Clay catalysed synthesis of dihydropyrimidinones under solvent-free conditions

Article abstract of DOI:10.1055/s-2003-40828

A fast and high yielding one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones from β-keto esters, urea and various aliphatic and aromatic aldehydes using montmorillonite KSF clay as a catalyst in solvent-free condition under microwave irradiation is descr

Full text of DOI:10.1055/s-2003-40828

LETTER
1509
Clay Catalysed Synthesis of Dihydropyrimidinones under Solvent-free
Conditions
Clay
C
atalyzed Sy
l
nthesis
o
of
D
ihydrop
k
yrimidinone
s
Kumar Mitra,* Krishna Banerjee
Department of Chemistry, University of Calcutta, 92 Acharya P.C. Road, Calcutta – 700 009, India
Fax +91(33)3519755; E-mail: akmitra@cucc.ernet.in
Received 4 November 2002
an eco-friendly system. Currently, much emphasises has
been given to the use of inorganic reagents18 in organic re-
actions, as these reactions often provide the milder condi-
tions and easier work up than similar reactions using
organic reagents. Montmorillonite KSF clay has been ex-
tensively used in various organic reactions such as alkyla-
tions,19 acylations,20 Beckmann rearrangement21 and,
under microwave irradiation, in the Fischer indole synthe-
sis,22 ortho-ester Claisen rearrangement,23 acetal
formation24 and deprotection of aldehyde derivatives.25
In continuation of our ongoing programme26 to develop
synthetic protocols utilising microwave radiation under
solvent-free conditions, we report herein the synthesis of
a variety of 3,4-dihydropyrimidin-2(1H)-ones using
montmorillonite KSF clay as a catalyst in the condensa-
tion reaction of acetoacetic esters with urea and various
aliphatic and aromatic aldehydes under microwave irradi-
ation without any organic solvent. The reactions
(Scheme 1) proceed efficiently in high yields (80–98%) at
ambient pressure in open vessels within a very short time
(5–17 min, Table 1). By this method strong acids or sol-
vents such as CH3CN have been avoided. Montmorillo-
nite KSF may be regenerated easily as an active catalyst
by washing with ethanol, followed by drying at 110ºC for
12 hours, and could be reused. By conventional heating
method (oil bath) at 110 ºC, the reaction completed after
6 hours. To the best of our knowledge, this is the first re-
port of the synthesis of 3,4-dihydropyrimidin-2(1H)-ones
using montmorillonite KSF clay.
Abstract: A fast and high yielding one-pot synthesis of 3,4-dihy-
dropyrimidin-2(1H)-ones from b-keto esters, urea and various ali-
phatic and aromatic aldehydes using montmorillonite KSF clay as a
catalyst in solvent-free condition under microwave irradiation is
described. The catalyst can also be recycled in these syntheses.
Key words: dihydropyrimidinones, montmorillonite KSF, micro-
wave activation, solvent-free condition
Recently, dihydropyrimidinone derivatives1 have been
shown to exhibit important pharmacological activities as
the integral backbone of several calcium channel block-
ers, antihypertensive agents, alpha-1a-antagonists, and
neuropeptide Y(NPY) antagonists.2 Moreover, several
isolated marine alkaloids with interesting biological prop-
erties were also found to contain the dihydropyrimidino-
ne-5-carboxylate moiety.3 Most important among them
are the batzelladine alkaloids, which are potent HIV gp-
120-CD4 inhibitors.4 Thus, synthesis of this heterocyclic
nucleus is of much current importance. The first synthesis
was carried out by Biginelli,5 involving condensation of
ethyl acetoacetate, benzaldehyde and urea under strong
acidic conditions. However, serious drawbacks of the
Biginelli reaction are the use of strong acid as well as the
low yields in the case of substituted aromatic and aliphatic
aldehydes.6 As Biginelli reaction for the synthesis of dihy-
dropyrimidinone has received renewed interest, several
improved procedures have recently been reported7–14. But
these methods suffer from one or other disadvantages like
use of protic acids,7,8 strong Lewis acids,7,9,10 expensive
lanthanide reagents11,12 and are generally not environmen-
tally benign.13–15
In conclusion, we have developed a much improved Big-
inelli protocol exploiting inexpensive, easily available
