Efficient syntheses of ethyl 2-methylthio-and ethyl 2-benzylthio-6-methyl(aryl)pyrimidine-4-carboxylates and their carboxylic acid derivatives

Article abstract of DOI:10.1055/s-0034-1379696

A simple and efficient procedure for the synthesis of ethyl 2-methylthio-and ethyl 2-benzylthio-6-methyl(aryl)-pyrimidine-4-carboxylates and their corresponding acid derivatives is reported. The products are obtained in good yields via the cyclocondensation reaction of ethyl 4-alkoxy-2-oxo-4-methyl(aryl)-but-3-enoates with 2-methylisothiourea sulfate or 2-benzylisothiourea hydrochloride, under mild, basic, aqueous conditions.

Full text of DOI:10.1055/s-0034-1379696

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 827–835
paper
827
N. Zanatta et al.
Paper
Synthesis
Efficient Syntheses of Ethyl 2-Methylthio- and Ethyl 2-Benzylthio-
6-methyl(aryl)pyrimidine-4-carboxylates and Their Carboxylic
Acid Derivatives
Nilo Zanatta*
CO2Et
Andressa S. Fortes
Carlos E. Bencke
N
R1
N
SR2
Mário A. Marangoni
Adriano F. Camargo
Cassio A. Fantinel
Helio G. Bonacorso
Marcos A. P. Martins
O
OMe
SR2
NH.X
(14 examples)
+
EtO2C
R1
H2N
CO2H
N
Núcleo de Química de Heterociclos (NUQUIMHE),
Departamento de Química, Universidade Federal de
Santa Maria, 97105-900, Santa Maria, Brazil
nilo.zanatta@ufsm.br
R1
N
SR2
(12 examples)
Received: 15.10.2014
Accepted after revision: 17.11.2014
Published online: 05.01.2015
but-3-enoates as dielectrophiles, and also employs different
reaction conditions to achieve the target compounds. The
sixth method, reported by Piotrowski et al.,13 is similar to
that described by Xu et al.,7 in which a single enamino py-
ruvate was generated and reacted with 2-methyliso-
thiourea sulfate to afford ethyl 2-(methylthio)-5,6,7,8-tetra-
hydropyrido[4,3-d]pyrimidine-4-carboxylate; this product
has been used in further derivatization reactions. From
these six methods, the example reported by Matsushita et
al.8 is the most similar to ours. However, there are three
major points of difference in comparison with our study: (i)
Matsushita used alkyl 4-alkoxy-2-oxo-4-but-3-enoates,
whereas we used ethyl 4-alkoxy-2-oxo-4-substituted-but-
3-enoates; consequently, Matsushita only obtained 5,6-un-
substituted alkyl 2-methylthiopyrimidine-4-carboxylates,
and in fact, in their patent, they prepared only two pyrimi-
dines, namely methyl- and ethyl 2-methylthiopyrimidine-
4-carboxylates.8 (ii) The reaction conditions were very dif-
ferent: Matsushita et al.8 used organic solvents (e.g., propio-
nitrile, acetonitrile, N,N-dimethylformamide, n-butyl ace-
tate, tert-butyl alcohol), and reaction conditions employing
triethylamine at 96 °C for six hours under a nitrogen atmo-
sphere, and when necessary, additives were used to in-
crease the yields (e.g., potassium iodide). On the other
hand, in our study, the optimized reaction conditions used
a mixture of water (1 M aqueous sodium carbonate solu-
tion) and ethanol at reflux temperature for one hour. (iii)
Matsushita et al.8 did not describe the synthesis of any 2-
methylthiopyrimidine-4-carboxylic acids or any alkyl 2-
benzylthiopyrimidine-4-carboxylic acids or esters.
DOI: 10.1055/s-0034-1379696; Art ID: ss-2014-m0631-op
Abstract A simple and efficient procedure for the synthesis of ethyl 2-
methylthio- and ethyl 2-benzylthio-6-methyl(aryl)-pyrimidine-4-car-
boxylates and their corresponding acid derivatives is reported. The
products are obtained in good yields via the cyclocondensation reaction
of ethyl 4-alkoxy-2-oxo-4-methyl(aryl)-but-3-enoates with 2-meth-
ylisothiourea sulfate or 2-benzylisothiourea hydrochloride, under mild,
basic, aqueous conditions.
Key words 2,4,6-trisubstituted pyrimidines, 2-thiopyrimidines, ethyl
pyrimidine-4-carboxylates, pyrimidine-4-carboxylic acids, cycloconden-
sation
Studies on 4- and 6-substituted 2-thiopyrimidines have
shown that they exhibit antimalarial,1 antitumor,2 anti-
HIV,3 and antitubercular4 activity. Additionally, these py-
rimidines have been used as the starting materials for the
synthesis of bioactive molecules in the fields of medicine5
and agriculture.6
In a search of the literature, we found six methods de-
scribed for the preparation of alkyl 2-methylthiopyrimi-
dine-4-carboxylates and/or their corresponding carboxylic
acid derivatives, which were, in some ways, similar to our
reported method.7–14 Four of these patented methods re-
ported only the synthesis of 6-unsubstituted alkyl 2-meth-
ylthiopyrimidine-4-carboxylates and/or their correspond-
ing carboxylic acid derivatives.7–10 A fifth method, widely
used in two patents by Haddida11 and Bolli,12 relied on the
preparation of an extended series of 6-substituted alkyl 2-
methylthiopyrimidine-4-carboxylates, and/or their corre-
sponding carboxylic acid derivatives, via the cycloconden-
sation of alkyl 2,4-dioxopentanoates and/or their carboxylic
acid derivatives with 2-methylisothiourea sulfate.11,12 This
method is similar to our method, but instead uses alkyl 2,4-
dioxopentanoates instead of 4-alkoxy-2-oxo-4-substituted-
Other methods to obtain 2-methylthiopyrimidine-4-
carboxylates (esters and acids), but not related to this study
include: (i) direct insertion of the carboxylic group in 4-
halo-2-methylthiopyrimidines14 or insertion by coupling of
the aryl group in 6-halo-2-thiopyrimidines;15 (ii) oxidation
of pyrimidine-4-carbaldehyde with silver nitrate;16 (iii) ba-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 827–835

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N. Zanatta et al.
