A General, Efficient and Green Procedure for Synthesis of Dihydropyrimidine-5-carboxamides in Low Melting Betaine Hydrochloride/Urea Mixture

Article abstract of DOI:10.1002/cjoc.201500862

A simple, facile and convenient strategy has been developed for the synthesis of dihydropyrimidine-5-carboxamides in low melting mixture of betaine hydrochloride/urea. In this procedure, the low melting mixture of betaine hydrochloride/urea plays a triple

Full text of DOI:10.1002/cjoc.201500862

FULL PAPER
DOI: 10.1002/cjoc.201500862
A General, Efficient and Green Procedure for Synthesis of
Dihydropyrimidine-5-carboxamides in Low Melting
Betaine Hydrochloride/Urea Mixture
Peng Liu, Jianwu Hao, and Zhanhui Zhang*
College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang, Hebei 050024, China
A simple, facile and convenient strategy has been developed for the synthesis of dihydropyrimidine-5-carbox-
amides in low melting mixture of betaine hydrochloride/urea. In this procedure, the low melting mixture of betaine
hydrochloride/urea plays a triple role: as a catalyst, solvent and reactant. The present green protocol has advantages
such as high yield of products, short reaction times, operational simplicity, no chromatographic separation,
eco-friendliness, and applicability for large-scale synthesis.
Keywords low melting mixture, deep eutectic solvent, dihydropyrimidine-5-carboxamide, green chemistry
Introduction
friendly and economically viable processes for the syn-
thesis of DHPM-5-carboxamides is still a challenge in
synthetic chemistry.
Dihydropyrimidine (DHPM)-5-carboxamides are
one of the important class of N-heterocycles and have
attracted significant attention due to their various bio-
logical and pharmacological activities such as antitu-
bercular,[1] antihypertensive,[2] antiinflammatory,[3] anti-
cancer,[4] antimicrobial,[5] anti-HIV-1[6] and antimyco-
bacterial activities.[7] They also show activity specifi-
cally against dormant TB bacilli[8] and herpes simplex
virus.[9] In addition, DHPM-5-carboxamide analogues
have proven to be excellent templates for selective α1a
receptor subtype antagonists to warrant further consid-
eration for the treatment of benign prostatic hyperplasia
(BPH).[10] In view of their biological importance, sev-
eral synthetic methods have been developed.[11,12] The
most simple and straightforward method for the synthe-
sis of DHPM-5-carboxamides is a one-pot Biginelli
condensation of 3-ketoamides, aldehydes and urea un-
der strong acidic conditions.[1-4] Recently, replacement
of strong acids by more efficient catalysts such as eti-
dronic acid,[13] chloroacetic acid,[14,15] tangstophosphoric
The replacement of conventional hazardous organic
solvents by nontoxic and biodegradable and recyclable
media for green synthesis of fine chemicals, particularly
in the pharmaceutical industry has become an important
research area.[20] In this regard, deep eutectic solvents
(DESs) or low melting mixtures (LMMs), have emerged
as new generation of solvents in organic transforma-
tions.[21,22] DESs do not only share most of advantages
of conventional ionic liquids such as low vapor pressure,
wide liquid range and tunable physicochemical proper-
ties, but also overcome some of their limitations. Com-
pared with ILs, the synthetic process of these eutectic
mixtures is relatively simple, which is only by mixing
two or more compounds under heating until a homoge-
neous liquid is formed without any purification with
100% atom utilization rate. From the practical point of
view, these solvents are very appealing, especially con-
sidering the use of inexpensive and bio-renewable natu-
ral compounds as starting materials. In addition, in some
procedures, DES played a triple role of being catalyst,
solvent and reagent.[23]
acid (H3PW12O40),[16] uranyl nitrate hexahydrate
[19]
[UO2(NO3)2•6H2O],[17] ZrCl4,[18] and Yb(OTf)3
has
been developed. Although these catalytic systems are
efficient for synthesis of DHPM-5-carboxamides, they
possess several disadvantages such as the use of harmful
and toxic organic solvents as well as unavailable and
costly catalysts, high temperature, long reaction times,
cumbersome work up procedures or low yields. There-
fore, the further development of simple, efficient, eco-
With our continuous interest in developing environ-
mentally benign synthetic methodologies,[24] herein, we
report a novel and effective protocol for synthesis of
dihydropyrimidine-5-carboxamides through a one-pot
condensation of N-acetoacetanilide with various alde-
hydes in betaine hydrochloride/urea (Scheme 1).
*
E-mail: zhanhui@126.com; Tel.: 0086-0311-80787431
Received December 9, 2015; accepted February 16, 2016; published online March 23, 2016.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500862 or from the author.
Chin. J. Chem. 2016, 34, 637—645
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
637

Liu, Hao & Zhang
Table 1 Optimization of reaction conditionsa
FULL PAPER
Scheme 1 Synthesis of dihydropyrimidine-5-carboxamides in
betaine hydrochloride/urea
Entry
1d No
DESb
t/℃ Time/minYieldc/%
R
80
80
80
100
90
10
71
80
O
O
betaine hydrochloride/urea
80 oC
R1CHO
+
2
3
ChCl/urea (54∶46)
N
H
1
2
ZnCl2/urea (39∶61)
Tartaric acid/mannitol/urea
(30∶20∶50)
60
R
O
4
5
6
80
80
80
60
60
60
78
21
30
HN
N
H
Fructose/urea (50∶50)
Fructose/urea /NaCl
(50∶40∶10)
O
N
R1
H
3
Glucose/urea/NH4Cl
(60∶30∶10)
7
80
80
80
50
60
70
80
90
80
80
80
60
60
60
60
60
60
20
20
20
20
20
41
15
83
49
76
82
92
92
44
53
79
Results and Discussion
Glucose/urea/CaCl2
(50∶40∶10)
A series of low melting mixtures were prepared by
mixing one or two compounds with urea in an appropri-
ate molar ratio. The mixture was heated slowly until
forming a homogeneous colorless liquid. Then, it was
cooled to room temperature and directly used without
any further purification.
8
Citric acid/mannitol/urea
(30∶20∶50)
9
Betaine hydrochloride/urea
(39∶61)
10
11
12
13
14
15
16
17
Subsequently, the reaction of acetoacetanilide (1
mmol) and benzaldehyde (1 mmol) was investigated in
different low melting mixtures and the results are sum-
marized in Table 1. In order to assess the role of low
melting mixtures, the reaction was attempted in the ab-
sence of solvent but containing urea (1 mmol) at 80 ℃,
and it was observed that only trace amount of product
was detected (Table 1, Entry 1). The product 3a could
be obtained in 71% yield when the reaction was carried
out in choline chloride (ChCl)/urea (Table 1, Entry 2). A
noticeable improvement of the yield was observed when
the reaction was conducted in low melting mixtures
such as ZnCl2/urea or tartaric acid/mannitol/urea. Fur-
ther studies showed that the yield could be increased to
as high as 92% when the reaction was performed in be-
taine hydrochloride/urea based on DES without the use
of any promoter or additional urea (Table 1, Entry 13).
In addition, screening indicated that the choice of tem-
perature was also very crucial for the reaction. The yield
of product 3a decreased when the temperature was de-
creased to 70 ℃. However, no increase in the yield of
product was observed when the reaction temperature
was raised from 80 to 90 ℃. It is noteworthy that de-
creasing the amount of solvent resulted in a significant
decrease in yield (Table 1, Entries 15－18). It may be
because urea is also used as a reactant, with the reduc-
tion of the solvent, the amount of urea is also reduced.
We found that 1.0 g betaine hydrochloride/urea was
necessary in order to achieve the best result.
Betaine hydrochloride/urea
(39∶61)
Betaine hydrochloride/urea
(39∶61)
Betaine hydrochloride/urea
(39∶61)
Betaine hydrochloride/urea
(39∶61)
Betaine hydrochloride/urea
(39∶61) 0.25 g
Betaine hydrochloride/urea
(39∶61) 0.50 g
Betaine hydrochloride/urea
(39∶61) 0.75 g
Betaine hydrochloride/urea
(39∶61) 1.50 g
18
80
80
20
20
93
90
Betaine hydrochloride/urea
(39∶61)
a Reaction condition: N-acetoacetanilide (1 mmol), benzaldehyde
(1 mmol), solvent (1.0 g) unless otherwise specified in the Table.
b The ratio is given in weight%. c Isolated yield. d Urea (1 mol)
was added. e The reaction was carried out in 100 g scale.
