Crystal structure of (R)-5-[(R)-3-(4-chlorophenyl)-5-methyl-4,5-dihydroisoxazol-5-yl]-2-methylcyclohex-2-enone

The title compound is a pure diastereoisomer built up from a central five-membered dihydroisoxazole ring substituted in the 3 and 5 positions by a p-chlorophenyl group and a cyclohex-2-enone ring. The cyclohex-2-one and the isoxazoline rings both exhibit an envelope conformation. The crystal packing features C—H⋯O, C—H⋯N and C—H⋯π interactions.


Chemical context
In recent years, isoxazole and isoxazoline derivatives have been considered to be good drug candidates because of their broad spectrum of pharmaceutical activities, such as antitumoral (Kamal et al., 2010), antibacterial (Calí et al., 2004), antiviral (Deng et al., 2009) and anti-inflammatory (Pedada et al., 2016). Cycloaddition and heterocyclization reactions have been widely used as synthetic methods for obtaining isoxazoles (Nieto et al., 2019). In terms of selectivity, 1,3-dipolar cycloaddition reactions of nitrilimines with dipolarophiles, such as C C, C S or C N, give high stereoselectivity (Ait Itto et al., 2013), while nitrile oxides, which are less sterically hindered dipoles, lead to poor stereoselectivity (Feddouli et al., 2006). This was confirmed in our recent work (Oubella et al., 2019) in which the 1,3-cycloaddition reaction of diarylnitrilimines with (R)-carvone gave the corresponding pyrazoles isolated as the unique (3aR,5R,7aR) diastereoisomer, while the isoxazoles prepared with nitrile oxides were isolated as (R,R)/(R,S) diastereoisomeric mixtures with a slight predominance of (R, R). In the present work, we report the separation, identification by 1 H NMR spectroscopy, and X-ray structural analysis of the slightly major diastereoisomer of the isoxazole obtained by the 1,3-dipolar cycloaddition of 4-chlorobenzonitrile oxide with (R)-carvone.

Structural commentary
The title compound is built up from a central five-membered dihydroisoxazol ring to which a p-chlorophenyl group and a cyclohex-2-enone ring are attached to atoms C2 and C1 at the ISSN 2056-9890 3 and 5 positions, respectively (Fig. 1). Atom C1 also bears a methyl group. The absolute configuration of R/R at atoms C1 and C11 were confirmed by the Flack parameter (Parsons et al., 2013). This structure is closely related to the previously reported isoxazole derivative having a methyl group in place of atom Cl 3 (Oubella et al., 2019). The isoxazole ring has an envelope conformation on C1 as indicated by the puckering parameters of Q 2 = 0.145 (3) Å and ' 2 = 138.1 (11) . The puckering parameters for the cyclohexene ring, Q = 0.449 (3) Å , = 126.0 (4) and ' = 189.2 (5) , agree with an envelope conformation on C11. The mean plane of the isoxazole ring makes a dihedral angle of 13.4 (2) with the C21-C26 benzene ring, whereas it makes a dihedral angle of 66.2 (1) with the mean plane of the C11-C16 ring.

Supramolecular features
The packing of the structure features weak C-HÁ Á ÁN and C-HÁ Á ÁO interactions (C4-H42Á Á ÁN1 i and C12-H12BÁ Á ÁO13 ii ; symmetry codes as in Table 1). The C-HÁ Á ÁN interactions build up a linear chain along the a-axis direction, while the C-HÁ Á ÁO interactions make a helical chain along the b-axis direction, forming a layer parallel to the ab plane (Fig. 2). Between the layers, a C-HÁ Á Á interaction is observed (C23-H23Á Á ÁCg1 iii ; Table 1), where Cg1 is the centroid of the C21-C26 benzene ring.

Database survey
A search in the Cambridge Structural Database (CSD, version 5.40, update August 2019; Groom et al., 2016) for organic compounds with structures containing a 2-isoxazoline ring revealed 284 hits. Introducing a methyl group on position 5 reduced this number to 15 and searching for structures containing a phenyl ring attached to position 3 gave only seven hits. A comparison of related distances and angles within the 2-isoxazoline ring shows a good agreement between all these structures, with a systematically short C2-N1 bond with lengths ranging from 1.274 to 1.285 Å , corresponding to a C N double bond. A larger discrepancy is observed for the dihedral angle between the isoxazol mean plane and the benzene ring in the (S)-3-(2,6-dichlorophenyl)-5-[(2,5-diphenylpyrrolidin-1-yl)carbonyl]-5-methyl-4,5-dihydroisoxazole compound (Houk et al., 1984); at 66.8 , this is much larger than the value of 13.4 (2) observed for the title compound. This larger dihedral angle is related to the occurrence of two Cl atoms in the 2 and 5 positions on the phenyl ring.

Figure 1
Molecular structure of the title compound with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are represented as small circles of arbitrary radii. according to our recently described methodology (Oubella et al., 2019). The corresponding isoxazole, 3, was obtained in 80% yield, as an (R,R)/(R,S) diastereoisomeric mixture. The 1 H NMR spectrum of 3 clearly shows a splitting of both the methyl and methylene groups in the position of the newly formed stereogenic center of the isoxazole nucleus (Fig. 4a). The former gave rise to two singlets at 1.44 ppm and 1.48 ppm, respectively, while the latter is seen as two pairs of doublets, one at 2.90 and 3.20 ppm (J = 16.9 Hz) and the other at 2.75 and 3.30 ppm (J = 16.7 Hz). Integrating the corresponding 1 H NMR signals allowed us to quantify the ratio of the diastereoisomereric mixture as 58:42. After several attempts at separation, either by column chromatography or a series of fractional crystallizations by slow evaporation from a chloroform solution of 3, we managed to separate the diastereoisomer 3a, the title compound, as pure single crystals suitable for crystallographic analysis. Its 1 H NMR spectrum (Fig. 4b) is mainly characterized by the isoxazolic methyl group resonating as a singlet at 1.44 ppm, and the methylene group appeared as two doublets at 2.90 ppm (J = 16.9 Hz) and 3.20 ppm (J = 16.9 Hz).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All H atoms attached to C atoms were fixed geometrically and treated as riding with C-H = 0.99 Å (methylene), 0.98 Å (methyl) or 0.95 Å (methine), and with U iso (H) = 1.2U eq (C) for methylene and methine or U iso (H) = 1.5U eq (C) for methyl H atoms.

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.