Synthesis of Novel 3,7-Diazabicyclo[3.3.1]nonane Derivatives

• Main Authors: A. Ye. Malmakova, K. D. Praliyev, J. T. Welch, T. K. Iskakova, S. S. Ibraeva
• Format: Article
• Language: English
• Published: al-Farabi Kazakh National University 2014-01-01
• Series: Eurasian Chemico-Technological Journal
• Subjects: piperidone; 3,7-diazabicyclo[3.3.1]nonan-9-ones; 3,7-diazabicyclo[3.3.1]nonanes; Dieckman condensation; double Mannich reaction; Wolff-Kischner reduction
• Online Access: http://ect-journal.kz/index.php/ectj/article/view/173

A series of 3-(3-ethoxypropyl)-7-heterocyclylalkyl-3,7-diazabicyclo[3.3.l]nonan-9-ones have been prepared by Mannich cyclocondensation of 1-(3-ethoxypropyl)-4-oxopiperidine with paraformaldehyde and primary amines followed by Wolff-Kischner reduction of the obtained bispidinones. The starting 1-(3-ethoxypropyl)-4-oxopiperidine was synthesized by Dickmann condensation of 3-ethoxypropylamine with ethylacrylate. The 3,7-diazabicyclo[3.3.1]nonanones were obtained in acceptable yields by condensation of 1-(3-ethoxypropyl)piperidin-4-one with primary amines: 1-(3-aminopropyl)imidazole or 1-(2-aminoethyl) piperazine and formaldehyde in the presence of acetic acid in methanol medium. Reduction of the obtained bispidinones with hydrazine hydrate was carried out in the presence of KOH in triethylene glycol at 160-170 °C for 5 hours. The syntheses were performed under the atmosphere of N2. As the reaction products are viscous oils, the column chromatography (on III activity aluminum oxide, eluent – benzene: dioxane 5:1) was used for purification of novel bicyclic ketones and bicyclic nonanes. The completion of the reactions was monitored by TLC. Methods of 1H and 13C NMR spectroscopy were used to determine the structures of the substances synthesized. The prior studies have demonstrated that variation on the substituents at nitrogen atoms in 3- and 7-positions of bispidine cycle could result in the increase of biological activity and effect on compound spectral characteristics. Spatial structures of bispidinones and related bispidines were determined on the basis of the data of the 13C and 1H NMR spectra. A doublet of doublets of equatorial protons at C2.4 and C6.8 with large geminal constants of 10.5-11 Hz and vicinal constants of 3.0-6.0 Hz in 1H NMR spectrum revealed that those 3,7-diazabicyclo[3.3.1]nonane derivatives have a “chair-chair” conformation of both piperidine rings.