Biginelli-type reaction: Efficient synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2-ones and thiones from gem-dibromomethylarenes

Article abstract of DOI:10.1002/jhet.4066

In the present study, we are reporting a simple and efficient method for the one-pot synthesis of the biologically important heterocyclic molecules 5-unsubstituted 3,4-dihydropyrimidin-2-ones and thiones using gem-dibromomethylarenes, oxalacetic acid, and urea or thiourea. Gem-dibromomethylarenes are used as aldehyde equivalent for the efficient synthesis of 3,4-dihydropyrimidin-2-ones/thiones. This reaction offers advantages for the synthesis of these compounds, including ready availability of the starting materials, experimental simplicity and in good yields. Besides, the synthesized molecules are interesting for their biological and pharmacological actions.

Full text of DOI:10.1002/jhet.4066

Received: 13 April 2020
DOI: 10.1002/jhet.4066
Revised: 8 June 2020
Accepted: 10 June 2020
A R T I C L E
Biginelli-type reaction: Efficient synthesis of
-unsubstituted 3,4-dihydropyrimidin-2-ones and thiones
5
from gem-dibromomethylarenes
1
1
Vinaya Kambappa | Chandrashekara Ganganahalli Kotturappa
|
1
2
Raghavendra Sheshachar Manjunath | Prasanna Doddakunche Shivaramu
1
Department of Chemistry, Government
Abstract
First Grade College, Kadur, India
2
In the present study, we are reporting a simple and efficient method for the one-
pot synthesis of the biologically important heterocyclic molecules 5-unsubstituted
Department of Nanotechnology,
Visvesvaraya Technological University,
Center for Postgraduate Studies,
3,4-dihydropyrimidin-2-ones and thiones using gem-dibromomethylarenes, oxa-
Bengaluru Region, Chikkaballapur, India
lacetic acid, and urea or thiourea. Gem-dibromomethylarenes are used as alde-
hyde equivalent for the efficient synthesis of 3,4-dihydropyrimidin-2-ones/
thiones. This reaction offers advantages for the synthesis of these compounds,
including ready availability of the starting materials, experimental simplicity and
in good yields. Besides, the synthesized molecules are interesting for their biologi-
cal and pharmacological actions.
Correspondence
Vinaya Kambappa, Department of
Chemistry, Government First Grade
College, Kadur 577548, India.
Email: vinayk_chem@yahoo.co.in
Prasanna Doddakunche Shivaramu,
Department of Nanotechnology,
Visvesvaraya Technological University,
Center for Postgraduate Studies,
Bengaluru Region, Muddenahalli,
Chikkaballapur 562101, India.
Email: prasuds@gmail.com
[
9]
[10]
[11]
1
| INTRODUCTION
CeCl Á7H O,
ZnCl2,
NiCl Á6H O,
FeCl Á6H O,
3
2
12]
2
2
[14]
3
[15]
2
[
[13]
Zeolites,
Yb(OTf)2,
Cu(OTf) ,
Zn(OTf) ,
and
2
2
[16]
The Biginelli reaction is a simple and versatile procedure
for the synthesis of dihydro-pyrimidinones in a three-
component reaction of aliphatic or aromatic aldehyde,
acetoacetate ester, and urea. This type of multicomponent
reactions is very promising to generate extremely diverse
organic molecules of varied biological and pharmacological
importance. Since dihydropyrimidinones display good bio-
logical activity, synthesis of their derivatives has been the
very interesting field for the researchers working in the area
of organic, medicinal chemistry, and related fields.
number of multistep reactions have been developed and
reported by researchers starting with aldehydes
acetoacetate equivalents in Biginelli-type reactions.
Bi(OTf)2 as active catalysts. Even though these methods
are effective, many of them are associated with drawbacks
such as harsh reaction conditions such as strongly acidic
condition, prolonged reaction times, meticulous work-up
protocols, expensive and moisture sensitive starting mate-
rials and unsatisfactory yields.
Even though, Biginelli reaction has history of over a
century, and lot of work is being published by the
researchers in the recent past,
ture precedent for the use of gem-dibromomethylarene as
substrates for the synthesis of 5-unsubstituted
3,4-dihydropyrimidin-2-ones and thiones. The substitution
of aldehyde component with another functional group has
not been explored so far. However, quite recently, synthe-
sis of 5-unsubstituted 3,4-dihydropyrimidin-2-ones was
reported by replacing alkyl acetoacetate with oxalacetic
[1]
[
17–19]
there is a lack litera-
[
2–4]
A
[
5]
or
[6]
In addition, several methods based on metal-catalyzed
Biginelli-type reactions have also been reported by the
researchers using simple metal salts like LiBr, NH Cl,
[7]
[8]
4
J Heterocyclic Chem. 2020;1–8.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals LLC.
1

2
KAMBAPPA ET AL.
acid as a substrate for the Biginelli reaction due to in situ
Under the above-mentioned reaction conditions, oxalacetic
acid emerged as an excellent substrate for the Biginelli reac-
tion. Cyclization and followed by in situ decarboxylation
yielded 5-unsubstituted 3,4-dihydropyrimidin-2-ones/
thiones in good yield. Plausible reaction mechanism is
shown in Scheme 2.
As gem-dibromomethylarenes are very stable and eas-
ily accessible alternates for some of the expensive non-
commercial and unstable aldehydes, this transformation
reaction would extend the scope in the organic synthesis.
