Crystal structure of ethyl 4-[4-(dimethylamino)phenyl]-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

In the title racemic compound, the 1,4-dihydropyridine (1,4-DHP) ring adopts a flat-boat conformation, which is bisected by the plane of the pseudo-axial aryl ring, while the cyclohexanone ring adopts an envelope conformation. In the crystal, molecules are linked via N—H⋯O and C—H⋯O hydrogen bonds, forming layers parallel to (10).


Chemical context
1,4-Dihydropyridine (DHP) derivatives are well known for their calcium-channel blocking activity and many of these compounds, such as nifedipine, nicardipine, and amlodipine, have been used in the treatment of angina pectoris and systemic hypertension. (Wishart et al., 2006) 4-Aryl-1,4-dihydropyridines that bind the L-type voltage-gated calcium channels (VGCC) have been in general medical practice for over three decades (Zamponi, 2005). Many modifications on 1,4-DHP have been performed to obtain active compounds as calcium-channel agonists or antagonists (Martín et al., 1995;Rose, 1990;Rose & Drä ger 1992). One such modifications is fusing a cyclohexanone ring to form hexahydroquinolone, 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 moderate calcium-channel antagonistic activity, as well as antiinflammatory modes and stem-cell differentiation properties, and has been implicated in slowing neurodegenerative disorders (Trippier et al., 2013). Recently, these compounds were found to have distinct selectivity profiles to different calcium channel subtypes (Schaller et al., 2018). Another report also showed that the 4-aryl-hexahydroquinolones, especially the ones containing a methoxy moiety, exhibit good antioxidant property as radical scavengers (Yang et al., 2011). It has been revealed that the aryl group in the 4-position of the 1,4-DHP ring is the basic requirement for optimal activity and the type of electron-withdrawing groups on the phenyl group would affect the receptor-binding activity (Takahashi et al., 2008). It has also been proven that the flattened boat conformation of the 1,4-DHP ring is one factor that leads to higher calciumchannel activity (Linden et al., 2004). In a continuation of our ISSN 2056-9890 study on the structure-activity relationship of this class of 1,4-DHP derivatives, i.e. 4-aryl-hexahydroquinolones, we report herein the crystal structure of a compound we synthesized, ethyl 4-(4-dimethylaminophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate.

Structural commentary
The asymmetric unit of the title compound contains one independent molecule crystallizing racemically in the monoclinic space group P2 1 /n. A displacement ellipsoid plot showing the atomic numbering is presented in Fig. 1.
In the title compound, the 1,4-DHP ring is characterized by a shallow or flattened boat conformation, which is one of the factors that leads to higher calcium-channel activity. The flattened boat conformation is visually obvious with the flat base formed by atoms C2, C3, C10, and C9 and the bow and stern formed by the slightly raised C4 and N1 atoms. The mean plane defined by atoms C2, C3, C9, and C10 is planar, with an r.m.s. deviation of 0.008 Å . The shallowness of the boat conformation is indicated by the marginal displacements of atoms N1 [0.1332 (15) Å ] and C4 [0.3047 (16) Å ] from this mean plane, and is also implied by the small puckering amplitude Q [0.2583 (10) Å ].
Examination of the fused C5-C10 cyclohexanone ring using puckering parameters also showed that the ring adopts an envelope conformation, with atom C7 protruding in the same direction as the 4-aryl group at a distance of 0.6453 (15) Å from the mean plane through the other five C atoms. The orientation of ring atom C7 makes the axial bond C7-C11 syn-periplanar to the 4-aryl group, i.e. the torsion angle between C7-C11 and C4-C17 is 6.91 (7) .
The pseudo-axial position of the 4-aryl group is conserved in the title compound. The C17-C22 phenyl ring is almost orthogonal to the base of the 1,4-DHP ring formed by atoms C2, C3, C10, and C9, with the dihedral angles between the C2-C3-C10-C9 mean plane and the ring being 89.59 (3) . The very small pseudo-torsion angle [2.44 (8) ] between N1-C4 and C17-C18 also implies a bisecting orientation of the 4-aryl group to the 1,4-DHP ring in this compound.
As in other 1,4-DHP compounds (Linden et al., 2004), the ester group is coplanar and at a cis orientation to the adjacent endocyclic C2 C3 double bond. The planarity extends out through the ester chains.
The nitrogen atom in the dimethylamino group is almost in the same plane as the phenyl ring, at a distance of 0.0420 (16) Å from the mean plane. However, the plane formed by N2-C23-C24 is slightly bent from the phenyl group with the angle of 27.24 (11) rather than being coplanar with the phenyl ring, which seems to be common in N,N-dimethylaniline type of compounds (Dahl, 2000). In conclusion, the parameters reported here demonstrate that the conformational features usually observed in cyclohexanone-fused 1,4-DHP derivatives have been conserved. As a promising base structure for calcium-channel antagonists, different substitutions and more structural modifications are being carried out in our group. Progress will be reported in due course.

Figure 1
The asymmetric unit of the title compound showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level

Database survey
A search in the Cambridge Structural Database (Version 5.39, November 2017) for related compounds with a 4-aryl-hexahydroquinolone-3-carboxylate fragment gave 30 hits. All these compounds share the common structural features such as the flat-boat conformation of the1,4-dihydropyridine (1,4-DHP) ring, the envelope conformation of the fused cyclohexanone ring, and the substituted phenyl ring at the pseudo-axial position and orthogonal 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.  m. 14.37, 19.55, 27.42, 29.54, 32.82, 35.38, 40.86, 41.17, 50.85, 59.84, 106.61, 112.46, 128.70, 135.94, 142.95, 147.85, 149.06, 167.79, 195.75

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The H atoms on methyl groups were constrained to an ideal geometry, with C-H = 0.98 Å and U iso (H) = 1.5U eq (C), and were allowed to rotate freely about the C-C bonds. The rest of the H atoms were placed in calculated positions with C-H = 0.95-1.00 Å and refined as riding on their carrier atoms with U iso (H) = 1.2U eq (C). The positions of the amine H atoms and hydroxyl H atoms were determined from difference-Fourier maps and freely refined. Three low-angle reflections were omitted from the refinement because their observed intensities were much lower than the calculated values as a result of being partially obscured by the beam stop.

Figure 2
A view normal to plane (101)   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.