Convenient synthesis of 2-(methylsulfonyl)pyrimidine derivatives

Article abstract of DOI:10.1080/00397911.2017.1421664

An efficient and convenient approach for the preparation of functionalized 2-(methylsulfonyl)pyrimidine derivatives has been developed through cyclic condensation of malonate derivatives with S-methylisothiouronium sulfate followed by derivation and oxidation in water–acetone mixture using oxone as the oxidant. This synthetic strategy provides an efficient and environmentally friendly approach for easy access to 2-(methylsulfonyl)pyrimidine derivatives with considerable yields.

Full text of DOI:10.1080/00397911.2017.1421664

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Convenient synthesis of 2-
(methylsulfonyl)pyrimidine derivatives
Tong-Hui Huang, Shan-Shan Zhou, Xin Wu, Lin An & Xiao-Xing Yin
To cite this article: Tong-Hui Huang, Shan-Shan Zhou, Xin Wu, Lin An & Xiao-Xing Yin (2018):
Convenient synthesis of 2-(methylsulfonyl)pyrimidine derivatives, Synthetic Communications, DOI:
10.1080/00397911.2017.1421664
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SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1421664
Convenient synthesis of 2-(methylsulfonyl)pyrimidine
derivatives
Tong-Hui Huang, Shan-Shan Zhou, Xin Wu, Lin An, and Xiao-Xing Yin
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical
University, Xuzhou, China
ABSTRACT
ARTICLE HISTORY
Received 26 September 2017
An efficient and convenient approach for the preparation of
functionalized 2-(methylsulfonyl)pyrimidine derivatives has been
developed through cyclic condensation of malonate derivatives with
S-methylisothiouronium sulfate followed by derivation and oxidation
in water–acetone mixture using oxone as the oxidant. This synthetic
strategy provides an efficient and environmentally friendly approach
for easy access to 2-(methylsulfonyl)pyrimidine derivatives with
considerable yields.
KEYWORDS
2-(Methylsulfonyl)
pyrimidine; 2-(methylthio)
pyrimidine; Cyclization;
oxidation
GRAPHICAL ABSTRACT
Introduction
Drugs containing pyrimidine moieties have received much attention for their pharmacologi-
cal and biological effects.[1] Ambrisentan and darusentan, for example, are highly selective
endothelin receptor antagonists for the treatment of pulmonary hypertension.[2] Avanafil
is phosphodiesterase type 5 inhibitor used to treat erectile dysfunction.[3] Etravirine and
rilpivirine are non-nucleoside reverse transcriptase inhibitors used for the treatment of
HIV infection.[4] Pazopanib is a multitargeted receptor tyrosine kinase inhibitor that has
been approved for the treatment of renal cell carcinoma and soft tissue sarcoma.[5] A number
of pyrimidine derivatives were recently reported to be antimalarial agents,[6] adenosine
receptors (ARs) antagonists,[7] CRF1 receptor antagonists,[8] and anti-HIV agents[9] in a
range of therapeutic areas. Overall, many of the pyrimidine derivatives are synthesized by
using 2-(methylsulfonyl)pyrimidines as key intermediates.
The literature survey identified one principal method for the preparation of such
compounds. The synthesis were accomplished through cyclic condensation of 1,3-dicarbo-
nyl derivatives with thiourea, followed by the S-methylation and subsequent oxidation of
2-methylthio group to form a 2-methysulfonyl group, which can then undergo a substi-
tution reaction at C2.[10,11] However, this approach usually suffers from multistep
CONTACT Xiao-Xing Yin
yinxx@xzhmu.edu.cn
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy,
Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data (full experimental detail, H and 13C NMR spectra) can be accessed on the publisher’s website.
1
© 2018 Taylor & Francis