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Synthesis
OR1
R2
O
O
O
OR1
R2
CX3
EtO2C
n
X3C
R3
III
R1 = Me, Et, Bu
2 = H, alkyl, aryl, hetaryl
R3 = H, Me
R3
Y
II
I
X = F, Cl
Y = C, O
n = 1, 2
X = F, Cl
R1 = Me, Et, Bu
2 = H, alkyl, aryl, hetaryl
3 = H, Me
R
R
R
Figure 1 General structures of enones I–III
sic hydrolysis of alkyl pyrimidine-4-carboxylates12 or py-
rimidine-4-carbonitrile.17 The latter two methods furnish
only 2-thiopyrimidine-4-carboxylic acids.
- alcohols
- aldehydes
- amides
- amines
- hydrazides
- etc.
CO2R1
- alkoxy
- amines
- azides
- hydrazines
- sulfones
- sulfoxides
- etc.
Although trifluoromethyl- and trichloromethyl-enones
of general structures I and II (Figure 1) have been widely
used as building blocks for the preparation of a large num-
ber of compounds, especially heterocycles,18 the significant
potential of 4-alkoxy-2-oxo-4-substituted-but-3-enoates
(structure III, Figure 1) as versatile building blocks in or-
ganic synthesis has attracted very little attention thus far.19
Hence, this study reports a simple and efficient one-pot
procedure for the synthesis of a series of 6-substituted ethyl
2-methylthiopyrimidine-4-carboxylates and their corre-
sponding carboxylic acid derivatives, as well as a series of 6-
substituted ethyl 2-benzylthiopyrimidine-4-carboxylates
and their corresponding carboxylic acid derivatives, from
the cyclocondensation reaction of ethyl 4-alkoxy-2-oxo-4-
substituted-but-3-enoates with 2-methylisothiourea sul-
fate and 2-benzylisothiourea hydrochloride, under mild,
basic, aqueous conditions.
Furthermore, pyrimidines such as those synthesized in
this study (Figure 2), are attractive compounds because
they are obtained easily via a simple one-pot reaction, and
provide a highly substituted pyrimidine core that contains
interesting functional groups such as aryl, carboxylic esters
and carboxylic acids, methythio and benzylthio, which have
already demonstrated potential biological activity by them-
selves.20 Additionally, carboxylic esters and acids can be
easily converted into many other functional groups, as can
the 2-methylthio and 2-benzylthio substituents – these
substituents can be oxidized into sulfones, which are useful
moieties for nucleophilic aromatic substitution reactions.
These possibilities for further derivatization render these
molecules as versatile templates for combinatorial chemis-
try.
N
N
R
SR2
Figure 2 General structure of the pyrimidines synthesized in this study
alkoxides,21 hydrazines,22 azides,23 or hydroxide.21 There
have been reports in which the nucleophilic substitution is
performed directly on the 2-methylthio group without the
need for prior oxidation.24
CO2Et
CO2Et
CO2Et
HY
i
N
N
N
N
ref. 21
ref. 11, 12
N
N
Ph
SO2Me
Ph
Y
Ph
SMe
this study
CO2H
C(O)Cl
C(O)Y
ii
ref. 25
HY
N
N
N
ref. 11
Ph
N
SMe
Ph
N
SMe
Ph
N
SMe
Y = NR1R2, RO, NHNHR, N3, OH; R1, R2 = H, alkyl, aryl, etc.
Scheme 1 Reagents and conditions: (i) Oxone, H2O, MeOH, r.t.; (ii)
SOCl2, benzene, DMF, reflux, 20 min.
Derivatization of ethyl carboxylates can be achieved via
hydrolysis into carboxylic acids (as in this study), followed
by the conversion of this group into the corresponding acid
chloride25 and subsequent treatment with nucleophiles
such as primary or secondary amines, alkoxides, and hydra-
zines, which furnish amides, esters and hydrazides, respec-
tively.11
The synthesis of ethyl 2-methylthio- and ethyl 2-benz-
ylthio-6-substituted-pyrimidine-4-carboxylates 4a–g and
5a–g, via the cyclocondensation reaction of ethyl 4-meth-
Scheme 1 illustrates some of the available pathways for
the derivatization of the pyrimidine core shown in Figure 2.
The most common procedure for the derivatization of the
2-methylthio position is via its oxidation to give a methyl-
sulfone, by employing Oxone21 or m-chloroperoxybenzoic
acid.22 The sulfone group is a good leaving group and can
easily be replaced by nucleophiles such as amines,11,12
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 827–835

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N. Zanatta et al.
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Synthesis
oxy-2-oxo-4-substituted-but-3-enoates 1a–g with 2-meth-
ylisothiourea sulfate (2) or 2-benzylisothiourea hydrochlo-
ride (3), performed in a mixture of ethanol and a 1 M solu-
tion of sodium carbonate in water (5:1), at reflux
temperature for one hour, is outlined in Scheme 2. The
enoates 1a–f were prepared from the reaction of the re-
spective acetals, which were themselves obtained from the
corresponding acetophenone by treatment with trimethyl
orthoformate catalyzed by p-toluenesulfonic acid, with eth-
yl oxalyl chloride in chloroform and pyridine according to
previous publications.19a,b The enoate 1g was obtained by
direct acylation of 2-methoxyprop-1-ene with ethyl oxalyl
chloride according to previous studies.19a,b
Table 1 Optimization of the Reaction Conditions for the Synthesis of
Compound 4a
Entry Base
Molar ratioa
Solvent
Temp
(°C)
Time Yield
(h)
(%)b
1
2
Na2CO3
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:1:1
1:1.2:1.2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
EtOH–H2O
H2O
30
4
64
53
46
42
41
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaOH
30
6
12
16
24
3
30
4
30
5
30
6
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
0.5 44
7
1
4
76
51
35
8
O
MeO
R
OMe
i
9
24
1
SMe
NH
R
CO2Et
c
10
11
12
13
14
15
16
17
–
H2N
2·H2SO4
1
50
57
2
N
N
ii
iii
1
R
R
SMe
SBn
d
py
1
–
4a–g
O
OMe
R
SBn
Et3N
1
43
23
73
71
CO2Et
EtO2C
H2N
NH·HCl
Na2CO3
Na2CO3
Na2CO3
1
3
iv
1a R = Ph
CH2Cl2–H2O
MeCN–H2O
1
N
1b R = 4-FC6H4
1c R = 4-BrC6H4
1d R = 4-MeC6H4
1e R = 4-MeOC6H4
1f R = 4-O2NC6H4
1g R = Me
1
N
a Molar ratio of the enoate/isothiourea/base.
b Yield after purification.
