Ethyl 4-{1-[(2,4-dinitro­phen­yl)hydrazono]eth­yl}-5-(2-naphthyl­methoxy­meth­yl)isoxazole-3-carboxyl­ate

Nicholas R Natale; Monica I Szabon-Watola; Brendan Twamley; Richard J Bridges; Sarjubhai Patel; Trideep Rajale

doi:10.1107/S1600536808041901

. 2008 Dec 17;65(Pt 1):o144–o145. doi: 10.1107/S1600536808041901

Ethyl 4-{1-[(2,4-dinitrophenyl)hydrazono]ethyl}-5-(2-naphthylmethoxymethyl)isoxazole-3-carboxylate

Nicholas R Natale ^a,^*, Monica I Szabon-Watola ^b, Brendan Twamley ^b, Richard J Bridges ^a, Sarjubhai Patel ^a, Trideep Rajale ^a,^‡

PMCID: PMC2968060 PMID: 21581603

Abstract

The title compound, C₂₆H₂₃N₅O₈, was prepared and its structure investigated to further develop a working hypothesis for the essential binding pharmacophore for ligands of the System Xc- transporter [Patel et al. (2004 ▶). Neuropharmacology, 46, 273–284]. The hydrazone group displays an E geometry and the isoxazole double bond and C=N group of the hydrazone are in an s-cis relationship. The secondary amino NH group forms an intramolecular N—H⋯O hydrogen bond to a ring nitro group. There is a dihedral angle of 44.27 (5)° between the isoxazole plane and the hydrazone group plane.

Related literature

For a related structure, see: Burkhart et al. (1999 ▶, 2001 ▶). For general background, see: Davis et al. (1993 ▶); Honore & Lauridsen (1980 ▶); Krogsgaard-Larsen, Honore, Hansen, Curtis & Lodge (1980 ▶); Natale et al. (2006 ▶); Patel et al. (2004 ▶, 2006 ▶); Stables & Kupferberg (2008 ▶); Twamley et al. (2007 ▶); Zhou & Natale (1998 ▶).

Experimental

Crystal data

C₂₆H₂₃N₅O₈
M _r = 533.49
Triclinic,
a = 7.0839 (6) Å
b = 12.176 (1) Å
c = 14.184 (2) Å
α = 90.581 (1)°
β = 95.925 (2)°
γ = 99.251 (2)°
V = 1200.7 (2) Å³
Z = 2
Mo Kα radiation
μ = 0.11 mm⁻¹
T = 90 (2) K
0.47 × 0.33 × 0.30 mm

Data collection

Bruker SMART APEX diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2007 ▶) T _min = 0.949, T _max = 0.971
18560 measured reflections
4357 independent reflections
4009 reflections with I > 2σ(I)
R _int = 0.023

Refinement

R[F ² > 2σ(F ²)] = 0.035
wR(F ²) = 0.092
S = 1.02
4357 reflections
354 parameters
H-atom parameters constrained
Δρ_max = 0.28 e Å⁻³
Δρ_min = −0.23 e Å⁻³

Data collection: SMART (Bruker, 2007 ▶); cell refinement: SAINT-Plus (Bruker, 2007 ▶); data reduction: SAINT-Plus; program(s) used to solve structure: XS in SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: XL in SHELXTL; molecular graphics: XP in SHELXTL; software used to prepare material for publication: publCIF (Westrip, 2009 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808041901/hg2449sup1.cif

e-65-0o144-sup1.cif^{(22.1KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808041901/hg2449Isup2.hkl

e-65-0o144-Isup2.hkl^{(213.5KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N28—H28A⋯O37	0.88	1.96	2.6028 (14)	128

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Acknowledgments

The authors thank NIH for grants NS038444(NN), NINDS NS30570 (RJB), P20RR015583 (RJB, SP, NN), and the Malcolm and Carol Renfrew Scholarship (MIS, TR). The Bruker SMART APEX diffraction facility was established at the University of Idaho with the assistance of the NSF–EPSCoR program and the M. J. Murdock Charitable Trust, Vancouver, WA, USA.

