Structural study and Hirshfeld surface analysis of (Z)-4-(2-methoxybenzylidene)-3-phenylisoxazol-5(4H)-one

The asymmetric unit of the title compound contains one molecule and the molecule adopts a Z configuration about the C=C bond. The crystal structure features C—H⋯O and C—H⋯N hydrogen bonds together with C—H⋯π contacts and π–π stacking interactions. The crystal packing was further investigated by Hirshfeld surface analysis and the included surface areas from the title compound and an isomeric form were also investigated.


Chemical context
Isoxazolones are known to be inhibitors of the factorization of tumor necrosis alpha (TNF-) (Laughlin et al., 2005), antimicrobial agents (Mazimba et al., 2014), as drugs for the treatment of cerebrovascular disorders and as muscle relaxants. In agriculture, they are used as herbicides (Guo, et al., 2020) and fungicides (Miyake et al., 2012). They undergo various chemical transformations (Batra et al., 1994) and are excellent intermediates in the synthesis of various heterocycles, including pyridopyrimidines (Tu et al., 2006), quinolines (Abbiati et al., 2003) and polycycles (Badrey & Gomha, 2014). Because of their importance, these compounds have been studied extensively and several procedures for their synthesis are described using a three-component polycondensation between an aromatic aldehyde, ethyl acetoacetate and hydroxylamine hydrochloride under different conditions (Liu et al., 2011;Fozooni et al., 2013).
We report here on the use of K 2 CO 3 as very inexpensive, highly available and safe catalyst in an organic medium for isoxazolone formation and we describe the synthesis, molecular and crystal structures, and Hirshfeld surface analysis of the title isoxazole derivative, 1 (Fig. 1).

Structural commentary
The asymmetric unit contains one molecule and the molecule adopts a Z configuration about the C8 C10 bond. The entire (Z)-4-(2-methoxybenzylideneisoxazolone) segment of the molecule is almost planar with an r.m.s. deviation from the mean plane through all 15 non-hydrogen atoms of the frag-ment of only 0.0927 Å . This conformation is supported by the formation of an intramolecular C12-H12Á Á ÁO1 hydrogen bond (Table 1), which links the isoxazole ring and the benzene ring of the 2-methoxybenzylidene substituent. These two rings are inclined to one another at an angle of 9.63 (7) . The (C1-C6) phenyl substituent is twisted out of this plane, the phenyl and isoxazole rings being inclined to one another by 46.22 (4) . Bond lengths and angles agree well with those found in the isomeric derivative 2 (Zhang et al., 2015) and also with the values observed for the related compound (4Z)-4benzylidene-2-phenyl-1,3-oxazol5(4H)-one (Asiri et al., 2012).

Figure 2
Sheets of molecules of 1 in the ac plane.

Figure 3
Double rows of molecules of 1 along the a-axis direction. Cg2 is the centroid of the C1-C6 phenyl ring, shown here as an orange sphere, with the C-HÁ Á Á contacts drawn as orange dashed lines.

Figure 1
The molecular structure of the title compound, with atom labelling and displacement ellipsoids drawn at the 50% probability level. The intramolecular hydrogen bond is shown as a black dashed line.

Analysis of the Hirshfeld surfaces
Further details of the intermolecular interactions in 1 were obtained using Hirshfeld surface analysis (Spackman & Jayatilaka, 2009) with Hirshfeld surfaces and two-dimensional fingerprint plots (McKinnon et al., 2007) generated using CrystalExplorer (Turner et al. 2017). Fig. 5 shows the Hirshfeld surfaces for opposite faces of the asymmetric unit of molecule 1. The bright red circles correspond to C-HÁ Á ÁN and C-HÁ Á ÁO hydrogen bonds while a weaker C-HÁ Á Á contact appears as a faint red circle. Fingerprint plots for 1 are shown in Fig. 6. As the CIF file for the isomeric molecule, 2, was available from the CCD, it was of interest to compare and contrast contributions to the included surface areas from the two isomers as shown in Table 2. As expected, HÁ Á ÁH contacts are the most prolific in both cases. Other contributions were generally very similar, the sole exception being that the CÁ Á ÁO/OÁ Á ÁC contacts made up almost twice the surface area for 2 as for 1. The change from the 2-to the 4-position in 2 may allow the methoxy substituent in 2 to contribute more substantially to the surface of the molecule. Hirshfeld surfaces for opposite faces of the molecule of 1, mapped over d norm in the range À0.1701 to 1.4088 a.u. contacts for 1 stacking molecules along the b-axis direction. Cg1 and Cg3 are the centroids of the N1/O2/C7-C9 isoxazole and the C11-C16 benzene rings, respectively. The two discretecontacts Cg1Á Á ÁCg3 = 3.7049 (9) and 3.9200 (9) Å are shown as green and blue dashed lines, respectively.

Synthesis and crystallization
2-Methoxybenzaldehyde (1 mmol), hydroxyamine hydrochloride (1 mmol), ethyl benzoylacetate (1 mmol) and K 2 CO 3 (5 mol%) were mixed in a 25 ml flask equipped with a magnetic stirrer. The mixture was refluxed in 5 ml of water for 2.5 h (the reaction was monitored by TLC). On completion of the reaction, the mixture was gradually poured into ice-cold water. Stirring was maintained for a few minutes and the resulting solid was filtered and purified by crystallization from ethanol.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 3. H atoms were positioned geometrically (C-H = 0.93-0.96 Å ) and refined as riding with U iso (H) = 1.2U eq (C) or 1.5U eq (C-methyl). (a) The two-dimensional fingerprint plot for all interactions, together with those (b)-(h) delineated into individual contact types with included surface areas for the major individual contacts. Minor contacts contributing less than 1% to the total surface area are not shown here but, for completeness, are included in Table 2.  program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL2018/3 (Sheldrick, 2015); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2020); software used to prepare material for publication: WinGX publication routines (Farrugia, 2012).

(Z)-4-(2-Methoxybenzylidene)-3-phenylisoxazol-5(4H)-one
Crystal data where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.09 e Å −3 Δρ min = −0.16 e Å −3 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.