5a–g
c The formation of 4a and other (unidentified) compounds was observed.
d The expected product was not isolated.
Scheme 2 Reagents and conditions: (i) HC(OMe)3, TsOH, reflux, 4 h; (ii)
ethyl oxalyl chloride, py, CHCl3, 0–65 °C, 5 h; (iii) Na2CO3 (1 M), EtOH,
reflux, 1 h; (iv) Na2CO3 (1 M), EtOH, reflux, 1 h.
solution (2 M) at reflux temperature for one hour. 1-(4-Bro-
mophenyl)ethanone was isolated from this reaction in 57%
yield, and we also observed two minor compounds in the
1H NMR spectrum, which were not identified. The second
test was carried out by reacting 1c with 2-methyliso-
thiourea sulfate (2) under the same conditions as those
Initially, the synthesis of compound 4a was optimized
(Table 1). The best yield of 4a (76%) was obtained when the
reaction was carried out in ethanol–water at reflux tem-
perature over one hour, employing enoate 1a, 2-methyliso-
thiourea sulfate (2) and sodium carbonate in the molar ra-
tio 1:2:2 (Table 1, entry 7). These reaction conditions were
then used for the synthesis of a series of 2-methylthiopy-
rimidines 4b–g (Table 2). Table 1 also shows that when us-
ing less than a twofold excess of 2-methylisothiourea sul-
fate, the reactions did not furnish good yields (Table 1, en-
tries 10 and 11), and longer reaction times, even at 30 °C,
led to hydrolysis of the carboxylic ester to give the corre-
sponding carboxylic acid (Table 1, entries 1–9). When reac-
tions were performed with sodium hydroxide we believe
that partial decomposition of the enoate may have oc-
curred26 and/or that hydrolysis took place to give the re-
spective 4-substituted 4-methoxy-2-oxobut-3-enoic acid.
We confirmed this proposition by running two test re-
actions as shown in Scheme 3. In the first reaction, ethyl 4-
(4-bromophenyl)-4-methoxy-2-oxobut-3-enoate (1c) was
subjected to the reaction with aqueous sodium hydroxide
reaction test 1
O
OMe
O
i
two minor compounds
(not identified)
+
EtO2C
1c
Br
Br
(57%)
reaction test 2
O
CO2Et
CO2H
OMe
R
O
i
N
N
N
+ 2
+
+
EtO2C
R
1c
R
N
SMe
R
SMe
4c (57%)
6c (15%)
(5%)
R = 4-BrC6H4
Scheme 3 Reagents and conditions: (i) NaOH (2 M aq solution), EtOH,
reflux, 1 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 827–835

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N. Zanatta et al.
Paper
Synthesis
used in test 1. In this case, we observed the formation of a
mixture of compounds 4c, 6c, and 1-(4-bromophenyl)etha-
none, but the formation of 4-(4-bromophenyl)-4-methoxy-
2-oxobut-3-enoic acid was not observed in either of the
two tests.
The reactions of enoates 1a–g with 2-benzylisothiourea
hydrochloride (3) were performed by using the same meth-
od described for the reactions of enoates 1a–g with 2-me-
thylisothiourea sulfate (2). However, we found that the best
molar ratio was 1:1.2:1.2 of the enoate, 2-benzyliso-
thiourea hydrochloride, and sodium carbonate, respective-
ly. Table 2 shows the obtained yields of the pyrimidines 4a–
g and 5a–g prepared using the optimized reaction condi-
tions.
sulfate (2) or 2-benzylisothiourea hydrochloride (3) in eth-
anol containing one equivalent of 1 M sodium carbonate
solution, followed by an in situ basic hydrolysis with 10%
aqueous sodium hydroxide solution (Scheme 4). The sec-
ond method gave a better overall yield than the first, be-
cause it was not necessary to isolate the intermediate ester
and since hydrolysis of the ester to give the corresponding
acid occurred, to a certain extent, during the cycloconden-
sation step.
CO2H
i
N
R
R
N
SMe
SBn
O
OMe
R
6a–e,g
CO2H
EtO2C
Table 2 Yields of Pyrimidines 4a–g and 5a–g Obtained Using the Op-
timized Reaction Conditions
1a R = Ph
ii
1b R = 4-FC6H4
1c R = 4-BrC6H4
1d R = 4-MeC6H4
1e R = 4-MeOC6H4
1f R = 4-O2NC6H4
1g R = Me
N
Enoatea
R
Isothiourea Product
Yield (%)d
N
1a
1b
1c
1d
1e
1f
Ph
2b
2b
2b
2b
2b
2b
2b
3c
3c
3c
3c
3c
3c
3c
4a
4b
4c
4d
4e
4f
76
62
80
58
52
58
63
94
64
89
84
62
94
77
7a–e,g
4-FC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
Me
Scheme 4 Reagents and conditions: (i) (a) 2-methylisothiourea sulfate
(2), Na2CO3 (1 M aq), EtOH, reflux, 1 h; (b) 10% NaOH, reflux, 1 h; (ii) (a)
2-benzylisothiourea hydrochloride (3), Na2CO3 (1 M aq), EtOH, reflux, 1
h; (b) 10% NaOH, reflux, 1 h.
1g
1a
1b
1c
1d
1e
1f
4g
5a
5b
5c
5d
5e
5f
The yields obtained for the synthesis of pyrimidine-4-
carboxylic acids 6a–e,g and 7a–e,g from the one-pot, two-
step procedure (see Scheme 4), using the optimized reac-
tion conditions, are shown in Table 3.
An attempt to obtain the pyrimidines 6 and 7 via a one-
step reaction, which involved performing the cycloconden-
sation and the basic hydrolysis simultaneously with 10%
sodium hydroxide solution, led to partial decomposition of
the enoate26 as shown in Scheme 3.
The pyrimidine-4-carboxylic acids 6a–e,g and 7a–e,g,
were isolated by cooling the reaction mixture to approxi-
mately 0 °C and adding concentrated hydrochloric acid un-
til pH 3. The products 6a–e and 7a–e precipitated and were
collected by filtration, washed with cold water and with hot
hexane, and then dried in desiccator. Compounds 6g and 7g
were isolated by extraction with chloroform. Despite sever-
al experimental attempts using both methods presented in
this paper, it was not possible to isolate, or and identify
compounds 6f and 7f by NMR spectroscopy and mass spec-
trometry. Coincidentally, compounds 6f and 7f would pres-
ent a substituent with the strongest electron-withdrawing
effect at position 6 of the pyrimidine ring of the series 6 and
7 (R = 4-O2NC6H4).
