Synthesis and crystal structures of a bis(3-hydroxy-cyclohex-2-en-1-one) and two hexahydroquinoline derivatives

The syntheses and crystal structures of three compounds, 2,2′-[(2-nitrophenyl)methylene]bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (I), ethyl 4-(4-hydroxy-3,5-dimethoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (II), and ethyl 4-(anthracen-9-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (III), are reported.


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 hexahydroquinolone (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), as well as possess anti-inflammatory and stem-cell differentiation properties, and has been implicated in slowing neurodegenerative disorders. (Trippier et al., 2013). In the HHQ literature, specific substitution of the cyclohexenone ring can confer sub-type selectivity at the voltage-gated calcium channel (Schaller et al., 2018). Our group has been interested in bioisosteric 4-isoxazolyl-dihydropyridines at the VGCC (Schauer et al., 1986;Zamponi et al., 2003;Natale et al., 2014) and MDR (Steiger et al., 2017), and continue our studies towards understanding stereoelectronic effects, which define selectivity, as well as to explore the scope and limitations of our synthetic methodologies (Steiger et al., 2016). These interests led us to continue our pursuit of crystallographic studies in this area (Steiger et al., 2014a,b;. ISSN 2056-9890

Structural commentary
Compound I crystallizes in the triclinic P1 space group with one independent molecule in the asymmetric unit ( Fig. 1). As in other bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) compounds, in compound I the 1,3-ketone-enol conformation is stabilized by two internal hydrogen bonds between two pairs of enols and ketones that bridge the two hydroxycyclohexenones, in addition to the bridging carbon C7. The two hydroxycyclohexenones are arranged along a pseudo-mirror plane formed by atoms C15, C11, C8, C7, C16, C19, and C22, which has a root-mean-square deviation (RMSD) of 0.025 Å . The phenyl ring attached to C7 flaps to one side of the above plane, with a plane normal angle of 44.34 (4) .
Both 3-hydroxy-5,5-dimethyl-cyclohex-2-en-1-one rings adopt an envelope conformation, with both methyl groups C14 and C23 having an axial orientation being trans to each other. As a result of the steric effect of the neighboring atoms and groups, instead of being on the same plane as the phenyl ring, the mean plane formed by the NO 2 group is rotated out of the plane of the aromatic system with an angle of 52.85 (6) . This may indicate a possibleinteraction between the NO 2 group and the ketone-enol C C bond, evidenced by a shortcontact N1Á Á ÁC16 distance of 2.816 (2) Å and a short distance of 2.860 Å between N1 and the midpoint of the C16 C17 double bond. The interaction of the NO 2 group and the enol C16 C17 double bond were analyzed using Hirshfeld surface analysis and quantified using the associated two-dimensional fingerprint plot (Fig. 2), both performed with Crystal-Explorer17.5 (Turner et al., 2017). The electrostatic potentials were calculated using TONTO integrated within Crystal-Explorer. Hirshfeld surfaces of the NO 2 group and C16 C17 mapped over curvedness are shown in Fig. 2(c). The flat yellowish surfaces confirm that an intramolecularinteraction takes place between the NO 2 group and the enol double bond. This is also evidence that the -hole interaction can stabilize conformers when the interacting atom is four or five bonds away from the N atom of a nitro aromatic compound (Franconetti et al., 2019).
Compounds II and III both crystallized racemically in the monoclinic space group P2 1 /n. The asymmetric unit of compound II contains two independent molecules (A and B), both in the same enantiomeric configuration. The overall unit cell is racemic with four pairs of racemates.    The asymmetric unit of compound I showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level. The dashed lines indicate intramolecular O-HÁ Á ÁO hydrogen bonds. only one independent molecule in the asymmetric unit. The displacement ellipsoid plots showing the atomic numbering of compounds II and III are presented in Figs. 3 and 4, respectively.
In the molecule of compound II, the orientations of the ethyl groups on the ester and of the methoxy groups on the phenyl rings are different in molecules A and B. The hydroxyl and methoxy groups are mostly co-planar with the phenyl ring to which they are attached in both molecules A and B. The exception is one of the methyl groups in molecule A, C24A, which protrudes out of the phenyl plane with a displacement of 1.2802 (12) Å . The angle between the O6A-C24A bond and the normal to the phenyl plane is 154.38 (5) . Similarly, the ethyl group on the ester group in molecule B is co-planar with the ester atoms O2B, O3B, and C14B whereas in molecule A, the ethyl group is folded with an angle of 14.94 (10) between the C15A-C16A bond and the normal to the O2A/ O3A/C14A plane with atom C16A displaced by 1.656 (3) Å from the plane. These orientations imply that these two functional groups are flexible in the structure.
Although compounds II and III share the same structural features, such as the envelope conformation of the cyclohexanone ring and the pseudo-axial position of the 4-aryl group, they exhibit differences, especially in the conformation of the 1,4-DHP ring. In compound III, atoms N1 and C4 are only slightly displaced from C2/C3/C5/C10 mean plane at distances of 0.107 (2) and 0.092 (2) Å , respectively. There is a short contact of 1.88 Å between hydrogen atoms H4 and H27. A C-HÁ Á Á contact of 2.47 Å also exists between C19-H19 and the C5-C10 bond.
In compound III, the anthracenyl group bisects the basal plane of the 1,4-DHP ring, with N1Á Á ÁC4-C17-C18 torsion angle of 2.09 (15) . As a result of the elongated aromatic system, the ethyl group on the ester is stabilized in a folded position by a weak C-HÁ Á Á interaction between C16-H16B and C25-C30 ring, with an H16-to-plane distance of 2.82 Å . The O C-O ester group is no longer co-planar with the 1,4-DHP basal plane and the O2-C14-C3-C2 torsion angle is À25.10 (19) .

