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

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.

The title compound, C 15 H 16 N 2 O 5 , 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.   Table 1 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) Àx þ 1; Ày þ 1; Àz þ 1; (ii) x; Ày þ 1; z À 1 2 .

Comment
Recently, the discovery of monastrol [ethyl 6-methyl-4-(3-hydroxyphenyl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5carboxylate] (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-CH 2 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.
Crystals suitable for the X-ray analysis were obtained by a slow crystallization from ethanol.
supplementary materials sup-2 Refinement H atoms were visible in difference maps and were subsequently treated as riding atoms with distances C-H = 0.93 Å (CH arom ), 0.97 (CH 2 ) or 0.98 Å (CH), 0.96 Å (CH 3 ) and N-H = 0.86 Å; U iso of the H atoms were set to 1.2 (1.5 for the methyl H atoms) times U eq of the parent atom. Because of the indication from Hirshfeld test (Hirshfeld, 1976), 54 rigid-bond restraints on anisotropic displacement parameters for all bonds involving the non-H atoms were applied during the least-squares refinement. Reflection 110, affected by secondary extinction, was deleted from the refinement. Fig. 1. Displacement ellipsoid plot of (1) with the labelling scheme for the non-H atoms, which are drawn as 35% probability ellipsoids. Methyl 6-methoxycarbonylmethyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate

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 F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating Rfactors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.