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Acta Crystallogr Sect E Struct Rep Online. 2010 July 1; 66(Pt 7): o1651.
Published online 2010 June 16. doi:  10.1107/S1600536810021355
PMCID: PMC3006922

rac-Ethyl 4-hy­droxy-6-(2-hy­droxy­phen­yl)-2-oxo-4-(trifluoro­methyl)per­hydro­pyrimidine-5-carboxyl­ate

Abstract

In the title compound, C14H15F3N2O5, prepared by reaction of 2-hy­droxy­benzaldehyde, ethyl 4,4,4-trifluoro-3-oxobutano­ate and urea, the tetra­pyrimidine ring adopts a half-chair conformation. The crystal structure is stabilized by five inter­molecular hydrogen bonds, three O—H(...)O and two N—H(...)O, giving cyclic dimers (through three hydrogen bonds) which are further extended into a two-dimensional network.

Related literature

For the bioactivity of dihydro­pyrimidines, see: Brier et al. (2004 [triangle]); Cochran et al. (2005 [triangle]); Moran et al. (2007 [triangle]); Zorkun et al. (2006 [triangle]). For the bioactivity of organofluorine compounds, see: Hermann et al. (2003 [triangle]); Ulrich (2004 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-66-o1651-scheme1.jpg

Experimental

Crystal data

  • C14H15F3N2O5
  • M r = 348.28
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-66-o1651-efi1.jpg
  • a = 12.0940 (15) Å
  • b = 8.665 (1) Å
  • c = 14.3110 (18) Å
  • β = 93.987 (6)°
  • V = 1496.1 (3) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.14 mm−1
  • T = 113 K
  • 0.26 × 0.22 × 0.20 mm

Data collection

  • Rigaku Saturn724 CCD diffractometer
  • Absorption correction: multi-scan (CrystalClear; Rigaku, 2009 [triangle]) T min = 0.965, T max = 0.973
  • 15222 measured reflections
  • 3558 independent reflections
  • 2461 reflections with I > 2σ(I)’
  • R int = 0.043

Refinement

  • R[F 2 > 2σ(F 2)] = 0.033
  • wR(F 2) = 0.075
  • S = 0.96
  • 3558 reflections
  • 234 parameters
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.29 e Å−3
  • Δρmin = −0.17 e Å−3

Data collection: CrystalClear-SM Expert (Rigaku, 2009 [triangle]); cell refinement: CrystalClear-SM Expert; data reduction: CrystalClear-SM Expert; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: CrystalStructure (Rigaku, 2009 [triangle]); software used to prepare material for publication: CrystalStructure.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810021355/zs2042sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810021355/zs2042Isup2.hkl

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

Acknowledgments

This work was supported by Natural Science Foundation of Henan Province, China (grant No. 082300420110) and the Natural Science Foundation of Henan Province Education Department, China (grant No. 2007150036).

supplementary crystallographic information

Comment

Dihydropyrimidine (DHPM) derivatives can be used as potential calcium channel blockers (Zorkun et al., 2006), inhibitors of mitotic kinesin Eg5 for treating cancer (Cochran et al., 2005; Brier et al., 2004) and as TRPA1 modulators for treating pain (Moran et al., 2007). In addition, compounds that contain fluorine have special bioactivity, e.g. flumioxazin is a widely used herbicide (Hermann et al., 2003; Ulrich, 2004). This led us to focus our attention on the synthesis and bioactivity of these important fused perfluoroalkylated heterocyclic compounds. During the synthesis of DHPM derivatives, the title compound, an intermediate C14H15F3N2O5 (I) was isolated and the structure confirmed by X-ray diffraction, in order to elucidate the reaction mechanism.

In the structure of the title molecule, the dihydropyrimidine ring adopts a half-chair conformation. The crystal structure is stabilized by five intermolecular hydrogen bonds, three O—H···O and two N—H···O (Table 1), giving cyclic dimers which are further extended into a two-dimensional network (Fig. 2).

dimension?

