Sodium tetrafluoroborate as a new and highly efficient catalyst for one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones and thiones

Article abstract of DOI:10.1002/jccs.200700038

Sodium tetrafluoroborate (NaBF₄) is found to catalyze the three component condensation of an aldehyde, 1,3-dicarbonyl compound and urea or thiourea to afford the corresponding 3,4-dihydropyrimidin-2(1H)-ones and thiones in high yields. This met

Full text of DOI:10.1002/jccs.200700038

Journal of the Chinese Chemical Society, 2007, 54, 263-266
263
Communication
Sodium Tetrafluoroborate as a New and Highly Efficient Catalyst for
One-pot Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones and Thiones
B. P. Bandgar,* V. T. Kamble, S. N. Bavikar and Abasaheb Dhavane
Organic Chemistry Research Laboratory, School of Chemical Sciences,
Swami Ramananad Teerth Marathwada University, Nanded-431 606, India
Sodium tetrafluoroborate (NaBF4) is found to catalyze the three component condensation of an alde-
hyde, 1,3-dicarbonyl compound and urea or thiourea to afford the corresponding 3,4-dihydropyrimidin-
2(1H)-ones and thiones in high yields. This method is very useful for the synthesis of a wide range of 3,4-
dihydropyrimidin-2(1H)-ones and thiones from aromatic, heterocyclic, a,b-unsaturated aldehydes and
aliphatic aldehydes.
Keywords: Sodium tetrafluoroborate; Aldehyde; 1,3-Dicarbonyl compound; Urea; Thiourea.
INTRODUCTION
Dihydropyrimidinones and their derivatives have
such as H2SO4, HOAc, conc. HCl, etc.8 as promoters. Many
other methods including microwave irradiation, ionic liq-
uids, and clays9 have also been reported. However, many of
these methods are associated with disadvantages like ex-
pensive and toxic reagents, stoichiometric amounts of cata-
lysts, strongly acidic conditions, long reaction times, unsat-
isfactory yields, incompatibility with other functional
groups and involve difficult product isolation procedures.
Moreover, some of the methods are only practical for aro-
matic aldehydes.7a,k,9c Thus a practical and more efficient
alternative using an inexpensive and environment friendly
reagent is still of interest for one-pot synthesis of dihydro-
pyrimidinones and thiones under mild conditions.
emerged as the integral backbones of several calcium chan-
nel blockers, a1a-adrenergic antagonists, antihypertensives,
and neuropeptide Y (NPY) antagonists.1 3,4-Dihydropyr-
imidinones and their sulfur analogues were found to exhibit
a wide spectrum of biological activities such as antiviral,
antitumor, antibacterial and antiinflammatory behavior.2
Furthermore, several alkaloids containing the dihydropyr-
imidine core structure have been isolated from marine
sources, which also exhibit interesting biological proper-
ties. Most notably, among these are the batzelladine alka-
loids that are found to be potent HIV gp-120-CD4 inhibi-
tors.3 Therefore, the synthesis of this heterocyclic core unit
is of much current importance. The simplest and direct pro-
cedure originally reported by Biginelli4 involves three-
component one-pot condensation of an aldehyde, b-keto-
ester, and urea under strongly acidic conditions. However,
this method often suffers from low yields of products par-
ticularly in the case of substituted aromatic and aliphatic al-
dehydes.5 This has led to the disclosure of multi-step syn-
thetic strategies, which produce relatively higher yields but
lack the simplicity of the original one-pot-Biginelli proto-
col.6 Recently several methods have been reported for pre-
paring dihydropyrimidinones using different Lewis acids
such as BF3.OEt2, LaCl3, La(OTf)3, Yb(OTf)3, InCl3, InBr3,
ZrCl4, BiCl3, Bi(OTf)3, LiBr, LiClO4, Mn(Oac)3, CAN,
FeCl3.6H2O, NiCl2.6H2O, N-butyl-N,N-dimethyl-a-phen-
ylethylammonium bromide, etc.7as well as protic acids
Fluoroboric acid (HBF4) and its salt, particularly lith-
ium tetrafluoroborate (LiBF4), have been used widely as
Lewis catalysts in a variety of reactions.10 However, HBF4
is a strong acid and LiBF4 is very expensive and moisture
sensitive. On the other hand, sodium tetrafluoroborate is
readily available and inexpensive. However, attention has
so far been mainly paid to using HBF4 and LiBF4 as a cata-
lyst for various transformations, while the use of sodium
tetrafluoroborate has been seldom reported in the literature
in association with other reagents.11 The literature survey
reveals that the potentiality of this reagent uniquely for or-
ganic transformations has not been explored. Thus we
thought to employ this reagent for organic transformations
and found that sodium tetrafluoroborate is able to catalyze
the synthesis of dihydropyrimidinones and thiones. More-
over, no additive or protic/Lewis acid is necessary in this
procedure.