supplementary crystallographic information

Comment

In the course of our continuing studies on the synthesis and structure activity relationships of analogs of AMPA (II) (see Figure 2; Krogsgaard-Larsen et al., 1980; Honore, & Lauridsen, 1980) for glutamate receptors and transporters (Natale et al., 2006), we have found that a simple isoxazole hydrazone (IIIb) (Burkhart et al., 1999) exhibited significant binding at the System Xc- transporter (SXc-) (Patel et al., 2004), and that this correlated with anticonvulsant activity in vivo (Stables & Kupferberg, 2008). Since the three dimensional structure of the SXc- is unsolved at this writing we have developed a preliminary pharmacophore model for ligand binding which indicates that lipophilic groups appear to be tolerated (Patel et al., 2006), which is also promising from the perspective of increasing the likelihood of delivering such ligands past the blood brain barrier. Therefore we carried out the synthesis of (Ia) and also examined its structure, see Figure 1. We had previously examined the structure of (IIIa), (see Figure 2) and found it adopted an s-trans-E geometry at the juncture between the isoxazole and the hydrazone double bond, respectively (Burkhart et al., 1999). The naphthyloxy analog (Ia) adopts a similar E-geometry at the C=N double bond, but an s-cis conformation at the C-4 bond between the isoxazole and the hydrazone. The observation that (Ib) exhibits no significant glutamate inhibition at SystemXc- represents a negative control in the Structure Activity Relationship. This raises interesting questions as to the relationship between conformation and geometry vis-a-vis biological effect, and this will be the subject of forthcoming manuscripts.

Experimental

The title compound (Ia) was prepared from ethyl 5-methyl-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)isoxazole-3-carboxylate (Zhou & Natale, 1998) via lateral metalation (Burkhart et al., 2001), and electrophilic quenching using the Davis oxaziridine (Davis et al., 1993), to the corresponding 5-methyl alcohol. This alcohol can also be prepared by bromination followed by nucleophilic substitution by water (Twamley et al., 2007). The title compound was obtained from the 5-methyl alcohol by Williamson ether synthesis, deprotection and hydrazone formation (Burkhart et al., 1999).

4-{1-[(2,4-Dinitro-phenyl)-hydrazono]-ethyl}-5-(naphthalen-2-ylmethoxymethyl)-\ isoxazole-3-carboxylic acid ethyl ester (Ia)

To a stirred solution of ethyl 5-(naphthalen-2-yl-methoxymethyl)-4-acetyl-isoxazole-3-carboxylate (0.650 g, 1.93 mmol), in 10 ml of THF, a solution of 12 ml (1.0 eq.) of reagent 2,4-DNP was added and the reaction mixture was monitored by TLC (ether/hexane as a mobile phase). During reaction the reddish precipitate formed which was separated and purified by column chromatography. The fast moving, major isomer was examined by crystallography. Yield 57% The major isomer, yellow crystals, m.p.= 105–107 °C, ¹H NMR (deuteriochloroform): δ 1.45 (t, 3H, J=7.1 Hz), 2.34 (s, 3H), 4.48 (q, 2H, J=7.1 Hz), 4.77 (s, 2H), 4.83 (s, 2H), 7.42 (m, 3H), 7.56 (d, 1H, J=9.5 Hz), 7.80 (m, 4H), 8.03 (dd, 1H, J=2.4, 9.5 Hz), 9.00 (d, 1H, J=2.6 Hz), 9.99 (brs, 1H, NH). ¹³C NMR (500 MHz) δ 14.1, 17.3, 60.6, 62.7, 73.1, 116.0, 118.3, 123.2, 125.4, 126.3, 126.4, 127.0, 127.5, 127.6, 128.4, 129.8, 132.9, 133.0, 134.1, 138.6, 143.8, 144.2, 154.1, 159.8, 168.8. The minor isomer, ¹H NMR (deuteriochloroform):δ 1.40 (t, 3H, J=7.1 Hz), 2.43 (s, 3H), 4.46 (q, 2H, J=7.1 Hz), 4.80 (s, 2H), 4.93 (s, 2H), 7.22 (d, 1H, J=9.5 Hz), 7.42 (m, 3H), 7.80 (m, 4H), 8.03 (dd, 1H, J=2.4, 9.5 Hz), 8.65 (d, 1H, J=2.6 Hz), 10.75 (brs, 1H, NH).