An efficient one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones catalysed by 2-thienylboronic acid

Article abstract of DOI:10.3184/174751912X13318375421203

A simple efficient one-pot three-component condensation for synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones in good to excellent yields using 2-thienylboronic acid as a catalyst was described.

Full text of DOI:10.3184/174751912X13318375421203

200 RESEARCH PAPER
APRIL, 200–202
JOURNAL OF CHEMICAL RESEARCH 2012
An efficient one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones
catalysed by 2-thienylboronic acid
Zhenfang Fu, Tianhua Shen, Zhiping Du, Zhiguo Qiao and Qingbao Song*
College of Chemical Engineering and Material Science, Zhejiang University ofTechnology, Hangzhou, 310032, P. R. China
A simple efficient one-pot three-component condensation for synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones
in good to excellent yields using 2-thienylboronic acid as a catalyst was described.
Keywords: three-component condensation, 2-thienylboronic acid, Biginelli reaction, 3,4-dihydropyrimidin-2-(1H)-ones/thiones
Recently, the synthesis of 3,4-dihydropyrimi-din-2(1H)-ones/
thiones (DHPMs) has attracted interest of organic chemists.
This interest can be attributed to 3,4-dihydropyrimidin-2(1H)-
ones/thionesshowingpotenttherapeuticalandpharmacological
properties, such as anti-inflammatory, antitumor, and
antibacterial activity. Some have been successfully used as
calcium channel blockers1, antihypertensive agents2, and
a1a-antagonists3. Several alkaloids containing the dihydropy-
rimidine core unit, exhibiting anticancer activity and antiviral
activities, have been studied. The DHPM monastrol (1, Fig. 1)
as a novel cell-permeable molecule can block normal bipolar
spindle assembly in mammalian cells causing cell cycle
arrest4,5. Thus the synthesis and investigation of dihydro-
pyrimidines are of much current importance.
In the past, the Biginelli reaction had not attracted much
attention. In 1978, Khanna first discovered the cardiovascular
activity of Biginelli compounds arousing interest. This
reaction suffers from long reaction times, acidic reaction
conditions and low-yields of the products. A variety of
catalysts have been reported to improve the efficiency of the
Biginellireaction,suchasNiCl2·6H2O,7 p-TsOH,8 LaCl3·7H2O,9
Cu(OTf)2,10 FeCl3,11 ZrCl4,12 Bi(OTf)3,13 [bmim][FeCl4],14
TCICA,15 NH2SO3H,16 CuI,17 CuCl2·H2O,18 BiCl3,19
Mn(OAc)3·2H2O,20 InBr3,21 BF3·OEt2,22 LiClO4,23 YbOTf,24
NH4Cl,25 InCl326 or MTSA27 and so on. Asymmetric syntheses
using such as CeCl3/InCl3,28 Yb(OTf)329 attached to chiral
ligands were recently reported. Other studies using microwave
irradiation,30 solid phase reagents,31 and polymer-supported
catalysts,32 have been also reported.
is commonly used in Biginelli reaction, was chosen as solvent.
The results are summarised in table 1. Initially, the combina-
tion of 4 (0.2 mol%), 5 (0.3 mol%), 6 (0.2 mol%) and phenyl-
boronic acid(0.02 mol%) as catalyst were selected for
study, and the desired 1a was isolated in 54% yield (entry 1).
Arylboronic acids with electron-donating group showed
less improvement (entries 2 and 3), while having electron-
withdrawing group exhibited good activity, furnishing 1a in
74–95% yield (entries 4–6). The above results indicated that
the structure of the acid was crucial for the present reaction. At
the same time, we examined naphthalen-1-ylboronic acid (2g)
and 1,1′-ferrocenediboronic acid (2h), yet both were not as
efficient as 3,4-difluorophenylboronic acid (entry 7 and 8).
When we tested 2-thienylboronic acid (2i), we were surprised
that the yield rose to 97% (entry 9). Then the effects of the
solvent on the reaction were studied and acetonitrile was found
to be the best. Finally, we studied the reaction times and found
the perfect reaction time was 5 hours (entry 9). On the basis of
these investigations, the preferred reaction condition is ethyl
acetoacetate:aldehydes:urea/thiourea:2-thienylboronic acid =
1:1:1.5:0.1 in CH3CN (5 mL) 85 °C for 5 hours.
