Microwave-assisted facile one-step carbamoylation of 6-aminouracils

Article abstract of DOI:10.1055/s-2005-872099

Carbamoylation of 6-aminouracils was achieved by reacting 6-aminouracils with isocyanates under computer-controlled microwave irradiation for a short reaction time. Under known thermal conditions, most of carbamoylated uracils are obtained in poor yields

Full text of DOI:10.1055/s-2005-872099

PAPER
2713
Microwave-Assisted Facile One-Step Carbamoylation of 6-Aminouracils
M
icrowa
l
ve-Ass
l
iste
d
Facile
O
Y
ne-Pot Carbamoy
o
lation of 6-A
u
minouracilsng Lee,* Jin Young Lee, Young-Dae Gong*
The Center for High Throughput Synthesis Platform Technology, Korea Research Institute of Chemical Technology,
P.O. Box 107, Yusong, Taejon 305-600, Korea
Fax +82(42)8611291; E-mail: iylee@krict.re.kr
Received 4 April 2005
of 6-aminouracils. We concentrated our efforts on apply-
ing microwave to introduce a carbamoyl group at the C-5
position of 6-aminouracil.
Abstract: Carbamoylation of 6-aminouracils was achieved by re-
acting 6-aminouracils with isocyanates under computer-controlled
microwave irradiation for a short reaction time. Under known ther-
mal conditions, most of carbamoylated uracils are obtained in poor
yields with long reaction times.
O
RNH2
O
O
ClCO2Ph
N
N
NHR
NH2
previous method
RNCO/microwave
Key words: microwave, 6-aminouracil, isocyanates, heterocycles,
carbamoylation
O
N
NH2
O
N
trial work
2
1a
Figure 1
6-Aminouracils and their derivatives are of great impor-
tance in medicinal chemistry and have interesting biolog-
ical properties.1,2 Among 6-aminouracil derivatives, 5-
carbamoyl-6-aminouracils have attracted attention be-
cause of their effect on c-Jun N-terminal kinase inhibition
and anti-inflammatory properties.3,4 The C-5 position of
6-aminouracil is the preferred site for electrophilic substi-
tution with various isocyanates, such as ethyl isocyanato-
formate, phenyl isocyanate and chlorosulfonyl isocy-
anate.5 5-Carbamoyl-6-aminouracils have been used as
key intermediates for the synthesis of fused pyrimidines,
such as pyrimido[4,5-d]pyrimidines5a,6 and isooxazo-
lo[3,4-d]pyrimidines.7 In previous studies, we reported a
method for derivatizing the C-5 position of 6-amino-
uracils by coupling an aryldiazonium salt with 1-cyano-
3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylamino)-2-
methylisothiourea.8 With the continuing interest in the de-
velopment of 6-aminouracil derivatives, we sought to in-
troduce a carbamoyl group at the C-5 position of 6-
aminouracils using various isocyanates to construct small
novel drug-like organic molecules.
Following the pioneering work of Gedye et al. and
Giguere et al.,9 microwave applications in organic chem-
istry have become more prevalent.10 The principal advan-
tages of microwave mediation are reaction acceleration
and an accompanying minimization of product decompo-
sition.10,11 The current literature includes a growing num-
ber of examples, including our report of the formation of
a heterocycle, mediated by microwave irradiation.12 Here,
we report our investigation of carbamoylation at the C-5
position of 6-aminouracils 1 under microwave conditions.
