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Acta Crystallogr Sect E Struct Rep Online. 2008 June 1; 64(Pt 6): o1092.
Published online 2008 May 17. doi:  10.1107/S1600536808012683
PMCID: PMC2961528

Ethyl 6-ethoxy­carbonyl­methyl-4-(2-hydroxy­phen­yl)-2-oxo-1,2,3,4-tetra­hydro­pyrimidine-5-carboxyl­ate

Abstract

The title compound, C17H20N2O6, belongs to the monastrol-type of anti­cancer agents and was selected for crystal structure determination in order to confirm its mol­ecular structure and explore some aspects of its structure–activity relationships. The central tetra­hydro­pyrimidine ring has a flat-envelope conformation. The 4-hydroxy­phenyl group occupies a pseudo-axial position and is inclined at an angle of 87.7 (2)° to the mean plane of the heterocyclic ring. Of the two ethyl ester groups, one (in the 5-position) is in a coplanar and the other (in the 6-position) is in a perpendicular orientation with respect to the heterocyclic plane. There is a three-dimensional hydrogen-bonding network in which all hydrogen-bond donors and acceptors are involved.

Related literature

For related literature, see: Allen (2002 [triangle]); Azizian et al. (2007 [triangle]); Qing-Fang et al. (2007 [triangle]); Endow & Baker (2003 [triangle]); Kettmann & Svetlík (1997 [triangle]); Světlík et al. (1991 [triangle]); Wood & Bergnes (2004 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-64-o1092-scheme1.jpg

Experimental

Crystal data

  • C17H20N2O6
  • M r = 348.35
  • Triclinic, An external file that holds a picture, illustration, etc.
Object name is e-64-o1092-efi1.jpg
  • a = 8.783 (2) Å
  • b = 9.336 (3) Å
  • c = 11.415 (4) Å
  • α = 71.47 (4)°
  • β = 82.78 (5)°
  • γ = 75.05 (4)°
  • V = 856.5 (5) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.10 mm−1
  • T = 296 (2) K
  • 0.30 × 0.25 × 0.20 mm

Data collection

  • Siemens P4 diffractometer
  • Absorption correction: none
  • 5849 measured reflections
  • 4950 independent reflections
  • 3935 reflections with I > 2σ(I)
  • R int = 0.040
  • 3 standard reflections every 97 reflections intensity decay: none

Refinement

  • R[F 2 > 2σ(F 2)] = 0.057
  • wR(F 2) = 0.174
  • S = 1.04
  • 4950 reflections
  • 229 parameters
  • H-atom parameters constrained
  • Δρmax = 0.31 e Å−3
  • Δρmin = −0.32 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, 2003 [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/S1600536808012683/wk2083sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808012683/wk2083Isup2.hkl

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

Acknowledgments

This work was supported by the Grant Agency of the Slovak Republic, project Nos. 1/4298/07 and 1/4299/07.

supplementary crystallographic information

Comment

Recently, while we have been continuing in our programme aimed at synthesis of monastrol (1) analogues as valuable antitumour drugs (Wood & Bergnes, 2004), a related tetrahydropyrimidine compound (2) has been described by another group (Azizian et al., 2007). As we had reported earlier (Světlík et al., 1991; Kettmann & Svetlík, 1997) that classical Biginelli condensation with salicylaldehyde gives oxygen-bridged pyrimidine (3) rather than the 'open' molecule (4), the formation of (2) was accordingly unexpected. Thus, to verify the correctness of the title structure (2), an X-ray analysis was undertaken. As the cytotoxic activity of these derivatives is related to inhibition of the kinesin Eg5 protein (Endow & Baker, 2003), another purpose of this work was to determine detailed molecular conformation which is indispensable for an analysis of structure-activity relationships.

The structure determination has confirmed (Fig. 1) that the compound studied here has indeed the structure (2) (Fig. 2). As retrieved from the Cambridge Structural Database (Version of 2007; Allen, 2002), the bond lengths and angles (Table 1) within the tetrahydropyrimidine ring are equal within experimental error to those previously reported for a number of structures incorporating this molecular fragment (see, e.g., Qing-Fang et al., 2007). Bonding characteristics in other parts of the molecule also agree with those generally expected.