Experimental

The title compound was synthesized refluxing for 3 h, a stirred solution of 2-hydroxybenzaldehyde (0.61 g, 5 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate (1.11 g, 6 mmol) and urea (0.45 g, 7.5 mmol) in 5 ml of ethanol, the reaction catalyzed by sulfamic acid (0.15 g). The solvent was evaporated in vacuo and the residue was washed with water. The title compound was recrystallized from 50% aqueous ethanol and single crystals of (I) were obtained by slow evaporation.

Refinement

Hydrogen atoms involved in hydrogen-bonding inetractions were located by difference methods and their positional and isotropic displacement parameters were refined. Other H atoms were placed in calculated positions, with C—H(aromatic) = 0.95 Å and C—H(aliphatic) = 0.98 or 0.99 Å, and treated as riding, with Uiso(H) = 1.2Ueq(C).

Figures

Fig. 1.
Molecular configuration and atom numbering scheme for (I), with displacement ellipsoids drawn at the 30% probability level.
Fig. 2.
The packing diagram of the title compound. Intermolecular hydrogen bonds are shown as dashed line.

Crystal data

C14H15F3N2O5F(000) = 720
Mr = 348.28Dx = 1.546 Mg m3
Monoclinic, P21/nMo Kα radiation, λ = 0.71075 Å
Hall symbol: -P 2ynCell parameters from 4600 reflections
a = 12.0940 (15) Åθ = 1.7–28.0°
b = 8.665 (1) ŵ = 0.14 mm1
c = 14.3110 (18) ÅT = 113 K
β = 93.987 (6)°Prism, colorless
V = 1496.1 (3) Å30.26 × 0.22 × 0.20 mm
Z = 4

Data collection

Rigaku Saturn724 CCD diffractometer3558 independent reflections
Radiation source: rotating anode2461 reflections with I > 2σ(I)'
multilayerRint = 0.043
Detector resolution: 14.222 pixels mm-1θmax = 27.9°, θmin = 2.1°
ω scansh = −15→15
Absorption correction: multi-scan (CrystalClear; Rigaku, 2009)k = −10→11
Tmin = 0.965, Tmax = 0.973l = −18→15
15222 measured reflections

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)] = 0.033Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.075H atoms treated by a mixture of independent and constrained refinement
S = 0.96w = 1/[σ2(Fo2) + (0.0366P)2] where P = (Fo2 + 2Fc2)/3
3558 reflections(Δ/σ)max < 0.001
234 parametersΔρmax = 0.29 e Å3
0 restraintsΔρmin = −0.17 e Å3

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 (Å2)

