Highly Regioselective Synthesis of 3,6-Disubstituted 2-(Methylsulfanyl)pyrimidin-4(3 H)-ones

Article abstract of DOI:10.1055/s-0035-1560470

This study reports a simple and highly regioselective synthesis of a new series of 3,6-disubstituted 2-(methylsulfanyl)pyrimidin-4(3H)-ones, in which the 6-substituents are methyl or aryl groups and the 3-substituents are alkyl, allyl, phenyl, benzyl, or 2-phenylethyl groups. The products are obtained in good yields by cyclocondensation of the appropriate 4-substituted 4-methoxy-1,1,1-trichloroalk-3-en-2-ones with nonsymmetric 1-substituted 2-methylisothiourea sulfates under mild basic conditions.

Full text of DOI:10.1055/s-0035-1560470

SYNTHESIS
0
0
3
9
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7
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8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3947–3955
paper
3947
J. M. dos Santos et al.
Paper
Synthesis
Highly Regioselective Synthesis of 3,6-Disubstituted 2-(Methylsul-
fanyl)pyrimidin-4(3H)-ones
O
Josiane M. dos Santos
Alessandra S. da Silveira
Laura A. Souza
OMe
R1
R2
SMe
NH
N
H2SO4
O
R2HN
70–95%
2
R1
N
SMe
CCl3
Marcio M. Lobo
Helio G. Bonacorso
Marcos A. P. Martins
Nilo Zanatta*
R1 = Me, Ar
2 = Me, s-Bu, All, Ph, Bn, PhCH2CH2
27 examples
R
Núcleo de Química de Heterociclos (NUQUIMHE),
Departamento de Química, Universidade Federal
de Santa Maria, 97105-900, Santa Maria, Brazil
nilo.zanatta@ufsm.br
Received: 06.07.2015
Accepted after revision: 13.08.2015
Published online: 16.09.2015
6-(cyclohexylmethyl)-2-(alkylsulfanyl)pyrimidin-4(3H)-ones
exhibit significant anti-HIV activities.3–6 N-Substituted 6-
phenyl-2-(methylsulfanyl)pyrimidinones have shown hy-
potensive and antiinflammatory activities.7 2-Sulfanyl-
4(3H)-quinazolinone derivatives have exhibited protein ty-
rosine phosphatase 1B inhibition, which makes them po-
tential therapeutic targets, particularly for the treatment of
type 2 diabetes.8 5,6-Disubstituted 2-(alkylsulfanyl)pyrimi-
din-4(3H)-ones exhibit an interesting antimicrobial profile,
with dual antibacterial and antifungal effects against Staph-
ylococcus aureus and Candida albicans, respectively.9
DOI: 10.1055/s-0035-1560470; Art ID: ss-2015-m0418.op
Abstract This study reports a simple and highly regioselective synthe-
sis of a new series of 3,6-disubstituted 2-(methylsulfanyl)pyrimidin-
4(3H)-ones, in which the 6-substituents are methyl or aryl groups and
the 3-substituents are alkyl, allyl, phenyl, benzyl, or 2-phenylethyl
groups. The products are obtained in good yields by cyclocondensation
of the appropriate 4-substituted 4-methoxy-1,1,1-trichloroalk-3-en-2-
ones with nonsymmetric 1-substituted 2-methylisothiourea sulfates
under mild basic conditions.
In a search of the literature, we found four methods for
preparing 3,6-disubstituted 2-(methylsulfanyl)pyrimidin-
4(3H)-ones. The most widely reported method involves the
cyclocondensation reaction of a β-keto ester with 2-meth-
ylisothiourea, followed by N-alkylation; alternatively, the
compounds can be prepared by the reaction of β-keto esters
with thiourea followed by S- and N-alkylation (Scheme 1).
This is a simple method, but has the disadvantage of giving
mixtures of N1-, N3-, and O-alkylated products.1,7,10–16
Key words pyrimidines, cyclocondensations, thio ethers, regioselec-
tivity, enones
The synthesis of 3,6-disubstituted 2-(methylsulfa-
nyl)pyrimidin-4(3H)-ones is of considerable practical inter-
est because of the important biological activities shown by
such compounds, which has been discovered mainly over
the last two decades. For example, some pyrimidine deriva-
tives are potent calcium-channel blockers.1,2 6-Benzyl- and
R4
O
N
O
O
O
N
SMe
R2
R1
R2
R1
R2
R1
H
R2
R1
R4
N
N
N
N
H2N
NH.HX
N-alkylation
SMe
N
R4
SMe
N
O
SMe
SMe
O
O
R1
OR3
Me2SO4 or
MeI
mixture of compounds
R2
S
β-keto ester
R2
R1
H
N
1) N-alkylation
2) S-alkylation
H2N
NH2
N
H
S
Scheme 1 Synthesis of N-substituted 2-(methylsulfanyl)pyrimidin-4(3H)-ones by alkylation methods
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3947–3955

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Synthesis
An attractive method for the regioselective synthesis of
N3-substituted
2-(methylsulfanyl)pyrimidin-4(3H)-ones,
two phases were formed as a result of the insolubility of the
enones 1a–f in the aqueous medium. The reaction was con-
sidered to be complete when the formation of a precipitate
or oil was observed at the bottom of the flask. (We also test-
ed an alternative approach based on a method developed
previously by our research group,23 in which a 1 M aqueous
solution of sodium hydroxide was used instead of the 1 M
solution of sodium carbonate, but this reaction produced
more impurities and gave lower yields.) The reaction,
which proceeds through the base-assisted elimination of
the trichloromethyl group, gave the N3-substituted 2-
(methylsulfanyl)pyrimidin-4-ones exclusively. Base-assist-
ed eliminations of trichloromethyl groups in cycloconden-
sation reactions have been reported elsewhere.23,24 Solid
products were purified by recrystallization from a chloro-
form–methanol mixture, and oily products were purified
by column chromatography. The yields ranged from 70 to
95% (Table 1).
The 4-substituted 4-methoxy-1,1,1-trihalo-alk-3-en-2-
ones 1a–f were prepared by the reported method.25 The 1-
substituted 2-methylisothioureas sulfates 2–4 were ob-
tained by S-methylation of the corresponding commercially
available thioureas by refluxing them in water and dimeth-
yl sulfate, in accordance with the reported method.26 The 1-
substituted 2-methylisothiourea sulfates 5–7 were pre-
pared by the reaction of benzoyl isothiocyanate with ben-
zylamine, phenethylamine, or sec-butylamine, respectively,
followed by S-methylation of the resulting thiourea in ac-
cordance with the reported method.27 1,2-Dimethyliso-
thiourea sulfate is commercially available.
reported by Mahajan and co-workers, involves a [4+2] cy-
cloaddition reaction of 1,3-diazabuta-1,3-dienes with
ketenes.17–19 Recently, Meslin and co-workers made use of a
similar cycloaddition method by treating 1,3-diazadienes
with acid chlorides instead of ketenes to prepare a series of
N3-substituted 2-(methylsulfanyl)pyrimidin-4(3H)-ones.20
Gupta et al. reported an interesting method for the syn-
thesis of 6-substituted 3-aryl-2-(alkylsulfanyl)pyrimidin-
4(3H)-ones by cyclocondensation of 2-(alkylsulfanyl)-1-
arylisothioureas with alkynoates.21,22 This method, howev-
er, does not permit the introduction of substituents at the
5-position of the pyrimidine ring.
