(S)-tert-Butyl 3-(3-phenyl-1,2,4-oxa­diazol-5-yl)piperidine-1-carboxyl­ate

Lin Liu; Guangxin Xia; Xuejun Liu; Jieshu Xie; Jingkang Shen

doi:10.1107/S1600536810018714

. 2010 Jun 5;66(Pt 7):o1576. doi: 10.1107/S1600536810018714

(S)-tert-Butyl 3-(3-phenyl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate

Lin Liu ^a, Guangxin Xia ^b, Xuejun Liu ^b, Jieshu Xie ^b, Jingkang Shen ^a,^*

PMCID: PMC3007067 PMID: 21587817

Abstract

The title compound, C₁₈H₂₃N₃O₃, crystallized with two independent molecules (A and B) in the asymmetric unit. The phenyl ring and the 1,2,4-oxadiazole ring are inclined to one another by 19.9 (3)° in molecule A and 7.3 (3)° in molecule B. The absolute structure of the title compound was referred to the transfered chiral center (S) of one of the starting reactants. In the crystal, A molecules are linked by C—H⋯N interactions involving the two oxadiazole N atoms.

Related literature

For the oxadiazole nucleus as a core structural unit of various muscarinic agonists, see: Orlek & Blaney (1991 ▶). For benzodiazepine receptor partial agonists, see: Watjen & Baker (1989 ▶). For dopamine transporters, see: Gray & Abrahm (1993 ▶). For 5-HT agonists, see: Swain & Baker (1991 ▶). For inhibitors of HIV, see: Matthew et al. (2007 ▶). For GABAA receptor agonists, see: Michaela & Holger (2008 ▶). For bond-length data, see: Allen et al. (1987 ▶).

Experimental

Crystal data

C₁₈H₂₃N₃O₃
M _r = 329.39
Monoclinic,
a = 6.464 (3) Å
b = 15.515 (8) Å
c = 17.847 (9) Å
β = 99.880 (7)°
V = 1763.2 (15) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 293 K
0.24 × 0.15 × 0.12 mm

Data collection

Bruker SMART CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2008 ▶) T _min = 0.980, T _max = 0.990
7378 measured reflections
3258 independent reflections
2520 reflections with I > 2σ(I)
R _int = 0.073

Refinement

R[F ² > 2σ(F ²)] = 0.073
wR(F ²) = 0.198
S = 1.01
3258 reflections
440 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.29 e Å⁻³
Δρ_min = −0.44 e Å⁻³

Data collection: SMART (Bruker, 2007 ▶); cell refinement: SAINT (Bruker, 2007 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: SHELXL97 and PLATON.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810018714/su2175sup1.cif

e-66-o1576-sup1.cif^{(31.2KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810018714/su2175Isup2.hkl

e-66-o1576-Isup2.hkl^{(284.2KB, 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
C13—H13A⋯N2ⁱ	0.97	2.61	3.352 (7)	133
C18—H18A⋯N1ⁱ	0.96	2.61	3.490 (9)	153

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Symmetry code: (i) Inline graphic .

supplementary crystallographic information

Comment

The oxadiazole nucleus is a well studied pharmacophoric scaffold that has emerged as a core structural unit of various muscarinic agonists (Orlek & Blaney, 1991), benzodiazepine receptor partial agonists (Watjen & Baker, 1989), dopamine transporters (Gray & Abrahm, 1993), 5-HT agonists (Swain & Baker, 1991), inhibitors of HIV (Matthew, 2007), and GABAA receptor agonists (Michaela & Holger,2008). Among the oxadiazoles, 1,2,4-oxadiazole derivatives have gained importance in medicinal chemistry. The interest in five-membered systems containing one oxygen and two nitrogen atoms (positions 1, 2, and 4) is due to the occurrence of 1,2,4-oxadiazoles in biological activite compounds and natural products. In spite of extensive investigations, there are few studies on the crystal structures of oxadiazol-piperidines. Herein, we report on the crystal structure of the title compound, a new oxadiazol-piperidine. It can be reacted with acid, sulfonlchloride and chloride, followed by deprotection of the protective group, to give many usefull compounds.

The title compound crystallized in the chiral monoclinic space group P2₁, with two independent molecules (A and B) in the asymmetric unit (Fig. 1). It was obtained from a chiral source, hence its absolute structure, (S), was confirmed by the transfered chiral center; atom C9 in molecule A and atom C27 in molecule B (Fig. 1). The bond distances in the two molecules are very similar and close to normal values (Allen et al., 1987). The two molecules differ in the orientation of the phenyl ring with respect to the oxadiazole mean plane. In molecule A this dihedral angle is 19.9 (3)°, while in molecule B it is only 7.3 (3)°. In both molecules the piperidine ring has a chair conformation.

In the crystal symmetry related A molecules are linked via C-H···N interactions (see Table 1 and Fig. 2 for details).

Experimental

A suspension of hydroxylamine hydrochloride (4.09 g), potassium carbonate (2.76 g), benzonitrile (1.03 g) in absolute ethanol (200 mL) was heated at reflux for 10 h. After the reaction was completed, monitored by TLC, the mixture was cooled, filtered to remove inorganic salts, and concentrated under vacuum. The residue was purified by column chromatography, by use of a gradient elution of dichloromethane to 40% acetone in dichloromethane, to give (E)-N-hydroxybenzamidine (1.36g). ¹H NMR (300 MHz, DMSO-d6): 9.59 (s, 1H), 7.62-7.67 (m, 2H), 7.32-7.37 (m, 3H), 5.77 (s, 2H); EI (M+) 136 A mixture of (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (1.15 g) in absolute THF (50 mL), isobutyl carbonochloridate (5ml) and trimethylamine (2ml) were mixted together and stirred for 30min at rt, followed by slow dropwise addition of (E)-N-Hydroxy-benzamidine (1.36g) in THF (15mL). After the reaction was completed, monitored by TLC, the mixture was injected into n-Bu4NF (1 M in THF, 3 mL), warmed to reflux and was stirred for 24 h. After this reaction was completed, monitored by TLC, the mixture was poured into EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography by use of a gradient elution of EtOAc/hexanes. The material was crystallized from EtOH to give the title compound as a white solid. Colourless-rod-like crystals, suitable for X-ray analysis, were obtained by recrystallization from EtOH. ¹H NMR (300MHz, CDCl3): 8.05,-8.08 (m, 2H), 7.43-7.48 (m, 3H), 3.95 (d, 1H, J=8.4 Hz), 3.12-3.17 (m, 1H), 3.98 (t, 1H, J=12.6 Hz), 2.42 (d, 1H, J=12.6 Hz), 1.86 (t, 2H, J=12.6 Hz), 1.55-1.65 (m, 1H), 1.45 (s, 9H), 0.83-0.92 (m, 2H); ESI (M++23) 352.