Synthesis and structural characterization of the 5-(2-haloethyl)pyrimidines - hydrogen-bonded chains in α-(1-carbamyliminomethylene)-γ- butyrolactone

Article abstract of DOI:10.3390/molecules13112786

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-hydro

Full text of DOI:10.3390/molecules13112786

Molecules 2008, 13, 2786-2795; DOI: 10.3390/molecules13112786
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Structural Characterization of the 5-(2-
Haloethyl)pyrimidines – Hydrogen-Bonded chains in α-(1-
Carbamyliminomethylene)-γ-Butyrolactone
Tatjana Gazivoda 1, Silvana Raić-Malić 1, Antonija Hergold-Brundić 2 and Mario Cetina 3, *
1
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of
Zagreb, Marulićev trg 20, P.O. Box 177, HR-10000 Zagreb, Croatia
2
Laboratory of General and Inorganic Chemistry, Faculty of Science, University of Zagreb,
Horvatovac 102a, HR-10000 Zagreb, Croatia
3
Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, Prilaz
baruna Filipovića 28a, HR-10000 Zagreb, Croatia
* Author to whom correspondence should be addressed; E-mail: mario.cetina@ttf.hr; Tel.: +385 1
3712 590; Fax: ++385 1 3712 599.
Received: 21 August 2008; in revised form: 26 September 2008 / Accepted: 13 October 2008 /
Published: 6 November 2008
Abstract: Three novel 5-(2-haloethyl)pyrimidine derivatives were synthesized and
1
13
characterized by H-NMR, C-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.
Keywords: 5-(2-Haloethyl)pyrimidine, Synthesis, X-ray crystal structure, Hydrogen bonds
Introduction
A number of 5-substituted pyrimidine nucleoside analogues have been shown to have potent and
selective cytotoxic activity in cells transfected with the HSV-1 TK gene [1-3]. The (E)-5-(2-
halovinyl)-2’-deoxyuridines are among the most potent and selective agents that undergo selective
phosphorylation by the viral-encoded enzyme [4]. Pyrimidine nucleoside analogues, e.g. 5-(2-

Molecules 2008, 13
2787
fluoroethyl)-2’-deoxyuridine, labelled with radioisotopes have applications in positron emission
tomography (PET) to monitor the successful transfection of gene products in vivo during cancer-
prodrug 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 [6-11]. In view of the
importance of 5-substituted uracil derivatives in cancer chemotherapy [12] and as antiviral agents [13-
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-(1-
carbamyliminomethylene)-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.
Scheme 1. Synthesis of the 5-(2-haloethyl)pyrimidines 4-6.
O
O
5
4
2
O
3
i
O
NH2
ii
O
O
1'
3'
N
H
NaO
O
1
2
iii
O
OH
2'
4
2
HN
5
6
O
N
H
3
iv
v
Cl
O
OCH3
Cl
I
Cl
vi
N
HN
N
Cl
O
N
N
H
H3CO
N
6
5
4
Reagents and conditions: (i) NaOMe, ether, HCOOCH3, 24 h; (ii) urea, 3M HCl,
4 °C, 24 h; (iii) NaOEt, ethanol, reflux, 6 h; (iv) HI, -5 °C, 90 min; (v) POCl3,
reflux, 1h; (vi) NaOMe, reflux, 6 h.

Molecules 2008, 13
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Results and Discussion
Synthesis
The sodium derivative 1, prepared by reaction of γ-butyrolactone with methylformate in dry ether
with the presence of sodium methoxide, was subsequently reacted with urea to give α-(1-
carbamyliminomethylene)-γ-butyrolactone (2) [16, 17]. Reaction of 2 with sodium ethoxide afforded
5-(2-hydroxyethyl)uracil (3), which with 57% solution of hydroiodic acid gave 5-(2-iodoethyl)uracil
(4). Chlorination of compound 3 with phosphoryl chloride afforded the chlorinated pyrimidine
derivative 5, which was subsequently methoxylated giving 5-(2-chloroethyl)-2,4-dimethoxyuracil (6).
1
13
The newly prepared compounds 4-6 were fully characterized by H- and C-NMR spectra, mass and
IR spectra, as well as elemental analysis (see Experimental section).
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
O1/O2/C2/C3/C4/C5 is 7.17(8)o.
Figure 1. A molecular structure of 2, with the atom-numbering scheme. Displacement
ellipsoids for nonhydrogen atoms are drawn at the 40 % probability level.
A survey of the Cambridge Structural Database [18] (CSD; error-free and disorder-free structures of
organic compounds with R<0.075) revealed 16 structures in which the carbon atom is double bonded
to the butyrolactone ring (Figure 2, fragment I) and only one structure possessing a
carbamyliminomethylene moiety [19] (Figure 2, fragment II).

