Expedient microwave-assisted synthesis of 5-benzoylamino-2- (aralkylsulfanyl)pyrimidin-4(3 H)-ones

Article abstract of DOI:10.1055/s-0029-1218841

A rapid and efficient microwave-assisted synthesis of novel 5-benzoylamino-2-(aralkylsulfanyl)pyrimidin-4(3H)-ones by rearrangement of 4-(1-ethoxyalkylidene)-2-phenyloxazol-5(4H)-ones in the presence of S-aralkyl-substituted isothiouronium halides and triethylamine is reported. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218841

PAPER
2583
Expedient Microwave-Assisted Synthesis of
5-Benzoylamino-2-(aralkylsulfanyl)pyrimidin-4(3H)-ones
5
-Benzoylami
i
n
r
alkylsulfany
n
l)pyrimidin-4(3
H
)
K
-ones . Hansen, Detlef Geffken*
Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany
Fax +49(40)428386573; E-mail: geffken@chemie.uni-hamburg.de
Received 18 February 2010; revised 12 April 2010
Azlactones represent versatile building blocks for the syn-
thesis of a great variety of multifunctional compounds.5
Among the numerous different azlactones, 4-(ethoxymeth-
ylidene)-2-phenyl-1,3-oxazol-5(4H)-one (1a) deserves
particular interest as an intermediate in organic chemistry
because of its ambivalent behavior towards nucleophiles.5
Abstract: A rapid and efficient microwave-assisted synthesis of
novel 5-benzoylamino-2-(aralkylsulfanyl)pyrimidin-4(3H)-ones by
rearrangement of 4-(1-ethoxyalkylidene)-2-phenyloxazol-5(4H)-
ones in the presence of S-aralkyl-substituted isothiouronium halides
and triethylamine is reported
Key words: microwave-assisted synthesis, azlactones, ring expan-
sion, rearrangement, 2-(aralkylsulfanyl)pyrimidin-4(3H)-ones
For example, the reaction of 1a with benzylisothiouroni-
um chloride (2a) in the presence of triethylamine has been
reported to produce N-[2-(benzylsulfanyl)-6-oxo-1,6-di-
hydropyrimidin-5-yl]benzamide (3a) in 74% yield, al-
though the assigned structural conformation of 3a was
only based on IR spectroscopy and microanalysis.6
Polyfunctional pyrimidines play an important role in me-
dicinal chemistry because of their different biological
properties,1–3 and various synthetic methods have been
developed.4 For instance, trimethoprim (I) and py-
rimethamine (II) act as dihydrofolate reductase inhibitors
and are valuable for antibacterial and antimalarial therapy
(Figure 1). Barbiturates are well known as sedative, hyp-
notic, anxiolytic and anticonvulsant drugs with phenobar-
bital (III) being still the most widely used antiepileptic
drug (AED) in the developing world and remaining a pop-
ular choice in many industrialized countries.1 Dihydro-
alkyloxy-benzyl-oxopyrimidines (DABOs) have been
characterized as strongly active nonnucleoside reverse
transcriptase inhibitors (NNRTIs),2 which, on structural
modification, delivered S-DABO compounds (IV) as ex-
cellent anti-HIV agents with low cytotoxicity.3
During our studies on polyfunctional pyrimidines, we be-
came interested in the transformation of 1a into 3a and de-
veloped an efficient microwave-assisted protocol for the
targeted 5-benzoylamino-2-(aralkylsulfanyl)pyrimidin-
4(3H)-one derivatives 3, 4, and 5. After conducting the re-
action of 1a with benzylisothiouronium chloride accord-
ing to literature6 several times, we found that the reported
yield (74%) could not be reproduced.
Due to higher efficiency, microwave-assisted reactions
may offer a considerable advantage over conventional re-
action conditions.7 We therefore tried to optimize the for-
mation of 3a by means of microwave irradiation by
monitoring the reaction using IR spectroscopy and TLC
whilst varying the temperature and power. Best results
(67% yield within five minutes) were achieved at high
temperatures (see experimental). Moreover, 3a was ob-
tained in a pure crystalline state that was suitable for X-
ray analysis by crystallization from methanol; this al-
lowed the structure of 3a to be proved unambiguously
(Figure 2).8
Cl
OMe
N
N
H2N
N
NH2
OMe
OMe
H2N
N
NH2
trimethoprim (I)
pyrimethamine (II)
By applying this method to the reaction of 1a with the S-
aralkyl-substituted isothiouronium halides 2b–g, a set of
novel benzoylamino-2-(aralkylsulfanyl)pyrimidin-4(3H)-
R4
R3
R2
O
O
N
HN
S
N
R1
H
O
N
O
H
phenobarbital (III)
S-DABOs (IV)
Figure 1 Selected biologically active polyfunctional pyrimidines
SYNTHESIS 2010, No. 15, pp 2583–2587
x
x.
x
x
.
