One-Pot Synthesis of 2-Arylindole Derivatives under Transition-Metal-Free Conditions

Abstract

A new and simple method for preparing 2-arylindole derivatives under transition-metal-free conditions has been developed. When N-(2-methyl-3-nitrophenyl)acetamide was treated with 2-fluorobenzaldehydes in the presence of Cs₂CO₃ in DMF at 60 °C, the desired indoles were typically obtained in moderate to good yields (up to 83%). When other aniline substrates were employed, only a Knoevenagel condensation occurred, giving the corresponding diarylethenes in moderate to excellent yields.

Key words

indoles - one-pot synthesis - transition-metal-free synthesis - cascade reaction - Knoevenagel condensation

Publikationsverlauf

Eingereicht: 11. Februar 2022

Angenommen nach Revision: 14. März 2022

Accepted Manuscript online:
14. März 2022

Artikel online veröffentlicht:
12. April 2022

• References and Notes

• 1 Gribble GW. Indole Ring Synthesis: From Natural Products to Drug Discovery. Wiley; Chichester: 2016
• 2a Fischer E, Jourdan F. Ber. Dtsch. Chem. Ges. 1883; 16: 2241
• 2b Robinson B. Chem. Rev. 1969; 69: 227
• 2c Heravi MM, Rohani S, Zadsirjan V, Zahedi N. RSC Adv. 2017; 7: 52852
• 3a Larock RC, Yum EK. J. Am. Chem. Soc. 1991; 113: 6689
• 3b Chinchilla R, Nájera C. Chem. Rev. 2014; 114: 1783
• 4a Bartoli G, Palmieri G, Bosco M, Dalpozzo R. Tetrahedron Lett. 1989; 30: 2129
• 4b Bartoli G, Dalpozzo R, Nardi M. Chem. Soc. Rev. 2014; 43: 4728
• 5 Fouad MA, Ferretti F, Formenti D, Milani F, Ragaini F. Eur. J. Org. Chem. 2021; 2021: 4876
• 6 Song H, Yang Z, Tung C.-H, Wang W. ACS Catal. 2020; 10: 276
• 7 Li B, Ju Z, Zhou M, Su K, Yuan D. Angew. Chem. Int. Ed. 2019; 58: 7687
• 8 Xia X.-D, Xuan J, Wang Q, Lu L.-Q, Chen J.-R, Xiao W.-J. Adv. Synth. Catal. 2014; 356: 2807
• 9 Yan X, Ye R, Sun H, Zhong J, Xiang H, Zhou X. Org. Lett. 2019; 21: 7455
• 10 Daniels M, de Jong F, Vandermeeren T, Van Meervelt L, Van der Auweraer M, Dehaen W. J. Org. Chem. 2019; 84: 13528
• 11a Thanetchaiyakup A, Rattanarat H, Chuanopparat N, Ngernmeesri P. Tetrahedron Lett. 2018; 59: 1014
• 11b Thongaram P, Borwornpinyo S, Kanjanasirirat P, Jearawuttanakul K, Kongsema M, Chuanopparat N, Ngernmeesri P. Tetrahedron 2020; 76: 131473
• 12 Taweesak P, Thongaram P, Kraikruan P, Thanetchaiyakup A, Chuanopparat N, Hsieh H.-P, Uang B.-J, Ngernmeesri P. J. Org. Chem. 2021; 86: 1955
• 13a Yao X, Sun X, Jin S, Yang L, Xu H, Rao Y. J. Med. Chem. 2019; 62: 6561
• 13b Eberle C, Burkhard JA, Stump B, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F. ChemMedChem 2009; 4: 2034
• 14 2-(2-Fluorophenyl)-4-nitro-1H-indole(11a); Typical Procedure DMF (3 mL) and 2-fluorobenzaldehyde (10a) (170 μL, 1.60 mmol) were added sequentially to a mixture of N-(2-methyl-3-nitrophenyl)acetamide (9) (194 mg, 1.00 mmol) and Cs₂CO₃ (1.17 g, 3.60 mmol), and the mixture was stirred at 60 °C for 5 h then cooled to rt. The mixture was diluted with H₂O (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layer was dried (Na₂SO₄) and concentrated under reduced pressure, and the residue was purified by flash column chromatography [silica gel, EtOAc–hexanes (1:5)] to give a yellow solid; yield: 213 mg (83%); mp 190–191 °C. IR (neat): 3363, 1577, 1504, 1489, 1477, 1371, 1335 cm^–1. ¹H NMR (400 MHz, DMSO): δ = 12.36 (s, 1 H), 8.08 (dd, J = 8.0, 0.8 Hz, 1 H), 8.00 (td, J = 7.9, 1.7 Hz, 1 H), 7.93 (dt, J = 8.0, 0.9 Hz, 1 H), 7.51–7.46 (m, 1 H), 7.44–7.37 (m, 2 H), 7.35 (t, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, DMSO): δ = 159.3 (d, J = 249.8 Hz), 139.1, 139.0, 136.6 (d, J = 2.5 Hz), 130.7 (d, J = 8.8 Hz), 128.6 (d, J = 3.0 Hz), 125.2 (d, J = 3.3 Hz), 122.00 (d, J = 1.4 Hz), 121.2, 119.1, 118.8 (d, J = 11.7 Hz), 117.9, 116.7 (d, J = 22.0 Hz), 102.0 (d, J = 9.6 Hz). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₉FN₂NaO₂: 279.0540; found: 279.0558.
• 15 Bergman J, Sand P. Tetrahedron 1990; 46: 6085