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Acta Crystallogr Sect E Struct Rep Online. 2010 May 1; 66(Pt 5): o1083.
Published online 2010 April 14. doi:  10.1107/S1600536810013127
PMCID: PMC2979242

Ethyl 6-[4-(dimethyl­amino)phen­yl]-4-hydr­oxy-2-oxo-4-(trifluoro­methyl)­hexa­hydro­pyrimidine-5-carboxyl­ate

Abstract

The title compound, C16H20F3N3O4, was prepared by reaction of 4-(dimethyl­amino)benzaldehyde, ethyl 4,4,4-trifluoro-3-oxo­butanoate and urea. In the title mol­ecule, the pyrimidine ring adopts a half-chair conformation and there is an intra­molecular hydrogen bond (O—H(...)O). The crystal structure is stabilized by two types inter­molecular hydrogen bonds (N—H(...)O and N—H(...)N).

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-o1083-scheme1.jpg

Experimental

Crystal data

  • C16H20F3N3O4
  • M r = 375.35
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-66-o1083-efi1.jpg
  • a = 13.319 (4) Å
  • b = 7.923 (2) Å
  • c = 16.530 (5) Å
  • β = 92.720 (5)°
  • V = 1742.3 (9) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.12 mm−1
  • T = 116 K
  • 0.24 × 0.20 × 0.14 mm

Data collection

  • Rigaku Saturn CCD area-detector diffractometer
  • Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2005 [triangle]) T min = 0.971, T max = 0.983
  • 11487 measured reflections
  • 3081 independent reflections
  • 2522 reflections with I > 2σ(I)
  • R int = 0.030

Refinement

  • R[F 2 > 2σ(F 2)] = 0.037
  • wR(F 2) = 0.107
  • S = 1.07
  • 3081 reflections
  • 250 parameters
  • 3 restraints
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.17 e Å−3
  • Δρmin = −0.24 e Å−3

Data collection: CrystalClear (Rigaku/MSC, 2005 [triangle]); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: CrystalStructure (Rigaku/MSC, 2005 [triangle]).

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810013127/om2331sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810013127/om2331Isup2.hkl

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

Acknowledgments

This work was supported by the 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). Besides, compounds that contain fluorine have special bioactivity, for example, flumioxazin is a widely used herbicide (Hermann et al., 2003; Ulrich, 2004). This led us to pay much attention to the synthesis and bioactivity of these important fused perfluoroalkylated heterocyclic compounds. During the synthesis of DHPM derivatives, the title compound, an intermediate, was isolated and confirmed by X-ray diffraction to elucidate the reaction mechanism. We report here the crystal structure of the title compound(Fig. 1).

In the title molecule, the pyrimidine ring adopts a half-chair conformation, and there is an intramolecular hydrogen bond (O—H···O). The crystal structure is stabilized by two types intermolecular hydrogen bonds (N—H···O, and N—H···N).

Experimental

The title compound was synthesized by 4-(dimethylamino)-benzaldehyde (2.98 g, 20 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate(4.42 g, 24 mmol), and urea (1.80 g, 30 mmol), catalyzed by sulfamic acid(0.6 g), in the solvent of ethanol(20 ml), by refluxing for 3 h under the conditions of stirring. The solvent was evaporated in vacuo and the residue was washed with water. The title compound was recrystallized from ethanol and single crystals of (I) were obtained by slow evaporation.

Refinement

H atoms of N and O were positioned freely refined. The other H atoms were placed in calculated positions, with C—H = 0.93, 0.96, 0.97 or 0.98 Å, and included in the final cycles of refinement using a riding model, with Uiso(H) = 1.2Ueq(C).

Figures

Fig. 1.
The asymmetric unit of the title compound, (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

C16H20F3N3O4F(000) = 784
Mr = 375.35Dx = 1.431 Mg m3
Monoclinic, P21/nMo Kα radiation, λ = 0.71073 Å
a = 13.319 (4) ÅCell parameters from 6970 reflections
b = 7.923 (2) Åθ = 1.5–27.9°
c = 16.530 (5) ŵ = 0.12 mm1
β = 92.720 (5)°T = 116 K
V = 1742.3 (9) Å3Prism, colorless
Z = 40.24 × 0.20 × 0.14 mm

