5-fluoro-5-halo- and 5-fluoro-5-nitro-substituted uracil derivatives. synthesis and structure

Article abstract of DOI:10.1007/s10593-015-1737-y

[MediaObject not available: see fulltext.] 5-Bromo-5-fluoro- and 5-chloro-5-fluoro-6-hydroxy-5,6-dihydrouracils were obtained in high yields by oxidative halogenation of 5-fluorouracil. Nitration of 5-fluorouracil gave 5-fluoro-6-hydroxy-5-nitro-5,6-dihydrouracil. Theoretical calculations in B3LYP/6-311+G(d,p) // B3LYP/6-311G(d,p) + IEFPCM approximation and GIAO simulation of ¹³C NMR spectra and spin-spin coupling constants agree with the structure of the compounds obtained, which manifest an equatorial orientation of the fluorine atom and an axial orientation of the hydroxy group at position 6 of the dihydrouracil ring. The principal possibility of oxidative iodination of 5-halouracils was studied in B3LYP/CEP-121G approximation. It was found that reversible elimination of iodine by a nucleophilic agent to give the original compounds is the main transformation pathway of the intermediate in this process.

Full text of DOI:10.1007/s10593-015-1737-y

DOI 10.1007/s10593-015-1737-y
Chemistry of Heterocyclic Compounds 2015, 51(6), 568–572
5-Fluoro-5-halo- and 5-fluoro-5-nitro-substituted
uracil derivatives. Synthesis and structure
Inna B. Chernikova1*, Sergey L. Khursan1, Leonid V. Spirikhin1, Marat S. Yunusov1
1 Ufa Institute of Chemistry, Russian Academy of Sciences,
71 Oktyabrya Ave., Ufa 450054, Russia; е-mail: leben_87@mail.ru
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(6), 568–572
Submitted 5.05.2015
Accepted after revision 23.06.2015
(For X = Cl, Br):
KCl or KBr, 33% H2O2
20% H2SO4, rt, 5 h
O
O
X
F
HN
HN
F
X = Cl (93%),
X = Br (95%),
X = NO2 (95%)
(For X = NO2):
HNO3, H2SO4
O
N
H
H
O
N
H
OH
0 to 100°C, 5 h
5-Bromo-5-fluoro- and 5-chloro-5-fluoro-6-hydroxy-5,6-dihydrouracils were obtained in high yields by oxidative halogenation of 5-fluoro-
uracil. Nitration of 5-fluorouracil gave 5-fluoro-6-hydroxy-5-nitro-5,6-dihydrouracil. Theoretical calculations in B3LYP/6-311+G(d,p) //
B3LYP/6-311G(d,p) + IEFPCM approximation and GIAO simulation of 13C NMR spectra and spin-spin coupling constants agree with
the structure of the compounds obtained, which manifest an equatorial orientation of the fluorine atom and an axial orientation of the
hydroxy group at position 6 of the dihydrouracil ring. The principal possibility of oxidative iodination of 5-halouracils was studied in
B3LYP/CEP-121G approximation. It was found that reversible elimination of iodine by a nucleophilic agent to give the original com-
pounds is the main transformation pathway of the intermediate in this process.
Keywords: 5-fluorouracil, 5-fluoro-5-halouracils, 5-fluoro-5-nitrouracil.
As a result of the similarity of the steric volumes of F
and H atoms and the difference in their behavior due to
different electronegativity, many fluorine-containing com-
pounds act as antimetabolites with respect to a correspond-
ing substrate containing no halogen.
Uracil and its derivatives play an important role in
processes occurring in living organisms and are used in
practical medicine as pharmaceuticals.1,2 Certain 5-fluoro-
uracil-containing pharmaceutical compounds are converted
to 5-fluorouracil in the organism.3,4 In some cases, the
formation of 5-fluorouracil from these compounds occurs
in a tumor tissue, thus minimizing a systemic action of
5-fluorouracil on healthy tissues. Thus, these compounds are
prodrugs; activities aimed at synthesis of this kind of
compounds are being undertaken continually.
