A rapid and convenient synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2- ones and thiones

Article abstract of DOI:10.1016/j.tet.2010.11.075

A rapid and convenient synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2- ones and thiones was developed. The reaction involves a one-pot reaction between oxalacetic acid, thiourea/urea, and aldehyde under microwave irradiation and provides the products

Full text of DOI:10.1016/j.tet.2010.11.075

Tetrahedron 67 (2011) 1294e1297
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A rapid and convenient synthesis of 5-unsubstituted 3,4-dihydropyrimidin-
2-ones and thiones
*
Zhanxiong Fang, Yulin Lam
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 11754, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 August 2010
Received in revised form 29 October 2010
Accepted 23 November 2010
Available online 27 November 2010
A rapid and convenient synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2-ones and thiones was de-
veloped. The reaction involves a one-pot reaction between oxalacetic acid, thiourea/urea, and aldehyde
under microwave irradiation and provides the products in good yields and much shorter reaction times.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cyclocondensation
Chemoselectivity
Multicomponent reaction
Biginelli reaction
Microwave reaction
1. Introduction
Typically, dihydropyrimidinones obtained via Biginelli reaction5
would house an ester at the C5 position (Fig. 1b). However Busso-
3,4-Dihydropyrimidine-2-ones/thiones are useful targets in
chemical synthesis as they have been associated with a diverse
range of therapeutic and medicinal properties.1 The dihydropyr-
imidinone scaffold is also found in various marine alkaloids, which
have been shown to possess antiviral, antitumor, antibacterial, and
anti-inflammatory activities.2 In particular, the batzelladine alka-
loids are known to be potent HIV gp-120-CD4 inhibitors.3 Our
group has earlier explored the sodium channel blockade activities
of pyrimidi-2-ones and pyrimidi-2-thiones and identified two
compounds, 1 and 2 (Fig. 1a), which possess neuronal sodium
channel blockade activities.4 In continuing our interest in the in-
vestigation of pyrimidi-2-ones and pyrimidi-2-thiones for their
sodium channel blockade activities, the synthesis of these com-
pounds carrying different substituents from 1 and 2 was explored.
lari and McDonnell had demonstrated that replacing alkyl acetoa-
cetate with oxalacetic acid 3 as a substrate for the Biginelli reaction
led to the formation of 5-unsubstituted 3,4-dihydropyrimidin-2-
ones due to in-situ decarboxylation after cyclization.6 These com-
poundsare ofinterestto us asthey bear resemblance to compounds 1
and 2. However, the major drawback of this reaction is the long re-
action time (12 h). For library preparation, it would be desirable if the
reaction could be (i) conducted expeditiously with good yield and (ii)
appliedtoavarietyofreagents. Toachievethis,weexploredtheuseof
microwave irradiation and also expanded the diversity by applying
thiourea and substituted urea/thiourea to the reaction (Scheme 1).
O
O
X
X
R1
1
NH
3
N
TFA
R2 CHO
H2N
NHR1
+
OH
+
HO2C
R2
4
6
(b)
(a)
S
O
X
HO2C
4 (X = O, S)
5
3
6
HN
N
HN
N
HN
NH
Scheme 1.
R
R"
COOR'
X = O, S
5
Br
2. Results and discussion
OMe
1
2
According to Bussolari and co-worker, 5-unsubstituted 3,4-
dihydropyrimidin-2-ones could be effectively synthesized from
oxalacetic acid, urea, and aldehyde when trifluoroacetic acid was
used as a catalyst and dichloroethane as the solvent. In our initial
synthesis of 6-phenyl-2-thioxo-1,2,3,6-tetrahydro-pyrimidine-4-
Fig. 1. (a) Pyrimidi-2-thione 1 and pyrimidi-2-one 2 with sodium channel blockage
ability; (b) Typical Biginelli product.