Data collection

Rigaku Saturn CCD area-detector diffractometer3081 independent reflections
Radiation source: rotating anode2522 reflections with I > 2σ(I)
multilayerRint = 0.030
Detector resolution: 14.63 pixels mm-1θmax = 25.0°, θmin = 1.9°
ω and [var phi] scansh = −15→15
Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2005)k = −9→9
Tmin = 0.971, Tmax = 0.983l = −19→18
11487 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)] = 0.037Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.107H atoms treated by a mixture of independent and constrained refinement
S = 1.07w = 1/[σ2(Fo2) + (0.0725P)2] where P = (Fo2 + 2Fc2)/3
3081 reflections(Δ/σ)max = 0.001
250 parametersΔρmax = 0.17 e Å3
3 restraintsΔρmin = −0.24 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
F20.76872 (7)0.70609 (12)1.19210 (5)0.0422 (3)
F30.87687 (7)0.90599 (12)1.18384 (5)0.0419 (3)
F10.73912 (7)0.91322 (12)1.11033 (6)0.0434 (3)
O10.93596 (8)0.60732 (13)1.11199 (6)0.0292 (3)
O20.96896 (7)0.91625 (12)0.90354 (6)0.0262 (3)
O30.78789 (9)0.36331 (13)1.10635 (6)0.0385 (3)
O40.63911 (8)0.47358 (14)1.06174 (7)0.0362 (3)
N10.90896 (9)0.83310 (15)1.02318 (7)0.0231 (3)
N20.87955 (8)0.67473 (14)0.90588 (7)0.0216 (3)
N30.57474 (8)0.09436 (13)0.76740 (7)0.0214 (3)
C10.81144 (11)0.81114 (19)1.14029 (9)0.0296 (4)
C20.86240 (10)0.71282 (17)1.07362 (8)0.0220 (3)
C30.78493 (10)0.60970 (16)1.02222 (8)0.0208 (3)
H30.73170.68501.00070.025*
C40.84102 (10)0.53309 (17)0.95139 (8)0.0198 (3)
H40.89800.46690.97360.024*
C50.92246 (10)0.81105 (16)0.94208 (8)0.0202 (3)
C60.73872 (11)0.46902 (19)1.06923 (9)0.0275 (3)
C70.58484 (14)0.3318 (2)1.09539 (11)0.0478 (5)
H7A0.52310.37171.11760.057*
H7B0.62560.27991.13880.057*
C80.56152 (16)0.2067 (2)1.03137 (11)0.0555 (6)
H8A0.52350.25970.98760.083*
H8B0.52290.11641.05300.083*
H8C0.62300.16251.01180.083*
C90.77484 (10)0.41978 (16)0.89851 (8)0.0190 (3)
C100.79225 (10)0.24776 (18)0.89719 (8)0.0213 (3)
H100.84790.20400.92620.026*
C110.72844 (10)0.13904 (17)0.85356 (8)0.0219 (3)
H110.74190.02390.85350.026*
C120.64423 (10)0.20114 (16)0.80974 (8)0.0195 (3)
C130.63014 (10)0.37648 (17)0.80716 (8)0.0225 (3)
H130.57720.42150.77540.027*
C140.69393 (10)0.48298 (17)0.85123 (8)0.0226 (3)
H140.68270.59880.84930.027*
C150.58978 (11)−0.08702 (17)0.77979 (8)0.0254 (3)
H15A0.6557−0.11790.76400.038*
H15B0.5403−0.14830.74760.038*
H15C0.5832−0.11370.83590.038*
C160.46919 (10)0.14840 (19)0.77106 (9)0.0301 (4)
H16A0.45640.18300.82530.045*
H16B0.42560.05610.75570.045*
H16C0.45680.24120.73460.045*
H10.9050 (13)0.5138 (16)1.1199 (12)0.054 (6)*
H1A0.9442 (11)0.9186 (15)1.0458 (9)0.032 (4)*
H2A0.8942 (11)0.6524 (19)0.8542 (6)0.032 (4)*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
F20.0505 (6)0.0475 (6)0.0302 (5)−0.0197 (5)0.0198 (4)−0.0068 (4)
F30.0473 (6)0.0502 (6)0.0291 (5)−0.0227 (5)0.0115 (4)−0.0174 (4)
F10.0429 (6)0.0419 (6)0.0464 (6)0.0076 (4)0.0123 (5)−0.0114 (4)
O10.0280 (6)0.0337 (6)0.0254 (6)−0.0022 (5)−0.0052 (4)0.0032 (5)
O20.0299 (6)0.0269 (5)0.0219 (5)−0.0110 (4)0.0029 (4)0.0007 (4)
O30.0505 (8)0.0332 (6)0.0315 (6)−0.0106 (5)−0.0021 (5)0.0088 (5)
O40.0305 (7)0.0399 (7)0.0393 (6)−0.0165 (5)0.0135 (5)−0.0066 (5)
N10.0258 (7)0.0239 (6)0.0197 (6)−0.0091 (5)0.0022 (5)−0.0034 (5)
N20.0252 (7)0.0218 (6)0.0180 (6)−0.0073 (5)0.0039 (5)−0.0013 (5)
N30.0208 (6)0.0217 (6)0.0215 (6)−0.0029 (5)0.0001 (5)−0.0020 (5)
C10.0296 (9)0.0324 (8)0.0274 (8)−0.0096 (7)0.0076 (6)−0.0048 (7)
C20.0199 (7)0.0257 (8)0.0206 (7)−0.0034 (6)0.0013 (5)0.0006 (6)
C30.0198 (7)0.0216 (7)0.0209 (7)−0.0017 (5)0.0010 (5)0.0001 (6)
C40.0182 (7)0.0199 (7)0.0213 (7)−0.0013 (5)0.0014 (5)0.0012 (6)
C50.0176 (7)0.0215 (7)0.0216 (7)0.0001 (6)0.0002 (5)−0.0010 (6)
C60.0317 (9)0.0284 (8)0.0227 (7)−0.0091 (7)0.0055 (6)−0.0051 (7)
C70.0497 (11)0.0533 (11)0.0422 (10)−0.0325 (9)0.0220 (8)−0.0074 (9)
C80.0750 (15)0.0473 (11)0.0461 (11)−0.0330 (10)0.0243 (10)−0.0123 (9)
C90.0187 (7)0.0203 (7)0.0181 (7)−0.0021 (5)0.0029 (5)0.0003 (5)
C100.0188 (7)0.0236 (7)0.0214 (7)0.0022 (6)−0.0006 (5)0.0007 (6)
C110.0247 (8)0.0166 (7)0.0244 (7)0.0005 (6)0.0021 (6)−0.0005 (6)
C120.0188 (7)0.0242 (7)0.0159 (6)−0.0029 (5)0.0037 (5)−0.0014 (5)
C130.0194 (7)0.0250 (8)0.0227 (7)0.0014 (6)−0.0028 (6)0.0013 (6)
C140.0258 (8)0.0170 (7)0.0250 (7)0.0014 (6)0.0006 (6)0.0016 (6)
C150.0295 (8)0.0238 (8)0.0229 (7)−0.0064 (6)0.0005 (6)−0.0007 (6)
C160.0216 (8)0.0375 (9)0.0312 (8)−0.0033 (6)0.0012 (6)−0.0079 (7)