19e
general, aromatic aldehydes containing electron-neutral,
electron-rich or electron-poor groups reacted well with
acetoacetanilide to afford the desired products in high
yields. Halogen atoms such as fluorine, chloride, and
bromine on the aromatic ring were unaffected under the
present reaction conditions to provide the corresponding
products in high yields, which could allow for further
synthetic transformation. In addition, more bulky
substrate such as 1-naphthaldehyde also reacted well to
provide the desired product in high yield (Table 2, Entry
21). It should be noted that the acid-sensitive hetero
aromatic aldehyde such as 2-thiophene-carbaldehyde
To illustrate the practical synthetic utility of this
method, a 100 gram scale experiment was performed
and product 3a was obtained by recrystallization in 90%
yield (Table 1, Entry 19). This satisfying result is very
promising and encouraging from practical point of view.
Having established the optimum reaction conditions,
we set out to survey the generality and scope of this
reaction and the results were summarized in Table 2. In
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Chin. J. Chem. 2016, 34, 637—645

Synthesis of Dihydropyrimidine-5-carboxamides in Low Melting Betaine Hydrochloride/Urea Mixture
Table 2 Synthesis of DHPM-5-carboxamide derivatives in betaine hydrochloride/ureaa
m.p./℃
Reported
Entry
Aldehyde
R
Product
3a
Time/min
Yieldb/%
Found
1
PhCHO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
20
30
30
30
40
25
25
35
25
30
18
20
20
20
20
20
20
15
15
15
25
20
30
120
15
20
30
40
20
20
15
20
30
40
20
20
92
86
87
89
84
85
86
90
90
88
90
89
90
92
90
92
93
92
93
93
84
85
90
40
92
91
94
85
88
90
90
87
91
82
86
89
247－249
186－187
184－186
242－244
265－268
262－263
286－288
190－192
254－256
278－279
227－230
225－228
221－222
245－247
140－141
118－120
294－297
260－263
258－259
268－271
164－166
174－176
＞330
246－248[25]
2
2-MeO-C6H4CHO
3-MeO-C6H4CHO
4-MeO-C6H4CHO
3,4-(MeO)2-C6H3CHO
3-OH-C6H4CHO
4-OH-C6H4CHO
3-OPh-C6H4CHO
4-Me-C6H4CHO
4-t-Bu-C6H4CHO
2-F-C6H4CHO
3b
3c
3d
3e
3f
3
180－185[14]
240－242[17]
4
3
6
7
3g
3h
3i
8
9
10
11
12
13
14
13
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
3j
3k
3l
2-Cl-C6H4CHO
226－228[25]
244－246[25]
3-Cl-C6H4CHO
3m
3n
3o
3p
3q
3r
3s
4-Cl-C6H4CHO
2-Br-C6H4CHO
3-Br-C6H4CHO
4-Br-C6H4CHO
292－294[26]
262－264[25]
256－258[25]
3-NO2-C6H4CHO
4-NO2-C6H4CHO
4-CN-C6H4CHO
1-Naphthaldehyde
2-Thiophene-carbaldehyde
Terephthalaldehyde
CH3CH2CHO
3t
3u
3v
3w
3x
174－178[14]
230－232
263－264
256－258
269－271
226－229
245－248
＞330
PhCHO
Me 3y
Me 3z
Me 3aa
Me 3ab
Me 3ac
Me 3ad
Cl 3ae
Cl 3af
Cl 3ag
Cl 3ah
Cl 3ai
Cl 3aj
4-Me-C6H4CHO
4-NO2-C6H4CHO
1-Naphthaldehyde
2-Thiophene-carbaldehyde
Terephthalaldehyde
PhCHO
268－269
249－251
297－298
234－236
221－223
310－312
265－266[27]
294－295[1]
220－222[5]
4-Me-C6H4CHO
4-NO2-C6H4CHO
1-Naphthaldehyde
2-Thiophene-carbaldehyde
Terephthalaldehyde
a Reaction condition: N-acetoacetanilide (1 mmol), aldehyde (1 mmol), betaine hydrochloride/urea (1.0 g). b Isolated yield.
was subjected to the optimized conditions to give
expected product in 85% yield (Table 2, Entry 22).
However, the yield decreased if aliphatic aldehyde was
used as a substrate (Table 2, Entry 24).
Similarly, a variety of N-acetoacetanilides containing
both electron-rich and electron-poor groups on the phenyl
ring were employed under the above conditions and the
corresponding DHPM-5-carboxamides were obtained in
high yields.
method, we carried out the reaction of p-phthalaldehyde
with 2 equiv. of N-acetoacetanilide. As expected, the
bis-DHPM-5-carboxamides (4a－4c) could be obtained
in high yields under the identical conditions (Scheme 2).
A possible mechanism for the Biginelli reaction of
aldehydes, urea and N-acetoacetanilide is proposed in
Scheme 3. The first step in this reaction involves the
acid-catalyzed reaction of the aldehyde (2) with urea to
form intermediate A, which then dehydrates to give acyl
imine intermediate B. Subsequently, addition of enol
To further explore the generality of the current
Chin. J. Chem. 2016, 34, 637—645
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Liu, Hao & Zhang
FULL PAPER
Scheme 2 Synthesis of bis-DHPM-5-carboxamides in betaine
hydrochloride/urea
ers and used without further purification. Melting points
were determined on an X-4 apparatus and are uncor-
rected. IR spectra were obtained on a Thermo Scientific
Nicolet 50 spectrometer using KBr disks. NMR spectra
were recorded at room temperature on a Bruker DRX-
500 spectrometer at 500 MHz (1H), 125 MHz (13C) us-
ing DMSO-d6 as the solvent with TMS as internal stan-
dard. Mass spectra were operated at a 3200 Qtrap in-
strument with an ESI source. High-resolution mass
spectra (HRMS) were measured on a Thermo Fisher
Scientific LTQ FT Ultra mass spectrometer.
CHO
R
O
O
betaine hydrochloride/urea
80 oC
2
+
N
H
CHO
1
R
O
HN
N
H
O
N
H
H
N
O
Preparation of betaine hydrochloride/urea
H
N
4a R = H, 35 min, 89%
4b R = Me, 25 min, 88%
4c R = Cl, 30 min, 81%
NH
A mixture of betaine hydrochloride (100 mmol) and
urea (400 mmol) was added to a round-bottomed flask.
The mixture was stirred at 100 ℃ until a clear liquid
appeared. It can be directly used without any further
purification.
O
R
tautomer of N-acetoacetanilide (1) to the electron-defi-
cient acyl imine intermediate B produces an open-chain
ureide intermediate C, which subsequently cyclizes and
dehydrates to obtain the DHPM-5-carboxamide (3). As
can be seen from Scheme 3, a proton source is neces-
sary for this process. The hydrogen ion not only helps
the dehydration of intermediate A but also enolizes of
N-acetoacetanilide to form enolate intermediate. In this
procedure, the low melting mixture of betaine hydro-
chloride/urea plays the triple role of being a reactant, a
catalyst, and a solvent.
General procedure for synthesis of DHPM-5-car-
boxamides
N-Acetoacetanilide (1 mmol) and aldehyde (1 mmol)
were added in betaine hydrochloride/urea. The mixture
was heated with stirring at 80 ℃ for the appropriate
time. The progress of the reaction was monitored by
TLC. After completion of the reaction, the mixture was
cooled to room temperature. Then water was added to
dissolve DES and the reaction mixture was extracted
with ethyl acetate. The combined organic layer was
dried over anhydrous Na2SO4 and evaporated under re-
duced pressure. The resulting crude product was recrys-
tallized using EtOH to obtain the pure DHPM-5-car-
boxamide derivatives.
Scheme 3 Proposed mechanism
R1
R1
H
OH
NH2
O
H+
- H2O
R1CHO
+
N
NH2
N
H2N
NH2
2
6-Methyl-2-oxo-N,4-diphenyl-1,2,3,4-tetrahydro-
B
O
O
pyrimidine-5-carboxamide (3a)
White solid. 1H
A
NMR (DMSO-d6, 500 MHz) δ: 2.03 (s, 3H), 5.40 (d,
J＝2.5 Hz, 1H), 6.99 (t, J＝7.5 Hz, 1H), 7.22－7.28 (m,
5H), 7.32 (t, J＝7.5 Hz, 2H), 7.53 (d, J＝8.5 Hz, 2H),
7.57 (s, 1H), 8.71 (s, 1H), 9.55 (s, 1H); 13C NMR
(DMSO-d6, 125 MHz) δ: 16.9, 54.9, 105.3, 119.5, 122.9,
126.1, 127.2, 128.3, 128.4, 138.2, 139.1, 144.2, 152.5,
165.2; IR (KBr) v: 3406, 3281, 3117, 1710, 1645, 1629,
1437, 1323, 1246 cm1; m/z: 308 (M＋1)＋.