Table 1 Studies of the Optimization of Carbamoylation with 6-
Aminouracil 1a
O
O
BuNCO (1.2 equiv)
N
NHBu
NH2
2a
1a
O
N
Entry Reaction conditions
Time
24 h
Yield (%)
trace [75]a
26 [51]a
55
1
2
3
4
5
6
Thermal/pyridine/refluxing
Thermal/DMF/140 °C
5-Phenylcarbamoyl-6-amino-1,3-dimethyluracil was pre-
pared in 63% yield by reacting 6-amino-1,3-dimethylu-
racil (1a) with phenyl isocyanate in pyridine.5c However,
for alkylisocyanates, we could not obtain the desired 5-
alkylcarbamoylated-6-aminouracil under the same reac-
tion conditions as noted in the literature.5c The known
preparation of 5-alkylcarbamoyl-6-aminouracils involves
a two-step procedure from 6-aminouracil, requiring long
reaction times with fairly low yields (Figure 1). Phenyl-
carbamoylation at the C-5 position of 6-amino-1,3-di-
methyluracil with substituted phenylisocyanates has also
been achieved using this two-step procedure.5c,6a We de-
cided to investigate the possibility of a more efficient car-
bamoylation with various isocyanates at the C-5 position
24 h
Thermal/nitrobenzene/210 °C
Microwave/pyridine/120 °C
Microwave/DMF/150 °C
Microwave/nitrobenzene/210 °C
4 h
40 min
40 min
20 min
38 [51]a
45 [38]a
72
a Recovered starting materials.
As a starting point for developing direct alkyl carbamoyl-
ation, we studied the reaction of 6-amino-1,3-dimethyl
uracil (1a) with butyl isocyanate for optimizing the reac-
tion conditions, as shown in Table 1. Carbamoylation of
6-amino-1,3-dimethyl uracil (1a) with butyl isocyanate
for 24 hours in refluxing pyridine in a pressure vessel gave
a trace amount of 2a with most of the starting material 1a
SYNTHESIS 2005, No. 16, pp 2713–2717
x
x.
x
x
.
2
0
0
5
Advanced online publication: 25.07.2005
DOI: 10.1055/s-2005-872099; Art ID: F06205SS
© Georg Thieme Verlag Stuttgart · New York

2714
J. Y. Lee et al.
PAPER
being recovered, as was also reported previously (entry
1).5c When we tried the same reaction at 140 °C in DMF
instead of pyridine, the desired product 2a was obtained in
26% yield (entry 2). The yield was not improved by add-
ing an excess of butyl isocyanate, adding a base (Et3N,
DBU, K2CO3, Cs2CO3, or NaH), or refluxing for 48 hours.
In order to increase the reaction temperature we changed
the solvent to nitrobenzene. Reaction at 210 °C gave 2a in
better yield (55%) without recovering the starting material
(entry 3). Based on these results, the reaction was per-
formed under microwave conditions. With pyridine or
DMF, the reaction was not completed within 40 minutes
(entries 4 and 5). However, nitrobenzene at 210 °C and 20
minutes proved to be the most effective condition (entry
6).
Table 2 Microwave-Assisted Synthesis of 6-Amino-5-carbamoyl-
uracil 2
O
O
O
R2
R4
R2
R4NCO (1.2 equiv)
N
N
N
H
O
N
NH
O
N
NH
PhNO2, 210 °C
microwave
R1 R3
R1 R3
2
1
Entry 6-Aminouracil R4
Time (min) Product (yielda)
1
2
1a
1a
1a
1b
1b
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Bu
20
20
20
20
20
10
10
10
10
10
10
10
10
10
10
20
20
10
10
2a (72)
2b (81)
2c (65)
2d (81)
2e (83)
2f (92)
2g (82)
2h (88)
2i (78)
2j (85)
2k (84)
2l (62)
2m (87)
2n (82)
2o (75)
2p (58)
2q (70)
2r (72)
2s (76)
c-C6H11
Et
3
4
Bn
5
c-C6H11
Ph
O
N
O
O
Bu
6
N
N
N
O
NH2
O
N
NH2
O
N
NH2
7
4-MeOPh
4-ClPh
2-BrPh
2-EtPh
Ph
Bu
1c
Ph
1a
1b
8
O
O
O
9
4-MeOBn
N
N
N
O
N
NH2
O
10
11
12
13
14
15
16
17
18