The fourth method, which originated from our group
and was published in 2010, is a synthesis that relies on the
cyclocondensation reaction of 4-alkoxy-1,1,1-trichloroalk-
3-en-2-ones (trichloromethylated enones) with 1,2-di-
methylisothiourea sulfate.23 This reaction showed high re-
gioselectivity and gave excellent yields, but the reaction
was not well explored because only three pyrimidines were
synthesized by using the trichloromethylated enones, and
these pyrimidines only support very small groups, such as
N-methyl and 6-H, 6-methyl, or 6-O-alkyl groups (Scheme
2).
O
R2
OR3
R1
SMe
NH·H2SO4
R2
R1
Me
NaOH
N
MeHN
O
CCl3
N
SMe
All compounds were fully analyzed by GC/MS and by
1H- and 13C-NMR spectroscopy, and their regiochemistry
was unequivocally assigned by means of two-dimensional
HMBC NMR experiments and confirmed by X-ray diffrac-
tion analysis of compound 11a (Figure 1). The strategy for
the assignment of the correct position of the N-substituent
group in 2-(methylsulfanyl)pyrimidines, based on two-di-
mensional HMBC NMR experiments, has been reported for
related compounds,23,28,29 and is shown in Figure 2. In this
experiment, when the N-substituent group is at the N1-po-
sition, two cross-peaks between the N1-α-hydrogens and
C2 and C6 atoms should be observed (Figure 2; structure I).
When the N-substituent group is at the N3-position, two
cross-peaks between the N-α-hydrogens and the C2 and C4
carbon atoms should be observed (Figure 2; structure II).
The cross-peak between the hydrogens of the thiomethyl
group and the C2 assigns this carbon in both structures I
and II. The N-substituent was located at the N3-position in
all the compounds synthesized in this study, and the forma-
tion of the N1-substituted regioisomer was not observed in
any of the reactions.
A–C
A R1 = R2 = H
B R1 = Me, R2 = H
C R1–R2 = –O(CH2)3–
Scheme 2 Regioselective synthesis of N3-methyl-2-(methylsulfanyl)py-
rimidin-4(3H)-ones
We therefore investigated a wider scope of substrates
with larger substituents at both the 6- and the N3-positions
to obtain clear evidence of the steric and electronic effects
that govern the regioselectivity in the synthesis of the title
compounds. For this study, we prepared a series of N-sub-
stituted 2-methylisothiourea sulfates, as well as a series of
4-substituted 4-alkoxy-1,1,1-trichloroalk-3-en-2-ones. The
combination of these two series of starting materials gave
27 compounds, of which 21 were new compounds.
The 3,6-disubstituted 2-(methylsulfanyl)pyrimidin-
4(3H)-ones 8–13 were synthesized by the cyclocondensa-
tion reactions of the appropriate 4-substituted 4-alkoxy-
1,1,1-trichloroalk-3-en-2-ones 1a–f with the nonsymmet-
ric 1-substituted 2-methylisothiourea sulfates 2–7 in the
presence of a 1 M aqueous solution of sodium carbonate at
room temperature (Table 1). Vigorous stirring was neces-
sary to ensure complete mixing of the reactants, because
A proposed mechanism for the synthesis of pyrimidines
8–13 by the cyclocondensation reaction of 4-alkoxy-1,1,1-
trichloroalk-3-en-2-ones with nonsymmetric 1-substituted
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Table 1 Optimized Reaction Conditions and Yields for the Synthesis Pyrimidines 8–13
O
R2
OMe
SMe
N
H2SO4
R1
O
R2HN
2–7
R2
Me
NH
R1
N
SMe
CCl3
1a–f
2
8–13
Enone
R1
Me
Isothiourea
Timea (h)
Product
Yieldb (%)
Ref
23
1a
1b
1c
1d
1e
1f
2
2
2
2
2
2
3
3
3
3
3
3
4
4
4
5
5
5
6
6
6
7
7
7
7
7
7
2.4
2.0
3.0
3.0
3.5
3.0
3.0
2.0
3.5
3.0
3.0
4.0
4.0
3.5
3.5
4.0
4.0
4.0
3.0
2.0
2.0
0.6
2.0
2.0
1.0
1.2
2.0
8a
8b
95
86
91
80
82
90
91
81
80
90
82
85
70
80
75
88
90
86
86
91
78
91
88
83
85
90
81
7
Ph
Me
Me
Me
Me
Me
All
All
All
All
All
All
Ph
Ph
Ph
Bn
Bn
Bn
4-Tol
8c
4-MeOC6H4
4-FC6H4
4-BrC6H4
Me
8d
8e
8f
10b
1a
1b
1c
1d
1e
1f
9a
Ph
9b
4-Tol
9c
4-MeOC6H4
4-FC6H4
4-BrC6H4
Me
9d
9e
9f
21
22
1a
1b
1e
1a
1b
1e
1a
1b
1e
1a
1b
1e
1c
1e
1f
10a
10b
10e
11a
11b
11e
12a
12b
12e
13a
13b
13c
13d
13e
13f
Ph
4-FC6H4
Me
Ph
4-FC6H4
Me
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
s-Bu
Ph
4-FC6H4
Me
Ph
s-Bu
4-Tol
s-Bu
4-MeOC6H4
4-FC6H4
4-BrC6H4
s-Bu
s-Bu
s-Bu
a Reaction conditions: 1 M aq Na2CO3, r.t.
b Yield of isolated products.
2-methylisothiourea sulfates is outlined in Scheme 3. Pre-
sumably, the reaction starts with the Michael addition of
the least-hindered amino group of the 2-methylisothiourea
to the β-carbon of the enone to give structure I, which is in
equilibrium with its tautomer II (Scheme 3). The hemiami-
nal group of the structures I and II is stable under basic
conditions. After the addition of the least-substituted nitro-
gen of the 2-methylisothiourea to the β-carbon of the
enone, the carbonyl becomes activated because it is at-
tached to a highly electron-withdrawing trichloromethyl
group and is no longer conjugated to a carbon–carbon dou-
ble bond. Therefore, the addition of the second nitrogen
should be a fast reaction step, furnishing the tetrahydropy-
rimidine III; this compound has previously been isolated
for the case when R1 = H.23 The base-assisted elimination of
the trichloromethyl group leads to structure IV, which fur-
ther eliminates a methanol molecule and furnishes the
products 8–13.
In conclusion, we have developed a simple and highly
regioselective synthesis of a new series of 3,6-disubstituted
2-(methylsulfanyl)pyrimidin-4(3H)-ones in good yields by
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3947–3955

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J. M. dos Santos et al.
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Synthesis
methyl group assisted by the base, and it was observed that
in all the pyrimidines obtained the regiochemistry of the
reaction gave the N3-substituted 2-(methylsulfanyl)pyrimi-
din-4-one exclusively.