2
0
1
0
Advanced online publication: 29.06.2010
DOI: 10.1055/s-0029-1218841; Art ID: T04210SS
© Georg Thieme Verlag Stuttgart · New York
Figure 2 X-ray crystal structure of compound 3a (illustrated as a
dimer)

2584
F. K. Hansen, D. Geffken
PAPER
R1
Table 1 Synthesis of 5-Benzoylamino-2-(aralkylsulfanyl)pyrimi-
din-4(3H)-ones 3–5a
EtO
R1
H
N
NH
Ph
Et3N
O
R2
⋅HX
N
Product R1
R2
Hold time (min) Yield (%)
N
EtOH
microwaves
S
NH2
R2
O
O
S
N
H
O
3a
3b
3c
3d
3e
3f
H
Bn
5
5
67
70
64
69
66
65
73
48
45
55
52
56
60
70
52
60
60
69
67
Ph
1a: R1 = H
1b: R1 = Me
1c: R1 = Et
3: R1 = H
2: X = Cl, Br
H
4-FC6H4CH2
2-ClC6H4CH2
3-ClC6H4CH2
4-ClC6H4CH2
4-BrC6H4CH2
4-MeC6H4CH2
Bn
4: R1 = Me
5: R1 = Et
H
5
Scheme 1 Synthesis of 5-benzoylamino-2-(aralkylsulfanyl)pyrimi-
din-4(3H)-ones 3–5
H
5
H
5
ones 3b–g could be prepared in 64–73% yield (Scheme 1,
Table 1).
H
5
3g
4a
4b
4c
4d
4e
4f
H
5
Analogously, the easily available 4-(1-ethoxyalkylidene)-
2-phenyloxazol-5(4H)-ones 1b and 1c furnished the de-
sired 6-methyl-substituted 5-benzoylamino-2-(aralkylsul-
fanyl)pyrimidin-4(3H)-ones 4a–g in 45–70% yield and
the 6-ethyl-substituted 5-benzoylamino-2-(aralkylsulfa-
nyl)pyrimidin-4(3H)-ones 5a–e in 52–69% yield within
only 5–10 minutes (Scheme 1, Table 1). Again, the reac-
tion was monitored by IR spectroscopy and by TLC.
Me
Me
Me
Me
Me
Me
Me
Et
10
10
10
5
4-FC6H4CH2
2-ClC6H4CH2
3-ClC6H4CH2
4-ClC6H4CH2
4-BrC6H4CH2
4-MeC6H4CH2
Bn
10
5
Structure determination of all synthesized compounds
was based on IR, 1H, and 13C NMR spectroscopic data and
on elemental analysis.
4g
5a
5b
5c
5d
5e
10
10
5
In conclusion, an efficient microwave-assisted synthetic
method for 5-benzoylamino-2-(aralkylsulfanyl)pyrimi-
din-4(3H)-one derivatives 3–5 from 4-(1-ethoxyalkyl-
idene)-2-phenyl-1,3-oxazol-5(4H)-ones 1 and S-aralkyl-
substituted isothiouronium halides 2, has been elaborated.
Et
4-FC6H4CH2
3-ClC6H4CH2
4-BrC6H4CH2
4-MeC6H4CH2
Et
10
5
Et
Melting points (uncorrected) were determined with an Electrother-
mal 9100 apparatus. Elemental analyses were carried out with a
Heraeus CHN-O-Rapid instrument. IR spectra were recorded with
a Varian 800 FT-IR. 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded with a Bruker AMX 400 spectrometer using
tetramethylsilane as internal standard and DMSO-d6 as solvent. X-
ray crystal analysis was performed with a Bruker Smart APEX
CCD diffractometer with Mo Ka-radiation at 100 K. 4-(Ethoxy-
methylidene)-2-phenyl-1,3-oxazol-5(4H)-one (1a) was purchased
from Acros Organics. 4-(1-Ethoxyethylidene)-2-phenyl-1,3-ox-
azol-5(4H)-one9 (1b) and 4-(1-ethoxypropylidene)-2-phenyl-1,3-
oxazol-5(4H)-one10 (1c) were prepared according to the literature.