As noted above, from the biological standpoint, the conformational properties of the molecule are of prime interest here. First, the conformation of the central heterocycle can best be described as a flat envelope with atom C4 (at the flap) deviating by 0.433 (2) Å from the mean plane of the remaining atoms. As to the ring substituents, the 4-hydroxyphenyl group occupies the pseudoaxial position and is in a perpendicular orientation with respect to the tetrahydropyrimidine ring [dihedral angle 87.7 (2)°]; the conformation of the substituent on the exocyclic C4—C7 bond is synperiplanar, i.e. the hydroxy group is on the same side as the H atom on C4 (Fig.1). The ester group on C5 lies approximately in the plane of the C5=C6 double bond, with the carbonyl function oriented cis relative to this double bond. By contrast, the ethoxycarbonyl moiety of the 6-substituent is oriented, due to rather free rotation about the two C16 methylenic bonds, perpendicularly with respect to the mean plane of the heterocycle.

The crystal packing is dominated by hydrogen bonding. As shown in Table 2 and Fig. 3, each molecule forms two pairs of hydrogen bonds (N1-H···O1 and O2-H···O3) across centres of symmetry, which results in formation of chains of hydrogen-bonded molecules. The chains are interconnected by another independent hydrogen bond, N3-H···O5.

Experimental

Synthesis of the title compound, (2), has been described (Azizian et al., 2007). In short, heating of salicylaldehyde (0.52 ml, 5 mmol) with diethyl acetone-1,3-dicarboxylate (0.91 ml, 5 mmol) and urea (0.36 g, 6 mmol) under p-toluenesulfonic acid (0.04 g, 0.2 mmol) catalysis without solvent at 353–363 K for 3 h gave the desired product (50% yield; m.p. 488–490 K). Crystalssuitable for the X-ray analysis were obtained by a slow crystallization from ethanol.

Refinement

H atoms were visible in difference maps and were subsequently treated as riding atoms with distances C—H = 0.93 Å (CHarom), 0.97 (CH2) or 0.98 Å (CH), 0.96 Å (CH3) and N—H = 0.86 Å and O—H = 0.82 Å; Uiso of the H atoms were set to 1.2 (1.5 for the methyl and hydroxy H atoms) times Ueq of the parent atom.

Figures

Fig. 1.
Displacement ellipsoid plot of (2) with the labelling scheme for the non-H atoms, which are drawn as 35% probability ellipsoids.
Fig. 2.
The structure of compounds (1)–(4).
Fig. 3.
View of the crystal packing along the a axis, showing system of hydrogen bonds (dashed lines).

Crystal data

C17H20N2O6Z = 2
Mr = 348.35F000 = 368
Triclinic, P1Dx = 1.351 Mg m3
Hall symbol: -P 1Melting point: 489 K
a = 8.783 (2) ÅMo Kα radiation λ = 0.71073 Å
b = 9.336 (3) ÅCell parameters from 20 reflections
c = 11.415 (4) Åθ = 7–18º
α = 71.47 (4)ºµ = 0.10 mm1
β = 82.78 (5)ºT = 296 (2) K
γ = 75.05 (4)ºPrism, colourless
V = 856.5 (5) Å30.30 × 0.25 × 0.20 mm

Data collection

Siemens P4 diffractometerRint = 0.040
Radiation source: fine-focus sealed tubeθmax = 30.0º
Monochromator: graphiteθmin = 1.9º
T = 296(2) Kh = −1→12
ω/2θ scansk = −12→12
Absorption correction: nonel = −16→16
5849 measured reflections3 standard reflections
4950 independent reflections every 97 reflections
3935 reflections with I > 2σ(I) intensity decay: none

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.057H-atom parameters constrained
wR(F2) = 0.174  w = 1/[σ2(Fo2) + (0.0972P)2 + 0.1877P] where P = (Fo2 + 2Fc2)/3
S = 1.04(Δ/σ)max = 0.001
4950 reflectionsΔρmax = 0.31 e Å3
229 parametersΔρmin = −0.31 e Å3
Primary atom site location: structure-invariant direct methodsExtinction correction: none