19
N
NH
Bn
O
N
NH
Pr
Ph
1d
1e
1f
O
N
Ph
O
O
HN
HN
HN
Ph
O
NH2
O
N
NH2
O
N
H
NH
Ph
Ph
Ph
1g
1h
1i
Ph
Figure 2 Various 6-aminouracils used for carbamoylation
1g
1g
1g
1h
Bu
We further investigated the carbamoylation of 6-amino-
uracils using various isocyanates and uracils in order to
determine the scope and limitations of the reaction
(Table 2). For this reaction, 6-aminouracils were prepared
by the known method13 except for the commercially avail-
able 1a and lg (Figure 2). Alkyl carbamoylation of 6-ami-
no-1,3-disubstitued uracils gave the corresponding
products 2a–e under similar reaction conditions in good
yield (entries 1–5). The reactions of 6-amino-1,3-disub-
stitued uracils 1a–1d with substituted aryl isocyanates
were completed in ten minutes, showing no effects from
electronic-donating, electron-withdrawing, or ortho sub-
stituents (entries 6–13). The reaction of 6-alkylamino-
uracils 1e and 1f with phenyl isocyanate gave similar
yields (entries 14 and 15). Finally, we tried carbamoyla-
tion of N-3 unsubstituted uracil because the hydrogen at
the N-3 position mimics that of uracil derivatives and their
nucleosides. The N-3 hydrogen of uracil is essential for
hydrogen bonding with purine bases in RNA.14 Carbam-
oylation of 6-aminouracil 1g with butyl isocyanate gave
2p in 58% yield. When we attempted the synthesis of 2p
by reacting 1g with butyl isocyanate under thermal condi-
tions (nitrobenzene at 210 °C for 24 h), the starting mate-
rial 1g was recovered in 79% yield along with a trace
amount of desired product 2p. Other examples of N-3-un-
Bn
Ph
Ph
a Isolated yields.
substituted 6-amino uracils gave yields of 70–76% (en-
tries 17–19).
Recently, carbamoylated 6-arylaminouracils 2t–v have
shown biological activity as a c-Jun N-terminal kinase in-
hibitor which is a member of the mitogen-activated pro-
tein (MAP) kinase family.3b The synthetic method of 2t–
v was published in 5 steps from dimethyl N-cyanodithio-
iminocarbonate. However synthesis of 2t–v was achieved
in two steps with high overall yield. The desired 2t–v
were obtained by heating of commercially available 6-
chlorouracil in aniline13c followed by carbarmoylation un-
der microwave condition (Scheme 1).
In summary, we have established a rapid, one-pot alkyl
carbamoylation of 6-aminouracils under microwave irra-
diation conditions. This procedure has been extended to
aryl carbamoylation of 6-aminouracils. The reaction fea-
tures a short reaction time and high yield. For N-unsubsti-
tuted 6-aminouracil, the carbamoylated uracils were
Synthesis 2005, No. 16, 2713–2717 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Facile One-Step Carbamoylation of 6-Aminouracils
ATR–IR: 3325, 1663, 1591, 1536, 1446 cm–1.
2715
O
O
RNCO (2.0 equiv), PhNO2
1H NMR (500 MHz, DMSO-d6): d = 11.12 (s, 1 H), 9.73–9.74 (m,
1 H), 7.86 (s, 1 H), 3.31 (s, 3 H), 3.21–3.27 (m, 2 H), 3.16 (s, 3 H),
1.09 (t, J = 7.3 Hz, 3 H).
HN
NHR
1i
210 °C, 40 min
microwave
O
N
H
NH
Ph
PhNH2
180 °C
30 min
91%
2t R = Ph (82%)
2u R = 4-FPh (85%)
2v R = 4-MeOPh (78%)
13C NMR (125 MHz, DMSO-d6): d = 167.9, 162.9, 157.8, 149.8,
O
82.0, 33.7, 28.6, 28.1, 14.8.
HN
O
MS: m/z (%) = 182 (42), 200 (100), 227 (23) [M + H+].
N
H
Cl
6-Amino-3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyri-
midine-5-carboxylic Acid Benzylamide (2d)
Mp 193 °C.
