Diketene-based neat four-component synthesis of the dihydropyrimidinones and dihydropyridine backbones using silica sulfuric acid (SSA)

Article abstract of DOI:10.1016/j.cclet.2012.06.008

Heterocyclic skeleton building blocks to afford dihydropyrimidinones and dihydropyridines based on neat adducts of diketene, alcohols and aldehydes via silica sulfuric acid (SSA) catalyzed ring opening of diketene in four-component Biginelli-type and Hant

Full text of DOI:10.1016/j.cclet.2012.06.008

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 930–932
www.elsevier.com/locate/cclet
Diketene-based neat four-component synthesis of the
dihydropyrimidinones and dihydropyridine backbones using silica
sulfuric acid (SSA)
*
Sadegh Rostamnia , Kamran Lamei
Organic and Nano Group (ONG), Department of Chemistry, Faculty of Science, University of Maragheh, P.O. Box 55181-83111, Maragheh, Iran
Received 9 April 2012
Available online 4 July 2012
Abstract
Heterocyclic skeleton building blocks to afford dihydropyrimidinones and dihydropyridines based on neat adducts of diketene,
alcohols and aldehydes via silica sulfuric acid (SSA) catalyzed ring opening of diketene in four-component Biginelli-type and
Hantzsch-type reactions are presented.
# 2012 Sadegh Rostamnia. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Diketene; Dihydropyrimidinone; Dihydropyridine; Heterocyclic skeleton; Silica sulfuric acid
1. Introduction
Dihydropyrimidinones (DHPMs) and dihydropyridines (DHPs) are found to exhibit a wide spectrum of
biological activities [1,2]. However a number of the reported protocols to synthesize DHPMs [3] and DHPs [4] in
high yields requiring solvents and catalysts such as heavy metals are not acceptable in the context of costs or green
catalyst. The developments in this area demand further searches for neat methods and diversity in reagents that
could be superior to the existing ones with regard to generality, simplicity, high yields and handling. In other hand,
after introduction of the silica sulfuric acid (SSA) as a useful heterogeneous solid acid by Zolfigol in 2001, many
research papers have been published on its application in organic synthetic methodology and multicomponent
reactions [5]. In this respect, we are interested in presenting potential neat diketene, alcohols and aldehydes adduct
for preparation of the DHPMs and DHPs heterocyclic skeleton to overcome these limitations in presence of silica
sulfuric acids (SSAs). In this new heterogeneous neat method which is based on using diketene as original, in situ
source of variable b-ketoesters in four-component synthesis of DHPMs and DHPs is described. The neat
approach, easiness and variability in derivatives of the present four-component procedure make it an interesting
alternative to three-component approaches.
* Corresponding author.
E-mail addresses: rostamnia@maragheh.ac.ir, srostamnia@gmail.com (S. Rostamnia).
1001-8417/$ – see front matter # 2012 Sadegh Rostamnia. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.008

