Methyl 6-methoxy­carbonyl­methyl-2-oxo-4-phenyl-1,2,3,4-tetra­hydro­pyrimidine-5-carboxyl­ate

Viktor Kettmann; Jan Světlík; Lucia Veizerová

doi:10.1107/S1600536808026135

. 2008 Aug 16;64(Pt 9):o1776. doi: 10.1107/S1600536808026135

Methyl 6-methoxycarbonylmethyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Viktor Kettmann ^a,^*, Jan Světlík ^a, Lucia Veizerová ^a

PMCID: PMC2960603 PMID: 21201756

Abstract

The title compound, C₁₅H₁₆N₂O₅, belongs to the class of monastrol-type anti-cancer agents and was selected for crystal structure determination in order to determine the conformational details needed for subsequent structure–activity relationship studies. The central tetrahydropyrimidine ring has a flat-envelope conformation. The 4-phenyl group occupies a pseudo-axial position and is inclined at an angle of ca 90° to the mean plane of the heterocyclic ring. Of the two methyl ester groups, one (in the 5-position) is in a coplanar and the other (in the 6-position) in a perpendicular orientation with respect to the heterocyclic plane. The coplanar 5-ester group has its carbonyl bond oriented cis with respect to the pyrimidine C=C double bond. By comparison of the structural results for the present compound with those determined previously for its diethyl analogue, we have identified the molecular factors which control the dual course of the Biginelli reaction with salicylaldehyde. The crystal structure is dominated by two hydrogen bonds which link the molecules into chains of dimers.

Related literature

For related literature, see: Haggarty et al. (2000 ▶); Hirshfeld (1976 ▶); Kettmann et al. (2008 ▶); Klein et al. (2007 ▶); Mayer et al. (1999 ▶); Světlík et al. (2008 ▶). graphic file with name e-64-o1776-scheme1.jpg

Experimental

Crystal data

C₁₅H₁₆N₂O₅
M _r = 304.35
Monoclinic,
a = 23.498 (5) Å
b = 12.072 (2) Å
c = 10.933 (5) Å
β = 99.15 (2)°
V = 3061.9 (16) Å³
Z = 8
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
5187 measured reflections
4466 independent reflections
2308 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)] = 0.046
wR(F ²) = 0.118
S = 0.90
4466 reflections
201 parameters
54 restraints
H-atom parameters constrained
Δρ_max = 0.13 e Å⁻³
Δρ_min = −0.27 e Å⁻³

Data collection: XSCANS (Siemens, 1991 ▶); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2003 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808026135/bv2102sup1.cif

e-64-o1776-sup1.cif^{(18.7KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808026135/bv2102Isup2.hkl

e-64-o1776-Isup2.hkl^{(219KB, hkl)}

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

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O1ⁱ	0.86	2.06	2.8326 (17)	149
N3—H3⋯O4ⁱⁱ	0.86	2.32	3.0730 (17)	146

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Symmetry codes: (i) Inline graphic ; (ii) .

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, the discovery of monastrol [ethyl 6-methyl-4-(3-hydroxyphenyl)- 2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate] (Mayer et al., 1999), a lead structure for development of new anticancer agents (Klein et al., 2007), has stimulated considerable interest in preparing its congeners (Haggarty et al., 2000). To follow this research, our strategy was to synthesize conformationally restricted dihydropyrimidine heterocycles by employing a Biginelli-like condensation of salicylaldehyde with dialkyl acetone-1,3-dicarboxylates (Světlík et al., 2008). Unexpectedly, formation of two types of products was detected depending on the ester alkyl group of the starting dialkyl 3-oxopentanedioate: for the methyl ester the reaction proceeded in a 'normal' way to produce the rigid tricyclic structure (3), while the ethyl analogue gave the structure (2), i.e. the final cyclization did not occur. To provide structural basis for this product dichotomy, we selected compounds (1) and (2) for a single-crystal X-ray analysis. As the structure of (2) was described previously (Kettmann et al., 2008), we report herein the structure of the title compound (1); it is the de-hydroxy derivative (to prevent cyclization of the molecule) of its normal tricyclic compound.

As mentioned above, the analysis of the structural results (Fig.1, Table 1) is focused on the conformational characteristics of the present structure (1) in comparison with those obtained recently for (2). The comparison has shown that, apart from the conformation of the 5-ester substituent (cis and trans in (1) and (2), respectively), the only significant difference between (1) and (2) concerns rotation around the ROOC-CH₂ single bond as measured by the torsion angle C6—C15—C16—O4 which is ca 0° in (1) and ca 180° in (2). As this is the only difference which affect the vicinity of the critical C6-position, it should be responsible for the dichotomy in the reactivity of methyl and ethyl acetone-1,3-dicarboxylates. Indeed, as shown in Fig.1, the hydroxy oxygen of the 2-hydroxyphenyl derivative of (1) would have an unrestricted access to C6 and hence the oxygen-bridged pyrimidine (3) would easily be formed. By contrast, due to the different geometry of the ester-methylene grouping in (2), the bulky ethoxy moiety points towards the heterocycle where it sterically hinders the nucleophilic addition of the ortho-hydroxyl on the pyrimidine C5=C6 double bond, with the net result being the 'open', uncyclized molecule (2).

The crystal packing is governed by hydrogen bonding. As shown in Table 2, there are two independent hydrogen bonds, one joins the molecules into dimers and the other links the dimers into chains.

Experimental

Synthesis of the title compound, (1), has been described (Světlík et al., 2008). In short, heating of benzaldehyde (0.51 ml, 5 mmol) with dimethyl acetone-1,3-dicarboxylate (0.73 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 desired product (39% yield; m.p. 453–455 K). Crystals suitable for the X-ray analysis were obtained by a slow crystallization from ethanol.