S-Benzylisothiouronium chloride (2a), S-(4-fluorobenzyl)isothio-
uronium bromide (2b), S-(2-chlorobenzyl)isothiouronium chloride
(2c), S-(3-chloro)benzylisothiouronium chloride (2d), S-(4-chlo-
robenzyl)isothiouronium chloride (2e), S-(4-bromobenzyl)isothio-
uronium bromide (2f) and S-(4-methylbenzyl)isothiouronium
bromide (2g) were prepared from thiourea and the respective
aralkyl halide according to literature procedures.11 Microwave-
assisted syntheses of compounds 3–5 were carried out with a CEM
Focused Microwave System, Model Discover.
Et
5
a Microwave-assisted synthesis of compounds 3–5 was carried out us-
ing a CEM Corporation Focused Microwave System, Model Discov-
er. Parameters for compounds 3–5: Discover mode; power: 150 W;
ramp time: 0.5 min; temperature: 100 °C; pressure: 10 bar; Power-
Max-cooling.
as indicated in Table 1; temperature: 100 °C; pressure: 10 bar;
PowerMax-cooling mode). The reaction mixture was allowed to
cool to r.t. and transferred to a round-bottomed flask. The solvent
was evaporated, EtOH–H2O (1:1, 10 mL) was added, and the pre-
cipitate was collected. Recrystallization from MeOH furnished an-
alytically pure products.
Compounds 4; Procedure B
4-(1-Ethoxyethylidene)-2-phenyl-1,3-oxazol-5(4H)-one (1b; 463
mg, 2 mmol), the respective S-aralkyl-substituted isothiouronium
halogenide 2 (2 mmol), Et3N (400 mg, 4 mmol) and EtOH (5 mL)
were reacted according to Procedure A. After completion, the sol-
vent was evaporated, EtOH–H2O (1:1, 15 mL) was added, and the
precipitate was collected. Recrystallization from MeOH furnished
analytically pure products.
Preparation of 3, 4 and 5; General Procedures
Compounds 3; Procedure A
4-(Ethoxymethylidene)-2-phenyl-1,3-oxazol-5(4H)-one (1a; 217
mg, 1 mmol), the respective S-aralkyl-substituted isothiouronium
halogenide 2 (1 mmol), Et3N (200 mg, 2 mmol) and EtOH (5 mL)
were added into a 10 mL glass pressure microwave tube equipped
with a magnetic stirrer bar. The tube was closed with a silicon sep-
tum and the reaction mixture was subjected to microwave irradia-
tion (Discover mode; power: 150 W; ramp time: 30 sec.; hold time
Compounds 5; Procedure C
4-(1-Ethoxypropylidene)-2-phenyl-1,3-oxazol-5(4H)-one (1c; 245
mg, 1 mmol), the respective S-aralkyl-substituted isothiouronium
halogenide 2 (1 mmol), Et3N (200 mg, 2 mmol) and EtOH (5 mL)
were reacted according to Procedure A. After completion, the sol-
vent was evaporated, EtOH–H2O (1:1, 10 mL) was added, and the
Synthesis 2010, No. 15, 2583–2587 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-Benzoylamino-2-(aralkylsulfanyl)pyrimidin-4(3H)-ones
2585
precipitate was collected. Recrystallization from MeOH furnished
analytically pure products.
13C NMR (DMSO-d6): d = 32.8, 127.3, 128.3, 128.5, 130.8, 131.9,
131.9, 133.5, 136.4, 154.8, 158.9, 165.1.
Anal. Calcd for C18H14ClN3O2S: C, 58.14; H, 3.79; N, 11.30; S,
8.62. Found: C, 58.01; H, 3.78; N, 11.25; S, 8.88.
N-[2-(Benzylsulfanyl)-6-oxo-1,6-dihydropyrimidin-5-yl]benz-
amide (3a)
Yield: 227 mg (67%); colorless solid; mp 254 °C (Lit.6 251–
253 °C).
