Ethyl 2-( { 6-amino-2-( benzylsulfanyl )-5-[ 2-( ethoxy-carbonyl ) prop-2-enyl ] pyrimidin-4-yloxy } methyl )-acrylate

# 2006 International Union of Crystallography Printed in Great Britain – all rights reserved A new synthesis of carbon–carbon bonds at the 5-position of 2-thiosubstituted pyrimidines via the Claisen rearrangement is reported. A direct route towards the synthesis of carbon bonds at the 5-position of 2-thiobenzyl pyrimidines when reacted with ethyl 2-(bromomethyl)acrylate at 328 K delivered the unexpected title compound, C23H27N3O5S. Structural elucidation showed this compound to have undergone O-allylation followed by ortho-Claisen rearrangement and subsequent secondary O-allylation with excess ethyl 2-(bromomethyl)acrylate. Disorder about the centre of symmetry allows it to exist as two conformers with different orientations of the phenyl group.

A new synthesis of carbon-carbon bonds at the 5-position of 2-thiosubstituted pyrimidines via the Claisen rearrangement is reported. A direct route towards the synthesis of carbon bonds at the 5-position of 2-thiobenzyl pyrimidines when reacted with ethyl 2-(bromomethyl)acrylate at 328 K delivered the unexpected title compound, C 23 H 27 N 3 O 5 S. Structural elucidation showed this compound to have undergone O-allylation followed by ortho-Claisen rearrangement and subsequent secondary O-allylation with excess ethyl 2-(bromomethyl)acrylate. Disorder about the centre of symmetry allows it to exist as two conformers with different orientations of the phenyl group.

Comment
In order to extend and illustrate our endeavours to develop further the C-5 carbon-carbon bond formation of 2-thiosubstituted pyrimidines (Huggan et al., 2005;La Rosa et al., 2002) we sought to utilize the Claisen rearrangement (Claisen & Tietze, 1925) within the context of designing routes towards the synthesis of pyrido[2,3-d]-pyrimidines, (I), and pyrrolo[2,3-d]-pyrimidines, (II), as potential inhibitors of enzymes in the folic acid biosynthesis pathway. When an N atom is present at the 2-position, the formation of C-C bonds at the 5-position is relatively straightforward. However, our solid phase route (Gibson et al., 2003) utilizes an S atom at the 2-position and previous attempts at C-C bond formation in solution phase with sulfur at the 2-position have proved unsuccessful.
The molecular structure of (IV) is shown in Fig. 1, and selected bond distances and angles are given in Table 1. As can be seen in Fig. 1, structural elucidation showed this compound to have been formed through O-allylation followed by ortho-Claisen rearrangement and subsequent secondary O-allylation with excess ethyl 2-(bromomethyl)acrylate.
Disorder about a centre of symmetry allows (IV) to exist as two conformers with different orientations of the phenyl group. An alternative solution in the non-centrosymmetric space group P1 was rejected as the disorder was still present. The two vinyl groups adopt different geometries. The torsion angles C13-C12-C14-O4 and C7-C6-C8-O2 [À13.1 (2) and 176.8 (2) , respectively] indicate the syn and anti relationship of the vinyl and ketone groups and, whilst the presence of O1 allows the C7-centred group to bo coplanar with the heterocyclic ring, the absence of an equivalent atom forces the C13-centred substituent out of this plane. A search of the Cambridge Structural Database (Version 5 with updates to October 2005; Allen, 2002) found 140 similar non-cyclic vinyl fragments and indicated that the geometric parameters of (IV) ( Table 1) are all within normal ranges. A similar search showed that the geometry of the hetrocyclic fragment is also in agreement with the known literature.
In the crystal structure of (IV) both the amine H atoms form hydrogen bonds with atoms O4 and N2 of symmetryrelated molecules acting as acceptors (Table 2). This results in the formation of hydrogen-bonded chains of molecules.

D-HÁ
After several trial calculations, the disordered CH 2 Ph group was modelled over two sites each with occupancy 0.5. The methylene H atoms of this group were found in a difference synthesis and then constrained to ride on the parent C atom. The amine H atoms were refined freely, but all other H atoms were positioned geometrically at distances of 0.95 (CH and vinyl CH 2 ), 0.98 (CH 3 ) or 0.99 Å (CH 2 ) from the parent C atoms; a riding model was used [U iso (H) = 1.5U eq (C) for CH 3 and U iso (H) = 1.2U eq (C) for all others] during refinement.

S1. Comment
In order to extend and illustrate our endeavours to develop further the C-5 carbon-carbon bond formation of 2-thiosubstituted pyrimidines (Huggan et al., 2005;La Rosa et al., 2002) we sought to utilize the Claisen rearrangement (Claisen & Tietze, 1925) within the context of designing routes towards the synthesis of pyrido[2,3-d]-pyrimidines, (I), and pyrrolo[2,3-d]-pyrimidines, (II), as potential inhibitors of enzymes in the folic acid biosynthesis pathway. When an N atom is present at the 2-position, the formation of C-C bonds at the 5-position is relatively straightforward. However, our solid phase route (Gibson et al., 2003) utilizes an S atom at the 2-position and previous attempts at C-C bond formation in solution phase with sulfur at the 2-position have proved unsuccessful.
The molecular structure of (IV) is shown in Fig. 1, and selected bond distances and angles are given in Table 1 Table 1) are all within normal ranges. A similar search showed that the geometry of the hetrocyclic fragment is also in agreement with the known literature.
In the crystal structure of (IV) both the amine H atoms form hydrogen bonds with atoms O4 and N2, acting as acceptors, of symmetry-related molecules (

S2. Experimental
Compound (III) (0.69 g, 2.95 mmol) was dissolved in dimethylformamide (12 ml, anhydrous) at room temperature under nitrogen. Ethyl 2-(bromomethyl)acrylate (610 µl, 4.40 mmol, 1.5 equivalents) and K 2 CO 3 (0.50 g, 3.62 mmol, 1.2 equivalents) were added and the reaction was stirred in an oil bath at 328 K for 24 h. Once the reaction was complete (by thin-layer chromatography) the mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane, extracted with brine, and then collected, dried (MgSO 4 ) and concentrated under reduced pressure to give a yellow oil. The title compound (IV) was separated by column chromatography using ethyl acetate/hexane (1:1) as eluant and was isolated as a white solid (0.114 g, 0.25 mmol, 8%).

S3. Refinement
After several trial calculations, the disordered CH 2 Ph group was modelled over two sites each with occupancy 0.5. The methylene H atoms of this group were found in a difference synthesis and then constrained to ride on the parent C atom.
The amine H atoms were refined freely, but all other H atoms were positioned geometrically at distances of 0.95 (CH and vinyl CH 2 ), 0.98 (CH 3 ) or 0.99 Å (CH 2 ) from the parent C atoms; a riding model was used [U iso (H) = 1.5U eq (C) for CH 3 and U iso (H) = 1.2U eq (C) for all others] during refinement.  Molecular structure of (IV), with displacement ellipsoids drawn at the 50% probability level. Only one position of the disordered benzyl unit is shown for clarity. 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 R-factors(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.