H
R
R
O
O
O
O
NH
H2N
N
H
Dehydration
1
R1
3
O
N
H
C
Conclusions
4-(2-Methoxyphenyl)-6-methyl-2-oxo-N-phenyl-1,
In conclusion, we have successfully developed a new,
highly efficient and environmentally-benign method for
the synthesis of dihydropyrimidine-5-carboxamide de-
rivatives in deep eutectic solvents. This method can be
effectively scaled up and a broad spectrum of dihydro-
pyrimidine-5-carboxamides can be rapidly obtained in
high to excellent yields. This deep eutectic solvent
serves simultaneously as a reactant, a solvent and a cat-
alyst. Notably, mild experiment conditions, short re-
action time, high yield and green solvent render this
new procedure useful in organic synthesis and industry.
2,3,4-tetrahydropyrimidine-5-carboxamide
(3b)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.02 (s,
3H), 3.67 (s, 3H), 5.64 (s, 1H), 6.90－6.99 (m, 3H),
7.10 (s, 1H), 7.20－7.26 (m, 4H), 7.17 (d, J＝8.0 Hz,
2H), 8.61 (s, 1H), 9.53 (s, 1H); 13C NMR (DMSO-d6,
125 MHz) δ: 16.7, 49.4, 55.2, 104.8, 110.9, 119.2, 120.2,
122.7, 126.8, 128.3, 128.5, 131.3, 138.2, 139.3, 153.0,
156.0, 165.2; IR (KBr) v: 3427, 3302, 3101, 1701, 1675,
1631, 1437, 1332, 1244, 1024 cm1; m/z: 338 (M＋1)＋.
4-(3-Methoxyphenyl)-6-methyl-2-oxo-N-phenyl-1,
2,3,4-tetrahydropyrimidine-5-carboxamide
(3c)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.04 (s,
3H), 3.68 (s, 3H), 5.39 (s, 1H), 6.80－6.87 (m, 3H),
7.00 (t, J＝7.0 Hz, 1H), 7.24 (t, J＝7.5 Hz, 3H), 7.56 (s,
Experimental
All reagents were obtained from commercial suppli-
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Chin. J. Chem. 2016, 34, 637—645

Synthesis of Dihydropyrimidine-5-carboxamides in Low Melting Betaine Hydrochloride/Urea Mixture
3H), 8.73 (s, 1H), 9.57 (s, 1H); 13C NMR (DMSO-d6,
125 MHz) δ: 16.9, 54.8, 105.2, 112.1, 112.2, 118.2,
119.5, 123.0, 128.4, 129.5, 138.3, 139.1, 145.7, 152.6,
159.2, 165.2; IR (KBr) v: 3394, 3281, 3109, 1712, 1648,
1629, 1437, 1319, 1244, 1037 cm1; m/z: 338 (M＋1)＋.
4-(4-Methoxyphenyl)-6-methyl-2-oxo-N-phenyl-1,
8.5 Hz, 2H), 7.01 (t, J＝7.5 Hz, 1H), 7.06－7.10 (m,
2H), 7.23－7.29 (m, 4H), 7.34 (t, J＝7.5 Hz, 1H), 7.52
(d, J＝8.0 Hz, 2H), 7.60 (s, 1H), 8.73 (s, 1H), 9.56 (s,
1H); 13C NMR (DMSO-d6, 125 MHz) δ: 16.9, 54.7,
105.1, 116.4, 117.2, 118.3, 119.6, 121.1, 123.0, 123.3,
128.4, 129.8, 130.0, 138.3, 139.0, 146.4, 152.4, 156.2,
156.4, 165.1; IR (KBr) v: 3446, 3290, 3101, 1718, 1655,
1627, 1437, 1327, 1244, 1072 cm1; m/z: 400 (M＋1)＋;
HRMS calcd for C24H22N3O3 (M＋H)＋ : 400.1655;
found 400.1658.
6-Methyl-2-oxo-N-phenyl-4-(p-tolyl)-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (3i) White solid.
1H NMR (DMSO-d6, 500 MHz) δ: 2.02 (s, 3H), 2.24 (s,
3H), 5.36 (d, J＝2.5 Hz, 1H), 6.99 (t, J＝7.5 Hz, 1H),
7.10－7.16 (m, 4H), 7.23 (t, J＝7.5 Hz, 2H), 7.52－
7.54 (m, 3H), 8.67 (s, 1H), 9.52 (s, 1H); 13C NMR
(DMSO-d6, 125 MHz) δ: 16.9, 20.5, 54.7, 105.4, 119.4,
122.9, 126.0, 128.3, 128.8, 136.3, 138.0, 139.1, 141.3,
152.4, 165.2; IR (KBr) v: 3402, 3275, 3117, 1707, 1643,
1626, 1437, 1327, 1244, 1101 cm1; m/z: 322 (M＋1)＋;
HRMS calcd for C19H20N3O2 (M＋H)＋ : 322.1550;
found 322.1553.
2,3,4-tetrahydropyrimidine-5-carboxamide
(3d)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.03 (s,
3H), 3.70 (s, 3H), 5.35 (s, 1H), 6.87 (d, J＝8.5 Hz, 2H),
6.98 (t, J＝7.5 Hz, 1H), 7.18－7.25 (m, 4H), 7.50 (s,
1H), 7.54 (d, J＝8.0 Hz, 2H), 8.67 (s, 1H), 9.50 (s, 1H);
13C NMR (DMSO-d6, 125 MHz) δ: 16.9, 54.4, 54.9,
105.5, 113.7, 119.4, 122.9, 127.4, 128.4, 136.3, 138.1,
139.1, 152.4, 158.4, 165.2; IR (KBr) v: 3402, 3277,
3117, 1707, 1649, 1627, 1437, 1325, 1246, 1031 cm1;
m/z: 338 (M＋1)＋.
4-(3,4-Dimethoxyphenyl)-6-methyl-2-oxo-N-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamide
(3e)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.03 (s,
3H), 3.65 (s, 3H), 3.69 (s, 3H), 5.35 (s, 1H), 6.80 (d, J＝
7.0 Hz, 1H), 6.85－6.89 (m, 2H), 6.99 (t, J＝7.5 Hz,
1H), 7.24 (t, J＝7.5 Hz, 2H), 7.49 (s, 1H), 7.54 (d, J＝
8.0 Hz, 2H), 8.85 (s, 1H), 9.52 (s, 1H); 13C NMR
(DMSO-d6, 125 MHz) δ: 16.9, 54.6, 55.3, 55.4, 105.3,
110.3, 111.6, 118.0, 119.4, 122.9, 128.4, 136.6, 138.0,
139.1, 148.0, 148.5, 152.4, 165.3; IR (KBr) v: 3354,
3286, 3117, 1716, 1644, 1629, 1437, 1321, 1247, 1018
cm1; m/z: 368 (M＋1)＋; HRMS calcd for C20H22N3O4
(M＋H)＋: 368.1604; found 368.1606.
4-(4-(tert-Butyl)phenyl)-6-methyl-2-oxo-N-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamide
(3j)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 1.23 (s,
9H), 2.04 (s, 3H), 5.38 (s, 1H), 6.88 (t, J＝7.5 Hz, 1H),
7.19－7.26 (m, 4H), 7.34 (d, J＝8.0 Hz, 2H), 7.53 (s,
1H), 7.56 (d, J＝8.0 Hz, 2H), 8.69 (s, 1H), 9.56 (s, 1H);
13C NMR (DMSO-d6, 125 MHz) δ: 16.9, 31.0, 34.1,
54.5, 105.5, 119.4, 122.9, 125.1, 125.7, 128.4, 138.3,
139.2, 141.3, 149.5, 152.6, 165.3; IR (KBr) v: 3389,
3273, 3124, 1691, 1647, 1624, 1545, 1442, 1249, 1072
cm1; m/z: 364 (M＋1)＋; HRMS calcd for C22H26N3O2
(M＋H)＋: 364.2019; found 364.2022.
4-(3-Hydroxyphenyl)-6-methyl-2-oxo-N-phenyl-1,
2,3,4-tetrahydropyrimidine-5-carboxamide
(3f)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.01 (s,
3H), 5.32 (s, 1H), 6.61 (d, J＝8.0 Hz, 1H), 6.67－6.70
(m, 2H), 6.99 (t, J＝7.5 Hz, 1H), 7.08 (t, J＝7.5 Hz,
1H), 7.24 (t, J＝7.5 Hz, 2H), 7.51 (s, 1H), 7.55 (d, J＝
8.5 Hz, 2H), 8.66 (s, 1H), 9.37 (s, 1H), 9.52 (s, 1H); 13C
NMR (DMSO-d6, 125 MHz) δ: 16.9, 54.9, 105.5, 113.0,
114.1, 116.6, 119.5, 122.9, 128.3, 129.2, 138.0, 139.1,
145.8, 152.5, 157.3, 165.2; IR (KBr) v: 3371, 3263,
3064, 1707, 1645, 1595, 1437, 1319, 1251, 1155 cm1;
m/z: 324 (M＋1)＋; HRMS calcd for C18H18N3O3 (M＋
H)＋: 324.1342; found 324.1343.
