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

Full text of DOI:10.1134/S1070428014070252

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 7, pp. 1064–1065. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © G.I. Borodkin, I.R. Elanov, V.G. Shubin, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 7, pp. 1079–1080.
SHORT
COMMUNICATIONS
Eco-Friendly 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 January 17, 2014
DOI: 10.1134/S1070428014070252
6-Methyluracil is used as anti-inflammatory, ana-
bolic, and anticatabolic drug [1]. Introduction of
a fluorine atom into molecules of drugs often enhances
their therapeutic effect [2]. Schuman et al. [3] patented
a procedure for the synthesis of 5-fluoro-6-methyl-
uracil by fluorination of 6-methyluracil with elemental
fluorine. However, fluorine cannot be regarded as
environmentally safe reagent because of its extremely
high aggressivity toward many materials, as well as of
its toxicity and risks of handling. In recent time N–F
reagents are used as fluorine source for mild and selec-
tive fluorination of organic compounds. One of these
reagents is 4-chloromethyl-1-fluoro-1,4-diazoniabicy-
clo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-BF4)
[4]. This reagent is quite reactive and soluble in water,
and it exhibits a moderate oxidizing ability. At present
water is considered to be a promising eco-friendly
solvent suitable for conducting various chemical
reactions [5].
With a view of developing an environmentally safe
procedure for the synthesis of fluorinated uracils we
examined the reaction of 6-methyl- and 1,3,6-trimeth-
Me
Me
F
R
R
F-TEDA-BF4
N
N
H
O
N
R
O
O
N
R
O
I, II
Me
Me
OH
Me
N
F
F
R
O
F
R
O
R
O
F-TEDA-BF4
H2O
–H+
N
N
F
F
–H+
N
R
O
N
R
O
N
R
O
III, IV
V, VI
–H2O
OH
Me
N
F
H2O
–H+
R
O
H
N
R
O
I, III, V, R = H; II, IV, VI, R = Me.
1064

ECO-FRIENDLY FLUORINATION OF 6-METHYL- AND 1,3,6-TRIMETHYLURACIL
1065
yluracils with F-TEDA-BF4 in water (cf. [6]). Apart
from 5-fluoro-6-methyluracil (III) and 5-fluoro-1,3,6-
trimethyluracil (IV), the reaction produced 5,5-di-
fluoro-6-hydroxy-6-methyl-5,6-dihydrouracil (V) and
5,5-difluoro-6-hydroxy-1,3,6-trimethyl-5,6-dihydro-
uracil (VI); the formation of compounds V and VI
may be rationalized by reaction of cationic σ-com-
plexes with water.
5-Fluoro-6-methyluracil (III). A solution of 0.2 g
(1.59 mmol) of 6-methyluracil (I) and 0.86 g
(2.43 mmol) of F-TEDA-BF4 in 8 mL of water was
heated for 4 h at 80°C. The mixture was evaporated
under reduced pressure, and 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 [3]: mp 313, 318°C (decomp.).
1H 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). 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 (IV). A solution of
0.05 g (0.32 mmol) of 1,3,6-trimethyluracil (II) 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-
tract was dried over MgSO4, the solvent was distilled
off, and the residue was purified by column chroma-
tography on silica gel 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). 19F NMR spectrum (CDCl3):
δF –165.14 ppm, q.q (J = 3.6, 0.6 Hz). Mass spectrum,
m/z 172.0645 [M]+. C7H9FN2O2. Calculated:
M 172.0643.
5,5-Difluoro-6-hydroxy-6-methyl-5,6-dihydro-
uracil (V). A solution of 0.2 g (1.59 mmol) of
6-methyluracil 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%), white crystals, mp 194–
196°C. 1H NMR spectrum (DMSO-d6), δ, ppm: 1.42 d
(3H, 6-CH3, J = 1.5 Hz), 7.07 br.s (1H, OH), 8.8 br.m
(1H, NH), 11.1 br.s (1H, NH). 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. Calculated, %:
C 33.34; H 3.36; F 21.10; N 15.55.
5,5-Difluoro-6-hydroxy-1,3,6-trimethyl-5,6-dihy-
drouracil (VI). A solution of 0.1 g (0.65 mmol) of
1,3,6-trimethyluracil 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). 19F NMR
spectrum (CDCl3), δF, ppm: –116.93 d.m (J =
272.4 Hz), –129.79 d (J = 272.4 Hz). Mass spectrum,
m/z 208.0652 [M]+. C7H10F2N2O3. Calculated:
M 208.0654.
1
The H and 19F NMR spectra were recorded on
a Bruker AV-300 spectrometer using chloroform
1
(δ 7.24 ppm) or DMSO (δ 2.50 ppm, H) and PhCF3
(δF −63.73 ppm, 19F) as internal standards. The high-
resolution mass spectra were obtained on a Thermo
Scientific instrument.
This study was performed under financial support
by the Chemistry and Materials Science Department of
the Russian Academy of Sciences (project no. 5.1.4).
REFERENCES
1. Mashkovskii, M.D., Lekarstvennye sredstva (Medicines),
Moscow: Novaya Volna, 2010, 16th ed., p. 698.
2. Gouverneur, V. and Müller, K., Fluorine in Pharma-
ceutical and Medicinal Chemistry. From Biophysical
Aspects to Clinical Applications, London: Imperial
College, 2012.
3. Schuman, P.D., Tarrant, P., Warner, D.A., and Westmore-
land, G., US Patent no. 3954758, 1976; Chem. Abstr.,
1976, vol. 85, no. P123964e.
4. Borodkin, G.I. and Shubin, V.G., Russ. Chem. Rev., 2010,
vol. 79, no. 4, p. 259.
5. Li, C.-J. and Chan, T.-H., Comprehensive Organic Reac-
tions in Aqueous Media, Hoboken: Wiley, 2007.
6. Lal, G.S., Pastore, W., and Pesaresi, R., J. Org. Chem.,
1995, vol. 60, p. 7340.
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