Tetrabutylammonium hydrogen sulfate: An efficient catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones under solvent-free conditions

Article abstract of DOI:10.1080/10426500490474815

Tetrabutylammonium hydrogen sulfate (TBAHS) as a solid protic acid and phase-transfer reagent catalyzed the three-component condensation reactions of aldehydes, 1,3-dicarbonyl compounds, and urea or thiourea under solvent-free conditions leading to 3,4-dihydropyrimidin-2(1H)-ones in high yields at 80 C.

Full text of DOI:10.1080/10426500490474815

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TETRABUTYLAMMONIUM
HYDROGEN SULFATE: AN
EFFICIENT CATALYST FOR
THE SYNTHESIS OF 3,4-
DIHYDROPYRIMIDIN-2(1H)-
ONES UNDER SOLVENT-FREE
CONDITIONS
Ahmad Shaabani a , Ayoob Bazgir a & Sakineh Arab-
Ameri a
a Department of Chemistry, Shahid Beheshti
University , Tehran, Iran
Published online: 06 Sep 2010.
To cite this article: Ahmad Shaabani , Ayoob Bazgir & Sakineh Arab-Ameri (2004)
TETRABUTYLAMMONIUM HYDROGEN SULFATE: AN EFFICIENT CATALYST FOR THE
SYNTHESIS OF 3,4-DIHYDROPYRIMIDIN-2(1H)-ONES UNDER SOLVENT-FREE CONDITIONS,
Phosphorus, Sulfur, and Silicon and the Related Elements, 179:11, 2169-2175, DOI:
10.1080/10426500490474815
To link to this article: http://dx.doi.org/10.1080/10426500490474815
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Phosphorus, Sulfur, and Silicon, 179:2169–2175, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490474815
TETRABUTYLAMMONIUM HYDROGEN SULFATE: AN
EFFICIENT CATALYST FOR THE SYNTHESIS
OF 3,4-DIHYDROPYRIMIDIN-2(1H)-ONES UNDER
SOLVENT-FREE CONDITIONS
Ahmad Shaabani, Ayoob Bazgir, and Sakineh Arab-Ameri
Department of Chemistry, Shahid Beheshti University,
Tehran, Iran
(Received March 16, 2004; accepted March 18, 2004)
Tetrabutylammonium hydrogen sulfate (TBAHS) as a solid pro-
tic acid and phase-transfer reagent catalyzed the three-component
condensation reactions of aldehydes, 1,3-dicarbonyl compounds, and
urea or thiourea under solvent-free conditions leading to 3,4-
dihydropyrimidin-2(1H)-ones in high yields at 80◦C.
Keywords: Biginelli reaction; condensation reaction; dihydropyrimidi-
nones; solvent free; tetrabutylammonium hydrogen sulfate
INTRODUCTION
Dihydropyrimidinones (DHPMs) and their derivatives are pharma-
cologically important compounds as calcium channel blockers, an-
tihypertensive agents, α-1-a-antagonists, and neuropeptide Y(NPY)
antagonists.1 In addition, the dihydropyrimidinone-5-carboxylate core
unit is found in many marine natural products, including the batzella-
dine alkaloids, which have been found to be potent HIVgp-120-CD4
inhibitors.2 Therefore, many synthetic methods for preparing such
compounds under classical reflux3–8 or solvent-free conditions9–15 and
microwave16–19 or ultrasonic irradiation20,21 have been reported.
Very recently, we and Reddy groups reported ammonium chloride13
and N-butyl-N,N-dimethyl-α-phenylethyl ammonium bromide15 as ef-
ficient reagents for accelerating Biginelli reaction under solvent-free
Financial support of the Research Council of Shahid Beheshti University is
acknowledged.
Address correspondence to Ahmad Shaabani, Department of Chemistry, Shahid
Beheshti University, P. O. Box 19839-4716, Tehran, Iran. E-mail: a-shaabani@cc.sbu.ac.ir
2169