With the optimised conditions in hand, a variety of new
dihydropyrimidines were synthesised in good to excellent
yields, as show in Table 2. We found that aromatic aldehydes
all gave higher yields than heteroaromatic aldehydes.
In conclusion, we have developed a simple and efficient
method for a one-pot three-component synthesis of 3,4-dihy-
dropyrimidin-2(1H)-ones/thiones using 2-thienylboronic acid
asthecatalyst.Thisprocessmaybeusefulinthepharmaceutical
and biochemical fields.
Boronic acids are effective catalysts for the Biginelli
reaction,33,34 but to our knowledge, heterocyclic boronic acid,
ferrocenic boronic acid or substituted phenylboronic acids
have not been tested as catalysts in the Biginelli reaction.
We now report our research on arylboronic acids as catalysts
for the Biginelli reaction. We found that 2-thienylboronic
acid as a simple efficient catalyst for the synthesis of 3,4-
dihydropyrimidin-2-(1H)-ones/thiones, the yield was up to
97%. A variety of new dihydropyrimidines were synthesised
using 2-thiophenylboric acid as a catalyst in 5 hours.
Experimental
1H spectra and 13C NMR spectra were recorded on a Bruker Avance III
500 MHz spectrometer and using d-DMSO (500 MHz for 1H or
125 MHz for 13C, respectively) as solvent. IR spectra (film) were
recorded on a NEXUS FI/IR spectrometer. Melting points were taken
on Büchi M-560. Mass spectra (MS) were carried out on Varian1200
and measured by the EI method. The reaction mixture was monitored
by TLC on silica gel plates (60 F-254). Microanalyses were performed
on a LECO CHNS-932 Elemental Analyser. All boronic acids were
purchased from Fluka (Buchs, Switzerland) chemical company.
Results and discussion
Synthesis of 3,4-dihydropyrimi din-2(1H)-ones/thiones (1a–n);
general procedure
We optimised the reaction conditions in terms of catalyst,
solvent and reaction time. 4-Chloro-benzaldehyde was selected
as the model substrate and acetonitrile which is less toxic, and
The mixture of ethyl acetoacetate (2 mmol), aromatic aldehyde
(2 mmol), urea/thiourea (3 mmol), CH3CN (5 mL) and 2-thienylboronic
acid (0.1 mmol) was refluxed for 5 hours. The reaction mixture was
monitored by TLC. After completion, the reaction mixture was poured
into crushed ice, filtrated washed with 95% ethanol, dried, and recrys-
tallised from 95% ethanol. The structures and yields of the products
are given in Table 2.
5-Ethoxycarbonyl-6-methyl-4(4-hydroxy-3-nitrophenyl)-3,4-
dihydropyrimidin-2(1H)-one (1e): Yellow solid; IR (film) 1697, 1643
cm–1; 1H NMR (500 MHz, d-DMSO) δ 1.09 (t, J = 7.0 Hz, 3H), 2.25
(s, 3H), 3.99 (m, 2H), 5.14 (s, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.41 (dd,
J = 2.2, 8.6 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 3.4 Hz, 1H),
9.27 (s, 1H), 10.97 (s, 1H); 13C NMR (125 MHz, d-DMSO) δ 165.1,
151.7, 151.3, 148.7, 136.2, 136.0, 133.3, 122.7, 119.4, 98.6, 59.3,
Fig. 1 3,4-dihydropyrimidin-2(1H)-ones/thiones.
* Correspondent. E-mail: qbsong@zjut. edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 201
Table 1 Optimisation for synthesis of 3,4-dihydropyrimidin-
2(1H)-ones/thiones (DHPMs)a
Table 2 Synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones
via 2-thiophenylboric acid cascade processa
Products and yield
Catalyst
Entry
Catalyst
Solvent
Time/h
Yieldb/%
1
2
2a
2b
2c
2d
2e
2f
2g
2h
2i
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
MeOH
EtOH
5
5
5
5
5
5
5
5
5
5
5
5
5
1
2.5
3
54
21
3
10
4
76
5
95
6
75
7
Trace
Trace
97
8c
9
10
11
12
13
14
15
16
2i
23
2i
34
2i
77
2i
Toluene
CH3CN
CH3CN
CH3CN
54
2i
30
2i
82
2i
95
a Reaction conditions: 4 (0.2 mol%), 5 (0.3 mol%), 6 (0.2 mol%)
catalyst (0.02 mol%), Solvent (5 mL), reflux. b Isolated yield.
c Reaction conditions: 4 (0.2 mol%), 5 (0.3 mol%), 6 (0.2 mol%)
catalyst (0.01 mol%), Solvent (5 mL), reflux.
