Synthesis, crystal structures, and Hirshfeld analysis of three hexahydroquinoline derivatives

Three hexahydroquinoline derivatives were synthesized and crystallized in an effort to study the structure–activity relationships of these calcium-channel antagonists. n these hexahydroquinoline derivatives, common structural features such as a flat-boat conformation of the 1,4-dihydropyridine (1,4-DHP) ring, an envelope conformation of the fused cyclohexanone ring, and a substituted phenyl group at the pseudo-axial position are retained. Hydrogen bonds are the main contributors to the packing of the molecules in these crystals.


Chemical context
4-Aryl-1,4-dihydropyridines (DHPs) that bind the L-type voltage-gated calcium channels (VGCC) have been applied in general medical practice for over three decades (Zamponi, 2016). Many modifications on 1,4-DHP have been performed to obtain active compounds such as calcium-channel agonists or antagonists (Martín et al., 1995;Rose, 1990;Rose & Drä ger, 1992;Trippier et al., 2013). One such modification is fusing a cyclohexanone ring to form hexahydroquinoline (HHQ), in which the orientation of the carbonyl group of the ester substituent at the 5-position in the 1,4-DHP ring has been fixed. This class of compounds has been shown to have calcium-channel antagonistic activity (Aygü n Cevher et al., 2019), inhibit the multidrug-resistance transporter (MDR) (Shahraki et al., 2017(Shahraki et al., , 2020, as well as possessing antiinflammatory and stem-cell differentiation properties, and have been implicated in slowing neurodegenerative disorders (Trippier et al., 2013). Recently, specific substitutions of the cyclohexenone ring were found to have distinct selectivity profiles to different calcium channel subtypes (Schaller et al., 2018). Another report also showed that the 4-aryl-hexahydroquinolines, especially the ones containing a methoxy moiety, exhibit good antioxidant property as radical scavengers (Yang et al., 2011). In a continuation of our study on the structure-activity relationship of this class of 4-aryl-hexahydroquinolines (Steiger et al., 2014(Steiger et al., , 2018(Steiger et al., , 2020, and to understand stereoelectronic effects, which define selectivity, as well as to explore the scope and limitations of our synthetic methodologies (Steiger et al., 2016), we report herein the crystal structures of three 4-aryl-hexahydroquinoline derivatives.

Structural commentary
The asymmetric unit of the title compound I contains one independent molecule, which crystallizes in the triclinic P1 space group (Fig. 1). Compounds II and III both crystallize in the monoclinic space group P2 1 /n. The asymmetric unit of compound II contains two independent molecules, A and B (Fig. 2), while compound III has only one independent molecule in the asymmetric unit (Fig. 3). Similar to the other 4aryl-hexahydroquinoline derivatives that we have reported (Steiger, et al., 2014;, compounds I, II, and III all share the common structural features such as a flattened boat conformation on the 1,4-DHP ring, envelope conformation of the cyclohexanone ring, and the pseudo-axial position of the 4aryl group. The shallow-boat confirmation of the 1,4-DHP ring is one of the factors that leads to higher calcium-channel activity (Linden et al., 2004) The shallowness of the boat conformation in these three compounds are indicated by the marginal displacements of atom N1 and C4 from the mean plane (the base of the boat) defined by the two double bonds (C2 C3 and C9 C10). The distances between N1 and the mean plane formed by C2/C3/C9/C10 are 0.159 (3), 0.110 (2), 0.110 (3), and 0.181 (2) Å for compounds I, IIA, IIB, and III, respectively. The corresponding distances between C4 and the same mean plane are 0.341 (3), 0.295 (3), 0.253 (3), and 0.399 (2) Å for compounds I, IIA, IIB, and III, respectively.
The pseudo-axial position of the C4-aryl group to the 1,4-DHP ring is another key factor that is essential for pharmacological activity (Langs et al., 1987). In the title compounds, the substituted phenyl rings are almost orthogonal to the base of the 1,4-DHP ring, with the mean plane normal to normal angles being 89.09 (7), 92.52 (6), 93.52 (6), and 90.59 (5) for compounds I, IIA, IIB, and III, respectively (see Table 1 for calculated parameters). It is noteworthy that the para-methoxy group on the phenyl ring is flexible and can be either antior syn-periplanar to the H atom on C4, i.e. pointing either to (IIA) or away from (IIB) the 1,4-DHP ring. The asymmetric unit of compound II showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level. The intermolecular hydrogen bond between N1A-H1A and O1B is shown as a dashed line.