This paper presents results on a synthesis of 5-sub-
stituted derivatives of 5-fluorouracil and a study of their
structures, including stereochemistry. Methods to synthesize
5-fluoro-5-halo- and 5-fluoro-6-hydroxy-5-nitro-5,6-di-
hydrouracils by fluorination of 5-halouracils or 5-nitro-
uracil with a F2/N2 gas mixture were reported in literature.
The yields of the products obtained by this method were
82–92%.5
KHal–H2O2 mixture in 20% H2SO4.6 This method gave
5-chloro-5-fluoro-6-hydroxy-5,6-dihydrouracil (2) and
5-bromo-5-fluoro-6-hydroxy-5,6-dihydrouracil (3) in 93
and 95% yields, respectively (Scheme 1). The structures of
the compounds were determined by 1H and 13C NMR
spectroscopy. The 13C NMR spectra of compounds 2, 3
show doubling of signals for the C-4,5,6 atoms due to spin-
spin coupling with the nucleus of the fluorine atom.7
Scheme 1
(For X = Cl, Br):
KCl or KBr, 33% H2O2
20% H2SO4, rt, 5 h
O
O
X
F
HN
HN
F
(For X = NO2):
HNO3, H2SO4
0 to 100°C, 5 h
O
N
H
1
H
O
N
H
OH
2 X = Cl (93%),
3 X = Br (95%),
4 X = NO2 (95%)
The synthesis of 5-fluoro-6-hydroxy-5-nitro-5,6-di-
hydrouracil (4) was carried out by nitration of compound 1
with a mixture of nitric and sulfuric acids. The yield of
compound 4 was 95% (Scheme 1). Like in the case of
5,5-dihalogenated uracil derivatives 2, 3, the 13C NMR
spectrum of compound 4 shows doubling of signals for the
C-4,5,6 atoms.
We proposed a synthesis of 5-substituted fluorouracil
derivatives using 5-fluorouracil (1) as the substrate. Oxi-
dative halogenation of compound 1 was carried out using
0009-3122/15/5106-0568©2015 Springer Science+Business Media New York
568

Chemistry of Heterocyclic Compounds 2015, 51(6), 568–572
Spectral data do not allow us to identify the spatial
structure of the compounds obtained unambiguously,
therefore we performed theoretical calculations of
equilibrium geometry parameters of compounds 2–4 in
B3LYP/6-311+G(d,p) // B3LYP/6-311G(d,p) + IEFPCM
approximation. Previously, we successfully used this level
of theory to study the structure of 5-halo-6-methyluracils
and the regularities of ipso substitution in these com-
pounds.8 When designing the structures of compounds 2–4,
we took into consideration that the hydroxy substituent at
position 6 of the dihydropyrimidinedione ring is oriented
axially because of anomeric stabilization due to coupling of
an unshared electron pair on the N-1 atom with the
σ*-antibonding orbital of the C(6)–O bond.9 Furthermore,
it was believed that in the polar solvent (DMSO used in the
spectral measurements), the hydroxy group in compounds
2–4 is bound by an intermolecular hydrogen bond with a
solvent molecule: Me2S=O···H–O–C(6). Under these model
restrictions, the possible isomers of compounds 2–4 will
differ only in the mutual orientation of substituents at
position 5 of the dihydrouracil ring, namely, the F atom
and the X moiety (X = Cl, Br, NO2). The equilibrium
structures of isomers 2–4 a,b were found by full
optimization of their geometry parameters (Fig. 1). The
Gibbs free energies of 1:1 complexes (2–4)–DMSO were
calculated with the thermal correction, taking into account
the solvation effect, and the most probable conformations
of the studied compounds were determined (Table 1). The
data presented in Table 1 indicate that the isomer with an
equatorially oriented fluorine atom is the most
thermodynamically stable isomer of all the compounds
studied. The population values of isomers 2–4 b are 92, 98,
and 86%, respectively.