4-(2-Fluorophenyl)-6-methyl-2-oxo-N-phenyl-1,2,
3,4-tetrahydropyrimidine-5-carboxamide
(3k)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.02 (s,
3H), 5.65 (s, 1H), 6.98 (t, J＝7.0 Hz, 1H), 7.09－7.13
(m, 1H), 7.17 (t, J＝7.5 Hz, 1H), 7.22 (t, J＝8.0 Hz,
2H), 7.26－7.30 (m, 1H), 7.34 (t, J＝7.5 Hz, 1H),
7.48－7.51 (m, 3H), 8.72 (s, 1H), 9.59 (s, 1H); 13C
NMR (DMSO-d6, 125 MHz) δ: 16.8, 49.7, 104.1, 115.4
(d, 2JCF＝21.3 Hz), 119.4, 123.0, 124.4, 128.4, 128.6 (d,
4JCF＝3.9 Hz), 129.3 (d, 3JCF＝8.1 Hz), 130.8 (d, 3JCF＝
4-(4-Hydroxyphenyl)-6-methyl-2-oxo-N-phenyl-1,
2,3,4-tetrahydropyrimidine-5-carboxamide
(3g)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.02 (s,
3H), 5.29 (s, 1H), 6.68 (d, J＝8.0 Hz, 2H), 6.98 (t, J＝
7.5 Hz, 1H), 7.07 (d, J＝8.0 Hz, 2H), 7.23 (t, J＝8.0 Hz,
2H), 7.44 (s, 1H), 7.52 (d, J＝8.0 Hz, 2H), 8.62 (s, 1H),
9.33 (s, 1H), 9.47 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ: 16.9, 54.5, 105.7, 115.0, 119.5, 122.9, 127.4,
128.4, 134.7, 137.8, 139.1, 152.4, 156.5, 165.3; IR (KBr)
v: 3429, 3246, 3115, 1701, 1641, 1627, 1442, 1336,
1244, 1170 cm1; m/z: 324 (M＋1)＋; HRMS calcd for
C18H18N3O3 (M＋H)＋: 324.1342; found 324.1344.
13.6 Hz), 138.4, 139.1, 152.4, 159.2 (d, JCF＝245 Hz),
1
164.9; IR (KBr) v: 3439, 3296, 3107, 1716, 1645, 1622,
1438, 1321, 1246, 1103 cm1; m/z: 326 (M＋1)＋ ;
HRMS calcd for C18H17FN3O2 (M＋H)＋: 326.1299;
found 326.1302.
4-(2-Chlorophenyl)-6-methyl-2-oxo-N-phenyl-1,2,
3,4-tetrahydropyrimidine-5-carboxamide
(3l)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.02 (s,
3H), 5.78 (d, J＝2.0 Hz, 1H), 6.98 (t, J＝7.5 Hz, 1H),
7.21－7.28 (m, 3H), 7.35 (t, J＝7.5 Hz, 2H), 7.45－
7.50 (m, 4H), 8.78 (s, 1H), 9.66 (s, 1H); 13C NMR
(DMSO-d6, 125 MHz) δ: 16.7, 52.6, 104.5, 119.3, 122.9,
127.5, 128.3, 129.0, 129.2, 129.3, 131.3, 138.2, 139.0,
141.0, 152.0, 164.8; IR (KBr) v: 3394, 3232, 3128, 2933,
6-Methyl-2-oxo-4-(3-phenoxyphenyl)-N-phenyl-1,
2,3,4-tetrahydropyrimidine-5-carboxamide
(3h)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.02 (s,
3H), 5.39 (s, 1H), 6.84 (d, J＝9.5 Hz, 1H), 6.93 (d, J＝
Chin. J. Chem. 2016, 34, 637—645
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
641

Liu, Hao & Zhang
FULL PAPER
1693, 1645, 1631, 1531, 1440, 1259, 1041 cm1; m/z:
6-Methyl-4-(3-nitrophenyl)-2-oxo-N-phenyl-1,2,3,
4-tetrahydropyrimidine-5-carboxamide (3r) White
solid. H NMR (DMSO-d6, 500 MHz) δ: 2.07 (s, 3H),
342 (M＋1)＋.
1
4-(3-Chlorophenyl)-6-methyl-2-oxo-N-phenyl-1,2,
3,4-tetrahydropyrimidine-5-carboxamide
(3m)
5.51 (d, J＝2.5 Hz, 1H), 7.01 (t, J＝7.5 Hz, 1H), 7.25 (t,
J＝7.5 Hz, 1H), 7.51 (d, J＝8.0 Hz, 2H), 7.65 (t, J＝8.0
Hz, 1H), 7.73 (d, J＝7.5 Hz, 1H), 7.76 (s, 1H), 8.12－
8.15 (m, 2H), 8.90 (s, 1H), 9.62 (s, 1H); 13C NMR
(DMSO-d6, 125 MHz) δ: 17.6, 55.0, 105.0, 120.2, 121.5,
122.9, 123.7, 129.0, 130.6, 133.6, 139.5, 140.0, 146.9,
148.3, 152.8, 165.5; IR (KBr) v: 3409, 3272, 2974, 1710,
1671, 1627,1534, 1346, 1247 cm1; m/z: 353 (M＋1)＋.
6-Methyl-4-(4-nitrophenyl)-2-oxo-N-phenyl-1,2,3,
4-tetrahydropyrimidine-5-carboxamide (3s) White
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.04 (s,
3H), 5.38 (s, 1H), 7.00 (t, J＝7.5 Hz, 1H), 7.22－7.37
(m, 6H), 7.52 (d, J＝8.0 Hz, 2H), 7.61 (s, 1H), 8.76 (s,
1H), 9.57 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ:
17.0, 54.5, 104.7, 119.6, 123.1, 124.9, 126.1, 127.2,
128.4, 130.3, 133.0, 138.8, 139.0, 146.5, 152.3, 165.1;
IR (KBr) v: 3410, 3279, 3122, 1712, 1645, 1627, 1438,
1321, 1244, 1103 cm1; m/z: 342 (M＋1)＋; HRMS calcd
for C18H17ClN3O2 (M＋H)＋: 342.1003; found 342.1005.
4-(4-Chlorophenyl)-6-methyl-2-oxo-N-phenyl-1,2,
1
solid. H NMR (DMSO-d6, 500 MHz) δ: 2.07 (s, 3H),
3,4-tetrahydropyrimidine-5-carboxamide
(3n)
5.51 (d, J＝2.5 Hz, 1H), 7.02 (t, J＝7.5 Hz, 1H), 7.26 (t,
J＝8.0 Hz, 1H), 7.53－7.55 (m, 4H), 7.76 (s, 1H), 8.23
(d, J＝9.0 Hz, 1H), 8.89 (s, 1H), 9.63 (s, 1H); 13C NMR
(DMSO-d6, 125 MHz) δ: 17.6, 55.2, 104.9, 120.2, 123.7,
124.3, 128.0, 129.0, 139.5, 139.8, 147.2, 152.0, 152.8,
165.5; IR (KBr) v: 3375, 3267, 3104, 2930, 1723, 1666,
1622, 1517, 1346, 1239 cm1; m/z: 353 (M＋1)＋.
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.03 (s,
3H), 5.38 (d, J＝2.5 Hz, 1H), 7.00 (t, J＝7.0 Hz, 1H),
7.22－7.29 (m, 4H), 7.32 (d, J＝8.5 Hz, 2H), 7.53 (d,
J＝8.0 Hz, 2H), 7.61 (s, 1H), 8.77 (s, 1H), 9.56 (s, 1H);
13C NMR (DMSO-d6, 125 MHz) δ: 16.9, 54.4, 104.9,
119.5, 123.0, 128.0, 128.3, 128.4, 131.7, 138.6, 139.0,
143.1, 152.3, 165.1; IR (KBr) v: 3404, 3273, 3117, 1707,
1645, 1627, 1437, 1321, 1244, 1101 cm1; m/z: 342
(M＋1)＋.