Scheme 1
ATR–IR: 3336, 2930, 1692, 1644, 1595, 1513, 1446 cm–1.
obtained in good yield in contrast to conventional thermal
conditions. This methodology might be applied to the par-
allel synthesis of 5-carbamoylated 6-aminouracils and
new fused pyrimidines.
1H NMR (500 MHz, DMSO-d6): d = 10.73 (br s, 1 H), 10.18–10.20
(m, 1 H), 7.56–7.61 (m, 3 H), 7.43 (d, J = 7.4 Hz, 2 H), 7.31–7.36
(m, 4 H), 7.25–7.27 (m, 1 H), 6.56 (br s, 1 H), 4.47 (d, J = 5.9 Hz,
2 H), 3.18 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 167.7, 163.0, 157.6, 149.1,
139.6, 133.7, 130.0, 129.8, 129.3, 128.4, 127.2, 126.8, 80.3, 41.8,
27.4.
Melting points were measured on a digital Mettler Tolledo FP90 ap-
paratus and are uncorrected. ATR–IR spectra were recorded on a
SensIR Technologies TravelIR spectrometer. 1H NMR (500 MHz)
and 13C NMR (125 MHz) spectra were recorded on a Bruker AMX
500 spectrometer in DMSO-d6 with the solvent signals as reference.
Mass spectra were obtained with a Waters ZQ mass spectrometer
with an electrospray ionization source. Microwave experiments
were carried out on an Emrys Creator from Personal Chemistry.
MS: m/z (%) = 85 (31), 126 (25) 244 (91), 262 (100), 285 (35)
[M + H+].
6-Amino-3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyri-
midine-5-carboxylic Acid Cyclohexylamide (2e)
Mp 225 °C.
ATR–IR: 3348, 1692, 1644, 1600, 1514, 1444, 1368 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 10.83 (br s, 1 H), 9.85–9.87
(m, 1 H), 7.55–7.70 (m, 3 H), 7.41–7.43 (m, 2 H), 6.49 (br s, 1 H),
3.74–3.76 (m, 1 H), 3.18 (s, 3 H), 1.80–1.82 (m, 2 H), 1.64–1.67 (m,
2 H), 1.51–1.54 (m, 1 H), 1.25–1.37 (m, 5 H).
Carbamoylation of 6-Aminouracils under Microwave Irradia-
tion; General Procedure
To a microwave reaction vessel were added 6-aminouracil 1 (1
mmol), isocyanate (1.2 mmol) and nitrobenzene (1 mL). The reac-
tion vessel was irradiated at 210 °C for the appropriate time
(Table 2). The reaction mixture was transferred to a round-bot-
tomed flask and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel (EtOAc–hex-
ane) or recrystallization (EtOH) to provide the corresponding car-
bamoylated 6-aminouracil 2 as a solid.
13C NMR (125 MHz, DMSO-d6): d = 166.7, 162.9, 157.5, 149.1,
133.7, 130.0, 129.8, 129.3, 80.3, 46.4, 32.4, 27.4, 25.2, 24.1.
MS: m/z (%) = 85 (24), 262 (26), 343 (22) [M + H+], 365 (100)
[M + Na+].
6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic Acid Butylamide (2a)
6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic Acid Phenylamide (2f)
Mp 125 °C (Lit.5c mp 130 °C).
Mp 244 °C (Lit.5c mp 250 °C).
ATR–IR: 3327, 2929, 1705, 1639, 1534, 1025 cm–1.
ATR–IR: 3453, 1695, 1578, 1527, 1439, 1368 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 11.11 (br s, 1 H), 9.77 (br s, 1
H), 7.85 (br s, 1 H), 3.30 (s, 3 H), 3.19–3.22 (m, 2 H), 3.15 (s, 3 H),
1.43–1.47 (m, 2 H), 1.30–1.32 (m, 2 H), 0.90 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 167.6, 162.4, 157.8, 149.3,
81.2, 37.6, 31.3, 29.5, 27.6, 19.6, 13.6.
