Methyl 9-(1-methyl-1H-indol-3-yl)-9-oxononanoate

Abstract

Methyl 9-(1-methyl-1H-indol-3-yl)-9-oxononanoate was synthesized using Friedel–Crafts acylation between N-methyl indole and methyl 9-chloro-9-oxononanoate. The structure of the newly synthesized compound was elucidated using ¹H-NMR, ¹³C-NMR, NOESY-1D, ESI-MS, FT-IR, and UV-Vis spectroscopy.

1. Introduction

Friedel–Crafts acylation [1,2,3,4] is one of the most used reactions in organic synthesis to attach an acyl group to an aromatic ring. It occurs with a plethora of aromatics and heteroaromatics; the keto derivative produced can be, in turn, subjected to many transformations. Friedel–Crafts acylation on 1-substituted indoles occurs regioselectively on the 3-position and the products are key structural units in alkaloids, drugs, and pharmaceuticals, including anticancer agents [5,6,7]. Recently, antiproliferative activity against a panel of human cancer cell lines has been showed using hybrid compounds bearing a heterocyclic moiety (i.e., pyridinyl-, pyrimidinyl-, and benzothiazolyl-) connected to an azelayl chain [8,9]. Herein, we report the synthesis of a new hybrid of possible interest as an anti-cancer agent, namely methyl 9-(1-methyl-1H-indol-3-yl)-9-oxononanoate, obtained using Friedel–Crafts acylation between N-methyl indole and methyl 9-chloro-9-oxononanoate.

2. Results

The synthesis of methyl 9-(1-methyl-1H-indol-3-yl)-9-oxononanoate (3) was performed using Friedel–Crafts acylation in chloroform at room temperature on N-methyl indole (1) with methyl 9-chloro-9-oxononanoate (2) in an equimolar amount and in the presence of AlCl₃ (Scheme 1). The reaction course was monitored using thin layer chromatography (TLC) that showed the presence of compound 3 together with other unidentified by-products. At the end of the reaction, the product was purified and recovered in a 40% yield using column chromatography on silica gel with a mixture of light petroleum and diethyl ether, 3/7 v/v ratio, as the eluent. The newly synthesized compound was characterized using ¹H-NMR, ¹³C-NMR, DEPT, NOESY-1D, ESI-MS, FT-IR, and UV-Vis spectroscopy.

In particular, the diagnostics to ascertain the structure of compound 3 were: the presence of the IR bands at ν = 1725 cm⁻¹ and 1642 cm⁻¹ due to ester and carbonyl stretching modes, respectively, and the NOESY-1D experiment (see Supplementary Materials Figure S4). In the latter case, when irradiating the signal at 7.71 ppm (CH adjacent to the nitrogen atom of the heterocyclic indole ring), a positive NOE effect was recorded with the methyl group bound to the nitrogen atom and the methylene in the alpha position to the carbonyl group.

3. Materials and Methods

The ¹H-NMR, ¹³C-NMR, NOESY-1D and DEPT (Distortionless Enhancement by Polarization Transfer) spectra were recorded on an Inova 600 (Varian, Palo Alto, CA, USA) spectrometer operating at 600 MHz (for ¹H-NMR) and at 150 MHz (for ¹³C-NMR). The chemical shifts are referenced to the solvent for ¹H and ¹³C-NMR (δ = 7.26 ppm and δ = 77.0 ppm, respectively, for CDCl₃). The signal multiplicities were established using DEPT experiments. The chemical shifts were measured in δ (ppm). The J values are provided in Hertz. The electron spray ionization mass spectra (ESI-MS) were recorded using a WATERS 2Q 4000 instrument (Waters Corporation, Milford, MA, USA). The IR spectra were recorded on a Perkin Elmer FT-IR Mod. 1600 spectrophotometer (Perkin Elmer, Waltham, MA, USA). The UV/Vis spectra were recorded on a PerkinElmer Lambda 12 spectrophotometer (Perkin Elmer, Waltham, MA, USA), at 20 °C in CDCl₃ and in quartz cells (path length cell: 1 cm). The melting points (m.p.) were measured on Büchi 535 apparatus (Büchi, Flawil, Switzerland). The chromatographic purifications (FC) were carried out on glass columns packed with silica gel (Merck grade 9385, 230−400 mesh particle size, 60 Å pore size) at medium pressure (Merck & Co., Readington, NJ, USA). Thin layer chromatography (TLC) was performed on silica gel 60 F₂₅₄-coated aluminum foils (Fluka, Buchs, Switzerland). The methyl 9-chloro-9-oxononanoate was prepared as previously reported [8], while the N-methyl indole was purchased by Sigma-Aldrich (Milan, Italy), as well as all the other reagents and solvents used.

Methyl 9-(1-methyl-1H-indol-3-yl)-9-oxononanoate (3)

The methyl 9-chloro-9-oxononanoate (2) (110 mg, 0.5 mmol) was dissolved in chloroform (5 mL) in a round bottomed flask then AlCl₃ (80 mg, 0.6 mmol) was introduced. The mixture was magnetically stirred for 15 min then the N-methyl indole (1, 65.5 mg, 0.5 mmol) was added. The reaction course was monitored using TLC (eluent diethyl ether/petroleum ether 8/2). After 3 h, the reaction was quenched with water (5 mL) then 10% aq. NaHCO₃ was added until the pH~8. After extraction with CH₂Cl₂, the organic layer was dried over anhydrous MgSO_4, filtered and concentrated ‘in vacuo’. The purification of the residue using a chromatography column on silica gel (eluent diethyl ether/petroleum ether 7/3) provided pure product isolated in 40% (63 mg).

Red solid, m.p.: 43.4–44.9 °C; ¹H-NMR (600 MHz, CDCl₃, 25 °C) δ, ppm: 8.40–8.37 (m, 1H, aromatic CH), 7.72 (s, 1H, aromatic CH), 7.35–7.28 (m, 3H, aromatic CH), 3.84 (s, 3H, CH₃N), 3.66 (s, 3H, COOCH₃), 2.82 (t, J = 7.5 Hz, 2H, CH₂CON), 2.30 (t, J = 7.6 Hz, 2H, CH₂COOCH₃), 1.80–1.74 (m, 2H, CH₂CH₂CON), 1.66–1.59 (m, 2H, CH₂CH₂COOCH₃), 1.44–1.30 (m, 6H, aliphatic CH₂); ¹³C-NMR: (150 MHz, CDCl₃, 25 °C) δ, ppm: 195.9 (C), 174.3 (C), 137.4 (C), 135.2 (CH), 126.3 (C), 123.2 (CH), 122.6 (CH), 122.5 (CH), 116.6 (C), 109.5 (CH), 51.4 (CH₃), 39.8 (CH₂), 34.0 (CH₂), 33.4 (CH₃), 29.3 (CH₂), 29.1 (CH₂), 28.9 (CH₂), 25.1 (CH₂), 24.9 (CH₂); FT-IR (CDCl₃) ν (cm⁻¹): 3012, 2933, 2860, 1725, 1642, 1526, 1470, 1377, 1215, 1080; UV-Vis λ_max = 243 nm, 300 nm; ESI-MS (m/z): 316 [M + H]⁺, 338 [M + Na]⁺, 354 [M + K]⁺; Elemental Analysis for C₁₉H₂₅NO₃, Calculated C, 72.35; H, 7.99; N, 4.44; found C, 72.38; H, 7.97; N, 4.42.