264 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Bandgar et al.
RESULTS AND DISCUSSION
Entry 30). Thiourea has been used with similar success to
produce the corresponding thio-derivatives of dihydropyri-
midinones which are also of much interest with respect to
their biological activities (Table 1, Entries 13, 14, 15, 16,
17, 22 and 29).2a Besides the b-keto esters, 1,3-diketone
was employed to produce a dihydropyrimidinone (Table 1,
Entries 27, 28 and 29). It has been found that methanol or
ethanol is a much better solvent in terms of conversion than
all the other tested solvents, which included acetonitrile,
dichloromethane and tetrahydrofuran. Furthermore, the
use of just 20 mol% of NaBF4 in ethanol is sufficient to
promote the reaction and no additives such as HCl or
CH3COOH7e are required for this conversion. Thus, the
present protocol provides an easy access to the preparation
of substituted dihydropyrimidinones with a wide range of
substitution patterns on all three components.
In this report, we would like to disclose our economic
approach for the synthesis of dihydropyrimidinones and
thiones by a three-component one-pot condensation of an
aldehyde, b-keto ester and urea employing sodium tetra-
fluoroborate as a novel promoter. The catalyst is mild, inex-
pensive and highly efficient for open chained 1,3-dicar-
bonyl compounds. The method is highly efficient and free
from the aforesaid drawbacks. The reaction of aldehydes,
b-keto ester and urea/thiourea using NaBF4 in ethanol pro-
ceeded smoothly to afford the corresponding dihydropyr-
imidinones and thiones in high yields (Scheme I).
The results presented in Table 1 indicate the scope
and generality of the method, which is efficient, not only
for urea or thiourea but also for a wide range of substrates
including aromatic, aliphatic, heterocyclic and a,b-unsatu-
rated aldehydes. Most importantly, aromatic aldehydes car-
rying either electron donating or withdrawing substituents
reacted well under the reaction conditions to give the cor-
responding dihydropyrimidinones in good to excellent
yields with high purity. The important feature of the pres-
ent methodology is the ability to tolerate the variations in
all the three components as well as the survival of a vari-
ety of functional groups such as olefins, ethers, nitro, and
halide under the reaction conditions. In comparison to ear-
lier methods, which are only practical for aromatic alde-
hydes,6a,b,7a,b,k the present method is found to be superior as
it is even effective with aliphatic aldehydes (Table 1, En-
tries 23, 24, and 25). Furthermore, the present protocol af-
fords the excellent yield of corresponding dihydropyrimi-
dinone when a,b-unsaturated aldehyde reacted with 1,3-
dicarbonyl compound and urea, which normally show ex-
tremely low conversion in the Biginelli reaction (Table 1,
In conclusion, we have developed a simple and gen-
eral method for the synthesis of biologically significant
aryl-substituted dihydropyrimidinones by means of a three-
component condensation of an aldehyde, 1,3-dicarbonyl
compound and urea or thiourea in a one-pot operation using
sodium tetrafluoroborate as a novel catalyst. This method
is applicable for a wide range of substrates including aro-
matic, aliphatic, a,b-unsaturated and heterocyclic alde-
hydes and provides a variety of biologically relevant dihy-
dropyrimidinones in good to excellent yields. Even though
Lewis acids and other protic acids are known to catalyze
this reaction, this is the first report using sodium tetrafluo-
roborate as a catalyst. The catalyst is inexpensive, mild and
commercially available and also offers several advantages
including cleaner reactions, higher yields of the products as
well as a simple experimental and isolation procedure
which makes it a useful and attractive process for the syn-
thesis of biologically relevant dihydropyrimidinones.
Scheme I

