Synthesis, structural and conformational studies of Z- and E-isomers of fluorinated C-6 isobutenyl N-methyl thymine derivatives

Article abstract of DOI:10.1016/j.jfluchem.2011.06.002

A new series of conformationally restricted pyrimidine derivatives bearing C-6 isobutenyl side-chain (2-9) has been prepared. The novel fluoroalkenyl pyrimidine nucleoside mimetic 3 as model compound for development of tracer molecule in positron emission

Full text of DOI:10.1016/j.jfluchem.2011.06.002

Journal of Fluorine Chemistry 132 (2011) 573–578
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis, structural and conformational studies of Z- and E-isomers of
fluorinated C-6 isobutenyl N-methyl thymine derivatives
Svjetlana Kristafor , Andrijana Mescic , Mario Cetina b,2, Silvija Korunda a,1, Damjan Makuc c,d,3
a,1
,
ˇ
ˇˇ ´ a,1
a,1,
Janez Plavec c,d,e,3, Silvana Raic-Malic
*
´
´
a Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulic´ev trg 20, HR-10000 Zagreb, Croatia
b
´
Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, Prilaz baruna Filipovica 28a, HR-10000 Zagreb, Croatia
c Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
d EN-FIST Centre of Excellence, Dunajska 156, SI-1000 Ljubljana, Slovenia
e
ˇ
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva cesta 5, SI-1000 Ljubljana, Slovenia
A R T I C L E I N F O
A B S T R A C T
Article history:
A new series of conformationally restricted pyrimidine derivatives bearing C-6 isobutenyl side-chain (2–
9) has been prepared. The novel fluoroalkenyl pyrimidine nucleoside mimetic 3 as model compound for
development of tracer molecule in positron emission tomography (PET) was synthesized by fluorination
reaction of methoxytritylated pyrimidine derivative using diethylaminosulfur trifluoride (DAST).
Conversion of one hydroxyl group to methoxytritylated, fluorinated, mesylated and acetylated
pyrimidine derivatives (2, 3, 5–7 and 9) afforded a mixture of Z- and E-isomers in which Z-isomers were
predominant. Conformational study of 1, and its fluorinated structural congeners 3 and 4 by the use of
NOE experiments revealed predominant conformation of compounds where vinyl H-10 proton is
spatially close to N-1 methyl and H-30b methylene protons and on the other hand H-30a methylene
protons are close to C-5 methyl protons. The stereostructure of 1,3-dihydroxyisobutenyl N-methyl
thymine 1 was unambiguously confirmed by X-ray crystal structure analysis.
Received 14 March 2011
Received in revised form 27 May 2011
Accepted 2 June 2011
Available online 13 June 2011
Keywords:
Mono- and difluorinated N-methyl thymine
derivatives
C-6 unsaturated side-chain
Z- and E-isomers
NMR conformational analysis
Positron emission tomography (PET)
ß 2011 Elsevier B.V. All rights reserved.
1. Introduction
increase molecules’ binding affinity to a target protein and enhance
its metabolic stability or modulate its physicochemical properties,
An interest in acyclic nucleoside analogs began in mid-1970s
when acyclovir was first reported as a potent anti-herpes drug. The
expressed selectivity of acyclovir as an antiviral drug and the
understanding of its mechanism of action towards viral enzymes
provided the impetus for further synthesis of related compounds
and their screening as potential antiherpetic drugs [1–3]. Among
these acyclonucleosides, ganciclovir [4] and penciclovir [5,6] arose
and became the therapeutic compounds of choice to interfere with
severe herpes virus infections. Fluoro derivatives of ganciclovir and
penciclovir were evaluated as tracers for non-invasive positron
emission tomography (PET) imaging of herpes simplex virus type 1
thymidine kinase (HSV-1 TK) gene expression [7,8]. Moreover, in
the area of medicinal chemistry, incorporation of fluorine has
played a significant role in the development of new anti-cancer and
anti-viral agents. The presence of fluorine in a molecule can
such as its lipophilicity, acidity or basicity [9]. For this reason, the
development of synthetic methods for fluorine-containing hetero-
cyclic compounds has been an important field in both organo-
fluorine chemistry and organic synthesis.