The 4-alkoxy-1,1,1-trichloromethyl-alk-3-en-2-ones 1a–f were pre-
pared by the reported method.25 The 1-substituted 2-methyliso-
thioureas sulfates 2–4 were obtained by S-methylation of the corre-
sponding commercially available thioureas by refluxing in H2O and
Me2SO4 as previously described.26 1-Benzylthiourea, 1-(2-phenyleth-
yl)thiourea and 1-(sec-butyl)thiourea were synthesized by the reac-
tion of benzoyl isothiocyanate with BnNH2, Ph(CH2)2NH2, and s-
BuNH2, respectively,27 followed by S-methylation with Me2SO4. The 1-
substituted 2-methylisothioureas sulfates 2–7 were obtained by S-
methylation of the corresponding thioureas by refluxing in water and
Me2SO4 according to the reported method.26
Melting points were determined on a Kofler Reichert Thermovar or a
MQAPF-301 apparatus and are uncorrected. High-resolution mass
spectra were recorded on a Bruker QTOF spectrometer operated in
the ESI mode. GC/MS spectra were obtained by using a HP 5973 MSD
connected to a HP 6890 GC. 1H and 13C NMR spectra were acquired on
a Bruker DPX200 or DPX400 spectrometer with CDCl3 or DMSO-d6 as
solvent and TMS as the internal reference. Crystallographic measure-
ments were made on a Bruker Kappa Apex II CCD area detector, with
graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). The struc-
ture was solved by direct methods (SHELXS-97) and additional atoms
were located in the difference Fourier map and refined on F2
(SHELXL-97).
Figure 1 ORTEP diagram for compound 11a; CCDC no. 1423129
O
O
H
H
H
4
3 N
4
5
6
3N
2
R2
5
6
2
Me
1
N
1
N
R1
S
R1
S
N3-Substituted 2-(Methylsulfanyl)pyrimidin-4(3H)-ones 8–13;
General Procedure
CH2
H
R2
H
I
II
A 1.0 M aqueous solution of Na2CO3 (2.0 mmol) and the appropriate
2-methylisothiourea sulfate 2–7 (2 mmol) were added with vigorous
magnetic stirring to the enone 1a–f (1.0 mmol). The mixture was
stirred at r.t. until the reaction was complete and then extracted with
CHCl3 (3 × 15 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated. The products were purified by recrystallization or col-
umn chromatography.
Figure 2 Strategy used for assigning the regioisomers of the products
by two-dimensional HMBC NMR
the cyclocondensation reaction of 4-alkoxy-1,1,1-trichloro-
alk-3-en-2-ones with nonsymmetric 1-substituted 2-meth-
ylisothiourea sulfates under mild basic conditions. The
reaction proceeds with the elimination of the trichloro-
3,6-Dimethyl-2-(methylsulfanyl)pyrimidin-4(3H)-one (8a)
This compound was prepared by the reported method.23
R1
H
R1
H
H
OMe
R1
OMe
NH
H
OMe
NH
HN
Cl3C
Cl3C
H
SMe
O
R2HN
O
CCl3
O
N
SMe
N
SMe
R2
R2
I
II
O
N
O
B:
H
H
O
CCl3
B:
H
H
R1
H
R2
R2
R2
N
N
N
H
R1
– CCl3
– MeOH
R1
N
SMe
N
SMe
SMe
MeO
MeO
8–13
III
IV
B = base
Scheme 3 Proposed mechanism for the synthesis of compounds 8–13
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Synthesis
3-Methyl-2-(methylsulfanyl)-6-phenylpyrimidin-4(3H)-one (8b)7
1H NMR (200 MHz, CDCl3): δ = 7.81 (d, J = 8.4 Hz, 2 H, Ar), 7.55 (d, J =
8.4 Hz, 2 H, Ar), 6.58 (s, 1 H, H–5), 3.52 (s, 3 H, NMe), 2.67 (s, 3 H,
SMe).
13C NMR (100 MHz, CDCl3): δ = 162.8 (C-2), 162.5 (C-4), 157.6 (C-6),
131.9 (C-Ar), 128.3 (2 C, C-Ar), 125.0 (C-Ar), 104.0 (C-5), 30.0 (NMe),
15.1 (SMe).
Brown solid; yield: 199 mg (86%); mp 117–119 °C.
1H NMR (400 MHz, CDCl3): δ = 7.98–7.96 (m, 2 H, Ar), 7.44–7.42 (m, 3
H, Ar), 6.64 (s, 1 H, H–5), 3.53 (s, 3 H, NMe), 2.69 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3): δ = 162.8 (C-2), 162.5 (C-4), 158.8 (C-6),
136.5, 130.4, 128.6, 126.8 (C-Ar), 103.9 (C-5), 30.0 (NMe), 15.1 (SMe).
GC-MS (EI, 70 eV): m/z (%) = 232 (79) [M+], 217 (9), 195 (12), 187 (66),
145 (23), 102 (16), 83 (100).
GC-MS (EI, 70 eV): m/z (%) = 295 (4) [M – 15], 239 (100), 185 (13), 157
(8), 116 (25), 101 (18), 89 (18), 59 (25).
Anal. Calcd for C12H11BrN2OS: C, 46.31; H, 3.56; N, 9.00. Found: C,
46.18; H, 3.44; N, 8.97.
Anal. Calcd for C12H12N2OS: C, 62.04; H, 5.21; N, 12.06. Found: C,
61.97; H, 5.18; N, 11.71.
3-Allyl-6-methyl-2-(methylsulfanyl)pyrimidin-4(3H)-one (9a)10b
3-Methyl-2-(methylsulfanyl)-6-(4-tolyl)pyrimidin-4(3H)-one (8c)
Reddish brown oil; yield: 178 mg (91%).
Brown solid; yield: 224 mg (91%); mp 97–99 °C.
1H NMR (400 MHz, CDCl3): δ = 6.05 (s, 1 H, H–5), 5.82–5.90 (m, 1 H,
=CH), 5.20–5.25 (m, 2 H, =CH2), 4.65–4.67 (m, 2 H, NCH2), 2.55 (s, 3 H,
SMe), 2.22 (s, 3 H, Me).
13C NMR (100 MHz, CDCl3): δ = 162.4 (C-2), 162.0 (C-4), 161.5 (C-6),
130.3 (=CH), 118.4 (=CH2), 107.6 (C-5), 45.8 (NCH2), 23.6 (Me), 14.9
(SMe).
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.3 Hz, 2 H, Ar), 7.24 (d, J =
7.8 Hz, 2 H, Ar), 6.62 (s, 1 H, H-5), 3.53 (s, 3 H, NMe), 2.68 (s, 3 H,
SMe), 2.39 (s, 3 H, Me).
13C NMR (100 MHz, CDCl3): δ = 163.0 (C-2), 162.3 (C-4), 158.8 (C-6),
140.8 (C-Ar), 133.5 (C-Ar), 129.3 (CH-Ar), 126.7 (CH-Ar), 103.2 (C-5),
29.6 (NMe), 21.3 (Me), 15.1 (SMe).
GC-MS (EI, 70 eV): m/z (%) 196 (36) [M], 181 (100), 163 (8), 149 (37),
126 (28), 109 (12), 67 (8).
GC-MS (EI, 70 eV): m/z (%) = 246 (100) [M+], 201 (54), 159 (13), 115
(13), 83 (36).
HRMS (ESI): m/z [M + Na] calcd for C9H12N2NaOS: 219.0568; found:
219.0566.
Anal. Calcd for C13H14N2OS: C, 63.39; H, 5.73; N, 11.37. Found: C,
62.99; H, 5.36; N, 11.05.
3-Allyl-2-(methylsulfanyl)-6-phenylpyrimidin-4(3H)-one (9b)
6-(4-Methoxyphenyl)-3-methyl-2-(methylsulfanyl)pyrimidin-
4(3H)-one (8d)
Brown oil; yield: 209 mg (81%).
