α-zirconium sulfophenylphosphonate as a catalyst for the synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives under solvent free conditions

Article abstract of DOI:10.1007/s10562-011-0604-4

3,4-Dihydropyrimidin-2(1H)-one derivatives were synthesized using layered α-zirconium sulfophenylphosphonate as a recyclable heterogeneous catalyst. Several classes of reagents, such as functionalized aromatic and aliphatic aldehydes, β-dicarbonyl derivat

Full text of DOI:10.1007/s10562-011-0604-4

Catal Lett (2011) 141:850–853
DOI 10.1007/s10562-011-0604-4
a-Zirconium Sulfophenylphosphonate as a Catalyst
for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-One
Derivatives Under Solvent Free Conditions
Ornelio Rosati
Morena Nocchetti
•
Massimo Curini
•
•
Francesca Montanari
•
Salvatore Genovese
Received: 10 March 2011 / Accepted: 8 April 2011 / Published online: 23 April 2011
Ó Springer Science+Business Media, LLC 2011
Abstract 3,4-Dihydropyrimidin-2(1H)-one derivatives were
synthesized using layered a-zirconium sulfophenylphosph-
onate as a recyclable heterogeneous catalyst. Several classes
of reagents, such as functionalized aromatic and aliphatic
aldehydes, b-dicarbonyl derivatives and 2-aminobenzimid-
azole, were used to synthesize different 3,4-dihydropyrimi-
din-2(1H)-one derivatives under solvent free conditions.
heterocyclic systems (i.e. Paal-Knorr and Knorr reactions)
[11–13].
For these reasons we thought to investigate the use of
a-zirconium sulfophenylphosphonate in an important topic
of organic synthesis represented by the possibility to carry
out a multicomponent process [14–16], such as Biginelli-
type reaction, in solvent free condition (Scheme 1).
Since 1893 [17], Biginelli reaction represented a useful
multicomponent synthetic tool and until now it represents
one of the most studied one pot processes for the synthesis
of 3,4-dihydropyrimidin-2(1H)-one derivatives [18, 19].
Keywords Heterogeneous catalysis Á Multicomponent
reaction Á Heterocycles Á Biginelli reaction Á 3,4-
dihydropyrimidin-2(1H)-ones
3,4-Dihydropyrimidin-2(1H)-one derivatives are con-
sidered of large interest as their heterocyclic system can be
found in a large variety of biologically active compounds
1
Introduction
[
20–25].
Until now a large number of methods for the synthesis
During the last decades, we demonstrated the effectiveness
of the application of a-zirconium sulfophenylphosphonate
of 3,4-dihydropyrimidin-2(1H)-ones has been reported
[26–28], but only few examples were developed with the
aim of replacing conventional toxic and polluting Bronsted
and Lewis acid catalysts with reusable solid acid hetero-
geneous catalysts, for the development of eco-friendly
processes with reduced environmental impact [27, 29–32].
This is one of the most important goal in the sustainable
chemistry [33, 34] and, among different possibilities, the
development of synthetic methodologies mediated by het-
erogeneous catalysts [35, 36] in solvent free processes,
plays a relevant role [37, 38].
[
Zr(O PCH ) (O PC H SO H)0.8] as strong acid solid
3 3 1.2 3 6 4 3
layered catalyst [1] (pKa between -5.6 and -8.4: mea-
2
sured by Hammet acidity, and a surface area of 24 m /g:
B.E.T. method) [2] in many synthetic processes such as
protection and deprotection of functional groups [3–9],
carbon–heteroatom bonds formation [10] and synthesis of
O. Rosati (&) Á M. Curini Á F. Montanari
Dipartimento di Chimica e Tecnologia del Farmaco, Universita`
degli Studi, via del Liceo 1, 06123 Perugia, Italy
e-mail: ornros@unipg.it
2
Results and Discussion
M. Nocchetti
Dipartimento di Chimica, Universit a` degli Studi, Via Elce di
Sotto 8, 06123 Perugia, Italy
Our first approach to the Biginelli-type reaction was
achieved by standard reagents such as ethyl acetoacetate or
S. Genovese
Dipartimento di Scienze del Farmaco, Universit a` G.
D’Annunzio, Via dei Vestini 31, 66100 Chieti, Italy
2,4-pentanedione, urea and aromatic aldehyde in the pres-
ence of 12 mol % a-Zr(O PCH ) (O PC H SO H) as
3
3 1.2
3
6
4
3
0.8
1
23