Figure 1. Spatial structure of compounds 2 (X = Cl), 3 (X = Br),
and 4 (X = NO2) based on B3LYP/6-311G(d,p) optimization of
geometry parameters of the molecules.
To support our conclusions additionally, we calculated
the theoretical 13C NMR chemical shifts by the GIAO
B3LYP/6-311+G(d,p) method, as well as spin-spin
1
2
coupling constants JCF and JCF responsible for the
observed splitting of signals for the C(4)–C(6) atoms (see
above). The calculation results presented in Table 2
confirm the conclusion that compounds 2–4 b are formed
under conditions of our experiments. First, the regressional
relationship between the experimental values of the 13C NMR
chemical shifts and the theoretical isotropic screening constants
for compounds 2–4 b is observed with a larger correlation
coefficient than for compounds 2–4 a. The same is observed in
a study of the relationship between the theoretical and
1
experimental JCF values for the C-5 atom in the series of
compounds 2–4 b. Finally, the theory predicts a correct order
of spin-spin coupling constants (2JC(4)F > 2JC(6)F) for compounds
2–4 b and an inverse one for compounds 2–4 a (Table 2).
The issue of preferential equatorial orientation of the
fluorine atom and axial orientation of electronegative
Table 1. Full energies (Etotal), thermal corrections (TC), absolute Gibbs free energies (G°298), solvation energies in DMSO (Gsolv),
relative Gibbs energies (ΔG°298), and isomer population (g) of isomers of compounds 2–4
Orientation
Compound
E
total, Hartree
TC, Hartree
G
solv, kcal/mol
G°298, Hartree
ΔG°298, kcal/mol
g, %
of fluorine atom
Axial
–1603.570744
–1603.573096
–3717.489195
–3717.492571
–1348.501450
–1348.503602
0.131377
0.131924
0.129761
0.130173
0.141424
0.141134
–14.50
–14.84
–14.52
–14.89
–16.10
–15.66
–1603.462474
–1603.464821
–3717.382573
–3717.386126
–1348.385683
–1348.387424
2a
2b
3a
3b
4a
4b
0.00
–1.47
0.00
–2.23
0.00
8
92
2
98
14
86
Equatorial
Axial
Equatorial
Axial
Equatorial
–1.09
Table 2. Calculated and experimental 13C NMR spectral characteristics of compounds 2–4 a,b
Chemical shift, δ, ppm
Spin-spin coupling constants, Hz
Compound
C-2
C-4
C-5
C-6
C-2 (4JCF
)
C-4 (2JCF
)
C-5 (1JCF
)
C-6 (2JCF
)
2a (Theoretical)
2b (Theoretical)
2 (Experimental)
3a (Theoretical)
3b (Theoretical)
3 (Experimental)
4a (Theoretical)
4b (Theoretical)
4 (Experimental)
152.7
151.5
151.0
152.8
151.5
150.8
152.3
151.7
150.9
160.6
162.1
163.0
160.8
163.0
163.6
159.2
157.7
158.4
110.4
102.7
97.1
117.2
105.9
91.0
106.7
108.2
107.1
76.6
76.6
77.0
77.2
77.1
77.6
74.0
73.5
73.6
0.7
0.6
0.0
0.7
0.7
0.0
0.5
0.8
0.0
22.4
27.0
27.1
20.7
24.8
25.2
23.1
25.6
26.1
317.0
342.2
255.5
326.7
353.2
264.4
312.9
328.0
245.7
27.3
22.6
26.6
25.6
21.3
24.9
29.8
21.5
24.7
569

Chemistry of Heterocyclic Compounds 2015, 51(6), 568–572
Scheme 2
moiety X in the compounds studied is seemed an interplay
of stabilization/destabilization effects and deserves a more
detailed examination. It can be assumed as a working
hypothesis that the axial orientation of X moiety is
stabilized by partial population of the σ*(C(5)–X) orbital
due to π(C(4)=O) → σ*(C(5)–X) coupling. The possibility
of this stabilization is confirmed by the results of NBO
analysis of electron density in molecules of compounds 2–4.
