Design of new anti-Alzheimer drugs: ring-expansion synthesis and synchrotron X-ray diffraction study of dimethyl 4-ethyl-11-fluoro-1,4,5,6,7,8-hexahydroazonino[5,6-b]indole-2,3-dicarboxylate

The nine-membered azoninoindole dimethyl 4-ethyl-11-fluoro-1,4,5,6,7,8-hexahydroazonino[5,6-b]indole-2,3-dicarboxylate, representing a candidate for the design of new Alzheimer drugs, has been studied by synchrotron X-ray diffraction.

The title compound, C 20 H 23 FN 2 O 4 , is the product of a ring-expansion reaction from a seven-membered fluorinated hexahydroazepine to a nine-membered azonine. The nine-membered azonine ring of the molecule adopts a chair-boat conformation. The C C and C-N bond lengths [1.366 (3) and 1.407 (3) Å , respectively] indicate the presence of conjugation within the enamine CH 2 -C C-N-CH 2 fragment. The substituent planes at the C C double bond of this fragment are twisted by 16.0 (3) as a result of steric effects. The amine N(Et) N atom has a trigonal-pyramidal configuration (sum of the bond angles = 346.3 ). The interplanar angle between the two carboxylate substituents is 60.39 (8) . In the crystal, molecules form zigzag chains along [010] by intermolecular N-HÁ Á ÁO hydrogen-bonding interactions, which are further packed in stacks toward [100]. The title azoninoindole might be considered as a candidate for the design of new Alzheimer drugs.

Chemical context
Eight-, nine-, and ten-membered heterocycles, often referred to as medium-sized rings, remain largely unexplored because of the lack of general convenient routes for their synthesis. Meanwhile, such medium-sized heterocycles, in particular azonine, frequently occur in natural products, such as alkaloids (Neuss et al., 1959(Neuss et al., , 1962Uprety & Bhakuni, 1975), and thus they are considered to be promising fragments in drug design.
The title compound I, C 20 H 23 FN 2 O 4 , is the product of a ring expansion reaction from a seven-membered fluorinated hexahydroazepine to a nine-membered azonine. The molecular structure of I is unambiguously confirmed by the X-ray diffraction study (Fig. 2).

Supramolecular features
In the crystal, molecules of I form zigzag chains along [010] by intermolecular N-HÁ Á ÁO i hydrogen-bonding interactions (

Figure 2
The molecular structure of I. Displacement ellipsoids are drawn at the 50% probability level. H atoms are shown as small spheres of arbitrary radius.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The X-ray diffraction study was carried out on the "Belok" beamline of the National Research Center "Kurchatov Institute" (Moscow, Russian Federation) using a Rayonix SX165 CCD detector. A total of 360 images were collected using an oscillation range of 1.0 (' scan mode, two different crystal orientations) and corrected for absorption using the SCALA program (Evans, 2006). The data were indexed, integrated and scaled using the utility iMOSFLM in the CCP4 program suite (Battye et al., 2011). The hydrogen atoms of the amino groups were localized in the difference-Fourier map and refined isotropically with fixed displacement parameters [U iso (H) = 1.2U eq (N)]. The other hydrogen atoms were placed in calculated positions with C-H = 0.95-0.99 Å and refined in the riding model with fixed isotropic displacement parameters [U iso (H) = 1.2U eq (C)].

Funding information
This work was supported by the RUDN Program "5-100". Xray crystallographic studies using synchrotron radiation were performed at the unique scientific facility Kurchatov Synchrotron Radiation Source supported by the Ministry of Education and Science of the Russian Federation (project code RFMEFI61917X0007).     (3) 153 (2) Symmetry code: (i) Àx þ 1; y þ 1 2 ; Àz þ 1 2 .

Figure 3
The SHELXL2014 (Sheldrick, 2015b); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).  (2) Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.