadsirjan V, Zahedi N. RSC Adv. 2017; 7: 52852
• 5 Gore S, Baskaran S, König B. Org. Lett. 2012; 14: 4568
• 6a Hughes DL. Org. Prep. Proced. Int. 1993; 25: 607
• 6b Rao SP, Lakshminarayana SB, Kondreddi RR, Herve M, Camacho LR, Bifani P, Kalapala SK, Jiricek J, Ma NL, Tan BH, Ng SH, Nanjundappa M, Ravindran S, Seah PG, Thayalan P, Lim SH, Lee BH, Goh A, Barnes WS, Chen Z, Gagaring K, Chatterjee AK, Pethe K, Kuhen K, Walker J, Feng G, Babu S, Zhang L, Blasco F, Beer D, Weaver M, Dartois V, Glynne R, Dick T, Smith PW, Diagana TT, Manjunatha UH. Sci. Transl. Med. 2013; 5: 214ra168
• 6c Kondreddi RR, Jiricek J, Rao SP, Lakshminarayana SB, Camacho LR, Rao R, Herve M, Bifani P, Ma NL, Kuhen K, Goh A, Chatterjee AK, Dick T, Diagana TT, Manjunatha UH, Smith PW. J. Med. Chem. 2013; 56: 8849
• 6d Yang X, Zhang X, Yin D. Org. Process Res. Dev. 2018; 22: 1115
• 7a With TiCl₄ as the catalyst: Ackermann L, Born R. Tetrahedron Lett. 2004; 45: 9541
• 7b With ZnCl₂ as the catalyst: Lipínska TM, Czarnocki SJ. Org. Lett. 2006; 8: 367
• 8a Müller S, Webber MJ, List B. J. Am. Chem. Soc. 2011; 133: 18534
• 8b Martínez A, Webber MJ, Müller S, List B. Angew. Chem. Int. Ed. 2013; 52: 9486
• 8c Kötzner L, Webber MJ, Martínez A, De Fusco C, List B. Angew. Chem. Int. Ed. 2014; 53: 5202
• 8d Kötzner L, Leutzsch M, Sievers S, Patil S, Waldmann H, Zheng Y, Thiel W, List B. Angew. Chem. Int. Ed. 2016; 55: 7693
• 9 Ghosh B, Balhara R, Jindal G, Mukherjee S. Angew. Chem. Int. Ed. 2021; 60: 9086

pK _a1 = 7.6 for 2,2′-biphenol:
• 10a Jonsson M, Lind J, Merényi G. J. Phys. Chem. A 2002; 106: 4758

pK _a = 9.1 for B(OH)₃:
• 10b Schott J, Kretzschmar J, Tsushima S, Drobot B, Acker M, Barkleit A, Taut S, Brendler V, Stumpf T. Dalton Trans. 2015; 44: 11095
• 11a Sugimoto K, Oshiro M, Hada R, Matsuya Y. Chem. Pharm. Bull. 2019; 67: 1019
• 11b Sugimoto K, Yoshida R, Matsuya Y. Tetrahedron Lett. 2022; 102: 153922
• 12 The ratio of 3:1 suggested that the cyclic boroxinate A, which was similar to the VAPOL boroxinate complex reported by Wulff and co-workers¹³ from VAPOL (1 equiv) and B(OPh)₃ (3 equiv), would be generated in situ. However, we have not succeeded in the isolation of the actual active species.
• 13 For the VAPOL boroxinate catalyst, see: Hu G, Huang RH, Wulff WD. J. Am. Chem. Soc. 2009; 131: 15615
• 14 9-Benzyl-3-phenyl-2,3,4,9-tetrahydro-1H-carbazole (12a); Typical Procedure A screw-top test tube equipped with a magnetic stir bar was charged with 1-benzyl-1-phenylhydrazine (13a) (1 equiv, 27.9 mg, 0.141 mmol) and toluene (0.28 mL, 0.5 M). To the solution were added 4-phenylcyclohexanone (14a) (1 equiv, 24.6 mg, 0.141 mmol), 2,2′-biphenol (10 mol%, 2.62 mg, 0.0141 mmol), B(OH)₃ (30 mol%, 2.63 mg, 0.0432 mmol), and MgSO₄ (anhydrous, 3 equiv, 50.0 mg, 0.417 mmol) at room temperature. After stirring in refluxing toluene for 4 h using a heating block, the reaction mixture was filtered through a pad of Celite and the filter cake was washed with EtOAc. The organic phase was washed with saturated aqueous NaHCO₃ and brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: n-hexane/EtOAc = 90:10) to afford the indole 12a (42.4 mg, 89%) as a yellow solid. R_f = 0.68 (n-hexane/EtOAc = 80:20). ¹H NMR (500 MHz, CDCl₃): δ = 7.48 (dd, J = 6.6, 1.6 Hz, 1 H), 7.34–7.29 (m, 4 H), 7.26–7.17 (m, 5 H), 7.13–7.06 (m, 2 H), 6.99 (d, J = 6.9 Hz, 2 H), 5.26 (d, J = 16.9 Hz, 1 H), 5.20 (d, J = 16.9 Hz, 1 H), 3.15–3.01 (m, 2 H), 2.88–2.84 (m, 1 H), 2.74–2.73 (m, 2 H), 2.21–2.17 (m, 1 H), 2.13–2.05 (m, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 146.6, 138.1, 136.8, 135.1, 128.7, 128.4, 127.2, 127.0, 126.2, 126.1, 120.9, 119.0, 117.8, 109.7, 109.0, 46.3, 40.9, 30.3, 29.4, 22.2. The ¹H and ¹³C NMR spectra were identical with those previously reported.^8a