1H NMR (500 MHz, DMSO-d6): d = 12.16 (s, 1 H), 10.87 (br s, 1
H), 8.64 (br s, 1 H), 7.58 (d, J = 8.6 Hz, 2 H), 7.27–7.34 (m, 2 H),
7.04–7.07 (m, 1 H), 3.45 (s, 3 H), 3.22 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 166.2, 163.0, 158.1, 149.1,
138.6, 128.9, 123.1, 119.8, 80.5, 29.7, 27.8.
MS: m/z (%) = 74 (11), 173 (100), 182 (16), 255 (32) [M + 1].
MS: m/z (%) = 85 (100), 126 (58), 200 (50), 275 (35) [M + H+].
6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic Acid Cyclohexylamide (2b)
Mp > 375 °C.
ATR–IR: 3324, 2927, 1639, 1592, 1530, 1445 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 11.13 (br s, 1 H), 9.84–9.86
(m, 1 H), 7.86 (br s, 1 H), 3.73–3.74 (m, 1 H), 3.32 (s, 3 H), 3.16 (s,
1 H), 1.41–1.80 (m, 5 H), 1.22–1.36 (m, 5 H).
6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic Acid (4-Methoxyphenyl)amide (2g)
Mp 185 °C.
ATR–IR: 3438, 1702, 1664, 1584, 1534, 1447, 1238 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.00 (s, 1 H), 10.91 (br s, 1
H), 7.49 (d, J = 7.9 Hz, 2 H), 6.90 (d, J = 8.9 Hz, 2 H), 3.78 (s, 3 H),
3.36 (s, 3 H), 3.23 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 165.9, 162.9, 158.0, 149.2,
131.7, 121.3, 114.0, 80.4, 55.2, 29.7, 27.8.
MS: m/z (%) = 139 (52), 159 (100), 273 (82), 305 (12) [M + H+].
13C NMR (125 MHz, DMSO-d6): d = 166.8, 162.5, 157.9, 149.1,
80.2, 46.4, 32.4, 29.5, 27.6, 25.2, 24.1.
MS: m/z (%) = 69 (28), 85 (42), 281 (32) [M + H+], 303 (100) [M +
Na+].
6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic Acid (4-Chlorophenyl)amide (2h)
Mp 291 °C (Lit.3a mp > 270 °C).
6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic Acid Ethylamide (2c)
Mp 158 °C (Lit.5c mp 172 °C).
Synthesis 2005, No. 16, 2713–2717 © Thieme Stuttgart · New York

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J. Y. Lee et al.
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ATR–IR: 3467, 1708, 1658, 1570, 1526, 1364 cm–1.
6-Amino-3-(4-methoxybenzyl)-2,4-dioxo-1-phenyl-1,2,3,4-tet-
rahydropyrimidine-5-carboxylic Acid Phenylamide (2m)
Mp 212 °C.
ATR–IR: 3454, 1699, 1653, 1611, 1511, 1423, 1247 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.25 (s, 1 H), 10.77 (br s, 1
H), 8.19 (br s, 1 H), 7.62 (d, J = 8.9 Hz, 2 H), 7.37 (d, J = 8.8 Hz, 2
H), 3.36 (s, 3 H), 3.22 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 166.3, 163.0, 158.1, 149.1,
1H NMR (500 MHz, DMSO-d6): d = 12.10 (s, 1 H), 10.64 (br s, 1
H), 7.58–7.61 (m, 5 H), 7.49–7.51 (m, 2 H), 7.31–7.34 (m, 4 H),
6.88–6.90 (m, 3 H), 4.99 (s, 2 H), 3.73 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 166.2, 163.1, 158.4, 158.0,
149.0, 138.5, 133.5, 130.1, 129.9, 129.3, 129.2, 128.9, 123.3, 119.9,
113.7, 80.6, 55.0, 43.4.
137.6, 128.7, 126.6, 121.3, 80.4, 29.8, 27.9.
