3-(4-Chloro­anilino)-2,5-dimethyl­cyclo­hex-2-en-1-one

Henry North; Kwame Wutoh; M’egya K Odoom; Pradeep Karla; Kenneth R Scott; Ray J Butcher

doi:10.1107/S1600536811005678

. 2011 Apr 29;67(Pt 5):o1283–o1284. doi: 10.1107/S1600536811005678

3-(4-Chloroanilino)-2,5-dimethylcyclohex-2-en-1-one

Henry North ^a, Kwame Wutoh ^b, M’egya K Odoom ^c, Pradeep Karla ^a, Kenneth R Scott ^a, Ray J Butcher ^d,^*

PMCID: PMC3089366 PMID: 21754564

Abstract

In the title compound, C₁₄H₁₆ClNO, the dihedral angle between the benzene ring and the conjugated part of the cyclohexene ring is 61.7 (2)°. Part of the cyclohexene ring and one of the attached methyl groups are disordered over two orientations with occupancies of 0.602 (7) and 0.398 (7). In addition, the crystal studied was a racemic twin [Flack parameter = 0.58 (4)]. In the crystal, the molecules are linked into chains in the b-axis direction by intermolecular N—H⋯O hydrogen bonds. C—H⋯O and C—H⋯Cl interactions are also observed.

Related literature

The title compound 3-(4-chlorophenylamino)-2,5-dimethylcyclohex-2-enone possesses significant anticonvulsant properties. For the anticonvulsant properties of enaminones, see: Edafiogho et al. (1992 ▶); Eddington et al. (2003 ▶); Scott et al. (1993 ▶, 1995 ▶). For related structures see: Alexander et al. (2010 ▶, 2011 ▶).

Experimental

Crystal data

C₁₄H₁₆ClNO
M _r = 249.73
Monoclinic,
a = 6.0775 (5) Å
b = 8.8106 (5) Å
c = 12.5794 (7) Å
β = 99.904 (7)°
V = 663.5 (1) Å³
Z = 2
Cu Kα radiation
μ = 2.41 mm⁻¹
T = 295 K
0.45 × 0.28 × 0.10 mm

Data collection

Oxford Diffraction Xcalibur Ruby Gemini diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009 ▶) T _min = 0.679, T _max = 1.000
2292 measured reflections
1705 independent reflections
1417 reflections with I > 2σ(I)
R _int = 0.029

Refinement

R[F ² > 2σ(F ²)] = 0.054
wR(F ²) = 0.150
S = 1.00
1705 reflections
171 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.22 e Å⁻³
Δρ_min = −0.17 e Å⁻³
Absolute structure: Flack (1983 ▶), 259 Friedel pairs
Flack parameter: 0.58 (4)

Data collection: CrysAlis PRO (Oxford Diffraction, 2009 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536811005678/hg2794sup1.cif

e-67-o1283-sup1.cif^{(20.4KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536811005678/hg2794Isup2.hkl

e-67-o1283-Isup2.hkl^{(84KB, 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
N1—H1⋯O1ⁱ	0.86	2.10	2.897 (4)	155
C6—H6A⋯O1ⁱⁱ	0.93	2.42	3.340 (4)	172
C12A—H12A⋯O1ⁱⁱ	0.97	2.58	3.439 (9)	147
C12B—H12D⋯Cl1ⁱⁱⁱ	0.97	2.95	3.79 (3)	146

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

Acknowledgments

The authors are indebted to Mr James P. Stables, Epilepsy Branch, Division of Convulsive, Developmental and Neuromuscular Disorders, National Institute of Neurological Disorders and Stroke, for helpful discussions and initial data. The authors wish to acknowledge E. Jeannette Andrews, EdD, Deputy Director of the Center of Excellence at Howard University College of Pharmacy, Nursing and Allied Health Sciences, for her generous assistance in completing this project. RJB wishes to acknowledge the NSF–MRI program (grant CHE-0619278) for funds to purchase the diffractometer.

supplementary crystallographic information

Comment

The study of enaminones has led to several compounds possessing anticonvulsant properties (Edafiogho et al., 1992; Eddington et al., 2003; Scott et al., 1993, 1995; Alexander et al., 2010, 2011). Our group has extensively studied the effects of modification of the enaminone with substitutions at the methyl ester, ethyl ester, and without the ester group. Early in our work, the N–H binding site was confirmed when it was found that no compound was active with the N–H proton missing. All of the active compounds were para-substituted with an electron-withdrawing group. A series of compounds with vinyl proton substitution has recently synthesized. The title compound, 3-(4-chlorophenylamino)-2,5-dimethylcyclohex-2-enone was exclusively active in the maximal electroshock seizure evaluation (MES) in mice, indicative of protection against tonic-clonic convulsions in humans. The MES test with mice revealed no activity at the 30 mg kg^-1 dose, however in the 100 mg kg^-1 dose, 3/3 of the animals were protected at 30 minutes and 0/3 of the animals were protected at 4 h. At a dose of 300 mg kg^-1, 1/1 animals were protected 30 min and 4 h. There was toxicity at 30 min in 2/4 animals. In the rat MES study, at a dose of 30 mg kg^-1, 1/4 of the animals were protected at 1 and 2 h with no toxicity.

Since the shape of the molecule is important in determining binding to the receptor sites it is of interest to note that the dihedral angle between the phenyl ring and the conjugated part of the cyclohexene ring is 61.7 (2)°. The backbone of the cyclohexene ring is disordered over two conformations with occupancies of 0.602 (7) and 0.398 (7), respectively. In addition the compound is a racemic twin (Flack parameter of 0.58 (4)). The molecules are linked in chains in the b direction by intermolecular N—H···O hydrogen bonds.

Experimental

Iodomethane (11.2 ml, 0.18 mol, 1.5 equiv) was added to a solution of 5-methyl-1,3-cyclohexanedione (15.0 g, 0.119 mol) in 4 N aqueous sodium hydroxide (30 mL, 1.0 equiv of NaOH) in a two-neck 250 ml round bottom flask fitted with a magnetic stirrer and condenser. The solution was refluxed for 20 h and cooled to room temperature, then refrigerated at 0°C overnight. Vacuum filtration of the reaction mixture gave a crystalline mass dried to yield 9.24 g (54%). The crystalline mass, 2,5-dimethyl-1,3-cyclohexadione (2.10 g, 15 mmol), mp 170–172°C (lit. mp 130–131.5°C), 4-chloroaniline (2.32 g, 18 mmol), and toluene (60 ml) was added to a 150 ml single neck round bottom flask containing a stir bar. The solution was refluxed and stirred for 6 h with azeotropic removal of water by Dean-Stark trap. After standing overnight, crystals appeared. Evaporation under reduced pressure yielded crystals that were recrystallized from EtOAc, 44.3% yield (mp 183–185°C).