1-[2-(4-Nitro­phen­yl)-5-(5-phenyl-1,2-oxazol-3-yl)-1,2,3,4-tetra­hydro­quinolin-4-yl]pyrrolidin-2-one monohydrate

Margarita Gutierrez; Gabriel Vallejos; Carlos Fernández; Alejandro Cárdenas; Iván Brito

doi:10.1107/S1600536810052463

. 2010 Dec 18;67(Pt 1):o175–o176. doi: 10.1107/S1600536810052463

1-[2-(4-Nitrophenyl)-5-(5-phenyl-1,2-oxazol-3-yl)-1,2,3,4-tetrahydroquinolin-4-yl]pyrrolidin-2-one monohydrate

Margarita Gutierrez ^a, Gabriel Vallejos ^b, Carlos Fernández ^a, Alejandro Cárdenas ^c, Iván Brito ^d,^*

PMCID: PMC3050245 PMID: 21522681

Abstract

The title compound, C₂₈H₂₄N₄O₄·H₂O, crystallizes with two organic molecules and two solvent water molecules in the asymmetric unit. The most obvious difference between the molecules is the torsion angles between the isoxazole ring and the benzene and phenyl rings [47.0 (2)/56.4 (2) and 33.3 (2)/11.0 (2)°, respectively]. Another important difference is observed in the rotation of the nitro group with respect to the phenyl groups [3.5 (6) and 31.1 (6)°]. The pyrrolidinone fragment is cis oriented with respect to the 4-nitrophenyl fragment. In the crystal, molecules are linked into centrosymmetric R ₄ ²(8) and R ₄ ⁴(20) motifs by O—H⋯O and N—H⋯O interactions.

Related literature

For pharmacological activity of quinoline, see: Shi et al. (2008 ▶); Lunniss et al. (2009 ▶); He et al. (2005 ▶); Eswaran et al. (2010 ▶). For the synthesis and medicinal uses of quinolines, see: Kalita et al. (2006 ▶); Kouznetsov et al. (2005 ▶); Sankaran et al. (2010 ▶). For reactions of isoxazoles see: Taldone et al. (2008 ▶); Narlawar et al. (2008 ▶); Velaparthi et al. (2008 ▶); Rizzi et al. (2008 ▶); Lautens & Roy (2000 ▶); Broggini et al. (2005 ▶); Kotera et al. (1970 ▶). For hydrogen-bond motifs, see: Bernstein et al. (1995 ▶).

Experimental

Crystal data

C₂₈H₂₄N₄O₄·H₂O
M _r = 498.53
Triclinic,
a = 13.516 (8) Å
b = 14.193 (6) Å
c = 14.987 (11) Å
α = 70.151 (10)°
β = 79.62 (2)°
γ = 69.700 (9)°
V = 2530 (3) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 293 K
0.39 × 0.17 × 0.12 mm

Data collection

Nonius KappaCCD diffractometer
21159 measured reflections
11596 independent reflections
7891 reflections with I > 2σ(I)
R _int = 0.090

Refinement

R[F ² > 2σ(F ²)] = 0.098
wR(F ²) = 0.240
S = 1.16
11596 reflections
691 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.34 e Å⁻³
Δρ_min = −0.33 e Å⁻³

Data collection: COLLECT (Nonius, 2000 ▶); cell refinement: DENZO-SMN (Otwinowski & Minor, 1997 ▶); data reduction: DENZO-SMN; program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶) and PLATON (Spek, 2009 ▶); software used to prepare material for publication: WinGX (Farrugia, 1999 ▶).

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810052463/om2389sup1.cif

e-67-0o175-sup1.cif^{(39.7KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810052463/om2389Isup2.hkl

e-67-0o175-Isup2.hkl^{(555.5KB, 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
O1W—H1WA⋯O4ⁱ	0.83 (7)	2.07 (7)	2.904 (5)	173 (6)
O1W—H1WB⋯O4ⁱⁱ	1.03 (8)	1.87 (8)	2.877 (5)	167 (6)
O2W—H2WB⋯O7	0.97 (8)	1.80 (9)	2.754 (5)	165 (8)
N6—H6N⋯O2Wⁱⁱⁱ	0.83 (4)	2.13 (4)	2.958 (5)	179 (5)
O2W—H2WA⋯O1W	0.80 (6)	2.09 (6)	2.883 (6)	175 (6)

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

Acknowledgments

LAS thanks FONDECYT (project No. 1100481) and PBCT ADI-38. We thank the Spanish Research Council (CSIC) for providing us with a free-of-charge licence for the CSD system.

supplementary crystallographic information

Comment

Nitrogen containing heterocycles are indispensable structural units for medicinal chemists (Sankaran et al., 2010). Compounds possessing the quinoline system have wide applications as drugs and pharmaceuticals and also occur as structural frameworks in natural products (Kalita et al., 2006). They also have several pharmacological activities such as anti-breast cancer (Shi et al., 2008), selective PDE4 inhibition (Lunniss et al., 2009), immuno modulatory (He et al., 2005), antimycobacterial agents (Eswaran et al., 2010), among others.

