Synthesis and Structural Characterization of the 5-(2-Haloethyl)pyrimidines – Hydrogen-Bonded chains in α-(1-Carbamyliminomethylene)-γ-Butyrolactone

Three novel 5-(2-haloethyl)pyrimidine derivatives were synthesized and characterized by 1H-NMR, 13C-NMR, MS, IR spectra and elemental analysis. Iodine and chlorine atoms in the C-5 side chain were introduced by reaction of 5-(2-hydroxyethyl)pyrimidine with hydroiodic acid and phosphoryl chloride, respectively. The structure of the intermediate α-(1-carbamyliminomethylene)-γ-butyrolactone was determined by X-ray crystal structure analysis. The molecule deviates very slightly from planarity. Three N−H···O hydrogen bonds link the molecules into one-dimensional chains of edge-fused rings.


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fluoroethyl)-2'-deoxyuridine, labelled with radioisotopes have applications in positron emission tomography (PET) to monitor the successful transfection of gene products in vivo during cancerprodrug therapy [5]. Recently, we have reported that some C-5 and/or C-6 substituted pyrimidine derivatives exhibited cytostatic activities against human tumor cell lines [6][7][8][9][10][11]. In view of the importance of 5-substituted uracil derivatives in cancer chemotherapy [12] and as antiviral agents [13][14][15] we became interested in the synthesis of the novel 5-substituted uracils that we describe in this paper (Scheme 1). In addition, we also present herein the X-ray crystal structure of α-(1carbamyliminomethylene)-γ-butyrolactone, a precursor in the synthesis of these 5-substituted uracils. This compound, possessing two hydrogen-bonding donor groups and two acceptors, is very interesting from the supramolecular point of view, because it can form intricate hydrogen-bonded networks including chain motifs, rings, chains of rings and chains of edge-fused rings.

X-ray crystal structure study
Compound 2 ( Figure 1) consists of a carbamyliminomethylene moiety bonded to the butyrolactone ring. The whole molecule deviates very slightly from planarity, as the dihedral angle between the mean planes of the carbamyliminomethylene atoms N2/C7/O3/N1/C6 and butyrolactone ring atoms  The bond lengths and angles in 2 (Table 1) present no unexpected features and are within the ranges of equivalent ones in structures found in the CSD [18]. Table 1. Bond distances (Å) and bond angles ( o ) for 2.
The carbamyliminomethylene moiety nitrogen atoms N1 and N2 and carbonyl oxygen atoms O2 and O3 participate in the supramolecular assembly of 2. The N2 atom is a double proton donor and O2 atom is a double proton acceptor ( Table 2).
The N1···O2 i and N2···O2 i intermolecular hydrogen bonds in 2 form a ( )   The crystal packing diagram along b axis ( Figure 4) reveals that the hydrogen-bonded chains are parallel to the ( 2 , 0, 1). The distance between the planes passing through the center of the hydrogenbonded molecules is approximately 3.05 Å. Very similar one-dimensional hydrogen-bonded chains generate N−H···O hydrogen bonds in 1-carbamyliminomethylenetetrahydropyrrol-2-one [19].

Experimental Section
General Melting points were determined on a Kofler micro hot-stage apparatus (Reichert, Wien) and are uncorrected. The electron impact mass spectra were recorded with an EXTREL FT MS 2002 instrument with ionizing energy of 70 eV. 1 H-and 13 C-NMR spectra were recorded on a Bruker Avance 600 MHz spectrometer, operating at 600 MHz ( 1 H) and 150.92 MHz ( 13 C), respectively. The samples were dissolved in DMSO-d 6 and measured in 5 mm NMR tubes. The 1 H-and 13 C-NMR chemical shift values (δ) are expressed in ppm referred to tetramethylsilane (TMS) and coupling constants (J) in Hz. The infrared spectra were recorded by a Fourier transform infrared (FTIR) spectrometer Bruker Vertex 70 equipped with an attenuated total reflection (ATR) accessory with a diamond crystal. Sixteen scans were collected for each measurement over the spectral range of 400-4000 cm -1 with resolution of 4 cm -1 . Precoated Merck Silica Gel 60F-254 plates were used for thin layer chromatography (TLC) and the spots were detected under UV light (254 nm). Column chromatography (CLC) was performed using silica gel (0.063-0.2 mm) Fluka; glass column was slurry-packed under gravity. Compound purity was analyzed by HPLC with DAD detector.

Crystal structure determination of 2
A single crystal of 2 suitable for X-ray structure analysis was prepared by growth under slow evaporation at room temperature of a very dilute ethanol solution (v/v 96 %). The intensities were collected at 295 K on a Philips PW1100 diffractometer updated by Stoe and Cie [21,22] using Mo-K α radiation (0.71073 Å). Details of crystal data, data collection and refinement parameters are given in Table 3. Table 3. X-ray crystallographic data for 2. The structure was solved by direct methods [23]. All non-hydrogen atoms were refined anisotropically by full-matrix least-squares calculations based on F 2 [23]. The hydrogen atoms bonded to nitrogen atoms were found in a difference Fourier map and their coordinates and isotropic thermal parameters have been refined freely. All other hydrogen atoms were included in calculated positions as riding atoms, with SHELXL97 [23] defaults. PLATON [24] program was used for structure analysis and molecular and crystal structure drawings preparation. CCDC 695308 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.