In addition, it is very important to that the groups such as
chloro, bromo, nitrile, methoxy, and trifluoromethyl on
aromatic gem-dibromomethylarenes survived the reaction
conditions without any transformation and corresponding
5-unsubstituted 3,4-dihydropyrimidin-2-ones/thiones are
produced in good yield.
[20–21]
decarboxylation after cyclization,
Therefore, the
development of a simple and stable substitute for the alde-
hydes by using gem-dibromomethylarenes would extend
the scope of the reaction in organic synthesis. Recently,
gem-dibromomethylarenes have received considerable
attention due to their application in the preparation of
[
22]
[23]
aldehydes,
α,β-unsaturated carboxylic
acids,
[
24]
[25]
[26]
esters,
benzimidazoles,
quinazolinones, oxadiazoles,
benzothiazoles,
aryl
and others. In
[
27]
[28]
oximes,
continuation of our efforts in developing useful synthetic
methodologies from gem-dibromomethylarenes, in this
study, we are reporting the one-step synthesis of
3
,4-dihydropyrimidin-2-ones/thiones by conversion of
gem-dibromomethylarenes.
2
| RESULTS AND DISCUSSION
3
| CONCLUSION
3
,4-dihydropyrimidin-2-ones/thiones were synthesized
using oxalacetic acid, urea or thiourea, pyridine, and cat-
alytic amount of piperidine at reflux conditions as shown
in Scheme 1. Reaction conditions were optimized for
obtaining 3,4-dihydropyrimidin-2-ones/thiones in good
yield by varying the molar ratio of the reactants, reaction
temperature, and reaction time. Molar ratio of 1:1:1 with
respect to gem-dibromomethylarene 1, oxalacetic acid 2,
and urea or thiourea 3 in a one-pot Biginelli reaction
proceeded with highest yield in shorter reaction times as
shown in Table 1, entry 9.
In summary, gem-dibromomethylarenes with electron-
rich as well as electron-deficient substituent have been
exploited as excellent substrate for the synthesis of
5-unsubstituted 3,4-dihydropyrimidin-2-ones/thiones via
cyclocondensation in high yield. It is anticipated that this
methodology will have versatile applications in the prac-
tical syntheses of biologically important heterocyclic mol-
ecules with dihydropyrimidinone moiety. The carboxylic
acid attachment on C suggested functionality competent
6
of a wide variety of conversions.
As shown in Table 2, one equivalent of pyridine with
respect to the gem-dibromomethylarene is found to be suf-
ficient for complete conversion of the starting materials to
the corresponding products. The obtained products are
interesting building blocks of 3,4-dihydropyrimidin-2-one/
thione molecules containing α-amino acid. Catalysts
including DABCO, K CO , Cs CO triethylamine, DBU,
4 | EXPERIMENTAL SECTION
4.1 | General information
Melting points were recorded (uncorrected) on a Buchi
Melting Point B-545 instrument. Infrared (IR) spectra were
recorded using a Jasco FTIR-4100 series. All reagents and
solvents used were commercially procured and used as
2
3
2
3,
and piperidine, which promote base catalysis were
employed to improve the yield of the synthesis of
3,4-dihydropyrimidin-2-ones/thiones. Piperidine-catalyzed
1
reaction gave a quantitative yield in 10 hours, whereas the
other bases used in the study did not promote the reaction.
received. The H-NMR spectra were measured on a Bruker
DPX-400 at 400 MHz with TMS as internal standard. The
SCHEME 1 Synthesis of
5
3
-unsubstituted
,4-dihydropyrimidin-2-ones/
thiones

KAMBAPPA ET AL.
3
TABLE 1 Optimization of the synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2-ones and thiones
ꢀ
Sl.No
1 in equivalents
2 in equivalents
3 in equivalents
Time (h)
6 hours
8 hours
10 hours
6 hours
8 hours
10 hours
6 hours
8 hours
10 hours
6 hours
8 hours
10 hours
Temperature ( C)
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
25
25
22
31
39
40
56
71
74
87
94
70
74
81
25
50
50
50
80
80
80
1
1
1
0
1
2
100
100
100
TABLE 2 Preparation of 3,4-dihydropyrimidin-2(1H)-ones and
thiones using gem-dibromomethylarenes
4.1.1 | General procedure for the
synthesis of 2-oxo/thio-6-phenyl-
1
,2,3,6-tetrahydropyrimidine-4-carboxylic
a
ꢀ
MP ( C)
b
Compound
R
X
O
O
O
O
O
O
O
O
O
O
S
Yield (%)
94
acid derivatives 4(a-t)
[
20]
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
H
221-223
227-228
227-228
225-226
227-228
225-226
218-219
229-230
216-217
236-237
234-235
211-212
210-211
211-212
215-216
212-213
209-210
224-225
213-214
211-212
4-Cl
4-Br
4-F
82
Substituted gem-dibromomethylarene 1(a-t), oxalacetic acid,
and urea/thiourea were taken in N,N-dimethylformamide,
pyridine, and piperidine were added to the reaction mix-
83
[
21]
80
ꢀ
ture. The reaction mixture was refluxed at 80 C for 10 hours.