S. Rostamnia, K. Lamei / Chinese Chemical Letters 23 (2012) 930–932
931
2. Experimental
To a magnetically stirred of equivalent amount of neat adduct diketene (1 mmol) and aldehyde (1 mmol) and
alcohol in excess amount of equivalent (4 mL) in SSA (10 mol%) for 5 min at reflux condition, urea or ammonium
acetate (1.2 mmol) was added, and then heated in neat state with stirring in refluxing condition, for an appropriate time
(TLC monitoring). After that hot ethanol (20 mL) was added and the mixture was filtered to remove the catalyst. The
reaction was cooled to room temperature and the solid was washed with cooled water, petroleum ether/ether. All the
products were previously reported and were characterized by comparing physical data with those. Spectral data for
selected products: methyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3a). M.P. 207–211
(207–210). IR (KBr): 3325, 3316, 1698, 1661, 1585, 1422. 1H NMR (300.1 MHz, CDCl3): 2.35 (3, s, CH3), 3.62 (3, s,
OCH3), 5.40 (1, d, J 2.1 Hz, CHNH), 5.53 (1, br, NH), 7.25–7.33 (5, m, C6H5), 7.56 (1, br, NH). Diethyl 2,6-dimethyl-
4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (4d). M.P. 150–153 (154–159). IR (KBr): 3345, 1703, 1657, 1473,
1
1198, 1130. H NMR (300.1 MHz, CDCl3): 1.20 (6, t, J 7.0 Hz, OCH2CH3), 2.31 (6, s, CH3), 4.09 (4, q, J 7.0 Hz,
OCH2CH3), 5.01 (1, s, CH), 6.20 (1, s, NH), 7.10–7.39 (5, m, C6H5).
3. Result and discussion
Although the three-component synthesis of DHPMs and DHPs via Biginelli and Hantzsch condition has been
studied [3,4,8,9]. To our surprise, one-pot reaction between diketene, urea, and aldehydes in presence of SSA as a
heterogeneous catalyst and methanol as solvent, produced Biginelli product dihydropyrimidin-2(1H)-ones, methanol
is main partial of heterocycle skeleton in this reaction. So, based on this founding, in a new plan in heterocycle
synthesis, we explored the potential neat adduct of diketene/alcohols/aldehydes for four-component condensation of
this adduct with NH4OAc and urea at reflux condition. Recently, we have reported and developed the multicomponent
heterocyclic skeleton synthesis such as DHPMs, DHPs [6], rhodanine, furans and others [7] herein we wish to report a
simple and potential DHPMs and DHPs heterocycle synthesis based on diketene/alcohols/aldehydes neat adduct, in
the presence of SSA as a heterogeneous solid acid catalyst in one-pot four-component Biginelli-type and Hantzsch-
type condensation protocols, respectively.
The neat reaction of diketene, aldehydes 1, alcohols 2, with urea in the presence of catalytic amount SSA underwent
an Biginelli cyclocondensation reaction at refluxing condition, to produce 3,4-dihydropyrimidin-2-(1H)-one
derivatives 3 (Table 1).
Table 1
The neat four-component synthesis of DHPMs.
[TD$INLE]
O
SSA
O
O
SO3H
SO3H
Silica Sulfuric Acid
(SSA)
SiO2
HN
NH
(10 mol%)
ArCHO
ROH
+
+
+
H2N
NH2
6h, reflux
O
Ar
2
1
3
COOR
Ar
R
M.P. (8C)
%Yielda
Found
Reported
3a
3b
3c
3d
3e
3f
C6H5
C6H5
Me
Et
207–211
200–204
255–257
210–212
210–213
190–194
201–203
214–215
237–238
209–211
207–2108a
201–2038a
252–2538b
215–2188a
208–2103b
192–1933a
204–2073a
210–2123a
235–2378a
207–2108a
90
80
81
88
88
81
91
93
90
90
2-Cl–C6H4
2-Cl–C6H4
3-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
4-Cl–C6H4
4-NO2–C6H4
4-NO2–C6H4
Me
Et
Me
Et
3g
3h
3i
Me
Et
Me
Et
3j
a
Isolated and non-optimized yields.

932
S. Rostamnia, K. Lamei / Chinese Chemical Letters 23 (2012) 930–932
Table 2
The neat four-component Hantzsch-type condensation of dihydropyridines.
[TD$INLE]
Ar
O
SSA
RO2C
CO2R
SO3H
SO3H
(10 mol%)
SiO2
ArCHO
ROH
NH4OAc
+
+
+
O
8h, reflux
Silica Sulfuric Acid
(SSA)
N
H
1
2
4
R
Ar
M.P. (8C)
%Yielda
Found
Reported
4a
4b
4c
4d
4e
4f
Me
Me
Me
Et
2-OMe–C6H4
3-OMe–C6H4
4-NO2–C6H4
C6H5
160–162
168–169
163–165
150–153
122–126
123–124
146–149
125–129
170–1714a
168–1704a
165–1684b
154–1599a
125–1264b
120–1219a
144–1489a
129–1329a
73
77
83
87
77
77
79
87
Et
2-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
4-NO2–C6H4
Et
4g
4h
Et
Et
a
Isolated and non-optimized yields.
The reaction was found to be general with respect to a NH4OAc affording the 1,4-dihydropyridines (DHPs) 4
products in good yields. The results are summarized in Table 2.
4. Conclusion
In summary, we have described a simple catalitic one-pot neat synthesis of 3,4-dihydropyrimidin-2-(1H)-one and
1,4-dihydropyridin derivatives via a four-component cyclocondensation reaction of diketene, alcohols, aldehydes with
urea and NH4OAc, respectively. In addition, the present method carries the advantage that, not only is the reaction
performed under one-pot neat conditions, but also, in addition of aldehyde component, the alcohols component can be
modified to synthesize derivatives, too. The retrieval, easiness and variation in derivatives in presence of
heterogeneous catalitic solid acids of the present four-component procedure make it an interesting alternative to
three-component approaches.
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