5-Methyl-3-(5-methyl­isoxazol-3-yl)cyclo­hex-2-enone

The X-ray crystal structure of the title compound, C₁₁H₁₄N₂O₂, has been determined and its structure correlated with its anti­convulsant activity in mice and rats. An intramolecular C—H...N hydrogen bond links the two rings.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.003 Å
• Disorder in main residue
• R factor = 0.052
• wR factor = 0.143
• Data-to-parameter ratio = 13.4

checkCIF/PLATON results

No syntax errors found



Alert level B
PLAT031_ALERT_4_B Refined Extinction Parameter within Range ......       2.31 Sigma
PLAT063_ALERT_3_B Crystal Probably too Large for Beam Size .......       0.95 mm

Alert level C
PLAT094_ALERT_2_C Ratio of Maximum / Minimum Residual Density ....       3.09
PLAT128_ALERT_4_C Non-standard setting of Space group P21/c   ....    P21/a
PLAT199_ALERT_1_C Check the Reported _cell_measurement_temperature        293 K
PLAT200_ALERT_1_C Check the Reported _diffrn_ambient_temperature .        293 K
PLAT301_ALERT_3_C Main Residue  Disorder .........................      21.00 Perc.
PLAT366_ALERT_2_C Short? C(sp?)-C(sp?) Bond  C1     -   C2     ...       1.35 Ang.
PLAT720_ALERT_4_C Number of Unusual/Non-Standard Label(s) ........         16

   0 ALERT level A = In general: serious problem
   2 ALERT level B = Potentially serious problem
   7 ALERT level C = Check and explain
   0 ALERT level G = General alerts; check

   2 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   2 ALERT type 2 Indicator that the structure model may be wrong or deficient
   2 ALERT type 3 Indicator that the structure quality may be low
   3 ALERT type 4 Improvement, methodology, query or suggestion

---

S1. Comment

Our research on the anticonvulsant activity of the enaminones has been augmented by X-ray analysis (Kubicki & Codding, 1993; Laws et al., 1998; Foster et al., 1999; Kubicki et al., 2000; Eddington et al., 2002; Anderson et al., 2006; Hanson et al., 2006). Recently, our investigation has led to the evaluation of various isoxazoles from which the title compound, (I), and 3-(5-methylisoxazol-3-yl)-5,5-dimethylcyclohex-2-enone, (II) (Hanson et al., 2006), have emerged (Hanson, 2005). Although structurally similar to (II) (Hanson et al., 2006), (I) was active in the maximal electroshock seizure evaluation (MES) in mice, indicative of protection against tonic–clonic convulsions in humans (1/3 animals protected at 100 mg kg⁻¹ at 15 min, and 2/3 protected at 300 mg kg⁻¹ at 1 h). Compound (I) also displayed activity in the subcutaneous pentylenetetrazol assessment (scPTZ), indicative of protection against absence seizures. This activity was shown in mice [3/4 animals protected at 300 mg kg⁻¹ at 30 min, with toxicity noted at 100 mg kg⁻¹ at 30 min (3/8 animals showed neurotoxicity at 100 mg kg⁻¹ and 3/4 displayed toxicity at 300 mg kg⁻¹ at 15 min)]. In rats, (I) provided an MES ED₅₀ (median effective dose) of 66 mg kg⁻¹ and a TD₅₀ (median toxic dose) of >120 mg kg⁻¹, providing a protective index PI (defined as the ratio of the median toxic dose to the median effective dose) of >1.8. The dimethyl compound, (II) (Hanson et al., 2006), produced a compound that was exclusively MES active and more toxic (3/7 animals protected at 100 mg kg⁻¹ at 30 min, 4/5 animals protected at 300 mg kg⁻¹ at 30 min and at 4 h; toxicity evaluation: 2/8 toxic at 100 mg kg⁻¹ at 30 min, 3/4 toxic at 300 mg kg⁻¹ at 30 min and 1/2 toxic at 300 mg kg⁻¹ at 4 h). Single-crystal X-ray analyses carried out on (I) (this work) and (II) (Hanson et al., 2006) point to the importance of intramolecular hydrogen bonding.

The molecular structure of (I) is shown in Fig. 1. As noted and in agreement with our previous studies, hydrogen bonding occurs between the vinyl H atom and the aromatic/heterocyclic ring system (Fig. 2). In (I), this bonding occurs between the H atom on atom C2 and the lone pair on atom N2 on the isoxazole ring. Geometric parameters for this compound are similar to those observed in other related enaminones (Kubicki & Codding, 1993; Laws et al., 1998; Foster et al.,1999; Kubicki et al., 2002 Or 2000?; Eddington et al., 2002; Anderson et al., 2006; Hanson et al., 2006).