2-Cl,6-F
3-Br
4-OMe
4-CN
78
The progress of reaction was monitored by TLC. Upon com-
pletion, the solvent was removed under reduced pressure
and residue was taken in water and extracted with ethyl
acetate. The organic layer was dried with anhydrous
sodium sulphate, the solvent was evaporated to get 2-oxo/
thio-6-phenyl-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid
derivatives.
83
g
h
i
92
84
3-CF
3
83
j
4-Br,2-Cl
H
79
[
[
21]
21]
k
l
92
4-Cl
S
83
m
n
o
p
q
r
4-Br
S
83
4
1
.1.2 | 2-Oxo-6-phenyl-
4-F
S
80
,2,3,6-tetrahydropyrimidine-4-carboxylic
2-Cl, 6-F
3-Br
S
78
acid (4a)
S
82
The product obtained was pale yellow solid from
4-OMe
4-CN
S
91
(
dibromomethyl)benzene (1a) (0.1 g, 0.400 mmol), oxa-
S
82
lacetic acid (2) (0.052 g, 0.400 mmol), urea (0.030 g,
s
3-CF
3
S
81
0
0
.400 mmol), pyridine (2 mL), and piperidine (0.044 g,
.520 mmol). Yield: 0.109 g; 94%; IR (KBr) ν 3403,
t
4-Br,2-Cl
S
80
max
a
−1 1
Isolated yields of product.
Literature reported compounds.
3238, 3100, 1723, 1667 cm ; H-NMR (400 MHz, DMSO-
b
d ): δ 8.30 (s, 1H), 7.85 (s, 1H), 7.40 to 7.33 (m, 5H), 5.85
6
13
to 5.81 (m, 1H), 5.21 to 5.18 (m, 1H) ppm; C NMR
(100.6 MHz, DMSO-d ): δ 173.1, 162.91, 153.02, 144.24,
129.89, 127.90, 126.98, 125.95, 109.06, 54.94 ppm; MS
(ESI) m/z: 219.21.
1
3
C NMR spectra were measured on a Bruker DPX-400 at
00.6 MHz. The mass spectra were recorded on a JEOL
6
1
JMS-AX505HA mass spectrometer.

4
KAMBAPPA ET AL.
SCHEME 2 Proposed reaction mechanism for the synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2-ones
1
3
4
1
.1.3 | 6-(4-Chlorophenyl)-2-oxo-
,2,3,6-tetrahydropyrimidine-4-carboxylic
1H) ppm; C NMR (100.6 MHz, DMSO-d ): δ 173.9, 162.7,
6
161.8, 160.3, 151.5, 141.5, 139.2, 128.2, 127.3, 126.8, 118.0,
117.5, 108.5, and 53.9 ppm; MS (ESI) m/z: 298.11.
acid (4b)
The product obtained was pale yellow solid from 1-chloro-
4
-(dibromomethyl)benzene (1b) (0.1 g, 0.351 mmol), oxal-
4.1.5 | 6-(4-Fluorophenyl)-2-oxo-
1,2,3,6-tetrahydropyrimidine-4-carboxylic
acid (4d)
aceticacid (2) (0.046 g, 0.351 mmol), urea (0.021 g,
0
0
3
.351 mmol), pyridine (2 mL), and piperidine (0.038 g,
.457 mmol). Yield: 0.073 g, 82%; IR (KBr) ν 3389, 3227,
102, 1712, 1685, 1521 cm ; H-NMR (400 MHz, DMSO-
max
−1 1
The product obtained was off white solid from
1-(dibromomethyl)-4-fluorobenzene (1d) (0.1 g,
0.373 mmol), oxalacetic acid (2) (0.049 g, 0.373 mmol),
urea (0.022 g, 0.373 mmol), pyridine (2 mL) and piper-
idine (0.041 g, 0.485 mmol). Yield: 0.070 g, 80%; IR
d6): δ 8.38 (s, 1H), 7.88 (s, 1H), 7.39 to 7.34 (m, 2H), 7.24 to
7
1
1
1
.21 (m, 2H), 5.83 to 5.80 (m, 1H), 5.25 (dd, J = 1.9, 4.4 Hz,
H) ppm; C NMR (100.6 MHz, DMSO-d ): δ 173.2, 162.9,
62.0, 160.1, 150.3, 141.2, 138.5, 128.9, 128.0, 127.6, 117.2,
16.2, 109.0, and 54.4 ppm; MS (ESI) m/z: 253.98.
13
6
−
1
(KBr) ν
3396, 3221, 3108, 1719, 1681, 1515 cm ;
max
1
H-NMR (400 MHz, DMSO-d ): δ 8.28 (s, 1H), 7.83 (s,
6
1
H), 7.40 to 7.38 (m, 2H), 7.27 to 7.26 (m, 2H), 5.80 to
1
3
4
1
.1.4 | 6-(4-Bromophenyl)-2-oxo-
,2,3,6-tetrahydropyrimidine-4-carboxylic
5.78 (m, 1H), 5.21 (dd, J = 1.9, 4.4 Hz, 1H) ppm;
C
NMR (100.6 MHz, DMSO-d ): δ 173.2, 163.4, 162.1,
160.5, 150.8, 140.9, 139.4, 129.3, 128.1, 127.3, 115.8,
6
acid (4c)
1
15.2, 108.1, and 53.6 ppm; MS (ESI) m/z: 237.20.
