A practical and green approach towards synthesis of dihydropyrimidinones without any solvent or catalyst

Article abstract of DOI:10.1021/op0255478

A simple, efficient, green, and cost-effective procedure has been developed for the synthesis of dihydropyrimidinones by a solvent-free and catalyst-free Biginelli's condensation of 1,3-dicarbonyl compound, aldehyde, and urea. This approach of direct reaction in neat without solvent and catalyst shows a new direction in green synthesis.

Full text of DOI:10.1021/op0255478

Organic Process Research & Development 2002, 6, 817−818
A Practical and Green Approach towards Synthesis of Dihydropyrimidinones
without Any Solvent or Catalyst
Brindaban C. Ranu,* Alakananda Hajra, and Suvendu S. Dey
Department of Organic Chemistry, Indian Association for the CultiVation of Science, JadaVpur, Calcutta - 700032, India
Abstract:
towards green synthesis, we have discovered that Biginelli’s
reaction proceeds very efficiently by stirring a mixture of
neat reactants at 100-105 °C for an hour, requiring no
solvent and catalyst, and producing dihydropyrimidinones
in high yields7 (Scheme 1).
In a typical experimental procedure,8 a mixture of 1,3-
dicarbonyl compound, aldehyde, and urea was heated at
A simple, efficient, green, and cost-effective procedure has been
developed for the synthesis of dihydropyrimidinones by a
solvent-free and catalyst-free Biginelli’s condensation of 1,3-
dicarbonyl compound, aldehyde, and urea. This approach of
direct reaction in neat without solvent and catalyst shows a new
direction in green synthesis.
(6) (a) Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998, 63, 3454-
3457. (b) Lu, J.; Ma, H. Synlett 2000, 63-64. (c) Ranu, B. C.; Hajra, A.;
Jana, U. J. Org. Chem. 2000, 65, 6270-6272. (d) Ramalinga, K.;
Vijayalakshmi, P.; Kaimal, T. N. B. Synlett 2001, 863-865. (e) Lu, J.;
Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron Lett. 2000, 41, 9075-
9078. (f) Yadav, J. S.; Reddy, B. V. S.; Srinivas, R.; Venugopal, C.;
Ramalingam, T. Synthesis 2001, 1341-1345. (g) Kumar, K. A.; Kast-
huraiah, M.; Reddy, C. S.; Reddy, C. D. Tetrahedron Lett. 2001, 42, 7873-
7875. (h) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Raj, K. S.; Prasad,
A. R. J. Chem. Soc., Perkin Trans. 1 2001, 1939-1941. (i) Ma, Y.; Qian,
C.; Wang, L.; Yang, M. J. Org. Chem. 2000, 65, 3864-3868. (j) Bigi, F.;
Carloni, S.; Frullanti, B.; Maggi, R.; Sartori, G. Tetrahedron Lett. 1999,
40, 3465-3468. (k) Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 5917-
5919.
The toxicity and volatile nature of many organic solvents,
particularly chlorinated hydrocarbons, that are widely used
in huge amounts for organic reactions have posed a serious
threat to the environment.1 Thus, design of solventless
catalytic reaction has received tremendous attention in recent
times in the area of green synthesis.2 However, it has been
observed that the catalysts employed are not always eco-
friendly, and because of this severe environmental pollution
often results during the process of waste disposal. This
prompted us to initiate a systematic investigation to look into
the feasibility of a solvent-free and catalyst-free reaction3
under modified experimental conditions towards development
of real green methodology for useful molecules.
Dihydropyrimidinone derivatives are of considerable
interest in industry as well as in academia because of their
promising biological activities as calcium channel blockers,
antihypertensive agents, and anticancer drugs.4 Thus, syn-
thesis of this heterocyclic nucleus is of much importance,
and quite a number of synthetic procedures based on the
modifications of the century-old Biginelli’s reaction5 involv-
ing acid-catalyzed three-component condensation of 1,3-
dicarbonyl compound, aldehyde, and urea, have been de-
veloped during past few years.4,6 Basically, these methods
are all similar, using different Lewis acid catalysts such as
BF3,6a FeCl3,6b InCl3,6c BiCl3,6d LaCl3,6e LiClO4,6f Mn-
(OAc)3,6g CAN,6h in a solvent such as CH3CN, CH2Cl2, or