xyzUiso*/Ueq
F10.63046 (7)0.13597 (8)0.56068 (5)0.0284 (2)
F20.70104 (6)−0.07799 (8)0.61474 (5)0.02243 (19)
F30.52483 (6)−0.04190 (9)0.61064 (5)0.0278 (2)
O10.73825 (7)0.17971 (10)0.73408 (6)0.0166 (2)
O20.57743 (7)−0.12700 (9)0.92883 (6)0.0155 (2)
O30.61021 (7)0.46053 (9)0.68641 (6)0.0188 (2)
O40.44283 (7)0.37553 (9)0.63011 (6)0.0189 (2)
O50.57096 (8)0.57378 (10)0.88466 (7)0.0226 (2)
N10.62882 (9)−0.02277 (12)0.79262 (7)0.0144 (2)
N20.52802 (9)0.11947 (11)0.89483 (8)0.0151 (2)
C10.63604 (10)0.10070 (14)0.72522 (9)0.0136 (3)
C20.54011 (10)0.21315 (13)0.73746 (8)0.0128 (3)
H20.46930.15720.72010.015*
C30.53875 (10)0.26147 (13)0.84121 (8)0.0139 (3)
H30.61030.31340.86140.017*
C40.57828 (10)−0.01283 (14)0.87496 (9)0.0137 (3)
C50.62326 (10)0.02811 (14)0.62678 (9)0.0169 (3)
C60.53918 (10)0.36240 (14)0.68090 (8)0.0144 (3)
C70.41216 (11)0.52976 (14)0.59613 (10)0.0219 (3)
H7A0.47040.57230.55820.026*
H7B0.40240.60030.64940.026*
C80.30531 (11)0.51220 (17)0.53746 (10)0.0273 (3)
H8A0.31660.44330.48470.033*
H8B0.28060.61350.51370.033*
H8C0.24890.46830.57570.033*
C90.44302 (10)0.37055 (13)0.85540 (8)0.0145 (3)
C100.46361 (10)0.52609 (14)0.87614 (8)0.0157 (3)
C110.37451 (11)0.62576 (15)0.88661 (9)0.0203 (3)
H110.38820.73120.90140.024*
C120.26690 (11)0.57248 (15)0.87573 (9)0.0233 (3)
H120.20710.64120.88360.028*
C130.24560 (12)0.41890 (15)0.85339 (10)0.0248 (3)
H130.17150.38240.84520.030*
C140.33378 (11)0.31964 (15)0.84326 (9)0.0204 (3)
H140.31940.21460.82770.024*
H10.7889 (15)0.1108 (18)0.7422 (12)0.046 (5)*
H40.6684 (12)−0.1011 (15)0.7884 (9)0.021 (4)*
H50.4973 (12)0.1248 (15)0.9477 (11)0.025 (4)*
H60.5734 (13)0.6771 (19)0.8967 (11)0.043 (5)*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
F10.0430 (5)0.0269 (4)0.0157 (4)0.0048 (4)0.0052 (4)0.0046 (3)
F20.0214 (4)0.0232 (4)0.0232 (4)0.0060 (3)0.0047 (3)−0.0049 (3)
F30.0180 (4)0.0365 (5)0.0285 (5)−0.0054 (4)−0.0001 (3)−0.0131 (4)
O10.0097 (4)0.0138 (5)0.0264 (5)−0.0005 (4)0.0010 (4)0.0003 (4)
O20.0196 (5)0.0110 (4)0.0161 (5)0.0002 (4)0.0029 (4)0.0015 (4)
O30.0161 (5)0.0168 (5)0.0234 (5)−0.0030 (4)−0.0004 (4)0.0028 (4)
O40.0151 (5)0.0168 (5)0.0241 (5)0.0006 (4)−0.0041 (4)0.0051 (4)
O50.0165 (5)0.0134 (5)0.0381 (6)−0.0009 (4)0.0021 (4)−0.0064 (4)
N10.0154 (5)0.0115 (5)0.0168 (6)0.0045 (4)0.0049 (4)0.0010 (4)
N20.0197 (6)0.0118 (5)0.0146 (6)0.0027 (4)0.0065 (4)0.0009 (4)
C10.0105 (6)0.0133 (6)0.0172 (7)−0.0007 (5)0.0014 (5)0.0020 (5)
C20.0114 (6)0.0120 (6)0.0150 (7)0.0009 (5)0.0013 (5)0.0010 (5)
C30.0135 (6)0.0131 (6)0.0152 (7)0.0001 (5)0.0017 (5)0.0014 (5)
C40.0113 (6)0.0132 (6)0.0163 (7)−0.0022 (5)−0.0009 (5)−0.0015 (5)
C50.0148 (6)0.0171 (6)0.0189 (7)0.0016 (5)0.0027 (5)0.0010 (5)
C60.0128 (6)0.0166 (7)0.0138 (7)0.0021 (5)0.0020 (5)−0.0009 (5)
C70.0209 (7)0.0161 (7)0.0282 (8)0.0041 (5)−0.0009 (6)0.0072 (6)
C80.0217 (7)0.0306 (8)0.0291 (8)0.0048 (6)−0.0013 (6)0.0094 (6)
C90.0148 (6)0.0139 (6)0.0153 (7)0.0023 (5)0.0036 (5)0.0024 (5)
C100.0149 (6)0.0150 (6)0.0172 (7)0.0009 (5)0.0015 (5)0.0004 (5)
C110.0209 (7)0.0143 (7)0.0257 (8)0.0033 (5)0.0018 (6)−0.0028 (6)
C120.0178 (7)0.0223 (7)0.0302 (8)0.0081 (6)0.0045 (6)−0.0003 (6)
C130.0150 (7)0.0246 (7)0.0353 (8)0.0003 (6)0.0049 (6)−0.0016 (6)
C140.0183 (7)0.0147 (7)0.0289 (8)−0.0005 (5)0.0059 (6)−0.0017 (6)