The product obtained was pale brown solid from 1-bromo-
4-(dibromomethyl)benzene (1c) (0.1 g, 0.304 mmol), oxal-
aceticacid (2) (0.040 g, 0.304 mmol), urea (0.018 g,
4.1.6 | 6-(2-Chloro-6-fluorophenyl)-2-oxo-
1,2,3,6-tetrahydropyrimidine-4-carboxylic
acid (4e)
0
0
3
.304 mmol), pyridine (2 mL), and piperidine (0.033 g,
.395 mmol). Yield: 0.075 g, 83%); IR (KBr) ν 3395, 3235,
max
−1 1
111, 1705, 1681, 1518 cm ; H-NMR (400 MHz, DMSO-
d6): δ 8.32 (s, 1H), 7.88 (s, 1H), 7.40 to 7.37 (m, 2H), 7.26 to
.22 (m, 2H), 5.80 to 5.78 (m, 1H), 5.32 (dd, J = 1.9, 4.4 Hz,
The product obtained was pale yellow solid from 1-chloro-
2-(dibromomethyl)-3-fluorobenzene (1e) (0.1 g, 0.330 mmol),
7

KAMBAPPA ET AL.
5
oxalaceticacid (2) (0.043 g, 0.330 mmol), urea (0.019 g,
oxalaceticacid (2) (0.048 g, 0.363 mmol), urea (0.021 g,
0.330 mmol), pyridine (2 mL), and piperidine (0.036 g,
0.363 mmol), pyridine (2 mL), and piperidine (0.040 g,
0
3
.429 mmol). Yield: 0.069 g, 78%; IR (KBr) ν 3410, 3225,
108, 1732, 1660, 1270, 752, 695 cm ; H-NMR (400 MHz,
0.472 mmol). Yield: 0.074 g, 84%; IR (KBr) ν
3104, 2255, 1705, 1681, 1495 cm ; H-NMR (400 MHz,
3387, 3214,
max
max
−1
1
−1
1
DMSO-d ): δ 8.38 (s, 1H), 7.90 (s, 1H), 7.48 (d, 1H), 7.39 (d,
DMSO-d ): δ 8.28 (s, 1H), 7.78 (s, 1H), 7.36 to 7.33 (m, 2H),
6
6
1
H), 7.13 (t, 1H), 6.20 (d, J = 4.8 Hz, 1H), 5.15 (dd, J = 2.4,
7.23 to 7.21 (m, 2H), 5.84 to 5.81 (m, 1H), 5.28 (dd, J = 1.9,
13
13
4.8 Hz, 1H) ppm; C NMR (100.6 MHz, DMSO-d ): δ 173.1,
4.4 Hz, 1H) ppm; C NMR (100.6 MHz, DMSO-d ): δ 174.0,
6
6
1
63.5, 160.2, 141.9, 132.3, 128.1, 127.5, 124.2, 111.3, 109.8,
162.9, 162.0, 160.8, 151.9, 142.7, 138.9, 130.1, 128.4, 127.1,
114.6, 113.1, 108.1, and 54.2 ppm; MS (ESI) m/z: 244.24.
and 53.5 ppm; MS (ESI) m/z: 271.75.
4
1
.1.7 | 6-(3-Bromophenyl)-2-oxo-
,2,3,6-tetrahydropyrimidine-4-carboxylic
4.1.10 | 2-oxo-6-(3-[trifluoromethyl]
phenyl)-1,2,3,6-tetrahydropyrimidine-
4-carboxylic acid (4i)
acid (4f)
The product obtained was pale brown solid from
The product obtained was pale yellow solid from
1
0
-bromo-3-(dibromomethyl)benzene
.304 mmol), oxalaceticacid (2) (0.040 g, 0.304 mmol),
(1f)
(0.1
g,
1-(dibromomethyl)-3-(trifluoromethyl)benzene
(1i)
(0.1 g, 0.314 mmol), oxalaceticacid (2) (0.041 g,
0.314 mmol), urea (0.018 g, 0.314 mmol), pyridine
(2 mL), and piperidine (0.034 g, 0.408 mmol). Yield:
urea (0.018 g, 0.304 mmol), pyridine (2 mL), and piperi-
dine (0.033 g, 0.395 mmol). Yield: 0.075 g, 83%; IR (KBr)
−
1
1
νmax 3392, 3241, 3097, 1735, 1675, 643 cm ; H-NMR
400 MHz, DMSO-d ): δ 8.19 to 8.17 (m, 2H), 8.01 (s, 1H),
0.074 g, 83%; IR (KBr) ν
1615, 1564, 1506 cm ; H-NMR (400 MHz, DMSO-d ): δ
3237, 3103, 3002, 1709, 1672,
max
−
1 1
(
6
6
7
.91 (s, 1H), 7.80 (d, J = 7.70 Hz, 1H), 7.70 (dd, J = 7.63
8.35 (s, 1H), 8.25 to 8.22 (m, 2H), 8.01 (s, 1H), 7.92 (d,
J = 7.70 Hz, 1H), 7.79 (dd, J = 7.63 and 7.70 Hz, 1H),
7.62 (bs, 1H), 5.87 to 5.86 (m, 1H), 5.45 to 5.43 (m, 1H)
and 7.70 Hz, 1H), 7.50 (bs, 1H), 5.87 to 5.86 (m, 1H), 5.38
to 5.36 (m, 1H) ppm; C NMR (DMSO-d ): δ 173.2,
1
1
13
6
13
63.6, 153.2, 148.7, 145.4, 133.7, 130.2, 129.2, 123.0, 121.1,
09.1, 54.5 ppm; MS (ESI) m/z: 298.20.
ppm; C NMR (100.6 MHz, DMSO-d ): δ 172.8, 162.3,
6
154.0, 148.1, 145.0, 135.1, 131.2, 130.5, 125.3, 123.7, 122.5,
110.4, and 53.8 ppm; MS (ESI) m/z: 287.21.