6-Methyl-4-(4-cyanophenyl)-2-oxo-N-phenyl-1,2,3,
4-tetrahydropyrimidine-5-carboxamide (3t) White
1
solid. H NMR (DMSO-d6, 500 MHz) δ: 2.06 (s, 3H),
4-(2-Bromophenyl)-6-methyl-2-oxo-N-phenyl-1,2,
5.46 (d, J＝2.5 Hz, 1H), 7.01 (t, J＝7.5 Hz, 1H), 7.26 (t,
J＝8.0 Hz, 2H), 7.46 (d, J＝8.5 Hz, 2H), 7.54 (t, J＝8.0
Hz, 2H), 7.72 (s, 1H), 7.83 (d, J＝8.5 Hz, 2H), 8.87 (s,
1H), 9.63 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ:
17.6, 55.3, 105.0, 110.6, 120.1, 123.7, 127.8, 129.0,
130.0, 139.5, 139.8, 150.0, 153.0, 160.1, 165.6; IR (KBr)
v: 3308, 3279, 2927, 1707, 1663, 1622, 1429, 1326,
1242, 1150 cm1; m/z: 333 (M＋1)＋; HRMS calcd for
C19H17N4O2 (M＋H)＋: 333.1346; found 333.1347.
3,4-tetrahydropyrimidine-5-carboxamide
(3o)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.03 (s,
3H), 5.76 (s, 1H), 6.98 (t, J＝7.0 Hz, 1H), 7.16－7.23
(m, 3H), 7.39 (t, J＝7.5 Hz, 1H), 7.47－7.52 (m, 5H),
8.78 (s, 1H), 9.66 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ: 16.7, 55.2, 104.9, 119.3, 121.7, 123.0, 128.2,
128.4, 129.4, 129.5, 132.6, 138.0, 139.0, 142.6, 152.0,
164.8; IR (KBr) v: 3406, 3246, 3119, 1697, 1665, 1597,
1438, 1323, 1238, 1024 cm1; m/z: 386 (M＋1)＋ ;
HRMS calcd for C18H17BrN3O2 (M＋H)＋: 386.0498;
found 386.0501.
6-Methyl-4-(naphthalen-1-yl)-2-oxo-N-phenyl-1,2,
3,4-tetrahydropyrimidine-5-carboxamide
(3u)
Yellow solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.11 (s,
3H), 6.25 (d, J＝2.5 Hz, 1H), 6.95 (t, J＝7.5 Hz, 1H),
7.18 (t, J＝8.0 Hz, 2H), 7.45 (d, J＝8.0 Hz, 2H), 7.50－
7.53 (m, 3H), 7.58 (d, J＝8.0 Hz, 2H), 7.84 (d, J＝8.5
Hz, 1H), 7.92 (d, J＝5.0 Hz, 1H ), 8.31 (d, J＝5.0 Hz,
1H), 8.81 (s, 1H), 9.61 (s, 1H); 13C NMR (DMSO-d6,
125 MHz) δ: 17.5, 52.1, 106.0, 120.0, 123.5, 124.1,
125.6, 126.1, 126.5, 128.5, 128.9, 129.0, 130.6, 134.0,
138.8, 139.5, 140.1, 152.9, 165.7; IR (KBr) v: 3404,
3248, 2972, 1707, 1667, 1628, 1442, 1318, 1246, 1047
cm1; m/z: 358 (M＋1)＋; HRMS calcd for C22H20N3O2
(M＋H)＋: 358.1550; found 358.1553.
4-(3-Bromophenyl)-6-methyl-2-oxo-N-phenyl-1,2,
3,4-tetrahydropyrimidine-5-carboxamide
(3p)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.06 (s,
3H), 5.39 (s, 1H), 7.00 (t, J＝7.5 Hz, 1H), 7.23－7.31
(m, 4H), 7.42－7.48 (m, 2H), 7.51－7.56 (m, 3H), 8.71
(s, 1H), 9.52 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ:
17.0, 54.6, 104.8, 119.6, 121.7, 123.1, 125.3, 128.4,
129.0, 130.1, 130.7, 131.6, 139.0, 146.8, 152.0, 165.1;
IR (KBr) v: 3446, 3275, 3012, 1716, 1645, 1624, 1437,
1323, 1244, 1047 cm1; m/z: 386 (M＋1)＋; HRMS calcd
＋
for C18H17BrN3O2 (M ＋ H) : 386.0498; found
386.0500.
6-Methyl-4-(thiophen-2-yl)-2-oxo-N-phenyl-1,2,3,
4-tetrahydropyrimidine-5-carboxamide (3v) White
solid. H NMR (DMSO-d6, 500 MHz) δ: 2.07 (s, 3H),
4-(4-Bromophenyl)-6-methyl-2-oxo-N-phenyl-1,2,
3,4-tetrahydropyrimidine-5-carboxamide
1
(3q)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.03 (s,
3H), 5.37 (d, J＝2.5 Hz, 1H), 7.00 (t, J＝7.0 Hz, 1H),
7.21－7.25 (m, 4H), 7.52－7.54 (m, 4H), 7.61 (s, 1H),
8.77 (d, J＝1.5 Hz, 1H), 9.56 (s, 1H); 13C NMR
(DMSO-d6, 125 MHz) δ: 16.9, 54.4, 104.8, 119.5, 120.2,
123.0, 128.4, 131.2, 138.5, 139.0, 143.5, 152.3, 165.0;
IR (KBr) v: 3404, 3271, 3117, 1707, 1653, 1627, 1438,
1321, 1246, 1101 cm1; m/z: 387 (M＋1)＋.
5.68 (d, J＝3.0 Hz, 1H), 6.93－6.95 (m, 2H), 7.02 (t,
J＝7.5 Hz, 1H), 7.27 (t, J＝8.0 Hz, 2H), 7.38 (dd, J＝
1.5, 5.0 Hz, 1H), 7.58 (t, J＝7.5 Hz, 2H), 7.79 (s, 1H),
8.85 (s, 1H), 9.56 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ: 17.6, 51.1, 105.8, 120.2, 123.6, 124.0, 125.4,
127.2, 129.0, 139.7, 140.0, 149.2, 152.9, 165.4; IR (KBr)
v: 3405, 3277, 3115, 1715, 1645, 1627, 1518, 1322,
1248, 1079 cm1; m/z: 314 (M＋1)＋.
642
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 637—645

Synthesis of Dihydropyrimidine-5-carboxamides in Low Melting Betaine Hydrochloride/Urea Mixture
4-(4-Formylphenyl)-6-methyl-2-oxo-N-phenyl-1,2,
3,4-tetrahydropyrimidine-5-carboxamide (3w)
6-Methyl-4-(naphthalen-1-yl)-2-oxo-N-(p-tolyl)-1,
2,3,4-tetrahydropyrimidine-5-carboxamide (3ab)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.03 (s,
3H), 5.36 (s, 1H), 5.65 (s, 1H), 7.00 (t, J＝7.5 Hz, 1H),
7.22－7.25 (m, 5H), 7.30 (s, 1H), 7.53 (d, J＝8.0 Hz,
3H), 8.69 (s, 1H), 9.53 (d, J＝4.5 Hz, 1H); 13C NMR
(DMSO-d6, 125 MHz) δ: 17.5, 55.0, 109.1, 117.6, 120.1,
123.5, 126.2, 126.8, 129.0, 139.7, 143.8, 153.1, 161.6,
165.8, 191.7; IR (KBr) v: 3405, 3280, 3110, 1712, 1666,
1624, 1525, 1441, 1245, 1094 cm1; m/z: 336 (M＋1)＋;
HRMS calcd for C19H18N3O3 (M＋H)＋ : 336.1342;
found 336.1343.
Pale yellow solid. H NMR (DMSO-d6, 500 MHz) δ:
2.10 (s, 3H), 2.19 (s, 3H), 6.23 (d, J＝1.5 Hz, 1H), 6.99
(d, J＝8.0 Hz, 2H), 7.32 (d, J＝8.5 Hz, 2H), 7.50－7.53
(m, 4H), 7.57 (d, J＝6.5 Hz, 1H), 7.84 (d, J＝8.0 Hz,
1H), 7.92 (t, J＝5.0 Hz, 1H), 8.31 (t, J＝5.0 Hz, 1H),
8.74 (s, 1H), 9.50 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ: 17.4, 20.8, 52.1, 106.1, 120.0, 124.1, 125.5,
126.0, 126.1, 128.4, 129.3, 130.6, 132.4, 134.0, 137.0,
138.4, 140.1, 152.9, 165.5; IR (KBr) v: 3405, 3283,
3119, 1706, 1655, 1633, 1518, 1349, 1244, 1109 cm1;
m/z: 372 (M＋1)＋; HRMS calcd for C23H22N3O2 (M＋
H)＋: 372.1707; found 372.1708.