2170
A. Shaabani et al.
conditions. Product yields were good, but both of these methods carried
at relatively high temperature, at 100◦C. In addition, although NH4Cl
is a very cheap reagent, N-butyl-N,N-dimethyl-α-phenylethyl ammo-
nium bromide is relatively expensive. Therefore, the introduction of an
alternative and an inexpensive new phase transfer reagent for the ac-
celerating of Biginelli reaction under solvent-free conditions and lower
temperature is of prime importance.
In continuation of our previous work on solvent-free organic
transformations22–24 and using tetrabutylammonium hydrogen sulfate
as catalyst,25 we wish to report the results obtained from a study of
the preparation of 3,4-dihydropyrimidin-2(1H)-ones using tetrabuty-
lammonium hydrogen sulfate under solvent-free conditions at 80◦C
(Scheme 1).
SCHEME 1
RESULTS AND DISCUSSION
Tetrabutylammonium hydrogen sulfate with dual properties as solid
protic acid and phase-transfer reagent efficiently catalyzed the Biginelli
reaction under solvent-free conditions at 80◦C. Table I summarizes the
results for the application of this procedure to a series of reactants. The
procedure gives products in good yields and avoids problems connected
with solvent use (cost, handling, safety, and pollution). Decreased reac-
tion times are also realized because of increased reactivity of the reac-
tants in the solid state and the fact that water, as a reaction product,
is evaporated at the reaction temperature at 80◦C. Even for aliphatic
aldehydes which normally show extremely poor yields in the Biginelli
reaction,17 68 and 59% yields of the corresponding dihydropyrimidin-
2(1H)-ones 4f and 4g could be obtained. Importantly, aromatic aldehy-
des carrying either electron-donating ( OMe) or electron-withdrawing
( NO2) substituents all reacted very well, giving moderate-to-excellent
yields of the desired products using this catalyst.
In order to improve the yield, we have tested various amounts
of tetrabutylammonium hydrogen sulfate with a model reaction

Dihydropyrimidones
2171
TABLE I Tetrabutylammonium Hydrogen Sulfate Catalyzed Syntheses of
3,4-dihydropyrimidin-2(1H)-ones under Solvent-Free Conditions at 80◦C
m.p. (◦C)
DHMP
R1
C6H5
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
3-O2NC6H4
C3H7
R2
X
Yield (%)a
Found
Reported
4a
4b
4c
4d
4e
4f
4g
4h
4i
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
Me
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
90
88
85
85
77
68
59
93
78
91
75
88
73
87
83
87
85
81
91
92
202–203
200–201
209–211
206–208
224–226
153–154
154–156
210–211
235–236
193–194
206–208
280–282
231–232
180–181
228 (dec)
204–205
138–139
203–205
166–168
187–188
201–203b
199–201b
210–212b
207–210b
226–228c
153–155d
157–158b
207–210b
235–237b
191–193b
204–207e
—
C4H9
C6H5
4-O2NC6H4
4-MeOC6H4
4-ClC6H4
3-O2NC6H4
C6H5
4-MeOC6H4
4-O2NC6H4
C6H5
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
233–236b
178–180b
230 (dec)b
205–207c
140 f
Me
Me
OEt
OEt
OEt
OBn
OBn
4-MeOC6H4
3-O2NC6H4
C6H5
S
S
O
O
206–207c
—
4-MeOC6H4
—
aIsolated yield.
bReddy et al.5
cShaabani et al.13
dEynde et al.26
ePeng and Deng.14
f Singh et al.27
using benzadehyde (1 mmol), ethyl acetoacetate (1 mmol), and urea
(1.5 mmol) at different temperatures. As shown in Table II, increasing
the quantity of the catalyst can improved the reaction yields at each
temperature. The best results were obtained by carrying out the reac-
tion at 80◦C in the presence of 0.30 mmol of catalyst. Higher amount of
catalyst or temperature did not improve the yield to a greater extent.
Also we scaled up the reaction to the level producing multigrams
of product using electron-donating ( OMe) or electron-withdrawing
( NO2) substituents without any problems (see the Experimental sec-
tion below).
In summary, with the use of tetrabutylammonium hydrogen sul-
fate as an inexpensive and available catalyst under solvent-free re-
action conditions, the yields of the Biginelli reaction are identical to
those obtained under NH4Cl and N-butyl-N,N-dimethyl-α-phenylethyl