4
1
.1.8 | 6-(4-Methoxyphenyl)-2-oxo-
,2,3,6-tetrahydropyrimidine-4-carboxylic
4.1.11 | 6-(4-Bromo-2-chlorophenyl)-
acid (4g)
2-oxo-1,2,3,6-tetrahydropyrimidine-
4-carboxylic acid (4j)
The product obtained was pale brown solid from
1
0
-(dibromomethyl)-4-methoxybenzene (1g) (0.1 g,
.357 mmol), oxalaceticacid (2) (0.047 g, 0.357 mmol),
The product obtained was pale brown solid from 4-bromo-
2-chloro-1-(dibromomethyl)benzene (1j) (0.1 g, 0.275 mmol),
oxalaceticacid (2) (0.036 g, 0.275 mmol), urea (0.016 g,
0.275 mmol), pyridine (2 mL), and piperidine (0.030 g,
0.357 mmol). Yield: 0.072 g, 79%; IR (KBr) νmax 3436, 3290,
urea (0.021 g, 0.357 mmol), pyridine (2 mL), and piperi-
dine (0.036 g, 0.428 mmol). Yield: 0.081 g, 92%; IR (KBr)
−
1
ν
3390, 3245, 3104, 2823, 1736, 1681, 1217 cm ;
max
1
−1 1
H-NMR (400 MHz, DMSO-d ): δ 8.35 (s, 1H), 7.82 (s, 1H),
3265, 2923, 1721, 1681, 1619, 1502, 769, 646 cm ; H-NMR
6
7
.01 (d, J = 8.2 Hz, 1H), 6.68 to 6.65 (m, 2H), 5.95 to 5.91
(400 MHz, DMSO-d ): δ 7.71 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H),
6
(
m, 1H), 5.83 (s, 3H), 5.38 (dd, J = 2.5, 4.4 Hz, 1H) ppm;
7.05 (s, 1H), 6.55 to 6.51 (m, 2H), 5.70 (d, J = 4.4 Hz, 1H),
5.23 (dd, J = 1.9, 4.4 Hz, 1H) ppm; C NMR (100.6 MHz,
1
3
13
C NMR (100.6 MHz, DMSO-d ): δ 173.1, 164.4, 162.0,
6
1
5
60.8, 155.5, 126.1, 125.1, 123.2, 110.5, 104.8, 55.2, and
4.5 ppm; MS (ESI) m/z: 249.24.
DMSO-d ): δ 173.6, 163.5, 160.3, 156.9, 152.5, 127.9, 127.2,
123.8, 107.8, 105.3, 98.2, 55.6 ppm; MS (ESI) m/z: 332.60.
6
4
1
.1.9 | 6-(4-cyanophenyl)-2-oxo-
,2,3,6-tetrahydropyrimidine-4-carboxylic
4.1.12 | 6-Phenyl-2-thioxo-
1,2,3,6-tetrahydropyrimidine-4-carboxylic
acid (4k)
acid (4h)
The product obtained was pale yellow solid from
The product obtained was pale yellow solid from
4-(dibromomethyl)benzonitrile (1h) (0.1 g, 0.363 mmol),
(dibromomethyl)benzene (1a) (0.1 g, 0.400 mmol),

6
KAMBAPPA ET AL.
oxalaceticacid (2) (0.052 g, 0.400 mmol), thiourea
thiourea (0.028 g, 0.373 mmol), pyridine (2 mL), and
piperidine (0.041 g, 0.485 mmol). Yield: 0.075 g, 80%; IR
(0.030 g, 0.400 mmol), pyridine (2 mL) and piperidine
−
1
(
3
0.044 g, 0.520 mmol). Yield: 0.086 g, 92%; IR (KBr) ν
261, 3095, 3006, 1710, 1675, 1560 cm ; H-NMR
(KBr) ν
3280, 3108, 3005, 1710, 1674, 1620, 1561 cm ;
max
max
−
1
1
1
H-NMR (400 MHz, DMSO-d ): δ 9.17 (s, 1H), 8.52 (s,
6
(
400 MHz, DMSO-d ): δ 9.20 (s, 1H), 8.52 (s, 1H), 7.40 to
1H), 7.35 to 7.31 (m, 2H), 7.27 to 7.23 (m, 2H), 6.12 (dd,
6
7
4
1
5
.31 (m, 5H), 6.02 (d, J = 4.8 Hz, 1H), 5.15 (dd, J = 2.4,
J = 1.3, 3.2 Hz, 1H), 5.25 (dd, J = 2.5, 5.1 Hz, 1H) ppm;
13
13
.8 Hz, 1H) ppm; C NMR (100.6 MHz, DMSO-d ): δ
C NMR (100.6 MHz, DMSO-d ): δ 173.3, 163.8, 161.9,
6
6
74.2, 162.5, 142.1, 128.8, 127.7, 126.6, 125.8, 110.and
, 54.9 ppm; MS (ESI) m/z: 235.28. MS (ESI) m/z: 235.28.