6-Methyl-2-oxo-4-(thiophen-2-yl)-N-(p-tolyl)-1,2,3,
4-tetrahydropyrimidine-5-carboxamide (3ac) Pale
yellow solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.06 (s,
3H), 2.24 (s, 3H), 5.67 (d, J＝3.0 Hz, 1H), 6.93－6.95
(m, 2H), 7.07 (d, J＝8.5 Hz, 2H), 7.38 (dd, J＝1.0, 4.5
Hz, 1H), 7.46 (d, J＝8.5 Hz, 2H), 7.76 (s, 1H), 8.80 (s,
1H), 9.45 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ:
17.6, 20.9, 51.1, 105.9, 120.3, 124.0, 125.4, 127.1,
129.3, 132.5, 137.2, 149.2, 152.9, 165.2; IR (KBr) v:
3429, 3250, 3111, 1708, 1645, 1628, 1519, 1332, 1248,
1089 cm1; m/z: 328 (M ＋ 1) ＋ ; HRMS calcd for
C17H18N3O2S (M＋H)＋: 328.1114; found 328.1116.
4-(4-Formylphenyl)-6-methyl-2-oxo-N-(p-tolyl)-1,
1
4-Ethyl-6-methyl-2-oxo-N-phenyl-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (3x) White solid.
1H NMR (DMSO-d6, 500 MHz) δ: 0.85 (s, 3H), 1.44－
1.49 (m, 2H), 1.96 (s, 3H), 4.22 (s, 1H), 7.02－7.07 (m,
2H), 7.28 (t, J＝7.5 Hz, 2H), 7.61 (d, J＝7.5 Hz, 2H),
8.43 (s, 1H), 9.57 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ: 8.78, 17.3, 30.1, 53.2, 105.7, 120.2, 123.6,
129.0, 138.4, 139.8, 153.7, 166.4; IR (KBr) v: 3472,
3216, 2921, 1705, 1676, 1632, 1593, 1438, 1249, 1073
cm1; m/z: 260 (M＋1)＋; HRMS calcd for C14H18N3O2
(M＋H)＋: 260.1393; found 260.1394.
6-Methyl-2-oxo-4-phenyl-N-(p-tolyl)-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (3y) White solid.
1H NMR (DMSO-d6, 500 MHz) δ: 2.04 (s, 3H), 5.39 (d,
J＝2.0 Hz, 1H), 7.04 (d, J＝8.5 Hz, 2H), 7.21－7.23 (m,
1H), 7.28－7.32 (m, 4H), 7.39 (d, J＝8.5 Hz, 3H), 8.52
(s, 1H), 9.32 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ:
16.8, 20.2, 55.0, 105.4, 119.5, 126.1, 127.1, 128.2,
128.6, 131.8, 136.5, 137.8, 144.1, 152.4, 165.0; IR (KBr)
v: 3405, 3277, 3115, 1710, 1645, 1627, 1518, 1320,
1246, 1099 cm1; m/z: 322 (M＋1)＋; HRMS calcd for
C19H20N3O2 (M＋H)＋: 322.1550; found 322.1553.
6-Methyl-2-oxo-N,4-di-p-tolyl-1,2,3,4-tetrahy-
2,3,4-tetrahydropyrimidine-5-carboxamide
(3ad)
1
Pale yellow solid. H NMR (DMSO-d6, 500 MHz) δ:
2.23 (s, 3H), 2.51 (s, 3H), 5.36 (s, 1H), 7.04 (d, J＝8.5
Hz, 4H), 7.23 (s, 2H), 7.41 (d, J＝8.5 Hz, 3H), 7.50 (s,
1H), 8.63 (s, 1H), 9.42 (s, 1H); 13C NMR (DMSO-d6,
125 MHz) δ: 17.5, 20.9, 55.1, 105.9, 106.0, 120.2, 126.7,
126.8, 129.3, 130.4, 132.4, 137.1, 138.7, 143.8, 143.9,
153.2, 165.6, 193.1; IR (KBr) v: 3399, 3265, 3112, 1705,
1665, 1626, 1518, 1327, 1243, 1090 cm1; m/z: 350
(M＋1)＋ ; HRMS calcd for C20H20N3O3 (M＋H)＋ :
350.1499; found 350.1501.
1
dropyrimidine-5-carboxamide (3z) White solid. H
NMR (DMSO-d6, 500 MHz) δ: 2.03 (s, 3H), 2.23 (s,
3H), 2.26 (s, 3H), 5.36 (d, J＝2.0 Hz, 1H), 7.05 (d, J＝
8.5 Hz, 2H), 7.12 (d, J＝8.0 Hz, 2H), 7.16 (d, J＝8.0 Hz,
2H), 7.43 (d, J＝8.5 Hz, 2H), 7.48 (s, 1H), 8.82 (s, 1H),
9.41 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ: 17.5,
20.9, 21.1, 55.3, 106.1, 120.1, 126.7, 129.3, 129.4,
132.4, 136.9, 137.2, 138.4, 141.9, 153.1, 165.6; IR (KBr)
v: 3402, 3279, 3115, 1719, 1672, 1626, 1519, 1326,
1245, 1101 cm1; m/z: 336 (M＋1)＋; HRMS calcd for
C20H22N3O2 (M＋H)＋: 336.1706; found 336.1708.
6-Methyl-4-(4-nitrophenyl)-2-oxo-N-(p-tolyl)-1,2,3,
4-tetrahydropyrimidine-5-carboxamide (3aa) Pale
yellow solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.05 (s,
3H), 2.23 (s, 3H), 5.51 (d, J＝2.5 Hz, 1H), 7.06 (d, J＝
8.5 Hz, 2H), 7.42 (d, J＝8.5 Hz, 2H), 7.53 (d, J＝9.0 Hz,
2H), 7.74 (s, 1H), 8.23 (d, J＝9.0 Hz, 2H), 8.86 (s, 1H),
9.54 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ: 17.6,
20.9, 55.2, 105.0, 120.2, 124.3, 128.0, 129.4, 132.6,
137.0, 139.6, 147.2, 152.8, 165.3; IR (KBr): v 3409,
3257, 3125, 1715, 1688, 1622, 1516, 1347, 1240, 1107
cm1; m/z: 367 (M＋1)＋; HRMS calcd for C19H19N4O4
(M＋H)＋: 367.1400; found 367.1401.
N-(4-Chlorophenyl)-6-methyl-2-oxo-4-phenyl-1,2,
3,4-tetrahydropyrimidine-5-carboxamide
(3ae)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.05 (s,
3H), 5.40 (s, 1H), 7.21－7.24 (m, 1H), 7.26－7.31 (m,
6H), 7.42 (s, 1H), 7.55 (d, J＝8.0 Hz, 2H), 8.57 (s, 1H),
9.54 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ: 16.9,
66.8, 105.0, 120.9, 126.0, 126.4, 127.1, 128.2, 128.3,
138.0, 138.8, 144.1, 152.4, 165.2; IR (KBr) v: 3446,
3273, 3117, 1712, 1645, 1629, 1458, 1396, 1244, 1089
cm1; m/z: 342 (M＋1)＋.
N-(4-Chlorophenyl)-6-methyl-2-oxo-4-(p-tolyl)-1,
2,3,4-tetrahydropyrimidine-5-carboxamide
(3af)
White solid. 1H NMR (DMSO-d6, 500 MHz) δ: 2.01 (s,
3H), 2.23 (s, 3H), 5.34 (d, J＝2.0 Hz, 1H), 7.09－7.13
(m, 4H), 7.27 (d, J＝9.0 Hz, 2H), 7.52 (s, 1H), 7.55 (d,
J＝9.0 Hz, 2H), 8.69 (s, 1H), 9.62 (s, 1H); 13C NMR
(DMSO-d6, 125 MHz) δ: 17.5, 21.1, 55.2, 105.7, 121.5,
126.6, 127.1, 128.8, 129.4, 136.9, 138.7, 139.3, 141.8,
153.0, 165.9; IR (KBr) v: 3406, 3285, 3125, 1759, 1675,
1628, 1539, 1346, 1246, 1109 cm1; m/z: 356 (M＋1)＋;
Chin. J. Chem. 2016, 34, 637—645
© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
643

Liu, Hao & Zhang
FULL PAPER
HRMS calcd for C19H19ClN3O2 (M＋H)＋: 356.1161;
found 356.1163.
MHz) δ: 17.5, 55.0, 55.2, 105.8, 105.9, 120.1, 123.5,
126.7, 126.8, 129.0, 138.9, 139.0, 139.7, 143.8, 143.9,
153.0, 153.1, 165.6, 165.8; IR (KBr) v: 3401, 3273,
3111, 1710, 1670, 1629, 1525, 1440, 1335, 1245, 1049
cm1; m/z: 537 (M＋1)＋; HRMS calcd for C30H29N6O4
(M＋H)＋: 537.2244; found 537.2248.