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
N10.10214 (15)0.47412 (12)0.13671 (11)0.0350 (3)
H10.07490.54650.06920.042*
C20.11515 (15)0.32189 (14)0.13967 (13)0.0315 (3)
O10.06497 (13)0.29448 (11)0.05495 (10)0.0408 (3)
N30.17844 (14)0.21317 (12)0.24052 (11)0.0344 (3)
H30.16150.12180.25840.041*
C40.27587 (15)0.24302 (13)0.32230 (12)0.0304 (3)
H40.26690.17040.40510.037*
C50.21064 (15)0.40660 (14)0.33107 (12)0.0307 (3)
C60.13046 (15)0.51589 (13)0.23577 (12)0.0302 (3)
C70.44794 (15)0.21163 (14)0.27695 (12)0.0315 (3)
C80.51674 (18)0.32744 (17)0.19754 (16)0.0431 (3)
H80.45840.42970.17530.052*
C90.6717 (2)0.2929 (2)0.15072 (18)0.0521 (4)
H90.71610.37150.09750.063*
C100.75860 (19)0.1417 (2)0.18372 (18)0.0519 (4)
H100.86170.11820.15190.062*
C110.69370 (19)0.02481 (19)0.26383 (17)0.0469 (4)
H110.7536−0.07680.28670.056*
C120.53881 (16)0.05890 (15)0.31031 (14)0.0353 (3)
O20.46665 (14)−0.05252 (12)0.38635 (12)0.0489 (3)
H20.5328−0.13410.41060.073*
C130.24784 (17)0.43413 (15)0.44190 (13)0.0367 (3)
O30.31840 (19)0.33335 (14)0.52678 (12)0.0602 (4)
O40.19773 (16)0.58055 (12)0.44378 (11)0.0485 (3)
C140.2312 (3)0.6194 (2)0.55027 (18)0.0582 (5)
H14A0.34410.60370.55510.070*
H14B0.19120.55420.62600.070*
C150.1516 (3)0.7858 (2)0.5332 (2)0.0668 (6)
H15A0.19920.84970.46240.100*
H15B0.16270.81310.60550.100*
H15C0.04170.80160.52080.100*
C160.06044 (17)0.68574 (14)0.22359 (14)0.0363 (3)
H16A−0.01090.72740.15620.044*
H16B−0.00220.69250.29880.044*
C170.17511 (19)0.78803 (15)0.20076 (15)0.0403 (3)
O50.13786 (18)0.91436 (13)0.21651 (16)0.0651 (4)
O60.31602 (15)0.72710 (13)0.15956 (13)0.0521 (3)
C180.4286 (3)0.8264 (3)0.1244 (3)0.0778 (7)
H18A0.40170.90490.04600.093*
H18B0.42400.87860.18640.093*
C190.5842 (3)0.7343 (3)0.1139 (4)0.0954 (9)
H19A0.61290.66130.19310.143*
H19B0.65720.80040.08640.143*
H19C0.58700.67920.05530.143*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
N10.0449 (6)0.0191 (5)0.0410 (6)−0.0060 (4)−0.0108 (5)−0.0068 (4)
C20.0302 (6)0.0220 (5)0.0430 (7)−0.0070 (4)−0.0017 (5)−0.0100 (5)
O10.0490 (6)0.0278 (5)0.0503 (6)−0.0086 (4)−0.0120 (5)−0.0145 (4)
N30.0371 (6)0.0183 (4)0.0485 (6)−0.0078 (4)−0.0076 (5)−0.0076 (4)
C40.0316 (6)0.0192 (5)0.0374 (6)−0.0034 (4)−0.0032 (5)−0.0057 (4)
C50.0309 (6)0.0208 (5)0.0386 (6)−0.0023 (4)−0.0031 (5)−0.0086 (4)
C60.0301 (6)0.0200 (5)0.0400 (6)−0.0040 (4)−0.0043 (5)−0.0086 (4)
C70.0306 (6)0.0246 (5)0.0377 (6)−0.0014 (4)−0.0050 (5)−0.0098 (5)
C80.0376 (7)0.0299 (6)0.0546 (9)−0.0049 (5)0.0012 (6)−0.0062 (6)
C90.0421 (8)0.0477 (9)0.0610 (10)−0.0127 (7)0.0082 (7)−0.0108 (7)
C100.0331 (7)0.0566 (10)0.0660 (11)−0.0028 (7)0.0024 (7)−0.0262 (8)
C110.0364 (7)0.0375 (7)0.0644 (10)0.0053 (6)−0.0075 (7)−0.0210 (7)
C120.0345 (6)0.0257 (6)0.0450 (7)−0.0006 (5)−0.0095 (5)−0.0118 (5)
O20.0458 (6)0.0227 (5)0.0677 (8)−0.0004 (4)−0.0063 (5)−0.0039 (5)
C130.0402 (7)0.0268 (6)0.0403 (7)−0.0018 (5)−0.0062 (5)−0.0094 (5)
O30.0838 (10)0.0372 (6)0.0517 (7)0.0105 (6)−0.0301 (7)−0.0116 (5)
O40.0702 (8)0.0307 (5)0.0453 (6)0.0010 (5)−0.0188 (5)−0.0164 (4)
C140.0785 (13)0.0520 (10)0.0517 (10)−0.0078 (9)−0.0171 (9)−0.0264 (8)
C150.0932 (16)0.0557 (11)0.0642 (12)−0.0218 (11)0.0058 (11)−0.0351 (10)
C160.0368 (6)0.0207 (5)0.0507 (8)0.0016 (5)−0.0126 (6)−0.0121 (5)
C170.0508 (8)0.0217 (5)0.0483 (8)−0.0047 (5)−0.0154 (6)−0.0082 (5)
O50.0715 (9)0.0265 (5)0.1037 (11)−0.0072 (5)−0.0159 (8)−0.0272 (6)
O60.0534 (7)0.0329 (5)0.0741 (8)−0.0180 (5)0.0064 (6)−0.0185 (5)
C180.0722 (14)0.0501 (11)0.116 (2)−0.0352 (10)0.0059 (13)−0.0184 (12)
C190.0650 (14)0.0790 (17)0.154 (3)−0.0359 (13)0.0172 (16)−0.0439 (18)

