3-Hy­droxy-1-(4-meth­oxy­benz­yl)piperidin-2-one

Daniel P Pienaar; Sanaz Khorasani; Charles B de Koning; Joseph P Michael

doi:10.1107/S1600536812049501

. 2012 Dec 8;69(Pt 1):o51. doi: 10.1107/S1600536812049501

3-Hydroxy-1-(4-methoxybenzyl)piperidin-2-one

Daniel P Pienaar ^a, Sanaz Khorasani ^a, Charles B de Koning ^a, Joseph P Michael ^a,^*

PMCID: PMC3588348 PMID: 23476435

Abstract

The title compound, C₁₃H₁₇NO₃, adopts a conformation in which the aromatic ring and the mean plane of the piperidine ring are almost perpendicular to each other [dihedral angle = 79.25 (6)°]. The presence of the carbonyl group alters the conformation of the piperidine ring from a chair to a twisted half-chair conformation. In the crystal, pairs of strong O—H⋯O hydrogen bonds link the molecules into inversion dimers. Weak C—H⋯O interactions extend the hydrogen-bonding network into three dimensions.

Related literature

For the use of related lactams in the synthesis of febrifugine analogues, see: Michael et al. (2006 ▶). For information on the biological activity of febrifugine, a quinazoline alkaloid with potent antimalarial activity, see: Murata et al. (1998 ▶). For the use of chiral oxaziridines in asymmetric hydroxylation, see: Davis et al. (1990 ▶). For the conformation of six-membered rings, see: Boeyens (1978 ▶).

Experimental

Crystal data

C₁₃H₁₇NO₃
M _r = 235.28
Monoclinic,
a = 12.980 (3) Å
b = 7.6143 (17) Å
c = 12.189 (3) Å
β = 90.497 (5)°
V = 1204.6 (5) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 173 K
0.32 × 0.26 × 0.18 mm

Data collection

Bruker APEXII CCD diffractometer
8378 measured reflections
2895 independent reflections
2271 reflections with I > 2σ(I)
R _int = 0.027

Refinement

R[F ² > 2σ(F ²)] = 0.042
wR(F ²) = 0.124
S = 1.08
2895 reflections
158 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.52 e Å⁻³
Δρ_min = −0.22 e Å⁻³

Data collection: APEX2 (Bruker, 2005 ▶); cell refinement: SAINT-NT (Bruker, 2005 ▶); data reduction: SAINT-NT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012 ▶) and SCHAKAL99 (Keller, 1999 ▶); software used to prepare material for publication: WinGX (Farrugia, 2012 ▶) and PLATON (Spek, 2009 ▶).

Supplementary Material

Click here for additional data file.^{(21.1KB, cif)}

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812049501/bh2468sup1.cif

e-69-00o51-sup1.cif^{(21.1KB, cif)}

Click here for additional data file.^{(139.2KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812049501/bh2468Isup2.hkl

e-69-00o51-Isup2.hkl^{(139.2KB, 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
O2—H2⋯O1ⁱ	0.96 (2)	1.84 (2)	2.7708 (16)	161.6 (19)
C6—H6B⋯O1ⁱⁱ	0.99	2.43	3.3142 (17)	148
C14—H14B⋯O2ⁱⁱⁱ	0.98	2.52	3.449 (2)	158

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

Acknowledgments

This work was supported by the University of the Witwatersrand and the National Research Foundation, Pretoria (grant No. 78837).

supplementary crystallographic information

Comment

The title piperidinone was prepared as an early intermediate for the total synthesis of febrifugine, a quinazoline alkaloid with potent antimalarial activity (Murata et al., 1998). Ongoing investigations in our laboratories have made use of similar lactams for the synthesis of febrifugine analogues (Michael et al., 2006). It should be noted that, although the 3-hydroxy substituent was introduced by attempted asymmetric hydroxylation of the enolate of 1-(4-methoxybenzyl)piperidin-2-one with (+)-camphorsulfonyloxaziridine (Davis et al., 1990), partial racemization occurred; the crystals selected for analysis proved to be racemic.

The title organic compound (Fig. 1) adopts a conformation in which the aromatic ring and the piperidine ring are almost perpendicular to each other. Ring puckering analysis, as implemented in PLATON (Spek, 2009), indicates that the piperidine ring adopts a twisted half-chair conformation owing to the presence of the carbonyl group (Boeyens, 1978). Several hydrogen bonds exist in the structure (Table 1), with the most significant being an O—H···O hydrogen bond. These result in the formation of hydrogen bonded pairs of molecules which are related to each other by a center of inversion (Fig. 1). These molecules interact further through C—H···O interactions (Fig. 2) resulting in an extensive hydrogen bonding network of molecules.

Experimental

To a solution of lithium hexamethyldisilazide, prepared from n-butyllithium (1.6 M in hexane, 1.83 ml, 2.93 mmol) and hexamethyldisilazane (0.63 ml) in THF (10 ml) at -70 °C was added a solution of 1-(4-methoxybenzyl)piperidin-2-one (322 mg, 1.47 mmol) in THF (20 ml). The solution was stirred at this temperature for 1 h, after which a solution of (+)-camphorsulfonyloxaziridine (0.67 g, 2.9 mmol) in THF (20 ml) was added dropwise. Stirring was maintained for a further 16 h at temperatures kept between -70 and -60 °C. The reaction was quenched by addition of saturated aqueous ammonium chloride solution (10 ml) and allowed to warm to ambient temperature. The organic components were extracted with dichloromethane (4 × 15 ml), the combined organic layers were washed with brine (20 ml), dried over MgSO₄, and concentrated in vacuo. Purification by column chromatography on silica gel with hexane-ethyl acetate mixtures (9:1 to 1:1 v/v) yielded the title compound, which was recrystallized from hexane-ethyl acetate to yield the product as irregularly shaped colourless crystals (261 mg, 75%), m.p. 347–349 K.