* Corresponding author. Tel.: þ65 6516 2688; fax: þ65 6779 1691; e-mail address:
chmlamyl@nus.edu.sg (Y. Lam).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.075

Z. Fang, Y. Lam / Tetrahedron 67 (2011) 1294e1297
1295
carboxylic acid 6a, we adopted Bussolari’s procedure but replaced
urea with thiourea and obtained the product in 64%. This result was
encouraging as it demonstrated the first synthesis of 2-thioxo-
1,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid. To optimize the
reaction, we explored microwave irradiation under different re-
action conditions (Table 1) and found that 6a was obtained in good
yields when the reaction was performed in solvents like dichloro-
methane, THF or dichloroethane (entries ii, viii and x, Table 1). To
demonstrate the versatility of these reaction conditions for the
the sides of the microwave vessel. Hence the reaction condition
shown in entry viii of Table 1 was used as the general procedure
for our synthesis and a diverse set of 6 was prepared in good
yields with both electron-withdrawing and electron-donating al-
dehydes (Table 2). For reactions with substituted thiourea/urea,
the reaction was observed to proceed chemoselectively to provide
only the N3-substituted 3,4-dihydropyrimidin-2-ones/thiones (as
determined by the X-ray structure of 6w7 and the 1D NoE of
6p and 6r).
Table 1
Optimization of the synthesis of 6a
O
O
S
S
TFA (0.6 equiv)
+
+
C H CHO
6 5
HO C
OH
H N NH
HN NH
HO C C H
6 5
2
2
2
MW
2
4a
5a
6a
Entry
Equivalents of 3
Equivalents of 4a
Equivalents of 5a
Solvent
Time (min)
Temp (ꢀC)
Yield (%)
i
ii
1
1
1
1
1
1
1
1.2
1
1.5
1.3
1.3
1.3
1.3
1.3
1.3
1.2
1.3
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1
EtOH
10
10
15
10
10
15
15
15
10
10
120
90
90
90
90
90
95
95
90
90
60
79
74
0
61
69
76
82
78
84
CH2Cl2
CH2Cl2
Toluene
THF
THF
THF
THF
ClCH2CH2Cl
ClCH2CH2Cl
iii
iv
v
vi
vii
viii
ix
x
1.2
1
1.2
3. Conclusion
Table 2
Library of compound 6
In summary, we have demonstrated an expeditious and high
yielding synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2-thi-
ones and 5-unsubstituted 3,4-dihydropyrimidin-2-ones. We have
shown that under microwave irradiation, the reaction time was
shortened from 12 h to 15 min. These results further demonstrate
the value of microwave-assisted synthesis in increasing yield,
shortening reaction time and streamlining high throughput
synthesis.
Compound
X
R1
R2
Yield (%)a
82 (64b)
83
83
93
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
S
S
S
S
S
S
O
O
O
O
O
O
S
S
S
S
S
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
allyl
allyl
allyl
CH3
CH3
CH3
allyl
allyl
allyl
C6H5
4-FC6H4
2,4-(CH3O)2C6H3
2-furyl
2-thienyl
2-naphthyl
C6H5
4-FC6H4
2,4-(CH3O)2C6H3
2-furyl
2-thienyl
2-naphthyl
C6H5
4-FC6H4
C6H5
3-ClC6H4
2-naphthyl
C6H5
4-FC6H4
2,4-(CH3O)2C6H3
C6H5
4. Experimental section
4.1. General
76
82
94 (88c)
73
91
All chemical reagents were obtained from Aldrich, Merck, Lan-
caster or Fluka and used without further purification. Analytical TLC
was carried out on pre-coated plates (Merck silica gel 60, F254) and
83
71 (72
89
c
)
89
84
78
75
79
84
83
76
visualized with UV light or stained with ninhydrin. 1H NMR and 13
C
NMR spectra were measured at 298 K on a Bruker AMX 500 Fourier
Transform spectrometer. Chemical shifts were reported in (ppm),
d
relative to the internal standard of TMS. The signals observed were
described as: s, d, t, q, m. The number of protons (n) for a given
resonance was indicated as nH. Mass spectrometry was performed
on a Finnigan MAT 95/XL-T spectrometer under electron impact (EI)
or electrospray ionization (ESI) technique. Microwave reactions
were performed on a Biotage InitiatorÔ microwave synthesizer.
O
O
O
O
O
O
6s
6t
6u
6v
6w
83
77
81
3,5-Br2C6H3
2-naphthyl
a
Isolated yield.
b
Using the conventional heating method as reported by Bussolari et al. (Ref. 6)
Yield reported in Ref. 6.
4.2. General procedure for the synthesis of 6ae6l
c
To a mixture of oxalacetic acid (2.6 mmol), aldehyde (2.0 mmol),
and urea/thiourea (2.6 mmol) in THF (3 mL) was added TFA
(0.10 mL). The mixture was heated at 95 ꢀC for 15 min using mi-
crowave irradiation in a sealed tube. Thereafter, the mixture was
cooled and the solvent was removed under reduced pressure. The
residue obtained was washed with Et2O and dried under vacuum to
afford the final product.
synthesis of 6, we carried out the reaction with different aldehydes.