Figure 3
The asymmetric unit of compound III showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 1
The asymmetric unit of compound I showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level. The intramolecular hydrogen bond between C13-H13B and O2 is shown as a dashed line. The crystal disintegrated below 273 K and the X-ray structure was acquired at room temperature.
In all three compounds, the cyclohexanone rings adopt the envelope conformation, which can be quantified using Cremer & Pople's ring-puckering parameters. Ideally, the envelope conformation would have = 54.7 (or =125.3 in the case of an absolute configuration change) and ' = n Â 60 . The and ' values of the title compounds are very close to the ideal angles with deviations less than 10 and are listed in Table 2.
Although the carbonyl on the ester group is conjugated to the adjacent endocyclic double bond and is co-planar to the 1,4-DHP mean plane, the whole ester group is flexible. The C O bond can be either cis (I, IIA and IIB) or trans (III) to the adjacent double bond, and the extended or curled orientations of the ethyl group are observed in these crystal structures. The disordered ethyl groups in compound I and compound II also indicate the flexibility of the ester group.

Supramolecular features
In compound I, hydrogen bonds between N1-H1 and O1 form a chain perpendicular to the (100) plane. Short contact C23-H23AÁ Á ÁO2 links alternate enantiomers to form a pair perpendicular to the (001) plane (Table 3, Fig. 4).
In compound II, hydrogen bonds N1A-H1AÁ Á ÁO1B and N1B-H1BÁ Á ÁO1A link the two independent molecules A and B to form a chain perpendicular to the (010) plane. Close contacts C23B-H23BÁ Á ÁO2A and C23A-H23DÁ Á ÁO2B link the two independent molecules zigzaggedly along the c-axis direction (

Figure 4
The packing of compound I. Intermolecular hydrogen bonds are shown as dashed lines, and H atoms not involved in these hydrogen bonds are removed for clarity.

Figure 5
The

Figure 6
The packing of title compound III. Intermolecular hydrogen bonds (shown in dashed lines) cross link the molecules to form a sheet parallel to the (010) plane. H atoms not involved in these hydrogen bonds are removed for clarity.

Figure 7
Hirshfeld surface of I mapped over d norm . Short and long contacts are indicated as red and blue regions, respectively. Contacts with distances approximately equal to the sum of the van der Waals radii are colored white. Ainteraction between C15-H15 and phenyl ring is shown as green dashed lines. Hydrogen bond C23-H23AÁ Á ÁO2 is shown as red dashed lines.
The Hirshfeld surface of the title compound III is mapped over d norm in a fixed color scale of À0.7001 (red) to 3.4800 (blue) arbitrary units (Fig. 11). Besides the obvious short contacts from hydrogen bonds, a short contact of 2.6137 (14) Å between H8A and C20 is also observed, indi-  Hirshfeld surface of II mapped over d norm . Short and long contacts are indicated as red and blue regions, respectively. Contacts with distances approximately equal to the sum of the van der Waals radii are colored white. Ainteraction (C6A-H6AB to double bond C2A C3A) is shown as red dashed lines. Hydrogen bonds between N-H and O are shown as green dashed lines.

Figure 11
Hirshfeld surface of III mapped over d norm . Short and long contacts are indicated as red and blue regions, respectively. Contacts with distances approximately equal to the sum of the van der Waals radii are colored white. The close contact between H8A and C20 is shown as a dashed line.