Molecules 2008, 13
Figure 2. Fragments from a Cambridge Structural Database survey.
2789
H
O
H
H
N
O
C
O
H
N
H
H
H
C
H
II
I
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.
N1−C6
1.363(2)
O3−C7
C2−C3
C3−C6
C3−C4
C4−C5
1.2251(19)
1.453(2)
1.333(2)
1.495(2)
1.518(2)
N1−C7
1.3900(18)
1.339(2)
N2−C7
O1−C2
1.3417(17)
1.450(2)
O1−C5
O2−C2
1.2173(19)
121.43(13)
110.77(12)
120.86(14)
129.10(15)
110.02(12)
121.18(13)
130.00(14)
C6−N1−C7
C2−O1−C5
O2−C2−O1
O2−C2−C3
O1−C2−C3
C6−C3−C2
C6−C3−C4
C2−C3−C4
C3−C4−C5
O1−C5−C4
C3−C6−N1
O3−C7−N2
O3−C7−N1
N2−C7−N1
108.73(12)
102.74(13)
107.73(12)
125.09(13)
124.88(15)
121.05(15)
114.07(13)
Table 2. Hydrogen-bonding geometry for 2.
D−H
(Å)
0.85(2)
0.90(2)
0.93(2)
H···A
(Å)
2.06(2)
2.16(2)
1.96(2)
D···A
(Å)
2.869(2)
2.974(2)
2.884(2)
D−H···
A
158(2)
150(2)
174(2)
D−H···A
N1−H1···O2i
N2−H2A···O2i
N2−H2B···O3ii
Symmetry codes: (i) x, −1+y, z; (ii) 1−x, −1/2+y, 3/2−z.
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···O2i and N2···O2i intermolecular hydrogen bonds in 2 form a
[20] chain of rings
R12
6
( )
parallel to the b axis (Figure 3). The N2···O3ii hydrogen bond links the molecules into C(4) chains that
R33
14
( )
are also parallel to the b axis. The combination of these two motifs forms new ring of type.

Molecules 2008, 13
2790
These three N−H···O hydrogen bonds generate mutually parallel one-dimensional chains of edge-
fused rings (Figure 3).
Figure 3. A crystal packing diagram of 2, viewed along the a axis, showing
chains of edge-fused rings formed by N−H···O hydrogen bonds.
Figure 4. A crystal packing diagram of 2, viewed along the b axis, showing parallel chains
of hydrogen-bonding molecules.