However further experimentation showed that when dichloro-
methane and dichloroethane were used in the synthesis of certain
analogs, in particular 6b and 6c, the desired product was not
obtained and instead a black tar-like substance was found coated to

1296
Z. Fang, Y. Lam / Tetrahedron 67 (2011) 1294e1297
4.2.1. 6-Phenyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic
128.2, 128.2, 127.8, 115.5, 115.4, 108.7, 54.0; HRMS (EI): calcd for
C11H9FN2O3, 236.0597; found 236.0594.
acid 6a. Yellow solid, mp 234e235 ꢀC; IR (KBr): 3259, 3100, 3001,
1711,1674, 1561; 1H NMR (300 MHz, DMSO-d6)
d 9.21 (s, NH, 1H),
8.47 (s, NH, 1H), 7.43e7.27 (m, ArH, 5H), 6.05 (d, CCHCH, J¼4.8 Hz,
4.2.8. 6-(2,4-Dimethoxyphenyl)-2-oxo-1,2,3,6-tetrahydropyr-
imidine-4-carboxylic acid 6i. Yellow solid, mp 204e205 ꢀC; IR
(KBr): 3441, 3294, 2932, 1714, 1674, 1615, 1506; 1H NMR (500 MHz,
1H), 5.18 (dd, CHCHPh, J¼2.4, 4.8 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6)
d 174.4, 162.3, 142.6, 128.8, 127.9, 126.3, 125.8, 110.8,
54.6; HRMS (ESI) [MꢁH]ꢁ: calcd for C11H9N2O2S, 233.0379; found
DMSO-d6)
d
7.63 (s, NH, 1H), 7.10 (d, ArH, J¼8.2 Hz, 1H), 7.02 (s, NH,
233.0383.
1H), 6.58e6.55 (m, ArH, 2H), 5.75 (d, CCHCH, J¼4.4 Hz, 1H), 5.31
(dd, CHCHPh, J¼1.9, 4.4 Hz, 1H), 3.81 (s, OCH3, 3H), 3.76e3.75 (d,
4.2.2. 6-(4-Fluorophenyl)-2-thioxo-1,2,3,6-tetrahydropyrimidine-4-
carboxylic acid 6b. Pale yellow solid, mp 211e212 ꢀC; IR (KBr):
3269, 3100, 3004,1716,1676,1614,1567; 1H NMR (500 MHz, DMSO-
OCH3, J¼5.1 Hz, 3H); 13C NMR (125 MHz, DMSO-d6)
d 163.0, 160.0,
156.3, 152.9, 127.5, 127.0, 123.4, 108.2, 104.9, 98.5, 55.6, 55.3, 49.2;
HRMS (EI): calcd for C13H14N2O5, 278.0903; found 279.0913.
d6)
d 9.22 (s, NH, 1H), 8.50 (s, NH, 1H), 7.33e7.30 (m, ArH, 2H),
7.26e7.22 (m, ArH, 2H), 6.04 (dd, CCHCH, J¼1.3, 3.2 Hz, 1H), 5.20
4.2.9. 6-(Furan-2-yl)-2-oxo-1,2,3,6-tetrahydropyrimidine-4-carbox-
(dd, CHCHPh, J¼2.5, 5.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
ylic acid 6j. Dark brown solid, mp 176e178 ꢀC; IR (KBr): 3254, 1722,
d
174.3, 163.3, 162.3, 160.1, 138.9, 138.8, 128.5, 128.4, 126.0, 115.8,
1672, 1468; 1H NMR (500 MHz, DMSO-d6)
d 7.85 (s, NH, 1H), 7.62, (s,
115.5, 110.6, 53.9; HRMS (EI): calcd for C11H9FN2O2S, 252.0369;
found 252.0363.
ArH, 1H), 7.34 (s, NH, 1H), 6.42e6.41 (m, ArH, 1H), 6.25 (d, ArH,
J¼3.2 Hz,1H), 5.75 (dd, CCHCH, J¼1.9, 3.2 Hz,1H), 5.21 (dd, CHCHPh,
J¼2.5, 5.1 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d 162.8, 154.7,
4.2.3. 6-(2,4-Dimethoxyphenyl)-2-thioxo-1,2,3,6-tetrahydropyr-
imidine-4-carboxylic acid 6c. Yellow solid, mp 209e210 ꢀC; IR
(KBr): 3237, 3103, 3002, 1709, 1672, 1615, 1564, 1506; 1H NMR
152.3, 142.8, 129.3, 110.5, 106.1, 105.5, 48.5; HRMS (EI): calcd for
C9H8N2O4, 208.0484; found 208.0479.