MS: m/z (%) = 85 (100), 126 (95), 229 (38), 291 (18), 309 (8) [M +
H+].
6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic Acid (2-Bromophenyl)amide (2i)
Mp 285 °C.
MS: m/z (%) = 69 (42), 85 (100), 126 (80), 443 (33) [M + H+].
ATR–IR: 3378, 1702, 1653, 1610, 1525, 1435, 1290 cm–1.
6-Benzylamino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyri-
midine-5-carboxylic Acid Phenylamide (2n)
Mp > 375 °C.
ATR–IR: 3111, 1698, 1659, 1582, 1450, 1347 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.36 (s, 1 H), 10.77 (s, 1 H),
8.30–8.32 (m, 1 H), 8.21 (br s, 1 H), 7.65–7.38 (m, 1 H), 7.34–7.38
(m, 1 H), 7.01–7.04 (m, 1 H), 3.37 (s, 3 H), 3.23 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 166.5, 162.8, 158.2, 149.2,
1H NMR (500 MHz, DMSO-d6): d = 12.19 (s, 1 H), 11.44 (br s, 1
H), 7.51–7.53 (m, 2 H), 7.40–7.41 (m, 4 H), 7.29–7.36 (m, 3 H),
7.04–7.07 (m, 1 H), 4.70 (d, J = 5.2 Hz, 2 H), 3.49 (s, 3 H), 3.24 (s,
3 H).
13C NMR (125 MHz, DMSO-d6): d = 166.1, 163.1, 162.0, 150.4,
138.3, 137.6, 128.9, 128.8, 127.8, 127.7, 120.0, 118.2, 84.6, 50.0,
36.4, 28.0.
137.0, 132.6, 127.9, 124.7, 122.9, 113.5, 80.6, 29.8, 27.9.
MS: m/z (%) = 85 (96), 126 (100), 164 (42), 229 (38), 377 (35) [M
+ H+].
6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic Acid (2-Ethylphenyl)amide (2j)
Mp > 375 °C.
ATR–IR: 3471, 1704, 1579, 1534, 1443 cm–1.
MS: m/z (%) = 85 (33), 126 (27), 272 (100), 365 (18) [M + H+].
1,3-Dimethyl-2,4-dioxo-6-propylamino-1,2,3,4-tetrahydropyri-
midine-5-carboxylic Acid Phenylamide (2o)
Mp 154 °C.
ATR–IR: 2959, 1703, 1642, 1585, 1537, 1441, 1231 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.01 (s, 1 H), 10.94 (br s, 1
H), 8.12 (br s, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 7.23 (d, J = 7.5 Hz, 1
H), 7.18 (t, J = 7.8 Hz, 1 H), 7.04 (t, J = 7.4 Hz, 1 H), 3.36 (s, 3 H),
3.24 (s, 3 H), 2.66 (q, J = 7.5 Hz, 2 H), 1.19 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 166.3, 163.1, 158.2, 149.2,
136.2, 133.7, 128.5, 126.1, 123.7, 122.1, 80.7, 29.7, 27.9, 24.3,
14.2.
1H NMR (500 MHz, DMSO-d6): d = 12.22 (s, 1 H), 11.14 (br s, 1
H), 7.58 (d, J = 5.0 Hz, 2 H), 7.27–7.30 (m, 2 H), 6.97 (t, J = 7.3 Hz,
1 H), 3.42–3.45 (m, 5 H), 3.23 (s, 3 H), 1.62–1.65 (m, 2 H), 0.97 (t,
J = 7.4 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 166.3, 163.0, 162.0, 150.4,
138.4, 128.3, 123.3, 120.0, 84.0, 48.5, 36.2, 27.9, 23.4, 11.1.
MS: m/z (%) = 182 (57), 200 (100), 223 (30), 303 (65) [M + H+].
6-Amino-3-methyl-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyri-
midine-5-carboxylic Acid Phenylamide (2k)
Mp 227 °C.
MS: m/z (%) = 85 (19), 224 (100), 317 (25) [M + H+].
