tert-Butyl 4-(3,4-dichloro­anilino)piperidine-1-carboxyl­ate

Mehr-un-Nisa; Munawar Ali Munawar; Gabriel B Hall; Sue A Roberts; Victor J Hruby

doi:10.1107/S1600536812051896

. 2013 Jan 9;69(Pt 2):o205. doi: 10.1107/S1600536812051896

tert-Butyl 4-(3,4-dichloroanilino)piperidine-1-carboxylate

Mehr-un-Nisa ^a, Munawar Ali Munawar ^a, Gabriel B Hall ^b, Sue A Roberts ^b,^*, Victor J Hruby ^b

PMCID: PMC3569265 PMID: 23424488

Abstract

In the title compound, C₁₆H₂₂Cl₂N₂O₂, the substituted piperidine ring adopts a chair conformation with both substituents in equatorial positions. In the crystal, N—H⋯O and C—H⋯O hydrogen bonds connect molecules into ribbons along the a-axis direction.

Related literature

For the biological activity of piperazine derivatives, see: Hamed et al. (2012 ▶); Joergen et al. (1997 ▶); Peter et al. (2009 ▶). For the synthesis of the title compound, see: Vardanyan et al. (2009 ▶).

Experimental

Crystal data

C₁₆H₂₂Cl₂N₂O₂
M _r = 345.25
Orthorhombic,
a = 9.7825 (6) Å
b = 10.6075 (6) Å
c = 16.8215 (10) Å
V = 1745.53 (18) Å³
Z = 4
Mo Kα radiation
μ = 0.38 mm⁻¹
T = 100 K
0.40 × 0.40 × 0.30 mm

Data collection

Bruker Kappa APEXII DUO CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2009 ▶) T _min = 0.662, T _max = 0.749
34136 measured reflections
13197 independent reflections
11079 reflections with I > 2σ(I)
R _int = 0.024

Refinement

R[F ² > 2σ(F ²)] = 0.034
wR(F ²) = 0.079
S = 1.00
13197 reflections
202 parameters
H-atom parameters constrained
Δρ_max = 0.44 e Å⁻³
Δρ_min = −0.19 e Å⁻³
Absolute structure: Flack (1983 ▶), 6110 Friedel pairs
Flack parameter: −0.01 (2)

Data collection: APEX2 (Bruker, 2009 ▶); cell refinement: SAINT (Bruker, 2009 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: OLEX2 (Dolomanov et al., 2009 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Click here for additional data file.^{(25.4KB, cif)}

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812051896/zl2529sup1.cif

e-69-0o205-sup1.cif^{(25.4KB, cif)}

Click here for additional data file.^{(645.2KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812051896/zl2529Isup2.hkl

e-69-0o205-Isup2.hkl^{(645.2KB, hkl)}

Click here for additional data file.^{(6.1KB, cml)}

Supplementary material file. DOI: 10.1107/S1600536812051896/zl2529Isup3.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
N1—H1⋯O2ⁱ	0.88	2.12	2.9740 (8)	163
C3—H3⋯O2ⁱ	0.95	2.58	3.3486 (9)	138

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Symmetry code: (i) Inline graphic .

Acknowledgments

We gratefully acknowledge a grant from the Higher Education Commission of Pakistan under the IRSIP programme to support PhD students. The Bruker Kappa APEXII DUO was purchased with funding from NSF grant CHE-0741837. The work was supported in part by grants from the US Public Health Service and National Institutes of Health (DA06284 and DA13449).

supplementary crystallographic information

Comment

Piperazine derivatives have been shown to inhibit re-uptake of the monoamines dopamine, noradrenaline and serotonin in synaptosomes (Joergen et al., 1997), and their use for the treatment of protozoal infections, particularly malaria, has also been reported (Hamed et al., 2012). Selective serotonin reuptake inhibitors (SSRI) provide efficacy in the treatment of numerous CNS disorders, including depression and panic disorders, and are usually observed to be effective, well tolerated and simply administered (Peter et al., 2009)). During our search to find new synthetic novel multivalent ligands for the treatment of pain and depression, the title compound was synthesized as an intermediate. Compounds prepared from this intermediate are now under study for possible opioid and SSRIs activities.

The piperidine ring is in a chair conformation with both substituents in equatorial positions. An intermolecular hydrogen bond is present between N1—H1 and O2 with a donor-hydrogen-acceptor angle of 163.40° and a donor-aceptor distance of 2.9740 (8) Å. Hydrogen bonds connect molecules into ribbons extending in the crystallographic a direction. The hydrogen bonding graph set is C1,1(8)a.

Experimental

tert-Butyl 4-((3,4-dichlorophenyl)amino)piperidine-1-carboxylate (1) was synthesized by modification of a reported method (Vardanyan et al., 2009) by refluxing N-Boc-4-piperidone (5.0 g, 25.1 mmol) and 3,4-dichloroaniline (4.07 g, 25.1 mmol) in toluene (100 ml) with a catalytic amount of p-toluene sulphonic acid using a Dean and Stark apparatus for 4–5 h. The reaction was left to cool overnight. Toluene was evaporated under reduced pressure. The crude product was dissolved in diethyl ether, passed through a bed of neutral alumina, and the ether evaporated under reduced pressure. The residue was dissolved in CH₃OH (50 ml) and NaBH₄ (1.05 g, 27.6 mmol) was added slowly at room temperature. The reaction mixture was left to stir overnight. The reaction was quenched with aqueous NaHCO₃ (5 ml). The solvent was removed under reduced pressure and the residue was dissolved in diethyl ether, dried over anhydrous MgSO₄, filtered and evaporated under reduced pressure. The residue was recrystallized from CH₃OH to obtain (1) as a white crystalline solid. Crystals appropriate for X-ray diffraction were grown from methanol by slow evaporation at room temperature. 8.22 g (95%) yield; m.p. 155–157 °C; MS (ESI): m/z: [M+H]⁺: 345; HRMS: Calcd for C₁₆H₂₃Cl₂N₂O₂: 345.113; found: 345.1131.