160.9, 139.5, 138.3, 128.2, 127.8, 126.4, 115.9, 115.2, 110.8,
and 54.3 ppm; MS (ESI) m/z: 253.27.
4
1
.1.13 | 6-(4-Chlorophenyl)-2-thioxo-
,2,3,6-tetrahydropyrimidine-4-carboxylic
4.1.16 | 6-(2-Chloro-6-fluorophenyl)-
2-thioxo-1,2,3,6-tetrahydropyrimidine-
4-carboxylic acid (4o)
acid (4l)
The product obtained was off white solid from 1-chloro-
The product obtained was pale yellow solid from
1-chloro-2-(dibromomethyl)-3-fluorobenzene (1e) (0.1 g,
0.330 mmol), oxalaceticacid (2) (0.043 g, 0.330 mmol),
thiourea (0.025 g, 0.330 mmol), pyridine (2 mL), and
piperidine (0.036 g, 0.429 mmol). Yield: 0.074 g, 78%; IR
(KBr) νmax 3421, 3233, 3102, 1740, 1667, 1264,
4-(dibromomethyl)benzene (1b) (0.1 g, 0.351 mmol), oxal-
aceticacid (2) (0.046 g, 0.351 mmol), thiourea (0.026 g,
0
0
3
.351 mmol), pyridine (2 mL) and piperidine (0.038 g,
.457 mmol). Yield: 0.078 g, 83%; IR (KBr) ν 3272, 3105,
max
−1 1
002, 1720, 1675, 1560, 1380, 692 cm ; H NMR (400 MHz,
−1 1
DMSO-d ): δ 9.20 (s, 1H), 8.53 (s, 1H), 7.35 to 7.31 (m, 2H),
748, 691 cm ; H-NMR (400 MHz, DMSO-d ): δ 9.20 (s,
6
6
7
.24 to 7.20 (m, 2H), 6.01 (dd, J = 1.3, 3.2 Hz, 1H), 5.23 (dd,
1H), 8.55 (s, 1H), 7.50 (d, 1H), 7.41 (d, 1H), 7.18 (t, 1H),
13
1H, J = 2.5, 5.1 Hz) ppm; C NMR (100.6 MHz, DMSO-d6):
6.21 (d, J = 4.8 Hz, 1H), 5.18 (dd, J = 2.4, 4.8 Hz, 1H)
13
δ 173.9, 163.1, 162.5, 160.5, 139.0, 138.4, 128.9, 128.6, 126.3,
16.2, 115.2, 111.2, 54.2 ppm; MS (ESI) m/z: 269.72.
ppm; C NMR (100.6 MHz, DMSO-d ): δ 174.0, 162.8,
6
1
159.8, 142.3, 131.7, 128.8, 127.8, 123.7, 112.5, 110.9,
54.4 ppm; MS (ESI) m/z: 287.72.
4
1
.1.14 | 6-(4-bromophenyl)-2-thioxo-
,2,3,6-tetrahydropyrimidine-4-carboxylic
4.1.17 | 6-(3-Bromophenyl)-2-thioxo-
1,2,3,6-tetrahydropyrimidine-4-carboxylic
acid (4p)
acid (4m)
The product obtained was pale brown solid from
1
0
-bromo-4-(dibromomethyl)benzene
.304 mmol), oxalaceticacid (2) (0.040 g, 0.304 mmol),
(1c)
(0.1
g,
The product obtained was pale brown solid from 1-bromo-
3-(dibromomethyl)benzene (1f) (0.1 g, 0.304 mmol), oxal-
aceticacid (2) (0.040 g, 0.304 mmol), thiourea (0.023 g,
0.304 mmol), pyridine (2 mL), and piperidine (0.033 g,
thiourea (0.023 g, 0.304 mmol), pyridine (2 mL), and
piperidine (0.033 g, 0.395 mmol). Yield: 0.079 g, 83%; IR
−
1
(
KBr) νmax 3268, 3100, 3007, 1724, 1670, 1563, 632 cm ;
H-NMR (400 MHz, DMSO-d ): δ 9.24 (s, 1H), 8.51 (s,
0.395 mmol). Yield: 0.078 g, 82%; IR (KBr) ν
3402,
max
1
−1
1
3255, 3103, 1741, 1681, 640 cm ; H-NMR (400 MHz,
6
1
H), 7.33 to 7.30 (m, 2H), 7.25 to 7.22 (m, 2H), 6.06 (dd,
DMSO-d ): δ 9.30 (s, 1H), 8.52 (s, 1H), 8.14 to 8.11 (m,
6
J = 1.3, 3.2 Hz, 1H), 5.31 (dd, J = 2.5, 5.1 Hz, 1H) ppm;
2H), 7.78 (d, J = 7.70 Hz, 1H), 7.72 (dd, J = 7.63 and
13
C NMR (100.6 MHz, DMSO-d ): δ 174.3, 162.8, 162.1,
7.70 Hz, 1H), 7.47 (bs, 1H), 5.85 to 5.82 (m, 1H), 5.35 to
6
13
1
60.0, 139.5, 137.8, 129.1, 128.5, 126.6, 115.8, 115.0, 110.7,
5.33 (m, 1H) ppm; C NMR (100.6 MHz, DMSO-d ): δ
6
and 53.8 ppm; MS (ESI) m/z: 314.18.