2
T.-H. HUANG ET AL.
reactions, harsh reaction conditions, and/or unsatisfactory yields in the actual operation.
For example, the use of dimethyl sulfate[11,12] or methyl iodide[13,14] in the S-methylation
reaction suffers from the drawback of toxicity. The identified oxidants for the 2-methylthio
group oxidation include meta-chloroperoxybenzoic acid,[15,16] peracetic acid,[17] sodium
periodate,[18] hydrogen peroxide,[11] and chlorine gas.[10] While these oxidation conditions
are still less than ideal, particularly for scale-up, due to their safety profile and/or difficulty
in product isolation. As shown in Scheme 1, we report herein an efficient and convenient
approach for the preparation of highly functionalized 2-(methylsulfonyl)pyrimidine
derivatives. Alternative to the reported approaches, we performed the synthesis through
cyclic condensation of malonate derivatives with S-methylisothiouronium sulfate,
derivation and oxidation using oxone as the oxidant to give the corresponding 2-(methylsul-
fonyl)pyrimidine derivatives. This synthetic route provides the advantage of less synthetic
steps, avoids hazardous reaction conditions and proceeds with considerable yields.
Results and discussion
The reaction of ethyl acetoacetate with 2-methyl-2-thiopseudourea sulfate in the presence
of potassium carbonate was reported to give 6-methyl-2-(methylthio)pyrimidin-4-ol.[19]
However, when the approach is adopted to the synthesis of 2-(methylthio)pyrimidine-
4,6-diol according to the reported procedure, the low yields appeared in our attempt even
heated at 80 °C in a lengthened reaction time (48 h, Table 1, entry 1). Hence, we performed
the model reaction experiment with diethyl malonate and 2-methyl-2-thiopseudourea
sulfate in different reaction media. A preliminary screening of catalysts for the reaction
revealed that the use of sodium hydroxide is crucial for this cyclic condensation. Among
the solvents screened, polar solvent such as ethanol gave the best reaction profiles (Table 1,
entries 6 and 7). The use of water as solvent retarded the reaction, presumably in part due
Scheme 1. General scheme for synthesis of 2-(methylsulfonyl)pyrimidine derivatives.
Table 1. Optimization of reaction conditions and yields.
Entry
Catalyst
Solvent
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
K2CO3
NaOH
H2SO4
K2CO3
H2SO4
NaOH
NaOH
H2O
80
80
48
24
24
24
24
24
4
Trace
Trace
–
Trace
–
60
82
H2O
H2O
80
EtOH
EtOH
EtOH
EtOH
Reflux
RT
RT
reflux
aIsolated yields after simple filtration.

SYNTHETIC COMMUNICATIONS®
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to the low solubility of the substrate (Table 1, entries 2). The following optimal conditions
were used in the subsequent investigation: malonate derivatives (1 equiv), 2-methyl-2-
thiopseudourea sulfate (1.2 equiv), sodium hydroxide (2.5 equiv), ethanol (2 mL/mmol),
reflux 2–4 h. After completion of the reaction, the product was obtained after a simple
filtration, and the results are summarized in Table 1.
Having established the optimal conditions for the cyclization, we intended to determine
the substrate scope. Various substituted malonate derivatives were reacted with 2-methyl-
2-thiopseudourea sulfate smoothly. After cyclization, the intermediate 3 was not purified
and submitted to chlorination and/or derivation yielding the corresponding
2-(methylthio)pyrimidine derivatives according to the reported procedure.[19] As shown
in Table 2, most of the reactions gave considerable yields (Table 2, entries 1, 2, 3, 7, and
8), and relatively low yields were observed in the cases of 4d, 4e, and 4f (Table 2, entries
4, 5, and 6). Hence, we speculate that the presence of electron-withdrawing and steric
hindrance group at the 2 position of 1,3-dicarbonyl derivatives may obstruct the cyclization.
As mentioned above, 2-(methylsulfonyl)pyrimidine derivatives can be viewed as the
precursors of multifunctionalized pyrimidines through the oxidation of the 2-sulfane
pyrimidines. Thomann et al.[20] recently described a practical procedure for the oxidation
of 2-sulfane pyrimidines using Oxone as oxidant in MeOH. We also attempted the
Thomann’s method, while the conversion to 4,6-dichloro-2-(methylsulfonyl)-5-phenylpyr-
imidine 5d was quite unsatisfying (Table 3, entries 2), as indicated by TLC and crude NMR
monitoring (less than 50% by NMR). There were no increases in yield and conversion in
different solvents and lengthened reaction time (Table 3, entries 1, 3, and 4). We postulated
that the oxidation process should mainly occur in organic phase, whereas the low
conversion may be attributed to low solubility of Oxone in reaction solvent.
The phase transfer catalyst would be helpful to promote the oxidation. Thus, tetrabuty-
lammonium bromide (TBAB) in catalytic amount (10 mol%) was attempted to raise the
concentration of Oxone in solvent and accelerate the reaction, and good yields in shortened
reaction times were obtained (Table 3, entries 5). Meanwhile, different phase transfer
catalysts, TBAB and triethylbenzylammonium bromide (TEBAB) have no obvious effect
on the yields (Table 3, entries 5, 6). Thus, all reactions proceeded well in acetone–water
solution in the presence of Oxone (5 equiv), and TBAB (10 mol%). As shown in Table 4,
Table 2. Preparation of 2-(methylthio)pyrimidines.
Entry
Compound no.
R1
R2
R3
Yielda (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
H
Cl
Cl
Cl
Cl
72
81
75
52
55
35
70
75
Et
Bu
Ph
Bz
NO2
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
4g
4h
OMe
NMe2
Cl
H
NMe2
aIsolated yields.