ATR–IR: 3363, 1690, 1661, 1588, 1495, 1432, 1376 cm–1.
6-Amino-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylic Acid Butylamide (2p)
Mp > 375 °C.
ATR–IR: 3269, 2957, 1693, 1605, 1531, 1414, 1377 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.17 (s, 1 H), 10.58 (br s, 1
H), 7.58–7.62 (m, 5 H), 7.46–7.48 (m, 2 H), 7.32–7.33 (m, 2 H),
7.05–7.08 (m, 1 H), 6.78 (br s, 1 H), 3.25 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 166.2, 163.4, 157.8, 148.9,
1H NMR (500 MHz, DMSO-d6): d = 11.09 (s, 1 H), 10.96 (s, 1 H),
9.71–9.73 (m, 1 H), 7.87 (s, 1 H), 3.19–3.24 (m, 5 H), 1.41–1.45 (m,
2 H), 1.29–1.35 (m, 2 H), 0.86–0.91 (t, J = 7.3 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 167.7, 163.3, 159.2, 148.7,
80.1, 37.5, 31.3, 28.4, 19.6, 13.7.
138.6, 133.6, 130.1, 129.9, 129.3, 128.9, 123.2, 119.8, 80.6, 27.7.
MS: m/z (%) = 85 (100), 126 (48), 244 (65), 262 (53), 337 (22)
[M + H+].
6-Amino-1,3-dibutyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylic Acid Phenylamide (2l)
Mp 124 °C.
MS: m/z (%) = 85 (43), 165 (72), 241 (55) [M + H+], 263 (100)
[M + Na+].
ATR–IR: 3364, 2957, 1697, 1648, 1594, 1546, 1440 cm–1.
6-Amino-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylic Acid Benzylamide (2q)
Mp 295 °C.
ATR–IR: 3270, 3180, 1725, 1644, 1602, 1521, 1439 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 11.00 (s, 2 H), 10.11–10.13 (m,
1 H), 7.94 (s, 1 H), 7.32–7.35 (m, 2 H), 7.25–7.29 (m, 3 H), 4.44 (d,
J = 5.9 Hz, 2 H), 3.26 (s, 3 H).
1H NMR (500 MHz, DMSO-d6): d = 12.21 (s, 1 H), 11.06 (br s, 1
H), 8.19 (br s, 1 H), 7.57–7.59 (m, 2 H), 7.29–7.34 (m, 2 H), 7.04–
7.06 (m, 1 H), 3.93–4.02 (m, 2 H), 3.85–3.87 m, 2 H), 1.53–1.55 (m,
4 H), 1.30–1.34 (m, 4 H), 0.90–0.93 (m, 6 H).
13C NMR (125 MHz, DMSO-d6): d = 166.4, 162.7, 157.4, 148.7,
138.5, 128.8, 123.2, 119.9, 80.4, 41.8, 40.8, 29.5, 28.9, 19.6, 19.2,
13.7, 13.6.
13C NMR (125 MHz, DMSO-d6): d = 167.9, 163.4, 159.2, 148.7,
139.7, 128.3, 127.1, 126.8, 80.1, 41.6, 28.5.
MS: m/z (%) = 213 (40), 235 (68), 276 (100), 359 (50) [M + H+].
MS: m/z (%) = 85 (36), 165 (100), 186 (20), 275 (8) [M + H+].
Synthesis 2005, No. 16, 2713–2717 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Facile One-Step Carbamoylation of 6-Aminouracils
2717
6-Amino-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylic Acid Phenylamide (2r)
Mp 320 °C.
ATR–IR: 3270, 3180, 1711, 1670, 1585, 1530, 1443 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.14 (s, 1 H), 11.24 (s, 1 H),
10.84 (s, 1 H), 8.16 (s, 1 H), 7.56 (d, J = 8.1 Hz, 2 H), 7.27–7.33 (m,
2 H), 7.05 (t, J = 7.2 Hz, 1 H).
Acknowledgment
We are grateful to The Center for High Throughput Synthesis Plat-
form Technology and the Ministry of Commerce Industry for the fi-
nancial support of this research.