Quinoline and derivatives represent the major class of heterocycles, and a number of preparations have been known since the late 1800's. The quinoline skeleton is often used for the design of many synthetic compounds with diverse pharmacological properties. Several syntheses of quinolines are known, but due to their importance, the development of new synthetic approaches remains an active research area (Kouznetsov et al., 2005).

The isoxazoles form a relevant group of biologically active compounds with a wide range of applications, including Hsp90 super chaperone complex inhibitors (Taldone et al., 2008), tau aggregation inhibitors for treatment of Alzheimer's disease (Narlawar et al., 2008), Mycobacterium tuberculosis pantothenate synthetase inhibitors (Velaparthi et al., 2008) and neuronal nicotinic acetylcholine receptor agonist effect (Rizzi et al., 2008).

A considerable number of methods to synthesize substituted isoxazoles have been published including approaches based on intramolecular cycloadditions, condensations, and intramolecular cyclizations of amino acids. These methods sometimes suffer in their versatility, convenience and yield (Lautens & Roy, 2000). The isoxazole ring can be synthesized by 1,3-dipolar cycloaddition reactions between nitrile oxide and alkyne, and that reaction may be catalyzed by copper(II). Cycloaddition reactions are among the most useful reactions in synthetic and mechanistic organic chemistry (Broggini et al., 2005).

Isoxazoles have a rich chemistry because of their easy reductive cleavage and susceptibility to ring transformations (Kotera et al., 1970). Depending on the substitution patterns, isoxazoles can be used as reagents for the imino-Diels-Alder condensation between anilines, aldehydes and electron-rich alkenes to generate tetrahydroquinolines with different selected substitution patterns. Due to this fact, the combination of the two heterocycles rings into a new chemical entityis of interest as no examples are known on chemical literature to date. Many molecules widely used today consist of fusions of rings; an example is the case of penicillins, where in the isoxazole ring incorporation allowed obtaining stable derivatives catalyzed degradation by gastric acid level (flucloxacillin and cloxacillin).

We report here the crystal structure of a novel synthetic derivative cis quinoline-isoxazole by imino Diels-Alder cycloaddition, Fig. 2. The title compound, C₂₈H₂₄N₄O₄.H₂O, crystallizes with two organic molecules and two solvent water molecule in the asymmetric unit., Fig. 1. The most obvious difference between the molecules is the torsion angles between the isoxazole ring and the benzene and phenyl rings [47.0 (2); 56.4 (2) and 33.3 (2); 11.0 (2)°] respectively. Anther important difference is observed in the rotation of the nitro group with respect to the phenyl group [3.5 (6)°; 31.1 (6)°]. The pyrrolidinone fragment is cis oriented with respect to the 4-nitrophenyl fragment. In the crystal the molecules are linked into centrosymmetric R²₄(8) and R⁴₄(20) motifs by O—H···O and N—H···O interactions, (Bernstein et al., 1995). There are six intramolecular hydrogen bonds which stabilized the molecular conformation in both molecules, Table 1.

Experimental

A mixture of 3-(3-aminophenyl)-5-phenylisoxazole (2.8 mmol) 3 and 4-nitrobenzaldehyde (3.4 mmol) 1 in anhydrous CH₃CN (15 ml) was stirred at room temperature for 30 min. BiCl₃ (20 mol%) was added. Over a period of 20 min, a solution the N-vinyl-2-pyrrolidone (NVP) (5.5 mmol) 4 in CH₃CN (10 ml) was added dropwise. The resulting mixture was stirred for 10–14 h. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (3× 15 ml). The organic layer was separated and dried (Na₂SO₄), concentrated in vacuum and the resulting product was purified by column chromatography (silica gel) using PE and EtOAc mixtures. Results for derivatives trans and cis quinoline-isoxazole 5 and the title compound, see Figure 2. Solid crystalline mp 215–217 °C. The crystals were obtaned by slow evaporation of a solution of the title compound in a THF:H₂O (1:1v/v) mixture. RMN-¹H(CDCl₃), 400 MHz, δ): 8.14 (2H, d, J = 4.0); 7.77 (1H, d, J= 8.0); 7.59 (2H, d, J = 8.0); 7.42(2H, d, J = 8.0); 7.17 (1H, t, J = 8.0); 6.93 (1H, s); 6.86 (2H, dd, J = 8.0 and 2.0); 6.80 (1H, d, J = 8.0); 6.65 (1H, s); 4.59 (1H, d, J = 12.0 and 1.0); 4.51 (1H, br.s); 4.41 (1H, s); 2.93 (2H, m); 1.98 (2H, m); 1.71 (2H, m), 1.57 (2H, m). RMN-¹³H(CDCl₃), 400 MHz,?d): 174.58, 168.95, 162.92, 149.97,147.26, 146.71, 130.03, 129.61, 128.87, 128.54, 127.13, 127.08, 127.08, 125.82,123.74, 117.35, 116.58, 100.24, 54.76, 46.93, 42.32, 34.92, 30.46, 17.25. MS m/z (EI): 480. Anal. Calcd. for C₂₈H₂₄N₄O₄: C, 69.99;H,5.03; N, 11.66. Found: C, 69.92; H, 5.05; N, 11.79.