rac-Methyl 4-azido-3-hydr­oxy-3-(2-nitro­phen­yl)butanoate

Olivier Vallat; Ana-Maria Buciumas; Reinhard Neier; Helen Stoeckli-Evans

doi:10.1107/S1600536808043857

. 2009 Jan 28;65(Pt 2):o396–o397. doi: 10.1107/S1600536808043857

rac-Methyl 4-azido-3-hydroxy-3-(2-nitrophenyl)butanoate

Olivier Vallat ^a, Ana-Maria Buciumas ^a, Reinhard Neier ^a,^*, Helen Stoeckli-Evans ^b

PMCID: PMC2968186 PMID: 21581990

Abstract

In the title compound, C₁₁H₁₂N₄O₅, the mean plane through the nitro substituent on the benzene ring is inclined to the benzene mean plane by 85.8 (2)°, which avoids steric interactions with the ortho substituents. The hydroxy group is involved in bifurcated hydrogen bonds. The first is an intramolecular O—H⋯O hydrogen bond, involving the ester carbonyl O atom, which gives rise to the formation of a boat-like hydrogen-bonded chelate ring. The second is an intermolecular O—H⋯N hydrogen bond involving the first N atom of the azide group of a symmetry-related molecule. In the crystal structure this leads to the formation of a polmer chain extending in the c-axis direction.

Related literature

For literature related to the antitumor properties of rhazinilam, see: Bonneau et al. (2007 ▶). For literature related to the synthesis and structure–activity relationships of rhazinilam analogues, see: Decor et al. (2006 ▶); Baudoin et al. (2002 ▶); Ghosez et al. (2001 ▶); Rubio & Bornmann (2001 ▶); Dupont et al. (2000 ▶, 1999 ▶); Alazard et al. (1996 ▶). For details of the Mukaiyama reaction, see: Mukaiyama et al. (1974 ▶). For literature related to the synthesis of pyrrolinone precursors, see: Vallat (2004 ▶); Vallat et al. (2009 ▶).

Experimental

Crystal data

C₁₁H₁₂N₄O₅
M _r = 280.25
Monoclinic,
a = 9.4772 (11) Å
b = 14.0710 (12) Å
c = 10.1861 (12) Å
β = 110.496 (13)°
V = 1272.4 (2) Å³
Z = 4
Mo Kα radiation
μ = 0.12 mm⁻¹
T = 153 (2) K
0.40 × 0.30 × 0.30 mm

Data collection

Stoe IPDS diffractometer
Absorption correction: none
8743 measured reflections
2451 independent reflections
1587 reflections with I > 2σ(I)
R _int = 0.074

Refinement

R[F ² > 2σ(F ²)] = 0.036
wR(F ²) = 0.088
S = 0.87
2451 reflections
230 parameters
All H-atom parameters refined
Δρ_max = 0.23 e Å⁻³
Δρ_min = −0.21 e Å⁻³

Data collection: EXPOSE in IPDS Software (Stoe & Cie, 2000 ▶); cell refinement: CELL in IPDS Software; data reduction: INTEGRATE in IPDS Software; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 1997 ▶) and Mercury (Macrae et al., 2006 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536808043857/lh2749sup1.cif

e-65-0o396-sup1.cif^{(18.1KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808043857/lh2749Isup2.hkl

e-65-0o396-Isup2.hkl^{(120.5KB, 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
O3—H3O⋯O4	0.825 (19)	2.30 (2)	2.9439 (16)	135.5 (18)
O3—H3O⋯N2ⁱ	0.825 (19)	2.27 (2)	2.9193 (18)	135.6 (18)
C10—H10B⋯O4ⁱⁱ	0.95 (2)	2.557 (19)	3.350 (2)	141.0 (15)
C11—H11B⋯O1ⁱⁱⁱ	0.95 (3)	2.57 (2)	3.268 (3)	130.9 (16)

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

Acknowledgments

This work was partially financed by the Swiss National Science Foundation.

supplementary crystallographic information

Comment

Rhazinilam, a natural product, has been shown to possess antitumoral properties. It induces in vitro spiralization of microtubules [vinblastin effect] and inhibits the disassembly of these microtubules [paclitaxel effect](Bonneau et al., 2007). It has shown significant in vitro cytotoxicity towards various cancer cells, but it is not active in vivo. Several groups have been interested in synthesizing and studying the structure-activity relationship of rhazinilam analogues (Decor et al., 2006; Baudoin et al., 2002; Ghosez et al., 2001; Rubia & Bornmann, 2001; Dupont et al., 2000; Dupont et al., 1999; Alazard et al., 1996).

In the synthesis of Rhazinilam analogues developed in our group the Mukaiyama reaction, a versatile synthetic tool in organic chemistry, is a key step reaction (Mukaiyama et al., 1974). In one of our retrosynthetic approaches (1-methoxyvinyloxy)trimethysilane was used as a nucleophile, 2-azido-1-(2-nitrophenyl)ethanone as an electrophile and TiCl₄ as a Lewis acid, to synthesize the title hydroxyester, in high yield. This hydroxyester is a suitable precursor for the formation of the pyrrolinone required for the next step in the synthesis of Rhazinilam analogues (Vallat, 2004; Vallat et al., 2009).

The molecular structure of the title compound is illustrated in Fig. 1. The bond distances and angles are normal. The mean plane through the nitro group is inclined to the benzene mean plane by 85.8 (2)°, so avoiding steric interactions with the ortho substituents. The hydroxyl group (O3) is involved in bifurcated hydrogen bonds (Table 1). The first is an intramolecular O—H···O hydrogen bond, involving the ester carbonyl O-atom (O4), and gives rise to the formation of a boat-like hydrogen bonded chelate ring. The second is an intermolecular O—H···N hydrogen bond involving the first N-atom (N2) of the azide group (Table 1). This leads to the formation of a polymer chain extending in the c direction. (Fig. 2). There are also two weak intermolecular C—H···O interactions involving atoms O1 and O4 and the hydrogen atoms of the butanoate moiety (Table 1).

Experimental

Under an atmosphere of Ar, (1-methoxyvinyloxy)trimethylsilane (1.06 g, 7.3 mmol) was dissolved in dry CH₂Cl₂ (15 ml) and the temperature lowered to 243K. 2-Azido-1- (2-nitrophenyl)ethanone (0.5 g, 2.4 mmol) dissolved in dry CH₂Cl₂ (6 ml) was added to the reaction mixture dropwise. A solution of TiCl₄ (0.13 ml, 1.2 mmol), freshly distilled over polyvinylpyridine, in dry CH₂Cl₂ (4 ml), was added slowly. The solution became immediately red and then dark red. The reaction mixture was stirred at 243K for 15 min and then at 258K for 30 min. The cold mixture was then poured into an aqueous solution of 2 N NaOH (2.4 ml) and extracted with chloroform. The combined organic layers were washed with brine, dried over MgSO₄ and concentrated under vacuum. Purification of the residue by flash chromatography (silica gel, CH₂Cl₂) followed by crystallization (ether/hexane) gave a white solid (Yield 76%). Colourless plate-like crystals, suitable for X-ray analysis, were obtained by slow evaporation of a solution in ether/hexane (v:v = 1:1)