NaBF4 Helping to Form Dihydropyrimidinone and RCSs
J. Chin. Chem. Soc., Vol. 54, No. 2, 2007 265
Table 1. Sodium tetrafluoroborate catalyzed synthesis of dihydropyrimidinones and thiones
Time
(h)
Yielda,b
(%)
Entry
Product
R1
R2
X
Ref.
1
4a
4b
4c
4d
4e
4f
C6H5
4-ClC6H4
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
OEt
OEt
OEt
OEt
Me
O
O
O
O
O
O
O
O
O
O
O
O
S
3
4
85
92
90
89
87
88
90
83
86
84
83
84
89
90
91
90
88
87
86
85
88
86
81
80
78
80
90
89
88
86
7a
7e
7e
7e
7e
7m
7j
2
3
4-NO2C6H4
4-MeC6H4
4-OMeC6H4
2-(OH)C6H4
3,4-(OMe)2C6H3
3,4-(O-CH2-O)C6H3
2,5-(OMe)2C6H3
4-BrC6H4
4
4
4.5
4
5
6
5
7
4g
4h
4i
4.5
4
8
7m
7p
7p
7a
7m
7e
7e
7e
7e
7n
7e
7e
7e
7e
7o
7m
8b
7l
9
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
4j
5
4k
4l
4-FC6H4
5
3-(OMe)-4(OH)C6H3
C6H5
5
4m
4n
4o
4p
4q
4r
4.5
5
4-OMeC6H4
4-NO2C6H4
4-ClC6H4
S
S
5
S
5
3-(OH)C6H4
4-NO2C6H4
4-ClC6H4
S
5.5
4
O
O
O
O
S
4s
4t
4
3-OMeHC6H4
C6H5
4.5
3.5
3.5
5
4u
4v
4w
4x
4y
4z
4a
4b
4c
4d
C6H5
(CH3)2CH
O
O
O
O
O
O
S
CH3(CH2)4
CH3(CH2)5
2-Furyl
5,5
5.5
4
7e
7c
7c
7d
7e
4-NO2C6H4
4-OMeC6H4
C6H5
4.5
4
Me
Me
4
C6H5CH=CH
OEt
O
4
a Yields are of pure isolated products. b Products are characterized by their physical constants and
spectral analysis.
EXPERIMENTAL
Melting points were measured using a Buchi R-535
product was washed with water, filtered and recrystallized
from hot ethanol to afford pure dihydropyrimidinone.
apparatus. IR spectra were recorded on a Bomem MB FT-
IR spectrometer. 1H NMR spectra were recorded on a Varian
Gemini-200 spectrometer. Mass spectra were recorded on a
VG Micromass-7000 H (70 eV). CHN analyses were re-
corded on a Vario EL analyser.
Spectral Data of Some Compounds
Compound 4a: Solid; m.p. 200-202 °C; IR (KBr):
1595, 1650, 1710, 1725, 2920, 2950, 3125, 3250 cm.-1 1
H
NMR (300 MHz, DMSO-d6): d = 1.15 (t, 3H, J = 7.0 Hz),
2.35 (s, 3H), 4.10 (q, 2H, J = 7.0 Hz), 5.25 (s, 1H),
7.12-7.30 (m, 6H), 8.95 (br. s, NH); EIMS: m/z = 260 (M+).
Compound 4d: Solid; m.p. 171-172 °C; IR (KBr):
1650, 1660, 1690, 3115, 3245 cm-1; 1H NMR (300 MHz,
DMSO-d6): d = 1.23 (t, 3H, J = 7.0 Hz), 2.35 (s, 3H), 2.45
(s, 3H), 4.15 (q, 2H, J = 7.0 Hz), 5.45 (d, 1H, J = 2.4 Hz),
6.95-7.22 (m, 4H), 7.75 (br. s, NH), 9.10 (br. s, NH); EIMS:
m/z = 274 (M+).
Experimental Procedure
A mixture of aldehyde (1 mmol), b-keto ester (1
mmol), urea or thiourea (1.5 mmol) and NaBF4 (0.2 mmol)
in ethanol (10 mL) was refluxed for a certain period of time
as required to complete the reaction. The progress of the re-
action was monitered by TLC. On completion, the solvent
was removed under reduced pressure and the resulting
Compound 4u: solid; m.p. 206-207 °C; IR (KBr):

266 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Bandgar et al.
1655, 1650, 1695, 3110, 3245 cm-1; 1H NMR (300 MHz,
DMSO-d6): d = 2.30 (s, 3H), 3.45 (s, 3H), 5.20 (s, 1H),
7.25-7.30 (m, 5H), 7.75 (br. s, NH), 9.20 (br. s, NH).
Compound 4z: Solid; m.p. 205-207 °C; IR (KBr):
1485, 1590, 1690, 1710, 3110, 3245 cm-1; 1H NMR (300
MHz, DMSO-d6): d = 1.15 (t, 3H, J = 7.0 Hz), 2.33 (s, 3H),
4.20 (q, 2H, J = 7.0 Hz), 5.30 (d, 1H, J = 2.2 Hz), 6.15 (d,
1H, J = 2.2 Hz), 6.35 (s, 1H), 7.35 (m, 1H), 7.80 (br. s, NH),
9.20 (br. s, NH); EIMS: m/z = 250 (M+).
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Received May 22, 2006.
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