In an effort to develop more potent and selective antiviral
agents, structural modifications of the heterocyclic bases and/or
modifications on the sugar moiety of natural nucleosides can be
attempted. Among these transformations, the introduction of
alkenyl moieties into pyrimidines and pyrimidine nucleosides is of
great interest in view of their biological activities [10–12]. Thus, it
was found that introduction of a double bond gave a slight rigidity
to the unsaturated nucleoside analogs [12,13] which stabilized
these compounds in the best conformation to improve their
interactions with phosphorylating enzymes.
Recently, we have reported the synthesis and biological results
of a new type of C-6 fluoroalkylated and fluorophenylalkylated
pyrimidine derivatives as model compounds for development of
tracer molecules in positron emission tomography (PET) [14–18].
Besides, findings from the molecular docking of unsaturated C-6
substituted 1,3-dihidroxyisobutenyl N-methyl thymine into the
active site of HSV-1 TK indicated the same interactions of this
compound as for natural substrate thymidine [19].
* Corresponding author. Tel.: +385 1 4597 213; fax: +385 1 4597 224.
E-mail addresses: mario.cetina@ttf.hr (M. Cetina), janez.plavec@ki.si (J. Plavec),
´
´
sraic@fkit.hr (S. Raic-Malic).
1
Tel.: +385 1 4597 213; fax: +385 1 4597 224.
2
Tel.: +385 1 3712 590; fax: +385 1 3712 599.
3
Tel.: +386 1 4760 353; fax: +386 1 4760 300.
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.06.002

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S. Kristafor et al. / Journal of Fluorine Chemistry 132 (2011) 573–578
574
In this work, we report the synthesis and structural studies of C-
the same experimental conditions, both mono- and dimethoxy-
tritylated derivatives. The treatment of compound with
6 substituted isobutenyl thymine derivatives (2–9), a thymine-
based acyclic C–C nucleosides in which the unsaturated acyclic
sugar moiety is attached at C-6 position of the pyrimidine ring
rather than at N-1 position. In addition, X-ray crystal structural
study of C-6 substituted dihydroxyisobutenyl N-methyl thymine 1
is also presented. Since intermolecular interactions can provide
better solubility of pharmacologically active compounds in water,
we particularly pay attention on supramolecular assembling of 1
whose fluorinated structural analog 3 can be used as model
compound for development of tracer molecule in PET.
2
diethylaminosulphur trifluoride (DAST) and subsequent hydroly-
sis, gave monofluorinated 3 (as a mixture of Z- and E-isomers) and
difluorinated derivative 4 in 24% and 36% yield, respectively. In
comparison to a parent compound 2, the content of E-isomer in a
mixture of 3 is higher. Thus, the ratio of Z- and E-isomer is 5 to 4.
The formation of difluorinated compound 4 in this reaction could
be explained by hydrolysis of methoxytrityl protection, followed
by fluorination of two hydroxyl groups. Transformation of
hydroxyl group in 2 using mesyl chloride (MsCl) in pyridine gave
compound 5 containing 6-[2-(p-anisyldiphenylmethoxy)methyl-
3-mesylpropenyl] side-chain. Besides, chlorinated pyrimidine
derivative 6 was also obtained in this reaction. Similar to
fluorination reaction, mesylation of 2 afforded mesylated 5 and
chlorinated 6 as mixtures of Z- and E-isomers in which the contents
of E-isomers are higher (5 and 6; Z/E = 3/2) than that in starting
compound 2. Compound 1 was submitted to acetylation reaction
with acetic anhydride in the presence of 4-DMAP and triethyla-
mine to afford monoacetylated 7 (Z/E = 2/1) and diacetylated 8.
Monoacetylated compound 7 was subsequently converted to N-
methylpyrimidine 9 with 6-(2-acetoxymethyl-3-mesylpropenyl)
side-chain. The ratio of Z- and E-isomers in 9 is also 5 to 4 that is in
accord to fluorinated pyrimidine derivative 3.