Thus, it was found at the B3LYP/6-311+G(d,p) level of
theory that the population of the σ*(C(5)–X) orbital
increases in a row 0.0745 (compound 2b) – 0.0831
(compound 3b) – 0.1680 (compound 4b), and the energy of
O
O
I
F
.H O
.
H ...O
O
Path I
.
HN
HN
F
+
I
O
S
+
OH
O
N
H
1
H
O
N
H
H
5
+
H ...O
H ...–O
O
O
I
O
S
HO
O
HN
OH
F
S
+
6
O
OH
Path II
O
N
H
OH
7
the orbital coupling is about
3 kcal/mol. Another
stabilization interaction, namely, effect of the axial oxygen
atom is worth to be mentioned. According to NBO
analysis, the σ(C(6)–X) → σ*(C(5)–X) coupling may be an
important factor for the conformation behavior of
compounds 2–4: the stabilization energy in the series of
compounds 2b – 3b – 4b (2.34, 2.64, and 1.84 kcal/mol,
correspondingly) is somewhat higher than that in the row
of compounds 2–4 a. Finally, one cannot rule out, at least
for compound 4, a stereo-controlling repulsive interaction
of polar group dipoles, the minimum value of which is
apparently reached at a mutually perpendicular orientation
of the groups with large dipole moments, namely C(4)=O
(μ(H2C=O) = 2.33 D) and C(5)–NO2 (μ(H3C–NO2) = 3.46 D).
For comparison, μ(H3C–F) = 1.85 D (the dipole moments
were taken from a database).10
uracils. Second, objective difficulties exist in selection of a
theoretical model for the process studied, since the reaction
medium (20% aqueous solution of sulfuric acid) is directly
involved in the reaction to give strong solvate complexes
with ionic intermediates. We believe that a reasonable
compromise in this situation is provided by the theoretical
model where carbocation 5 reacts with nucleophilic particle
6, which is a 1:1 complex of a water molecule and a
hydrosulfate anion (Fig. 2). In the first place, we studied
the effect of a halogen atom at position 5 and examined the
changes in the series F – Cl – Br – I on semiquantitative
level.
Efficient oxidative halogenation requires that compe-
tition of the two paths (I and II) of carbocation 5 transfor-
mation be in favor of reaction II (Scheme 2). We per-
formed DFT calculations for these two paths (Table 3). In
the series of halogens from fluorine to iodine, a distinct
trend is observed: the Gibbs free energy of reaction I
decreases, whereas ΔG°298(II) increases. The considerable
negative ΔΔG°298 value (Table 3) for X = Cl or Br indicates
that reaction II occurs preferentially in comparison with the
reverse reaction I. This result agrees with the experiment
according to which compounds 2 and 3 are formed
smoothly and in high yields. In the case of X = I, ΔΔG°298
is close to zero under our model conditions, i.e., decompo-
sition of carbocation 5 to give the starting 5-fluorouracil (1)
begins to predominate. Considering the model restrictions
and the imperfection of the basis set used, it can be
concluded that the hypothesis on the easy reversible I+ ion
elimination as the main factor of the thermodynamic
instability of the carbocation formed in oxidative
halogenation of 5-fluorouracil (1) is quite reasonable,
though it cannot be considered as completely proven.