Molecules 2008, 13
The crystal packing diagram along b axis (Figure 4) reveals that the hydrogen-bonded chains are
2791
parallel to the ( , 0, 1). The distance between the planes passing through the center of the hydrogen-
2
bonded 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
1
instrument with ionizing energy of 70 eV. H- and 13C-NMR spectra were recorded on a Bruker
Avance 600 MHz spectrometer, operating at 600 MHz (1H) and 150.92 MHz (13C), respectively. The
1
samples were dissolved in DMSO-d6 and measured in 5 mm NMR tubes. The H- and 13C-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.
Synthesis
Sodium α-hydroxymethylene-γ-butyrolactone (1) [16]. To a cooled suspension of NaOMe (35.5 g, 0.66
mol) in dry ether (650 mL), a solution of methylformate (52.6 mL, 0.85 mol) and γ-butyrolactone (50
mL, 0.66 mol) was added dropwise. The stirring was continued at room temperature overnight. After
cooling of reaction mixture the precipitated product 1 was filtered off and washed with dry ether (37.5
1
g, 41.8 %, m.p. = 124 – 126 °C); MS m/z (EI) for C5H5NaO3 (M+•) calc. 136.0812; found 136.1; H-
13
NMR δ 8.46 (1H, s, H-1'), 4.24 (2H, t, J = 7.00 Hz, H-5), 2.44 (2H, dt, J = 9.97 Hz, 8 Hz, H-4); C-
NMR δ 176.96 (C-2), 166.54 (C-1'), 132.60 (C-3), 68.37 (C-5), 27.50 (C-4).
α-(1-Carbamyliminomethylene)-γ-butyrolactone (2) [17]. To a solution of urea (30 g, 0.5 mol) in cold
3M HCl (200 mL) was added sodium α-hydroxymethylene-γ-butyrolactone (1, 34 g, 0.25 mol). After
stirring at 4 °C overnight the precipitated product was filtered off and washed with cold water.
Recrystallization from water – ethanol gave white crystals of 2 (2 g, 5.2 %, m.p. = 246 – 247 °C); MS
m/z (EI) for C6H8N2O3 (M+•) calc. 156.1394; found 156.1; 1H NMR δ 8.96 (1H, d, J = 11.71 Hz, NH),
7.60 (1H, d, J = 11.97 Hz, H-1'), 6.38 (2H, s, NH2), 4.28 (2H, t, J = 7.5 Hz, H-5), 2.75 (2H, dt, J = 7.5
13
Hz, 2.3 Hz, H-4); C-NMR δ 172.69 (C-3'), 154.35 (C-2), 132.60 (C-1'), 99.30 (C-3), 65.07 (C-5),
24.19 (C-4).

Molecules 2008, 13
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5-(2-Hydroxyethyl)uracil (3). To a solution of NaOEt (0.277 g, 4 mmol) in ethanol (20 mL) was added
α-(1-carbamyliminomethylene)-γ-butyrolactone (2, 1.7 g, 0.01 mol). Reaction mixture was refluxed
for 6 h, during which time product precipitated. The solvent was removed under reduced pressure and
the residue was dissolved in the water and acidified to pH = 3. The precipitated product 3 was filtered
off, washed with ethanol and dried in vaccuo (1.55 g, 91.2 %); MS m/z (EI) for C6H8N2O3 (M+•) calc.
156.1394; found 156.1; 1H-NMR δ 11.41 (1H, s, NH), 11.13 (1H, s, NH), 7.21 (1H, s, H-6), 3.63 (1H,
t, J = 6.68 Hz, OH), 3.41 (2H, t, J = 6.62 Hz, H-2'), 2.29 (2H, t, J = 6.51 Hz, H-1'); 13C-NMR δ 164.32
(C-4), 151.50 (C-2), 135.19 (C-6), 110.38 (C-5), 60.21 (C-2'), 29.06 (C-1').
5-(2-Iodoethyl)uracil (4). To a cooled solution of 3 (100 mg, 0.6 mmol) in H2O (10 mL), a solution of
HI (57%, 1 mL) was added. The reaction mixture was stirred at -5 °C for 90 min, then solvent was
evaporated and residue was purified by column chromatography (CH2Cl2:CH3OH = 60:1) to give oily
product 4 (112 mg, 65 %); MS m/z (EI) for C6H7IN2O2 (M+•) calc. 266.0365; found 266; Anal. for
C6H7IN2O2 calc. C 27.09 %, H 2.65 %, N 10.53 %; found C 27.13 %, H 2.64 %, N 10.55 %; IR: 3110–
2992 (ν N–H, CH2), 1720 (ν C=O), 1650–1420 (ν C=C and C–H ring), 1480 (δ CH2), 1022–770 (δ
1
C=C–H, CH2), 940 (δ CH2–I), 520–480 (ν C–I) cm-1; H-NMR δ 10.97 (1H, s, NH), 10.62 (1H, s,
13
NH), 7.20 (1H, s, H-6), 4.52 (2H, t, J = 5.4 Hz, H-2'), 2.28 (2H, t, J = 6.60 Hz, H-1'); C-NMR δ
165.14 (C-4), 151.82 (C-2), 139.27 (C-6), 109.61 (C-5), 59.86 (C-2'), 20.03 (C-1').
5-(2-Chloroethyl)-2,4-dichloropyrimidine (5). The reaction mixture of 3 (600 mg, 4 mmol) and POCl3
(17.7 mL, 0.19 mol) was refluxed for 1 h. Solvent was evaporated and ice was added in the residue
which was then washed with ether and dried over Na2SO4. After drying the solvent was removed in
vacuo and residue was purified by column chromatography (CH2Cl2:CH3OH = 30:1) which gave
colourless oily product 5 (260 mg, 31%); MS m/z (EI) for C6H5Cl3N2 (M+•) calc. 211.4575; found
211.5; Anal. for C6H5Cl3N2 calc. C 34.08 %, H 2.38 %, N 13.25 %; found C 34.01 %, H 2.39 %, N
13.22 %; IR: 1633–1320 (ν C=C and C–H ring), 1430 (δs CH2), 1090 (δ CH2–Cl), 980-760 (δ C=C–H,
CH2), 580–510 (ν C–Cl) cm-1; 1H-NMR δ 8.82 (1H, s, H-6), 3.93 (2H, t, J = 6.78 Hz, H-2'), 3.19 (2H,
13
t, J = 6.78, H-1'); C-NMR δ 172.46 (C-4), 162.01 (C-2), 156.87 (C-6), 112.70 (C-5), 43.15 (C-2'),
31.51 (C-1').
5-(2-Chloroethyl)-2,4-dimethoxypyrimidine (6). To a solution of NaOMe (120 mg, 2.2 mmol) in
MeOH (15 mL) was added 5 (80 mg, 0.38 mmol), and the mixture was heated at reflux for 6 h. The
solvent was evaporated, and H2O was added to dissolve NaCl. The oily layer was extracted with
CH2Cl2, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column
chromatography (CH2Cl2:CH3OH = 30:1) which gave colourless oily product 6 (54 mg, 70.6 %); MS
m/z (EI) for C8H11ClN2O2 (M+•) calc. 202.6379; found 202.6; Anal. C 7.42 %, H 5.47 %, N 13.82 %;
found C 47.31 %, H 5.47 %, N 13.84 %; IR: 2960 (ν CH3), 1640–1330 (ν C=C and C–H ring), 1420 (δ
CH2), 1210 (νas C–O–C), 1100 (δ CH2–Cl), 1050 (νs C–O–C), 905–760 (δ C=C–H, CH2), 630–520 (ν
1
C–Cl) cm-1; H-NMR δ 8.19 (1H, s, H-6), 3.92 (3H, s, OCH3), 3.87 (3H, s, OCH3), 3.77 (2H, t, J =
6.93 Hz, H-2'), 2.89 (2H, t, J = 6.93 Hz, H-1'); 13C-NMR δ 169.30 (C-4), 164.56 (C-2), 158.87 (C-6),
111.44 (C-5), 54.85 (OCH3), 54.33 (OCH3), 43.75 (C-2'), 29.76 (C-1').