2. Results and discussion
2.1. Chemistry
6-(1,3-Dihydroxyisobutenyl) N-methyl pyrimidine derivative
(1) [19] was synthesized according to a multistep procedure, which
included lithiation reaction of appropriate pyrimidine derivative
and nucleophilic addition to 1,3-dibenzyloxy-2-propanone
[20,21], followed by various transformations both of the acyclic
side-chain at C-6 and of the heterocyclic base. In the next step, one
primary hydroxyl group in
1 was selectively converted to
methoxytritylated group (Scheme 1).
Thus, reaction of compound 1 and p-anisylchlorodiphenyl-
methane (MTrCl) in the presence of 4-DMAP gave C-6 isobutenyl
substituted pyrimidine derivative 2 in 52% yield, as a mixture of Z-
and E-isomers in which Z-isomer prevails. The ratio of Z- and E-
isomer is 5 to 2. Interestingly, the methoxytrytilation reaction of
the saturated analog of 1, 6-[3-hydroxy-2-(hydroxymethyl)pro-
pyl]-1,5-dimethylpyrimidin-2,4-dione (N-MeDHBT) gave, under
2.2. NMR spectroscopic analysis
The chemical identities of compounds 2–9 were confirmed by
1H, 13C and 19F NMR measurements. Proton, carbon and fluorine
NMR chemical shifts of 3–5 are reported in Table 1, whereas proton
and carbon NMR chemical shifts of 2, 5–9 are given in
O
O
O
CH3
CH3
CH3
HN
HN
vi)
HN
+
O
N
CH3
O
N
CH3
O
N
CH3
OAc OH
OAc OAc
OAc OMs
8
9
7
v)
O
O
O
O
CH3
CH3
CH3
CH3
HN
HN
HN
i)
iv)
HN
+
1'
2'
O
N
CH3
O
N
CH3
O
N
CH3
O
N
CH3
3'
OMTr OH
OH OH
OH Cl
OMTr OMs
5
6
1
2
ii) iii)
O
O
CH3
CH3
HN
HN
Ac
Ms
MTr
+
O
N
CH3
O
N
CH3
SO2Me
COMe C(Ph)3OMe
F
F
OH
F
3
4
Scheme 1. Synthesis of C-6 isobutenyl N-methyl thymine derivatives (2–9). Reagents and conditions: (i) MTrCl, 4-DMAP, DMF, room temperature, 3 h; (ii) DAST, CH2Cl2, ꢀ75 8C,
1 h, rt, 2 h; (iii) 5% methanolic HCl, reflux, 15 min; (iv) MsCl, pyridine, ꢀ8 to 0 8C, 3 h; (v) Ac2O, 4-DMAP, CH3CN, room temperature, 45 min; (vi) MsCl, pyridine, ꢀ5 8C, 4 h.

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S. Kristafor et al. / Journal of Fluorine Chemistry 132 (2011) 573–578
575
Table 1
1H, 13C and 19F NMR chemical shifts (
d
in ppm) and coupling constants (J in Hz) for monofluorinated (3) and difluorinated (4) pyrimidine derivatives.
Compd.
NH
H-10
H-30a
H-30b
N-1 Me
C-5 Me
OH-a
–
OH-b
5.04
3-(E)
11.28 (1H, s)/
11.30 (1H, s)a
6.27
5.10
3.87–3.95
3.13
1.65
(1H, s)
(1H, dd, J = 12.2, JHF = 46.8)
(2H, m)
(3H, s)
(3H, s)
(1H, t, J = 5.1)
5.14
(1H, dd, J = 12.2, JHF = 46.8)
3-(Z)
4
11.28 (1H, s)/
11.30 (1H, s)a
6.37
4.84
4.16–4.20
3.10
1.65
–
–
5.31
(1H, s)
(1H, dd, J = 11.4, JHF = 46.8)
4.87
(2H, m)
(3H, s)
(3H, s)
(1H, t, J = 5.3)
(1H, dd, J = 11.4, JHF = 46.8)
4.83–5.07
11.35
6.58
5.17
3.11
1.65
–
(1H, s)
(1H, s)
(2H, m)
(2H, d, JHF = 46.4)
(3H, s)
(3H, s)
Compd. C-5 Me N-1 Me C-2
C-4
C-5
C-6
C-10
118.1
C-20
C-30a
C-30b
57.4
3-(E)b
3-(Z)b
4
11.5
11.6
11.5
31.7
31.8
31.7
151.0 163.4 107.0 147.1
(d, JCF = 1.5)/147.0 (s)a (d, JCF = 12.2)
143.2
82.7
(d, JCF =13.0)
143.4
(d, JCF = 166.3)
79.6
151.0 163.3 107.0 147.1
118.7
60.7
(d, JCF = 1.5)/147.0 (s)a (d, JCF = 8.4)
(d, JCF =14.5)
138.0
(d, JCF = 160.2)
79.0
150.9 163.3 107.3 145.7 (m)
123.0
82.1
(dd, JCF =11.4, 7.6) (dd, JCF = 15.1, 14.0) (dd, JCF = 161.0, 2.7) (dd, JCF = 166.3, 3.4)
Compd.