The study of the structure of carbocation 5 does not
contradict this hypothesis, either. A regular variation of the
It has been shown previously8 that in acid medium or in
the presence of nucleophilic agents, 5,5-dihalo-substituted
uracils, where one of the halogen atoms is bromine, are
converted to 5-monohalo derivatives. This fact allows one
to assume that 5-fluoro-5-halouracil derivatives can, under
appropriate conditions, play the role of 5-fluorouracil
prodrugs. In view of this, we studied the behavior of
compounds 2 and 3 in an acidic medium. Heating of
compound 3 in 50% H2SO4 at 80°C gives 5-fluorouracil (1)
in 93% yield. The reaction of compound 2 under the
specified conditions did not give the expected 5-fluoro-
uracil. A similar behavior, viz., inertness of the chlorine
atom in C(5)–Cl bond cleavage, was observed by us
previously.8
We did not find data on 5-fluoro-6-hydroxy-5-iodo-5,6-
dihydrouracil in literature. Therefore, we made an attempt
to synthesize it. However, 5-fluorouracil did not react
under conditions of oxidative iodination with KI–H2O2 in
20% H2SO4. We believe that the most natural explanation
of this fact is that the intermediate cation of 5-fluoro-5-iodo-
5,6-dihydrouracil (5) (Scheme 2) is unstable under
oxidative iodination conditions and serves as a precursor of
the final molecular product, namely, 5-fluoro-6-hydroxy-
5-iodo-5,6-dihydrouracil (7).
Two circumstances make it difficult to check this
assumption theoretically. First, simulation of iodine-
containing compounds requires the use of basis sets with
effective core potential. To compare the results, all the
molecular systems were calculated in the B3LYP/CEP-121G
approximation. We used this theory level previously8 to
simulate ipso substitution in a series of 5-halo-6-methyl-
Figure 2. Ionic intermediates as the reagents in the reaction
studied; X = F, Cl, Br, I. Calculation in the B3LYP/CEP-121G
approximation.
570

Chemistry of Heterocyclic Compounds 2015, 51(6), 568–572
Table 4. The Gibbs free energies for interaction of carbocations
Table 3. Energy characteristics of the interaction of carbocation 5
with anion 6, the geometry and electron parameters of carbocation 5.
Calculation in B3LYP/CEP-121G + IEFPCM approximation
5, 8, 9 with anion 6 and the effective charges on the C-6 and I atoms.*
Calculation in the B3LYP/CEP-121G + IEFPCM approximation
X
Characteristics
ΔG°298(I), kcal/mol
5
8
9
Characteristics
F
35.3
Cl
4.4
Br
–3.5
–20.3*
> –16.8
2.026
1.506
I
–13.8
–17.5
> –3.7
+0.366
+0.485
–0.119
–14.6
–14.7
–0.1
–13.0
–12.1
+0.9
ΔG°298(I), kcal/mol
ΔG°298(II), kcal/mol
ΔΔG°298,** kcal/mol
r(C(5)–X),*** Å
r(C(5)–C(6)),*** Å
r(C(6)–N(1)),*** Å
q(C(6)),*4 a. u.
–13.8
–17.5*
> –3.7
2.227
1.313
1.320
+0.366
+0.485
–0.119
ΔG°298(II), kcal/mol
ΔΔG°298,** kcal/mol
q(C(6)), a. u.
–26.8
–62.1
1.410
1.533
1.301
+0.376
–0.142
+0.518
–23.9
–28.3
1.876
1.514
1.309
+0.407
+0.239
+0.168
+0.329
+0.537
–0.208
+0.311
+0.513
–0.202
q(I), a. u.
Δq, a. u.
1.313
* For designations, see the notes to Table 3.
+0.363
+0.350
+0.013
q(X),*4 a. u.
Δq,*5 a. u.
Thus, we have developed an efficient alternative
method to obtain 5-substituted 5-fluorouracil derivatives
and suggested their spatial structure based on quantum-
chemical calculations. Furthermore, we made an assump-
tion about the reasons that make it impossible to synthesize
5-substituted 5-iodouracil derivatives.
* The value is underestimated due to the formation of a C(6)–OH···F
intramolecular hydrogen bond in the reaction product.