N-{2-[(4-Bromobenzyl)sulfanyl]-6-oxo-1,6-dihydropyrimidin-
5-yl}benzamide (3f)
Yield: 271 mg (65%); colorless solid; mp 260 °C.
IR (KBr): 3368, 1671, 1638 cm–1.
1H NMR (DMSO-d6): d = 4.44 (s, 2 H, ArCH2), 7.24–7.64 (m, 8 H,
ArH), 7.94 (d, J = 7.3 Hz, 2 H, ArH), 8.55 (s, 1 H, ArH), 9.32 (br s,
1 H, NH), 13.25 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 32.7, 127.3, 127.4, 128.4, 128.5, 129.0,
131.9, 133.4, 137.0, 165.1.
IR (KBr): 3365, 1676, 1645 cm–1.
1H NMR (DMSO-d6): d = 4.41 (s, 2 H, ArCH2), 7.35–7.99 (m, 9 H,
ArH), 8.55 (s, 1 H, ArH), 9.30 (br s, 1 H, NH), 13.25 (br s, 1 H,
NH).
13C NMR (DMSO-d6): d = 32.9, 120.4, 127.3, 128.5, 131.1, 131.2,
131.9, 133.5, 136.8, 165.1.
Anal. Calcd for C18H15N3O2S: C, 64.08; H, 4.48; N, 12.45; S, 9.50.
Found: C, 63.97; H, 4.56; N, 12.37; S, 9.67.
Anal. Calcd for C18H14BrN3O2S: C, 51.93; H, 3.39; N, 10.09; S,
7.70. Found: C, 51.91; H, 3.44; N, 10.12; S, 7.81.
N-{2-[(4-Fluorobenzyl)sulfanyl]-6-oxo-1,6-dihydropyrimidin-
5-yl}benzamide (3b)
Yield: 250 mg (70%); colorless solid; mp 264 °C.
IR (KBr): 3369, 1674, 1643 cm–1.
N-{2-[(4-Methylbenzyl)sulfanyl]-6-oxo-1,6-dihydropyrimidin-
5-yl}benzamide (3g)
Yield: 257 mg (73%); colorless solid; mp 260 °C.
1H NMR (DMSO-d6): d = 4.43 (s, 2 H, ArCH2), 7.11–7.99 (m, 9 H,
ArH), 8.57 (s, 1 H, ArH), 9.30 (br s, 1 H, NH), 13.19 (br s, 1 H,
NH).
IR (KBr): 3363, 1642 cm–1.
1H NMR (DMSO-d6): d = 2.27 (s, 3 H, CH3), 4.39 (s, 2 H, ArCH2),
7.13 (d, J = 7.8 Hz, 2 H, ArH), 7.31 (d, J = 8.1 Hz, 2 H, ArH), 7.45–
7.66 (m, 3 H, ArH), 7.88–8.01 (m, 2 H, ArH), 8.56 (s, 1 H, ArH),
9.28 (br s, 1 H, NH), 13.21 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 20.6, 33.5, 127.4, 128.5, 128.9, 129.0,
131.9, 133.5, 133.8, 136.5, 165.1.
13C NMR (DMSO-d6): d = 32.9, 115.2 (d, 2JC–F = 20.8 Hz), 127.4,
3
4
128.5, 131.0 (d, JC–F = 8.5 Hz), 131.9, 133.4 (d, JC–F = 3.1 Hz),
133.5, 161.3 (d, 1JC–F = 243.5 Hz), 165.1.
Anal. Calcd for C18H14FN3O2S: C, 60.83; H, 3.97; N, 11.82; S, 9.02.
Found: C, 60.77; H, 4.22; N, 11.76; S, 9.12.
Anal. Calcd for C19H17N3O2S: C, 64.94; H, 4.88; N, 11.96; S, 9.12.
Found: C, 64.84; H, 4.83; N, 11.92; S, 9.06.
N-{2-[(2-Chlorobenzyl)sulfanyl]-6-oxo-1,6-dihydropyrimidin-
5-yl}benzamide (3c)
Yield: 237 mg (64%); colorless solid; mp 244 °C.
IR (KBr): 3368, 1670, 1639 cm–1.
N-[2-(Benzylsulfanyl)-4-methyl-6-oxo-1,6-dihydropyrimidin-5-
yl]benzamide (4a)
Yield: 338 mg (48%); colorless solid; mp 264 °C.