Ph
4-FC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
Me
1g
5g
a Reaction conditions: Na2CO3, EtOH–H2O (5:1), reflux, 1 h.
b Molar ratio = 1:2:2 (enoate/isothiourea/base).
c Molar ratio = 1:1.2:1.2 (enoate/isothiourea/base).
d Yield after purification.
The products 4 and 5 were isolated by partial evapora-
tion of the solvent followed by the addition of ice-cold wa-
ter to the reaction mixture. Under these conditions, the
products precipitated and were collected by filtration,
washed with water, and then dried in a desiccator. Com-
pounds 4a–f were purified by recrystallization from hex-
ane, and compounds 5a–f were recrystallized from a mix-
ture of acetone–hexane (1:1). Compounds 4g and 5g were
isolated by extraction with chloroform.
The pyrimidine-4-carboxylic acids 6a–e,g and 7a–e,g
were obtained by basic hydrolysis of the parent pyrimidine-
4-carboxylic esters 4a–e,g and 5a–e,g and/or by a one-pot,
two-step procedure, which involved the cyclocondensation
reaction of the enoates 1a–e,g with 2-methylisothiourea
In conclusion, we have described a simple and efficient
one-pot procedure for the synthesis of ethyl 2-methylthio-
and ethyl 2-benzylthio-6-substituted-pyrimidine-4-car-
boxylates 4a–g and 5a–g, and the corresponding carboxylic
acid derivatives 6a–e,g and 7a–e,g, The expected pyrimi-
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831
N. Zanatta et al.
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Synthesis
EtOH (5 mL) was added and the mixture was stirred at reflux tem-
perature for 1 h. The solvent was partially evaporated, then cold H2O
was added to the flask and the solid residue was collected by filtra-
tion and washed with H2O. The wet filter cake was dissolved in CHCl3,
dried over anhydrous Na2SO4, filtered, and then the solvent evaporat-
ed. Compounds 4a–f were recrystallized from hexane and com-
pounds 5a–f were recrystallized from a mixture of acetone–hexane
(1:1). Compounds 4g and 5g were isolated by extraction with CHCl3
(3 × 20 mL), and the combined organic layer was dried over anhy-
drous Na2SO4, filtered, and then the solvent was evaporated.
Table 3 Yields of Pyrimidines 6a–e,g and 7a–e,g Obtained Using the
Optimized Reaction Conditions
Enoatea
R
Isothiourea Product
Yield (%)d
1a
1b
1c
1d
1e
1g
1a
1b
1c
1d
1e
1g
Ph
2b
2b
2b
2b
2b
2b
3c
3c
3c
3c
3c
3c
6a
6b
6c
6d
6e
6g
7a
7b
7c
7d
7e
7g
79
80
84
75
73
40
75
80
83
79
71
35
4-FC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
Me
Ethyl 2-(Methylthio)-6-phenylpyrimidine-4-carboxylate (4a)
Yield: 208 mg (76%); white solid; mp 59–61 °C.
1H NMR (400 MHz, CDCl3): δ = 8.14–8.12 (m, 2 H), 7.99 (s, 1 H), 7.51–
7.46 (m, 3 H), 4.48 (q, J = 6.0 Hz, 2 H), 2.68 (s, 3 H), 1.44 (t, J = 6.0 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 173.7, 165.7, 164.2, 156.1, 135.8,
131.5, 128.9 (2 C), 127.3 (2 C), 111.2, 62.4, 14.3, 14.1.
GC–MS (EI, 70 eV): m/z (%) = 276 (4.5) [M + 2], 274 (75) [M+], 245
(12.5), 200 (100), 128 (55).
Ph
4-FC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4
Me
a Reaction conditions: (i) Na2CO3, EtOH–H2O (5:1), reflux, 1 h; (ii) 10%
NaOH, reflux, 1 h.
Anal. Calcd for C14H14N2O2S: C, 61.29; H, 5.14; N, 10.21. Found: C,
61.06; H, 5.23; N, 10.27.
b Molar ratio = 1:2:2 (enoate/isothiourea/base).
c Molar ratio = 1:1.2:1.2 (enoate/isothiourea/base).
d Yield after purification.
Ethyl 6-(4-Fluorophenyl)-2-(methylthio)pyrimidine-4-carboxyl-
ate (4b)
Yield: 181 mg (62%); white solid; mp 94–95 °C.
1H NMR (200 MHz, CDCl3): δ = 8.21–8.14 (m, 2 H), 7.98 (s, 1 H), 7.27–
7.15 (m, 2 H), 4.49 (q, J = 6.0 Hz, 2 H), 2.69 (s, 3 H), 1.43 (t, J = 6.0 Hz, 3
H).
13C NMR (50 MHz, CDCl3): δ = 173.9, 165.0 (d, 1JC–F = 255.0 Hz), 164.6,
164.3, 156.1, 131.9 (d, 4JC–F = 5.0 Hz), 129.5 (d, 3JC–F = 5.0 Hz, 2 C), 116.1
(d, 2JC–F = 20.0 Hz, 2 C), 111.0, 62.6, 14.4, 14.2.
dines are obtained in good yields via the cyclocondensation
of ethyl 4-substituted 4-alkoxy-2-oxobut-3-enoates with 2-
methylisothiourea sulfate or 2-benzylisothiourea hydro-
chloride under mild, basic, water–ethanol conditions.
GC–MS (EI, 70 eV): m/z (%) = 294 (3.3) [M + 2], 292 (50) [M+], 263
(8.3), 218 (100), 146 (88).
The ethyl 4-alkoxy-2-oxo-4-substituted-but-3-enoates 1a–g were
prepared according to the literature.19a,b All the products described in
this article were fully characterized by IR (for the carboxylic acids),
1H, 13C and 2D NMR, GC–MS or LC–MS, and HRMS or elemental analy-
sis. All melting points were determined on a Kofler Reichert Thermo-
var or on a MQAPF-301 apparatus and are uncorrected. IR spectra
were obtained using a Bruker Tensor 27 spectrometer in the 600–
4000 cm–1 range, and the samples were prepared as KBr pellets. 1H
and 13C NMR spectra were acquired using a Bruker DPX 200 (1H at
200.13 MHz and 13C at 50.32 MHz) or a Bruker DPX 400 (1H at 400.13
MHz and 13C at 100.62 MHz) spectrometer in CDCl3 or DMSO-d6, with
TMS as an internal reference. Liquid chromatography–mass spec-
trometry was performed on an LC–MS/MS Agilent 6460 instrument
in ESI mode. Gas chromatography–mass spectrometry was performed
in EI mode, using methane as the ionizing gas, on an Agilent 5975B
GC–MSD spectrometer. The GC was equipped with a split–splitless in-
jector, an auto-sampler, and a cross-linked HP-5 capillary column (30
m, 0.32 mm internal diameter); helium was used as the carrier gas.