1H NMR (400 MHz, CDCl3): δ = 8.01–7.96 (m, 2 H, Ar), 7.47–7.44 (m, 3
H, Ar), 6.67 (s, 1 H, H–5), 5.88–5.95 (m, 1 H, =CH), 5.26–5.30 (m, 2 H,
=CH2), 4.72–4.73 (m, 2 H, NCH2), 2.69 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3): δ = 162.5 (C-2), 161.0 (C-4), 158.8 (C-6),
136.2 (C-Ar), 130.5 (C-Ar), 130.1 (=CH), 128.6 (CH-Ar), 126.8 (CH-Ar),
118.6 (=CH2), 104.2 (C-5), 46.0 (NCH2), 15.2 (Me).
Brown solid; yield: 209 mg (89%); mp 135–138 °C.
1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 8.0 Hz, 2 H, Ar), 6.96 (d, J =
8.0 Hz, 2 H, Ar), 6.54 (s, 1 H, H–5), 3.84 (s, 3 H, OMe), 3.51 (s, 3 H,
NMe), 2.67 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3): δ = 162.8 (C-2), 162.2 (C-4), 161.8 (C-Ar),
158.4 (C-6), 128.8 (C-Ar), 128.4 (C-Ar), 114.1 (C-Ar), 102.4 (C-5), 55.3
(OMe), 29.9 (NMe), 15.0 (SMe).
GC-MS (EI, 70 eV): m/z (%) 258 (53) [M+], 243 (100), 211 (42), 188
(17), 19 (7), 102 (11).
GC-MS (EI, 70 eV): m/z (%) = 262 (100) [M+], 216 (56), 176 (15), 115
(14), 84 (38).
HRMS (ESI): m/z [M + Na] calcd for C14H14N2NaOS: 281.0725; found:
281.0724.
Anal. Calcd for C13H14N2O2S: C, 59.52; H, 5.38; N, 10.68. Found: C,
59.43; H, 5.24; N, 10.32.
3-Allyl-2-(methylsulfanyl)-6-(4-tolyl)pyrimidin-4(3H)-one (9c)
Yellow solid; yield: 218 mg (80%); mp 75–77 °C.
6-(4-Fluorophenyl)-3-methyl-2-(methylsulfanyl)pyrimidin-4(3H)-
one (8e)
1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.1 Hz, 2 H, Ar), 7.25 (d, J =
8.1 Hz, 2 H, Ar), 6.63 (s, 1 H, H–5), 5.84–5.95 (m, 1 H, =CH), 5.25–5.30
(m, 2 H, =CH2), 4.71–4.72 (m, 2 H, NCH2), 2.68 (s, 3 H, SMe), 2.40 (s, 3
H, Me).
13C NMR (100 MHz, CDCl3): δ = 162.6 (C-2), 161.9 (C-4), 158.9 (C-6),
140.9 (C-Ar), 133.3 (=CH), 130.2 (C-Ar), 129.3 (CH-Ar), 126.7 (CH-Ar),
118.5 (=CH2), 103.5 (C-5), 46.0 (NCH2), 21.3 (Me), 15.1 (SMe).
Brown solid; yield: 205 mg (82%); mp 152–155 °C.
1H NMR (200 MHz, CDCl3): δ = 7.98–7.95 (m, 2 H, Ar), 7.11 (t, JH–H
=
8.5 Hz, 3 H, Ar), 6.58 (s, 3 H, H–5), 3.53 (s, 3 H, NMe), 2.68 (s, 3 H,
SMe).
13C NMR (50 MHz, CDCl3): δ = 165.6 (C-2), 163.1 (C-Ar), 162.7 (C-4),
157.8 (C-6), 131.6 (d, JC–H = 3.3 Hz, C-Ar), 128.9 (d, JC–H = 8.5 Hz, CH-
Ar), 115.6 (d, JC–H = 21.8 Hz, CH-Ar), 103.6 (C-5), 30.0 (NMe), 15.1
(SMe).
GC-MS (EI, 70 eV): m/z (%) = 272 (57) [M+], 257 (100), 243 (9), 25 (48),
202 (19), 143 (9), 115 (18).
GC-MS (EI, 70 eV): m/z (%) = 250 (100) [M+], 205 (65), 163 (15), 134
(17), 120 (16), 83 (49).
Anal. Calcd for C15H16N2OS: C, 66.15; H, 5.92; N, 10.29. Found: C,
66.15; H, 6.06; N, 9.94.
Anal. Calcd for C12H11FN2OS: C, 57.58; H, 4.43; N, 11.19. Found: C,
57.52; H, 4.25; N, 11.19.
3-Allyl-6-(4-methoxyphenyl)-2-(methylsulfanyl)pyrimidin-4(3H)-
one (9d)
Beige solid; yield: 260 mg (90%); mp 96–98 °C.
6-(4-Bromophenyl)-3-methyl-2-(methylsulfanyl)pyrimidin-4(3H)-
one (8f)
Beige solid; yield: 280 mg (90%); mp 190–192 °C.
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1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 8.8 Hz, 2 H, Ar), 6.96 (d, J =
8.9 Hz, 2 H, Ar), 6.57 (s, 1 H, H–5), 5.94–5.87 (m, 1 H, =CH), 5.30–5.24
(m, 2 H, =CH2), 4.71 (m, 2 H, NCH2), 3.85 (s, 3 H, OMe), 2.67 (s, 3 H,
SMe).
13C NMR (100 MHz, CDCl3): δ = 162.5 (C-2), 161.8 (C-Ar), 161.7 (C-4),
158.5 (C-6), 130.4 (=CH), 128.7 (C-Ar), 128.5 (CH-Ar), 118.6 (=CH2),
114.0 (CH-Ar), 102.8 (C-5), 55.4 (OMe), 46.0 (NCH2), 15.2 (SMe).
1H NMR (400 MHz, CDCl3): δ = 8.06–8.09 (m, 2 H, Ar), 7.56–7.57 (m, 3
H, Ar), 7.50–7.52 (m, 3 H, Ar), 7.33–7.35 (m, 2 H, Ar), 6.80 (s, 1 H, H–
5), 2.60 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3): δ = 163.2 (C-2), 162.9 (C-4), 159.4 (C-6),
136.3 (C-Ar), 135.7 (C-Ar), 130.6 (CH-Ar), 130.0 (CH-Ar), 129.7 (CH-
Ar), 128.7 (CH-Ar), 128.6 (CH-Ar), 126.9 (CH-Ar), 104.9 (C-5), 15.6
(SMe).
GC-MS (EI, 70 eV): m/z (%) = 288 (57) [M+], 273 (100), 241 (47), 207
GC-MS (EI, 70 eV): m/z (%) = 294 (1.6) [M+], 281 (11), 264 (100), 207
(34), 159 (14), 133 (12), 109 (24), 89 (11).
(33), 145 (98), 119 (24), 104 (51).
Anal. Calcd for C15H16N2O2S: C, 62.48; H, 5.59; N, 9.71. Found: C,
62.12; H, 5.44; N, 10.05.
Anal. Calcd for C17H14N2OS: C, 69.36; H, 4.79; N, 9.52. Found: C, 69.12;
H, 4.74; N, 9.75.