C-30aF
C-30bF
3-(E)c
3-(Z)c
4
ꢀ219.3 (m, J = 46.8, 2.9)
ꢀ221.0 (m, J = 46.8, 2.1)
ꢀ222.2 (m, J = 46.4, 2.1)
–
–
ꢀ218.5 (m, J = 46.4, 2.8)
Compounds were recorded in Me2SO-d6.
a
d
of isomers could not be unambiguously assigned.
b
c
200 MHz.
282MHz.
supplementary data. Proton-decoupled 13C NMR spectra showed
C–F coupling constants that enabled straightforward identification
of fluorinated carbon atoms and their neighbors.
These results suggested predominant conformation of compound
4, where H-10 is spatially closer to N-1 methyl group.
In addition, Z- and E-isomers were observed for compounds 2,
5–7 and 9 with the ratio of 5:2, 3:2, 3:2, 2:1 and 5:4, respectively.
Conformational properties of compounds 1, 3 and 4 are assessed
with the use of 1D difference NOE enhancements (Table 2).
NMR spectra of compounds 2, 3, 5–7 and 9 exhibited two set of
signals which were attributed to Z- and E-isomers. Individual
resonances in isomeric pairs were assigned by NOE measurements,
which in addition revealed isomers’ conformational preferences.
The saturation of hydroxymethyl group H-30b in pyrimidine
derivative 3-(Z) with 6-(3-fluoromethyl-2-hydroxypropenyl) side-
chain gave moderate NOE enhancement at H-10 (4.8%, Fig. 1a).
In contrast, NOE interaction between fluoromethyl group H-30b
and H-10 proton was observed in 3-(E) isomer (5.5%, Fig. 1b).
Besides, NOE between hydroxymethyl group H-30b and C-5 methyl
group (3.2%) was in agreement with E-configuration.
The saturation of H-10 proton in difluorinated pyrimidine
derivative 4 resulted in strong NOE enhancement at N-1 methyl
(6.2%) and H-30b methylene (5.4%) protons, whereas weak NOE
was observed at C-5 methyl protons (2.0%, Fig. 1c). Furthermore,
saturation of H-30b methylene protons showed strong NOE
enhancement at H-10 (7.5%), whereas saturation of H-30a methy-
lene protons resulted in moderate NOE at C-5 methyl protons.
2.3. X-ray crystal structure of 1
1,3-Dihydroxyisobutenyl N-methyl thymine 1 crystallized in
¯
triclinic space group P1 as a hydrate (Fig. 2). The bond lengths in 1
present no unexpected features and those in pyrimidin-2,4-dione
ring are in agreement with equivalent ones in 1-methylthymine
[22,23] and 5-(2-acetoxyethyl)-6-methylpyrimidin-2,4-dione
[24]. Furthermore, the bond lengths are also within the range in
pyrimidin-2,4-diones we published recently [25–27], with the
exception of C(5)–C(6) bond in uracil- and 5-fluorouracyl N-
phthalimide protected 4-amino-2-butenyl derivatives [26] which
˚
is ca. 0.04–0.05 A shorter. It should be also noted that a survey of
Cambridge Structural Database [28] revealed that this is the first
structure comprising 1,3-dihydroxyisobutenyl chain. The C9/C10/
Fig. 1. Predominant conformations of fluorinated pyrimidine derivatives: isomeric pair 3-(Z)/3-(E) (a and b) and 4 (c) with key NOE enhancements (in %).

