Synthesis and Molecular Structure of N-{(1R,5S)-3-Methyl-8-Oxo-1,3,4,5,6,8-Hexahydro-2H-1,5-Methanopyrido[1,2-α] [1,5]Diazocin-9-yl}Acetamide

Abstract

Compound 2 was isolated by column chromatography over SiO2 in 67% yield and had mp 171–172°C (MeOH) and [ ]D 20 –16.0° (c 0.72, CHCl3). The crystal and molecular structure of 2 were established by an x-ray crystal structure analysis (XSA), for which crystals of 2 were grown by slow crystallization from MeOH. The asymmetric unit of the unit cell of 2 contained two molecules (2a and 2b) that had very similar structures. Figure 1 shows a general view of the symmetry independent molecules 2a and 2b. The compound crystallized in chiral space group P21 and contained two chiral centers (1R,5S). The absolute configuration was the same as that of starting (–)-cytisine. The diazabicyclononane had a chair–half-chair conformation, which is often observed in similar compounds [6–10]. The amide was practically coplanar with the aromatic ring. As we supposed, the trans-orientation of the C9–N1 (C9 –N1 in the second independent molecule) was explained mainly by steric considerations. Thus, the acidic amide proton and the carbonyl O1 atom were oriented on the same side. This favored the formation of the H-bonded dimer. In fact, the two symmetrically independent 2a and 2b were joined in the crystal structure into a dimer through N1–H1...O1 (H...O 2.37 A° , N...O 3.235(2) A° , 1, i.e., when the crystal structure consisted of more than a single independent molecule [11–14]. Apparently, this was due to limitations imposed by the symmetry, which prevented the molecules from adopting the optimum orientation relative to each other. Crystals of C14H19N3O2 (MW 261.32) at 100 K were monoclinic, a = 11.4769(10), b = 9.4595(8), c = 12.9183(11) A ° , = 106.697(2)°, V = 1343.4(2) A° 3, space group P21, Z = 4, dcalc = 1.292 mg/m 3. A data set of 19,378 reflections was collected on a Bruker Smart Apex2 CCD diffractometer ( Mo K -radiation, 2 max = 64°). The starting set of measured intensities was processed using the SAINT and SADABS programs included in the APEX2 program suite [15]. The structure was solved by direct methods and was refined by anisotropic full-matrix least-squares methods over Fhkl for non-hydrogen atoms. The H atoms were placed in geometrically calculated positions with the exception of the amide H, the position of which was located in a difference electron-density synthesis. Then, the N–H distance was normalized to 0.90 A° . The H atoms were refined using a rider model. A total of 4910 independent reflections (Rint = 0.0395) were used in the refinement. The refinement over all independent reflections gave wR2 = 0.1019 [R1 = 0.0422 over 4267 reflections with I > 2 (I)]. All calculations were performed using the SHELXTL programs [16]. Atomic coordinates and thermal factors were deposited in the Cambridge Crystallographic Data Centre (CCDC 981034). Thus, the structure of N-[(1R,5S)-3-methyl-8-oxo-1,3,4,5,6,8-hexahydro-2H-1,5-methanopyrido[1,2-a][1,5]diazocin9-yl]acetamide was characterized for the first time by an XSA. The existence of two symmetrically independent molecules in its crystal structure was explained. 1) Institute of Elementorganic Compounds, Russian Academy of Sciences, 119991, GSP-1, Moscow, B-334, Ul. Vavilova, 28; 2) Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, Prosp. Oktyabrya, 71, e-mail: tsipisheva@anrb.ru.; Translated from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2014, pp. 501–502, original article submitted January 17, 2014. N N