S2. Experimental

5-Methylcyclohexane-1,3-dione (27 mmol) and 3-amino-5-methylisoxazole (33 mmol) were added to a mixture of absolute ethanol (100 ml) and ethyl acetate (100 ml) and the solution was refluxed and stirred for 6 h. During that time, one-half of the solvents were slowly removed via a Dean–Stark trap and, after cooling, replaced with an equal volume of anhydrous ether. The mixture became cloudy while stirring was continued overnight, whereupon crystals of (I) spontaneously deposited. Recrystallization from ethyl acetate produced pale-yellow crystals (yield 2.81 g, 51%; mp 478–479 K). Spectroscopic analysis: ¹H NMR (DMSO-d₆, δ, p.p.m.): 1.0 (3H, d, J = 6.4 Hz, CH₃), 1.9–2.4 (5H, m, cyclohexene ring), 3.3 (3H, s, CH₃ on isoxazole ring), 6.0 (1H, s, ═ CH), 6.3 (1H, s, isoxazole CH═), 9.4 (1H, br s, NH); ¹³C (DMSO-d₆, δ, p.p.m.): 11.2, 32.1, 42.0, 42.0, 46.0, 50.0, 53.4, 95,5, 102.9, 105.2, 168.8, 197.4; IR (KBr, ν, cm⁻¹): 3342.8 (NH), 3139.8 (5-methylisoxazole stretch), 1680.2 (C═O).

S3. Refinement

The backbone of the cyclohexene ring was disordered over two conformations, with occupancies of 0.61 (3) and 0.39 (3). All H atoms were initially located in a difference Fourier map. The methyl H atoms were then constrained to an ideal geometry, with C—H distances of 0.98 Å and U_iso(H) = 1.5U_eq(C), but each group was allowed to rotate freely about its C—C bond. The position of the amine H atom was idealized, with an N—H distance of 0.86 Å and with U_iso(H) = 1.2U_eq(N). All other H atoms were positioned geometrically and constrained to ride on their parent atoms, with C—H distances in the range 0.95–1.00 Å and U_iso(H) = 1.2U_eq(C).

Computing details

Data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS; data reduction: SHELXTL (Bruker, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Figures

	Fig. 1. View of the molecule of (I), showing the atom-labelling scheme. Only the major disorder component is shown. Displacement ellipsoids are drawn at the 20% probability level and H atoms are represented by circles of arbitrary size.
	Fig. 2. The molecular packing of (I), viewed down the a axis.

5-Methyl-3-(5-methylisoxazol-3-yl)cyclohex-2-enone

Crystal data

C11H14N2O2	F(000) = 440
Mr = 206.24	Dx = 1.249 Mg m^−3
Monoclinic, P21/a	Cu Kα radiation, λ = 1.54180 Å
Hall symbol: -P 2yab	Cell parameters from 63 reflections
a = 11.1239 (10) Å	θ = 6.4–27.9°
b = 9.0159 (7) Å	µ = 0.71 mm^−1
c = 11.9664 (9) Å	T = 293 K
β = 113.970 (7)°	Needle, colourless
V = 1096.63 (18) Å^3	0.95 × 0.25 × 0.20 mm
Z = 4

Data collection

Bruker P4S diffractometer	1698 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.028
Graphite monochromator	θmax = 69.1°, θmin = 4.0°
2θ/ω scans	h = −1→13
Absorption correction: part of the refinement model (ΔF) (SHELXTL; Bruker, 1997)	k = −1→10
Tmin = 0.551, Tmax = 0.871	l = −14→13
2641 measured reflections	3 standard reflections every 97 reflections
2017 independent reflections	intensity decay: none

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.052	H-atom parameters constrained
wR(F^2) = 0.143	w = 1/[σ^2(Fo^2) + (0.0609P)^2 + 0.3446P] where P = (Fo^2 + 2Fc^2)/3
S = 1.07	(Δ/σ)max = 0.018
2017 reflections	Δρmax = 0.51 e Å^−3
151 parameters	Δρmin = −0.17 e Å^−3
6 restraints	Extinction correction: SHELXTL (Bruker, 1997), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0037 (16)