montmorillonite KSF clay as a catalyst without using
strong Brønsted or Lewis acids, or organic solvents with
increased yield, and reaction times shortened from several
hours to a few minutes under microwave irradiation.
The growth in interest in the application of microwave ra-
diation in chemical reaction enhancement16 is due to high
reaction rates and formation of cleaner products. The sol-
vent-free17 condition is especially appealing for providing
Scheme 1
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1509,1511,ftx,en;D25402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1510
A. K. Mitra, K. Banerjee
LETTER
Table 1 Montmorillonite KSF Clay Catalysed Synthesis of Dihydropyrimidinones
Entry
R1
R2
Time (min)
Isolated yield (%) Mp (ºC)
Found
Reported
1
2
CH3CH2
Et
10
8
87
82
80
85
98
95
85
92
93
88
92
90
90
91
88
92
97
91
89
88
170–172
152–154
170–172
178–180
202–203
201–202
215–216
208–209
227–228
185–186
256–258
202–204
231–232
176–177
188–189
209–211
192–194
236–237
220–222
150–152
–
CH3CH2CH2
(CH3)2-CH
Et
153–155
170–172
–
3
Et
17
16
10
16
8
4
(CH3)2-CH-CH2
C6H5
Et
5
Et
202–204
201–202
215–216
207–208.5
226–227.5
185–186
256–257
204.5–205
232–233
178–178.5
187–188
209–212
192–194
235–237
–
6
4-(CH3O)-C6H4
4-(Cl)-C6H4
Et
7
Et
8
4-(NO2)-C6H4
3-(NO2)-C6H4
3-(Br)-C6H4
Et
8
9
Et
7
10
11
12
13
14
15
16
17
18
19
20
Et
8
4-(NMe2)-C6H4
Furyl-
Et
15
8
Et
4-(OH)-3(OCH3)C6H3
3,4-(OCH3)2-C6H3
3,4-(OCH2O)-C6H3
C6H5
Et
5
Et
15
12
10
13
8
Et
Me
Me
Me
Me
Me
4-(CH3O)-C6H4
4-(NO2)-C6H4
4-(OH)-3-(OCH3)-C6H3
3,4-(OCH3)2-C6H3
5
10
–
General Procedure for the Synthesis of Dihydropyrimidinones
Ethyl acetoacetate/methyl acetoacetate (2 mmol), aldehyde (2
mmol), urea (3 mmol) were mixed thoroughly with montmorillonite
KSF (Aldrich Chemical Co., USA) (375 mg). The mixture was tak-
en in a 100 mL Erlenmeyer flask, placed in an alumina bath inside
a microwave oven (BPL, BMO, 700T, 1200 Watt) and irradiated for
a specified time (Table 1). This was removed from the oven and
poured into crushed ice (20 g). Now, it was stirred for several min-
utes and filtered. The residue was treated with hot EtOH and again
filtered to remove the clay catalyst. The filtrate was concentrated to
afford the recrystallised product. The products were characterised
by IR, 1H NMR and 13C NMR spectra and by comparison with melt-
ing points of the reported compounds. The new compounds (entries
1, 4, 19, 20) were characterised by spectral and analytical data.
Calcd for C10H16O3N2: C, 56.58; H, 7.60; N, 13.20. Found: C,
56.55; H, 7.26; N, 12.82.
4
1
IR (KBr): 3241, 3113, 2954, 1707, 1651, 1473 cm–1. H NMR
(CDCl3): d = 8.37 (s, 1 H), 6.09 (s, 1 H), 4.32 (dd, J = 6.7 Hz and
3.2 Hz, 1 H), 4.12 (q, J = 7.0 Hz, 2 H, OCH2), 2.27 (s, 3 H), 1.72–
1.70 (m, 1 H), 1.58–1.52 (m, 2 H), 1.27 (q, J = 7.0 Hz, 3 H,
OCH2CH3), 0.91 (d, J = 6.5 Hz, 6 H, Me2). 13C NMR (CDCl3):
d = 165.8 (C), 154.5 (C), 146.6 (C), 102.4 (C), 59.8 (CH2), 49.8
(CH), 45.8 (CH2), 23.7 (CH3), 21.2 (CH), 18.5 (CH3), 14.3 (CH3).
Anal. Calcd for C12H20O3N2: C, 59.98; H, 8.39; N, 11.66. Found: C,
59.76; H, 7.91; N, 11.47.
19
Spectroscopic Data of some 3,4-Dihydropyrimidin-2(1H)-ones
IR (KBr): 3389, 3254, 2951, 1694, 1677, 1517 cm–1. 1H NMR (DM-
SO-d6): d = 9.11 (s, 1 H), 7.61 (s, 1 H), 6.77 (d, J = 1.2 Hz, 1 H),
6.66 (d, J = 8.1 Hz, 1 H), 6.55 (dd, J = 8.1 Hz and 1.2 Hz, 1 H), 5.02
(d, J = 3.1 Hz, 1 H), 3.69 (s, 3 H, OCH3), 3.50 (s, 3 H, OCH3), 2.20
(s, 3 H, CH3). 13C NMR (DMSO-d6): d = 166.1 (C), 152.3 (C),
148.2 (C), 147.5 (C), 146.0 (C), 135.8 (C), 118.3 (CH), 115.4 (CH),
111.1 (CH), 99.5 (C), 55.8 (CH3), 53.6 (CH), 50.8 (CH3), 17.8
(CH3). Anal. Calcd for C14H16O5N2: C, 57.53; H, 5.52; N, 9.59.
Found: C, 56.86; H, 5.56; N, 9.31.
1
1
IR (KBr): 3248, 3120, 2464, 1717, 1646, 1471 cm–1. H NMR
(CDCl3): d = 8.24 (s, 1 H), 6.04 (s, 1 H), 4.19 (m, 1 H), 4.08 (q,
J = 7.1 Hz, 2 H, OCH2), 2.20 (s, 3 H, CH3), 1.52 (m, 2 H), 1.19 (t,
J = 7.1 Hz, 3 H, OCH2CH3), 0.83 (t, J = 7.2 Hz, 3 H). 13C NMR
(CDCl3): d = 165.9 (C), 154.6 (C), 146.7 (C), 101.3 (C), 59.8 (CH2),
52.9 (CH), 29.9 (CH2), 18.5 (CH3), 14.3 (CH3), 8.6 (CH3). Anal.
Synlett 2003, No. 10, 1509–1511 © Thieme Stuttgart · New York

