Crystal structure and Hirshfeld surface analysis of ethyl 5-phenylisoxazole-3-carboxylate

In the title isoxazole derivative, the phenyl and isoxazole rings are in the same plane, as indicated by the C—C—C—O torsion angle of 0.1 (3)°. The ester group has an extended conformation and is almost in the same plane with respect to the isoxazole ring, as indicated by the O—C—C—N torsion angle of −172.86 (18)°.


Chemical context
Nitrogen-containing heterocyclic rings are of great importance in medicinal and organic chemistry (Dou et al., 2013). Isoxazole derivatives are important heterocyclic pharmaceuticals having a broad spectrum of biological activity, which includes antagonism of the NMDA receptor, anti-inflammatory (Panda et al., 2009), anti-tumour, anticonvulsant, anti-psychotic, antidepressant and anti HIV activity (Conti et al., 2005;Srivastava et al., 1999). Considerable attention has been paid to isoxazole derivatives as a result of their prominent biological properties (Dou et al., 2013). Valdecoxib (Bextra), a selective cyclooxygenase-2 (COX-2) inhibitor used in the treatment of arthritis, contains an isoxazole moiety which is responsible for its biological activity (Waldo & Larock, 2007;Dadiboyena & Nefzi, 2010). In addition, isoxazole derivatives are also important intermediates in the preparation of various heterocyclic biologically active drugs (Dou et al., 2013). As part of our ongoing studies on isoxazole derivatives as kinase inhibitors, we have synthesized the title compound, and report herein on its crystal structure and the quantitative analysis of intermolecular interactions using the Hirshfeld surface and 2D fingerprint plot analysis. ISSN 2056-9890

Structural commentary
The molecular structure of the title compound, (I), is illustrated in Fig. 1. The molecule consists of three almost flat units: the phenyl ring, the isoxazole ring and the ester. The phenyl (C1-C6) and isoxazole (O1/N1/C7-C9) rings are almost coplanar, as indicated by the torsion angle C5-C6-C7-O1 = 0.1 (3) . The ester unit has an extended conformation and is almost in the same plane as the isoxazole ring, as indicated by the torsion angle O2-C10-C9-N1 = À172.86 (18) .

Supramolecular features
In the crystal of (I), molecules are linked via pairs of C-HÁ Á ÁO hydrogen bonds, both involving atom O2 as acceptor, forming inversion dimers with two R 1 2 (7) ring motifs (Table 1  and Fig. 2). The molecules stack in layers lying parallel to (103), as illustrated in Fig. 3.

Hirshfeld surface and fingerprint plot analysis
To explore the weak intermolecular interactions in (I), Hirshfeld surfaces and 2D fingerprint plots were generated using Crystal Explorer 3.1 to quantify the intermolecular interactions (McKinnon et al., 2007;Spackman & Jayatilaka, 2009). Hirshfeld surfaces are produced through the partitioning of space within a crystal where the ratio of promolecule to procrystal electron density is equal to 0.5, generating continuous, non-overlapping surfaces which are widely used to visualize and study the significance of weak interactions in the molecular packing (McKinnon et al., 2007). The Hirshfeld surface of title compound was mapped over d norm , shape index and curvedness. The d norm surface is the normalized function of d i and d e (Fig. 4a), with white-, red-and blue-coloured surfaces. The white surface indicates those contacts with distances equal to the sum of the van der Waals (vdW) radii, red indicates shorter contacts (< vdW radii) and blue the longer contact (> vdW radii). The Hirshfeld surface was also mapped over electrostatic potential (Fig. 4b) using a STO-3G basis set at the Hartee-Fock level of theory (Spackman & McKinnon, 2002;McKinnon et al., 2004). In the Hirshfeld surface, a pair of interactions between the aromatic C-HÁ Á ÁO C atoms can be seen as the bright-red area (1) in Fig. 5a. The 2D fingerprint plot analysis of the OÁ Á ÁH interactions revealed significant hydrogen-bonding spikes (d i = 1.3, d e = 0.9 Å and d e = 1.9, d i = 2.6 Å ); Fig. 6c.
The analysis indicates that there is a weak NÁ Á ÁH intermolecular interaction between the nitrogen atom of the 532 Shaik et al.  Table 1 Hydrogen-bond geometry (Å , ).

Figure 2
Crystal packing of compound (I), viewed along the a axis. Hydrogen bonds are shown as dashed lines (see Table 1).

Figure 1
The molecular structure of compound (I), with the atom labelling and displacement ellipsoid drawn at the 50% probability level.

Figure 3
isoxazole ring and the methylene hydrogen atom of the phenyl ring of a neighbouring molecule (Fig. 5b). The fingerprint plot analysis of NÁ Á ÁH contacts reveals a significant wing-like structure (d i = 1.2, d e = 1.5 Å and d e = 2.2, d i = 2.4 Å ) Fig. 6d.
The relative contributions to the Hirshfeld surface area for each type of intermolecular contact are illustrated in Figs. 6 and 7. The HÁ Á ÁH interactions appear as scattered points over nearly the entire plot and have a significant composition of 41% of the Hirshfeld surface. The HÁ Á ÁO contacts comprise of 18.7% and the CÁ Á ÁC interactions comprise 1.6% of the total Hirshfeld surface. The CÁ Á ÁH and NÁ Á ÁH interactions cover 23.2% and 9.2% of the surface, respectively. Thus, these weak interactions contribute significantly to the packing of (I). isoxazole-3-carboxylate (CSD refcode YAVRIY; Zhao et al., 2012). This compound crystallizes with two independent molecules in the asymmetric unit. One molecule is slightly more planar than the other, with the phenyl ring being inclined to the isoxazole ring by 1.77 (10) and 5.85 (10) . In the title compound, (I), this dihedral angle is 0.5 (1) .

Synthesis and crystallization
There are several methods available in the literature for the preparation of isoxazole derivatives. We have followed a simple preparation from a diketoester (Tourteau et al., 2013;Bastos et al., 2015). After the reaction of acetophenone with diethyoxalate in a basic solution (sodium ethoxide) of ethanol for 8 h, 1N HCl was added to neutralize the sodium ethoxide to obtain the diketoester (ethyl 2,4-dioxo-4-phenylbutanoate; see Fig. 8) as a yellow liquid. 1 g (4.5 mmol) of the diketoester in ethanol was added to hydroxyl amine hydrochloride (0.315 g, 4.5 mmol) at room temperature and the resulting mixture was stirred at 353 K for 12 h. The progress of the reaction was monitored by TLC. After the completion of starting materials, the reaction mixture was cooled to room temperature and the excess of ethanol removed. The resulting residue was dissolved in water and extracted with ethyl Relative contribution of each interaction in the two-dimensional fingerprint analysis.     acetate. The organic layer was dried with Na 2 SO 4 , filtered and the concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (3% ethyl acetate: Pet-ether) to afford the title compound, (I) (yield 76.9%, 0.75 g; m.p. 325-327 K).
Colourless crystals were obtained by slow evaporation of a solution in ethyl acetate.

Ethyl 5-phenylisoxazole-3-carboxylate
Crystal data 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.