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S. Kristafor et al. / Journal of Fluorine Chemistry 132 (2011) 573–578
576
Table 2
Key NOE enhancements for compound 1 and its monofluorinated (3) and difluorinated (4) pyrimidine derivatives (in %).
Saturated
Enhanced
C-5 Me
H-10
H-10
N-1 Me
H-10
H-30a
H-30b
H-30a
H-30b
C-5 Me
H-30a
H-30b
N-1 Me
C-5 Me
H-10
C-5 Me
H-10
1
1.3
0.5
0.6
1.5
1.3
0.0
0.5
2.2
0.1
0.5
0.0
0.0
2.7
0.9
2.0
2.0
0.6
3.7
0.0
0.0
3.0
0.0
2.3
5.4
7.2
4.5
7.0
6.2
3.3
2.0
2.9
3.3
2.9
0.5
5.5
0.0
0.0
0.5
3.2
0.0
0.0
4.3
0.0
4.8
7.5b
3-(E)
3-(Z)
4
0.0
2.9a
3.2a
a
High-field part of the multiplet was saturated.
Low-field part of the multiplet was saturated.
b
3-(18F)fluoromethyl-2-hydroxypropenyl at C-6 of pyrimidine moie-
ty. The methoxytritylation, fluorination, mesylation and acetylation
reactions of unsaturated pyrimidine derivatives gave compounds 2,
3, 5–7 and 9 as mixtures of Z- and E-isomers in which Z-isomers
prevailed. Conformational study of pyrimidine derivative 3 with 6-
(3-fluoromethyl-2-hydroxypropenyl) side-chain showed NOE en-
hancement between C-5 methyl and fluoromethyl group H-30a and
moderate NOE enhancement between H-10 and hydroxymethyl
protons H-30b in 3-(Z) that is in agreement with Z-configuration. On
the contrary, 3-(E) showed strong NOE between H-10 and
fluoromethyl group H-30a and moderate NOE between C-5 methyl
and hydroxymethyl group H-30b. Furthermore, NOE experiments of
1, and its fluorinated structural congeners 3 and 4 revealed
predominant conformation of compounds where vinyl H-10 proton
is spatially close to N-1 methyl and H-30b methylene protons and on
the other hand H-30a methylene protons are close to C-5 methyl
protons. The stereostructure of 1,3-dihydroxyisobutenyl N-methyl
thymine1showedthattwohydroxyloxygenatomsinside-chainof 1
have anticlinal and synperiplanar conformation with respect to the
C9 atom of ethenyl moiety.
Fig. 2. A molecular structure of compound 1, with the atom-numbering scheme.
Displacement ellipsoids for nonhydrogen atoms are drawn at the 30% probability
level.
4. Experimental
4.1. General
C11/C12 atoms of the 1,3-dihydroxyisobutenyl moiety form an
angle of 63.66(8)8 with respect to the ring. Such orientation could
be also described by the C5–C6–C9–C10 torsion angle of
ꢀ65.75(19)8. The planarity of ethenyl moiety is further confirmed
by the C6–C9–C10–C11 and C6–C9–C10–C12 torsion angles of
0.7(2)8 and 179.58(12)8, respectively. Two hydroxyl oxygen atoms
have different conformation with respect to the C9 atom of the
ethenyl moiety, anticlinal and synperiplanar [C9–C10–C11–
O3 = ꢀ138.42(13)8; C9–C10–C12–O4 = ꢀ10.83(19)8].