LETTER
Clay Catalysed Synthesis of Dihydropyrimidinones
1511
20
(15) Toussaint, M. W.; Rosencrance, A. B.; Brennan, L. M.;
Beaman, J. R.; Wolfe, M. J.; Hoffmann, F. J.; Gardner, H. S.
Jr. Environ. Health Perspect. 2001, 109, 35.
IR (KBr): 3549, 3451, 3234, 2952, 1695, 1635, 1515 cm–1. 1H NMR
(DMSO-d6): d = 8.95 (s, 1 H), 7.60 (s, 1 H), 6.80 (m, 2 H), 6.69 (d,
J = 8.3 Hz, 1 H), 5.10 (d, J = 3.1 Hz, 1 H), 3.71 and 3.70 (2 s,
2 × 3H, 2 × OCH3), 3.53 (s, 3 H, OCH3), 2.18 (s, 3 H, CH3). 13C
NMR (DMSO-d6): d = 166.6 (C), 153.0 (C), 148.4 (C), 148.2 (C),
148.0 (C), 136.7 (C), 118.2 (CH), 111.8 (CH), 110.2 (CH), 99.9 (C),
55.5 (2 × CH3), 53.5 (CH), 51.1 (CH3), 17.6 (CH3). Anal. Calcd for
C15H18O5N2: C, 58.81; H, 5.92; N, 9.15. Found: C, 58.57; H, 5.98;
N, 8.76.
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Acknowledgement
The authors thank CSIR, UGC, New Delhi and University of
Calcutta for financial assistance.
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Synlett 2003, No. 10, 1509–1511 © Thieme Stuttgart · New York