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Acta Crystallogr Sect E Struct Rep Online. 2010 June 1; 66(Pt 6): o1402.
Published online 2010 May 22. doi:  10.1107/S1600536810017848
PMCID: PMC2979478

rac-2-Methyl-3,4,5,6-tetra­hydro-2H-2,6-methano-1,3-benzoxazocin-4-one

Abstract

The title compound, C12H13NO2, represents a conformationally restricted 2-pyridone analogue of 1,4-dihydro­pyridine-type calcium antagonists and was selected for a crystal structure determination in order to explore some aspects of drug-receptor inter­action. In the mol­ecule, two stereogenic centres are of opposite chirality, whereas a racemate occurs in the crystal. It was found that the formally aminic N atom of the heterocycle is essentially sp 2-hybridized with the lone-pair electrons partially delocalized through conjugation with the adjacent carbonyl bond. As a result, the central pyridone ring assumes an unsymmetrical half-chair conformation. The critical 4-phenyl ring is fixed in a pseudo-axial and perpendicular orientation [dihedral angle 85.8 (1)°] with respect to the pyridone ring via an oxygen bridge. In the crystal a pair of centrosymmetric N—H(...)O hydrogen bonds connect mol­ecules of opposite chirality into a dimer. The dimers are packed by hydrophobic van der Waals inter­actions.

Related literature

For background to 1,4-dihydro­pyridines (DHPs) as the most potent class of calcium-channel antagonists, see: Goldmann & Stoltefuss (1991 [triangle]); Kettmann et al. (1996 [triangle]). For bond-lengths in cyclic amino acids, see: Benedetti et al. (1983 [triangle]). For the preparation of the title compound, see: Světlík et al. (1990 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-66-o1402-scheme1.jpg

Experimental

Crystal data

  • C12H13NO2
  • M r = 203.23
  • Triclinic, An external file that holds a picture, illustration, etc.
Object name is e-66-o1402-efi1.jpg
  • a = 5.564 (1) Å
  • b = 9.820 (2) Å
  • c = 10.596 (2) Å
  • α = 108.73 (1)°
  • β = 95.09 (2)°
  • γ = 103.60 (1)°
  • V = 524.37 (17) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.09 mm−1
  • T = 296 K
  • 0.30 × 0.25 × 0.20 mm

Data collection

  • Siemens P4 diffractometer
  • 3821 measured reflections
  • 2983 independent reflections
  • 2242 reflections with I > 2σ(I)
  • R int = 0.052
  • 3 standard reflections every 97 reflections intensity decay: none

Refinement

  • R[F 2 > 2σ(F 2)] = 0.049
  • wR(F 2) = 0.145
  • S = 1.03
  • 2983 reflections
  • 137 parameters
  • H-atom parameters constrained
  • Δρmax = 0.26 e Å−3
  • Δρmin = −0.17 e Å−3

Data collection: XSCANS (Siemens, 1991 [triangle]); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: PLATON (Spek, 2009 [triangle]); software used to prepare material for publication: SHELXL97.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810017848/kp2259sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810017848/kp2259Isup2.hkl

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

supplementary crystallographic information

Comment

1,4-Dihydropyridines (DHPs) are known as the most potent class of calcium-channel antagonists widely used in clinical medicine. It was reported that the essential pharmacophore, recognizable by the DHP receptor, consists of the NH moiety, (substituted) phenyl ring and two ester groups (Goldmann & Stoltefuss, 1991). Nevertheless, we have previously observed that the rigid compound (I), lacking the ester groups in positions 3 and 5, retains some level of activity (Kettmann et al., 1996). This implies that (I) presents its key pharmacophoric elements, viz. the NH and phenyl groups, in an optimal position and orientation for favourable binding to the complementary sites of the receptor. To establish the latter, a single-crystal X-ray analysis of (I) was undertaken.

The bond lengths and angles within the molecule (Fig. 1) are normal. As expected, there is a strong conjugation between N1 and the C2=O2 carbonyl bond, as usually observed for cyclic amino acids (Benedetti et al., 1983).

