Electrophilic fluorination of 6-methyl- and 1,3,6-trimethyluracils in water

Article abstract of DOI:10.1134/S1070428015070180

The reaction of 4-chloromethyl-1-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) with 6-methyl- and 1,3,6-trimethyluracil in water has been studied. According to the kinetic data, the fluorination follows a bimolecular mechanism with intermediate formation of cationic σ-complexes.

Full text of DOI:10.1134/S1070428015070180

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 7, pp. 1003–1007. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © G.I. Borodkin, I.R. Elanov, V.G. Shubin, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 7, pp. 1021–1025.
Electrophilic Fluorination
of 6-Methyl- and 1,3,6-Trimethyluracils in Water
G. I. Borodkin, I. R. Elanov, and V. G. Shubin
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: gibor@nioch.nsc.ru
Received April 22, 2015
Abstract—The reaction of 4-chloromethyl-1-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)
with 6-methyl- and 1,3,6-trimethyluracil in water has been studied. According to the kinetic data, the fluorina-
tion follows a bimolecular mechanism with intermediate formation of cationic σ-complexes.
DOI: 10.1134/S1070428015070180
Uracil derivatives exhibit antiviral activity, while
6-methyluracil is used in medicine as anti-inflamma-
tory, anabolic, and anti-catabolic drug [1]. Introduction
of fluorine atoms into organic molecules usually en-
hances their therapeutic properties [2]. Schuman et al.
[3] patented a procedure for the synthesis of 5-fluoro-
6-methyluracil by fluorination of 6-methyluracil with
gaseous fluorine in water. Cech et al. [4] later obtained
5-fluoro-6-methyluracil by the action of fluorine on
6-methyluracil in acetic acid, and the authors noted
that no 5-fluoro-6-methyluracil was formed when
acetic acid was replaced by water. Elemental fluorine
was widely used to synthesize a number of other
fluorinated uracils (see, e.g., [4, 5]). In addition, such
fluorinating agents as OF2 [6], AcOF [7, 8], CF3OF
[9, 10], XeF2 [11], and CsSO4F [12] were used. All
these compounds, as well as elemental fluorine, cannot
be regarded as environmentally safe [13]. Gaseous
fluorine is very aggressive toward many materials,
toxic, and dangerous in handling, OF reagents are toxic
and insufficiently stable, while XeF2 is toxic and ex-
pensive.
uracil in 82% yield. However, Rangwala et al. [20]
under analogous conditions obtained labeled 5-fluoro-
(2-13C)uracil in a much lower yield.
With a view to developing an efficient environ-
mentally acceptable procedure for the synthesis of
fluorinated uracil derivatives, in this work we exam-
ined the reactions of 6-methyluracil (1) and 1,3,6-tri-
methyluracil (2) with F-TEDA-BF4 in water. The
reactions with 1 and 2 at 80°C (3 h) afforded, respec-
tively, 5-fluoro-6-methyluracil (3) and 5-fluoro-1,3,6-
trimethyluracil (4) together with 5,5-difluoro-6-hy-
droxy-6-methylhexahydropyrimidine-2,4-dione (5) and
5,5-difluoro-6-hydroxy-1,3,6-trimethylhexahydropy-
rimidine-2,4-dione (6). The formation of compounds 5
and 6 may be rationalized by reaction of intermediate
cationic σ-complexes A with water (see table,
Scheme 1). Presumably, the primary intermediate is
σ-complex B which is capable of either losing a proton
to give compound 3 or 4 or reacting with water to
produce stereoisomeric hydroxy compounds 7 or 8.
The latter were detected in the reaction mixture by
19
1H and F NMR spectroscopy when the reaction was
carried out at lower temperature (40°C; see table).
Compounds 7 and 8 readily undergo dehydration;
therefore, we failed to isolate them in the pure state
and record their mass spectra.
Presumably, the gauche effect in the attack of com-
plex B by water molecule favors formation of cis
isomers 7b and 8b (cf. [7, 8]). According to the 1H and
19F NMR data, compound 8b (in a mixture of fluorina-
tion products) in water at 40°C is gradually converted
into 5-fluoro-1,3,6-trimethyluracil (4).