Supramolecular features
In compound I, C15-H15BÁ Á ÁO3 i and C20-H20BÁ Á ÁO5 ii and hydrogen bonds (Table 1) between the same enantiomers form a two-dimensional network parallel to (001), with one chain running along the a-axis direction and the other along the b-axis direction (Fig. 5). Other intermolecular O-H interactions such as C10-H10BÁ Á ÁO5 ii and C2-H2Á Á ÁO1 i between a pair of enantiomers form a chain of alternating enantiomers (Fig. 6  The asymmetric unit of compound III showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level. The C-HÁ Á Á interaction is indicated by a dashed line.

Figure 3
The asymmetric unit of compound II showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level. The dashed lines indicate the C9B-H9BÁ Á ÁO6A hydrogen bond and the C-HÁ Á Á interaction between H7A and the C17A-C22A bond. Other hydrogen atoms have been omitted for clarity. a C-HÁ Á Á interaction between C7B-H7A and the C17A-C22A bond with a distance of 2.6715 (6) Å . Links alternating between the two independent molecules form a column through hydrogen bonds N1A-H1AÁ Á ÁO1B ii and N1B-H1Á Á ÁO1A i , which run along the b-axis direction. This column branches out through the O4A-H4CÁ Á ÁO1A i and C24A-H24EÁ Á ÁO4B v hydrogen bonds to another parallel column, forming a sheet perpendicular to (101) (Fig. 7). Weak C23B-H23BÁ Á ÁO2B vi and C15B-H15AÁ Á ÁO5B iii interactions link the B molecules into a chain along the a-axis direction. A      The packing of compound I showing the two-dimensional network parallel to the (001) plane. For clarity, H atoms not participating in hydrogen bonds are omitted, and participating atoms are labeled once. Table 1 Hydrogen-bond geometry (Å , ) for (I). Symmetry codes: (i) Àx þ 1; Ày; Àz þ 1; (ii) Àx; Ày þ 1; Àz; (iii) x; y þ 1; z; (iv) x þ 1; y; z.
In compound III, an N1-H1Á Á ÁO1 i hydrogen bond (Table 3) alternating between two enantiomers results in a zigzag chain of racemic molecules running perpendicular to the (101) plane. The C13-H13BÁ Á ÁO2 ii hydrogen bond crosslinks a pair of enantiomers from different chains and forms a sheet of molecules parallel to (101) (Fig. 9). As a consequence of close packing, several short contacts are observed, i.e. an edge-to-edgecontact of 2.7636 (15) Å between C21 and C21 ii , H4Á Á ÁC29 i = 2.76 Å and H7AÁ Á ÁH24 i = 2.60 Å (symmetry codes as in Table 3).

Database survey
A search for arylbis(3-hydroxy-5,5-dimethylcyclohex-2enone) compounds in the Cambridge Structural Database (CSD Version 5.40, update of August 2019; Groom et al., 2016) gave 29 hits, among which are two NO 2 -phenylbis(3-hydroxy-5,5-dimethylcyclohex-2-enone) compounds. One is NO 2 substituted at the para position (CSD refcode IRODID; Yao et al., 2005) while the other is NO 2 substituted at the meta position (VUZYIZ; Palakshi Reddy et al., 2010) and both exhibit a similar structural configuration to that of compound I. However, with less steric effects surrounding the nitro group, both the p-and m-NO 2 groups are tilted only slightly from the aromatic ring with torsion angles between the N O and C C bonds of ca 8.25 and 4.58 , respectively. In contrast, in compound I (an o-NO 2 group), the torsion angle is 49.68 (6) . The database search also found 20 4-aryl-hexahydroquinoline-3-carboxylate derivatives. All of them display the same common structural features as compounds II and III in this report, such as the flat-boat conformation of the 1,4-DHP ring, the envelope conformation of the fused cyclohexanone ring, and the substituted phenyl ring at the pseudoaxial position and orthogonal to the 1,4-DHP ring.

Synthesis and crystallization
The synthesis was performed as outlined in the scheme. 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 (Wang et al., 2005). The mixture was then taken up in 30 ml of absolute ethanol, capped and placed 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 title compound was recrystallized by slow evaporation from hexane and ethyl acetate (v:v = 3:1).
2,2 0 -[(2-Nitrophenyl)methylene]bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) (I The packing of compound II showing the chains formed by A and B molecules along the a axis. For clarity, H atoms not participating in hydrogen bonds are omitted, and participating atoms are labeled once.

Figure 9
The packing of compound III. Cross-linked zigzag chains of alternating enantiomers form a sheet. For clarity, H atoms not participating in hydrogen bonds are omitted, and participating atoms are labeled once. Table 3 Hydrogen-bond geometry (Å , ) for (III).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 4. Hydrogen atoms attached to carbon were placed in calculated positions (C-H = 0.95-0.98 A) and refined with isotropic displacement parameters 1.2-1.5 times those of the parent atoms. Hydrogen atoms attached to nitrogen and oxygen were found in difference-Fourier maps and refined freely. In compound III, three reflections (101, 110, and 020) affected by the beam stop were omitted because of poor agreement between the observed and calculated intensities.