N-(4-Chlorophenyl)-6-methyl-4-(4-nitrophenyl)-
2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
(3ag) Pale yellow solid. H NMR (DMSO-d6, 500
1
MHz) δ: 2.07 (s, 3H), 5.51 (d, J＝2.5 Hz, 1H), 7.31 (d,
J＝8.5 Hz, 2H), 7.54 (d, J＝8.5 Hz, 2H), 7.58 (d, J＝
9.0 Hz, 2H), 7.78 (s, 1H), 8.23 (d, J＝9.0 Hz, 2H), 8.93
(s, 1H), 9.75 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ:
17.6, 55.1, 104.6, 121.7, 124.3, 127.3, 128.0, 128.9,
138.5, 140.4, 147.3, 151.9, 152.8, 165.6; IR (KBr) v:
3369, 3246, 3110, 1715, 1669, 1625, 1519, 1347, 1239,
1087 cm1; m/z: 388 (M＋1)＋.
4,4'-(1,4-Phenylene)bis(6-methyl-2-oxo-N-(p-tolyl)-
1,2,3,4-tetrahydropyrimidine-5-carboxamide)
(4b)
1
Pale yellow solid. m.p. >330 ℃; H NMR (DMSO-d6,
500 MHz) δ: 2.02 (s, 6H), 2.23 (s, 6H), 5.36 (s, 2H),
7.03 (d, J＝8.5 Hz, 4H), 7.23 (s, 4H), 7.41 (d, J＝8.5
Hz, 4H), 7.51 (s, 2H), 8.65 (s, 2H), 9.44 (s, 2H); 13C
NMR (DMSO-d6, 125 MHz) δ: 17.5, 20.9, 55.1, 120.2,
126.7, 126.8, 129.3, 137.2, 138.8, 143.8, 153.1, 165.6;
IR (KBr) v: 3450, 3261, 3110, 1705, 1675, 1626, 1519,
1331, 1243, 1090 cm1; m/z: 565 (M＋1)＋; HRMS calcd
for C32H33N6O4 (M＋H)＋: 565.2557; found 565.2559.
4,4'-(1,4-Phenylene)bis(N-(4-chlorophenyl)-6-
methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbox-
N-(4-Chlorophenyl)-6-methyl-4-(naphthalen-1-yl)-
2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
(3ah) Pale yellow solid. H NMR (DMSO-d6, 500
1
MHz) δ: 2.07 (s, 3H), 6.21 (d, J＝2.0 Hz, 1H), 7.22 (d,
J＝9.0 Hz, 2H), 7.45－7.50 (m, 5H), 7.53 (d, J＝6.5 Hz,
1H), 7.57 (s, 1H), 7.82 (d, J＝8.0 Hz, 1H), 7.89 (t, J＝
5.0 Hz, 1H), 8.26 (t, J＝5.0 Hz, 1H), 8.81 (s, 1H), 9.72
(s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ: 17.5, 49.1,
105.7, 121.4, 124.1, 125.5, 126.1, 126.5, 127.1, 128.5,
128.8, 129.0, 130.6, 134.0, 138.5, 139.2, 140.0, 152.9,
165.8; IR (KBr) v: 3400, 3281, 3130, 1707, 1672, 1635,
1503, 1327, 1243, 1089 cm1; m/z: 392 (M＋1)＋ ;
HRMS calcd for C22H19ClN3O2 (M＋H)＋: 392.1160;
found 392.1158.
1
amide) (4c) Pale yellow solid. m.p. 271－273 ℃; H
NMR (DMSO-d6, 500 MHz) δ: 2.00 (s, 6H), 5.33 (s,
2H), 7.19 (s, 4H), 7.25 (t, J＝7.0 Hz, 4H), 7.49－7.54
(m, 6H), 8.67 (s, 2H), 9.61 (d, J＝3.5 Hz, 2H); 13C
NMR (DMSO-d6, 125 MHz) δ: 17.5, 55.0, 55.1, 105.5,
105.6, 121.6, 126.7, 128.9, 138.6, 139.6, 143.8, 143.9,
153.1, 160.1, 165.8; IR (KBr) v: 3454, 3205, 3105, 1710,
1647, 1606, 1552, 1493, 1241, 1109 cm1; m/z: 605
(M＋1)＋; HRMS calcd for C30H27Cl2N6O4 (M＋H)＋:
605.1465; found 605.1468.
N-(4-Chlorophenyl)-6-methyl-2-oxo-4-(thiophen-
2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide
(3ai) Pale yellow solid. H NMR (DMSO-d6, 500
1
Acknowledgement
MHz) δ: 2.04 (s, 3H), 5.65 (d, J＝3.0 Hz, 1H), 6.89－
6.92 (m, 2H), 7.30 (d, J＝8.5 Hz, 2H), 7.36 (dd, J＝1.0,
J＝5.0 Hz, 1H), 7.59 (d, J＝9.0 Hz, 2H), 7.79 (s, 1H),
8.86 (s, 1H), 9.65 (s, 1H); 13C NMR (DMSO-d6, 125
MHz) δ: 17.6, 51.0, 105.6, 121.7, 124.0, 125.4, 127.1,
127.2, 128.9, 138.7, 140.6, 149.2, 152.8, 165.4; IR (KBr)
v: 3421, 3283, 3104, 1719, 1654, 1628, 1514, 1247,
1089 cm1; m/z: 349 (M＋1)＋.
This research was supported by generous grants
from the National Natural Science Foundation of China
(No. 21272053) and the Natural Science Foundation of
Hebei Province (No. B2015205182).
References
[1] Virsodia, V.; Pissurlenkar, R. R. S.; Manvar, D.; Dholakia, C.;
Adlakha, P.; Shah, A.; Coutinho, E. C. Eur. J. Med. Chem. 2008, 43,
2103.
[2] Alam, O.; Khan, S. A.; Siddiqui, N.; Ahsan, W.; Verma, S. P.; Gilani,
S. J. Eur. J. Med. Chem. 2010, 45, 5113.
N-(4-Chlorophenyl)-4-(4-formylphenyl)-6-methyl-
2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
1
(3aj) Pale yellow solid. H NMR (DMSO-d6, 500
MHz) δ: 2.03 (s, 3H), 5.36 (d, J＝2.0 Hz, 1H), 7.21 (s,
2H), 7.27－7.32 (m, 3H), 7.48 (d, J＝8.0 Hz, 1H), 7.55
(s, 1H), 7.57 (s, 2H), 7.79 (d, J＝8.0 Hz, 1H), 8.73 (s,
1H), 9.66 (s, 1H); 13C NMR (DMSO-d6, 125 MHz) δ:
17.6, 55.5, 104.9, 121.6, 126.8, 127.1, 127.2, 127.4,
128.8, 128.9, 130.4, 135.9, 138.5, 138.6, 140.0, 143.8,
151.1, 152.9, 153.0, 165.8, 193.1; IR (KBr) v: 3420,
3269, 2924, 1715, 1627, 1515, 1397, 1240, 1087 cm1;
m/z: 371 (M＋1)＋.
[3] Sawant, R. L.; Bansode, C. A.; Wadekar, J. B. Med. Chem. Res. 2013,
22, 1884.
[4] Desai, N. C.; Chhabaria, M. T.; Dodiya, A.; Bhavsar, A. M.;
Baldaniya, B. B. Med. Chem. Res. 2011, 20, 1331.
[5] Sedaghati, B.; Fassihi, A.; Arbabi, S.; Ranjbar, M.; Memarian, H. R.;
Saghaie, L.; Omidi, A.; Sardari, A.; Jalali, M.; Abedi, D. Med. Chem.
Res. 2012, 21, 3973.
[6] Zabihollahi, R.; Fassihi, A.; Aghasadeghi, M. R.; Memarian, H. R.;
Soleimani, M.; Majidzadeh, K. Med. Chem. Res. 2013, 22, 1270.
[7] Zalavadiya, P.; Tala, S.; Akbari, J.; Joshi, H. Arch. Pharm. 2009, 342,
469.
[8] Joshi, R. R.; Barchha, A.; Khedkar, V. M.; Pissurlenkar, R. R. S.;
Sarkar, S.; Sarkar, D.; Joshi, R. R.; Joshi, R. A.; Shah, A. K.;
Coutinho, E. C. Chem. Biol. Drug Des. 2015, 85, 201.
[9] Zabihollahi, R.; Fassihi, A.; Aghasadeghi, M. R.; Memarian, H. R.;
Soleimani, M.; Majidzadeh, K. Med. Chem. Res. 2013, 22, 1270.