53.0, 17.8, 14.0; MS m/z 321 (M+); Anal. Calcd for C14H15N3O6: C,
52.32; H, 4.72; N, 13.08. Found: C, 52.28; H, 4.64; N, 12.97%.
Ethyl-4-(4-hydroxy-3-nitrophenyl)-6-methyl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (1f): Yellow solid; IR (film)
1709, 1654 cm–1; 1H NMR (500 MHz, d-DMSO) δ 1.11 (t, J = 7.0 Hz,
3H), 2.30 (s, 3H), 4.02 (m, 2H), 5.16 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H),
7.38 (dd, J = 2.2, 8.6 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 9.65 (d,
J = 3.2 Hz, 1H), 10.40 (s, 1H) 13C NMR (125 MHz, d-DMSO)
δ 174.6, 165.3, 152.1, 145.9, 136.6, 135.1, 133.7, 123.4, 120.0, 100.6,
60.1, 53.4, 17.6, 14.4; MS m/z 337 (M+);Anal. Calcd for C14H15N3O5S:
C, 49.84; H, 4.49; N, 12.46. Found: C, 49.72; H, 4.31; N, 12.38%.
Ethyl-4-(3,5-dibromo-4-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (1g): White solid; IR (film) 3104,
1684 cm–1; 1H NMR (500 MHz, d-DMSO) δ 1.12 (t, J = 7.0 Hz, 3H),
2.26 (s, 3H), 4.01 (m, 2H), 5.08 (s, 1H), 7.33 (s, 2H), 7.74 (s, 1H),
9.26 (s, 1H); 13C NMR (125 MHz, d-DMSO) δ 165.6, 152.2, 150.3,
149.4, 139.6, 139.6, 130.5, 112.2, 99.0, 59.8, 53.2, 18.3, 18.2, 14.5;
MS m/z 432 (M+); Anal. Calcd for C14H14Br2N2O4: C, 38.90; H, 3.27;
N, 6.48. Found: C, 38.80; H, 3.18; N, 6.32%.
a Reaction conditions: 2i (0.02 mol%), 5 (0.3 mol%), 6 (0.2 mol%),
7 (0.2 mol%), CH3CN (5 mL), reflux, 5 h. b Melting point measured.
c Melting point from ref.27.
3H), 2.30 (s, 1H), 4.03 (m, 2H), 5.11 (s, 1H), 7.32 (s, 1H), 9.62 (s,
1H), 10.40 (s, 1H); 13C NMR (125 MHz, d-DMSO) δ 174.7, 165.4,
150.7, 146.0, 138.2, 130.7, 112.3, 100.5, 60.2, 53.2, 53.1, 17.7, 17.6,
14.5; MS m/z 448 (M+); Anal. Calcd for C14H14Br2N2O3S: C, 37.51; H,
3.16; N, 6.25. Found: C, 37.40; H, 3.02; N, 6.10%.
Ethyl-4-(3,5-dibromo-4-hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-
tetrahydropyrimid ine-5-carboxylate (1h): White solid; IR (film)
3307, 1667 cm–1; 1H NMR (500 MHz, d-DMSO) δ 1.12 (t, J = 7.0 Hz,

202 JOURNAL OF CHEMICAL RESEARCH 2012
Ethyl-6-methyl-2-oxo-4-(4-(trifluoromethyl) phenyl)-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (1i): White solid; IR (film) 3120, 1707
cm–1; 1H NMR (500 MHz, d-DMSO) δ 1.09 (t, J = 7.0 Hz, 3H), 2.27
(s, 3H), 3.99 (q, J = 7.0, J = 7.0 Hz, 2H), 5.24 (s, 1H), 7.46 (d, J =
8.0 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 3.1 Hz, 2H), 9.30
(s, 1H); 13C NMR (125 MHz, d-DMSO) δ 165.6, 152.4, 149.7, 149.5,
128.6, 128.2, 127.6, 126.0, 125.9, 123.3, 99.0, 59.8, 54.1, 18.2, 14.5;
MS m/z 328 (M+); Anal. Calcd for C15H15F3N2O3: C, 54.86; H, 4.62; N,
8.53. Found: C, 54.71; H, 4.46; N, 8.47%.
Open-Ended Fund of the State Key Laboratory Breeding
Base of Green Chemistry-Synthesis Technology, Zhejiang
University of Technology is gratefully acknowledged.