Geometric parameters (Å, °)

F2—C11.3403 (17)C4—H40.9800
F3—C11.3353 (17)C7—C81.472 (2)
F1—C11.3348 (18)C7—H7A0.9700
O1—C21.4149 (17)C7—H7B0.9700
O1—H10.860 (9)C8—H8A0.9600
O2—C51.2335 (16)C8—H8B0.9600
O3—C61.2119 (19)C8—H8C0.9600
O4—C61.3271 (19)C9—C101.3828 (19)
O4—C71.4601 (18)C9—C141.3938 (19)
N1—C51.3722 (18)C10—C111.3878 (19)
N1—C21.4273 (17)C10—H100.9300
N1—H1A0.896 (9)C11—C121.3956 (19)
N2—C51.3486 (18)C11—H110.9300
N2—C41.4578 (17)C12—C131.4021 (19)
N2—H2A0.902 (9)C13—C141.3805 (19)
N3—C121.4145 (17)C13—H130.9300
N3—C151.4640 (17)C14—H140.9300
N3—C161.4735 (18)C15—H15A0.9600
C1—C21.534 (2)C15—H15B0.9600
C2—C31.5397 (19)C15—H15C0.9600
C3—C61.5067 (19)C16—H16A0.9600
C3—C41.5429 (18)C16—H16B0.9600
C3—H30.9800C16—H16C0.9600
C4—C91.5079 (19)
C2—O1—H1104.5 (13)O4—C7—H7A109.8
C6—O4—C7117.02 (14)C8—C7—H7A109.8
C5—N1—C2124.51 (12)O4—C7—H7B109.8
C5—N1—H1A114.4 (11)C8—C7—H7B109.8
C2—N1—H1A119.6 (10)H7A—C7—H7B108.2
C5—N2—C4122.66 (11)C7—C8—H8A109.5
C5—N2—H2A118.1 (10)C7—C8—H8B109.5
C4—N2—H2A115.7 (10)H8A—C8—H8B109.5
C12—N3—C15115.84 (11)C7—C8—H8C109.5
C12—N3—C16114.14 (11)H8A—C8—H8C109.5
C15—N3—C16113.82 (11)H8B—C8—H8C109.5
F1—C1—F3107.46 (12)C10—C9—C14118.10 (12)
F1—C1—F2107.01 (12)C10—C9—C4120.13 (12)
F3—C1—F2106.92 (12)C14—C9—C4121.75 (12)
F1—C1—C2112.17 (12)C9—C10—C11121.39 (12)
F3—C1—C2111.93 (12)C9—C10—H10119.3
F2—C1—C2111.06 (12)C11—C10—H10119.3
O1—C2—N1110.21 (11)C10—C11—C12120.54 (13)
O1—C2—C1107.38 (11)C10—C11—H11119.7
N1—C2—C1107.45 (12)C12—C11—H11119.7
O1—C2—C3111.44 (11)C11—C12—C13117.92 (12)
N1—C2—C3109.29 (11)C11—C12—N3122.47 (12)
C1—C2—C3110.99 (11)C13—C12—N3119.60 (12)
C6—C3—C2112.79 (11)C14—C13—C12120.75 (12)
C6—C3—C4108.95 (11)C14—C13—H13119.6
C2—C3—C4106.95 (11)C12—C13—H13119.6
C6—C3—H3109.4C13—C14—C9121.09 (12)
C2—C3—H3109.4C13—C14—H14119.5
C4—C3—H3109.4C9—C14—H14119.5
N2—C4—C9111.69 (11)N3—C15—H15A109.5
N2—C4—C3106.48 (11)N3—C15—H15B109.5
C9—C4—C3112.54 (11)H15A—C15—H15B109.5
N2—C4—H4108.7N3—C15—H15C109.5
C9—C4—H4108.7H15A—C15—H15C109.5
C3—C4—H4108.7H15B—C15—H15C109.5
O2—C5—N2121.65 (12)N3—C16—H16A109.5
O2—C5—N1120.72 (12)N3—C16—H16B109.5