Database survey
A search for 4-phenyl-5-oxo-hexahydroquinoline-3-carboxylate in the Cambridge Structural Database (CSD version 5.43, November 2021 update; Groom et al., 2016) resulted in 53 hits, of which a meta-methoxyl-substituted 4-phenyl-5-oxo-hexahydroquinoline-3-carboxylate (refcode TANVUC; Li, 2017) should be mentioned. Similar to the title compounds I and IIA, the meta-methoxyl group in TANVUC is exo to the 1,4-DHP ring and carbonyl group on the ester is in a cis orientation to the endocyclic double bond. All of the resulting hits display common structural features, such as the flat-boat conformation of the 1,4-DHP ring, the envelope conformation of the fused cyclohexanone ring, and the substituted aryl ring at the pseudo-axial position to the 1,4-DHP ring.

Synthesis and crystallization
An oven-dried 100 ml round-bottom flask equipped with a magnetic stir bar was charged with 10 mmol of dimedone, 10 mmol of ethyl acetoacetate and 5 mol % of ytterbium(III) trifluoromethanesulfonate. The mixture was then taken up in 30 ml of absolute ethanol, capped and put under an inert atmosphere of argon, after which the solution was allowed to stir at room temperature for 20 min. the appropriate corresponding benzaldehyde (10 mmol) and 10 mmol of ammonium acetate were added to the stirring solution, the solution was allowed to stir at room temperature for 48 h. Reaction progress was monitored via TLC. Once the reaction was complete, excess solvent was removed via rotary evaporation. The solution was then purified via silica column chromatography. The products were crystallized from hexane and ethyl acetate (1:4 v/v) as white-to-yellow crystalline solids. Compounds I and III were recrystallized from a minimum of warm methanol, to which hexane was added dropwise to a faint opalescence, and slow evaporation produced diffractionquality crystals.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 6. Carbon-bound hydrogen atoms on all three compounds were fixed geometrically and treated as riding with C-H = 0.95-0.98 Å and refined with U iso (H) = 1.2U eq (CH, CH 2 ) or 1.5U eq (CH 3 ). Hydrogen atoms attached to nitrogen and oxygen were found in difference-Fourier map and refined freely. Eight reflections (010, 010, 011, 011, 001, 001, 002, and 002) in compound I and eight reflections (040, 020, 123, 723, 076, 031, 112, and 516) in compound III were omitted because of poor agreement between the observed and calculated intensities.
Data of compound I were acquired at room temperature due to the disintegration of the crystals at low temperatures. The sample measured was identified as two crystals, misoriented by 0.24 approximately about the [001] reciprocalspace axis. For the purposes of data collection and subsequent structure refinement, the structure was treated using facilities for handling twinning by non-merohedry, namely HKLF5 data in SHELXL (Sheldrick, 2015), yielding a ratio of 0.866 (2):0.134 (2) for the two crystals. In compound I, the ethyl group on the carboxylic ester is disordered and was modeled at 50% occupancy at each site. Atomic displacement equivalency restraints and bond-length restraints (Sheldrick, 2015) were applied to the carbon atoms and the single-bond oxygen atom of the disordered ester group.
The crystals of compound II were found to be pseudomerohedric twins by a 180 rotation about the c axis. Application of the twin operation (À1, 0, 0, 0, À1, 0, 0, 0, 1) yielded a twin component ratio of 0.6938 (8):0.3062 (8). The ester group on molecule B is also disordered. Atomic displacement equivalency restraints were applied to the two carbons and the single bond oxygen on the ethyl group. Restraints were applied to bond lengths on the atoms of the ester as well.
Compound III was co-crystallized with hexanes. However, being a mixture of disordered hexane isomers, the refinement around the hexanes did not give satisfactory results. The OLEX2 SMTBX (Rees et al., 2005) solvent-masking procedure was used to calculate and mask the solvent-accessible void. There are 192 electrons found in a volume of 464 Å 3 in one void per unit cell. This is consistent with the presence of one C 6 H 14 molecule per asymmetric unit, which accounts for 200 electrons per unit cell. 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. Refinement. Refined as a 2-component twin. Twin law (-1 0 0 0 -1 0 0.0123 -0.407 1) was applied and the structure was refined using HKLF5 data, yielding a ratio of 0.866 (2)  178 (2) C17-C18-C19-C20