Investigations on the Formation of 4-Aminobicyclo[2.2.2]-octanones

Benzylidene acetone reacts with thiocyanates derived from secondary amines in a one-pot reaction to give 4-aminobicyclo[2.2.2]octan-2-ones. The reaction mixture was investigated for the presence of possible intermediates using GC-MS. These intermediates – diketones and enamines – were prepared and exposed to the same reaction conditions to examine the reaction mechanism. The reaction of ethyl styryl ketone with thiocyanates of secondary amines yielded cyclohexanone derivatives instead of the expected bicyclo-octanones. Their structures were established by means of a single crystal structure analysis.


Introduction
Ammonium thiocyanates and benzylidene acetone have already been cyclized to products having the bicyclo [2.2.2]octan-2-one structure, which are useful precursors for compounds with antimalarial or antitrypanosomal activity [1]. In order to confirm the reaction mechanism authentic samples of proposed intermediates -diketones and enamines -were synthesized and the reaction mixtures then analyzed for their presence using GC-MS methods. In addition the reaction of ammonium thiocyanates with ethyl styryl ketone was investigated.

Results and Discussion
We have previously reported [2] the formation of 4-aminobicyclo [2.2.2]octan-2-ones from ammonium thiocyanates and benzylidene acetone in a one-pot reaction, proposing the following mechanism for this transformation: benzylidene acetone (1) reacts with dialkylammonium thiocyanates 2a-d in an initial step to give the enammonium salts 3a-d, followed by a Diels-Alder reaction of the latter with unreacted 1. The thus formed 4-acetylcyclohex-1-enylammonium salts 4a-d then cyclize to give the bicyclic compounds 5a-d (Scheme 1).

Scheme 1.
Ph Recently, Ramachary et al. [3] have reported amine-catalyzed self-Diels-Alder reactions of α,β-unsaturated ketones giving cyclohexanones. Therefore, the following alternative mechanism also ought to be considered to account for the formation of compounds 5a-d: the first step in this case is an amine catalyzed Diels-Alder reaction to give cyclohexanone 6, followed by the formation of enamine salts 4a-d which subsequently cyclize as mentioned above to afford the final bicyclo [2.2.2]octan-2-one products 5a-d (Scheme 2). We started our investigations with the synthesis of diketone 6 via an amine-catalyzed Diels-Alder reaction [3] giving selectively the symmetric diketone 7. Its diastereoisomer 8 was obtained by the reaction of 1 with 2-trimethylsilyloxy-4-phenyl-1,3-butadiene (9) [4]. The regioselective formation of enamines 10b-d, 11b and 12b was observed for the reaction of both diketones 7 and 8 with secondary amines by standard methods. In the case of diketone 8, an unseparable mixture of compounds 11b and 12b was produced (Scheme 3).

Scheme 2.
The enamine 10b and the mixture of 11b and 12b were exposed to the reaction conditions which are described by Morita and Kobayashi for the formation of 1-methyl-4-morpholinobicyclo- [2.2.2]octan-2-one from 4-acetyl-4-methyl-1-morpholino-1-cyclohexene [5]. However, the enamine 10b decomposed to the diketone 7 whereas the mixture of enamines 11b and 12b decomposed to a mixture of unseparable products. No 4-aminobicyclooctanone derivatives were detectable in these reaction mixtures by NMR experiments.
The diketone 7 was next refluxed with dimethylammonium thiocyanate in toluene at 160°C or in dimethylformamide at 200°C at a water separator but no reaction was observed. For the reaction of 7 with morpholinium thiocyanate in refluxing toluene we observed no formation of a bicyclic compound either. Diketone 8 reacts with morpholinium thiocyanate under the same conditions to give small but detectable amounts of 5b. The reaction of diketone 8 with morpholine in refluxing benzene under the catalysis of 4-toluenesulfonic acid yielded a mixture of 11b and 12b accompanied by small amounts of 5b. We monitored the reaction of benzylidene acetone with morpholinium thiocyanate in toluene using GC-MS methods. Each hour, we took a sample which was extracted with 2N NaOH and water to remove salts. The concentrations of benzylidene acetone and 5b formed during the progress of the reaction were calculated as the areas under the respective curves and are shown in Figure 1.

