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

Nathan S Duncan; Howard D Beall; Alison K Kearns; Chun Li; Nicholas R Natale

doi:10.1107/S1600536814003080

. 2014 Feb 19;70(Pt 3):o315–o316. doi: 10.1107/S1600536814003080

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

Nathan S Duncan ^a, Howard D Beall ^a, Alison K Kearns ^a, Chun Li ^b, Nicholas R Natale ^a,^*

PMCID: PMC3998422 PMID: 24765016

Abstract

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.

Related literature

For the synthesis of anthryl isoxazoles, see: Mosher & Natale (1995 ▶); Zhou et al. (1997 ▶); Han & Natale, (2001 ▶); Rider et al. (2010 ▶); Mirzaei et al. (2012 ▶). For previous studies on anthryl isoxazole crystallography, see: Mosher et al. (1996 ▶); Han et al. (2002 ▶, 2003 ▶); Li et al. (2006 ▶, 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′-Br-9′-heterocyclic anthrone crystal structure, see: Riant et al. (1994 ▶).

Experimental

Crystal data

C₂₁H₁₆ClNO₄
M _r = 381.80
Triclinic,
a = 10.0121 (3) Å
b = 12.6146 (4) Å
c = 14.9503 (4) Å
α = 77.9547 (14)°
β = 73.4361 (13)°
γ = 89.1187 (13)°
V = 1768.04 (9) Å³
Z = 4
Mo Kα radiation
μ = 0.24 mm⁻¹
T = 100 K
0.47 × 0.37 × 0.23 mm

Data collection

Bruker SMART BREEZE CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2008 ▶) T _min = 0.89, T _max = 0.95
48576 measured reflections
8722 independent reflections
8026 reflections with I > 2σ(I)
R _int = 0.023

Refinement

R[F ² > 2σ(F ²)] = 0.033
wR(F ²) = 0.089
S = 1.03
8722 reflections
491 parameters
H-atom parameters constrained
Δρ_max = 0.46 e Å⁻³
Δρ_min = −0.22 e Å⁻³

Data collection: APEX2 (Bruker, 2008 ▶); cell refinement: SAINT (Bruker, 2008 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick 2008 ▶); program(s) used to refine structure: SHELXL2013 (Sheldrick 2008 ▶); molecular graphics: OLEX2 (Dolomanov et al., 2009 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶) and OLEX2.

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536814003080/ff2125sup1.cif

e-70-0o315-sup1.cif^{(42.6KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536814003080/ff2125Isup2.hkl

e-70-0o315-Isup2.hkl^{(426.6KB, hkl)}

Click here for additional data file.^{(6.9KB, cml)}

Supporting information file. DOI: 10.1107/S1600536814003080/ff2125Isup3.cml

CCDC reference: 986226

Additional supporting information: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C2—H2⋯O1′	0.95	2.55	3.4902 (15)	171
C7—H7⋯N1′ⁱ	0.95	2.47	3.3294 (15)	151
C1′—H1′⋯O2′ⁱⁱ	0.95	2.57	3.4866 (12)	161
C2′—H2′⋯N1ⁱⁱⁱ	0.95	2.47	3.3041 (18)	146
C6′—H6′⋯O3′^iv	0.95	2.49	3.3224 (15)	146
C7′—H7′⋯O1^v	0.95	2.50	3.4275 (17)	167

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) ; (v) .

Acknowledgments

The Bruker single-crystal X-ray diffractometry facility at Ithaca College was established in 2012. The authors thank Dr Janet Hunting for helpful guidance and detailed discussions on the crystallography. NRN, HDB, AKK and NSD thank the National Institutes of Health for grants NINDS P20RR015583 Center for Structural and Functional Neuroscience (CSFN) and P20 RR017670 Center for Environmental Health Sciences (CEHS), and the Skaggs Family Foundation for generous support.

supplementary crystallographic information

1. 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, C₂₁H₁₆NO₄Cl, 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.