a-Zirconium Sulfophenylphosphonate as Catalyst in Biginelli Reaction
851
O
O
R1
R
H
O
O
O
H N
NH2
R
N
2
Kat
O
O
N
H
O
R
neat, 80°C
N
H
R
N
R1 CHO
O
N
N
H
N
H
Kat = α-Zr(CH3) (O PC H SO H)
1.2
3
6
4
3
0.8
O
R
1
a R = Me
H
O
2a R = Me
2b R = OEt
Scheme 1 Preparation of dihydropyrimidinones in the presence of
a-Zr(CH PC SO
EtO
N
1b R = OEt
3
)
1.2(O
3
H
6 4
3
H)0.8
N
H
Table 1 Reaction of b-dicarbonyl compounds with aromatic alde-
hydes and urea
3
3
a R = -(CH2)4CH3
b R = -(CH2)8CH=CH2
Entry
R
R
1
6
Yield %
Time (h)
Fig. 1 Examples of some dihydropyrimidinone derivatives
1
2
3
4
5
6
7
8
OEt
C
H
5
89
92
90
78
83
84
81
76
18
20
20
18
20
20
18
20
also been used to obtain dihydropyrimidinone derivatives
such as 3 (Table 2, entries 5–6) (Fig. 1).
OEt
4-NO
2
–C
6
H
4
4
OEt
3-Cl–C
6
H
4
The reaction was carried out at 80 °C in the presence of
Me
6 5
C H
1
2 mol % a-Zr(O PCH ) (O PC H SO H) under sol-
3
3 1.2
3
6
4
3
0.8
Me
4-NO
–C
2 6
H
vent free conditions.
Me
6 4
3-Cl-C H
The work-up of the reaction required a treatments with
hot ethyl acetate or methanol for a complete extraction of
adducts from the solid reaction mixture. The exception
were compounds 3a and 3b, that were easily dissolved by
dichloromethane. The catalyst, washed with methanol and
dried at 120 °C for 12 h can be reused for several experi-
ments. The reaction of benzaldehyde, ethylacetoacetate and
urea has been repeated three times with the following
yields: 86% (20 h), 84% (20 h), 81% (20 h).
p-OMe–C
6
H
4
–NH
C
C
6
H
5
5
[39]
[40]
6 5
C H
6
H
The reaction was carried out at 80 °C in the presence of 12 mol %
a-Zr(O PCH PC SO H)0.8 under solvent free conditions
3
3
)
1.2(O
3
H
6 4
3
heterogeneous catalyst, under solvent free condition at
0 °C (Table 1, entries 1–6). Under these reaction condi-
8
tions b-dicarbonyl compounds such as p-acetoacetanisidide
and benzoylacetone afforded to the respective 3,4-dihy-
dropyrimidin-2(1H)-one derivatives (Table 1, entries 7–8).
Although, in all entries the reaction time ranged from 18 to
Figure 2 show the SEM images of a-zirconium sul-
fophenylphosphonate before and after the use, respectively.
It is possible to observe for both pictures an high grade of
aggregation and the typical layered structure of the solid.
Furthermore the micrographs of unused solid show the
presence of several microparticles having submicron size
that disappeared in the recycled catalyst. It is important
highlight the conservation of the layered structure of
recycled material that resulted less compact then the pris-
tine catalyst.
2
0 h, the yields of the isolated compounds were interesting.
a-Zr(O PCH ) (O PC H SO H) showed a good
3
3 1.2
3
6
4
3
0.8
catalytic activity also using 2-aminobenzimidazole instead
of urea (Table 2, entries 1–2) and salicylaldehyde as aro-
matic aldehyde (Table 2, entries 3–4), affording the dihy-
dropyrimidinone derivatives 1 and 2, respectively (Fig. 1).
Aliphatic aldehydes (hexanal, undecylenic aldehyde) have
Table 2 Dihydropyrimidinone derivatives starting from 2,4-pentanedione or ethyl acetoacetate
Entry
Aldehyde
Azotate derivative
Adduct
Yield (%)
Time (h)
1
2
3
4
5
6
Benzaldehyde
Benzaldehyde
Salicylaldehyde
Salicylaldehyde
Hexanal
2-Amino-benzimidazole
1a [41]
1b [41]
2a [42]
2b [43]
3a [44]
3b
73
67
81
76
71
56
20
20
20
20
20
20
2-Amino-benzimidazole
Urea
Urea
Urea
Urea
Undec-10-enal
The reaction was carried out at 80 °C in the presence of 12 mol % a-Zr(O
3 3
PCH )
1.2(O
3
PC
6
H
SO H)0.8 under solvent free conditions
4 3
123

