2-Chloro-1-[4-(2-fluoro­benz­yl)piperazin-1-yl]ethanone

Cunlong Zhang; Xin Zhai; Furen Wan; Ping Gong; Yuyang Jiang

doi:10.1107/S1600536811006180

. 2011 Feb 26;67(Pt 3):o708. doi: 10.1107/S1600536811006180

2-Chloro-1-[4-(2-fluorobenzyl)piperazin-1-yl]ethanone

Cunlong Zhang ^a,^c, Xin Zhai ^a, Furen Wan ^b, Ping Gong ^a, Yuyang Jiang ^c,^d,^*

PMCID: PMC3052134 PMID: 21522451

Abstract

In the title compound, C₁₃H₁₆ClFN₂O, the piperazine ring is flanked by 1-(2-fluorobenzyl)piperazine and adopts a chair conformation. The dihedral angle between the fluorophenyl ring and the four planar C atoms (r.m.s. = 0.0055 Å) of the piperazine chair is 78.27 (7)°, whereas the dihedral angle between the four planar C atoms of the piperazine chair and the ethanone plane is 55.21 (9) Å; the Cl atom displaced by1.589 (2) Å out of the plane.

Related literature

For the synthesis of related compounds, see: Contreras et al. (2001 ▶); Capuano et al. (2002 ▶). For their use as intermediates in the synthesis of anti-inflammatory agents or CCR1 antagonists, see: Rolland & Duhault (1989 ▶); Kaufmann (2005 ▶); Tanikawa et al. (1995 ▶); Xie et al. (2007 ▶).

Experimental

Crystal data

C₁₃H₁₆ClFN₂O
M _r = 270.73
Orthorhombic,
a = 7.9350 (5) Å
b = 8.4610 (4) Å
c = 19.0040 (11) Å
V = 1275.89 (12) Å³
Z = 4
Mo Kα radiation
μ = 0.30 mm⁻¹
T = 291 K
0.30 × 0.30 × 0.20 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2001 ▶) T _min = 0.566, T _max = 0.716
12886 measured reflections
3001 independent reflections
2550 reflections with I > 2σ(I)
R _int = 0.033

Refinement

R[F ² > 2σ(F ²)] = 0.035
wR(F ²) = 0.085
S = 1.01
3001 reflections
165 parameters
H-atom parameters constrained
Δρ_max = 0.33 e Å⁻³
Δρ_min = −0.18 e Å⁻³
Absolute structure: Flack (1983 ▶), 1255 Friedel pairs
Flack parameter: 0.03 (7)

Data collection: APEX2 (Bruker, 2003 ▶); cell refinement: SAINT (Bruker, 2001 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: DIAMOND (Brandenburg, 1999) ▶; software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536811006180/si2316sup1.cif

e-67-0o708-sup1.cif^{(18.2KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536811006180/si2316Isup2.hkl

e-67-0o708-Isup2.hkl^{(115.7KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

The authors would like to thank the Ministry of Science and Technology of China (2007AA02Z160, 2009ZX09501–004) and the Chinese National Natural Science Foundation (20872077, 90813013) for financial support.

supplementary crystallographic information

Comment

Piperazine derivatives similar to the title compound are well known as being useful for a variety of pharmaceutical indication, particularly as cardiotonic, neurotropic or anti-inflammatory agents (Kaufmann, 2005). The synthesis of related pyridazine compounds and their medicinal and pharmaceutical activity were reported (Contreras et al., 2001; Capuano et al., 2002). The use of related compounds as intermediates in the synthesis of antiinflammatory agents or CCRI antagonists can be studied in various patents (Rolland & Duhault, 1989; Kaufmann, 2005; Tanikawa et al., 1995) and medicinal journal (Xie et al., 2007). Moreover, we recently identified a series of compounds bearing various substituted benzylpiperazine moiety with potent antitumor activity by virtual screening approach (paper was being revised).

Herein, we report the synthesis of the title compound as one important representative of piperazine derivatives and its X-ray crystal structure. The molecule of (I) is shown in Fig. 1. The bond lengths and angles are within normal ranges. The piperazine ring in the molecule adopts a chair conformation. The dihedral angle between the fluorophenyl ring and the four planar C atoms (r.m.s. = 0.0055 Å) of the piperazine chair is 78.27 (7)°. Whereas the dihedral angle between the four planar C atoms of the piperazine chair and the ethanone plane is 55.21 (9)Å with the Cl atom about 1.589 (2) Å out of plane. In the crystal, there are no strong intermolecular hydrogen bonds to link the molecules.

Experimental

All chemicals and solvents were obtained from commercial supplies and used without purification. To a solution of chloroacetic chloride (0.58 ml, 7.15 mmol) in CH₂Cl₂ (10 ml) was added, at 0 °C, 1-(2-fluorobenzyl)piperazine(II) (1.15 g, 5.90 mmol) dissolved in CH₂Cl₂ (20 ml) which was prepared from the reaction of anhydrous piperazine(III) and 1-(chloromethyl)-2-fluorobenzene(IV). The reaction mixture was stirred at room temperature for about 30 min until no 1-(2-fluorobenzyl)piperazine remained, as monitored by TLC. The mixture was poured into cold H₂O (50 ml) and rendered alkaline with a 10% NaHCO₃ aqueous solution and separated. The organic layer, dried over Na₂SO₄, was evaporated under reduced pressure to give 1.44 g of pure title compound as a yellow oil. Yield 90%; ¹H NMR (400 MHz, CDCl₃) δ 7.35 (dd, J = 7.4, 1.4 Hz, 1H), δ 7.23–7.29 (m, 1H), δ 7.12 (t, J = 7.2 Hz, 1H), δ 7.04 (t, J = 9.2 Hz, 1H), δ 4.05 (s, 2H), δ 3.64 (d, J = 5.2 Hz, 2H), δ 3.62 (d, J = 4.4 Hz, 2H), 3.52 (t, J = 5.0 Hz, 2H), δ 2.51 (dt, J = 15.6, 4.8 Hz, 4H); ¹³C NMR (100.6 MHz, CDCl₃) δ 161.16, 131.24, 128.88, 123.88, 123.75, 115.27, 115.05, 54.87, 52.41, 52.00, 46.06, 41.93, 40.67.