Synthesis of 6-methyluracil-5-sulfonyl chloride

Article abstract of DOI:10.1134/S1070427206040240

Sulfochlorination of 6-methyluracil with chlorosulfonic acid in the presence of thionyl chloride was studied. The lactam-lactim tautomerism of 6-methyluracil was considered. Ways to increase the yield of the sulfonyl chloride were suggested. The mechanism of the effect exerted by thionyl chloride additions was discussed. Pleiades Publishing, Inc., 2006.

Full text of DOI:10.1134/S1070427206040240

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2006, Vol. 79, No. 4, pp. 631 633.
Pleiades Publishing, Inc., 2006.
Original Russian Text
pp. 639 641.
I. P. Pogorelova, V. D. Orlov, A. D. Isak, 2006, published in Zhurnal Prikladnoi Khimii, 2006, Vol. 79, No. 4,
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Synthesis of 6-Methyluracil-5-sulfonyl Chloride
I. P. Pogorelova, V. D. Orlov, and A. D. Isak
Rubezhnoe Branch, Dal’ East-Ukrainian National University, Rubezhnoe, Lugansk oblast, Ukraine
Received November 25, 2005
Abstract Sulfochlorination of 6-methyluracil with chlorosulfonic acid in the presence of thionyl chloride
was studied. The lactam lactim tautomerism of 6-methyluracil was considered. Ways to increase the yield
of the sulfonyl chloride were suggested. The mechanism of the effect exerted by thionyl chloride additions
was discussed.
DOI: 10.1134/S1070427206040240
Sulfochlorination reactions are widely used in or-
ganic (in particular, pharmaceutical) chemistry. Sulfo-
nyl chlorides are intermediates in syntheses of active
and dispersible dyes, herbicides, and fungicides [1].
Among six-membered heterocyclic compounds con-
taining two nitrogen atoms, a prominent place is occu-
pied by pyrimidine derivatives used as drugs (sulf-
amide drugs such as Sulfadimethoxine, Sulfamono-
methoxine; antitumor agent Fluorouracil; antibiotic
Amecytin, etc.) [2, 3].
and transforms into 6-methyluracilsulfonic acid, which
was isolated from the solution by salting-out with
NaCl. Thus, the desired sulfonyl chloride is unstable
and is readily hydrolyzed in aqueous solution. To sup-
press the hydrolysis, the reaction mixture was poured
onto a 1 : 1 mixture of ice and acetic acid.
It was found in [9, 10] that the use of chlorosulfon-
ic acid in combination with thionyl chloride (volume
ratio 1.5 : 1) considerably increases the rate of forma-
tion and yield of 2 (see figure). In contrast to SOCl2,
addition of SO2Cl2 or POCl3 does not noticeably af-
Of particular interest in this respect is readily avail-
able methyluracil, which is used in syntheses of sul-
fonamides, sulfonyldiureides, sulfonylhydrazides, and
sulfonates; some of these compounds showed biologi-
cal activity.
Data on sulfochlorination of 6-methyluracil are
relatively few. As shown in [4 6], uracil and 6-meth-
yluracil 1 react with a tenfold excess of chlorosulfonic
acid to form uracil-6-sulfonyl chloride and 6-methyl-
uracil-5-sulfonyl chloride 2 in a low yield ( 22%).
To develop a more efficient procedure for prepar-
ing 6-methyluracilsulfonyl chloride, we examined
the effect of various factors on the sulfochlorination
of 1 [7, 8].
At 30 C, compound 1 does not noticeably react
with chlorosulfonic acid; the reaction starts only at
35 C, and the yield of 2 under these conditions does
not exceed 15%. With increasing temperature, the re-
action rate and sulfonyl chloride yield increase, but
even after the sulfochlorination for 7 h at 75 C the
yield of 2 does not exceed 28% (see figure). When
the reaction mixture is poured onto ice to isolate the
product, a considerable part of 2 undergoes hydrolysis
Yield of 6-methyluracilsulfonyl chloride W vs. time t
(1 4) in the absence and (5 9) in the presence of thionyl
chloride. T, C: (1, 5) 45, (2, 6) 55, (3, 7) 65, (4, 8) 75,
and (9) 85.
631