Geometric parameters (Å, °)

N1—C61.3761 (18)C12—O21.366 (2)
N1—C21.3859 (16)O2—H20.8200
N1—H10.8600C13—O31.2161 (19)
C2—O11.2319 (17)C13—O41.3299 (17)
C2—N31.3385 (19)O4—C141.456 (2)
N3—C41.4733 (18)C14—C151.490 (3)
N3—H30.8600C14—H14A0.9700
C4—C51.5172 (17)C14—H14B0.9700
C4—C71.5196 (19)C15—H15A0.9600
C4—H40.9800C15—H15B0.9600
C5—C61.3553 (19)C15—H15C0.9600
C5—C131.458 (2)C16—C171.505 (2)
C6—C161.5134 (17)C16—H16A0.9700
C7—C81.390 (2)C16—H16B0.9700
C7—C121.3997 (18)C17—O51.2047 (18)
C8—C91.393 (2)C17—O61.318 (2)
C8—H80.9300O6—C181.461 (2)
C9—C101.376 (3)C18—C191.428 (4)
C9—H90.9300C18—H18A0.9700
C10—C111.381 (3)C18—H18B0.9700
C10—H100.9300C19—H19A0.9600
C11—C121.391 (2)C19—H19B0.9600
C11—H110.9300C19—H19C0.9600
C6—N1—C2123.64 (12)C12—O2—H2109.5
C6—N1—H1118.2O3—C13—O4121.72 (14)
C2—N1—H1118.2O3—C13—C5123.83 (13)
O1—C2—N3124.46 (12)O4—C13—C5114.46 (12)
O1—C2—N1119.97 (13)C13—O4—C14118.33 (13)
N3—C2—N1115.52 (12)O4—C14—C15107.06 (16)
C2—N3—C4122.97 (11)O4—C14—H14A110.3
C2—N3—H3118.5C15—C14—H14A110.3
C4—N3—H3118.5O4—C14—H14B110.3
N3—C4—C5109.07 (11)C15—C14—H14B110.3
N3—C4—C7109.88 (11)H14A—C14—H14B108.6
C5—C4—C7113.81 (11)C14—C15—H15A109.5
N3—C4—H4108.0C14—C15—H15B109.5
C5—C4—H4108.0H15A—C15—H15B109.5
C7—C4—H4108.0C14—C15—H15C109.5
C6—C5—C13125.23 (12)H15A—C15—H15C109.5
C6—C5—C4119.05 (12)H15B—C15—H15C109.5
C13—C5—C4115.65 (11)C17—C16—C6116.62 (12)
C5—C6—N1119.39 (11)C17—C16—H16A108.1
C5—C6—C16127.74 (12)C6—C16—H16A108.1
N1—C6—C16112.86 (11)C17—C16—H16B108.1
C8—C7—C12118.38 (13)C6—C16—H16B108.1
C8—C7—C4122.55 (12)H16A—C16—H16B107.3
C12—C7—C4118.97 (12)O5—C17—O6124.41 (16)
C7—C8—C9121.11 (15)O5—C17—C16122.19 (16)
C7—C8—H8119.4O6—C17—C16113.38 (12)
C9—C8—H8119.4C17—O6—C18116.16 (15)
C10—C9—C8119.64 (16)C19—C18—O6109.59 (19)
C10—C9—H9120.2C19—C18—H18A109.8
C8—C9—H9120.2O6—C18—H18A109.8
C9—C10—C11120.39 (15)C19—C18—H18B109.8
C9—C10—H10119.8O6—C18—H18B109.8
C11—C10—H10119.8H18A—C18—H18B108.2
C10—C11—C12120.09 (15)C18—C19—H19A109.5
C10—C11—H11120.0C18—C19—H19B109.5
C12—C11—H11120.0H19A—C19—H19B109.5
O2—C12—C11122.69 (13)C18—C19—H19C109.5