As mentioned above, the main aim of this work was to determine the three-dimensional disposition of the key pharmacophoric groups, i.e. the phenyl and NH moieties (Fig. 1). The conformation of the central heterocycle acts as a scaffold to orient substituents in space. Thus, the pyridone ring adopts an unsymmetrical half-chair conformation in which atoms C6, N1, C2 and C3 are coplanar with r.m.s. deviation of 0.012 (1) Å, and atoms C4 and C5 are displaced from this plane by -0.348 (3) and 0.470 (3) Å, respectively. The phenyl ring at C4 occupies a pseudoaxial position (Fig. 1) and is fixed approximately in a perpendicular orientation with respect to the mean plane of the pyridone ring [dihedral angle 85.8 (1)°]; the ring is rotated on the C4—C7 bond in such a manner that it almost eclipses the C4—C5 bond [dihedral angle C5—C4—C7—C8 23.0 (2)°].

The crystal packing is governed by an intermolecular hydrogen bond NH···O(carbonyl) (Table 1); as a result, the molecules associate into pairs to form hydrogen-bonded dimers across the centre of symmetry at (1/2,1/2,1/2). The dimers are packed by van der Waals forces only.

Experimental

As described in details earlier (Světlík et al., 1990), the title compound, (I), was prepared by cyclocondensation of 4-(2-hydroxyphenyl)but-3-en-2-one with Meldrum's acid in refluxing ethanol for 4 hours (27% yield; m.p. 530-531 K). Single crystals suitable for an X-ray analysis were obtained by slow crystallization of ethanol solution.

Refinement

H atoms were visible in difference maps and were subsequently treated as riding atoms with distances N—H = 0.86, C—H 0.93 (CHarom), 0.97 (CH2) or 0.98 (CH) and 0.96 Å (CH3); Uiso of the H atoms were set to 1.2 (1.5 for the methyl H atoms) times Ueq of the parent atom.

Figures

Fig. 1.
Displacement ellipsoid plot of (I) with the labelling scheme for the non-H atoms, which are drawn as 35% probability level.

Crystal data

C12H13NO2Z = 2
Mr = 203.23F(000) = 216
Triclinic, P1Dx = 1.287 Mg m3
Hall symbol: -P 1Melting point: 530 K
a = 5.564 (1) ÅMo Kα radiation, λ = 0.71073 Å
b = 9.820 (2) ÅCell parameters from 20 reflections
c = 10.596 (2) Åθ = 7–18°
α = 108.73 (1)°µ = 0.09 mm1
β = 95.09 (2)°T = 296 K
γ = 103.60 (1)°Prism, colourless
V = 524.37 (17) Å30.30 × 0.25 × 0.20 mm

Data collection

Siemens P4 diffractometerRint = 0.052
Radiation source: fine-focus sealed tubeθmax = 30.0°, θmin = 2.1°
graphiteh = −1→7
ω/2θ scansk = −12→12
3821 measured reflectionsl = −14→14
2983 independent reflections3 standard reflections every 97 reflections
2242 reflections with I > 2σ(I) intensity decay: none

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.049Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.145H-atom parameters constrained
S = 1.03w = 1/[σ2(Fo2) + (0.0608P)2 + 0.0887P] where P = (Fo2 + 2Fc2)/3
2983 reflections(Δ/σ)max = 0.001
137 parametersΔρmax = 0.26 e Å3
0 restraintsΔρmin = −0.17 e Å3

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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 (Å2)