(500 MHz, DMSO-d6)
d
8.94 (s, NH, 1H), 8.38 (s, NH, 1H), 7.01 (d,
4.2.10. 6-(Naphthalen-2-yl)-2-oxo-1,2,3,6-tetrahydropyrimidine-4-
ArH, J¼8.2 Hz, 1H), 6.60e6.58 (m, ArH, 2H), 5.95e5.94 (m,
carboxylic acid 6l. Yellow solid, mp 224e226 ꢀC; IR (KBr): 3308,
CCHCH, 1H), 5.29 (dd, CHCHPh, J¼2.5, 4.4 Hz, 1H), 3.82 (s, OCH3,
3236, 1716, 1668, 1464; 1H NMR (500 MHz, DMSO-d6)
d 7.91e7.90
3H), 3.76 (s, OCH3, 3H); 13C NMR (125 MHz, DMSO-d6)
d
174.9,
(m, ArH, 3H), 7.80 (s, NH, 1H), 7.77 (s, ArH, 1H), 7.53e7.49 (m, ArH,
3H), 7.43 (s, NH, 1H), 5.87 (d, CCHCH, J¼4.4 Hz, 1H), 5.35 (dd,
162.4, 160.4, 156.3, 127.5, 125.6, 122.5, 110.2, 105.1, 98.6, 55.7, 55.3,
49.6; HRMS (ESI) [MþH]þ: calcd for C13H15N2O4S, 295.0747;
found 295.0753.
CHCHPh, J¼1.9, 4.4 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d 163.0,
152.5, 141.1, 132.9, 132.5, 128.6, 128.0, 127.8, 127.6,126.4, 126.1,124.7,
124.3, 108.6, 55.0; HRMS (EI): calcd for C15H12N2O3, 268.0848;
found 268.0838.
4.2.4. 6-(Furan-2-yl)-2-thioxo-1,2,3,6-tetrahydropyrimidine-4-car-
boxylic acid 6d. Dark brown solid, mp 184e186 ꢀC; IR (KBr): 3254,
3102, 3003, 1712, 1675, 1616, 1566; 1H NMR (500 MHz, DMSO-d6)
4.3. General procedure for the synthesis of 6me6w
d
9.23 (s, NH, 1H), 8.56 (s, NH, 1H), 7.67 (s, ArH, 1H), 6.46 (dd, ArH,
J¼1.9, 3.2 Hz, 1H), 6.30 (d, ArH, J¼3.2 Hz, 1H), 5.97e5.96 (m,
To a mixture of oxalacetic acid (2.6 mmol), aldehyde (2.0 mmol)
and N-substituted urea/thiourea (2.6 mmol) in THF (3 mL) was
added TFA (0.10 mL). The mixture was heated at 95 ꢀC for 15 min
using microwave irradiation in a sealed tube. Thereafter, the mix-
ture was cooled and the solvent was removed under reduced
pressure. 0.5 M NaOH (20 mL) was then added to the residue and
the resulting solution was extracted with EtOAc (3ꢂ15 mL). Sub-
sequently, the aqueous phase was acidified using concd HCl and
CCHCH, 1H), 5.26 (dd, CHCHPh, J¼2.6, 5.1 Hz, 1H); 13C NMR
(125 MHz, DMSO-d6) d 174.5, 162.2, 153.4, 143.2, 127.3, 110.7, 107.6,
107.2, 48.2; HRMS (EI): calcd for C9H8N2O3S, 224.0256; found
224.0250.
4.2.5. 6-(Thiophen-2-yl)-2-thioxo-1,2,3,6-tetrahydropyrimidine-4-
carboxylic acid 6e. Yellow solid, mp 215e216 ꢀC; IR (KBr): 3256,
3100, 2997, 1714, 1676, 1562; 1H NMR (500 MHz, DMSO-d6)
i
extracted with 10% PrOH in CH2Cl2 (3ꢂ15 mL). The combined or-
d
9.34 (s, NH, 1H), 8.61 (s, NH, 1H), 7.51 (dd, ArH, J¼1.9, 3.8 Hz,
ganic extract was dried over MgSO4 and concentrated under re-
duced pressure. The residue was washed with Et2O and dried under
vacuum to afford the final product.
