A Novel One-Pot Synthesis of N-Acylindoles from Primary Aromatic Amides

Abstract

A novel one-pot synthesis of N-acylindoles via tandem cycloalkylation-annelation is described. This approach is based on the use of a strong solid-acid catalyst, montmorillonite K-10, and microwave irradiation under solvent-free conditions. The tandem cycloalkylation of amides and annelation of intermediate pyrroles were completed in minutes and provided good yields with high selectivities for the indoles. The safe, easy to handle catalyst, and the convenience of the product isolation make this process an attractive, environmentally benign alternative for the synthesis of N-acylindoles.

Keywords

amides - solid-acid catalysis - microwave heating - N-acylindole

References and Notes

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• 10 All reactants including the catalyst, montmorillonite K-10, were purchased from Aldrich and used without further purification. The ¹H NMR and ¹³C NMR spectra were obtained on a 300 MHz Varian NMR spectrometer in CDCl₃. Tetramethylsilane or the residual solvent signal was used as reference. The mass spectrometric identification of the products was carried out on an Agilent 6850 GC and 5973 MS system (70 eV electron impact ionization) using a 30 m long DB-5 type column (J&W Scientific). The melting points were uncorrected and were recorded on a MEL-TEMP apparatus. General Procedure for the Synthesis of N -Acylindoles: An amide (1.0 mmol) and 2,5-dimethoxytetrahydrofuran (2.0 mmol) were dissolved in 3 mL of CH₂Cl₂ in a round-bottomed flask, then K-10 (500 mg) was added. After 5 min stirring, the solvent was removed to obtain the mixture of reactants adsorbed on the catalyst surface. The dry mixture was transferred into a glass reaction vial and irradiated in the microwave reactor (CEM Discover Benchmate, 80 °C). During optimization, the progress of the reaction was monitored by TLC and GC-MS to determine the necessary reaction times. After satisfactory conversion, CH₂Cl₂ was added to the cold mixture, and the product was separated from the catalyst by filtration. The products were isolated as crystals or oils and purified by flash chromatography. All products showed satisfactory spectral data (MS, ¹H and ¹³C NMR). Here, the full spectral characterization is given for only the previously unknown products. Such data for the known compounds synthesized in this study are available from the authors. 1-(4-Fluorobenzoyl) indole (Table 1, Entry 5): mp 82.9-84.3 °C (MeOH); ¹H NMR (300.12 MHz, CDCl₃): δ = 8.36 (d, J = 7.8 Hz, 1 H), 7.79-7.74 (m, 2 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.41-7.29 (m, 2 H), 7.27-7.18 (m, 3 H), 6.61 (d, J = 3.9 Hz, 1 H) ppm; ¹³C NMR (75.474 MHz, CDCl₃): d = 166.6, 132.0, 131.8, 127.4, 126.9, 125.1, 124.2, 123.6, 121.1, 120.1, 116.4, 115.8, 108.9 ppm; MS for C₁₅H₁₀FNO(239): m/z (%) = 239 (40) [M⁺], 123 (100), 116 (5), 95 (30), 75 (15). Biphenyl-4-yl(1 H -indole-1-yl)methanone (Table 1, Entry 8): mp 98.2-100.1 °C (MeOH); ¹H NMR (300.12 MHz, CDCl₃): δ = 8.43 (d, J = 8.1 Hz, 1 H), 7.84-7.80 (m, 2 H), 7.76-7.67 (m, 2 H), 7.66-7.60 (m, 3 H), 7.52 (m, 3 H), 7.37-7.32 (m, 3 H), 6.65 (d, J = 3.6 Hz, 1 H) ppm; ¹³C NMR (75.474 MHz, CDCl₃): δ = 166.0, 144.9, 130.0, 129.1, 128.4, 128.4, 127.7, 127.6, 127.4, 126.9, 121.0, 116.5, 108.7 ppm; MS for C₂₁H₁₅NO(297): m/z (%) = 297 (30) [M⁺], 181 (100), 152 (60), 116 (15), 77 (5)