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq	Occ. (<1)
O1	0.37259 (13)	0.51400 (16)	0.30704 (16)	0.0634 (5)
O2	0.35458 (14)	−0.09121 (18)	0.09492 (16)	0.0720 (5)
N1	0.63076 (14)	0.13327 (17)	0.24535 (15)	0.0479 (4)
H1A	0.7110	0.1095	0.2617	0.057*
N2	0.41139 (17)	0.0427 (2)	0.1545 (2)	0.0682 (6)
C1	0.61190 (16)	0.27119 (19)	0.28237 (16)	0.0429 (4)
C2	0.49270 (17)	0.3291 (2)	0.26277 (17)	0.0464 (4)
H2A	0.4171	0.2766	0.2154	0.056*
C3	0.48032 (17)	0.4689 (2)	0.31324 (18)	0.0471 (5)
C4A	0.5957 (17)	0.5668 (18)	0.3687 (15)	0.0469 (18)	0.61 (3)
H4AA	0.6236	0.5666	0.4567	0.056*	0.61 (3)
H4AB	0.5701	0.6674	0.3400	0.056*	0.61 (3)
C5A	0.711 (2)	0.522 (2)	0.340 (2)	0.0548 (7)	0.61 (3)
H5AA	0.6873	0.5435	0.2528	0.066*	0.61 (3)
C6A	0.7355 (19)	0.3557 (18)	0.3572 (13)	0.0445 (15)	0.61 (3)
H6AA	0.8053	0.3274	0.3325	0.053*	0.61 (3)
H6AB	0.7634	0.3311	0.4430	0.053*	0.61 (3)
C7A	0.835 (2)	0.611 (3)	0.413 (3)	0.0695 (13)	0.61 (3)
H7AA	0.8179	0.7145	0.3934	0.104*	0.61 (3)
H7AB	0.9055	0.5785	0.3928	0.104*	0.61 (3)
H7AC	0.8578	0.5966	0.4986	0.104*	0.61 (3)
C4B	0.610 (3)	0.552 (3)	0.391 (2)	0.0469 (18)	0.39 (3)
H4BA	0.5926	0.6575	0.3897	0.056*	0.39 (3)
H4BB	0.6424	0.5183	0.4750	0.056*	0.39 (3)
C5B	0.715 (3)	0.526 (3)	0.342 (4)	0.0548 (7)	0.39 (3)
H5BA	0.6811	0.5647	0.2588	0.066*	0.39 (3)
C6B	0.736 (3)	0.360 (3)	0.335 (2)	0.0445 (15)	0.39 (3)
H6BA	0.7852	0.3438	0.2848	0.053*	0.39 (3)
H6BB	0.7891	0.3229	0.4161	0.053*	0.39 (3)
C7B	0.844 (4)	0.606 (4)	0.415 (5)	0.0695 (13)	0.39 (3)
H7BA	0.8257	0.7075	0.4270	0.104*	0.39 (3)
H7BB	0.8991	0.6024	0.3711	0.104*	0.39 (3)
H7BC	0.8876	0.5587	0.4932	0.104*	0.39 (3)
C8	0.53717 (17)	0.0265 (2)	0.18471 (17)	0.0449 (4)
C9	0.5667 (2)	−0.1127 (2)	0.14681 (19)	0.0519 (5)
H9A	0.6489	−0.1493	0.1578	0.062*
C10	0.4500 (2)	−0.1797 (2)	0.09180 (18)	0.0531 (5)
C11	0.4069 (3)	−0.3253 (3)	0.0312 (2)	0.0705 (7)
H11A	0.4769	−0.3687	0.0149	0.106*
H11B	0.3313	−0.3117	−0.0443	0.106*
H11C	0.3847	−0.3897	0.0838	0.106*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0413 (7)	0.0513 (8)	0.1049 (12)	0.0020 (6)	0.0371 (7)	−0.0108 (8)
O2	0.0491 (8)	0.0584 (9)	0.0999 (12)	−0.0077 (7)	0.0214 (8)	−0.0242 (8)
N1	0.0366 (8)	0.0409 (8)	0.0707 (10)	0.0011 (6)	0.0264 (7)	−0.0027 (7)
N2	0.0409 (9)	0.0571 (11)	0.1022 (14)	−0.0046 (8)	0.0246 (9)	−0.0262 (10)
C1	0.0388 (9)	0.0390 (9)	0.0549 (10)	0.0006 (7)	0.0233 (8)	0.0032 (7)
C2	0.0350 (9)	0.0446 (10)	0.0627 (11)	−0.0018 (7)	0.0229 (8)	−0.0037 (8)
C3	0.0408 (9)	0.0431 (10)	0.0628 (11)	0.0019 (7)	0.0264 (8)	0.0015 (8)
C4A	0.039 (4)	0.042 (3)	0.058 (6)	0.0023 (19)	0.018 (4)	0.000 (3)
C5A	0.0434 (14)	0.0504 (14)	0.0728 (16)	−0.0043 (10)	0.0257 (13)	−0.0038 (11)
C6A	0.0345 (9)	0.0463 (13)	0.056 (5)	0.0017 (9)	0.022 (3)	0.001 (3)
C7A	0.045 (3)	0.0606 (19)	0.103 (2)	−0.010 (2)	0.031 (2)	−0.0164 (15)
C4B	0.039 (4)	0.042 (3)	0.058 (6)	0.0023 (19)	0.018 (4)	0.000 (3)
C5B	0.0434 (14)	0.0504 (14)	0.0728 (16)	−0.0043 (10)	0.0257 (13)	−0.0038 (11)
C6B	0.0345 (9)	0.0463 (13)	0.056 (5)	0.0017 (9)	0.022 (3)	0.001 (3)
C7B	0.045 (3)	0.0606 (19)	0.103 (2)	−0.010 (2)	0.031 (2)	−0.0164 (15)
C8	0.0418 (9)	0.0406 (9)	0.0547 (10)	0.0006 (7)	0.0220 (8)	−0.0001 (7)
C9	0.0487 (10)	0.0425 (10)	0.0683 (12)	0.0052 (8)	0.0278 (9)	0.0006 (9)
C10	0.0573 (12)	0.0444 (10)	0.0567 (10)	0.0008 (9)	0.0222 (9)	−0.0011 (8)
C11	0.0798 (16)	0.0519 (13)	0.0702 (14)	−0.0078 (11)	0.0206 (12)	−0.0100 (10)

