3-(4-Chlorobenzoyl)-4-(4-chlorophenyl)-1-phenethylpiperidin-4-ol

In the title compound, C26H25Cl2NO2, the piperidine ring adopts a chair conformation with a cis configuration of the carbonyl and hydroxy substituents. The dihedral angle between the aromatic rings of the chlorobenzene groups is 24.3 (2)°. The phenyl ring forms dihedral angles of 59.4 (3) and 44.1 (3)° with the benzene rings. In the crystal, molecules are linked by intermolecular O—H⋯N and C—H⋯O hydrogen bonds and C—H⋯π interactions into layers parallel to the bc plane.

In the title compound, C 26 H 25 Cl 2 NO 2 , the piperidine ring adopts a chair conformation with a cis configuration of the carbonyl and hydroxy substituents. The dihedral angle between the aromatic rings of the chlorobenzene groups is 24.3 (2) . The phenyl ring forms dihedral angles of 59.4 (3) and 44.1 (3) with the benzene rings. In the crystal, molecules are linked by intermolecular O-HÁ Á ÁN and C-HÁ Á ÁO hydrogen bonds and C-HÁ Á Á interactions into layers parallel to the bc plane.

Comment
The title compound, C 26 H 25 Cl 2 NO 2 , is a semicyclic mono Mannich base. Mannich bases are generally formed by the reaction between a compound containing reactive hydrogen atom, formaldehyde, and a secondary amine. On occasion, aldehydes other than formaldehyde may be employed, and the secondary amine may be replaced by ammonia and primary amines. The process whereby these compounds are formed is known as the Mannich reaction (Dimmock & Kumar, 1997).
Considerable anticancer activity was also attributed to Mannich bases (Dimmock & Kumar, 1997). It has been reported that these compounds have an inhibiting effect on DNA topoisomerase I (Canturk et al., 2008) and II (Yogeeswari et al., 2005).
The biological activities of Mannich bases were attributed to the thiol alkylation of α,β-unsaturated ketones produced from Mannich bases. Mannich bases which have at least one activated hydrogen atom at the β-position of amine can undergo deamination under simulated physiological condition in vitro or in vivo condition to produce α,β-unsaturated ketones which are biologically active species .
The title compound was tested against seven types of plant pathogenic fungi and three types of human pathogenic fungi using the agar dilution assay (Mete et al., 2010b). Cytotoxic activity of the title compound against androgen-independent prostate cancer cells (PC-3) and the biological activity on DNA topoisomerase I enzyme were also reported (Mete et al., 2010a).
We applied a semiempirical calculation AM1 of (I) with MOPAC (Dewar et al., 1985;Stewart, 1993). Figure 3 shows the conformation of the calculated molecule. The values of the structural parameters of (I) obtained by the results of the theoretical calculations (based on isolated molecules) and X-ray structural determinations in the solid state are almost identical within experimental error. The dihedral angles between the mean planes of the aromatic rings in (I) are listed in Table 2 for comparision. The calculated dipole moment of (I) is 2.119 D. The HOMO and LUMO energy levels are -9.22109 and supplementary materials sup-2 -0.56402 eV, respectively. We may state that the theoretical calculation of (I) supports the suggestion that the present intermolecular interactions in (I) influence crystal packing.
Experimental 4'-Chloroacetophenone (10.00 g), paraformaldehyde (1.95 g) and phenylethylamine hydrochloride (5.12 g) in the molar ratio 2:2:1 were stirred and heated in an oil bath. When the temperature reached 365 K, the solid mixture started to melt.
When heating continued, the reaction content solidified again totally. The reaction flask was quickly removed from the oil bath. The temperature of the reaction medium spontaneously increased to 377 K. Following the increase in temperature and removal of the flask from the oil bath, ethyl acetate (20 ml) was added to the reaction flask when the temperature had dropped to 338 K. Stirring was continued for 24 h. The formed precipitate was separated by filtration and crystallized from ethanol to obtain 1-(4-chlorophenyl)-3-phenethylamino-1-propanone hydrochloride. The ethyl acetate present in the reaction flask was removed under reduced pressure to obtain the title compound (I) as a viscous orange oil. The compound was purified by column chromatography using a basic Al 2 O 3 column with ethyl acetate/hexane (1:9 v/v) as eluent (yield 18%; m. p. 405-407 K). Crystals suitable for X-ray analysis were obtained by slow evaporation of a methanol solution.  5, 39.6, 48.9, 51.3, 52.3, 60.2, 73.1, 126.5, 127.7, 128.3, 128.9, 129.3, 129.4, 130.7, 131.8, 136.0, 138.9, 141.1, 147.2, 202.5 and refined as riding with U iso (H) = 1.5U eq (O) or 1.2U eq (C). The rather high R value (0.0967) is due to the poor quality of the crystal. Fig. 1. The molecular structure of the title compound with displacement ellipsoids drawn at the 30% probability level.