High-resolution mass spectra were recorded on a Bruker QTOF spec-
trometer in ESI mode. Microanalyses were performed on a Perkin El-
mer 2400 elemental analyzer.
Anal. Calcd for C14H13FN2O2S: C, 57.52; H, 4.48; N, 9.58. Found: C,
57.37; H, 4.59; N, 9.71.
Ethyl 6-(4-Bromophenyl)-2-(methylthio)pyrimidine-4-carboxyl-
ate (4c)
Yield: 281 mg (80%); light pink solid; mp 123–124 °C.
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 8.0 Hz, 2 H), 7.97 (s, 1 H),
7.63 (d, J = 8.0 Hz, 2 H), 4.49 (q, J = 8.0 Hz, 2 H), 2.68 (s, 3 H), 1.44 (t, J =
8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.0, 164.6, 164.2, 156.3, 134.7,
132.2 (2 C), 128.8 (2 C), 126.4, 111.0, 62.5, 14.3, 14.2.
GC–MS (EI, 70 eV): m/z (%) = 354 (50) [M + 2], 352 (48) [M+], 325
(11.6), 323 (10), 280 (100), 278 (86), 208 (46), 206 (45), 127 (70).
Anal. Calcd for C14H13BrN2O2S: C, 47.60; H, 3.71; N, 7.93. Found: C,
47.88; H, 3.81; N, 8.41.
Ethyl 2-(Methylthio)-6-(p-tolyl)pyrimidine-4-carboxylate (4d)
Yield: 167 mg (58%); beige solid; mp 96–97 °C.
1H NMR (200 MHz, CDCl3): δ = 8.08 (d, J = 8.0 Hz, 2 H), 8.01 (s, 1 H),
7.32 (d, J = 8.0 Hz, 2 H), 4.49 (q, J = 8.0 Hz, 2 H), 2.70 (s, 3 H), 2.44 (s, 3
H), 1.46 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 173.6, 165.7, 164.4, 155.9, 142.2,
133.0, 129.7 (2 C), 127.3 (2 C), 111.0, 62.4, 21.4, 14.3, 14.2.
Ethyl 2-Methylthio- and Ethyl 2-Benzylthio-6-substituted-pyrimi-
dine-4-carboxylates 4a–g and 5a–g; General Procedure
A solution of isothiourea 2 (0.278 g, 1.0 mmol) or 3 (0.243 g, 1.2
mmol) in aq Na2CO3 solution (1 M, 1 mL or 1.2 mL, respectively) was
stirred for 30 min at r.t. Next, a solution of enoate 1a–g (1 mmol) in
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GC–MS (EI, 70 eV): m/z (%) = 290 (4.5) [M + 2], 288 (67) [M+], 259 (10),
214 (100), 142 (55).
Ethyl 2-(Benzylthio)-6-(4-fluorophenyl)pyrimidine-4-carboxylate
(5b)
Yield: 235 mg (64%); yellow solid; mp 80–82 °C.
Anal. Calcd for C15H16N2O2S: C, 62.48; H, 5.59; N, 9.71. Found: C,
62.41; H, 5.64; N, 10.19.
1H NMR (200 MHz, CDCl3): δ = 8.17–8.10 (m, 2 H), 8.00 (s, 1 H), 7.55–
7.50 (m, 2 H), 7.31–7.15 (m, 5 H), 4.56–4.46 (m, 4 H), 1.48 (t, J = 8.0
Hz, 3 H).
Ethyl 6-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-4-carboxyl-
ate (4e)
13C NMR (100 MHz, CDCl3): δ = 173.0, 165.0 (d, JC–F = 250.0 Hz),
1
3
Yield: 158 mg (52%); light yellow solid; mp 85–86 °C.
164.9, 164.2, 156.1, 137.5, 131.9, 129.5 (d, JC–F = 10.0 Hz, 2 C), 129.1
(2 C), 128.4 (2 C), 127.2, 116.1 (d, 2JC–F = 20.0 Hz, 2 C), 111.4, 62.5, 35.6,
1H NMR (200 MHz, CDCl3): δ = 8.14 (d, J = 8.0 Hz, 2 H), 7.96 (s, 1 H),
7.00 (d, J = 10.0 Hz, 2 H), 4.48 (q, J = 6.0 Hz, 2 H), 3.88 (s, 3 H), 2.68 (s,
3 H), 1.44 (t, J = 6.0 Hz, 3 H).
14.2.
GC–MS (EI, 70 eV): m/z (%) = 370 (4.5) [M + 2], 368 (92) [M+], 339 (10),
13C NMR (100 MHz, CDCl3): δ = 173.5, 165.2, 164.5, 162.6, 155.8,
294 (100), 146 (28), 91 (53).
129.0 (2 C), 128.2, 114.3 (2 C), 110.5, 62.4, 55.4, 14.3, 14.2.
GC–MS (EI, 70 eV): m/z (%) = 306 (4.5) [M + 2], 304 (65) [M+], 275 (12),
Anal. Calcd for C20H17FN2O2S: C, 65.20; H, 4.65; N, 7.60. Found: C,
65.09; H, 4.58; N, 7.61.
230 (70), 158 (100).
Ethyl 2-(Benzylthio)-6-(4-bromophenyl)pyrimidine-4-carboxylate
(5c)
Anal. Calcd for C15H16N2O3S: C, 59.19; H, 5.30; N, 9.20. Found: C,
59.04; H, 5.34; N, 10.05.
Yield: 381 mg (89%); yellow solid; mp 106–107 °C.
Ethyl 2-(Methylthio)-6-(4-nitrophenyl)pyrimidine-4-carboxylate
(4f)
1H NMR (200 MHz, CDCl3): δ = 8.01–7.96 (m, 3 H), 7.64 (d, J = 10.0 Hz,
2 H), 7.54–7.50 (m, 2 H), 7.36–7.24 (m, 3 H), 4.57–4.46 (m, 4 H), 1.48
(t, J = 8.0 Hz, 3 H).
