Asian Journal of Chemistry; Vol. 26, No. 1 (2014), 313-314
NOTE
A Facile Synthesis of 4,6-Dimethoxy-2-methylsulfonylpyrimidine
*
DEFENG XU , ZHILING ZHU, HUI XU and ZIQIAO WANG
School of Pharmaceutical and Life Sciences, Changzhou University, Changzhou, Jiangsu 213164, P.R. China
*Corresponding author: Fax: +86 519 86334598; Tel: +86 519 86334597; E-mail: markxu@cczu.edu.cn
Received: 22 July 2013;
Accepted: 21 August 2013;
Published online: 26 December 2013;
AJC-14531
A facile and efficient synthesis of 4,6-dimethoxy-2-methylthiopyrimidine can be achieved by nucleophilic substitution of 2-chloro-4,6-
dimethoxypyrimidine with sodium methyl mercaptide for a 95.6 % yield. 4,6-Dimethoxy-2-methylsulfonylpyrimidine can be produced
via oxidation using hydrogen peroxide in the presence of sodium tungstate dihydrate in a 95 % yield.
Keywords: Nucleophilic substitution, Oxidation, 4,6-Dimethoxy-2-methyl sulfonylpyrimidine, 2-Chloro-4,6-dimethoxypyrimidine.
4,6-Dimethoxy-2-methylsulfonyl pyrimidine (5) was a key
intermediate of the preparation of some pyrimidinyloxybenzoic
acid herbicides, such as bispyribac sodium (1) and pyribenzoxim
(2)1,2. These herbicides, which belonged to the group of
acetolactate synthase (ALS) inhibiting herbicides, acted against
a broad spectrum of weeds associated with the rice crop3. It is
used for large-scale or whole water body control of submerged,
emergent and floating-leaf vegetation. Nezu et al.4 reported
the preparation of bispyribac sodium and its key intermediate
4,6-dimethoxy-2-methylthiopyrimidine (4). Several syntheses
of 4,6-dimethoxy-2-methylthiopyrimidine (4) had also been
reported in the literature5,6. Most of methods used high-toxic
reagents such as dimethyl sulphate and phosphorus oxychloride.
A large quantity of water pollution was produced in the pro-
cess7,8. A clean and environmentally friendly hydrogenation
technique needs to be used. This paper reports a facile and
efficient synthesis of 4,6-dimethoxy-2-methylthiopyrimidine
(4) utilizing 2-chloro-4,6-dimethoxy pyrimidine (3) via nucleo-
philic substitution and oxidation in good yield.
4,6-Dimethoxy-2-methylthiopyrimidine (4): A mixture
of 2-chloro-4,6-dimethoxy pyrimidine (17.5 g, 100 mmol),
tetrabutylammonium bromide (1.6 g, 5 mmol), 25 % sodium
methyl mercaptide (30.1 g, 107 mmol) and methanol (80
mmol) was heated to 45 ºC and maintained at 45-50 ºC for
2 h. An off-white precipitate formed which was collected by
vacuum filtration and washed by cool water, the solid was
recrystallized with isopropanol:water (2:1) to yield 4 as
colourless crystals (17.8 g, 95.6 % in yield), m.p. 52.5-53.8
ºC. (Lit9. m.p. 50-52 ºC). 1H NMR: (400 Hz, CDCl3), δ (ppm),
3.51 (s, 3H, SCH3), 3.84 (s, 6H, OCH3), 6.15 (s, 1H, CH). 13C
NMR: (400 Hz, CDCl3), δ (ppm), 171.30, 171.06, 85.53, 53.40,
14.14.
4,6-Dimethoxy-2-methylsulfonyl pyrimidine (5): A
mixture of 2-methylthio-4,6-dimethoxypyrimidine (18.6 g,
100 mmol), sodium tungstate dihydrate (1.5 g, 4.5 mmol),
tetrabutylammonium bromide (1.6 g, 5 mol) and acetic acid
(25 mL) was stirred at room temperature. To the vigorously
stirred solution, hydrogen peroxide (19.5 g, 200 mmol) as a
35 % aqueous solution was added slowly at 45 ºC. Stirring
was continued at 55 ºC for an additional 4 h. The excess hydrogen
peroxide was destroyed by the addition of an aqueous solution
of sodium sulfite, the solid filtered and recrystallized from
ethanol to give 5 as colourless crystals (21.6 g, 99.0 % in yield).
Reagents and solvents were obtained from commercial
suppliers and were used without further purification. All melt-
ing points were determined on a XT34 binocular microscope
(Beijing Tech Instrument Co., China) and were not corrected.
1H NMR spectra were recorded on Mercuryplus 400 (300
MHz) spectrometer, chemical shifts (δ) were reported in ppm
relative to TMS. Chemical shifts were reported in parts per
million relative to the solvent resonance as the internal standard
(CDCl3, δ = 7.16 ppm).Analytical TLC and column chromato-
9
1
m.p. 126.3-127.7 ºC. (Lit . m.p. 126-127.5 ºC). H NMR:
(400 Hz, CDCl3), δ (ppm), 3.34 (s, 3H, SCH3), 4.06 (s, 6H,
OCH3), 6.20 (s, 1H, CH), 13C NMR: (400 Hz, CDCl3), δ (ppm),
171.90, 164.42, 93.11, 55.11, 39.81.
graphy were performed on silica gel GF254
.