3-Allyl-6-(4-fluorophenyl)-2-(methylsulfanyl)pyrimidin-4(3H)-
6-(4-Fluorophenyl)-2-(methylsulfanyl)-3-phenylpyrimidin-4(3H)-
one (9e)
one (10e)
Brown hygroscopic solid; yield: 202 mg (82%).
Salmon-colored solid; yield: 234 mg (75%); mp 177–180 °C.
1H NMR (400 MHz, CDCl3): δ = 7.96–8.00 (m, 2 H, Ar), 7.13 (t, J = 8.6
Hz, 2 H, Ar), 6.60 (s, 1 H, H–5), 5.83–5.97 (m, 1 H, =CH), 5.23–5.31 (m,
2 H, =CH2), 4.69–4.72 (m, 2 H, NCH2), 2.67 (s, 3 H, SMe).
1H NMR (400 MHz, CDCl3): δ = 8.02–8.05 (m, 2 H, Ar), 7.52–7.54 (m, 3
H, Ar), 7.28–7.31 (m, 2 H, Ar), 7.13–7.17 (m, 2 H, Ar), 6.70 (s, 1 H, H–
5), 2.55 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3): δ = 165.5 (C-2), 163.0 (C-4), 162.3 (C-Ar),
157.7 (C-6), 132.3 (d, J = 3.0 Hz, C-Ar), 130.1 (=CH), 128.8 (d, J = 8.4 Hz,
CH-Ar), 118.7 (=CH2), 115.6 (d, J = 21.6 Hz, CH-Ar), 103.8 (C-5), 46.0
(NCH2), 15.1 (SMe).
13C NMR (100 MHz, CDCl3): δ = 165.6 (C-Ar), 163.4 (C-2), 162.7 (C-4),
158.3 (C-6), 135.6 (C-Ar), 132.4 (d, JC–F = 3.02 Hz, C-Ar), 130.0 (CH-Ar),
129.7 (CH-Ar), 129.0 (d, JC–F = 8.5 Hz, CH-Ar), 128.5 (CH-Ar), 115.7 (d,
JC–F = 21.7 Hz, CH-Ar), 104.5 (C-5), 15.5 (SMe).
GC-MS (EI, 70 eV): m/z (%) = 276 (51) [M+], 261 (100), 29 (41), 106
GC-MS (EI, 70 eV): m/z (%) = 312 (100) [M+], 297 (11), 279 (26), 265
(23), 120 (15).
(62), 145 (86), 77 (34).
Anal. Calcd for C14H13FN2OS: C, 60.85; H, 4.74; N, 10.14. Found: C,
60.71; H, 4.91; N, 10.15.
Anal. Calcd for C17H13N2OSF: C, 65.37; H, 4.19; N, 8.97. Found: C,
64.97; H, 4.25; N, 9.28.
3-Allyl-6-(4-bromophenyl)-2-(methylsulfanyl)pyrimidin-4(3H)-
3-Benzyl-6-methyl-2-(methylsulfanyl)pyrimidin-4(3H)-one (11a)
one (9f)
Yellow solid; yield: 216 mg (88%); mp 97–100 °C.
Salmon-colored solid; yield: 286 mg (85%); mp 131–134 °C.
1H NMR (400 MHz, CDCl3): δ = 7.26–7.31 (m, 5 H, Ar), 6.11 (s, 1 H, H–
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.5 Hz, 2 H, CH-Ar), 7.58 (d,
J = 8.5 Hz, 2 H, CH-Ar), 6.64 (s, 1 H, H–5), 5.87–5.96 (m, 1 H, =CH),
5.30–5.31 (m, 1 H, =CH2), 5.27 (m, 2 H, =CH2), 4.71–4.74 (m, 2 H,
NCH2), 2.68 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3): δ = 162.5 (C-2), 162.3 (C-4), 157.7 (C-6),
135.2 (CH-Ar), 131.9 (CH-Ar), 130.0 (=CH), 128.4 (CH-Ar), 125.1 (C-
Ar), 118.8 (=CH2), 104.3 (C-5), 46.1 (NCH2), 15.2 (SMe).
5), 5.27 (s, 2 H, NCH2), 2.50 (s, 3 H, SMe), 2.23 (s, 3 H, Me).
13C NMR (100 MHz, CDCl3): δ = 163.5 (C-2), 162.4 (C-4), 161.9 (C-6),
135.0 (C-Ar), 128.5 (CH-Ar), 127.6 (CH-Ar), 127.5 (CH-Ar), 107.6 (C-5),
46.7 (NCH2), 23.7 (Me), 15.1 (SMe).
GC-MS (EI, 70 eV): m/z (%) = 246 (100) [M+], 231 (21), 199 (29), 172
(38), 148 (19), 126 (41), 91 (80), 65 (21).
Anal. Calcd for C13H14N2OS: C, 63.39; H, 5.73; N, 11.37. Found: C,
63.34; H, 5.64; N, 11.38.
GC-MS (EI, 70 eV): m/z (%) = 337.9 (43) [M+], 322.9 (100), 289.0 (36),
265.9 (16), 207.0 (16), 182 (11), 101.1 (12).
Anal. Calcd for C14H13BrN2OS: C, 49.86; H, 3.89; N, 8.31. Found: C,
49.51; H, 3.71; N, 8.37.
3-Benzyl-2-(methylsulfanyl)-6-phenylpyrimidin-4(3H)-one (11b)
Yellow solid; yield: 277 mg (90%); mp 137–140 °C.
1H NMR (400 MHz, CDCl3): δ = 8.00–7.97 (m, 2 H, Ar), 7.47–7.43 (m, 3
H, Ar), 7.34–7.28 (m, 5 H, Ar), 6.73 (s, 1 H, H–5), 5.33 (s, 2 H, NCH2),
2.63 (s, 3 H, SMe).
13C NMR (100 MHz, CDCl3): δ = 162.9 (C-2), 162.5 (C-4), 158.7 (C-6),
136.1 (C-Ar), 134.9 (C-Ar), 130.6 (CH-Ar), 128.6 (CH-Ar), 128.5 (CH-
Ar), 127.7 (CH-Ar), 127.6 (CH-Ar), 126.8 (CH-Ar), 104.2 (C-5), 45.9
(NCH2), 15.4 (SMe).
6-Methyl-2-(methylsulfanyl)-3-phenylpyrimidin-4(3H)-one
(10a)21
Yellow solid; yield: 162 mg (70%); 135–138 °C.
1H NMR (400 MHz, CDCl3): δ = 7.51–7.48 (m, 3 H, Ar), 7.25–7.22 (m, 2
H, Ar), 6.14 (s, 1 H, H–5), 2.42 (s, 3 H, SMe), 2.28 (s, 3 H, Me).
13C NMR (100 MHz, CDCl3): δ = 162.9 (C-2), 162.5 (C-4), 162.3 (C-6),
135.7 (C-Ar), 129.8 (CH-Ar), 129.6 (CH-Ar), 128.6 (CH-Ar), 108.2 (C-5),
23.8 (Me), 15.3 (SMe).
GC-MS (EI, 70 eV): m/z (%) = 232 (71) [M+], 217 (13), 199 (23), 185
(100), 145 (29), 77 (29).
GC-MS (EI, 70 eV): m/z (%) = 308 (100) [M+], 293 (21), 261 (33), 234
(20), 207 (66), 188 (26), 148 (15), 91 (56).
Anal. Calcd for C18H16N2OS: C, 70.10; H, 5.23; N, 9.08. Found: C, 69.71;
H, 5.13; N, 9.05.