8
52
O. Rosati et al.
Fig. 2 SEM images of a-zirconium sulfophenylphosphonate before (a) and after (b) the use
3
Experimental
was added. The reaction mixture was warmed at 80 °C and
the progress of the reaction monitored by tlc. Stirring was
continued for the appropriate time (see Tables 1 and 2).
After cooling, the reaction mixture was washed with hot
ethylacetate (or methanol) (5 ml 9 4) and filtered on
buchner. The resulting solution was concentrated under
vacuum to afford the crude product. The purification of
adducts were obtained by crystallization from ethanol. All
products prepared by the above procedure were charac-
terized spectroscopically. The data of compounds in
Table 1 (entries 1–8) and in Table 2 (entries 1–5) resulted
identical with those already reported in the literature.
3
.1 General
All chemicals were purchased from the major chemical
suppliers as highest purity grade and used without any
further purification. Column chromatography was per-
formed with Merk silica gel 60 (70–230 mesh ASTM),
using dichloromethane/ethyl acetate or dichloromethane/
1
13
methanol mixture. H and C NMR were recorded in
CDCl or DMSO-d with a Brucker Avance DRX 200
3
6
spectrometer at a frequency of 200.1 and 50 MHz,
respectively or Brucker Avance DPX 400 spectrometer at
a frequency of 400.13 and 100.62 MHz, respectively.
GC–MS analysis were obtained with HP-6890 gas chro-
matograph (dimethyl silicone column, 12.5 m) equipped
with an HP-5973 mass-selective detector at an ionizing
voltage of 70 eV. Melting points are uncorrected.
3.3 Characterization Data
Compound 3b (Table 2, entry 6) white solid: mp
1
85–88 °C; H NMR (400 MHz, CDCl ) d 1.29 (m, 17H,
3
79CH , CH ), 2.04 (m, 2H, CH –C=), 2.29 (s, 3H, CH ),
2
3
2
3
4.21 (m, 2H, OCH ), 4.30 (m, 1H, H-4), 4.97 (m, 2H,
2
3
.2 General Experimental Procedure
CH=CH ), 5.82 (m, 1H, CH=CH ), 6.24 (bs, 1H, NH), 8.60
2 2
1
3
(
bs, 1H, NH); C NMR (100 MHz, CDCl ) d 14.7, 18.8,
3
To a stirred mixture of b-dicarbonyl compounds (1 mmol),
urea (1.2 mmol) and aldehyde (1 mmol), under solvent free
condition, a-Zr(O PCH ) (O PC H SO H) (12 mol %)
24.8, 29.3, 29.5, 29.7, 29.8, 29.9, 34.2, 37.3, 51.9, 60.2,
101.9, 114.5, 139.5, 147.3, 155.3, 166.3. GC–MS:
?
m/z = 322 [M ], 277, 207, 183, 155, 137.
3
3 1.2
3
6
4
3
0.8
1
23

a-Zirconium Sulfophenylphosphonate as Catalyst in Biginelli Reaction
853
4
Conclusion
14. Ugi I, Domling A, Horl W (1994) Endeavour 18:115
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1
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6. Mabry J, Ganem B (2006) Tetrahedron Lett 47:55
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In this paper we reported the use of layered zirconium
sulfophenyl phosphonate as heterogeneous catalyst in a
good yielding preparation of dihydropyrimidinone deriva-
tives, under solvent free conditions. This process resulted
of a general applicability, as shown by the use of several
classes of reagents that afforded different structured dihy-
dropyrimidinone derivatives. The use and the recyclable
nature of this catalyst makes the process simple with
negligible chemical waste. Thus this method can be an
environmentally acceptable synthetic tool for Biginelli
reaction.
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Acknowledgment Financial support from MIUR, National Project
2008 ‘‘Approccio ecocompatibile all’intensificazione di processo
nella sintesi organica’’ is gratefully acknowledged.
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