1H), 7.03e7.01 (m, ArH, 2H) 6.08e6.07 (m, CCHCH, 1H), 5.46
(dd, CHCHPh, J¼2.6, 5.1 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d
174.0, 162.2, 146.2, 127.1, 126.3, 126.2, 125.0, 110.0, 49.8;
HRMS (ESI) [MꢁH]ꢁ: calcd for C9H7N2O2S2, 238.9943; found
4.3.1. 3-Methyl-6-phenyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-4-
238.9944.
carboxylic acid 6m. Yellow solid, mp 88e90 ꢀC; IR (KBr): 3249,
2361, 1724, 1621, 1496; 1H NMR (500 MHz, DMSO-d6)
d 9.19 (s, NH,
4.2.6. 6-(Naphthalen-2-yl)-2-thioxo-1,2,3,6-tetrahydropyrimidine-4-
1H), 7.41e7.26 (m, ArH, 5H), 6.22 (d, CCHCH, J¼5.7 Hz, 1H), 5.00 (dd,
carboxylic acid 6f. Yellow solid, mp 248e251 ꢀC; IR (KBr): 3248,
CHCHPh, J¼3.2, 6.3 Hz, 1H), 3.39 (s, NCH3, 3H); 13C NMR (125 MHz,
3101, 3001, 1711, 1674, 1558; 1H NMR (500 MHz, DMSO-d6)
d
9.34 (s,
DMSO-d6) d 179.3, 163.5, 141.9, 131.9, 128.8, 127.8, 126.0, 115.5, 52.6,
NH, 1H), 8.56 (s, NH, 1H), 7.97e7.90 (m, ArH, 3H), 7.76 (s, ArH, 1H),
7.53e7.47 (m, ArH, 3H), 6.14 (d, CCHCH, J¼4.5 Hz, 1H), 5.39 (dd,
38.1; HRMS (EI): calcd for C12H12N2O2S, 248.0619; found 248.0622.
CHCHPh, J¼2.5, 4.4 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d
174.5,
4.3.2. 6-(4-Fluorophenyl)-3-methyl-2-thioxo-1,2,3,6-tetrahydropyr-
imidine-4-carboxylic acid 6n. Yellow solid, mp 86e88 ꢀC; IR (KBr):
3411, 2361, 1723, 1650, 1605, 1510; 1H NMR (500 MHz, DMSO-d6)
162.3, 140.0, 132.8, 132.6, 128.8, 127.9, 127.6, 126.6, 126.3, 126.0,
124.9, 124.6, 110.6, 54.9; HRMS (EI): calcd for C15H12N2O2S,
284.0619; found 284.0612.
d
9.21 (s, NH, 1H), 7.32e7.39 (m, ArH, 2H), 7.24e7.21 (m, ArH, 2H),
6.21 (d, CCHCH, J¼5.1 Hz, 1H), 5.02 (dd, CHCHPh, J¼3.2, 5.7 Hz, 1H),
3.39 (s, NCH3, 3H); 13C NMR (125 MHz, DMSO-d6)
179.2, 163.5,
4.2.7. 6-(4-Fluorophenyl)-2-oxo-1,2,3,6-tetrahydro-pyrimidine-4-
d
carboxylic acid 6h. Off-white solid, mp 225e226 ꢀC; IR (KBr): 3400,
162.7, 160.7, 138.1, 138.1, 132.1, 128.2, 128.2, 115.7, 115.5, 115.2, 51.9,
38.1; HRMS (EI): calcd for C12H11FN2O2S, 266.0525; found 266.0518.