Anal. Calcd for C12H12N2OS: C, 62.04; H, 5.21; N, 12.30. Found: C,
61.76; H, 5.17; N, 12.01.
3-Benzyl-6-(4-fluorophenyl)-2-(methylsulfanyl)pyrimidin-4(3H)-
one (11e)
2-(Methylsulfanyl)-3,6-diphenylpyrimidin-4(3H)-one (10b)22
Brown solid; yield: 235 mg (80%); mp 148–150 °C (Lit.22 150 °C).
Beige solid; yield: 280 mg (86%); mp 125–127 °C.
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1H NMR (400 MHz, CDCl3): δ = 7.95–8.03 (m, 2 H, Ar), 7.29–7.36 (m, 5
H, Ph), 7.13 (t, JH-F = 8.7 Hz, 2 H, Ar), 6.67 (s, 1 H, H–5), 5.33 (s, 2 H,
NCH2), 2.63 (s, 3 H, SMe).
3-sec-Butyl-6-methyl-2-(methylsulfanyl)pyrimidin-4(3H)-one
(13a)
Brown oil; yield: 192 mg (91%).
13C NMR (100 MHz, CDCl3): δ = 165.6 (C-Ar), 162.8 (C-2), 162.7 (C-4),
154.7 (C-6), 134.9 (C-Ar), 132.3 (C-Ar), 128.9 (d, JC–F = 8.6 Hz, CH-Ar),
128.5 (CH-Ar), 127.7 (CH-Ar), 127.6 (CH-Ar), 115.6 (d, JC–F = 21.7 Hz,
CH-Ar), 103.9 (C-5), 47.0 (NCH2), 15.3 (SMe).
GC-MS (EI, 70 eV): m/z (%) = 326 (100) [M+], 311 (17), 279 (27), 252
(24), 206 (26), 148 (12), 91 (38).
1H NMR (400 MHz, CDCl3): δ = 6.95 (s, 1 H, H–5), 4.22–4.29 (m, 1 H,
NCH), 2.52 (s, 3 H, SMe), 2.30–2.37 (m, 1 H, CH2), 2.19 (s, 3 H, Me),
1.81–1.95 (m, 1 H, CH2), 1.55 (d, J = 6.7 Hz, 3 H, Me), 0.86 (t, J = 7.5 Hz,
3 H, Me).
13C NMR (100 MHz, CDCl3): δ = 163.1 (C-2), 161.6 (C-4), 161.2 (C-6),
109.2 (C-5), 59.2 (N–CH), 25.9 (CH2), 23.2 (Me), 17.3 (CH2), 15.6
(SMe), 11.2 (Me).
Anal. Calcd for C18H15FN2OS: C, 66.24; H, 4.63; N, 8.58. Found: C,
65.88; H, 4.55; N, 8.41.
GC-MS (EI, 70 eV): m/z (%) = 212 (2) [M+], 197 (49), 156 (100), 126 (9),
110 (27).
6-Methyl-2-(methylsulfanyl)-3-(2-phenylethyl)pyrimidin-4(3H)-
one (12a)
HRMS (ESI): m/z [M + Na] calcd for C10H16N2NaOS: 235.0781; found:
235.0786.
Brown hygroscopic solid; yield: 223 mg (86%).
1H NMR (400 MHz, CDCl3): δ = 7.31 (s, 5 H, Ph), 6.06 (s, 1 H, H–5),
4.18–4.22 (m, 2 H, NCH2), 2.97–3.02 (m, 2 H, CH2Ar), 2.57 (s, 3 H,
SMe), 2.22 (s, 3 H, Me).
3-sec-Butyl-2-(methylsulfanyl)-6-phenylpyrimidin-4(3H)-one
(13b)
Yellow solid; yield: 241 mg (88%); mp 93–94 °C.
13C NMR (100 MHz, CDCl3): δ = 162.3 (C-2), 162.1 (C-4), 161.1 (C-6),
137.8 (C-Ar), 128.8 (CH-Ar), 128.6 (CH-Ar), 126.7 (C-Ar), 107.8 (C-5),
45.7 (NCH2), 33.6 (CH2Ar), 23.6 (Me), 14.9 (SMe).
1H NMR (400 MHz, CDCl3): δ = 7.96–8.01 (m, 2 H, Ar), 7.43–7.46 (m, 3
H, Ar), 6.57 (s, 1 H, H–5), 4.30–4.34 (m, 1 H, NCH), 2.67 (s, 3 H, SMe),
2.31–2.42 (m, 1 H, CH2), 1.86–1.99 (m, 1 H, CH2), 1.61 (d, J = 6.6 Hz, 3
H, Me), 0.90 (t, J = 7.4 Hz, 3 H, Me).
GC-MS (EI, 70 eV): m/z (%) = 260 (3) [M+], 245 (6), 156 (100), 104 (51),
13C NMR (100 MHz, CDCl3): δ = 163.5 (C-2), 162.4 (C-4), 157.7 (C-6),
136.2 (C-Ar), 130.4 (C-Ar), 128.6 (CH-Ar), 126.7 (CH-Ar), 105.9 (C-5),
59.5 (N–CH), 26.0 (Me), 17.3 (CH2), 15.8 (SMe), 11.3 (Me).
91 (8), 77 (10).
Anal. Calcd for C14H16N2OS: C, 64.58; H, 6.19; N, 10.76. Found: C,
64.58; H, 6.03; N, 10.46.
GC-MS (EI, 70 eV): m/z (%) = 274 (2) [M+], 259 (40), 218 (100), 172
2-(Methylsulfanyl)-6-phenyl-3-(2-phenylethyl)pyrimidin-4(3H)-
(17), 102 (8).
one (12b)
Anal. Calcd for C15H18N2OS: C, 65.66; H, 6.61; N, 10.21. Found: C,
66.01; H, 6.29; N, 9.89.
Brown hygroscopic solid; yield: 293 mg (91%).
1H NMR (400 MHz, CDCl3): δ = 8.0 (s, 2 H, Ar), 7.45 (s, 3 H, Ar), 7.25–
7.33 (m, 5 H, Ar), 6.70 (s, 1 H, H–5), 4.25–4.29 (m, 2 H, NCH2), 3.03–
3.07 (m, 2 H, CH2Ar), 2.71 (s, 3 H, SMe).
3-sec-Butyl-2-(methylsulfanyl)-6-(4-tolyl)pyrimidin-4(3H)-one
(13c)
13C NMR (100 MHz, CDCl3): δ = 162.6 (C-2), 161.7 (C-4), 158.8 (C-6),
137.6 (C-Ar), 136.2 (C-Ar), 130.5 (CH-Ar), 128.8 (CH-Ar), 128.6 (CH-
Ar), 126.8 (CH-Ar), 126.7 (CH-Ar), 104.4 (C-5), 45.8 (NCH2), 33.5
(CH2Ar), 15.1 (SMe).
Yellow solid; yield: 239 mg (83%); mp 69–71 °C.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.1 Hz, 2 H, Ar), 7.24 (d, J =
7.9 Hz, 2 H, Ar), 6.52 (s, 1 H, H–5), 4.29–4.31 (m, 1 H, NCH), 2.65 (s, 3
H, SMe), 2.39 (s, 3 H, Me; 1 H, CH2), 1.88–1.95 (m, 1 H, CH2), 1.60 (d,
J = 6.5 Hz, 3 H, Me), 0.89 (t, J = 7.4 Hz, 3 H, Me).