O2—C12—C7116.89 (13)H19A—C19—H19C109.5
C11—C12—C7120.39 (15)H19B—C19—H19C109.5
C6—N1—C2—O1168.78 (13)C8—C9—C10—C11−0.7 (3)
C6—N1—C2—N3−8.8 (2)C9—C10—C11—C121.0 (3)
O1—C2—N3—C4162.57 (13)C10—C11—C12—O2177.68 (15)
N1—C2—N3—C4−19.99 (19)C10—C11—C12—C7−0.3 (2)
C2—N3—C4—C536.47 (17)C8—C7—C12—O2−178.66 (14)
C2—N3—C4—C7−88.92 (15)C4—C7—C12—O2−2.32 (19)
N3—C4—C5—C6−27.05 (17)C8—C7—C12—C11−0.5 (2)
C7—C4—C5—C696.02 (15)C4—C7—C12—C11175.82 (13)
N3—C4—C5—C13155.91 (12)C6—C5—C13—O3179.07 (16)
C7—C4—C5—C13−81.02 (15)C4—C5—C13—O3−4.1 (2)
C13—C5—C6—N1−179.52 (13)C6—C5—C13—O4−0.8 (2)
C4—C5—C6—N13.74 (19)C4—C5—C13—O4176.03 (12)
C13—C5—C6—C16−1.2 (2)O3—C13—O4—C140.9 (3)
C4—C5—C6—C16−177.95 (12)C5—C13—O4—C14−179.27 (15)
C2—N1—C6—C516.6 (2)C13—O4—C14—C15−175.54 (17)
C2—N1—C6—C16−161.95 (13)C5—C6—C16—C1771.9 (2)
N3—C4—C7—C893.30 (16)N1—C6—C16—C17−109.73 (15)
C5—C4—C7—C8−29.33 (19)C6—C16—C17—O5−163.22 (15)
N3—C4—C7—C12−82.87 (15)C6—C16—C17—O618.42 (19)
C5—C4—C7—C12154.50 (12)O5—C17—O6—C18−3.9 (3)
C12—C7—C8—C90.8 (2)C16—C17—O6—C18174.44 (17)
C4—C7—C8—C9−175.40 (15)C17—O6—C18—C19164.6 (2)
C7—C8—C9—C10−0.2 (3)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N1—H1···O1i0.861.972.788 (2)159
O2—H2···O3ii0.821.952.772 (2)177
N3—H3···O5iii0.862.203.0014 (18)155

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: WK2083).

References

  • Allen, F. H. (2002). Acta Cryst. B58, 380–388. [PubMed]
  • Azizian, J., Mohammadi, A. A., Kohshari, M., Karimi, A. R. & Mohammadizadeh, M. R. (2007). J. Heterocycl. Chem.44, 455–458.
  • Endow, S. A. & Baker, D. S. (2003). Annu. Rev. Physiol.65, 161–180. [PubMed]
  • Kettmann, V. & Svetlík, J. (1997). Acta Cryst. C53, 1493–1495.
  • Qing-Fang, C., Xu, X.-Y., Bao, J.-Y. & Zhang, C.-F. (2007). Acta Cryst. E63, o2391–o2392.
  • 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. (2003). J. Appl. Cryst.36, 7–13.
  • Světlík, J., Hanus, V. & Bella, J. (1991). J. Chem. Res. (S), pp. 4–5.
  • Wood, K. W. & Bergnes, G. (2004). Annu. Rep. Med. Chem.39, 173–183.

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