Ethyl 2-[2-(4-Nitrobenzoyl)-1H-indol-3-yl]acetate

Abstract

Ethyl 2-[2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate was prepared in good yield and characterized by the aza-alkylation/intramolecular Michael cascade reaction of (E)-ethyl 3-[2-(tosylamino)phenyl]acrylate with 2-bromo-4′′-nitroacetophenone, followed by desulfonative dehydrogenation with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) The structure of the newly synthesized compound was determined using ¹H-,¹³C-NMR, IR and mass spectral data.

1. Introduction

Indoles are well established as privileged scaffolds, commonly encountered in many biologically active natural products and pharmaceuticals [1,2,3]. More than 10,000 biologically active indole derivatives have been identified, and more than 200 derivatives are currently known as pharmaceuticals or undergoing clinical trials [4]. Among the indoles, 2-aroyl indole-3-acetic acid derivatives, which are an important subclass of 2,3-disubstituted indoles [5], have attracted attention as a promising pro-drug for anticancer and antitumor activities [6,7]. In continuation of our research interest in 2-aminophenyl α,β-unsaturated carbonyl compounds for the synthesis of highly functionalized indole derivatives [8,9,10], we report here the preparation of a novel ethyl 2-[2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate [11,12,13].

The synthesis of the title compound 4 was achieved in one-pot, as presented in Scheme 1, which was performed by the aza-alkylation/intramolecular Michael cascade reaction of (E)-ethyl 3-[2-(tosylamino)phenyl]acrylate (1) with 2-bromo-4′-nitroacetophenone (2), followed by desulfonative dehydrogenation. The reaction was carried out in acetonitrile at 60 °C in the presence of triethylamine as a base and provided the indolineinter mediate 3 within 10 min. To the resulting mixture 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added and gave the desired product in good yield within 20 min. The structure of compound 4 was confirmed by ¹H- and ¹³C-NMR, IR, mass spectral data, and all data are in accordance with the assumed structure.

2. Experimental Section

2.1. General Information

All reagents were used as received without further purification. Chromatographic purification of the title compound 4 was accomplished using forced-flow chromatography on ICN 60 32-64 mesh silica gel 63 (Merck, Darmstadt, Germany). Thin-layer chromatography (TLC) (Merck, Darmstadt, Germany) was performed on EM Reagents 0.25 mm silica gel 60-F plates. Developed chromatograms werevisualized by fluorescence quenching and anisaldehyde stain. ¹H- and ¹³C-NMR spectra were recorded on a 400 MHz instrument (Bruker BioSpin GmbH, Karlsruhe, Germany) as noted, and are internally referenced to residual protio solvent signals. Data for ¹H-NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), integration, coupling constant (Hz) and assignment. Data for ¹³C-NMR are reported in terms of chemical shift. IR spectra were recorded on a Perkin-Elmer 1600 FT-IR spectrometer (Bruker Optics GmbH, Ettlingen, Germany), and reported in terms of frequency of absorption (cm⁻¹). High-resolution mass spectrometry data were recorded on a JEOL JMS-700 MStation mass spectrometer (JEOL, Tokyo, Japan).

2.2. Syntheis of ethyl 2-[2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate(4)

To a solution of (E)-ethyl 3-[2-(tosylamino)phenyl]acrylate (1, 35 mg, 0.10 mmol, 1.0 equiv) in CH₃CN (0.5 mL), 2-bromo-4′-nitroacetophenone (2, 37 mg, 0.15 mmol) and Et₃N (21 μL, 0.15 mmol,) were added at room temperature. After stirring the resulting mixture for 10 min at 60 °C, DBU (60 μL, 0.40 mmol) was added. The resulting mixture was stirred further for 20 min at 60 °C, and saturated aqueous NaHCO₃ was added. The mixture was then extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO₄, and concentrated in vacuo.The crude product waspurified on silica gel column chromatography using ethyl acetate and hexane (1/10) as eluents to afford the desired title compound 4 (89%, 31 mg).White solid; m.p. 163–165 °C; ¹H-NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H), 8.31 (d, J = 8.7 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.1 Hz, 1H), 7.45–7.34 (m, 2H), 7.19 (ddd, J = 8.0, 5.1, 2.8 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.76 (s, 2H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 186.46, 170.80, 149.62, 144.18, 136.83, 131.36, 129.69, 128.16, 127.29, 123.72, 121.30, 121.13, 117.51, 112.44, 61.23, 31.16, 14.17.; IR (film) 3322, 2934, 1722, 1616, 1598, 1522, 1433, 1370, 1331, 1257, 1215, 1170, 1103, 1028, 1008, 990 cm⁻¹; HRMS (EI) m/z calcd for [M]⁺ C₁₉H₁₆N₂O₅: 352.1059 Found: 352.1051.