Yield: 185 mg (58%); yellow solid; mp 137–138 °C.
13C NMR (100 MHz, CDCl3): δ = 173.1, 164.9, 164.2, 156.3, 137.5,
134.6, 132.2 (2 C), 129.1 (2 C), 128.8 (2 C), 128.4 (2 C), 127.2, 126.5,
111.4, 62.5, 35.6, 14.2.
GC–MS (EI, 70 eV): m/z (%) = 430 (69) [M + 2], 428 (71) [M+], 401 (7.6),
399 (7.6), 356 (89), 354 (84), 208 (23), 206 (20), 91 (100).
1H NMR (200 MHz, CDCl3): δ = 8.36–8.35 (m, 4 H), 8.09 (s, 1 H), 4.52
(q, J = 8.0 Hz, 2 H), 2.71 (s, 3 H), 1.47 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.6, 163.9, 163.4, 156.8, 149.7,
141.5, 128.3 (2 C), 124.1 (2 C), 111.8, 62.7, 14.4, 14.1.
GC–MS (EI, 70 eV): m/z (%) = 321 (3.7) [M + 2], 319 (55) [M+], 290 (10),
Anal. Calcd for C20H17BrN2O2S: C, 55.95; H, 3.99; N, 6.52. Found: C,
56.02; H, 4.06; N, 6.55.
245 (100).
Anal. Calcd for C14H13N3O4S: C, 52.66; H, 4.10; N, 13.16. Found: C,
52.81; H, 4.21; N, 13.79.
Ethyl 2-(Benzylthio)-6-(p-tolyl)pyrimidine-4-carboxylate (5d)
Yield: 306 mg (84%); yellow solid; mp 70–72 °C.
Ethyl 6-Methyl-2-(methylthio)pyrimidine-4-carboxylate (4g)
1H NMR (200 MHz, CDCl3): δ = 8.06–8.02 (m, 3 H), 7.53 (d, J = 6.0 Hz, 2
H), 7.33–7.27 (m, 5 H), 4.56–4.45 (m, 4 H), 2.44 (s, 3 H), 1.47 (t, J = 6.0
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.7, 166.0, 164.4, 155.9, 142.3,
137.7, 133.0, 129.7 (2 C), 129.1 (2 C), 128.4 (2 C), 127.3 (2 C), 127.1,
111.5, 62.4, 35.6, 21.5, 14.2.
Yield: 133 mg (63%); light yellow solid; mp 55–57 °C.
1H NMR (200 MHz, CDCl3): δ = 7.46 (s, 1 H), 4.44 (q, J = 8.0 Hz, 2 H),
2.61 (s, 3 H), 2.54 (s, 3 H), 1.42 (t, J = 8.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): δ = 173.3, 169.6, 164.3, 154.9, 115.4, 62.4,
24.3, 14.2 (2 C).
GC–MS (EI, 70 eV): m/z (%) = 214 (3.8) [M + 2], 212 (53) [M+], 183 (12),
166 (35), 138 (100).
GC–MS (EI, 70 eV): m/z (%) = 366 (4.5) [M + 2], 364 (92) [M+], 335 (10),
290 (100), 142 (35), 91 (48).
Anal. Calcd for C9H12N2O2S: C, 50.92; H, 5.70; N, 13.20. Found: C,
50.94; H, 5.98; N, 13.59.
Anal. Calcd for C21H20N2O2S: C, 69.20; H, 5.53; N, 7.69. Found: C,
69.14; H, 5.51; N, 7.54.
Ethyl 2-(Benzylthio)-6-phenylpyrimidine-4-carboxylate (5a)
Ethyl 2-(Benzylthio)-6-(4-methoxyphenyl)pyrimidine-4-carboxyl-
ate (5e)
Yield: 329 mg (94%); yellow solid; mp 71–72 °C.
1H NMR (400 MHz, CDCl3): δ = 8.10–8.08 (m, 2 H), 8.01 (s, 1 H), 7.51–
7.44 (m, 5 H), 7.30–7.26 (m, 2 H), 7.23–7.19 (m, 1 H), 4.52–4.46 (m, 4
H), 1.45 (t, J = 6.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.9, 166.1, 164.3, 156.1, 137.7,
135.8, 131.6, 129.1 (2 C), 129.0 (2 C), 128.4 (2 C), 127.4 (2 C), 127.1,
111.8, 62.4, 35.6, 14.2.
Yield: 235 mg (62%); yellow solid; mp 77–79 °C.
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 8.0 Hz, 2 H), 7.98 (s, 1 H),
7.54 (d, J = 4.0 Hz, 2 H), 7.33–7.23 (m, 3 H), 7.01 (d, J = 8.0 Hz, 2 H),
4.54–4.49 (m, 4 H), 3.89 (s, 3 H), 1.48 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.6, 165.5, 164.5, 162.7, 155.7,
137.8, 129.1 (4 C), 128.4 (2 C), 128.1, 127.1, 114.4 (2 C), 111.0, 62.4,
55.4, 35.5, 14.2.
GC–MS (EI, 70 eV): m/z (%) = 352 (4.5) [M + 2], 350 (92) [M+], 321 (10),
276 (100), 128 (25), 91 (46).
GC–MS (EI, 70 eV): m/z (%) = 382 (4.5) [M + 2], 380 (100) [M+], 351
(12), 306 (69), 158 (97), 91 (41).
Anal. Calcd for C20H18N2O2S: C, 68.55; H, 5.18; N, 7.99. Found: C,
68.95; H, 5.19; N, 7.79.
Anal. Calcd for C21H20N2O3S (380.12): C, 66.29; H, 5.30; N, 7.36.
Found: C, 66.01; H, 5.23; N, 7.08.
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Ethyl 2-(Benzylthio)-6-(4-nitrophenyl)pyrimidine-4-carboxylate
(5f)
1H NMR (400 MHz, DMSO-d6): δ = 8.33–8.29 (m, 2 H), 8.10 (s, 1 H),
7.39–7.35 (m, 2 H), 2.65 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 172.8, 165.5, 164.8 (d, 1JC–F = 250.0
Yield: 371 mg (94%); dark yellow solid; mp 112–114 °C.
Hz), 164.5, 157.8, 132.0, 130.3 (d, 3JC–F = 10.0 Hz, 2 C), 116.5 (d, 2JC–F
=
1H NMR (200 MHz, CDCl3): δ = 8.36 (d, J = 10.0 Hz, 2 H), 8.26 (d, J =
10.0 Hz, 2 H), 8.08 (s, 1 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.37–7.25 (m, 3 H),
4.58–4.48 (m, 4 H), 1.49 (t, J = 8.0 Hz, 3 H).