1H NMR (DMSO-d6): d = 4.53 (s, 2 H, ArCH2), 7.27–8.00 (m, 9 H,
ArH), 8.58 (s, 1 H, ArH), 9.30 (br s, 1 H, NH), 13.27 (br s, 1 H,
NH).
13C NMR (DMSO-d6): d = 31.8, 127.3, 127.4, 128.5, 129.4, 129.4,
131.4, 131.9, 133.3, 133.5, 134.4, 165.1.
IR (KBr): 3270, 1665, 1640 cm–1.
1H NMR (DMSO-d6): d = 2.18 (s, 3 H, CH3), 4.42 (s, 2 H, ArCH2),
7.22–7.63 (m, 8 H, ArH), 7.97 (d, J = 7.3 Hz, 2 H, ArH), 9.60 (br s,
1 H, NH), 12.93 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 20.4, 33.7, 127.2, 127.6, 128.3, 128.3,
129.0, 131.6, 133.7, 137.3, 165.2.
Anal. Calcd for C18H14ClN3O2S: C, 58.14; H, 3.79; N, 11.30; S,
8.62. Found: C, 57.99; H, 3.91; N, 11.22; S, 8.60.
Anal. Calcd for C19H17N3O2S: C, 64.94; H, 4.88; N, 11.96; S, 9.12.
Found: C, 64.87; H, 5.09; N, 11.99; S, 9.28.
N-{2-[(3-Chlorobenzyl)sulfanyl]-6-oxo-1,6-dihydropyrimidin-
5-yl}benzamide (3d)
Yield: 258 mg (69%); colorless solid; mp 237 °C.
IR (KBr): 3406, 1685, 1647 cm–1.
N-{2-[(4-Fluorobenzyl)sulfanyl]-4-methyl-6-oxo-1,6-dihydro-
pyrimidin-5-yl}benzamide (4b)
Yield: 332 mg (45%); colorless solid; mp 286 °C.
1H NMR (DMSO-d6): d = 4.44 (s, 2 H, ArCH2), 7.31–7.96 (m, 9 H,
ArH), 8.56 (s, 1 H, ArH), 9.30 (br s, 1 H, NH), 13.24 (br s, 1 H,
NH).
13C NMR (DMSO-d6): d = 32.9, 127.2, 127.4, 127.7, 128.5, 128.7,
130.2, 131.9, 132.8, 133.6, 139.9, 165.1.
IR (KBr): 3269, 1665, 1638 cm–1.
1H NMR (DMSO-d6): d = 2.18 (s, 3 H, CH3), 4.41 (s, 2 H, ArCH2),
7.08–7.20 (m, 2 H, ArH), 7.45–7.63 (m, 5 H, ArH), 7.97 (d,
J = 7.3 Hz, 2 H, ArH), 9.58 (br s, 1 H, NH), 12.92 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 20.4, 32.8, 115.1 (d, JC–F = 21.1 Hz),
2
Anal. Calcd for C18H14ClN3O2S: C, 58.14; H, 3.79; N, 11.30; S,
8.62. Found: C, 57.98; H, 3.86; N, 11.21; S, 8.60.
127.6, 128.3, 131.1 (d, 3JC–F = 8.3 Hz), 131.6, 133.7, 161.3 (d, 1JC–
F = 243.8 Hz), 165.2.
Anal. Calcd for C19H16FN3O2S: C, 61.78; H, 4.37; N, 11.37; S, 8.68.
Found: C, 61.92; H, 4.48; N, 11.38; S, 8.28.
N-{2-[(4-Chlorobenzyl)sulfanyl]-6-oxo-1,6-dihydropyrimidin-
5-yl}benzamide (3e)
Yield: 245 mg (66%); colorless solid; mp 265 °C.
IR (KBr): 3367, 1676, 1645 cm–1.
N-{2-[(2-Chlorbenzyl)sulfanyl]-4-methyl-6-oxo-1,6-dihydropy-
rimidin-5-yl}benzamide (4c)
Yield: 425 mg (55%); colorless solid; mp 272 °C.
IR (KBr): 3259, 1670, 1638 cm–1.
1H NMR (DMSO-d6): d = 4.43 (s, 2 H, ArCH2), 7.35–7.98 (m, 9 H,
ArH), 8.56 (s, 1 H, ArH), 9.30 (br s, 1 H, NH), 13.23 (br s, 1 H,
NH).