Reference
13C NMR (125 MHz, DMSO-d6): d = 167.3, 164.7, 160.4, 149.4,
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139.5, 129.6, 123.8, 120.4, 80.9, 28.8.
MS: m/z (%) = 64 (100), 101 (37), 157 (22), 261 (8) [M + H+].
6-Amino-2,4-dioxo-1-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylic Acid Phenylamide (2s)
Mp 311 °C.
ATR–IR: 3342, 3095, 1725, 1586, 1512, 1416 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.14 (s, 1 H), 11.39 (s, 1 H),
10.58 (s, 1 H), 7.57–7.61 (m, 5 H), 7.47–7.51 (m, 2 H), 7.31–7.34
(m, 2 H), 7.05–7.07 (m, 1 H), 6.81 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 166.2, 164.2, 159.2, 148.3,
138.6, 133.1, 130.1, 129.8, 123.1, 119.7, 80.4.
MS: m/z (%) = 85 (21), 126 (25), 248 (100), 323 (35) [M + H+].
2,4-Dioxo-6-phenylamino-1,2,3,4-tetrahydropyrimidine-5-car-
boxylic Acid Phenylamide (2t)
Mp 144 °C.
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ATR–IR: 3309, 3234, 3137, 1703, 1619, 1586, 1520 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.59 (s, 1 H), 12.12 (s, 1 H),
11.18 (br s, 1 H), 11.02 (s, 1 H), 7.56–7.60 (m, 2 H), 7.45–7.48 (m,
2 H), 7.32–7.37 (m, 3 H), 7.06–7.15 (m, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 166.5, 165.1, 156.8, 148.4,
138.3, 135.5, 129.6, 128.9, 126.8, 125.2, 123.3, 119.9, 81.0.
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MS: m/z (%) = 69 (25), 230 (30), 263 (28), 323 (23) [M + H+], 345
(100) [M + Na+].
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2,4-Dioxo-6-phenylamino-1,2,3,4-tetrahydropyrimidine-5-car-
boxylic Acid (4-Fluorophenyl)amide (2u)
Mp > 375 °C.
ATR–IR: 3384, 3113, 1727, 1663, 1612, 1497, 1372 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.55 (s, 1 H), 12.08 (s, 1 H),
11.18 (s, 1 H), 10.99 (br s, 1 H), 7.59–7.62 (m, 2 H), 7.45–7.48 (m,
2 H), 7.33–7.36 (m, 3 H), 7.15–7.19 (m, 2 H).
13C NMR (125 MHz, DMSO-d6): d = 166.4, 165.0, 156.7, 148.3,
135.4, 134.6, 135.4, 129.6, 126.9, 125.2, 121.8, 115.5, 115.4, 80.8.
MS: m/z (%) = 85 (100), 165 (67), 229 (34), 341 (18) [M + H+].
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2,4-Dioxo-6-phenylamino-1,2,3,4-tetrahydropyrimidine-5-car-
boxylic Acid (4-Methoxyphenyl)amide (2v)
Mp 268 °C.
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ATR–IR: 3408, 3404, 3042, 1712, 1665, 1588, 1555, 1441, 1415
cm–1.
1H NMR (500 MHz, DMSO-d6): d = 12.67 (s, 1 H), 11.91 (s, 1 H),
11.14 (s, 1 H), 10.99 (br s, 1 H), 7.44–7.50 (m, 4 H), 7.33–7.36 (m,
3 H), 6.90–6.92 (m, 2 H), 3.74 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 166.1, 165.0, 156.6, 148.3,
135.5, 132.9, 131.3, 129.6, 126.8, 125.2, 121.5, 119.9, 114.0, 80.9,
55.2.
MS: m/z (%) = 85 (75), 165 (100), 230 (40), 271 (50), 353 (43)
[M + H+].
Synthesis 2005, No. 16, 2713–2717 © Thieme Stuttgart · New York