Received 17 January 2012; 18 February 2012
Paper 1201111 doi: 10.3184/174751912X13318375421203
Published online: 17 April 2012
Ethyl-6-methyl-2-oxo-4-(3-(trifluoromethyl) phenyl)-1,2,3,4-tetrahy-
dropyrimidine-5-carboxylate (1j): White solid; IR (film) 2982, 1691
References
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cm–1; H NMR (500 MHz, d-DMSO) δ 1.08 (t, J = 7.0 Hz, H), 2.27
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Ethyl-4-(4-bromothiophen-2-yl)-6-methyl-2-oxo-1,2,3,4-tetrahy-
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3.82; N, 8.14. Found: C, 41.75; H, 3.67; N, 7.08%.
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Ethyl-6-methyl-2-oxo-4-(thiophen-3-yl)-1,2,3,4-tetrahydropyrimi-
1
dine-5-carboxylate (1l): White solid; IR (film) 2980, 1649cm–1; H
NMR (500 MHz, d-DMSO) δ 1.15 (t, J = 7.0 Hz, 3H), 2.22 (s, 3H),
4.05 (q, J = 7.0 Hz, 2H), 5.21 (s, 1H), 6.98 (d, J = 4.9 Hz, 1H), 7.15
(s, 1H), 7.45 (m, 1H), 7.74 (d, J = 2.9 Hz, 1H), 9.17 (s, 1H); 13C NMR
(125 MHz, d-DMSO) δ 165.8, 153.0, 148.8, 146.2, 127.1, 126.6,
121.2, 99.9, 59.7, 49.9, 18.1, 14.6; MS m/z 266 (M+); Anal. Calcd for
C12H14N2O3S: C, 54.12; H, 5.31; N, 10.52. Found: C, 54.06; H, 5.16;
N, 10.43%.
Ethyl-6-methyl-4-(thiophen-3-yl)-2-thioxo-1,2,3,4-tetrahydropyrimi-
dine-5-carboxylate (1m): Yellow solid; IR (film) 2980, 1665 cm–1;
1H NMR (500 MHz, d-DMSO) δ 1.15 (t, J = 7.0 Hz, 3H), 2.27 (s, 3H),
4.07 (m, 2H), 5.24 (s, 1H), 6.97 (d, J = 5.0 Hz, 1H), 7.16 (d, J =
2.3 Hz, 1H), 7.49 (dd, J = 2.9, 4.9 Hz, 1H); 13C NMR (125 MHz,
d-DMSO) δ 175.2, 165.5, 145.6, 144.8, 127.5, 126.5, 122.0, 101.3,
60.1, 50.0, 17.6, 14.6; MS m/z 282 (M+);Anal. Calcd for C12H14N2O2S2:
C, 51.05; H, 5.01; N, 9.93. Found: C, 50.97; H, 4.96; N, 9.80%.
Ethyl-6-methyl-4-(3-methylthiophen-2-yl)-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (1n): Grey solid; IR (film) 2980, 1699 cm–1;
1H NMR (500 MHz, d-DMSO) δ 1.08 (t, J = 7.0 Hz, 3H), 2.21 (s, 3H),
2.24 (s, 3H), 3.96 (m, 2H), 5.45 (s, 1H), 6.75 (d, J = 5.0 Hz, 1H), 7.21
(d, J = 5.0 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 9.28 (s, 1H); 13C NMR
(125 MHz, d-DMSO) δ 165.5, 152.1, 143.0, 133.3, 130.2, 126.1,
123.4, 100.5, 59.8, 48.0, 14.5, 18.1, 13.7; MS m/z 280 (M+); Anal.
Calcd for C13H16N2O3S: C, 55.70; H, 5.77; N, 10.00. Found: C, 55.66;
H, 5.58; N, 9.92%.
34 E.H. Hu, D.R. Slidler, and U.H. Dolling, J. Org. Chem., 1998, 63, 3454.

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