xyzUiso*/Ueq
N10.7300 (2)0.47999 (13)0.63412 (11)0.0368 (3)
H10.63900.53660.62390.044*
C20.7192 (3)0.36033 (16)0.52401 (13)0.0390 (3)
C30.8893 (3)0.26336 (19)0.53502 (14)0.0464 (3)
H3A1.02790.28430.48830.056*
H3B0.79570.15900.49000.056*
C40.9955 (3)0.28856 (17)0.68250 (14)0.0431 (3)
H41.13170.24100.68360.052*
C51.0990 (2)0.45662 (18)0.75980 (15)0.0432 (3)
H5A1.18540.47500.84980.052*
H5B1.21760.50150.71270.052*
C60.8791 (2)0.52435 (15)0.76906 (12)0.0353 (3)
C70.7943 (3)0.22442 (16)0.75190 (13)0.0391 (3)
C80.6692 (2)0.31756 (14)0.83327 (12)0.0345 (3)
C90.4875 (3)0.26224 (16)0.90078 (14)0.0405 (3)
H90.40770.32570.95550.049*
C100.4269 (3)0.11180 (18)0.88560 (16)0.0506 (4)
H100.30570.07450.93030.061*
C110.5454 (4)0.01657 (18)0.80448 (17)0.0570 (4)
H110.5035−0.08430.79420.068*
C120.7267 (3)0.07306 (18)0.73887 (16)0.0516 (4)
H120.80590.00880.68470.062*
C130.9524 (3)0.69372 (17)0.83480 (15)0.0470 (3)
H13A1.03880.72290.92600.071*
H13B0.80400.72760.83580.071*
H13C1.06080.73770.78420.071*
O10.72022 (17)0.46921 (10)0.85435 (9)0.0372 (2)
O20.5800 (2)0.33318 (13)0.41568 (10)0.0537 (3)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
N10.0382 (6)0.0428 (6)0.0337 (5)0.0192 (5)0.0020 (4)0.0147 (4)
C20.0442 (7)0.0449 (7)0.0338 (6)0.0194 (6)0.0061 (5)0.0170 (5)
C30.0549 (8)0.0582 (9)0.0383 (7)0.0329 (7)0.0129 (6)0.0197 (6)
C40.0413 (7)0.0589 (9)0.0421 (7)0.0304 (6)0.0100 (5)0.0228 (6)
C50.0308 (6)0.0599 (9)0.0457 (7)0.0161 (6)0.0043 (5)0.0257 (6)
C60.0323 (6)0.0418 (7)0.0331 (6)0.0104 (5)0.0020 (5)0.0160 (5)
C70.0433 (7)0.0459 (7)0.0332 (6)0.0208 (6)0.0016 (5)0.0158 (5)
C80.0362 (6)0.0375 (6)0.0311 (6)0.0132 (5)−0.0004 (5)0.0135 (5)
C90.0405 (7)0.0459 (7)0.0373 (6)0.0129 (6)0.0038 (5)0.0178 (5)
C100.0515 (8)0.0509 (9)0.0499 (8)0.0075 (7)0.0049 (6)0.0245 (7)
C110.0732 (11)0.0395 (8)0.0568 (9)0.0123 (7)0.0033 (8)0.0199 (7)
C120.0673 (10)0.0449 (8)0.0459 (8)0.0275 (7)0.0051 (7)0.0135 (6)
C130.0503 (8)0.0423 (7)0.0434 (7)0.0061 (6)0.0000 (6)0.0154 (6)
O10.0421 (5)0.0377 (5)0.0367 (5)0.0154 (4)0.0102 (4)0.0156 (4)
O20.0705 (7)0.0545 (6)0.0361 (5)0.0309 (5)−0.0060 (5)0.0104 (4)

Geometric parameters (Å, °)