Melting points (uncorrected) were determined with Kofler micro
hot-stage (Reichert, Wien). Precoated Merck silica gel 60F-254 plates
were used for thin layer chromatography and the spots were
detected under UV light (254 nm). Column chromatography was
performed using silica gel (0.063–0.2 mm) Fluka; glass column was
slurry-packed under gravity. 1H and 13C NMR spectra were acquired
on Varian Unity Inova 300 MHz, Varian NMR System 800 MHz and
Bruker 300 MHz NMR spectrometer (300 MHz for 1H, 75.47 and
200 MHz for 13C using TMS as internal standard). All data were
recorded in Me2SO-d6 and CDCl3 at 298 K. Chemical shifts were
2.4. Antitumoral activities
referenced to the residual solvent signal of Me2SO at
1H and 39.50 ppm for 13C, and CDCl3 at 7.24 ppm for 1H and
77.23 ppm for 13C. 19F chemical shifts were referenced externally
with respect to CCl3F ( 0.0 ppm). Individual resonances were
assigned on the basis of their chemical shifts, signal intensities,
multiplicity of resonances and H–H coupling constants. Mass
spectra were recorded on an Agilent 6410 instrument equipped
with electrospray interface and triple quadrupole analyzer (LC/MS/
MS). Highperformanceliquidchromatographywasperformed onan
Agilent 1100 series system with UV detection (photodiode array
detector) using Zorbax C18 reverse-phase analytical column
d 2.50 ppm for
Thenovelcompoundswereevaluatedfortheircytostaticactivities
againstmalignanthumantumorcelllines:cervicalcarcinoma(HeLa),
breast carcinoma (MCF-7), laryngeal carcinoma (HepG2), colon
carcinoma (SW 620), pancreatic carcinoma (MiaPaCa-2) as well as
human fibroblast cells (WI38). Of all the compounds, C-6 isobutenyl
pyrimidine derivative 2 containing methoxytrityl moiety exhibited
d
d
d
d
moderate activities (IC50 in the range 20.41–44.83
mM) against all
evaluated cell lines including normal human fibroblasts. Other
compounds did not display antiproliferative activity on the panel
tumor cell lines and normal human fibroblasts WI38.
(2.1 mm ꢁ 30 mm, 3.5
mm). All compounds used for biological
evaluation showed >95% purity in this HPLC system.
3. Conclusion
The syntheses of novel C-6 substituted isobutenyl N-methyl
thymine derivatives (2–9) are reported. Among them, monofluori-
nated thymine derivative 3 was prepared as model compound for
development of tracer molecule in PET, while compounds 5 and 9
with protected hydroxyl functionalities can be used as precursor
molecules for the synthesis of 18F labeled N-methyl thymine with
4.2. Procedures for the preparation of compounds
4.2.1. 6-[2-(p-Anisyldiphenylmethoxy)methyl-3-hydroxypropenyl]-
1,5-dimethylpyrimidin-2,4-dione (2)
To a cold solution of compound 1 (53 mg, 0.23 mmol) in DMF
(2 mL) and triethylamine (0.1 mL), 4-DMAP (0.52 mg) was added

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S. Kristafor et al. / Journal of Fluorine Chemistry 132 (2011) 573–578
577
under Ar. The mixture was stirred for 15 min at 0 8C and MTrCl
4.3. Crystal structure determination
(158.5 mg, 0.51 mmol) was added. The reaction mixture was
stirred for 3 h at room temperature, quenched by addition of
methanol (10 mL) and evaporated to dryness. The residue was
purified using column chromatography (CH2Cl2:MeOH = 10:1) to
obtain compound 2 (60 mg, 52%) as white crystals; mp 172–
174 8C; Anal. Calcd for C30H30N2O5: C, 72.27; H, 6.06. Found: C,
72.49; H, 6.05; ESI-MS: m/z 499 [MH]+.
The crystals suitable for X-ray single crystal structure study
were grown by slow evaporation from ethanol solution (96%). The
intensities were collected on an Oxford Diffraction Xcalibur2
diffractometer with a Sapphire 3 CCD detector using graphite-
˚
monochromated CuK radiation (l = 1.54184 A) and v scan-mode.
