Syntheses, characterizations, crystal structures and Hirshfeld surface analyses of methyl 4-[4-(difluoromethoxy)phenyl]-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, isopropyl 4-[4-(difluoromethoxy)phenyl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate and tert-butyl 4-[4-(difluoromethoxy)phenyl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

In the crystal structure of methyl 4-[4-(difluoromethoxy)phenyl]-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (I), molecules are linked by N—H⋯O and C—H⋯O interactions, forming a tri-periodic network, while molecules of isopropyl 4-[4-(difluoromethoxy)phenyl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (II) and tert-butyl 4-[4-(difluoromethoxy)phenyl]-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (III) are linked by N—H⋯O, C—H⋯F and C—H⋯π interactions, forming layers parallel to (002).


Chemical context
Inflammation is a defense tool developed by the immune system to eliminate abnormal conditions resulting from harmful stimuli caused by pathogens, damaged cells, toxic compounds and traumatic cells.Inflammatory processes are important in terms of providing hemostasis of the body.Inflammatory mediators such as cytokines, chemokines and leukocytes secreted by the immune system during inflammation regulate the vital functions of the cell such as survival, growth and proliferation.In some cases, persistent and uncontrolled acute inflammatory responses cause chronic inflammation (Chen et al., 2018;Aqdas & Sung, 2023).
Cancer is a dangerous disease with a high incidence all over the world.Although chemotherapy, radiotherapy and surgical interventions are among the current treatment methods, there are cases where these methods are insufficient.In addition, cancer is a disease that progresses rapidly and can recur even after treatment.Therefore, there is an urgent need for new treatments and new therapeutic agents (Shaheen et al., 2020).Tumor tissues are formed by the abnormal and damaged proliferation of cancer cells.Inflammation mediators multiply uncontrollably by immune cells in the microenvironment of tumor tissue (Aqdas & Sung, 2023).This uncontrolled development of inflammation is the root cause of many chronic diseases and cancers.Therefore, it is very important to develop new anti-inflammatory treatments (Wu et al., 2022).
1,4-DHPs and their condensed derivatives are heterocyclic compounds with many pharmacological and biological activities.These compounds were described in the literature for the first time with their calcium channel modulator activities, and then various activities such as anticancer and anti-ischemic were discovered (Bryzgalov et al., 2023).Lerkadipine, which is a calcium channel blocker in the pharmaceutical market, has also been shown by in vivo studies to be effective in melanoma and non-small-cell lung cancer.Based on this information, new compounds with anti-inflammatory effects have been obtained with modifications made on 1,4-DHPs and their activities have been proven (Pan et al., 2022) (Fig. 1).Hexahydroquinolines are heterocyclic rings obtained by the condensation of 1,4-DHPs with the cyclohexane ring.In recent years, it has been seen that hexahydroquinoline derivatives have many biological activities such as analgesic, anticancer, antibacterial, antituberculosis, antimalarial, antioxidant, antiinflammatory, anti-Alzheimer's.Therefore, the hexahydroquinoline ring system is a very well-established motif for medicinal chemistry and has been the subject of many studies in recent years (Ranjbar et al., 2019).

Figure 3
The molecular structure of (II) with displacement ellipsoids drawn at the 50% probability level.
In (II) (Fig. 3 Bond lengths and angles in all compounds are in agreement with those reported for the related compounds discussed in the Database survey section.

Supramolecular features and Hirshfeld surface analysis
In the crystal structure of (I), molecules are linked by N-H� � �O and C-H� � �O interactions, forming a tri-periodic network (Table 1; Figs. 5, 6 and 7 The molecular structure of (III) with displacement ellipsoids drawn at the 50% probability level.Only the major component of disorder is shown for clarity.

Figure 5
The N-H� � �O and C-H� � �O contacts (solid lines) of (I), shown along the a-axis.Only the major component of disorder is shown for clarity.

Figure 6
The N-H� � �O and C-H� � �O contacts (solid lines) of (I), shown along the b-axis.
( To quantify the intermolecular interactions between the molecules of (I), (II) and (III) in their respective crystal structures, the Hirshfeld surfaces and their corresponding two-

Figure 7
The N-H� � �O and C-H� � �O contacts (solid lines) of (I), shown along the c-axis.

Figure 8
The N-H� � �O and C-H� � �F contacts (solid lines) of (II), shown along the a-axis.

Figure 10
The N-H� � �O and C-H� � �F contacts (solid lines) of (II), shown along the c-axis.

Figure 9
The N-H� � �O and C-H� � �F contacts (solid lines) of (II), shown along the b-axis.
dimensional fingerprint plots were calculated using the software package Crystal Explorer 17.5 (Spackman et al., 2021).
The two-dimensional fingerprint plots are shown in Fig. 16.

Figure 11
The C-H� � �� contacts (solid lines) of (II), shown along the a-axis.

Figure 12
The N-H� � �O and C-H� � �F contacts (solid lines) of (III), shown along the a-axis.Only the major component of disorder is shown for clarity.

Figure 13
The N-H� � �O and C-H� � �F contacts (solid lines) of (III), shown along the b-axis.

Figure 14
The N-H� � �O and C-H� � �F contacts (solid lines) of (III), shown along the c-axis.
functional groups in the compounds leads to some differences in the remaining weak interactions.

Synthesis and crystallization
The target compounds were synthesized by 5,5-dimethylcyclohexane-1,3-dione/4,4-dimethylcyclohexane-1,3-dione (1 mmol), 4-difluoromethoxybenzaldehyde (1 mmol), methyl acetoacetate/isopropyl acetoacetate/tert-butyl acetoacetate (1 mmol), and ammonium acetate (5 mmol), which were refluxed for 8 h in absolute methanol (10 ml).The progress of the reactions were monitored by TLC and after the reactions were seen to be complete, they were cooled to room temperature.The obtained precipitates were filtered and recrystallized from methanol for further purification.The synthetic route is shown in Fig. 17.The structures of the

Figure 15
The C-H� � �� contacts (solid lines) of (III), shown along the a-axis.

Figure 17
Synthetic scheme

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 5.In (I), (II) and (III), the N-bound H atom was located in a difference Fourier map and refined freely [N1-H1N = 0.90 (3) A ˚for (I), N1-H1N = 0.863 (16) A ˚for (II) and N1-H1N = 0.88 (2) A ˚for (III)].The C-bound H atoms of all compounds were positioned geometrically [C-H = 0.95-1.00A ˚] and refined using a riding model withU iso (H) = 1.2 or 1.5U eq (C).In (I), the atoms of the 4difluoromethoxy-phenyl group are disordered over two sets of sites with refined occupancy factors of 0.647 (3):0.353(3).In (III), the carbon atoms (C10, C13-C24) of the methyl and tertbutyl formate group attached to the 1,4-dihydropyridine ring were refined isotropically for a stable structure.The atoms (C11/C11A and C12/C12A) of the dimethyl group attached to the cyclohexane ring, and the two carbon atoms (C7/C7A and C8/C8A) in the anticlockwise direction after the carbon atom to which the dimethyl group of the cyclohexane ring is attached, were refined as disordered over two sets of sites in a 0.646 (3):0.354(3) ratio.

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.

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.

Table 4
Percentage contributions of interatomic contacts to the Hirshfeld surface for the compounds.

Table 5
Experimental details.
Computer programs: APEX2 and SAINT