4-Hydroxy-1-methyl-7-(propan-2-yl)-4-azatricyclo [5.2.2.0^2,6]undec-8-ene-3,5-dione

Abstract

1-Methyl-7-(propan-2-yl)-4-oxatricyclo[5.2.2.0^2,6]undec-8-ene-3,5-dione (1) as starting material and hydroxylamine were used for the preparation of the title compound 4-hydroxy-1-methyl-7-(propan-2-yl)-4-azatricyclo[5.2.2.0^2,6]undec-8-ene-3,5-dione (2). This product was characterized by ¹H-NMR, ¹³C-NMR, MS and elemental analysis.

1. Introduction

The extensively studied class of cyclic imides is known for a wide spectrum of biological activities. Less examined, but also valuable for their activities are N-hydroxy analogues. They were synthesized as potential β-adrenolytic [1], anxiolytic [2], anti-inflammatory and analgesic agents [3]. Some of the reported derivatives possess metal-chelating abilities, and a number of these compounds inhibits the growth of microorganisms [4]. Additionally, cyclic imides were tested in vitro against various bacteria including Gram-positive cocci, Gram-negtive rods and fungi species (e.g., Candida) [5,6]. The large group of 4-azatricyclo[5.2.2.0^2,6]undec-8-ene was tested for their affinity to 5-HT_1A and 5-HT_2A receptors [7]. The most popular method to produce cyclic imides and N-hydroxy analogues is the well-known Diels-Alder reaction [8], but this work describes another conventional method for the synthesis of 4-azatricyclo[5.2.2.0^2,6]undec-8-ene derivatives [9,10,11]. This one is reserved for N-hydroxy derivatives. The aim of our present work was to prepare 4-hydroxy-1-methyl-7-(propan-2-yl)-4-aza­tricyclo[5.2.2.0^2,6]undec-8-ene-3,5-dione (2), starting from the corresponding anhydride 1-methyl-7-(propan-2-yl)-4-oxatricyclo[5.2.2.0^2,6]undec-8-ene-3,5-dione (1) using an aqueous solution of hydroxylamine (Scheme 1).

2. Experimental

2.1. General

The melting point was determined in an open capillary and is uncorrected. The NMR spectra were recorded on a Bruker AVANCE DMX400 spectrometer, operating at 400 MHz (¹H-NMR) and 100 MHz (¹³C-NMR). The chemical shift values are expressed in ppm relative to TMS as an internal standard. Mass spectra (ESI) measurements were carried out on a Waters ZQ Micro-mass instrument with a quadrupol mass analyzer. The spectra were recorded in positive ion mode at a declustering potential of 40–60 V. The sample was previously separated on a UPLC column (C18) using a Waters UPLC ACQUITY^TM system connected with a DPA detector. Flash chromatography was performed on Merck silica gel 60 (200–400 mesh) using a chloroform/methanol (19:1 vol) mixture as eluent. Analytical TLC was carried out on silica gel F₂₅₄ (Merck) plates (0.25 mm thickness).

2.2. Synthesis of 4-Hydroxy-1-methyl-7-(propan-2-yl)-4-azatricyclo[5.2.2.0^2,6]undec-8-ene-3,5-dione (2)

A mixture of the anhydride 1 (0.234 g, 1 mmol), K₂CO₃ (0.20 g, 1.4 mmol), NH₂OH·HCl (0.20 g, 2.9 mmol) and H₂O (5 mL) was refluxed for 5 h. The precipitate was filtered, washed with water, dried and purified by column chromatography (silica gel) to obtain a white solid.

Yield: 90%.

m.p.: 139–140 °C.

¹H-NMR (400 MHz, CDCl₃) δ (ppm): 5.97 (d, 1H, CH=, J = 8.4 Hz); 5.89 (d, 1H, CH=, J = 8.4 Hz); 4.18 (br s, 1H, OH); 2.93 (d, 1H, CH-C=O, J = 7.6 Hz); 2.58–2.51 (m, 2H, CH-C=O, CH=); 1.50–1.40 (m, 2H, CH₂); 1.46 (s, 3H, CH₃); 1.36–1.24 (m, 2H, CH₂); 1.08 (d, 3H, CH₃, J = 6.8 Hz); 0.98 (d, 3H, CH₃, J = 6.8 Hz).

¹³C-NMR (100 MHz, CDCl₃) δ (ppm):174.3, 172.5, 136.3, 48.9, 47.7, 45.1, 43.7, 36.9, 34.2, 29.7, 22.6, 18.4, 16.9.

ESI MS: m/z = 272.4 [M+Na] ⁺ (100%).

Elemental analysis: Calculated for C₁₄H₁₉NO₃ (249.306): C, 67.45%, H, 7.68%, N, 5.62%. Found: C, 67.48%, H, 7.50%, N, 5.72%.