In recent time, NF reagents, in particular 4-chloro-
methyl-1-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-
(tetrafluoroborate) (F-TEDA-BF4), have been widely
used as a source of fluorine for mild and selective
fluorination of organic compounds [13–18]. This
reagent is quite reactive and soluble in water and is
a moderate oxidant. Lal et al. [19] were the first to use
F-TEDA-BF4 to fluorinate pyrimidine bases, uracil and
thymine. According to the authors, the reaction of
uracil with F-TEDA-BF4 in water afforded 5-fluoro-
1003

BORODKIN et al.
1004
Scheme 1.
Me
N
Me
N
F
R
O
R
F-TEDA-BF4
N
N
H
O
O
O
R
R
1, 2
B
Me
Me
Me
HO
N
F
F
R
O
F
R
O
R
O
N
F-TEDA-BF4
N
F
H2O
–H+
F
–H+
N
R
O
N
O
N
R
O
R
3, 4
–H2O
OH
A
5, 6
OH
Me
N
Me
H
F
R
O
R
H2O
–H+
F
N
H
+
N
R
O
O
N
R
O
7a, 8a
7b, 8b
1, 3, 5, 7, R = H; 2, 4, 6, 8, R = Me.
Fluorination of 6-methyluracil (1) and 1,3,6-trimethyluracil (2) with F-TEDA-BF4 in water
Yield,a %
Compound Temperature,
Molar ratio
substrate–F-TEDA-BF4
Reaction
time, h
no.
°C
3 or 4
53
24
–
5 or 6
23
7a or 8a
7b or 8b
1
80
80
80
80
40
40
20
20
80
80
80
80
40
20
1:1
0.1:1.5
1:2
03
03
03
03
04
02
20
20
03
03
03
03
02
24
–
–
–
–
2
3
2
3
–
–
–
–
7
4
–
–
63
87
–
1:3
–
1000
08
–
0.1:1.2
b1:2b
0.1:1.2
1:2
35
12
21
17
67
51
11
–
20
68
31
58
–
07
04
22
2
1:1
17
0.1:1.5
1:2
48
–
89
–
1:3
b1:2b
1000
06
–
08
83
75
–
1:2
13
a
Determined by averaging the 1H and 19F NMR data.
Excess F-TEDA-BF4 was removed by adding KI and Na2S2O3 to the mixture.
b
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 7 2015

ELECTROPHILIC FLUORINATION OF 6-METHYL- AND 1,3,6-TRIMETHYLURACILS
1005
Scheme 2.
Me
Me
N
Me
Me
N
Me
F
F
–H+
H+
F-TEDA-BF4
HN
HN
HN
HN
H
HN
O
N
H
O
O
O
O
N
O
O
O
O
N
H
O
1
C
3
Me
Me
Me
N
OH
Me
HN
F
F
F
F
–H+
H+
F-TEDA-BF4
H2O
HN
HN
HN
F
F
O
N
O
O
N
O
O
O
O
N
H
O
D
5
The kinetics of the reaction of uracils 1 and 2 with
F-TEDA-BF4 in water conforms to the bimolecular
mechanism (Scheme 1):
higher rate of the bimolecular reaction of 5-fluoro-
6-methyluracil (3) with F-TEDA-BF4 [k40°C
=
(4.11 ±0.15)×10–3 L mol–1 s–1]. The fluorination of
5-fluoro-6-methyluracil is also a bimolecular reaction
(Fig. 2). The higher rate of fluorination of 3 may be
rationalized assuming participation of its anionic form
(Scheme 2). The presence of a fluorine atom in the
5-position should increase the acidity of 3, and the
reaction with anion D should be faster than with the
neutral species. It should be noted that the acidity of
5-fluorouracil is appresiably higher than the acidity
of uracil [21].
v = ∂[F-TEDA-BF4]/∂τ = k[Ur][F-TEDA-BF4],
where [Ur] is the concentration of 1 or 2. The
ln([Ur]/[F-TEDA-BF4]) values are linearly related to
the time τ (Fig. 1). The second-order rate constants for
the fluorination of 1 and 2 [k40°C = (2.71±0.03)×10–3
and (3.77±0.03)×10–3 L mol–1 s–1, respectively] indi-
cate higher reactivity of 2, which may be due to donor
effect of the methyl groups in positions 1 and 3. The
ratio of the fluorination rate constants of 2 and 1
weakly depends on the temperature. The calculated
ratio k40°C,2/k40°C,1 = 1.39 is close to that found by the
competing reaction method at 70°C, ([4] + [6])/([3] +
[5] + [7]) = 1.41. The reaction of 1 or 2 with F-TEDA-
BF4 is the rate-determining step. This follows from the
Thus, the use of F-TEDA-BF4 as fluorinating agent
and of water as solvent yields mono- and difluoro
uracil derivatives in moderate and high yields, respec-
tively. According to the kinetic data, the reactions
follow the bimolecular mechanism with intermediate
formation of cationic σ-complexes.