Geometric parameters (Å, °)

F1—C51.3370 (14)C2—C31.5438 (17)
F2—C51.3350 (14)C2—H21.0000
F3—C51.3418 (14)C3—C91.5191 (16)
O1—C11.4110 (14)C3—H31.0000
O1—H10.858 (17)C7—C81.4990 (19)
O2—C41.2547 (14)C7—H7A0.9900
O3—C61.2073 (14)C7—H7B0.9900
O4—C61.3347 (15)C8—H8A0.9800
O4—C71.4611 (14)C8—H8B0.9800
O5—C101.3599 (15)C8—H8C0.9800
O5—H60.912 (16)C9—C141.3922 (17)
N1—C41.3674 (15)C9—C101.3986 (17)
N1—C11.4472 (16)C10—C111.3971 (17)
N1—H40.836 (14)C11—C121.3795 (18)
N2—C41.3373 (16)C11—H110.9500
N2—C31.4606 (15)C12—C131.3886 (19)
N2—H50.867 (14)C12—H120.9500
C1—C21.5344 (16)C13—C141.3856 (18)
C1—C51.5407 (18)C13—H130.9500
C2—C61.5254 (16)C14—H140.9500
C1—O1—H1106.7 (11)F3—C5—C1111.93 (10)
C6—O4—C7116.81 (10)O3—C6—O4124.46 (11)
C10—O5—H6109.5 (10)O3—C6—C2125.69 (12)
C4—N1—C1125.39 (10)O4—C6—C2109.59 (10)
C4—N1—H4113.9 (9)O4—C7—C8106.41 (10)
C1—N1—H4119.4 (9)O4—C7—H7A110.4
C4—N2—C3123.51 (10)C8—C7—H7A110.4
C4—N2—H5117.4 (9)O4—C7—H7B110.4
C3—N2—H5118.2 (9)C8—C7—H7B110.4
O1—C1—N1113.07 (10)H7A—C7—H7B108.6
O1—C1—C2110.26 (10)C7—C8—H8A109.5
N1—C1—C2108.19 (9)C7—C8—H8B109.5
O1—C1—C5108.17 (9)H8A—C8—H8B109.5
N1—C1—C5107.50 (10)C7—C8—H8C109.5
C2—C1—C5109.58 (10)H8A—C8—H8C109.5
C6—C2—C1117.10 (9)H8B—C8—H8C109.5
C6—C2—C3106.28 (10)C14—C9—C10119.03 (11)
C1—C2—C3109.92 (10)C14—C9—C3120.77 (11)
C6—C2—H2107.7C10—C9—C3120.12 (11)
C1—C2—H2107.7O5—C10—C11122.76 (11)
C3—C2—H2107.7O5—C10—C9117.82 (10)
N2—C3—C9110.95 (9)C11—C10—C9119.42 (11)
N2—C3—C2106.50 (10)C12—C11—C10120.64 (12)
C9—C3—C2110.89 (10)C12—C11—H11119.7
N2—C3—H3109.5C10—C11—H11119.7
C9—C3—H3109.5C11—C12—C13120.35 (12)
C2—C3—H3109.5C11—C12—H12119.8
O2—C4—N2121.47 (11)C13—C12—H12119.8
O2—C4—N1120.20 (11)C14—C13—C12119.15 (13)
N2—C4—N1118.31 (11)C14—C13—H13120.4
F2—C5—F1107.99 (10)C12—C13—H13120.4
F2—C5—F3106.92 (10)C13—C14—C9121.39 (12)
F1—C5—F3107.15 (10)C13—C14—H14119.3
F2—C5—C1111.86 (10)C9—C14—H14119.3
F1—C5—C1110.74 (10)
C4—N1—C1—O198.15 (14)O1—C1—C5—F3−176.35 (10)
C4—N1—C1—C2−24.26 (16)N1—C1—C5—F361.24 (13)
C4—N1—C1—C5−142.52 (11)C2—C1—C5—F3−56.12 (13)
O1—C1—C2—C649.05 (14)C7—O4—C6—O3−13.82 (17)
N1—C1—C2—C6173.17 (10)C7—O4—C6—C2160.62 (10)
C5—C1—C2—C6−69.90 (13)C1—C2—C6—O3−60.93 (16)
O1—C1—C2—C3−72.30 (12)C3—C2—C6—O362.31 (15)
N1—C1—C2—C351.82 (13)C1—C2—C6—O4124.72 (11)
C5—C1—C2—C3168.75 (9)C3—C2—C6—O4−112.04 (11)
C4—N2—C3—C9158.86 (11)C6—O4—C7—C8176.95 (10)
C4—N2—C3—C238.09 (16)N2—C3—C9—C14−51.23 (16)
C6—C2—C3—N2174.26 (10)C2—C3—C9—C1466.90 (14)
C1—C2—C3—N2−58.11 (12)N2—C3—C9—C10132.13 (12)
C6—C2—C3—C953.45 (12)C2—C3—C9—C10−109.73 (13)
C1—C2—C3—C9−178.92 (9)C14—C9—C10—O5−177.92 (11)
C3—N2—C4—O2171.65 (11)C3—C9—C10—O5−1.22 (17)
C3—N2—C4—N1−10.02 (18)C14—C9—C10—C111.67 (18)
C1—N1—C4—O2−179.52 (11)C3—C9—C10—C11178.36 (11)
C1—N1—C4—N22.12 (18)O5—C10—C11—C12178.89 (12)
O1—C1—C5—F263.67 (12)C9—C10—C11—C12−0.68 (19)
N1—C1—C5—F2−58.74 (13)C10—C11—C12—C13−0.5 (2)
C2—C1—C5—F2−176.10 (9)C11—C12—C13—C140.7 (2)
O1—C1—C5—F1−56.85 (13)C12—C13—C14—C90.3 (2)
N1—C1—C5—F1−179.26 (10)C10—C9—C14—C13−1.49 (19)
C2—C1—C5—F163.38 (12)C3—C9—C14—C13−178.16 (12)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N1—H4···O1i0.836 (14)2.244 (14)3.0760 (13)174.1 (14)
N2—H5···O2ii0.867 (14)2.040 (15)2.9064 (14)177.4 (13)
O1—H1···O5i0.858 (17)2.588 (16)3.0983 (13)119.2 (13)
O1—H1···O3i0.858 (17)2.013 (17)2.8232 (13)157.1 (15)
O5—H6···O2iii0.912 (16)1.759 (17)2.6685 (12)175.8 (14)

