Ethyl 3-(9-chloro-10-oxo-9,10-dihydroanthracen-9-yl)-5-methylisoxazole-4-carboxylate

The asymmetric unit of the title compound, C21H16ClNO4, contains two independent molecules (A and B), each adopting a conformation wherein the isoxazole ring is roughly orthogonal to the anthrone ring. The dihedral angle between the mean plane of the isoxazole (all atoms) and the mean plane of the anthrone (all atoms) is 88.48 (3)° in one molecule and 89.92 (4)° in the other. The ester is almost coplanar with the isoxazole ring, with mean-plane dihedral angles of 2.48 (15) and 8.62 (5)°. In both molecules, the distance between the ester carbonyl O atom and the anthrone ketone C atom is about 3.3 Å. The anthrone ring is virtually planar (r.m.s. deviations of 0.070 and 0.065 Å) and adopts a shallow boat conformation in each molecule, as evidenced by the sum of the six intra-B-ring torsion angles [41.43 (15) and 34.38 (15)° for molecules A and B, respectively]. The closest separation between the benzene moieties of anthrones A and B is 5.1162 (7) Å, with an angle of 57.98 (5)°, consistent with an edge-to-face π-stacking interaction. In the crystal, weak C—H⋯O and C—H⋯N interactions link the molecules, forming a three-dimensional network.

The asymmetric unit of the title compound, C 21 H 16 ClNO 4 , contains two independent molecules (A and B), each adopting a conformation wherein the isoxazole ring is roughly orthogonal to the anthrone ring. The dihedral angle between the mean plane of the isoxazole (all atoms) and the mean plane of the anthrone (all atoms) is 88.48 (3) in one molecule and 89.92 (4) in the other. The ester is almost coplanar with the isoxazole ring, with mean-plane dihedral angles of 2.48 (15) and 8.62 (5) . In both molecules, the distance between the ester carbonyl O atom and the anthrone ketone C atom is about 3.3 Å . The anthrone ring is virtually planar (r.m.s. deviations of 0.070 and 0.065 Å ) and adopts a shallow boat conformation in each molecule, as evidenced by the sum of the six intra-B-ring torsion angles [41.43 (15) and 34.38 (15) for molecules A and B, respectively]. The closest separation between the benzene moieties of anthrones A and B is 5.1162 (7) Å , with an angle of 57.98 (5) , consistent with an edge-to-face -stacking interaction. In the crystal, weak C-HÁ Á ÁO and C-HÁ Á ÁN interactions link the molecules, forming a three-dimensional network.  (2002,2003); Li et al. (2006Li et al. ( , 2008. For the antitumor activity of aryl isoxazole amides (AIMs), see: Han et al. (2009);Gajewski et al. (2009). For a previous report of a 9 0 -Br-9 0heterocyclic anthrone crystal structure, see: Riant et al. (1994).  Table 1 Hydrogen-bond geometry (Å , ).

Comment
Isoxazolyl-anthracenyl amides (AIMs) have been found to possess significant antitumor activity (Han et al., 2009;Gajewski et al., 2009), and the title compound was isolated in the course of our continuing structure activity relationship studies. The edge-to-face π-stacking in the unit cell is noteworthy, as the current working hypothesis for the AIMs is that they exert their biological effect via an interaction with G-quadruplex DNA, by an analogous plausible stacking interaction. The title compound exhibited no cytotoxicity up to 25µM in an assay against human glioblastoma SNB-19 cells. However, the structural data in this report will be useful for interpretation of SAR studies with the AIMs that will be reported in due course.
The asymmetric unit of the title compound, C 21 H 16 NO 4 Cl, contains two independent molecules, each adopting a conformation wherein the isoxazole ring is roughly orthogonal to the anthrone ring. The angle between the mean plane of the isoxazole (all atoms) and the mean plane of the anthrone (all atoms) is 91.52 (3)° in one molecule and 90.08 (4)° in the other. The ester is almost co-planar with the isoxazole, with the mean plane angles of 2.48 (15)° and 8.62 (5)°. In both molecules, the distances between isoxazolyl ester carbonyl oxygen and the anthrone carbon of the ketone are about 3.3 Å in distance (O3-C10 and O3′-C10′). The anthrone is virtually planar, and adopts a shallow boat conformation, as evidenced by the sum of the six intra-B-ring torsional angles. The smallest intermolecular distance between the anthrone H2 of one molecule of the title compound is 3.1192 (13) Å from C5′ of the second molecule, also the closest centroids of the two anthrone A rings is 5.1162 (7) Å in distance (ring C1-C2-C3-C4-C11-C12 and ring C5′-C6′-C7′-C8′-C13′-C14′), with an angle of 57.98 (5)°, consistent with an edge-to-face π-stacking interaction.
The 10-Cl carboxylate (0.3312 g, 0.905 mmol) was taken up in 5 mL DMF to which was added a solution over 10 minutes of N-Chlorosuccinimide (NCS) (1.2 eq, 0.1451 g, 1.087 mmol) dissolved in 5 mL DMF. The solution was brought to 30°C and let stir for 43 hours whereupon the solution was poured into 50 mL ice/water which was allowed to stir for 1.5 hours, in which the product precipitated out. Product was filtered and washed with water. The solid was dissolved in minimal CH 2 Cl 2 and placed on a wet silica column prepared with hexanes. The solvent polarity increased using a stepwise elution of 10:1, 6:1, and finally 4:1 until all product collected. Ethyl 3-(9-chloro-10-oxo-9,10-dihydroanthracen-9-yl)-5-methylisoxazole-4-χarboxylate. Single crystals with sufficient quality for X-ray crystallographic analysis were prepared by a slow recrystallization from a chloroform/pentane

Refinement
All H atoms were placed at geometrically calculated positions and included in the refinement in the riding model approximation, with C-H lengths of 0.93 (aromatic CH), 0.96 (CH3) and 0.97 (CH2) Å. U iso of the H atoms was set at 1.5U eq of the parent C atom for the methyl group and at 1.2U eq for the remaining H atoms. The molecular structure of the title compound, with atom labels and 50% probability displacement ellipsoids for non-H atoms.

Computing details
Ethyl 3-(9-chloro-10-oxo-9,10-dihydroanthracen-9-yl)-5-methylisoxazole-4-carboxylate  Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.