Synthesis 2010, No. 15, 2583–2587 © Thieme Stuttgart · New York

2586
F. K. Hansen, D. Geffken
PAPER
1H NMR (DMSO-d6): d = 2.20 (s, 3 H, CH3), 4.52 (s, 2 H, ArCH2),
7.28–7.70 (m, 7 H, ArH), 7.97 (d, J = 7.3 Hz, 2 H, ArH), 9.61 (br s,
1 H, NH), 12.96 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 20.3, 31.8, 127.2, 127.6, 128.3, 129.4,
131.5, 133.3, 133.7, 134.7, 165.2.
IR (KBr): 3453, 3280, 1667, 1642 cm–1.
1H NMR (DMSO-d6): d = 1.15 (t, J = 7.6 Hz, 3 H, CH2CH3), 2.43–
2.56 (m, 2 H, CH2CH3, overlapping with solvent signal), 4.45 (s,
2 H, ArCH2), 7.22–7.62 (m, 8 H, ArH), 7.96 (d, J = 7.3 Hz, 2 H,
ArH), 9.52 (s, 1 H, NH), 12.91 (br s, 1 H, NH).
Anal. Calcd for C19H16ClN3O2S: C, 59.14; H, 4.18; N, 10.89; S,
8.31. Found: C, 59.09; H, 4.32; N, 10.84; S, 8.07.
13C NMR (DMSO-d6): d = 11.5, 26.0, 33.7, 127.2, 127.5, 128.3,
128.3, 128.9, 131.5, 133.8, 137.5, 165.6.
Anal. Calcd for C20H19N3O2S: C, 65.73; H, 5.24; N, 11.50; S, 8.77.
Found: C, 65.46; H, 5.27; N, 11.40; S, 9.06.
N-{2-[(3-Chlorobenzyl)sulfanyl]-4-methyl-6-oxo-1,6-dihydro-
pyrimidin-5-yl}benzamide (4d)
Yield: 402 mg (52%); colorless solid; mp 256 °C.
IR (KBr): 3269, 1665, 1638 cm–1.
N-{4-Ethyl-2-[(4-fluorobenzyl)sulfanyl]-6-oxo-1,6-dihydropyri-
midin-5-yl}benzamide (5b)
Yield: 231 mg (60%); colorless solid; mp 247 °C.
IR (KBr): 3277, 1670, 1642 cm–1.
1H NMR (DMSO-d6): d = 1.15 (t, J = 7.6 Hz, 3 H, CH2CH3), 2.43–
2.54 (m, 2 H, CH2CH3, overlapping with solvent signal), 4.44 (s,
2 H, ArCH2), 7.16 (t, J = 8.7 Hz, 2 H, ArH), 7.46–7.62 (m, 5 H,
ArH), 7.97 (d, J = 7.3 Hz, 2 H, ArH), 9.54 (br s, 1 H, NH), 12.93 (br
s, 1 H, NH).
1H NMR (DMSO-d6): d = 2.18 (s, 3 H, CH3), 4.41 (s, 2 H, ArCH2),
7.29–7.63 (m, 7 H, ArH), 7.97 (d, J = 7.6 Hz, 2 H, ArH), 9.59 (br s,
1 H, NH), 12.96 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 20.3, 33.0, 127.1, 127.6, 127.8, 128.3,
129.0, 130.1, 131.5, 132.7, 133.7, 140.2, 165.2.
Anal. Calcd for C19H16ClN3O2S: C, 59.14; H, 4.18; N, 10.89; S,
8.31. Found: C, 59.15; H, 4.24; N, 10.86; S, 7.94.
13C NMR (DMSO-d6): d = 11.6, 26.0, 32.8, 115.1 (d, JC–
2
N-{2-[(4-Chlorobenzyl)sulfanyl]-4-methyl-6-oxo-1,6-dihydro-
pyrimidin-5-yl}benzamide (4e)
F = 21.1 Hz), 127.6, 128.3, 130.9 (d, 3JC–F = 8.3 Hz), 131.6, 133.7,
133.8, 161.3 (d, 1JC–F = 243.8 Hz), 165.6.
Yield: 433 mg (56%); colorless solid; mp 287 °C.
IR (KBr): 3323, 3263, 1664, 1638 cm–1.
Anal. Calcd for C20H18FN3O2S: C, 62.65; H, 4.73; N, 10.96; S, 8.36.