** ΔΔG°298 = ΔG°298(II) – ΔG°298(I), the difference in the Gibbs free
energies of reactions II and I.
*** The interatomic distances in molecule of carbocation 5.
The effective charges on the atoms (for C-6 atom – the total charge
4
*
Experimental
including the hydrogen atom) in carbocation 5.
5
*
The difference between the effective charges on the C-6 and halogen
1H and 13C NMR spectra were recorded on a Bruker
AM-300 spectrometer (300 and 75 MHz, respectively) in
DMSO-d6, using the solvent signal as internal standard
(2.50 ppm for 1H nuclei, 39.5 ppm for 13C nuclei). Melting
points were determined in glass capillaries.
atoms.
geometry parameters and electron density distribution
features in compound 5 are observed upon step-by-step
replacement of X in the series from fluorine to iodine
(Table 3). It is noteworthy to compare the effective charges
on the reaction centers of reactions I and II, i.e., the X and
C-6 atoms, respectively. As it is seen from Table 3 data,
only in the case of X = I the effective charge on the
halogen atom exceeds the q value on the C-6 atom.
Hence, nucleophilic particle 6 will be preferentially
oriented toward the halogen atom only in the case of the
iodine-containing carbocation. In this case, reversible
decomposition of the latter, i.e., reaction I, will occur
preferentially only in the case of X = I, resulting in the
experimentally noted inertness of 5-fluorouracil in
oxidative iodination.
All previous attempts performed in our laboratory to
obtain dihalo-substituted uracils, with iodine as one of the
halogen atoms, failed. The results obtained in this study are
in reasonable agreement with these observations. Further-
more, we examined the stability of carbocation 5, in which
the fluorine atom was replaced by a chlorine (cation 8) or
bromine atom (cation 9), as well as the competition of the
corresponding reactions I and II for these cations. It was
found that the probability of reaction II for cations 8, 9
decreased even more in comparison with I+ ion elimination
from carbocation 5 caused by attack of nucleophile 6 (Table 4).
Thus, a theoretical simulation in the B3LYP/CEP-121G
approximation indicates that it is impossible to obtain 5-halo-
5-iodouracils by oxidative iodination, in agreement with the
results of our previous studies in this field.6
Quantum-chemical calculations were carried out using
the Gaussian-09 program, Revision C.1.11 Primary process-
ing and visualization of the results were performed using
the ChemCraft program.12 Complete optimization of the
geometry parameters of the compounds being studied and
calculations of the force constants were carried out using
the B3LYP hybrid electron density functional13,14 and the
6-311G(d,p) basis set.15 The total energies were determined
by single point calculation for optimized states, using the
6-311+G(d,p) diffusion basis set. Since the specified basis
sets are not applicable for compounds containing iodine
atoms, the stability of 5-fluoro-5-halo-5,6-dihydrouracil
carbocations was additionally analyzed with full optimi-
zation of the structures of all compounds and calculation of
total energies and force constants in the B3LYP/CEP-121G
approximation. Here CEP-121G is the basis set of triple
valent splitting with the use of effective potential for the
core (nonvalent) electrons.16,17 The conformity of the
structures found to the minima on the potential energy
surface was ascertained by the absence of negative
elements in the diagonalized Hessian matrix. Identification
of the PES saddle points relied on the existence of a single
negative (imaginary) frequency. The Gibbs free energies
G° of the compounds were calculated as G° = Etotal
+
+ ZPE + TC (where Etotal is the total energy of the
compound, ZPE is the zero point energy, and TC is the
thermal correction to the Gibbs energy calculated for the
temperature of the experiments T = 298 K). The effect of
the solvent (dimethyl sulfoxide or water) was taken into
account using the IEFPCM continuum model.18,19 The
chemical shifts of atoms and the spin-spin coupling
constants were calculated by the GIAO method20,21 in the
B3LYP/6-311+G(d,p) approximation.