Geometric parameters (Å, º)

O1—C3	1.239 (2)	C7A—H7AA	0.9600
O2—C10	1.341 (2)	C7A—H7AB	0.9600
O2—N2	1.414 (2)	C7A—H7AC	0.9600
N1—C1	1.365 (2)	C4B—C5B	1.518 (14)
N1—C8	1.387 (2)	C4B—H4BA	0.9700
N1—H1A	0.8600	C4B—H4BB	0.9700
N2—C8	1.303 (2)	C5B—C7B	1.522 (13)
C1—C2	1.354 (2)	C5B—C6B	1.524 (13)
C1—C6B	1.49 (3)	C5B—H5BA	0.9800
C1—C6A	1.508 (19)	C6B—H6BA	0.9700
C2—C3	1.429 (3)	C6B—H6BB	0.9700
C2—H2A	0.9300	C7B—H7BA	0.9600
C3—C4A	1.48 (2)	C7B—H7BB	0.9600
C3—C4B	1.56 (3)	C7B—H7BC	0.9600
C4A—C5A	1.517 (8)	C8—C9	1.418 (3)
C4A—H4AA	0.9700	C9—C10	1.338 (3)
C4A—H4AB	0.9700	C9—H9A	0.9300
C5A—C6A	1.522 (9)	C10—C11	1.481 (3)
C5A—C7A	1.523 (8)	C11—H11A	0.9600
C5A—H5AA	0.9800	C11—H11B	0.9600
C6A—H6AA	0.9700	C11—H11C	0.9600
C6A—H6AB	0.9700
C10—O2—N2	109.02 (15)	H7AB—C7A—H7AC	109.5
C1—N1—C8	128.36 (15)	C5B—C4B—C3	111.6 (19)
C1—N1—H1A	115.8	C5B—C4B—H4BA	109.3
C8—N1—H1A	115.8	C3—C4B—H4BA	109.3
C8—N2—O2	104.68 (15)	C5B—C4B—H4BB	109.3
C2—C1—N1	124.33 (17)	C3—C4B—H4BB	109.3
C2—C1—C6B	122.7 (10)	H4BA—C4B—H4BB	108.0
N1—C1—C6B	112.6 (10)	C4B—C5B—C7B	113.4 (19)
C2—C1—C6A	120.1 (6)	C4B—C5B—C6B	109.7 (17)
N1—C1—C6A	115.5 (6)	C7B—C5B—C6B	111.8 (18)
C1—C2—C3	121.52 (17)	C4B—C5B—H5BA	107.2
C1—C2—H2A	119.2	C7B—C5B—H5BA	107.2
C3—C2—H2A	119.2	C6B—C5B—H5BA	107.2
O1—C3—C2	121.42 (17)	C1—C6B—C5B	114.3 (18)
O1—C3—C4A	118.3 (6)	C1—C6B—H6BA	108.7
C2—C3—C4A	120.2 (6)	C5B—C6B—H6BA	108.7
O1—C3—C4B	121.3 (9)	C1—C6B—H6BB	108.7
C2—C3—C4B	116.8 (9)	C5B—C6B—H6BB	108.7
C3—C4A—C5A	113.6 (11)	H6BA—C6B—H6BB	107.6
C3—C4A—H4AA	108.8	C5B—C7B—H7BA	109.5
C5A—C4A—H4AA	108.8	C5B—C7B—H7BB	109.5
C3—C4A—H4AB	108.8	H7BA—C7B—H7BB	109.5
C5A—C4A—H4AB	108.8	C5B—C7B—H7BC	109.5
H4AA—C4A—H4AB	107.7	H7BA—C7B—H7BC	109.5
C4A—C5A—C6A	110.4 (11)	H7BB—C7B—H7BC	109.5