2172
A. Shaabani et al.
TABLE II Condensation of Benzaldehyde, Ethyl Acetoacetate, and Urea
under Different Conditions
Yield (%)a
Amount of
catalyst (mmol)
At 70◦C
At 80◦C
At 90◦C
At 100◦C
0
35
46
50
54
61
51
79
85
90
90
62
80
85
88
90
68
81
86
90
92
0.15
0.2
0.3
0.4
aBenzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea (1.5 mmol), reaction time
4 h at 80◦C.
ammonium bromide; however, the reaction temperature decreased from
100◦C to 80◦C. Due to its good reactivity and reduced hazardous pol-
lution, this reagent can be recommended as a practical catalyst for
aliphatic and aromatic aldehydes carrying either electron-releasing or
electron-withdrawing substitution with β-ketoester as well as β-diketo
compounds under solvent-free conditions.
EXPERIMENTAL
Melting points were measured on an Electrothermal 9100 apparatus
and are uncorrected. Mass spectra were recorded on a FINNIGAN-MAT
8430 mass spectrometer operating at an ionization potential of 70 eV. IR
spectra were recorded on a Shimadzu IR-470 spectrometer. 1H and 13
C
NMR spectra were recorded on a BRUKER DRX-500 AVANCE spec-
trometer at 500.13 and 125.77 MHz, respectively. NMR spectra were
obtained on solutions in DMSO-d6. The chemicals used in this work
were purchased from Fluka chemical company (Buchs, Switzerland).
All the products (except 4l, 4s, and 4t) are known compounds and were
characterized by IR and 1H NMR spectroscopic data, and their melting
points were compared with reported literature values.
Tetrabutylammonium Hydrogen Sulfate Catalyzed
Synthesis of 5-Ethoxycarbonyl-6-methyl-4-(4-
nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one under
Solvent-Free Conditions (4d)
Small Scale
A mixture of 4-nitrobenzaldehyde (0.15 g, 1 mmol), ethyl acetoac-
etate (0.13 g, 1 mmol), urea (0.09 g, 1.5 mmol), and Bu4NHSO4 (0.10 g,