2. Experimental

To a suspension of anthracene-9-carbaldehyde (4.0 g, 19.39 mmol; Sigma-Aldrich, 97%) in THF: Ethanol: H₂O (54 mL: 27 mL: 27 mL) was dissolved sodium acetate (3.5 eq., 5.57 g, 67.89 mmol) and hydroxylamine hydrochloride (2 eq, 2.69 g, 38.71 mmol). The reaction was covered with a septa and let stir at room temperature until TLC showed no starting material remained (ca. 49 hours). The solution was then transferred to a separatory funnel and washed 4 x 200 mL Brine and the combined aqueous layers washed 2 x 50 mL CHCl₃, dried over sodium sulfate, filtered, and the solvent removed under vacuum to yield anthracene-9-carbaldehyde oxime (99%).¹H NMR(CDCl₃) δ 9.22 (s, 1H), 8.51 (s, 1H), 8.42 (d, J=8.66 Hz, 2H), 8.03 (d, J=8.16 Hz, 2H), 7.50-7.59 (m, 4H).

The anthracene-9-carbaldehyde oxime (4.667 g, 21.09 mmol) was taken up in 120 mL of chloroform at room temperature, to which solution was added pyridine (10 mol%, 2.00 mL) and recrystallized NCS (1.1 eq, 3.098 g, 23.20 mmol). The solution brought to 45°C for 3.5 hours then cooled to room temperature. The organic layer was washed with 4 x 200 mL Brine and 2 x 150 mL H₂O, then the aqueous layer washed 2 x 150 mL CHCl₃, dried with sodium sulfate, filtered, and the solvent removed under reduced pressure to yield the nitrile oxide. The intermediate was purified only through extractive isolation using brine and CHCl₃ and taken on to the next reaction as is. To a solution of the nitrile oxide in absolute ethanol (100 mL) was added 1.4 equivalents of ethylacetoacetate (3.8425 g, 29.53 mmol). In a separate round bottom was added 50 mL absolute ethanol and 1.018 g Na(s). Once the sodium dissociation had completed, the warm solution was added to the nitrile oxide and the mixture was allowed to stir at room temperature under argon for 21.5 hours until TLC in 4:1 Hex/EtOAc revealed all nitrile oxide had been consumed. Finally, the ethanol was removed via rotary evaporation and the solid dissolved in CHCl₃, washed 4 x 200 mL Brine, and the aqueous layer washed 2 x 150 mL CHCl₃, dried sodium sulfate, and concentrated under reduced pressure. The solid was then chromatographed using 4:1 Hex/EtOAc. Ethyl 3-(anthracen-9-yl)-5-methylisoxazole-4-carboxylate. Yield 93%.¹H NMR(400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.06 (d, J=7.91, 2H), 7.66 (d, J=8.16 Hz, 2H), 7.41-7.50 (m, 4H), 3.70 (q, J=7.15 Hz, 2H), 2.93 (s, 3H), 0.33 (t, J=7.15 Hz, 3H). Spectral data are in accord with those reported previously. (Mirzaei, et al., 2012)

The carboxylate (0.300 g, 0.905 mmol) was taken up in 10 mL DMF to which was added a solution over 10 minutes of N-Chlorosuccinimide (NCS) (1.2 eq, 0.1461 g, 1.094 mmol) dissolved in 5 mL DMF. The solution was brought to 43°C and let stir for 4 hours whereupon the solution was poured into 50 mL ice/water which was allowed to stir for 1 hour, in which the 10-Cl carboxylate precipitated out, filtered and washed with 2 x 25 mL water. Yield 96%.¹H NMR(400 MHz, CDCl₃) δ 8.59 (d, J=8.91 Hz, 2H), 7.59-7.66 (m, 4H), 7.46-7.50 (m, 2H), 3.72 (q, J=7.15 Hz, 2H), 2.93 (s, 3H), 0.39 (t, J=7.15 Hz, 3H). Spectral data are in accord with those reported previously. (Mirzaei, et al., 2012).

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 CH₂Cl₂ 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 (3:1) solution. Yield 29%, ¹H NMR(CDCl₃) δ 8.38 (dd, J=1.38, 7.65 Hz, 2H), 7.51-7.61 (m, 4H), 7.34 (dd, J=1.13, 7.91 Hz, 2H), 3.56 (q, J=7.15 Hz, 2H), 2.70 (s, 3H), 0.65 (t, J=7.03 Hz, 3H); ¹³C NMR(CDCl₃) δ 182.58, 178.50,162.69, 159.76, 142.41, 133.92, 129.85, 129.13, 127.84, 127.58, 107.92, 62.51, 60.43, 13.78, 13.47. MS (EI) m/z 346(100, M-Cl), 347(28.33, M-Cl)⁺, 348(8.42, M-Cl)⁺².