Symmetry codes: (i) −x+3/2, y−1/2, −z+3/2; (ii) −x+1, −y, −z+2; (iii) x, y+1, z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: ZS2042).

References

  • Brier, S., Lemaire, D., DeBonis, S., Forest, E. & Kozielski, F. (2004). Biochemistry, 43, 13072–13082. [PubMed]
  • Cochran, J. C., Gatial, J. E., Kapoor, T. M. & Gilbert, S. P. (2005). J. Biol. Chem.280, 12658–12667. [PMC free article] [PubMed]
  • Hermann, B., Erwin, H. & Hansjorg, K. (2003). US Patent No. 2 003 176 284.
  • Moran, M. M., Fanger, C., Chong, J. A., McNamara, C., Zhen, X. G. & Mandel-Brehm, J. (2007). WO Patent No. 2 007 073 505.
  • Rigaku (2009). CrystalClear-SM Expert and CrystalStructure Rigaku/MSC, The Woodlands, Texas, USA.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Ulrich, H. (2004). US Patent No. 2 004 033 897.
  • Zorkun, I. S., Sarac, S., Celebi, S. & Erol, K. (2006). Bioorg. Med. Chem.14, 8582–8589. [PubMed]

Articles from Acta Crystallographica Section E: Structure Reports Online are provided here courtesy of International Union of Crystallography