2
3.0
2.6
2.2
1.8
1.4
2.4
2.2
2.0
1.8
1.6
1
0
2000 4000 6000 8000 10000 12000 14000
Time, s
0
1000 2000 3000 4000 5000 6000
Time, s
Fig. 1. Plot of ln([Ur]/[F-TEDA-BF4]) versus time for uracils
1 and 2.
Fig. 2. Plot of ln([5-fluoro-6-methyluracil]/[F-TEDA-BF4])
versus time.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 7 2015

BORODKIN et al.
tract was dried over MgSO4, the solvent was distilled
1006
EXPERIMENTAL
The 1H, 13C, and 19F NMR spectra were recorded on
off, and the residue was purified by silica gel column
chromatography using ethyl acetate as eluent. Yield
0.024 g (44%), white crystals, mp 127–129°C.
1H NMR spectrum (CDCl3), δ, ppm: 2.26 d (3H,
6-CH3, J = 3.6 Hz), 3.35 s (3H, NCH3), 3.38 d (3H,
NCH3, J = 0.6 Hz). 13C NMR spectrum (CDCl3), δC,
ppm: 11.96 d (6-CH3, J = 2.6 Hz), 28.21 d (NCH3, J =
1.4 Hz), 31.55 s (NCH3), 136.10 d (C6, J = 24.9 Hz),
137.97 d (C5, J = 225.8 Hz), 150.55 s (C2), 156.38 d
(C4, J = 26.2 Hz). 19F NMR spectrum (CDCl3):
δF –165.14 ppm, q.q (J = 3.6, 0.6 Hz). Found, %:
C 48.90; H 5.26; F 11.20; N 16.29. Calculated, %:
C 48.84; H 5.27; F 11.04; N 16.27. Mass spectrum: m/z
172.0645 [M]+. C7H9FN2O2. Calculated: M 172.0643.
1
13
Bruker AV-300 (300.1 MHz for H, 75.5 MHz for C,
and 282.4 MHz for 19F) and AV-400 spectrometers
(100.6 MHz for C). The chemical shifts were meas-
13
ured relative to the residual proton or carbon signal of
the solvent (CHCl3, δ 7.24 ppm, CDCl3, δC 76.9 ppm;
DMSO-d5, δ 2.50 ppm, DMSO-d6, δC 39.5 ppm)
or added CHCl2CHCl2 (δ 5.94 ppm) or PhCF3
(δF –63.73 ppm relative to CFCl3). The high-resolution
mass spectra were obtained on a Thermo Scientific
instrument.
4-Chloromethyl-1-fluoro-1,4-diazoniabicyclo-
[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-BF4)
was commercial product (>95%, Aldrich); DMSO-d6
and CDCl3 contained 99.8% of deuterium. 6-Methyl-
and 1,3,6-trimethyluracils were synthesized as de-
scribed in [22, 23].
5,5-Difluoro-6-hydroxy-6-methylhexahydropy-
rimidine-2,4-dione (5). A solution of 0.2 g
(1.59 mmol) of 6-methyluracil (1) and 1.685 g
(4.76 mmol) of F-TEDA-BF4 in 10 mL of water was
heated for 3 h at 80°C. The mixture was evaporated to
a volume of ~4 mL and extracted with diethyl ether
(3×30 mL), the extract was dried over MgSO4, and
the solvent was distilled off. Yield 0.263 g (92%),
Fluorination of 6-methyl- and 1,3,6-trimethyl-
uracils 1 and 2 (general procedure). A solution of
uracil 1 or 2 and F-TEDA-BF4 in water was stirred
under the conditions indicated in table, the solvent was
purged off with a stream of air, the residue was dis-
solved in DMSO-d6, and 1H and 19F NMR spectra were
recorded. In some cases (see table), excess F-TEDA-
BF4 was removed by adding KI and Na2S2O3 to the
reaction mixture before purging with air.