O
O
I
I
HN
HN
Cl
H
Br
H
+
+
O
N
H
8
O
N
H
9
571

Chemistry of Heterocyclic Compounds 2015, 51(6), 568–572
Synthesis of 5-fluoro-5-halo-6-hydroxy-5,6-dihydro-
References
uracils 2, 3 (General method). A portion of 33% H2O2
(0.6 ml, 6.0 mmol) was added dropwise to a mixture of
5-fluorouracil (1) (0.20 g, 1.5 mmol) and KCl or KBr
(3.0 mmol) in 20% H2SO4 (2.0 ml). The mixture was
stirred at room temperature for 6 h. The reaction mixture
was diluted with H2O and extracted with Et2O (3×25 ml).
The combined extracts were washed with H2O, dried over
Na2SO4, concentrated, and recrystallized from acetone.
5-Chloro-5-fluoro-6-hydroxy-5,6-dihydrouracil (2).
Yield 0.26 g (93%), white crystals, mp 143–145°C (mp
149–152°C (H2O).5 1H NMR spectrum, δ, ppm (J, Hz):
3.45 (1H, s, OH); 5.02 (1H, d, J = 3.8, 6-CH); 8.90 (1H, s,
1-NH); 11.05 (1H, s, 3-NH). 13C NMR spectrum, δ, ppm
(J, Hz): 77.0 (d, J = 26.6, C-6); 97.1 (d, J = 255.5, C-5);
151.0 (C-2); 163.0 (d, J = 27.1, C-4).
1. Rideout, J. L.; Henry, D. W.; Beachen, L. M. In Nucleosides,
Nucleotides and their Biological Application; Academic
Press: New York, 1983, p. 1.
2. Blackburn, G. M.; Gait, M. J.; Loakes, D.; Williams, D. M.
Nucleic Acids in Chemistry and Biology; 3rd ed.; RSC
Publishing: Cambridge, 2006, p. 93, 127.
3. González-Barón, M.; Feliu, J.; de la Gándara, I.; Espinosa, E.;
Colmenarejo, A.; Martínez-Martínez, B.; Blanco, E.; García-
Girón, C.; Juárez, F.; Garrido, P.; Ordóñez, A.; Zamora, P.
Eur. J. Cancer 1995, 31, 2215.
4. Mayer, R. J. J. Clin. Oncol. 2001, 19, 4093.
5. Cech, D.; Hein, L.; Wuttke, R.; von Janta-Lipinski, M.; Otto, A.;
Langen, P. Nucleic Acids Res. 1975, 2, 2177.
6. Kasradze, V. G.; Ignatyeva, I. B.; Khusnutdinov, R. A.;
Suponitskii, K. Yu.; Antipin, M. Yu.; Yunusov, M. S. Chem.
Heterocycl. Compd. 2012, 48, 1018. [Khim. Geterotsikl.
Soedin. 2012, 1095.]
7. Günther, H. NMR Spectroscopy. An Introduction; John Wiley
and Sons: Chichester, 1980, p. 379.
8. Chernikova, I. B.; Khursan, S. L.; Spirikhin, L. V.;
Yunusov, M. S. Russ. Chem. Bull. 2013, 62, 2445. [Izv. Akad.
Nauk, Ser. Khim. 2013, 2445.]
9. Chernikova, I. B.; Khursan, S. L.; Yunusov, M. S.;
Yumagulov, R. A. Mendeleev Commun. 2015, 25, 221.
10. NIST Computational Chemistry Comparison and Benchmark
Database, NIST Standard Reference Database Number 101,
Release 16a, August 2013; Johnson, R. D., III, Ed.; http://
cccbdb.nist.gov/
5-Bromo-5-fluoro-6-hydroxy-5,6-dihydrouracil (3).