Found: C, 62.36; H, 4.72; N, 10.87; S, 8.17.
1H NMR (DMSO-d6): d = 2.17 (s, 3 H, CH3), 4.41 (s, 2 H, ArCH2),
7.35–7.62 (m, 7 H, ArH), 7.97 (d, J = 7.3 Hz, 2 H, ArH), 9.58 (br s,
1 H, NH), 12.93 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 20.4, 32.9, 127.6, 128.3, 130.9, 131.5,
131.8, 133.7, 136.7, 165.2.
N-{2-[(3-Chlorobenzyl)sulfanyl]-4-ethyl-6-oxo-1,6-dihydropy-
rimidin-5-yl}benzamide (5c)
Yield: 239 mg (60%); colorless solid; mp 242 °C.
IR (KBr): 3269, 1671, 1643 cm–1.
1H NMR (DMSO-d6): d = 1.15 (t, J = 7.6 Hz, 3 H, CH2CH3), 2.43–
2.53 (m, 2 H, CH2CH3, overlapping with solvent signal), 4.43 (s,
2 H, ArCH2), 7.30–7.62 (m, 7 H, ArH), 7.96 (d, J = 7.6 Hz, 2 H,
ArH), 9.54 (br s, 1 H, NH), 12.96 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 11.5, 26.0, 32.9, 127.1, 127.5, 128.3,
128.8, 130.1, 131.5, 132.7, 133.7, 140.5, 165.6.
Anal. Calcd for C19H16ClN3O2S: C, 59.14; H, 4.18; N, 10.89; S,
8.31. Found: C, 59.11; H, 4.31; N, 10.83; S, 8.07.
N-{2-[(4-Bromobenzyl)sulfanyl]-4-methyl-6-oxo-1,6-dihydro-
pyrimidin-5-yl}benzamide (4f)
Yield: 516 mg (60%); colorless solid; mp 286 °C.
IR (KBr): 3327, 3264, 1664, 1638 cm–1.
Anal. Calcd for C20H18ClN3O2S: C, 60.07; H, 4.54; N, 10.51; S,
8.02. Found: C, 59.93; H, 4.48; N, 10.35; S, 7.78.
1H NMR (DMSO-d6): d = 2.17 (br s, 3 H, CH3), 4.39 (s, 2 H,
ArCH2), 7.36–7.64 (m, 7 H, ArH), 7.97 (d, J = 7.1 Hz, 2 H, ArH),
9.57 (br s, 1 H, NH), 12.92 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 20.4, 32.9, 120.3, 127.6, 128.3, 131.2,
131.3, 131.5, 133.7, 137.1, 165.2.
N-{2-[(4-Bromobenzyl)sulfanyl]-4-ethyl-6-oxo-1,6-dihydropy-
rimidin-5-yl}benzamide (5d)
Yield: 307 mg (69%); colorless solid; mp 264 °C.
IR (KBr): 3445, 3273, 1674, 1641 cm–1.
1H NMR (DMSO-d6): d = 1.14 (t, J = 7.5 Hz, 3 H, CH2CH3), 2.42–
2.54 (m, 2 H, CH2CH3, overlapping with solvent signal), 4.42 (s,
2 H, ArCH2), 7.38–7.62 (m, 7 H, ArH), 7.96 (d, J = 7.3 Hz, 2 H,
ArH), 9.53 (br s, 1 H, NH), 12.93 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 11.5, 26.0, 32.9, 120.2, 127.6, 128.3,
131.1, 131.2, 131.5, 133.8, 137.3, 165.6.
Anal. Calcd for C19H16BrN3O2S: C, 53.03; H, 3.75; N, 9.76; S, 7.45.
Found: C, 53.01; H, 3.87; N, 9.73; S, 7.14.
N-{4-Methyl-2-[(4-methylbenzyl)sulfanyl]-6-oxo-1,6-dihydro-
pyrimidin-5-yl}benzamide (4g)
Yield: 512 mg (70%); colorless solid; mp 274 °C.
IR (KBr): 3268, 1671, 1643 cm–1.
Anal. Calcd for C20H18BrN3O2S: C, 54.06; H, 4.08; N, 9.46; S, 7.22.
Found: C, 54.33; H, 4.07; N, 9.44; S, 7.13.