Dihydropyrimidones
2173
0.30 mmol) were finely mixed together. The reaction mixture in a screw-
capped vial containing a magnetic stirring bar was heated at 80◦C in
a preheated oil batch for 4 h. After cooling, the reaction mixture was
poured onto crushed ice (40 g) and stirred for 5–10 min. The solid sep-
arated was filtered under suction, washed with cold water (40 ml) and
then recrystallized from ethyl acetate:n-hexane (1:3) to afford the pure
product 4d (0.26 g, 85%). Mp 206–208◦C; IR (KBr) (νmax, cm−1): 3215,
1731, 1707, 1641; 1H NMR (DMSO-d6):δH 1.07 (3H, t, 3 J= 6.8 Hz, CH3),
2.26 (3H, s, CH3), 3.97 (2H, q, 3 J = 5.4 Hz, OCH2), 5.27 (1H, s, CH), 7.50
3
3
(2H, d, J = 7.3 Hz, arom), 7.87 (1H, s, NH), 8.20 (2H, d, J = 7.2 Hz,
arom), 9.33 (1H, s, NH); 13C NMR: δC 14.5, 18.3, 54.2, 59.8, 98.7, 124.2,
128.1, 147.2, 149.8, 152.2, 152.5, 165.5; MS (m/z, %) 305 (M+, 25), 276
(92), 260 (20), 183 (100).
It is important to note that we have to close the cap of the vial for
low boiling aldehydes (4f, 4g).
Large Scale
(1) 4-Nitrobenzaldehyde (1.50 g, 10 mmol), ethyl acetoacetate (1.30 g,
10 mmol), urea (0.90 g, 15 mmol), and Bu4NHSO4 (1.0 g, 3 mmol) were
finely mixed together. The reaction mixture was heated at 80◦C in a
preheated oil batch for 4 h in a 25 ml round-bottomed flask containing
a magnetic stirring bar. After cooling, the reaction mixture was poured
onto crushed ice and stirred for 5–10 min. The solid separated was
filtered under suction, washed with cold water, and then recrystallized
from ethyl acetate:n-hexane (1:3) to afford the pure product 4d (2.50 g,
8.2 mmol, 82%).
(2) Anisaldehyde (1.36 g, 10 mmol), ethyl acetoacetate (1.30 g,
10 mmol), urea (0.90 g, 15 mmol), and Bu4NHSO4 (1.0 g, 3 mmol) were
finely mixed together. The reaction mixture was heated at 80◦C in a
preheated oil batch for 4 h in a 25 ml round-bottomed flask containing
a magnetic stirring bar. After cooling, the reaction mixture was poured
onto crushed ice and stirred for 5–10 min. The solid separated was fil-
tered under suction, washed with cold water, and then recrystallized
from ethyl acetate:n-hexane (1:3) to afford the pure product 4b (2.31 g,
8.4 mmol, 84%).
5-Methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-3,4-
dihydropyrimidin-2(1H)-one (4l)
m.p. 280–282◦C. IR (KBr) (νmax, cm−1): 3340, 3200, 3088, 1690, 1631.
1H NMR (DMSO-d6): δH 2.27 (3H, s, CH3), 3.53 (3H, s, OCH3), 5.29 (1H,
s, CH), 7.61–8.12 (4H, m, arom), 7.90 (1H, s, NH), 9.37 (1H, s, NH). 13
C

2174
A. Shaabani et al.
NMR: δC δ 18.4, 51.4, 53.8, 98.6, 121.4, 122.8, 130.7, 133.4, 147.2, 148.3,
150.1, 152.3, 166.1. MS (m/z, %) 292 (M+ + H, 25), 232 (92),169 (100).
5-Benzyloxycarbonyl-6-methyl-4-(phenyl)-3,4-
dihydropyrimidin-2(1H)-one (4s)
m.p. 166–168◦C. IR (KBr) (νmax, cm−1): 3345, 3218, 3100, 1703, 1637. 1H
NMR (DMSO-d6): δH 2.26 (3H, s, CH3), 5.00 and 5.04 (2H, AB-system,
3 J = 12.7 Hz, OCH2), 5.16 (1H, d, 3 J = 2.9 Hz, CH), 7.13–7.30 (9H, m,
arom), 7.72 (1H, s, NH), 9.23 (1H, s, NH). 13C NMR: δC 18.3, 54.4, 65.3,
99.2, 126.7, 127.8, 128.0, 128.2, 128.7, 128.9, 137.0, 145.1, 149.7, 152.4,
165.5; MS (m/z, %) 322 (M+, 45), 231 (19), 187 (20), 77 (100).
5-Benzyloxycarbonyl-6-methyl-4-(4-methoxyphenyl)-3,4-
dihydropyrimidin-2(1H)-one (4t)
m.p. 187–188◦C; IR (KBr) (νmax, cm−1): 3340, 3210, 3100, 1695, 1630,
1
1603; H NMR (DMSO-d6): δH 2.25 (3H, s, CH3), 3.71 (3H, s, OCH3),
3
4.99 and 5.04 (2H, AB system, J = 12.7 Hz, OCH2), 5.12 (1H, s, CH),
6.83–7.27 (9H, m, arom), 7.68 (1H, s, NH). 9.21 (1H, s, NH). 13C NMR:
δC 18.3, 53.8, 55.5, 65.2, 99.5, 114.2, 127.9, 128.0, 128.2, 128.7, 137.0,
137.3, 149.4, 152.4, 159.0, 165.6. MS (m/z, %) 351 (M+, 37), 321 (59),
216 (20), 77 (100).
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