20.0 Hz, 2 C), 111.5, 14.1.
LC–MS (ESI, 50 eV): m/z = 265 [M + H]+.
13C NMR (100 MHz, CDCl3): δ = 173.6, 163.9, 163.7, 156.7, 149.7,
137.3, 141.5, 129.1 (2 C), 128.5 (2 C), 128.4 (2 C), 127.3, 124.1 (2 C),
112.2, 62.7, 35.7, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C12H10FN2O2S: 265.0447; found:
265.0452.
GC–MS (EI, 70 eV): m/z (%) = 397 (4.5) [M + 2], 395 (87) [M+], 366 (10),
321 (100), 121 (17), 91 (91).
6-(4-Bromophenyl)-2-(methylthio)pyrimidine-4-carboxylic Acid
(6c)
Yield: 272 mg (84%); light yellow solid; mp 170–172 °C.
IR (KBr): 3458, 1752, 1441–1396, 1335–1184, 982–844 cm–1
Anal. Calcd for C20H17N3O4S: C, 60.75; H, 4.33; N, 10.63. Found: C,
60.88; H, 4.47; N, 9.61.
.
1H NMR (400 MHz, DMSO-d6): δ = 8.19 (d, J = 8.0 Hz, 2 H), 8.12 (s, 1
H), 7.75 (d, J = 8.0 Hz, 2 H), 2.65 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 172.9, 165.4, 164.5, 157.9, 134.9,
132.5 (2 C), 129.7 (2 C), 126.1, 111.7, 14.1.
LC–MS (ESI, 50 eV): m/z = 327 [M + H + 2]+, 325 [M + H]+.
Ethyl 2-(Benzylthio)-6-methylpyrimidine-4-carboxylate (5g)
Yield: 222 mg (77%); brown oil.
1H NMR (200 MHz, CDCl3): δ = 7.53–7.48 (m, 3 H), 7.34–7.22 (m, 3 H),
4.51–4.38 (m, 4 H), 2.54 (s, 3 H), 1.44 (t, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.4, 169.7, 164.2, 155.0, 137.8,
129.3 (2 C), 128.3 (2 C), 127.1, 115.7, 62.3, 35.4, 24.2, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C12H10BrN2O2S: 324.9646; found:
324.9647.
GC–MS (EI, 70 eV): m/z (%) = 290 (4.5) [M + 2], 288 (66) [M+], 259
(7.6), 214 (100), 91 (71).
2-(Methylthio)-6-(p-tolyl)pyrimidine-4-carboxylic Acid (6d)
Anal. Calcd for C15H16N2O2S: C, 62.48; H, 5.59; N, 9.71. Found: C,
62.13; H, 5.58; N, 10.34.
Yield: 195 mg (75%); white solid; mp 165–167 °C.
IR (KBr): 3458, 3154, 1752, 1572–1535, 1335–1184, 844–777 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.12 (d, J = 8.0 Hz, 2 H), 8.06 (s, 1
H), 7.36 (d, J = 8.0 Hz, 2 H), 2.65 (s, 3 H), 2.40 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 172.7, 165.5 (2 C), 157.5, 142.4,
2-Methylthio- and 2-Benzylthio-6-substituted-pyrimidine-4-car-
boxylic Acids 6a–e,g and 7a–e,g; General Procedure
A solution of isothiourea 2 (0.278 g, 1.0 mmol) or 3 (0.243 g, 1.2
mmol) in aq Na2CO3 solution (1 M, 1 mL or 1.2 mL, respectively) was
stirred for 30 min at r.t. Next, a solution of enoate 1a–e,g (1 mmol) in
EtOH (5 mL) was added and the mixture was stirred at reflux tem-
perature for 1 h. A solution of NaOH (10%, 5 mL) was added and reflux
was continued for a further 1 h. The mixture was cooled in an ice bath
and concentrated HCl was added until a pH of approximately 3 was
reached. At this pH, compounds 6a–e and 7a–e precipitated and were
isolated by filtration, washed with H2O and hexane, and then dried in
a desiccator. After acidification of the reaction mixture to a pH of ap-
proximately 3, compounds 6g and 7g were isolated by extraction
with CHCl3 (3 × 20 mL), and the combined organic layer was dried
over anhydrous Na2SO4, filtered, and then the solvent evaporated.
132.9, 130.1 (2 C), 127.7 (2 C), 111.3, 21.4, 14.1.
LC–MS (ESI, 50 eV): m/z = 261 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H13N2O2S: 261.0698; found:
261.0697.
6-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-4-carboxylic
Acid (6e)
Yield: 201 mg (73%); light green solid; mp 139–140 °C.
IR (KBr): 3345, 1751, 1457–1389, 1300–1175, 1023–834 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 8.21 (d, J = 8.0 Hz, 2 H), 8.04 (s, 1
H), 7.09 (d, J = 8.0 Hz, 2 H), 3.86 (s, 3 H), 2.64 (s, 3 H).
.
13C NMR (100 MHz, DMSO-d6): δ = 172.5, 165.7, 165.1, 162.8, 157.2,
129.5 (2 C), 127.9, 114.9 (2 C), 110.8, 55.9, 14.1.
LC–MS (ESI, 50 eV): m/z = 277 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H13N2O3S: 277.0647; found:
2-(Methylthio)-6-phenylpyrimidine-4-carboxylic Acid (6a)
Yield: 194 mg (79%); light yellow solid; mp 142–145 °C.
IR (KBr): 3435, 1705, 1458–1394, 1348–1254, 1000–875 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 8.25–8.23 (m, 2 H), 8.12 (s, 1 H),
7.61–7.55 (m, 3 H), 2.67 (s, 3 H).
.
277.0650.
13C NMR (100 MHz, DMSO-d6): δ = 172.8, 165.6, 165.5, 157.7, 135.7,
6-Methyl-2-(methylthio)pyrimidine-4-carboxylic Acid (6g)
132.2, 129.5 (2 C), 127.7 (2 C), 111.7, 14.1.
LC–MS (ESI, 50 eV): m/z = 247 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C12H11N2O2S: 247.0541; found:
247.0542.
Yield: 73 mg (40%); dark yellow solid; mp 150–151 °C.