1
white crystals, mp 194–196°C. H NMR spectrum
(DMSO-d6), δ, ppm: 1.42 d (3H, 6-CH3, J = 1.5 Hz),
7.07 br.s (1H, OH), 8.80 br.m (1H, NH), 11.10 br.s
13
(1H, NH). C NMR spectrum (DMSO-d6), δC, ppm:
18.40 d (6-CH3, J = 0.6 Hz), 78.94 d.d (C6, J = 27.4,
26.4 Hz), 108.29 d.d (C5, J = 255.4, 247.7 Hz), 150.84 s
(C2), 161.70 d.d (C4, J = 31.5, 27.6 Hz). 19F NMR
spectrum (DMSO-d6), δF, ppm: –116.35 d.q (J = 261.3,
1.5 Hz), –139.66 d.t (J = 261.3, 3.8 Hz). Found, %:
C 33.66; H 3.56; F 21.46; N 15.75. C5H6F2N2O3. Cal-
culated, %: C 33.34; H 3.36; F 21.10; N 15.55.
5-Fluoro-6-methyluracil (3). A solution of 0.2 g
(1.59 mmol) of 6-methyluracil (1) and 0.86 g
(2.43 mmol) of F-TEDA-BF4 in 8 mL of water was
heated for 4 h at 80°C, and the mixture was evaporated
under reduced pressure. The solid residue was washed
with diethyl ether (2×10 mL) and acetonitrile (30 mL)
and dried under reduced pressure. Yield 0.084 g (37%),
white crystals, mp >300°C (decomp.); published data
5,5-Difluoro-6-hydroxy-1,3,6-trimethylhexahy-
dropyrimidine-2,4-dione (6). A solution of 0.1 g
(0.65 mmol) of 1,3,6-trimethyluracil (2) and 0.69 g
(1.95 mmol) of F-TEDA-BF4 in 10 mL of water was
stirred for 4 h at 80°C. The mixture was evaporated,
the solid residue was dissolved in diethyl ether, the
solution was filtered, and the filtrate was evaporated.
Yield 0.131 g (97%), white crystals, mp 84–86°C.
1H NMR spectrum (CDCl3), δ, ppm: 1.66 d.d (3H,
6-CH3, J = 2.4, 0.9 Hz), 3.07 d (3H, NCH3, J =
0.3 Hz), 3.23 d.d (3H, NCH3, J = 0.9, 0.6 Hz),
3.66 br.s (1H, OH). 13C NMR spectrum (CDCl3), δC,
ppm: 18.39 t (6-CH3, J = 1.9 Hz), 28.38 d (NCH3, J =
1.1 Hz), 28.79 d (NCH3, J = 1 Hz), 83.18 t (C6,
J = 26.5 Hz), 107.78 d.d (C5, J = 251.6, 250.7 Hz),
151.48 s (C2=O), 160.35 d.d (C4=O, J = 30.9,
28.4 Hz). 19F NMR spectrum (CDCl3), δF, ppm:
1
[3]; mp 313, 318°C (decomp.). H NMR spectrum
(DMSO-d6), δ, ppm: 2.04 d (3H, CH3, J = 3.3 Hz),
10.8 br.s (1H, NH), 11.4 br.s (1H, NH). 13C NMR
spectrum (DMSO-d6), δC, ppm: 11.80 d (CH3, J =
0.8 Hz), 136.73 d (C6, J = 26.1 Hz), 137.06 d (C5,
J = 221.6 Hz), 149.57 s (C2=O), 157.36 d (C4=O,
J = 25.9 Hz). 19F NMR spectrum (DMSO-d6):
δF –176.52 ppm, m. Mass spectrum: m/z 144.0331
[M]+. C5H5FN2O2. Calculated: M 144.0330.
5-Fluoro-1,3,6-trimethyluracil (4). A solution of
0.05 g (0.32 mmol) of 1,3,6-trimethyluracil (2) and
0.23 g (0.65 mmol) of F-TEDA-BF4 in 5 mL of water
was kept for 25 h at room temperature. The mixture
was extracted with diethyl ether (10×5 mL), the ex-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 7 2015

ELECTROPHILIC FLUORINATION OF 6-METHYL- AND 1,3,6-TRIMETHYLURACILS
1007
Aspects to Clinical Applications, London: Imperial
College, 2012.