N1—C21.3489 (17)C6—C131.518 (2)
N1—C61.4634 (16)C7—C121.402 (2)
N1—H10.8600C7—C81.4011 (18)
C2—O21.2399 (16)C8—O11.3873 (16)
C2—C31.5137 (19)C8—C91.3959 (19)
C3—C41.5399 (19)C9—C101.388 (2)
C3—H3A0.9700C9—H90.9300
C3—H3B0.9700C10—C111.386 (2)
C4—C71.518 (2)C10—H100.9300
C4—C51.526 (2)C11—C121.385 (3)
C4—H40.9800C11—H110.9300
C5—C61.5203 (18)C12—H120.9300
C5—H5A0.9700C13—H13A0.9600
C5—H5B0.9700C13—H13B0.9600
C6—O11.4568 (16)C13—H13C0.9600
C2—N1—C6127.38 (11)N1—C6—C5109.98 (11)
C2—N1—H1116.3C13—C6—C5114.61 (12)
C6—N1—H1116.3C12—C7—C8117.50 (14)
O2—C2—N1121.03 (12)C12—C7—C4122.47 (13)
O2—C2—C3120.90 (12)C8—C7—C4120.03 (12)
N1—C2—C3118.03 (12)O1—C8—C9115.93 (11)
C2—C3—C4113.10 (11)O1—C8—C7122.84 (12)
C2—C3—H3A109.0C9—C8—C7121.22 (13)
C4—C3—H3A109.0C10—C9—C8119.44 (14)
C2—C3—H3B109.0C10—C9—H9120.3
C4—C3—H3B109.0C8—C9—H9120.3
H3A—C3—H3B107.8C11—C10—C9120.64 (15)
C7—C4—C5108.71 (11)C11—C10—H10119.7
C7—C4—C3111.56 (12)C9—C10—H10119.7
C5—C4—C3108.61 (12)C12—C11—C10119.36 (15)
C7—C4—H4109.3C12—C11—H11120.3
C5—C4—H4109.3C10—C11—H11120.3
C3—C4—H4109.3C11—C12—C7121.84 (15)
C6—C5—C4107.95 (11)C11—C12—H12119.1
C6—C5—H5A110.1C7—C12—H12119.1
C4—C5—H5A110.1C6—C13—H13A109.5
C6—C5—H5B110.1C6—C13—H13B109.5
C4—C5—H5B110.1H13A—C13—H13B109.5
H5A—C5—H5B108.4C6—C13—H13C109.5
O1—C6—N1108.80 (10)H13A—C13—H13C109.5
O1—C6—C13105.03 (11)H13B—C13—H13C109.5
N1—C6—C13109.14 (11)C8—O1—C6116.70 (10)
O1—C6—C5109.04 (10)
C6—N1—C2—O2178.31 (13)C3—C4—C7—C8−96.72 (15)
C6—N1—C2—C3−3.9 (2)C12—C7—C8—O1179.75 (11)
O2—C2—C3—C4−165.37 (14)C4—C7—C8—O10.11 (18)
N1—C2—C3—C416.9 (2)C12—C7—C8—C91.13 (19)
C2—C3—C4—C771.70 (16)C4—C7—C8—C9−178.51 (11)
C2—C3—C4—C5−48.10 (17)O1—C8—C9—C10−179.60 (11)
C7—C4—C5—C6−54.82 (14)C7—C8—C9—C10−0.89 (19)
C3—C4—C5—C666.74 (14)C8—C9—C10—C110.1 (2)
C2—N1—C6—O1−97.04 (15)C9—C10—C11—C120.4 (2)
C2—N1—C6—C13148.87 (14)C10—C11—C12—C7−0.1 (2)
C2—N1—C6—C522.34 (18)C8—C7—C12—C11−0.6 (2)
C4—C5—C6—O166.77 (13)C4—C7—C12—C11178.99 (13)
C4—C5—C6—N1−52.46 (14)C9—C8—O1—C6−170.69 (10)
C4—C5—C6—C13−175.85 (11)C7—C8—O1—C610.63 (16)
C5—C4—C7—C12−156.59 (12)N1—C6—O1—C876.17 (13)
C3—C4—C7—C1283.67 (16)C13—C6—O1—C8−167.08 (10)
C5—C4—C7—C823.03 (16)C5—C6—O1—C8−43.79 (14)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N1—H1···O2i0.862.072.9274 (15)176

Symmetry codes: (i) −x+1, −y+1, −z+1.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: KP2259).

References

  • Benedetti, E., Bavoso, A., DeBlasio, B., Pavone, V. & Pedone, C. (1983). Biopolymers, 22, 305–317.
  • Goldmann, S. & Stoltefuss, J. (1991). Angew. Chem. 30, 1559–1578.
  • Kettmann, V., Dřímal, J. & Světlík, J. (1996). Pharmazie, 51, 747–750. [PubMed]
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Siemens (1991). XSCANS. Siemens Analytical X-ray Instruments Inc., Madison, Wisconsin, USA.
  • Spek, A. L. (2009). Acta Cryst. D65, 148–155. [PMC free article] [PubMed]
  • Světlík, J., Turecek, F. & Hanus, V. (1990). J. Chem. Soc. Perkin Trans. 1, pp. 1315–1318.

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