C4A—C5A—C7A	112.0 (11)	N2—C8—N1	124.09 (17)
C6A—C5A—C7A	111.9 (12)	N2—C8—C9	111.89 (17)
C4A—C5A—H5AA	107.4	N1—C8—C9	124.02 (16)
C6A—C5A—H5AA	107.4	C10—C9—C8	104.63 (17)
C7A—C5A—H5AA	107.4	C10—C9—H9A	127.7
C1—C6A—C5A	110.4 (12)	C8—C9—H9A	127.7
C1—C6A—H6AA	109.6	C9—C10—O2	109.78 (17)
C5A—C6A—H6AA	109.6	C9—C10—C11	134.2 (2)
C1—C6A—H6AB	109.6	O2—C10—C11	116.02 (19)
C5A—C6A—H6AB	109.6	C10—C11—H11A	109.5
H6AA—C6A—H6AB	108.1	C10—C11—H11B	109.5
C5A—C7A—H7AA	109.5	H11A—C11—H11B	109.5
C5A—C7A—H7AB	109.5	C10—C11—H11C	109.5
H7AA—C7A—H7AB	109.5	H11A—C11—H11C	109.5
C5A—C7A—H7AC	109.5	H11B—C11—H11C	109.5
H7AA—C7A—H7AC	109.5
C10—O2—N2—C8	−0.6 (2)	O1—C3—C4B—C5B	−153.7 (15)
C8—N1—C1—C2	−1.3 (3)	C2—C3—C4B—C5B	34 (2)
C8—N1—C1—C6B	−174.6 (9)	C4A—C3—C4B—C5B	−77 (9)
C8—N1—C1—C6A	174.3 (6)	C3—C4B—C5B—C7B	180 (2)
N1—C1—C2—C3	174.39 (17)	C3—C4B—C5B—C6B	−55 (3)
C6B—C1—C2—C3	−12.9 (10)	C2—C1—C6B—C5B	−11 (2)
C6A—C1—C2—C3	−1.0 (6)	N1—C1—C6B—C5B	162.9 (17)
C1—C2—C3—O1	−171.71 (19)	C6A—C1—C6B—C5B	−89 (9)
C1—C2—C3—C4A	11.5 (7)	C4B—C5B—C6B—C1	44 (3)
C1—C2—C3—C4B	0.5 (11)	C7B—C5B—C6B—C1	171 (2)
O1—C3—C4A—C5A	−163.4 (11)	O2—N2—C8—N1	179.74 (17)
C2—C3—C4A—C5A	13.5 (14)	O2—N2—C8—C9	0.4 (2)
C4B—C3—C4A—C5A	87 (9)	C1—N1—C8—N2	−1.2 (3)
C3—C4A—C5A—C6A	−46.2 (18)	C1—N1—C8—C9	178.05 (18)
C3—C4A—C5A—C7A	−171.6 (15)	N2—C8—C9—C10	−0.1 (2)
C2—C1—C6A—C5A	−32.7 (13)	N1—C8—C9—C10	−179.43 (18)
N1—C1—C6A—C5A	151.6 (10)	C8—C9—C10—O2	−0.3 (2)
C6B—C1—C6A—C5A	75 (8)	C8—C9—C10—C11	179.9 (2)
C4A—C5A—C6A—C1	55.1 (17)	N2—O2—C10—C9	0.5 (2)
C7A—C5A—C6A—C1	−179.4 (14)	N2—O2—C10—C11	−179.57 (19)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···O1^i	0.86	1.99	2.816 (2)	160
C2—H2A···N2	0.93	2.22	2.865 (3)	126

Symmetry code: (i) x+1/2, −y+1/2, z.