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26 July 2012

4-Hydroxy-1-methyl-7-(propan-2-yl)-4-azatricyclo [5.2.2.02,6]undec-8-ene-3,5-dione

and
Department of Medical Chemistry, 1st Faculty of Medicine, Medical University of Warsaw, 3 Oczki Street, 02-007 Warsaw, Poland
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Author to whom correspondence should be addressed.
Molbank2012, 2012(3), M767;https://doi.org/10.3390/M767
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Abstract

1-Methyl-7-(propan-2-yl)-4-oxatricyclo[5.2.2.02,6]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[5.2.2.02,6]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[5.2.2.02,6]undec-8-ene was tested for their affinity to 5-HT1A and 5-HT2A 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[5.2.2.02,6]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[5.2.2.02,6]undec-8-ene-3,5-dione (2), starting from the corresponding anhydride 1-methyl-7-(propan-2-yl)-4-oxatricyclo[5.2.2.02,6]undec-8-ene-3,5-dione (1) using an aqueous solution of hydroxylamine (Scheme 1).
Scheme 1. Synthesis of 4-hydroxy-1-methyl-7-(propan-2-yl)-4-azatricyclo[5.2.2.02,6]un­dec-8-ene-3,5-dione.

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 ACQUITYTM 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[5.2.2.02,6]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%.

Supplementary materials

Supplementary File 1Supplementary File 2Supplementary File 3

References

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