a
CrysAlis programs [29] were used for data collection and
processing. The intensities were corrected for absorption using
the multi-scan absorption correction method [29]. The crystal
structure was solved by direct methods [30] and all non-hydrogen
atoms were refined anisotropically by full-matrix least-squares
calculations [30] based on F2 using the programs integrated in
WinGX [31] program package. The hydrogen atoms attached to the
N3, O3, O4 and O5 atoms have been found in a difference Fourier
map and have been refined freely. All other hydrogen atoms were
treated using appropriate riding models, with SHELXL97 [30]
defaults. PLATON [32] program was used for structure analysis and
drawings preparation. CCDC 808738 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
4.2.2. 6-[3-Fluoromethyl-2-hydroxypropenyl]-1,5-
dimethylpyirimidin-2,4-dione (3) and 6-[3-fluoro-2-
(fluoromethyl)propenyl]-1,5-dimethylpyrimidin-2,4-dione (4)
The solution of compound 2 (60 mg, 0.12 mmol) in dry CH2Cl2
(25 mL) was cooled to ꢀ75 8C and DAST (0.08 mL, 0.61 mmol) was
added under Ar. The cooling bath was removed and the reaction
mixture was stirred at room temperature for 2 h. Methanol (5 mL)
was added to the reaction mixture and the solution was evaporated
to dryness. The residue was dissolved in 5% methanolic HCl (4 mL)
and refluxed for 15 min. After evaporation to dryness, the residue
was purified by column chromatography (CH2Cl2:MeOH = 20:1) to
yield compounds 3 (6.5 mg, 24%) and 4 (9.2 mg, 36%) as crystals.
3: mp 149–155 8C; Anal. Calcd for C10H13N2O3F: C, 52.63; H,
5.74. Found: C, 52.79; H, 5.76; ESI-MS: m/z 229 [MH]+.
Crystal
data
for
1:
crystal
dimension
4: mp 230–235 8C; Anal. Calcd for C10H12N2O2F2: C, 52.17; H,
5.25. Found: C, 52.01; H, 5.27; ESI-MS: m/z 231 [MH]+.
0.30 mm ꢁ 0.30 mm ꢁ 0.30 mm; C10H16N2O5, Mr = 244.25, triclinic
˚
¯
space group P1 (No. 2); a = 7.6949(2), b = 8.4584(3), c = 9.0650(3) A,
3
˚
a
= 81.867(3),
dx = 1.397 g cmꢀ3
wR = 0.0434/0.1253 for 176 parameters and 2096 reflections with
(I), R/wR = 0.0440/0.1259 for all 2141 unique reflections
b
= 84.643(2),
g
= 86.134(3)8; V = 580.64(3) A ; Z = 2;
4.2.3. 6-[2-(p-Anisyldiphenylmethoxy)methyl-3-mesylpropenyl]-
1,5-dimethylpyrimidin-2,4-dione (5) and 6-[3-chloro-2-
; T = 295 K; 5406 reflections measured, R/
(hydroxymethyl)propenyl]-1,5-dimethylpyrimidin-2,4-dione (6)
To a cold solution of compound 2 (10 mg, 0.02 mmol) in dry
pyridine (0.3 ml) mesyl chloride (0.05 ml, 0.65 mmol) was added
under Ar. The reaction mixture was stirred for 1 h at ꢀ8 8C. The
stirring was continued for 2 h at 0 8C, followed by addition of
methanol and water. The solvents were evaporated to dryness and
after purification bycolumn chromatography (CH2Cl2:MeOH = 20:1)
compounds 5 (3 mg, 26%) and 6 (3 mg, 50%) were isolated as oils.
5: Anal. Calcd for C31H32N2O7S: C, 64.57; H, 5.59. Found: C,
64.70; H, 5.61; ESI-MS: m/z 577 [MH]+.
I ꢂ 2
s
measured in the range 11.568–2u–139.988; S = 1.082.
Acknowledgments
Support of this study by the Ministry of Science and Technology
of Croatia (projects #125-0982464-2925 and 119-1193079-3069)
is gratefully acknowledged. The authors would like to thank K.
ˇ
Molcanov, PhD for data collection on X-ray diffractometer and S.
´
´
Kraljevic Pavelic, Assistant Professor, for cytostatic evaluations of
6: Anal. Calcd for C10H13N2O3Cl: C, 49.09; H, 5.36. Found: C,
49.24; H, 5.35; ESI-MS: m/z 245 [MH]+, 247 [MH + 2]+.
newly prepared compounds.
Appendix A. Supplementary data
4.2.4. 6-[2-Acetoxyomethyl-3-hydroxypropenyl]-1,5-
dimethylpyirimidin-2,4-dione (7) and 6-[3-acetoxy-2-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2011.06.002.
References
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