Molecules 2008, 13
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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-Kα
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.
Formula
Formula weight
Crystal system
Space group
Unit cell dimensions
a (Å)
C6H8N2O3
156.14
monoclinic
P 21/c
7.0522(8)
6.6691(6)
15.1031(16)
94.869(9)
707.76(13)
4
b (Å)
c (Å)
β (o)
V (Å3)
Z
D
calc. (g cm-3)
1.465
Absorption coefficient μ (mm-1)
0.119
F(000)
328
θ range (°)
2.71 - 27.99
-9 ≤ h ≤ 9
-8 ≤ k ≤ 8
-11 ≤ l ≤ 19
2941
Index ranges
Collected reflections No.
Independent reflections No. / Rint.
Reflections No. I ≥ 2σ(I)
1702 / 0.0231
1063
Refined parameters No.
112
Goodness-of-fit on F2, S
1.001
R [I ≥ 2σ(I)] / R [all data]
wR [I ≥ 2σ(I)] / wR [all data]
Max./min. electron density (e Å-3)
0.0398 / 0.0783
0.1061 / 0.1231
0.189 / -0.141
The structure was solved by direct methods [23]. All non-hydrogen atoms were refined
anisotropically by full-matrix least-squares calculations based on F2 [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

Molecules 2008, 13
2794
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.
Acknowledgements
Support for this study was provided by the Ministry of Science, Education and Sports of the
Republic of Croatia (Projects #125-0982464-2925 and #119-1193079-3069).
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Sample Availability: Samples of the compounds are available from T. Gazivoda.
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