GC-MS (EI, 70 eV): m/z (%) = 322 (8) [M+], 218 (100), 172 (25), 104
13C NMR (100 MHz, CDCl3): δ = 163.6 (C-2), 162.2 (C-4), 157.7 (C-6),
140.7 (C-Ar), 133.4 (C-Ar), 129.3 (CH-Ar), 126.7 (CH-Ar), 105.2 (C-5),
59.4 (NCH), 26.0 (Me), 21.3 (M), 17.3 (CH2), 15.9 (SMe), 11.3 (Me).
(32), 77 (17).
Anal. Calcd for C19H18N2OS: C, 70.78; H, 5.63; N, 8.69. Found: C, 70.71;
H, 5.56; N, 8.31.
GC-MS (EI, 70 eV): m/z (%) = 288 (1) [M+], 273 (34), 232 (100), 186
6-(4-Fluorophenyl)-2-(methylsulfanyl)-3-(2-phenylethyl)pyrimi-
(18), 115 (20).
din-4(3H)-one (12e)
Anal. Calcd for C16H20N2OS: C, 66.63; H, 6.99; N, 9.71. Found: C, 66.37;
H, 6.73; N, 9.58.
Yellow solid; yield: 265 mg (78%); mp 167–169 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.15–8.18 (m, 2 H, Ar), 7.27–7.34
(m, H, Ar), 6.76 (s, 1 H, H–5), 4.17–4.21 (m, 2 H, NCH2), 2.96–3.00 (m,
2 H, CH2Ar), 2.70 (s, 3 H, SMe).
3-sec-Butyl-6-(4-methoxyphenyl)-2-(methylsulfanyl)pyrimidin-
4(3H)-one (13d)
13C NMR (100 MHz, DMSO-d6): δ = 164.4 (C-2), 162.8 (C-4), 162.2 (C-
Ar), 160.8 (C-6), 156.1 (C-Ar), 137.1 (C-Ar), 132.0 (C-Ar), 129.0 (d,
JC–F = 8.7 Hz, CH-Ar), 128.3 (CH-Ar), 126.4 (CH-Ar), 115.1 (d, JC–F = 21.7
Hz, CH-Ar), 102.9 (C-5), 44.6 (NCH2), 32.3 (CH2Ar), 14.3 (SMe).
Brown solid; yield: 258 mg (85%); mp 108–110 °C.
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 8.9 Hz, 2 H, Ar), 6.94 (d, J =
8.8 Hz, 2 H, Ar), 6.47 (s, 1 H, H–5), 4.29–4.30 (m, 1 H, CH2), 3.85 (s, 3
H, OMe), 2.65 (s, 3 H, SMe), 2.33–2.36 (m, 1 H, CH2), 1.88–1.95 (m, 1
H, CH2), 1.60 (d, J = 6.6 Hz, 3 H, Me), 0.89 (t, J = 7.4 Hz, 3 H, Me).
GC-MS (EI, 70 eV): m/z (%) = 340 (3) [M+], 236 (100), 207 (12), 190
13C NMR (100 MHz, CDCl3): δ = 163.3 (C-2), 161.7 (C-Ar), 161.2 (C-6),
157.1 (C-6), 128.3 (C-Ar), 128.0 (CH-Ar), 113.7 (CH-Ar), 104.1 (C-5),
59.1 (NCH), 55.0 (OMe), 25.7 (Me), 17.1 (CH2), 15.5 (SMe), 11.01 (Me).
(10), 120 (11), 104 (29).
Anal. Calcd for C19H17FN2OS: C, 67.04; H, 5.03; N, 8.23. Found: C,
66.71; H, 4.89; N, 8.19.
GC-MS (EI, 70 eV): m/z (%) = 304 (6) [M+], 289 (49), 248 (100), 218
(12), 202 (17), 133 (14), 89 (7).
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Anal. Calcd for C16H20N2O2S: C, 63.13; H, 6.62; N, 9.20. Found: C,
62.97; H, 6.38; N, 9.20.
(3) He, Y.-P.; Long, J.; Zhang, S.-S.; Li, C.; Lai, C. C.; Zhang, C.-S.; Li,
D.-X.; Zhang, D.-H.; Wang, H.; Cai, Q.-Q.; Zheng, Y.-T. Bioorg.
Med. Chem. Lett. 2011, 21, 694.
(4) Petricci, E.; Mugnaini, C.; Radi, M.; Togninelli, A.; Bernardini, C.;
Manetti, F.; Parlato, M. C.; Renzulli, M. L.; Alongi, M.; Falciani, C.;
Corelli, F.; Botta, M. ARKIVOC 2006, (vii), 452.
(5) Wang, Y.; Chen, F.-E.; De Clercq, E.; Bolsarini, J.; Pannecouque, C.
Bioorg. Med. Chem. 2008, 16, 3887.
(6) Wang, Y.; Chen, F.-E.; De Clercq, E.; Bolsarini, J.; Pannecouque, C.
Eur. J. Med. Chem. 2009, 44, 1016.
(7) Skulnick, H. I.; Ludens, J. H.; Wendling, M. G. E.; Glenn, M.;
Rohloff, N. A.; Smith, R. J.; Wierenga, W. J. Med. Chem. 1986, 29,
1499.
3-sec-Butyl-6-(4-fluorophenyl)-2-(methylsulfanyl)pyrimidin-
4(3H)-one (13e)
Brown oil; yield: 263 mg (90%).
1H NMR (400 MHz, CDCl3): δ = 7.95–7.99 (m, 2 H, Ar), 7.12 (t, J = 8.7
Hz, 2 H, Ar), 6.50 (s, 1 H, H–5), 4.32–4.33 (m, 1 H, NCH), 2.66 (s, 3 H,
SMe), 2.32–2.37 (m, 1 H, CH2), 1.90–1.97 (m, 1 H, CH2), 1.60 (d, J = 6.7
Hz, 3 H, Me), 0.90 (t, J = 7.4 Hz, 3 H, Me).
13C NMR (100 MHz, CDCl3): δ = 164.2 (d, J = 250.9 Hz, C-Ar), 163.4 (C-
2), 162.5 (C-4), 156.8 (C-6), 132.4 (d, J = 2.9 Hz, C-Ar), 128.7 (d, J = 8.6
Hz, CH-Ar), 115.6 (d, J = 21.6 Hz, CH-Ar), 105.5 (C-5), 59.6 (NCH), 26.0
(Me), 17.3 (CH2), 15.8 (SMe), 11.3 (Me).
(8) Li, H.; Wang, J.-P.; Yang, F.; Liu, T.; Qiu, W.-W.; Li, J.-Y.; Li, J.;
Tang, J. Heterocycles 2012, 85, 1897.
(9) Attia, M. I.; Kansoh, A. L.; El-Brollosy, N. R. Monatsh. Chem. 2014,
145, 1825.
(10) (a) Wheeler, H. L.; McFarland, D. F. Am. Chem. J. 1909, 42, 101.
(b) Ajello, T.; Miraglia, A. Gazz. Chim. Ital. 1948, 78, 921.
(c) Lacey, R. N. J. Chem. Soc. 1954, 839. (d) Veronese, A. C.;
D’Angeli, F. Ann. Chim. (Rome) 1970, 60, 374.