173.8, 163.5, 154.1, 147.8, 145.0, 134.2, 131.0, 129.0, 123.5,
121.7, 109.0, and 53.8 ppm; MS (ESI) m/z: 314.23.
4
1
.1.15 | 6-(4-Fluorophenyl)-2-thioxo-
,2,3,6-tetrahydropyrimidine-4-carboxylic
4.1.18 | 6-(4-Methoxyphenyl)-2-thioxo-
1,2,3,6-tetrahydropyrimidine-4-carboxylic
acid (4q)
acid (4n)
The product obtained was yellow solid from
1
-(dibromomethyl)-4-fluorobenzene
(1d)
(0.1
g,
The product obtained was pale brown solid from
0
.373 mmol), oxalaceticacid (2) (0.049 g, 0.373 mmol),
1-(dibromomethyl)-4-methoxybenzene (1g) (0.1 g,

KAMBAPPA ET AL.
7
0
.357 mmol), oxalaceticacid (2) (0.047 g, 0.357 mmol),
0.275 mmol), oxalaceticacid (2) (0.036 g, 0.275 mmol),
thiourea (0.020 g, 0.275 mmol), pyridine (2 mL), and
piperidine (0.030 g, 0.357 mmol). Yield: 0.076 g, 80%; IR
(KBr) νmax 3282, 3109, 3000, 1721, 1692, 1552,
thiourea (0.027 g, 0.357 mmol), pyridine (2 mL), and
piperidine (0.036 g, 0.428 mmol). Yield: 0.086 g, 91%; IR
(KBr) ν
3237, 3103, 3002, 1709, 1672, 1615, 1564, and
max
−
1
1
−1 1
1
1
2
506 cm ; H-NMR (400 MHz, DMSO-d ): δ 9.04 (s,
H), 8.42 (s, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.64 to 6.61 (m,
H), 5.90 to 5.85 (m, 1H), 5.32 (dd, J = 2.5, 4.4 Hz, 1H)
769, 634 cm ; H-NMR (400 MHz, DMSO-d ): δ 9.13 (s,
6
6
1H), 8.48 (s, 1H), 7.83 (s, 1H), 7.75 (d, 1H), 7.03 (d, 1H),
6.10 (d, J = 4.8 Hz, 1H), 5.09 (dd, J = 2.4, 4.8 Hz, 1H)
13
13
ppm; C NMR (100.6 MHz, DMSO-d ): δ 174.9, 162.4,
ppm; C NMR (100.6 MHz, DMSO-d ): δ 173.8, 162.5,
6
6
1
5
60.4, 156.3, 127.5, 125.6, 122.5, 110.2, 105.1, 55.7, and
5.3 ppm; MS (ESI) m/z: 265.31.
144.1, 139.9, 131.5, 130.1, 129.8, 128.6, 121.7, 109.2, and
54.7 ppm; MS (ESI) m/z: 348.66.
ACKNOWLEDGMENTS
4
1
.1.19 | 6-(4-Cyanophenyl)-2-thioxo-
,2,3,6-tetrahydropyrimidine-4-carboxylic
Authors thank Vision Group on Science and Technology
(VGST), Department of IT, BT, and S&T, Government of
Karnataka for Financial Assistance under RGSF Scheme
to K. Vinaya (GRD No. 808/315).
acid (4r)
The product obtained was pale yellow solid from
4
-(dibromomethyl)benzonitrile (1h) (0.1 g, 0.363 mmol),
ORCID
oxalaceticacid (2) (0.048 g, 0.363 mmol), thiourea
Prasanna Doddakunche Shivaramu https://orcid.org/
(
(
0.027 g, 0.363 mmol), pyridine (2 mL) and piperidine
0.040 g, 0.472 mmol). Yield: 0.077 g, 82%; IR (KBr) ν
0000-0001-7071-6619
max
1
−
3
245, 3105, 3001, 2256, 2240, 1710, 1673, and 1559 cm ;
REFERENCES
1
H-NMR (400 MHz, DMSO-d ): δ 9.25 (s, 1H), 8.54 (s,
6
[
[
1] P. Biginelli, Gazz. Chim. Ital. 1893, 23, 360.
2] K. S. Atwal, G. C. Rovnyak, B. C. O'Reilly, J. Schwartz, J. Org.
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1
H), 7.53 (d, 2H), 7.45 (d, 2H), 6.06 (d, 1H, J = 4.8 Hz),
13
5
.13 (dd, 1H, J = 2.4, 4.8 Hz) ppm; C NMR (100.6 MHz,
DMSO-d ): δ 173.5, 163.1, 143.4, 133.5, 129.4, 126.2,
6
[3] C. O. Kappe, W. M. F. Fabian, M. A. Semones, Tetrahedron
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1
25.7, 110.6, 109.5, and 55.0 ppm; MS (ESI) m/z: 260.31.
[4] H. I. El-Subbagh, S. M. Abu-Zaid, M. A. Mahran, F. A. Badria,
A. M. Al-Obaid, J. Med. Chem. 2000, 43, 2915.
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5] A. A. A. Abdel-Fattah, Synthesis 2003, (15), 2358.