N2—C5—N1117.58 (12)H16A—C16—H16B109.5
O3—C6—O4125.44 (14)N3—C16—H16C109.5
O3—C6—C3123.25 (14)H16A—C16—H16C109.5
O4—C6—C3111.27 (13)H16B—C16—H16C109.5
O4—C7—C8109.59 (14)
C5—N1—C2—O193.48 (15)C2—N1—C5—N27.3 (2)
C5—N1—C2—C1−149.82 (13)C7—O4—C6—O3−5.4 (2)
C5—N1—C2—C3−29.31 (18)C7—O4—C6—C3172.21 (12)
F1—C1—C2—O1−179.00 (11)C2—C3—C6—O3−53.65 (18)
F3—C1—C2—O160.12 (15)C4—C3—C6—O364.94 (17)
F2—C1—C2—O1−59.30 (14)C2—C3—C6—O4128.71 (12)
F1—C1—C2—N162.46 (15)C4—C3—C6—O4−112.70 (13)
F3—C1—C2—N1−58.43 (15)C6—O4—C7—C8−94.93 (19)
F2—C1—C2—N1−177.85 (11)N2—C4—C9—C10128.63 (13)
F1—C1—C2—C3−56.98 (16)C3—C4—C9—C10−111.65 (14)
F3—C1—C2—C3−177.86 (11)N2—C4—C9—C14−52.72 (16)
F2—C1—C2—C362.72 (15)C3—C4—C9—C1467.00 (15)
O1—C2—C3—C652.81 (15)C14—C9—C10—C11−3.27 (19)
N1—C2—C3—C6174.86 (11)C4—C9—C10—C11175.43 (12)
C1—C2—C3—C6−66.81 (15)C9—C10—C11—C12−0.2 (2)
O1—C2—C3—C4−66.94 (13)C10—C11—C12—C134.00 (19)
N1—C2—C3—C455.11 (14)C10—C11—C12—N3−177.11 (11)
C1—C2—C3—C4173.44 (11)C15—N3—C12—C116.82 (18)
C5—N2—C4—C9165.79 (12)C16—N3—C12—C11141.96 (13)
C5—N2—C4—C342.56 (16)C15—N3—C12—C13−174.31 (12)
C6—C3—C4—N2177.15 (11)C16—N3—C12—C13−39.17 (16)
C2—C3—C4—N2−60.65 (13)C11—C12—C13—C14−4.37 (19)
C6—C3—C4—C954.46 (15)N3—C12—C13—C14176.70 (12)
C2—C3—C4—C9176.66 (11)C12—C13—C14—C91.0 (2)
C4—N2—C5—O2168.05 (12)C10—C9—C14—C132.89 (19)
C4—N2—C5—N1−14.73 (19)C4—C9—C14—C13−175.79 (12)
C2—N1—C5—O2−175.47 (12)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
O1—H1···O30.86 (1)1.97 (1)2.7601 (16)153 (2)
N1—H1A···O2i0.90 (1)1.91 (1)2.8049 (15)174 (2)
N2—H2A···N3ii0.90 (1)2.12 (1)3.0241 (18)178 (2)

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: OM2331).

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. 2003176284.
  • Moran, M. M., Fanger, C., Chong, J. A., McNamara, C., Zhen, X. G. & &Mandel-Brehm, J. (2007). WO Patent No. 2007073505.
  • Rigaku/MSC (2005). CrystalClear and CrystalStructure Rigaku/MSC, The Woodlands, Texas, USA.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Ulrich, H. (2004). US Patent No. 2004033897.
  • 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