632
POGORELOVA et al.
fect the sulfochlorination rate and yield of the target
product. Sulfochlorination of 6-methyluracil follows
the scheme
in the electronic structure and affect the substrate dif-
ferently. In contrast to the S atom in chlorosulfonic
acid and sulfuryl chloride, in which all the valence
electrons are fully involved in formation of six cova-
lent bonds, in thionyl chloride a lone p-electron pair
remains on the sulfur atom, and it may compensate
the electron density deficiency on the O atom in the
4-position of methyluracil, facilitating electrophilic
substitution of the H atom by the SO2Cl group:
H
N
H
N
O
CH3
O
CH3
SOCl2
+ HSO3Cl
N
N
H
H
SO2Cl
O
O
1
2
+ H2SO4 + SO2 + HCl.
As seen from the figure, addition of SOCl2 results
in that the rate of formation of 2 increases by a factor
of 3 4 even at 45 C, with the yield of 2 reaching
40%. Similar relationships are observed at higher tem-
peratures.
The highest yield of 2 (82%) was obtained after
heating at 85 C for 5 h. Further increase in the tem-
perature decreases the yield of the target product be-
cause of formation of the sulfone (see figure, curve 9).
The ready incorporation of the SO2Cl group in the
5-position of methyluracil is due to its lactam lactim
tautomerism. 6-Methyluracil can exist in the form of
five tautomers, four of which contain one or two hy-
droxy groups. Nonaqueous titration shows that 1 mol
of sodium methylate is spent per mole of methylura-
cil, suggesting the presence of only one OH group
(structures 4, 5):
The favorable effect of thionyl chloride on the rate
of formation and yield of sulfonyl chlorides is appar-
ently due to the presence of a lone electron pair at the
S(IV) atom. The S atoms in SO2Cl2 and SOCl2 differ
1
As shown by quantum-chemical calculations, H
The structures of 7 and 8 were confirmed by IR
NMR spectra, and certain chemical transformations,
structure 5 is the most favorable energetically. In this
structure, the 5-position will be the most reactive
owing to the concerted effect of CH3 and OH groups.
Sulfochlorination occurs at a higher rate via interme-
diate 3 (see above).
and NMR spectra and by elemental analysis.
EXPERIMENTAL
1
The H NMR spectra were recorded in CDCl3 on
a Tesla BS-487c spectrometer operating at 80 MHz.
The chemical shifts ( , ppm) are given relative to
TMS. The IR spectra were measured on a UR-20
spectrometer (KBr pellets).
Experiments showed that methyluracil reacts with
sodium methylate to form monosodium derivative 7,
which reacts with methyl iodide CH3I to form com-
pound 8:
6-Methyluracil-5-sulfonyl chloride 2. A four-
necked flask equipped with a power-driven stirrer,
a thermometer, a reflux condenser, and a dropping
funnel was charged with 7.6 g (0.054 mol) of 6-meth-
yluracil 1 dried in an oven at 110 115 C for 3 4 h.
The flask was placed on a water bath, and 10 ml
(16.5 g, 0.138 mol) of freshly distilled thionyl chlo-
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 79 No. 4 2006