3212, 3098, 1712, 1673, 1509; 1H NMR (500 MHz, DMSO-d6)
d 7.80
(s, NH, 1H), 7.35e7.32 (m, ArH, 2H), 7.22e7.19 (m, ArH, 2H),
5.78e5.77 (m, CCHCH, 1H), 5.18 (dd, CHCHPh, J¼1.9, 4.4 Hz, 1H); 13C
4.3.3. 3-Allyl-6-phenyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-4-car-
boxylic acid 6o. Yellow solid, mp 144e146 ꢀC; IR (KBr): 3172, 1693,
NMR (125 MHz, DMSO-d6)
d
162.9, 162.5, 160.6, 152.3, 140.0, 140.0,

Z. Fang, Y. Lam / Tetrahedron 67 (2011) 1294e1297
1297
1652, 1528; 1H NMR (500 MHz, DMSO-d6)
d
8.85 (s, NH, 1H),
7.52 (s, NH,1H), 7.41e7.38 (m, ArH, 2H), 7.31e7.28 (m, ArH, 3H), 5.91
(d, CCHCH, J¼4.4 Hz, 1H), 5.77e5.69 (m, CH2CHCH2, 1H), 5.10 (d,
CHCHPh, J¼5.0 Hz, 1H), 5.06e4.98 (m, CH2CHPh, 2H), 4.58 (dd,
CH2CHCH2, J¼3.8, 16.4 Hz, 1H), 4.33 (dd, CH2CHCH2, J¼6.3, 16.4 Hz,
6.97e6.94 (m, ArH, 2H), 6.88e6.62 (m, ArH, 3H), 5.78 (dd, CCHCH,
J¼1.3, 5.7 Hz, 1H), 5.26e5.18 (m, CH2CHCH2, 1H), 5.07e5.03 (m,
CHCHPh, 1H), 4.62e4.60 (m, CH2CHCH2, 2H), 4.54e4.50 (m,
CH2CHCH2, 1H), 4.19 (dd, CH2CHCH2, J¼7.0, 16.5 Hz, 1H); 13C NMR
1H); 13C NMR (125 MHz, DMSO-d6)
d 163.9, 153.7, 143.1, 135.2, 131.4,
(125 MHz, DMSO-d6)
d
178.9, 163.5, 141.8, 133.8, 130.5, 128.7, 127.8,
128.7, 127.6, 126.0, 116.3, 113.2, 53.3, 43.8; HRMS (EI): calcd for
C14H14N2O3, 258.1004; found 258.0996.
126.0, 117.3, 116.5, 52.6, 49.6; HRMS (EI): calcd for C14H14N2O2S,
274.0776; found 274.0770.
4.3.10. 3-Allyl-6-(3,5-dibromophenyl)-2-oxo-1,2,3,6-tetrahydropyr-
imidine-4-carboxylic acid 6v. Yellow solid, mp 185e187 ꢀC; IR (KBr):
3260, 3074, 1703, 1661, 1628, 1582; 1H NMR (500 MHz, DMSO-d6)
4.3.4. 3-Allyl-6-(3-chlorophenyl)-2-thioxo-1,2,3,6-tetrahydropyr-
imidine-4-carboxylic acid 6p. Yellow solid, mp 136e138 ꢀC; IR
(KBr): 3178, 3027, 2361, 1710, 1690, 1653, 1536; 1H NMR (500 MHz,
d
13.3 (s, CO2H, 1H), 7.77 (s, NH, 1H), 7.62 (s, ArH, 1H), 7.50 (s, ArH,
DMSO-d6)
d
13.5 (br, CO2H, 1H), 9.35 (s, NH, 1H), 7.46e7.24 (m, ArH,
2H), 5.96e5.95 (m, CCHCH, 1H), 5.73e5.67 (m, CH2CHCH2, 1H),
5.14e5.13 (m, CHCHPh,1H), 5.07e4.96 (m, CH2CHCH2, 2H), 4.56 (dd,
CH2CHCH2, J¼2.5, 16.4 Hz, 1H), 4.31 (dd, CH2CHCH2, J¼5.7, 16.4 Hz,
4H), 6.26 (d, CCHCH, J¼5.1 Hz, 1H), 5.66 (dd, CH2CHCH2, J¼5.0,
10.7 Hz, 1H), 5.49 (d, CHCHPh, J¼15.8 Hz, 1H), 5.08e5.06 (m,
CH2CHCH2, 2H), 4.96 (d, CH2CHCH2, J¼17.0 Hz, 1H), 4.64 (dd,
CH2CHCH2, J¼5.7, 15.8 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
1H); 13C NMR (125 MHz, DMSO-d6)
d 163.7, 153.5, 147.5, 134.9,
132.5, 132.3, 128.1, 122.8, 116.4, 111.8, 52.1, 43.8; HRMS (EI): calcd for
C14H12Br2N2O3, 413.9215; found 413.9201.
d
179.1, 163.5, 144.2, 133.7, 133.4, 131.1, 130.8, 127.7, 126.0, 124.6,
117.4, 115.8, 52.0, 49.6; HRMS (EI): calcd for C14H13ClN2O2S,
308.0386; found 308.0372.