4
T.-H. HUANG ET AL.
Table 3. The oxidation of 2-(methylsulfonyl)pyrimidine 5d at different conditions.
Entry
Oxidant
Additive
Solvent
Temp (°C)
Time (h)
Conversiona (%)
1
2
3
4
5
6
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
–
–
–
–
H2O
MeOH
MeOH/H2O
Acetone
Acetone/H2O
Acetone/H2O
Reflux
Reflux
Reflux
RT
RT
RT
48
48
48
48
4
NTb
<50
<10
<10
TBAB
TEBAB
>95 (81)c
>95 (80)c
4
b
c
aThe conversions of starting material were estimated based on crude NMR spectra; not detected; isolated yields.
Table 4. Preparation of 2-methylsulfonyl)pyrimidines.
Compound no.
R1
R2
R3
Yielda (%)
5a
5b
5c
5d
5e
5f
H
Cl
Cl
85
90
86
81
75
70
78
72
Et
Cl
Cl
Bu
Ph
Bz
NO2
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
5g
5h
OMe
NMe2
Cl
H
NMe2
aIsolated yields.
all reactions were completed within 4–6 h and respective 2-(methylsulfonyl)pyrimidines were
obtained in considerable yields. The products precipitated during the reactions and were
separated from the reaction mixtures through simple filtration or extraction.
Conclusion
In conclusion, an efficient and versatile synthesis of 2-(methylsulfonyl)pyrimidine
derivatives through the cyclic condensation, derivation, and subsequent oxidation has been
developed. The present synthetic route provided an alternative approach for the synthesis
of 2-(methylsulfonyl)pyrimidine derivatives. The key feature of this route possesses the
advantages of less synthetic steps, considerable yields and the aversion of hazardous
reaction conditions that other methods can’t easily access.
Experimental
General
All reagents and solvents used in the reaction were obtained from commercial sources and
used without any further purification. Melting points were determined on a Buchi B-545
melting point apparatus and uncorrected. NMR were recorded in CDCl3 on a Jeol

SYNTHETIC COMMUNICATIONS®
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GX-400 spectrometer. Chemical shifts are reported in parts per million (ppm) relative to
tetramethylsilane (TMS). Multiplicities are abbreviated as follows: singlet (s), doublet
(d), triplet (t), quartet (q), and multiplet (m). Mass spectra were measured on a LC-MS-
2010A spectrometer with ESI. Elementary analyses were taken on a Vario EL III elementary
analysis instrument.
General procedure for the synthesis of 2-(methylthio)pyrimidines (4a–4f)
To a stirred solution of 2-methyl-2-thiopseudourea sulfate (8.35 g, 60 mmol) in ethanol
120 mL was added 1,3-dicarbonyl derivatives (50 mmol) and sodium hydroxide (2.4 g,
60 mmol) at room temperature, and then heated at refluxed for 4 h. After this time, the
reaction mixture was cooled to room temperature, the residue was precipitated and filtered,
yielding compounds 3 as white solid. The solid was dried in vacuum and used directly to
react with POCl3 (40 mL) in the presence of NEt3 (5.05 g, 50 mmol) heated at reflux for 3 h.
The solvent was evaporated under reduced pressure, the residue was dissolved in 100 mL
ethyl acetate and washed with saturated sodium bicarbonate, saturated sodium chloride,
dried (MgSO4), filtered, and concentrated under reduced pressure. The desired products
4-chloro-2-(methylthio)pyrimidines 4a–4f were obtained by recrystallization from the
mixed solvent of EtOAc-petroleum ether. Yields, melting points and spectroscopic data
for selected 2-(methylsulfonyl)pyrimidines are listed as follows.
4,6-Dichloro-2-(methylthio)-5-phenylpyrimidine (4d)
White solid, yield 52%, mp 104–105 °C; IR (KBr, cm−1): 3453, 2925, 1550, 1474, 1361, 1231,
1
812; H NMR (400 MHz, CDCl3): δ 2.60 (s, 3H, SCH3), 7.28 (d, J ¼ 6.0 Hz, 2H, Ar-H),
7.45–7.49 (m, 3H, Ar-H). 13C NMR (100 MHz, CDCl3): δ 14.57, 127.98, 128.72, 129.17,
129.43, 129.66, 133.07; LC–MS (m/z): 269.9. Anal. Calcd for C11H8Cl2N2S: C, 48.72; H,
2.97; N, 10.33; Found: C, 48.76; H, 2.92; N, 10.28.
General procedure for the synthesis of 4-chloro-6-methoxy-2-(methylthio)
pyrimidine (4g)
To a solution of sodium (0.28 g, 12 mmol) in ethanol 20 mL was added in 4,6-dichloro-2-
(methylthio)pyrimidine 4a (1.95 g, 10 mmol) and the resulting mixture was stirred at room
temperature until disappearance of the starting material 4a as judged by TLC. The mixture
was evaporated under reduced pressure, water was added, and after workup (CH2Cl2
extraction, water washing, Na2SO4 drying of the organic phase), the residue was evaporated
under reduced pressure, and the residue was recrystallized from ethylether yielded the
desired product 4 g. White solid, yield 70%, mp 39–40 °C; IR (KBr, cm−1): 3003, 2939,
1
1544, 1328, 1274, 1505, 1030, 820; H NMR (400 MHz, CDCl3): δ 2.55 (s, 3H, SCH3),
3.97 (s, 3H, OCH3), 6.41 (s, 1H, pyrimidine-H). 13C NMR (100 MHz, CDCl3): δ
14.29,54.52, 102.43, 160.34, 169.90, 172.92; LC–MS (m/z): 190.0. Anal. Calcd for
C6H7ClN2OS: C, 37.80; H, 3.70; N, 14.69. Found: C, 37.72; H, 3.75; N, 14.78.
General procedure for the synthesis of N4,N4,N6,N6-tetramethyl-2-(methylthio)
pyrimidine-4,6-diamine (4h)
A mixture of 4a (2 mmol) and dimethylamine (0.54 g, 12 mmol) in butyl alcohol (40 mL) in
the presence of NEt3 (1.21 g, 12 mmol) was stirred for 3 h at 80 °C and subsequently cooled