(11) Bhabak, K. P.; Mugesh, G. Chem. Eur. J. 2010, 16, 1175.
(12) Gefenas, V.; Stankeviciute, Z.; Malinauskas, A. Chem. Heterocycl.
Compd. (Engl. Transl.) 2009, 45, 1413.
GC-MS (EI, 70 eV): m/z (%) = 292 (1) [M+], 277 (27), 236 (100), 190
(19), 120 (18).
HRMS (ESI): m/z [M + Na] calcd for C15H17FN2NaOS: 315.0944; found:
315.0948.
6-(4-Bromophenyl)-3-sec-butyl-2-(methylsulfanyl)pyrimidin-
4(3H)-one (13f)
Beige solid; yield: 286 mg (81%); mp 97–98 °C.
(13) Erkin, A. V.; Krutikov, V. I. Russ. J. Gen. Chem. 2005, 75, 639.
(14) Vainilavichyus, P. I.; Syadyaryavichyute, V. Yu. Chem. Heterocycl.
Compd. (Engl. Transl.) 1987, 23, 1216.
(15) Breeger, S.; von Meltzer, M.; Hennecke, U.; Carell, T. Chem. Eur. J.
2006, 12, 6469.
(16) Lu, Y.; Xiang, T.; Bartberger, M. D.; Bernard, C.; Bostick, T.;
Huang, L.; Liu, L.; Siegmund, A.; Sukay, G.; Guo, G.; Elipe, M. S.;
Tormos, W.; Dominguez, C.; Koch, K.; Burgess, L. E.; Basil, T. C.;
Ibrahim, P.; Hummel, C. Tetrahedron 2006, 62, 11714.
(17) Mazumdar, S. N.; Mahajan, M. P. Tetrahedron 1991, 47, 1473.
(18) Dey, P. D.; Sharma, A. K.; Rai, S. N.; Mahajan, M. P. Tetrahedron
1995, 51, 7459.
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.6 Hz, 2 H, Ar), 7.57 (d, J =
8.6 Hz, 2 H, Ar), 6.53 (s, 1 H, H–5), 4.31–4.33 (m, 1 H, NCH), 2.65 (s, 3
H, SMe), 2.34–2.39 (m, 1 H, CH2), 1.89–1.96 (m, 1 H, CH2), 1.61 (d, J =
6.6 Hz, 3 H, Me), 0.90 (t, J = 7.4 Hz, 3 H, Me).
13C NMR (100 MHz, CDCl3): δ = 163.3 (C-2), 162.7 (C-4), 156.7 (C-6),
135.2 (C-Ar), 131.8 (CH-Ar), 128.3 (CH-Ar), 124.9 (C-Ar), 105.9 (C-5),
59.6 (NCH), 26.0 (Me), 17.3 (CH2), 15.9 (Me), 11.3 (Me).
GC-MS (EI, 70 eV): m/z (%) = 352 (1) [M+], 339 (36), 296 (100), 252
(11), 182 (7).
Anal. Calcd for C15H17BrN2OS: C, 51.00; H, 4.85; N, 7.93. Found: C,
51.32; H, 4.45; N, 8.13.
(19) Dey, P. D.; Sharma, A. K.; Bharatam, P. V.; Mahajan, M. P. Tetra-
hedron 1997, 53, 13829.
(20) Friot, C.; Reliquet, A.; Reliquet, F.; Meslin, J. C. Synthesis 2000,
695.
Acknowledgment
(21) Gupta, K. A.; Saxena, A. K.; Jain, P. C. Synthesis 1981, 905.
(22) Gupta, K. A.; Saxena, A. K.; Jain, P. C.; Dua, P. R.; Prasad, C. R.;
Anand, N. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
1983, 22, 789.
(23) Zanatta, N.; Madruga, C. C.; Patricia, M. C.; da Rosa, L. S.; da
Silva, F. M.; Bonacorso, H. G.; Martins, M. A. P. J. Heterocycl.
Chem. 2010, 47, 1234.
The authors are grateful for financial support from the Fundação de
Apoio à Tecnologia e Ciência do Estado do Rio Grande do Sul
(FAPERGS Pq Gaucho 11/1608-8) and Conselho Nacional de Desen-
volvimento Científico e Tecnológico (CNPq; Universal grant No.
476341/2013-2), and for fellowships from CAPES (F.M.S.) and CNPq
(E.C.A).
(24) (a) Zanatta, N.; Fantinel, L.; Lourega, R. V.; Bonacorso, H. G.;
Martins, M. A. P. Synthesis 2008, 358. (b) Zanatta, N.; Fantinel,
L.; Fernandes, L. da. S.; Wouters, A. D.; Bonacorso, H. G.;
Martins, M. A. P. Synthesis 2008, 3492. (c) Zanatta, N.; Amaral, S.
S.; Esteves-Souza, A.; Echevarria, A.; Brondani, P. B.; Flores, D. C.
Bonacorso H. G.; Flores, A. F. C.; Martins, M. A. P. Synthesis 2006,
2305. (d) Bonacorso, H. G.; Ferla, A.; Cechinel, C. A.; Zanatta, N.;
Martins, M. A. P. Lett. Org. Chem. 2007, 4, 495. (e) Zanatta, N.;
Barichello, R.; Pauletto, M. M.; Bonacorso, H. G.; Martins, M. A.
P. Tetrahedron Lett. 2003, 44, 961. (f) Martins, M. A. P.; Cunico,
W.; Pereira, C. M. P.; Sinhorin, A. P.; Flores, A. F. C.; Bonacorso, H.
G.; Zanatta, N. Curr. Org. Synth. 2004, 1, 391.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560470.
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References
(1) Cosimelli, B.; Severi, E.; Novellino, E.; Cavaccini, A.; Cataldi, M.;
Budriesi, R.; Micucci, M.; Chiarini, A.; Ioan, P. J. Med. Chem.
2011, 54, 5597.
(2) Atwal, K. S.; Rovnyak, G. C.; Schwartz, J.; Moreland, S.; Hedberg,
A.; Gougoutas, J. Z.; Malley, M. F.; Floyd, D. M. J. Med. Chem.
1990, 33, 1510.
(25) (a) Hojo, M.; Masuda, R.; Sakaguchi, S.; Takagowa, M. Synthesis
1986, 1016. (b) Colla, A.; Martins, M. A. P.; Clar, G.; Krimmer, S.;
Fischer, P. Synthesis 1991, 483. (c) Siqueira, G. M.; Flores, A. F. C.;
Clar, G.; Zanatta, N.; Martins, M. A. P. Quim. Nova 1994, 17, 24.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3947–3955

3955
J. M. dos Santos et al.
Paper
Synthesis
(26) Shildneck, P. R.; Windus, W. Org. Synth. Coll. Vol. II; Wiley:
London, 1943, 411.
(27) Chen, B.-C.; Zhao, R.; Wang, B. US 7652146, 2010.
(28) Zanatta, N.; Faoro, D.; Fernandes, L. da. S.; Brondani, P. B.; Flores,
D. C.; Flores, A. F. C.; Bonacorso, H. G.; Martins, M. A. P. Eur. J.
Org. Chem. 2008, 5832.
(29) Zanatta, N.; Madruga, C. Da C.; Marisco, P. C.; Flores, D. C.;
Bonacorso, H. G.; Martins, M. A. P. J. Heterocycl. Chem. 2000, 37,
1213.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3947–3955