4.3.11. 3-Allyl-6-(naphthalen-2-yl)-2-oxo-1,2,3,6-tetrahydropyr-
imidine-4-carboxylic acid 6w. Yellow solid, mp 180e181 ꢀC; IR
(KBr): 3287, 3054, 1703, 1666, 1623, 1509; 1H NMR (500 MHz,
4.3.5. 3-Allyl-6-(naphthalen-2-yl)-2-thioxo-1,2,3,6-tetrahydropyr-
imidine-4-carboxylic acid 6q. Yellow solid, mp 169e171 ꢀC; IR
(KBr): 3189, 1693, 1651, 1525, 1450; 1H NMR (500 MHz, DMSO-d6)
DMSO-d6)
d 7.96e7.89 (m, ArH, 3H), 7.78 (s, ArH, 1H), 7.65 (s, NH,
1H), 7.53e7.50 (m, ArH, 3H), 6.00 (dd, CCHCH, J¼1.3, 5.1 Hz, 1H),
5.82e5.74 (m, CH2CHCH2 1H), 5.30 (dd, CHCHPh, J¼1.9, 5.0 Hz, 1H),
5.08e5.03 (m, CH2CHCH2, 2H), 4.64e4.60 (m, CH2CHCH2, 1H), 4.39
(dd, CH2CHCH2, J¼5.7, 16.4 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d
9.42 (s, NH, 1H), 7.98e7.87 (m, ArH, 3H), 7.74 (s, ArH, 1H),
7.54e7.47 (m, ArH, 3H), 6.33 (d, CCHCH, J¼5.1 Hz, 1H), 5.76e5.68
(m, CH2CHCH2, 1H), 5.52 (dd, CH2CHCH2, J¼4.5, 15.8 Hz, 1H),
5.25e5.24 (m, CHCHPh, 1H), 5.08e5.00 (m, CH2CHCH2 2H), 4.71
(dd, CH2CHCH2, J¼6.3, 15.8 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d
163.9, 153.7, 140.5, 135.2, 132.9, 132.5, 131.6, 128.6, 127.8, 127.6,
126.5, 126.1, 124.5, 124.3, 116.3, 113.0, 53.5, 43.9; HRMS (EI): calcd
for C18H16N2O3, 308.1161; found 308.1154.
d
179.0, 163.6, 139.2, 133.8, 132.7, 132.4, 130.8, 128.7, 127.7, 127.6,
126.6, 126.3, 124.6, 124.3, 117.5, 116.4, 52.9, 49.7; HRMS (EI): calcd
for C18H16N2O2S, 324.0932; found 324.0918.
Acknowledgements
4.3.6. 3-Methyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-4-car-
The authors thank the A*Star for the funding provided (BMRC
grant: R-143-000-348-305).
boxylic acid 6r. White solid, mp 166e168 ꢀC; IR (KBr): 3282, 2367,
1705, 1667, 1628; 1H NMR (500 MHz, DMSO-d6)
d 7.42 (s, NH, 1H),
7.41e7.28 (m, ArH, 5H), 5.89e5.88 (m, CCHCH, 1H), 5.05e5.04 (m,
CHCHPh, 1H), 3.07 (s, NCH3, 3H); 13C NMR (125 MHz, DMSO-d6)
Supplementary data
d
163.9, 154.2, 143.2, 132.5, 128.7, 127.5, 126.0, 112.3, 53.2, 31.5;
Supplementary data related to this article can be found online
version, at doi:10.1016/j.tet.2010.11.075.
HRMS (EI): calcd for C12H12N2O3, 232.0848; found 232.0841.
4.3.7. 6-(4-Fluorophenyl)-3-methyl-2-oxo-1,2,3,6-tetrahydropyr-
imidine-4-carboxylic acid 6s. Off-white solid, mp 170e171 ꢀC; IR
(KBr): 3281, 2360, 1710, 1694, 1659, 1605, 1509; 1H NMR (500 MHz,
References and notes
1. (a) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043; (b) Rovnyak, G. C.; Kimball, S.