IR (KBr): 3444, 1730, 1454–1340, 1271–1137, 1072–877 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 7.54 (s, 1 H), 2.56 (s, 3 H), 2.51 (s, 3
H).
.
13C NMR (100 MHz, DMSO-d6): δ = 172.1, 170.3, 165.5, 156.1, 115.9,
24.1, 13.9.
LC–MS (ESI, 50 eV): m/z = 185 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C7H9N2O2S: 185.0385; found:
6-(4-Fluorophenyl)-2-(methylthio)pyrimidine-4-carboxylic Acid
(6b)
Yield: 211 mg (80%); light yellow solid; mp 145–147 °C.
IR (KBr): 3241, 1760, 1452–1391, 1323–1212, 1012–911 cm–1
.
185.0380.
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2-(Benzylthio)-6-phenylpyrimidine-4-carboxylic Acid (7a)
2-(Benzylthio)-6-(4-methoxyphenyl)pyrimidine-4-carboxylicAcid
(7e)
Yield: 241 mg (75%); light red solid; mp 141 °C.
Yield: 179 mg (71%); light beige solid; mp 104–106 °C.
IR (KBr): 1722–1699, 1567–1532, 1337–1256 cm–1
.
IR (KBr): 3275, 1773, 1450–1395, 1306–1256 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.22 (d, J = 8.0 Hz, 2 H), 8.13 (s, 1
H), 7.61–7.52 (m, 5 H), 7.34–7.30 (m, 2 H), 7.26–7.23 (m, 1 H), 4.57 (s,
2 H).
13C NMR (100 MHz, DMSO-d6): δ = 171.9, 165.8, 165.5, 158.0, 138.3,
135.6, 132.2, 129.5 (2 C), 129.4 (2 C), 128.8 (2 C), 127.8 (2 C), 127.5,
112.1, 35.0.
1H NMR (400 MHz, DMSO-d6): δ = 8.19 (d, J = 6.0 Hz, 2 H), 8.05 (s, 1
H), 7.51 (d, J = 8.0 Hz, 2 H), 7.31 (t, J = 8.0 Hz, 2 H), 7.23 (t, J = 8.0 Hz, 1
H), 7.08 (d, J = 8.0 Hz, 2 H), 4.54 (s, 2 H), 3.85 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 171.7, 165.6, 165.4, 162.9, 157.4,
138.4, 129.6 (2 C), 129.3 (2 C), 128.8 (2 C), 127.9, 127.5, 115.0 (2 C),
111.3, 55.9, 34.9.
LC–MS (ESI, 50 eV): m/z = 323 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H15N2O2S: 323.0854; found:
LC–MS (ESI, 50 eV): m/z = 353 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2O3S: 353.0960; found:
323.0858.
353.0961.
2-(Benzylthio)-6-(4-fluorophenyl)pyrimidine-4-carboxylic Acid
(7b)
2-(Benzylthio)-6-methylpyrimidine-4-carboxylic Acid (7g)
Yield: 272 mg (80%); light brown solid; mp 157–160 °C.
Yield: 91 mg (35%); dark brown solid; mp 104–106 °C.
IR (KBr): 3338, 1774, 1450–1389, 1300–1232, 924–848 cm–1
.
IR (KBr): 3445, 1730, 1454–1340, 1271–1244, 922–877 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.16–8.13 (m, 2 H), 8.09 (s, 1 H),
7.46 (d, J = 8.0 Hz, 2 H), 7.35–7.31 (m, 2 H), 7.28–7.25 (m, 1 H), 7.22–
7.17 (m, 2 H), 4.51 (s, 2 H).
1H NMR (400 MHz, DMSO-d6): δ = 7.56 (s, 1 H), 7.48 (d, J = 8.0 Hz, 2
H), 7.29 (t, J = 8.0 Hz, 2 H), 7.22 (t, J = 8.0 Hz, 1 H), 4.44 (s, 2 H), 2.51 (s,
3 H).
1
13C NMR (50 MHz, DMSO-d6): δ = 171.8, 165.5, 164.8 (d, JC–F = 245.0
13C NMR (100 MHz, DMSO-d6): δ = 171.2, 170.6, 165.5, 156.1, 138.4,
129.5 (2 C), 128.7 (2 C), 127.5, 116.3, 34.7, 24.1.
LC–MS (ESI, 50 eV): m/z = 261 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H13N2O2S: 261.0698; found:
Hz), 164.7, 157.8, 138.2, 132.0 (d, 4JC–F = 5.0 Hz), 130.4 (d, JC–F = 10.0
3
Hz, 2 C), 129.4 (2 C), 128.9 (2 C), 127.6, 116.5 (d, 2JC–F = 25.0 Hz, 2 C),
112.0, 34.9.
LC–MS (ESI, 50 eV): m/z = 341 [M + H]+.
261.0698.
HRMS (ESI): m/z [M + H]+ calcd for C18H14FN2O2S: 341.0760; found:
341.0764.
Acknowledgment
2-(Benzylthio)-6-(4-bromophenyl)pyrimidine-4-carboxylic Acid
(7c)
The authors are grateful for the financial support from the Fundação
de Apoio à Tecnologia e Ciência do Estado do Rio Grande do Sul
(FAPERGS, PqG 11/1608-8) and Conselho Nacional de Desenvolvimen-
to Científico e Tecnológico (CNPq – Universal grant No. 476341/2013-
2), and for the fellowships from CAPES (A.S.F. and M.A.M.), CNPq
(C.E.B. and C.A.F.) and FAPERGS (A.F.C.).
Yield: 332 mg (83%); light brown solid; mp 125–127 °C.
IR (KBr): 3299, 1773, 1444–1342, 1305–1236, 1007–886 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.16 (d, J = 8.0 Hz, 2 H), 8.14 (s, 1
H), 7.74 (d, J = 8.0 Hz, 2 H), 7.52 (d, J = 8.0 Hz, 2 H), 7.32 (t, J = 8.0 Hz, 2
H), 7.24 (t, J = 8.0 Hz, 1 H), 4.55 (s, 2 H).
13C NMR (50 MHz, DMSO-d6): δ = 172.4, 165.8, 165.1, 158.2, 138.6,
135.1, 132.9 (2 C), 130.2 (2 C), 129.8 (2 C), 129.3 (2 C), 128.0, 126.6,
112.6, 35.3.
LC–MS (ESI, 50 eV): m/z = 403 [M + H + 2]+, 401 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H14BrN2O2S: 400.9959; found:
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 827–835

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