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

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 3and 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.


Introduction
Chemistry of piperidine compounds is one of the most promising and rapidly developing areas of modern heterocyclic chemistry. Bicyclic piperidine analogs are of great interest due to a broad spectrum of pharmacological action. In addition, derivatives of 3,7-diazabicyclo[3.3.1]nonane are convenient models for studying the structure of six-membered cyclic compounds, mechanisms and stereochemistry of reactions and conformational analysis [1][2][3][4][5][6][7].
Bispidine chemistry began in 1930 with Mannich and Mohs's discovery that simple mixing of 4-piperidone 3,5-diester with aqueous formaldehyde and methylamine in hot methanol leads to formation of bicyclic diamine. Mannich condensation is the simplest and most convenient way of preparative synthesis of 3-aza-, and 3,7-diazabicyclo[3.3.1]nonan-9-ones. Upon the reaction of aldehyde with primary amines, compounds exhibiting C-H acidity are necessary that the used amine was more nucleophilic than that participating in the reaction of C-H-acidic compound. Otherwise, aldehyde is reacted with preferably methylene component of aldol-type reaction. In some cases, instead of the expected ketone diazabicyclic ketone was obtained. The most common reason for this was that the reaction was carried out in highly concentrated solutions and in the components formaldehyde is used as aldehyde.
Typically, bispidinone derivatives are obtained via a modified Mannich condensation, where ketone, having acidic α-hydrogens, primary amine and aldehyde react in the presence of acid.
If conformationally homogeneous cyclic ketones are used in the Mannich reaction, the major product of the reaction yields are increased.

Methods and Instrumentation
IR spectra were taken on a «Nicolet 5700FT-IR» spectrometer as a thin film (υ in cm -1 ). 1 H and 13 C NMR spectra were recorded on a Jeol JNM-ECA-400 spectrometer with 1 H and 13 C being observed at 400 and 100.8 MHz, respectively. Chemical shifts (in δ values or ppm) for 1 H and 13 C NMR spectra are taken in CDCl 3 downfield from TMS [(CH 3 ) 4 Si], and coupling constants are reported as J in Hz. Thin layer and column chromatography were carried out on alumina of III activity. All reactions were performed in nitrogen atmosphere. Methanol was dehydrated with the Na metal. The reagents were used as received from commercial suppliers unless otherwise stated (Aldrich).

Results and Discussion
Piperidone for Mannich reaction was synthesized from 3-ethoxypropylamine by Dickmann condensation [12]. Thus, in step I of the process of the acrylate and the corresponding diesters 3-ethoxypropylamino-N,N-bis-(3-ethoxycarbonylethyl)-N-ethoxypropylamine was obtained. Next, in process step III is carried out by saponification and decarboxylation is obtained in step II carbalkoxypiperidine derivative to form the corresponding 1-(3-ethoxypropyl)-4-oxopiperidine:

MeONa HCl
The main disadvantage of the Mannich approach is that it always gives a carbonyl group at the C-9 position which might induce some unfavorable properties relative to the corresponding bispidine. Reduction of the keto group is almost exclusively achieved by the Wolff-Kishner method.
The subjects investigated in the present work were 3-(3-ethoxypropyl)-7-heterocyclyl-3,7-diazabicyclo[3.3.1]nonan-9-ones. The results on the investigation of their spatial structure with the aid of 1 H and 13 C NMR spectroscopy are given. On the basis of the data obtained on the vicinal coupling constants of protons, which bear important information on the geometry of the molecules [13], it was stated that the bispidinones studied exist in solution predominantly in a chair-chair conformation.
The chemical shifts of carbon atoms in the spectrum of bispidinonones (2, 3) are shown in Table 2.
In the spectrum of carbon compounds (2, 3) the most low field singlet signals at 214.4 and 214.8 ppm belong to the carbon atom of the carbonyl group. In the spectrum doublet signal of the ring atoms C 1.5 at 46.6 and 46.8 ppm and the signals of carbons of the substituents at the nitrogen atoms also indicated the formation of bicyclic products. Spatial structure of bispidinones (2, 3) was determined on the basis of the data on the 13

Synthesis of new 1-(3-ethoxypropyl)-7-heterocyclylalkyl-3,7-diazabicyclo[3.3.1]nonanes
Finally, as part of this study, we re-evaluated the Wolff-Kishner reduction of bispidinone (2,3) to bispidine (4,5). In our work the reaction with hydrazine hydrate/KOH was carried out at 160-170 °C. It should be noted that purification of the products was performed by column chromatography on aluminum oxide of III activity. Yields and physicalchemical characteristics of the bispidines (4, 5) are presented in Table 3.
The reaction was completed after 5 hours, the yields were 83% and 94%: The composition and structure of 3,7-diazabicyclononanes (4,5) are confirmed by elemental analysis, IR spectra and 13 C NMR spectra. Formation of bicyclic amines was indicated by the absence in the IR spectra of compounds (2, 3) of the absorption band of the carbonyl group. The assignment of the signals of carbon atoms were in position and shape of the multiplets in the 13 C NMR spectra monoresonance. The chemical shifts of carbon atoms in the 13 C NMR spectrum of 3,7-diazabicyclo[3.3.1]nonanes (4,5) are listed in Table 4.

Table 4
Chemical shifts of carbons (δ, ppm) (4,5) in CDCl 3 Compound In the 13 C NMR spectrum of bispidines 2 pairs of doublet of doublets and fragment of 3,7-diazabicyclo[3.3.1]nonanes (4,5) rings with large broadening coupling were observed. The 13 C NMR spectrum of 3,7-diazabicyclo[3.3.1]nonanes (4, 5) differ from the spectra of the initial bicyclic ketone (2,3) in that they lack the signal of carbon atoms, characteristic of carbonyl group, wherein in heavily dipole part of the spectrum there is a triplet signal of carbon atom of the methylene group in the ninth position (32.0 and 33.9 ppm). It should also be noted that reduction of the carbonyl group to methylene leads to significant displacement of the signal node of carbon atoms C 1.5 in a stronger field (27.4 and 29.9 ppm). NMR 1 H spectrum analysis revealed that 3,7-diazabicyclo[3.3.1]nonane derivatives has a bicyclic unit in a chair-chair conformation.