Scheme 3
Ph CH CH C O CH 3  Ph Ph Obviously the concentration of 5b increases parallel to the decrease of the concentration of 1. After 3.5 hours the maximum amount of 5b is reached and after this point, decomposition of 5b takes place. In addition to that, we found only very small amounts of 7, 8, 10b and 11b/12b and no significant change of concentrations was observed for these compounds during the course of the reaction. From these results, we assume that a formation of 5b via diketone 8 is possible.
Besides, the diketones 8 the ammonium salts 3a-d might be key intermediates during the formation of bicyclo-octanones. 4-Phenyl-3-buten-2-one-N-phenylimine was prepared by Brady et al. [6] by refluxing benzylidene acetone with aniline in benzene catalyzed by zinc chloride. The formation of cyclic products was not reported. However, when we replaced aniline by morpholine, we detected moderate amounts of 5b and small amounts of the diketones 7 and 8 instead of the expected imine. When ethyl styryl ketone (13) is used instead of benzylidene acetone (1) the reaction with morpholine under the same conditions gives compound 14, which is not stable, especially in an alkaline medium. The reaction of 13 with dimethylammonium thiocyanate in refluxing toluene yielded compounds 15 and 16, which were isolated by sequential crystallization from ethanol (Scheme 5). The structure of 16 was elucidated with the aid of a single crystal structure analysis (Figures 2 and 3). The probability ellipsoids are drawn at the 50% probability level. Besides, 10b-d were reduced regioselectively with Pd on charcoal to a mixture of 4-aminocyclohexanones 17b-d and 18b-d. Only compounds 17b-d were isolated in pure form by crystallization from ethanol (Scheme 3). The structure of 17b-d was determined with the aid of NMR spectroscopy. Small coupling constants (3Hz) of H-5 ax and H-3 ax to H-4 in the 1 H spectra of 17b indicate the equatorial position of H-4. Furthermore a NOE of 8.6% was observed from H-1 to H-3 ax and H-5 ax indicating the equatorial position of the acetyl group ( Figure 4).

Conclusions
Usually 4-aminobicyclo [2.2.2]octan-2-ones are prepared from benzylidene acetone and dialkylammonium thiocyanates in a one-pot reaction. During our investigations of the reaction mechanism we synthesized possible intermediates which were detected in the reaction mixtures by GC-MS methods. When one of them, a cyclic diketone, was used as starting material instead of benzylidene acetone the synthesis of the corresponding 4-aminobicyclo [2.2.2]octan-2-one was successful, but since only small amounts of the bicyclic compound were found we assume that this is not the main reaction path.

Acknowledgments
This work was supported by the Fonds zur Förderung der wissenschaftlichen Forschung (Austrian Science Fund, grant no. P-15928).

General
Melting points were obtained on an Electrothermal IA 9200 digital melting point apparatus and are uncorrected. IR spectra: infrared spectrometer system 2000 FT (Perkin Elmer). UV/VIS: Lambda 17 UV/VIS-spectrometer (Perkin Elmer). NMR spectra: Varian Inova 400 (300 K), 5 mm tubes, TMS resonance as internal standard. 1 H-and 13 C-resonances were assigned using 1 H, 1 H-and 1 H, 13 C-correlation spectra. HMBC spectra were optimized for 8 Hz. For NOE measurements oxygen was carefully removed by bubbling Ar through the solutions. 1  Benzylidene acetone (1, 46 g, 0.31 mol) and morpholine (27.4 g, 0.31 mol) were dissolved in benzene (125 mL) and zinc chloride (200 mg) was added. The mixture was refluxed at a water separator at 140°C over night, cooled to room temperature and filtered. The solvent was evaporated in vacuo giving a residue which was further purified by use of CC (eluent: 8:8:1 benzene/ chloroform/ethanol) affording 5b (15.4 g, 13.5%) as a yellowish resin. Spectral data corresponded well with those reported [2]. (7).

X-ray diffraction data of 16
All the measurements were performed using graphite-monochromatized Mo K α radiation at 95(2)K: C 24 H 30 NO + SCN -, M r 406.57, orthorhombic, space group P b c a, a = 9.777(2)Å, b = 15.746(3)Å, c = 28.318(5)Å, V = 4359.5(14)Å 3 , Z = 8, d calc = 1.239g cm -3 , µ = 0.167mm -1 . A total of 4771 reflections were collected (Θ max = 26.0°), from which 4272 were unique (R int = 0.0360), with 2847 having I > 2σ(I). The structure was solved by direct methods (SHELXS-97) [10] and refined by full-matrix leastsquares techniques against F 2 (SHELXL-97) [11]. The non-hydrogen atoms were refined with anisotropic displacement parameters without any constraints. The H atoms were refined with common isotropic displacement parameters for the H atoms bonded to the same acyclic C atom or to the same ring. The H atoms of the tertiary C-H groups were refined with all X-C-H angles equal at a C-H distance of 1.00Å. The H atoms of the CH 2 groups were refined with idealized geometry with approximately tetrahedral angles and C-H distances of 0.99Å. The H atoms of the methyl groups were refined with idealized geometry with tetrahedral angles, enabling rotation around the X-C bond, and C-H distances of 0.98 Å. The H atoms of the phenyl rings were put at the external bisector of the C-C-C angle at a C-H distance of 0.95Å. For 274 parameters final R indices of R = 0.0652 and wR 2 = 0.1325 (GOF = 1.050) were obtained. The largest peak in a difference Fourier map was 0.234eÅ -3 . The final atomic parameters, as well as bond lengths and angles are deposited at the Cambridge Crystallographic Data Centre (CCDC 231557). These data can be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk).