Benzyl 2-{[2,8-bis­(trifluoro­meth­yl)quinolin-4-yl](hy­droxy)meth­yl}piperidine-1-carboxyl­ate

Marcus V N de Souza; Raoni S B Gonçalves; James L Wardell; Solange M S V Wardell; Edward R T Tiekink

doi:10.1107/S1600536811047738

. 2011 Nov 16;67(Pt 12):o3313–o3314. doi: 10.1107/S1600536811047738

Benzyl 2-{[2,8-bis(trifluoromethyl)quinolin-4-yl](hydroxy)methyl}piperidine-1-carboxylate

Marcus V N de Souza ^a, Raoni S B Gonçalves ^a, James L Wardell ^b,^‡, Solange M S V Wardell ^c, Edward R T Tiekink ^d,^*

PMCID: PMC3238965 PMID: 22199814

Abstract

The title molecule, C₂₅H₂₂F₆N₂O₃, adopts an open conformation whereby the quinoline and carboxylate ester groups are orientated in opposite directions but to the same side of the piperidine ring so that the molecule has an approximate U-shape. The piperidine ring adopts a distorted boat conformation. In the crystal, inversion dimers linked by pairs of O—H⋯O hydrogen bonds generate R ₂ ²(14) loops.

Related literature

For background to the anti-mycobacterial activity of mefloquine, see: Gonçalves et al. (2010 ▶); Mao et al. (2007 ▶); Maguire et al. (2006 ▶). For the synthesis, see: Grellepois et al. (2005 ▶). For related structures, see: Gonçalves et al. (2011a ▶,b ▶); Wardell et al. (2010 ▶, 2011a ▶,b ▶); Pitaluga et al. (2010 ▶). For ring conformations, see: Cremer & Pople (1975 ▶).

Experimental

Crystal data

C₂₅H₂₂F₆N₂O₃
M _r = 512.45
Monoclinic,
a = 12.7793 (5) Å
b = 13.9970 (7) Å
c = 13.2188 (9) Å
β = 109.999 (8)°
V = 2221.9 (2) Å³
Z = 4
Mo Kα radiation
μ = 0.13 mm⁻¹
T = 100 K
0.15 × 0.11 × 0.04 mm

Data collection

Rigaku Saturn724+ diffractometer
Absorption correction: multi-scan (CrystalClear-SM Expert; Rigaku, 2011 ▶) T _min = 0.757, T _max = 1.000
10271 measured reflections
5060 independent reflections
4132 reflections with I > 2σ(I)
R _int = 0.026

Refinement

R[F ² > 2σ(F ²)] = 0.039
wR(F ²) = 0.107
S = 1.00
5060 reflections
328 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.34 e Å⁻³
Δρ_min = −0.32 e Å⁻³

Data collection: CrystalClear-SM Expert (Rigaku, 2011 ▶); cell refinement: CrystalClear-SM Expert; data reduction: CrystalClear-SM Expert; 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 DIAMOND (Brandenburg, 2006 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536811047738/hb6498sup1.cif

e-67-o3313-sup1.cif^{(24.4KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811047738/hb6498Isup2.hkl

e-67-o3313-Isup2.hkl^{(242.8KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811047738/hb6498Isup3.cml

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
O1—H1o⋯O3ⁱ	0.84 (1)	1.90 (1)	2.7294 (14)	172 (2)

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Symmetry code: (i) Inline graphic .

Acknowledgments

The use of the EPSRC X-ray crystallographic service at the University of Southampton, England and the valuable assistance of the staff there is gratefully acknowledged. JLW acknowledges support from CAPES and FAPEMIG (Brazil).

supplementary crystallographic information

Comment

For some decades, in combination with other drugs, mefloquine has been used in the prevention and treatment of malaria (Maguire et al., 2006). The activity of mefloquine has been investigated against other diseases more recently, for example, as anti-viral and anti-tubercular agents (Mao et al., 2007). In continuation of on-going structural and biological studies on mefloquine derivatives (Gonçalves et al., 2010, 2011a, 2011b; Wardell, et al., 2010; 2011a; 2011b; Pitaluga et al., 2010), we now report the crystal and molecular structure of the title compound, (I).

In the molecule of (I), Fig. 1, the hydroxyl group lies to one side of the plane through the quinolinyl residue and the substituted piperidine ring to other with the carboxylate ester directed away from the rest of the molecule. The residues lie to the same side of the piperidine ring so that the molecule has a U-shape. The piperidine ring has a distorted boat conformation with ring puckering parameters: q₂ = 0.7644 (16) Å; q₃ = -0.0283 (16) Å; QT = 0.7649 (16) Å; and θ = 92.12 (12) ° (Cremer & Pople, 1975). Mefloquine used as a reagent was a racemate. The sum of the angles at the trisubstituted N2 is 356° indicating a very near planar geometry, and hence an achiral centre. The configurations of the C12 and C13 in the illustrated molecule, Fig. 1, are R, S and R, respectively. The crystal structure contains an equal amount of the opposite enantiomer.

The most prominent intermolecular interactions in the crystal structure are O—H···O hydrogen bonds that lead to the formation of centrosymmetric dimeric aggregates via 14-membered {···HOC₂NCO}₂ synthons, Fig. 1 and Table 1.

Experimental

Benzyl 2-[[2,8-bis(trifluoromethyl)-4-quinolinyl](hydroxy)methyl]tetrahydro-1(2H)-pyridine carboxylate was prepared similarly to tert-butyl 2-[[2,8-bis(trifluoromethyl)-4-quinolinyl](hydroxy)methyl]tetrahydro-1(2H)-pyridine carboxylate, following a published procedure (Grellepois et al., 2005), from benzyl chloroformate and mefloquine in the presence of Et₃N. Colourless plates of (I) were grown from an EtOH solution; M.pt. 445–447 K. MS 535.3 [M + Na].