–116.93 d.m (J = 272.4 Hz), –129.79 d (J = 272.4 Hz).
Mass spectrum: m/z 208.0652 [M]+. C7H10F2N2O3. Cal-
culated: M 208.0654.
3. Schuman, P.D., Tarrant, P., Warner, D.A., and West-
moreland, G., US Patent no. 3954758, 1976; Chem.
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(5R,6R)- and (5R,6S)-5-Fluoro-6-hydroxy-6-
methylhexahydropyrimidine-2,4-diones 7a and 7b
and (5R,6R)- and (5R,6S)-5-fluoro-6-hydroxy-1,3,6-
trimethylhexahydropyrimidine-2,4-diones 8a and
8b. 1H NMR spectrum (DMSO-d6), δ, ppm, 7a: 1.36 d
(CH3, J = 2.2 Hz), 4.49 d (5-H, J = 48.1 Hz), 10.55 s
(NH), 10.76 s (NH); 7b: 1.40 s (CH3), 5.18 d (5-H, J =
47.1 Hz), 8.31 s (NH), 10.34 s (NH); 8a: 1.29 d (CH3,
J = 2.1 Hz), 2.84 s (NMe), 2.97 s (NMe), 4.98 d (5-H,
J = 47.7 Hz); 8b: 1.51 s (CH3), 2.89 s (NMe), 2.96 s
p. 1176.
7. Diksic, M., Farrokhzad, S., and Colebrook, L.D., Can.
J. Chem., 1986, vol. 64, p. 424.
8. Visser, G.W.M., Boele, S., Van Halteren, B.W.,
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Pechet, M.M., J. Chem. Soc., Perkin Trans. 1, 1974,
p. 2095.
19
(NMe), 5.26 d (5-H, J = 46.5 Hz). F NMR spectrum
(DMSO-d6), δF, ppm: 7a: –192.4 d.d (J = 48.3,
2.5 Hz); 7b: –213.7 d.t (J = 47.2, 2.7 Hz); 8a:
–202.98 d (J = 47.8 Hz); 8b: ‒208.60 d (J = 46.6 Hz).
Kinetic study of the reaction of 6-methyluracil
(1) with F-TEDA-BF4. Preliminarily prepared solu-
tions of compound 1 (c = 0.079 M) and F-TEDA-BF4
(c = 0.0159 M) were kept for 60 min at 40°C and were
then mixed together. The progress of the reaction was
monitored by the concentration of F-TEDA-BF4
(samples were withdrawn at definite time intervals),
which was determined by iodometric titration [24].
The kinetic study of the fluorination of compounds 2
and 3 was performed in a similar way.
10. Barton, D.H.R., Hesse, R.H., Toh, H.T., and
Pechet, M.M., J. Org. Chem., 1972, vol. 37, p. 329.
11. Yurasova, T.I., Zh. Obshch. Khim., 1974, vol. 44, p. 956.
12. Stavber, S. and Zupan, M., Tetrahedron, 1990, vol. 46,
p. 3093.
13. Borodkin, G.I. and Shubin, V.G., Russ. Chem. Rev.,
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14. Hiyama, T., Organofluorine Compounds: Chemistry and
Applications, Berlin: Springer, 2000.
15. Kirsch, P., Modern Fluoroorganic Chemistry. Synthesis,
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Blackwell, 2006.
17. Liang, T., Neumann, C.N., and Ritter, T., Angew. Chem.,
Int. Ed., 2013, vol. 52, p. 8214.
Competing fluorination of compounds 1 and 2
with F-TEDA-BF4. Compounds 1 and 2, 0.13 mmol
each, were dissolved in 4 mL of water, 0.032 mmol of
F-TEDA-BF4 was added, and the mixture was kept for
3 h at 70°C. The solvent was removed by purging with
a stream of air, the residue was dissolved in DMSO-d6,
18. Singh, R.P. and Shreeve, J.M., Acc. Chem. Res., 2004,
1
19
and the H and F NMR spectra were recorded. The
ratio of the fluorination products was determined from
the 1H and 19F NMR signal intensities.
vol. 37, p. 31.
19. Lal, G.S., Pastore, W., and Pesaresi, R., J. Org. Chem.,
1995, vol. 60, p. 7340.
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This study was performed under financial support
by the Chemistry and Materials Science Department,
Russian Academy of Sciences (project no. 5.1.4).
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 7 2015