SYNTHESIS OF 6-METHYLURACIL-5-SULFONYL CHLORIDE
633
1
ride was added with vigorous stirring. The contents
were stirred for 20 30 min, after which 16 ml
(28.6 g, 0.265 mol) of freshly distilled chlorosulfonic
acid was added dropwise at such a rate that the reac-
tion mixture temperature did not exceed 30 35 C.
The reflux condenser was connected through a CaCl2
tube with a beaker absorbing the released gases.
IR spectrum, cm : 1020 ( C=C); 1025 ( S(=C O C));
1245 ( as(=C O C)); 1055 1275 (C=N ); 1685, 1745
(
(
C=O, =N C=O); 1380 ( S(CH )); 2825 (OCH3); 2850
3
1
S(OCH )); 2870 ( S(CH )); 2965 ( as(CH )). H NMR
spectrum, , ppm (CDCl3): 2.11 s (33H, C6 CH3),
4.92 d (1H, C5 H), 4.01 s (3H, C4 OCH3), 11.92 s
(1H, N1 H).
3
3
The mixture was heated to 60 65 C and kept at
this temperature with vigorous stirring for 4.5 5 h,
after which it was heated to 75 80 C and kept for an
additional 5.5 6 h. The reaction progress was moni-
tored chromatographically on Silufol UV-254 plates,
eluent ethyl acetate. After the reaction completion, the
mixture was cooled to 0 5 C and poured with vigor-
ous stirring onto a mixture of 50 g of crushed ice and
35 ml of glacial acetic acid, keeping the temperature
in the range from 5 to 0 C. 6-Methyluracil-5-sulfo-
nyl chloride precipitated as a white crystalline sub-
stance; it was filtered off and washed several times
with ice-cold water and acetic acid. Yield 9.95 g
(82%). White needle-like crystals, mp 269 270 C
(from glacial acetic acid).
CONCLUSIONS
(1) Sulfonation of 6-methyluracil with a mixture
of chlorosulfonic acid and thionyl chloride allows the
rate of formation and yield of 6-methyluracil-5-sulfo-
nyl chloride to be appreciably increased, with the
yield reaching 82%.
(2) In solution, 6-methyluracil mainly occurs in
the lactim form (4-hydroxy-6-methyl-1,2-dihydro-
pyrimidin-2-one).
(3) The favorable effect of thionyl chloride on the
sulfochlorination rate and yield of sulfonyl chloride
is due to the fact that the lone electron pair of the S
atom of thionyl chloride eliminates the electron den-
sity deficiency on the oxygen atom, thus facilitating
the electrophilic substitution of hydrogen by the
SO2Cl group.
Found, %: C 26.91, H 2.61, N 12.40, Cl 15.94,
S 14.48.
C5H5ClN2O4S.
REFERENCES
Calculated, %: C 26.74, H 2.69, N 12.47, Cl 15.78,
S 14.27.
1. Vorozhtsov, N.N., Osnovy sinteza promezhutochnykh
produktov i krasitelei (Fundamentals of the Synthesis
of Intermediates and Dyes), Moscow: Goskhimizdat,
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1
IR spectrum, cm : 985, 1030 ( C=C); 1305
(C=N ); 1675, 1730 ( C=O, =N C=O); 3275 ( NH);
1355, 1380 ( S(CH )). 1H NMR spectrum, , ppm
2. Makarov, V.A., Sedov, A.L., and Nemeryuk, M.P.,
3
(CDCl3): 2.45 s (3H, C6 CH3); 11.68 d (1H, N1 H),
5.85 s (1H, C4 OH).
Khim.-Farm. Zh., 1993, no. 4, pp. 26 34.
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Kharkov: Torsing, 1997.
4-Methoxy-6-methyluracil. Sodium metal (1.25 g,
0.054 mol) was dissolved in 50 ml of absolute meth-
anol, and 6.25 g (0.050 mol) of methyluracil was
added. The mixture was heated at 65 C for 45 min
with stirring. To the resulting colorless solution,
3.7 ml (0.060 mol) of methyl iodide was added, and
the mixture was heated with weak refluxing for 4 5 h
until the methyluracil spot disappeared from the chro-
matogram (Silufol UV-254, eluent ethyl acetate). On
cooling, colorless needle-like crystals precipitated.
The precipitate was filtered off, washed with water,
and dried. Yield of 4-methoxy-6-methyluracil 6.31 g
(89.9%), mp 192 193 C.
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Bibik, T.S., in Nitrogen-Containing Heterocycles and
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Found, %: C 51.63, H 5.71, N 19.86.
C6H8N2O2.
Calculated, %: C 51.42, H 5.75, N 19.99.
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 79 No. 4 2006