D.; Beyer, B.; Cucinotta, G.; DiMarco, J. D.; Gougoutas, J.; Hedberg, A.; Malley, M.;
McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med. Chem. 1995, 38, 119; (c) Atwal, K. S.;
Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.; Swanson, B. N.;
Gougoutas, J. Z.; Schwartz, J.; Smillie, K. M.; Malley, M. F. J. Med. Chem. 1990, 33,
2629; (d) Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu, M.; Ohnaka,
Y.; Takeuchi, Y.; Hamaguchi, M.; Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda, M.;
Ishihara, T.; Funahashi, K.; Satoh, F.; Morita, M.; Noguchi, T. J. Med. Chem. 1989,
32, 2399; (e) Rovnyak, G. C.; Atwal, K. S.; Hedberg, A.; Kimball, S. D.; Moreland,
S.; Gougoutas, J. Z.; O’Reilly, B. C.; Schwartz, J.; Malley, M. F. J. Med. Chem. 1992,
35, 3254; (f) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.;
Hedberg, A.; O’Reilly, B. C. J. Med. Chem. 1991, 342, 806; (g) Sidler, D. R.; Larsen, R.
D.; Chartrain, M.; Ikemoto, N.; Roberge, C. M.; Taylor, C. S.; Li, W.; Bills, G. F. PCT
Int. Appl. 1999, WO 9907695; (h) Nagarathnam, D.; Wong, W. C.; Miao, S. W.;
Patane, M. A.; Gluchowski, C. PCT Int. Appl. 1997, WO 9717969; (i) Mishra, R.;
Mishra, B.; Moorthy, N. S. H. N. Trends Appl. Sci. Res. 2008, 3, 203; (j) Kruse, L. I.;
Ross, S. T. Eur. Pat. Appl. 1989, EP 323147.
DMSO-d6)
ArH, 2H), 5.88 (d, CCHCH, J¼4.5 Hz, 1H), 5.07 (d, CHCHPh, J¼3.2 Hz,
1H), 3.07 (s, NCH3, 3H); 13C NMR (125 MHz, DMSO-d6)
163.9,
162.5, 160.6, 154.2, 139.5, 139.4, 132.7, 128.2, 128.1, 115.6, 115.4,
112.0, 52.5, 31.5; HRMS (EI): calcd for C12H11FN2O3, 250.0754;
found 250.0746.
d 7.44 (s, NH, 1H), 7.35e7.32 (m, ArH, 2H), 7.23e7.19 (m,
d
4.3.8. 6-(2,4-Dimethoxyphenyl)-3-methyl-2-oxo-1,2,3,6-tetrahy-
dropyrimidine-4-carboxylic acid 6t. Yellow solid, mp 169e170 ꢀC; IR
(KBr): 3282, 1709, 1666, 1612, 1504; 1H NMR (500 MHz, DMSO-d6)
d
7.10 (s, NH, 1H), 7.06 (d, ArH, J¼8.2 Hz, 1H), 6.58e6.55 (m, ArH,
2H), 5.84 (d, CCHCH, J¼4.4 Hz, 1H), 5.16 (d, CHCHPh, J¼3.2 Hz, 1H),
3.80 (s, OCH3, 3H), 3.76 (s, OCH3, 3H), 3.05 (s, NH, 3H); 13C NMR
2. Snider, B. B.; Shi, Z. J. Org. Chem. 1993, 58, 3828.
(125 MHz, DMSO-d6) d 164.0, 160.1, 156.6, 154.9, 132.5, 126.9, 122.9,
111.9, 104.8, 98.6, 55.6, 55.3, 48.2, 31.6; HRMS (EI): calcd for
C14H16N2O5, 292.1059; found 292.1071.
3. Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A. J.; Debrosse, C.; Mai,
S.; Trunch, A.; Faulkner, D. J.; Carte, B.; Breen, A. L.; Hertzberg, R. P.; Johnson, R.
K.; Westley, J. W.; Ports, B. C. M. J. Org. Chem. 1995, 6, 1182.
4. Kong, K.-H.; Chen, Y.; Ma, X.; Chui, W. K.; Lam, Y. J. Comb. Chem. 2004, 6, 928.
5. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
6. Bussolari, J. C.; McDonnell, P. A. J. Org. Chem. 2000, 65, 6777.
7. X-ray crystal data has been deposited in the Cambridge Crystallographic Data
Centre and allocated the deposition number CCDC 783709.
4.3.9. 3-Allyl-2-oxo-6-phenyl-1,2,3,6-tetrahydropyrimidine-4-car-
boxylic acid 6u. Yellow solid, mp 181e183 ꢀC; IR (KBr): 3283, 1699,
1658, 1610, 1458; 1H NMR (500 MHz, DMSO-d6)
d 13.2 (s, CO2H, 1H),