Yield 0.33 g (95%), white crystals, mp 174–176°C (mp
181°C (H2O).5 1H NMR spectrum, δ, ppm (J, Hz): 3.68
(1H, s, OH); 5.07 (1H, d, J = 5.1, 6-CH); 8.85 (1H, s,
1-NH); 11.00 (1H, s, 3-NH). 13C NMR spectrum, δ, ppm
(J, Hz): 77.6 (d, J = 24.9, C-6); 91.0 (d, J = 264.4, C-5);
150.8 (C-2); 163.6 (d, J = 25.2, C-4).
5-Fluoro-6-hydroxy-5-nitro-5,6-dihydrouracil
(4).
5-Fluorouracil (1) (0.30 g, 2.3 mmol) was gradually added
to conc. H2SO4 (0.6 ml). After the starting compound
dissolved completely, the mixture was cooled to 0°C,
HNO3 (d 1.4 g/ml, 0.6 ml) and conc. H2SO4 (0.3 ml) were
successively added dropwise, and the mixture was kept at
0–10°C for 4 h. The reaction mixture was diluted with H2O
and extracted with Et2O (3×25 ml). The combined extracts
were washed with H2O, dried over Na2SO4, concentrated,
and recrystallized from acetone. Yield 0.42 g (95%), white
11. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.;
Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.;
Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.;
Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.;
Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;
Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.;
Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision
C.1; Gaussian, Inc.: Wallingford, 2009.
1
crystals, mp 171–173°C (mp 179–182°C (H2O)5). H NMR
spectrum, δ, ppm (J, Hz): 3.67 (1H, s, OH); 5.22 (1H, d,
J = 4.7, 6-CH); 9.00 (1H, s, 1-NH); 11.70 (1H, s, 3-NH).
13C NMR spectrum, δ, ppm (J, Hz): 73.6 (d, J = 24.7, C-6);
107.1 (d, J = 245.7, C-5); 150.9 (C-2); 158.4 (d, J = 26.1, C-4).
Reaction of 5-bromo-5-fluoro-6-hydroxy-5,6-dihydro-
uracil (3) with 50% H2SO4. Conc. H2SO4 (0.6 ml,
11.10 mmol) was added dropwise at 80°C to a suspension
of compound 3 (0.15 g, 0.66 mmol) in H2O (0.6 ml), and
the mixture was stirred at the same temperature for 7 h. The
resulting precipitate of compound 1 was filtered off, washed
with H2O to a neutral pH, and dried. Yield 0.08 g (93%).
The physicochemical properties of the obtained compound
1 matched those reported previously.22 The starting com-
pound 3 (0.01 g, 7%) was isolated from the filtrate.
12. ChemCraft. http://www.chemcraftprog.com.
13. Becke, D. J. Chem. Phys. 1993, 98, 5648.
14. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter
Mater. Phys. 1988, 37, 785.
15. Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem.
Phys. 1980, 72, 650.
16. Stevens, W. J.; Basch, H.; Krauss, M. J. Chem. Phys. 1984,
81, 6026.
This study was financially supported by a Grant of the
2014 Contest on Russian Science Foundation activity
''Fundamental scientific studies and research performed by
separate scientific groups" (application number 14-13-
01307). Information support: grant no. 13-00-14056 of the
Russian Foundation for Basic Research. Spectroscopic
studies and theoretical calculations were carried out using
equipment available at the ''Chemistry" User Facilities
Center, Ufa Institute of Chemistry of the Russian Academy
of Sciences.
17. Stevens, W. J.; Krauss, M.; Basch, H.; Jasien, P. G. Can. J.
Chem. 1992, 70, 612.
18. Mennucci, B.; Cancès, E.; Tomasi, J. J. Phys. Chem. B 1997,
101, 10506.
19. Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105,
2999.
20. Ditchfield, R. Mol. Phys. 1974, 27, 789.
21. Wolinski, K.; Hinton, J. F.; Pulay, P. J. Am. Chem. Soc. 1990,
112, 8251.
22. Duschinsky, R.; Pleven, E.; Heidelberger, C. J. Am. Chem.
Soc. 1957, 79, 4559.
572