1H NMR (DMSO-d6): d = 2.17 (s, 3 H, CH3), 2.28 (s, 3 H, CH3),
4.38 (s, 2 H, ArCH2), 7.13 (m, J = 7.8 Hz, 2 H, ArH), 7.33 (m,
J = 7.8 Hz, 2 H, ArH), 7.45–7.64 (m, 3 H, ArH), 7.97 (d,
J = 7.6 Hz, 2 H, ArH), 9.58 (br s, 1 H, NH), 12.89 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 20.4, 20.6, 33.6, 127.6, 128.3, 128.9,
129.0, 131.5, 133.8, 134.1, 136.4, 165.2.
N-{4-Ethyl-2-[(4-methylbenzyl)sulfanyl]-6-oxo-1,6-dihydropy-
rimidin-5-yl}benzamide (5e)
Yield: 255 mg (67%); colorless solid; mp 249 °C.
IR (KBr): 3300, 1665, 1639 cm–1.
1H NMR (DMSO-d6): d = 1.16 (t, J = 7.5 Hz, 3 H, CH2CH3), 2.28
(s, 3 H, CH3), 2.43–2.53 (m, 2 H, CH2CH3, overlapping with sol-
vent signal), 4.40 (s, 2 H, ArCH2), 7.13 (m, J = 7.8 Hz, 2 H, ArH),
7.33 (m, J = 7.8 Hz, 2 H, ArH), 7.47–7.62 (m, 3 H, ArH), 7.96 (d,
J = 7.5 Hz, 2 H, ArH), 9.53 (br s, 1 H, NH), 12.88 (br s, 1 H, NH).
Anal. Calcd for C20H19N3O2S: C, 65.73; H, 5.24; N, 11.50; S, 8.77.
Found: C, 65.68; H, 5.23; N, 11.46; S, 8.96.
N-[2-(Benzylsulfanyl)-4-ethyl-6-oxo-1,6-dihydropyrimidin-5-
yl]benzamide (5a)
Yield: 190 mg (52%); colorless solid; mp 239 °C.
Synthesis 2010, No. 15, 2583–2587 © Thieme Stuttgart · New York

PAPER
Synthesis of 5-Benzoylamino-2-(aralkylsulfanyl)pyrimidin-4(3H)-ones
2587
13C NMR (DMSO-d6): d = 11.5, 20.6, 26.0, 33.5, 127.6, 128.3,
128.8, 128.9, 131.5, 133.8, 134.3, 136.4, 165.6.
Robinson, R., Eds.; Princeton University Press: Princeton,
1949, 688.
(6) (a) Tripathy, P. K.; Mukerjee, A. K. Indian J. Chem., Sect.
B: Org. Chem. Incl. Med. Chem. 1986, 25, 1059.
(b) Tikdari, A. M.; Tripathy, P. K.; Mukerjee, A. K. J. Chem.
Soc., Perkin Trans. 1 1988, 1659. (c) Tikdari, A. M.;
Tripathy, P. K.; Mukerjee, A. K. Chem. Ind. (London) 1986,
825.
(7) (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(b) Wathey, B.; Tiemey, J.; Lidström, P.; Westman, J. Drug
Discovery Today 2002, 7, 373. (c) Lidström, P.; Tierney, J.;
Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
(d) Caddick, S.; Fitzmaurice, R. Tetrahedron 2009, 65,
3325.
(8) CCDC 765698 contains the supplementary crystallographic
data for the deposited structure. These data can be obtained
free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. Crystal
data for compound 3a: C18H15N3O2S; Mr = 337.40;
orthorhombic; Pca21; a = 17.284(5), b = 5.8034(17),
c = 31.641(9) Å; V = 3173.8(16) Å3; T = 100 K; Z = 8;
Dx = 1.412 Mg·m–3; m = 0.22 mm–1; l(Mo Ka) = 0.71073 Å;
F(000) = 1408; 6062 independent reflections (Rint = 0.062),
4502 reflections with I > 2d(I); refinement method, full-
matrix least-squares refinement on F2;
Anal. Calcd for C21H21N3O2S: C, 66.47; H, 5.58; N, 11.07; S, 8.45.
Found: C, 66.46; H, 5.59; N, 11.01; S, 8.34.
Acknowledgment
The authors thank Miss Isabelle Nevoigt for her valuable help in the
preparation of the X-ray crystal structure.
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Synthesis 2010, No. 15, 2583–2587 © Thieme Stuttgart · New York