6] K. Singh, J. Singh, P. K. Deb, H. Singh, Tetrahedron 1999, 55,
4
.1.20 | 2-Thioxo-6-(3-[trifluoromethyl]
phenyl)-1,2,3,6-tetrahydropyrimidine-
-carboxylic acid (4s)
1
2873.
7] G. Maiti, P. Kundu, C. Guin, Tetrahedron Lett. 2003, 44,
757.
8] A. Shaabani, A. Bazgir, F. Teimouri, Tetrahedron Lett. 2003,
44, 857.
4
[
[
2
The product obtained was pale yellow solid from
1
0
-(dibromomethyl)-3-(trifluoromethyl)benzene (1i) (0.1 g,
.314 mmol), oxalaceticacid (2) (0.041 g, 0.314 mmol),
[9] D. S. Bose, L. Fatima, H. B. Mereyala, J. Org. Chem. 2003,
8, 587.
10] Q. Sun, Y.-q. Wang, Z.-m. Ge, T.-m. Cheng, R.-t. Li, Synthesis
004, (7), 1047.
11] J. Lu, Y. Bai, Synthesis 2002, (4), 466.
12] S. R. Mistry, K. C. Maheria, J. Mol. Catal. A Chem. 2012,
6
thiourea (0.023 g, 0.314 mmol), pyridine (2 mL), and
piperidine (0.034 g, 0.408 mmol). Yield: 0.077 g, 81%; IR
[
2
(KBr) ν
3256, 3105, 3012, 1710, 1683, 1554, and
max
[
[
−1 1
1
8
5
510 cm . H-NMR (400 MHz, DMSO-d ): δ 9.41 (s, 1H),
.63 (s, 1H), 7.50 to 7.42 (m, 4H), 6.30 (d, J = 5.1 Hz, 1H),
.53 (d, J = 15.8 Hz, 1H) ppm; C NMR (100.6 MHz,
6
355, 210.
13
[
13] A. Dondoni, A. Massi, Tetrahedron Lett. 2001, 42, 7975.
DMSO-d ): δ 177.5, 164.3, 145.8, 133.1, 132.4, 130.9, 128.1,
[14] A. S. Paraskar, G. K. Dewkar, A. Sudalai, Tetrahedron Lett.
003, 44, 3305.
6
2
1
26.5, 124.1, 116.2, and 53.6 ppm; MS (ESI) m/z: 303.30.
[
[
[
15] H. Xu, Y. G. Wang, Chin. J. Chem. 2003, 21, 327.
16] R. Varala, M. M. Alam, S. R. Adapa, Synlett. 2003, (1), 67.
17] D. P. Narayanan, A. Gopalakrishnan, Z. Yaakob, S. Sugunan,
B. N. Narayanan, Arab. J. Chem. 2020, 13(1), 318.
4.1.21 | 6-(4-Bromo-2-chlorophenyl)-
2-thioxo-1,2,3,6-tetrahydropyrimidine-
4-carboxylic acid (4t)
[18] E. S. Filatova, O. V. Fedorova, K. A. Chistyakov, G. L.
Rusinov, V. N. Charushin, Chem. Heterocycl. Compd. 2020,
5
6, 1.
[19] V. Deepthi, S. Triloknadh, B. Nagaraju, C. V. Rao, Chem. Sci.
019, 8(2), 261.
The product obtained was pale brown solid from
-bromo-2-chloro-1-(dibromomethyl)benzene (1j) (0.1 g,
2
4

8
KAMBAPPA ET AL.
[
[
[
20] J. C. Bussolari, P. A. McDonnell, J. Org. Chem. 2000, 65, 6777.
SUPPORTING INFORMATION
21] Z. Fang, Y. Lam, Tetrahedron 2011, 67, 1294.
22] A. B. Mandal, J. K. Augustine, A. Quattropani, A. Bombrun,
Tetrahedron Lett. 2005, 46, 6033.
23] J. K. Augustine, Y. Arthoba Naik, A. B. Mandal, N.
Chowdappa, V. B. Praveen, J. Org. Chem. 2007, 72, 9854.
24] J. K. Augustine, Y. Arthoba Naik, S. Poojari, N. Chowdappa,
Synthesis 2009, 14, 2349.
25] S. Chandrappa, K. Vinaya, C. S. Ananda Kumara, K. S.
Rangappa, Tetrahedron Lett. 2010, 51, 6493.
26] S. Chandrappa, K. Vinaya, U. Muddegowda, K. S. Rangappa,
Tetrahedron Lett. 2011, 52, 5474.
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
[
[
[
[
[
[
How to cite this article: Kambappa V,
Ganganahalli Kotturappa C, Sheshachar
Manjunath R, Doddakunche Shivaramu P.
Biginelli-type reaction: Efficient synthesis of 5-
unsubstituted 3,4-dihydropyrimidin-2-ones and
thiones from gem-dibromomethylarenes. J
Heterocyclic Chem. 2020;1–8. https://doi.org/10.
27] S. Chandrappa, M. Umashankara, K. Vinaya, C. S. Ananda
Kumara, K. S. Rangappa, Tetrahedron Lett. 2012, 53, 2632.
28] K. Vinaya, G. K. Chandrashekara, D. S. Prasanna, Can.
J. Chem. 2019, 97(9), 690.
1002/jhet.4066