6
T.-H. HUANG ET AL.
to room temperature. The mixture was evaporated under reduced pressure, and the residue
was crystallized from ethylether yielded the desired product 4h. White solid, yield 75%, mp
1
95–96 °C; IR (KBr, cm−1): 2916, 2868, 1575, 1508, 1410, 976, 784; H NMR (400 MHz,
CDCl3): δ 2.47 (s, 3H, SCH3), 3.02 (s, 12H, NCH3), 5.04 (s, 1H, pyrimidine-H). 13C
NMR (100 MHz, CDCl3): δ 14.01, 37.27, 75.82, 162.90, 169.13; LC–MS (m/z): 212.1. Anal.
Calcd for C9H16N4S: C, 50.91; H, 7.60; N, 26.39. Found: C, 50.82; H, 7.52; N, 26.45.
General procedure for the synthesis of 2-(methylsulfonyl)pyrimidines (5a–5h)
A mixture of 2-(methylthio)pyrimidines (5 mmol), tetrabutylammonium bromide (0.16 g,
0.5 mmol, 10 mol%) and acetone (20 mL) was stirred at room temperature. The Oxone
(12.5 mmol, 2.5 equiv) in water (20 mL) was added slowly to the vigorously stirred
solution. After 4–6 h, TLC indicated the consumption of the starting material. The
products 5 were isolated by filtering through a Buechner funnel and washed with water,
and then dried to give the solid product.
4,6-Dichloro-2-(methylsulfonyl)-5-phenylpyrimidine (5d)
White solid, yield 81%, mp 151–152 °C; IR (KBr, cm−1): 3009, 2923, 1320, 1136, 965, 760;
1H NMR (400 MHz, CDCl3): δ 3.42 (s, 3H, SO2CH3), 7.31 (d, J ¼ 3.6 Hz, 2H, Ar-H),
7.53–7.55 (m, 3H, Ar-H). 13C NMR (100 MHz, CDCl3): δ 39.34, 128.85, 129.17, 130.17,
131.63, 136.96, 163.25, 163.72; LC–MS (m/z): 301.9. Anal. Calcd for C11H8Cl2N2O2S: C,
43.58; H, 2.66; N, 9.24. Found: C, 43.45; H, 2.72; N, 9.36.
Funding
This work was supported by the China Postdoctoral Science Foundation funded project
(2017M611916), Natural Science Foundation of Jiangsu Province (Grants No. BK20171184).
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