[10] Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K. L.; Rittle,
4,4'-(1,4-Phenylene)bis(6-methyl-2-oxo-N-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxamide)
(4a)
1
White solid. m.p. 296－298 ℃; H NMR (DMSO-d6,
500 MHz) δ: 2.03 (s, 6H), 5.37 (s, 2H), 7.00 (t, J＝7.5
Hz, 2H), 7.23 (s, 8H), 7.53 (d, J＝8.5 Hz, 6H), 8.69 (s,
2H), 9.53 (d, J＝4.0 Hz, 2H); 13C NMR (DMSO-d6, 125
644
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© 2016 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2016, 34, 637—645

Synthesis of Dihydropyrimidine-5-carboxamides in Low Melting Betaine Hydrochloride/Urea Mixture
K. E.; Gilbert, K. F.; Steele, T. G.; Homnick, C. F.; Freidinger, R. M.;
Ransom, R. W.; Kling, P.; Reiss, D.; Broten, T. P.; Schorn, T. W.;
Chang, R. S. L.; O'Malley, S. S.; Olah, T. V.; Ellis, J. D.; Barrish, A.;
Kassahun, K.; Leppert, P.; Nagarathnam, D.; Forray, C. J. Med.
Chem. 2000, 43, 2703.
2854; (g) Yan, N.; Xiong, Y. K.; Xia, J. H.; Rui, P. X.; Lei, Z. W.;
Liao, W. L.; Xiong, B. Chin. J. Org. Chem. 2015, 35, 384; (h) Tang,
B. K.; Row, K. H. Monatsh. Chem. 2013, 144, 1427; (i) Jérôme, F.;
Ferreira, M.; Bricout, H.; Menuel, S.; Monflier, E.; Tilloy, S. Green
Chem. 2014, 16, 3876; (j) De Oliveira Vigier, K.; Chatel, G.; Jérôme,
F. ChemCatChem 2015, 7, 1250; (k) Ferreira, M.; Jérôme, F.;
Bricout, H.; Menuel, S.; Landy, D.; Fourmentin, S.; Tilloy, S.;
Monflier, E. Catal. Commun. 2015, 63, 62; (l) van Osch, D. J. G. P.;
Zubeir, L. F.; van den Bruinhorst, A.; Rocha, M. A. A.; Kroon, M. C.
Green Chem. 2015, 17, 4518; (m) Kow, K. K.; Sirat, K. Chin. Chem.
Lett. 2015, 26, 1311; (n) Zhang, L. X.; Yu, H.; Yu, H. B.; Chen, Z.;
Yang, L. Chin. Chem. Lett. 2014, 25, 1132.
[11] Memarian, H. R.; Soleymani, M. Ultrason. Sonochem. 2011, 18,
745.
[12] Desai, B.; Dallinger, D.; Kappe, C. O. Tetrahedron 2006, 62, 4651.
[13] Pansuriya, A. M.; Savant, M. M.; Bhuva, C. V.; Singh, J.; Naliapara,
Y. T. Arkivoc 2009, (vii), 79.
[14] Couto, I.; Tellitu, I.; Dominguez, E. Arkivoc 2011, (ii), 115.
[15] Couto, I.; Tellitu, I.; Dominguez, E. J. Org. Chem. 2010, 75, 7954.
[16] Amini, M. M.; Shaabani, A.; Bazgir, A. Catal. Commun. 2006, 7,
843.
[17] Venkatesan, K.; Satyanarayana, V. S. V.; Sivakumar, A. J. Chin.
Chem. Soc. 2014, 61, 624.
[18] Soleymani, M.; Memarian, H. R. Z. Naturforsch. 2010, 65, 485.
[19] Stadler, A.; Kappe, C. O. J. Comb. Chem. 2001, 3, 624.
[20] Gu, Y. L.; Jerome, F. Chem. Soc. Rev. 2013, 42, 9550.
[21] (a) Zhang, Q. H.; De Oliveira Vigier, K.; Royer, S.; Jérôme, F. Chem.
Soc. Rev. 2012, 41, 7108; (b) Smith, E. L.; Abbott, A. P.; Ryder, K. S.
Chem. Rev. 2014, 114, 11060; (c) Paiva, A.; Craveiro, R.; Aroso, I.;
Martins, M.; Reis, R. L.; Duarte, A. R. C. ACS Sustainable Chem.
Eng. 2014, 2, 1063; (d) Russ, C.; König, B. Green Chem. 2012, 14,
2969; (e) García-Álvarez, J. Eur. J. Inorg. Chem. 2015, 5147; (f) Liu,
P.; Hao, J. W.; Mo, L. P.; Zhang, Z. H. RSC Adv. 2015, 5, 48675; (g)
Francisco, M.; van den Bruinhorst, A.; Kroon, M. C. Angew. Chem.,
Int. Ed. 2013, 52, 3074; (h) Wang, A.; Zheng, X.; Zhao, Z.; Li, C.;
Zheng, X. Prog. Chem. 2014, 26, 784.
[22] (a) Zhang, Z. H.; Zhang, X. N.; Mo, L. P.; Li, Y. X.; Ma, F. P. Green
Chem. 2012, 14, 1502; (b) Ma, F. P.; Cheng, G. T.; He, Z. G.; Zhang,
Z. H. Aust. J. Chem. 2012, 65, 409; (c) Wang, P.; Ma, F. P.; Zhang, Z.
H. J. Mol. Liq. 2014, 198, 259; (d) Li, P. H.; Ma, F. P.; Wang, P.;
Zhang, Z. H. Chin. J. Chem. 2013, 31, 757; (e) Hu, H. C.; Liu, Y. H.;
Li, B. L.; Cui, Z. S.; Zhang, Z. H. RSC Adv. 2015, 5, 7720; (f) Lu, J.;
Li, X. T.; Ma, E. Q.; Mo, L. P.; Zhang, Z. H. ChemCatChem 2014, 6,
[23] (a) Gore, S.; Baskaran, S.; König, B. Green Chem. 2011, 13, 1009;
(b) Gore, S.; Baskaran, S.; Koenig, B. Adv. Synth. Catal. 2012, 354,
2368; (c) Mahajan, H.; Bhardwaj, M.; Paul, S. Org. Prep. Proced.
Int. 2014, 46, 463; (d) Azizi, N.; Alipour, M. J. Mol. Liq. 2015, 206,
268; (e) Gore, S.; Chinthapally, K.; Baskaran, S.; König, B. Chem.
Commun. 2013, 49, 5052.
[24] (a) Deng, J.; Mo, L. P.; Zhao, F. Y.; Hou, L. L.; Yang, L.; Zhang, Z.
H. Green Chem. 2011, 13, 2576; (b) Liu, Y. H.; Deng, J.; Gao, J. W.;
Zhang, Z. H. Adv. Synth. Catal. 2012, 354, 441; (c) Guo, R. Y.;
Wang, P.; Wang, G. D.; Mo, L. P.; Zhang, Z. H. Tetrahedron 2013,
69, 2056; (d) Ma, F. P.; Li, P. H.; Li, B. L.; Mo, L. P.; Liu, N.; Kang,
H. J.; Liu, Y. N.; Zhang, Z. H. Appl. Catal. A: Gen. 2013, 457, 34; (e)
Li, P. H.; Li, B. L.; An, Z. M.; Mo, L. P.; Cui, Z. S.; Zhang, Z. H.
Adv. Synth. Catal. 2013, 355, 2952; (f) Li, B. L.; Zhang, M.; Hu, H.
C.; Du, X.; Zhang, Z. H. New J. Chem. 2014, 38, 2435; (g) Zhao, X.
N.; Hu, H. C.; Zhang, F. J.; Zhang, Z. H. Appl. Catal. A: Gen. 2014,
482, 258; (h) Li, P. H.; Li, B. L.; Hu, H. C.; Zhao, X. N.; Zhang, Z.
H. Catal. Commun. 2014, 46, 118; (i) Lu, J.; Ma, E. Q.; Liu, Y. H.;
Li, Y. M.; Mo, L. P.; Zhang, Z. H. RSC Adv. 2015, 5, 59167.
[25] Gein, V. L.; Zamaraeva, T. M.; Kurbatova, A. A.; Vakhrin, M. I.
Chem. Heterocycl. Compd. 2010, 46, 856.
[26] Duburs, G.; Khanina, E. L. Khim. Geterotsikl. Soedin. 1976, 2, 220.
[27] Baldev, A. D.; Vyas, K. B.; Patel, K. B.; Nimavat, K. S. J. Chem.
Pharm. Res. 2012, 4, 2972.
(Pan, B.; Qin, X.)
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www.cjc.wiley-vch.de
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