Crystal structure and Hirshfeld surface analysis of 4-(4-chlorophenyl)-5-methyl-3-{4-[(2-methylphenyl)methoxy]phenyl}-1,2-oxazole

In the crystal, the title molecules are linked by intermolecular C—H⋯N, C—H⋯Cl, C—H⋯π contacts and π–π stacking interactions. A Hirshfeld surface analysis was undertaken to quantify the intermolecular interactions.


Chemical context
Azoles are five-membered heterocycles that have been widely used as promising scaffolds in designing novel therapeutics, in particular anticancer agents (Ahmad et al., 2018). Among them, isoxazole, a five-membered heterocycle with consecutive nitrogen and oxygen atoms in the ring, is found to be a key structural component of many commercial drugs or drug candidates in clinical development (Barmade et al., 2016). Moreover, a number of vicinal diaryl isoxazoles reported in the literature exhibit anticancer and COX-2 inhibitory activities, such as luminesbip and valdexocib, respectively (Murumkar & Ghuge, 2018). One of the critical steps in rational drug design is obtaining knowledge of the structure of the new drug candidates, and single-crystal X-ray diffraction (SCXD) is one of the most powerful methods for gaining this fundamental information, which can be used to guide the drug-design studies in connection with other technologies such as pharmacophore model elaborations, 3D QSAR, docking, and de novo design. SCXD has thus become an essential tool for drug development to unambiguously determine the threedimensional structures of molecules, which eventually paves the way for rapid development of new molecules (Wouters & Ooms, 2001). Moreover, during the drug-development process, another important issue lies in understanding the crystal packing of the active pharmaceutical ingredient (drug substance) for suitable formulation development. Since most drug molecules comprise solid dosage forms in the crystalline state, it is imperative to truly understand the relationships between the crystal structures and the solid properties of pharmaceutically active substances, which helps the best form of an active pharmaceutical ingredient to be chosen for development into a drug product (Aitipamula & Vangala, 2017). Based on the above and our continuing interest in structural studies and biological applications of diaryl heterocycles Ç alışkan et al., 2011;Dü ndar et al., 2009;Eren et al., 2010;Ergun et al., 2010;Garscha et al., 2016;Levent et al., 2013;Pirol et al., 2014;Ü nlü et al., 2007), we report herein the crystal structure and Hirshfeld surface analysis of the title compound.

Figure 3
A view of the C-HÁ Á ÁN and C-HÁ Á Á andinteractions in the unit cell of the title compound. Dashed lines show short intermolecular contacts.

Hirshfeld surface analysis
Hirshfeld surface analysis (Hirshfeld, 1977;Spackman & Jayatilaka, 2009) of the title compound was carried out to investigate the location of atoms with potential to form hydrogen bonds and other intermolecular contacts, and the quantitative ratio of these interactions. Crystal Explorer17.5 (Turner et al., 2017) was used to generate the Hirshfeld surfaces and two-dimensional fingerprint plots (Rohl et al., 2008). The Hirshfeld surfaces were generated using a standard (high) surface resolution with the three-dimensional d norm surfaces mapped over a fixed colour scale of À0.0800 (red) to 1.5787 Å (blue) (Fig. 4).
The red points, which represent closer contacts and negative d norm values on the surface, correspond to the C-HÁ Á ÁN (C17-H17AÁ Á ÁN1), C-HÁ Á ÁCl (C8-Cl1Á Á ÁH1C-C1) and C-HÁ Á Á (C6-H6Á Á Áphenylene) interactions (Table 2). Except for the red spots, the overall surface mapped over d norm is white and blue, indicating that the distances between the contact atoms in intermolecular contacts are nearly the same as the sum of their van der Waals radii or longer.
The shape-index of the Hirshfeld surface is a tool for visualizing thestacking by the presence of adjacent red and blue triangles; if there are no such triangles, then there are nointeractions. The plot of the Hirshfeld surface mapped over shape-index clearly suggests that there areinteractions in the title compound (Fig. 5).  Table 2 Summary of selected van der Waals contacts (Å ) involving H atoms in the title compound.

Contact
Distance Symmetry operation

Figure 4
The Hirshfeld surface of the title compound mapped with d norm .

Figure 5
Hirshfeld surface of the title compound plotted over shape-index.
In compound (I), the asymmetric unit contains two molecules, A and B, with different conformations. In molecule A, the C O group of the ester points away from the benzene ring [C-C-C O = À170.8 (3) ], whereas in molecule B, it points back towards the benzene ring [C-C-C O = 17.9 (4) ]. The dihedral angles between the oxazole and benzene rings are also somewhat different [46.26 (13) and 41.59 (13) for molecules A and B, respectively]. Each molecule features an intramolecular C-HÁ Á ÁO interaction, which closes an S(6) ring. In the crystal, the B molecules are linked into C(12) chains along the c-axis direction by weak C-HÁ Á ÁCl interactions. In the crystal of (II), the components are linked by O-HÁ Á ÁN and N-HÁ Á ÁO hydrogen bonds, where the water molecule acts as both an H-atom donor and an acceptor, into a tape along the a-axis direction with an R 4 4 (16) graph-set motif. The water molecule is located on a twofold rotation axis. In (III), the dihedral angle between the benzene and isoxazole rings is 59.10 (7) . In the crystal, the components are linked by N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds into a three-dimensional network. The crystal structure is further stabilized by -stacking interactions [intercentroid distance = 3.804 (2) Å ].

Synthesis and crystallization
Step 1: To a solution of N-hydroxy-4-[(2-methylbenzyl)oxy]benzimidoyl chloride (275 mg, 1 mmol) in diethyl ether (6 ml) was added Et 3 N (139.4 mL, 1 mmol). The resulting mixture was stirred for 2 h in an ice bath, and the precipitate formed was filtered off. The filtrate was evaporated under vacuum to obtain the arylnitriloxide intermediate.
Step 2: To a solution of NaH (60% in mineral oil, 64 mg, 1.6 mmol) in dry THF (4 ml), 4-chlorophenylacetone (168,6 mg, 1.0 mmol) was added dropwise, and stirred for 1 h under a nitrogen atmosphere in an ice bath. At the end of the period, the arylnitriloxide intermediate was dissolved in dry THF (4 ml), and was added to the reaction mixture, then stirred at room temperature overnight. Upon completion of the reaction, aqueous ammonium chloride solution was added, and the product was extracted with EtOAc (2 Â 50 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered and evaporated to dryness. The crude product was purified by automated-flash chromatography on silica gel (12 g) eluting with a gradient of 0 to 40% EtOAc in hexane. The obtained pure product was recrystallized from methanol. Crystals for structural study were obtained by slow cooling of the solution, yield 77%, m.p. 387.2-388.6 K.  21, 18.42, 67.98, 113.96, 114.97, 120.84, 125.77, 128.15, 128.59, 128.86, 129.43, 130.12, 131.44, 132.57, 134.58, 136.64, 159.49, 160.09, 166.93
prepare material for publication: PLATON (Spek, 2020) and WinGX (Farrugia, 2012). 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.