THF. Recently, a number of procedures under solvent-free
conditions using Yb(OTf)3,6i montmorillonite6j and ionic
liquid6k as catalysts have also been reported. Obviously, many
of these catalysts and solvents are not at all acceptable in
the context of green synthesis. Thus, as a part of our program
(7) In a recent communication6k Peng and Deng reported that no desirable
product was detected when a mixture of benzaldehyde, ethyl acetate, and
urea (mol ratio 1:1:1.5) was heated at 100 °C for 30 min in the absence of
ionic liquid, indicating a catalyst must be needed for the Biginelli reaction.
However, when we found a very efficient reaction in neat without solvent
and catalyst under similar reaction conditions, we communicated our
observation to Professor Deng for his comments. We have not yet received
a reply.
(8) Representative Experimental Procedure: (a) Small-scale (milligram
level) (Entry 5). A mixture of 3-methoxybenzaldehyde (freshly distilled,
272 mg, 2 mmol), ethyl acetoacetate (freshly distilled, 260 mg, 2 mmol),
and urea (180 mg, 3 mmol, Loba-chemie, India) was heated under stirring
(magnetic stirrer) at 100-105 °C (oil bath). After few minutes with the
progress of reaction the solid started to separate out and after completion
(1 h, TLC) the resulting solid was crushed, washed with cold water, filtered,
and dried under vacuum to give the crude product which is reasonably
pure (>95% purity by 1H NMR). However, recrystallization from hot
ethanol provides the analytically pure product6c (476 mg, 82%), mp 207-
208 °C; IR 3242, 1701, 1651, 1598 cm-1; 1H NMR δ 9.17 (s, 1H), 7.70 (s,
1H), 7.23 (t, J ) 7.8 Hz, 1H), 6.79 (m, 3H), 5.09 (d, J ) 2.7 Hz, 1H), 3.97
(q, J ) 6.9 Hz, 2H), 3.70 (s, 3H), 2.22 (s, 3H), 1.09 (t, J ) 6.9 Hz, 3H);
13C NMR δ 165.7, 159.5, 152.5, 148.8, 146.6, 129.9, 118.8, 112.7, 102.6,
99.4, 59.5, 55.3, 54.6, 18.1, 14.4. Anal. Calcd for C15H18N2O4: C, 62.06;
H, 6.25; N. 9.65. Found: C, 61.89; H, 6.18; N, 9.49. This procedure is
followed for the preparation of all the dihydropyrimidinones listed in Table
1. All the products are reported earlier and are identified by comparison of
their mp, IR, 1H, and 13C NMR spectral data with those reported.6 (b)
Large-scale (1 kilogram level). A mixture of benzaldehyde (530 g, 5 mol),
ethyl acetoacetate (650 g, 5 mol), and urea (360 g, 6 mol) taken in a 2-L
round-bottomed flask was stirred by a mechanical stirrer at room temper-
ature for 2 min for uniform mixing, and then the temperature (oil bath)
was raised to 100-105 °C. No exothermic reaction was observed during
addition and mixing. Stirring was continued for another 1 h at that
temperature. With the progress of reaction (approximately during the first
20 min all the urea dissolved, and solids started to appear) the reaction
mixture became a thick slurry with the solids being deposited. At this stage,
although no efficient stirring or agitation can be made, the reaction was
not affected. After 1 h the reaction mixture was cooled in an ice-water
bath (0-5 °C), and water (200 mL) was added. The solid was broken into
pieces carefully with a spatula and filtered. The yellow solid was then
washed with cold water (100 mL) followed by cold rectified spirit (50
mL) to provide a colorless solid (1.025 kg, 79%) which was practically
pure, mp 201-202 °C (lit6a 202-204 °C). A portion of it was recrystallized
from hot ethanol to give analytically pure sample.
* To whom correspondence should be addressed. Fax: 91-33-4732805.
E-mail: ocbcr@mahendra.iacs.res.in.
(1) Nelson, W. M. In Green Chemistry; Anastas, P. T., Williamson, T. C.,
Ed.; Oxford University Press: Oxford, 1998; Chapter 12, p 200.
(2) (a) Tanaka, K.; Toda, F. Chem. ReV. 2000, 100, 1025-1074. (b) Cave, G.
W. V.; Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 2159-2169. (c)
Metzger, J. O. Angew. Chem., Int. Ed. 1998, 37, 2975-2978.
(3) For a recent report of a solvent-free and catalyst-free reaction: Joselink,
M.; Varma, R. S.; Polanc, S.; Kocevar, M. Chem. Commun. 2001, 1716-
1717.
(4) (a) Kappe, C. O. Tetrahedron 1993, 49, 6937-6963. (b) Kappe, C. O.
Acc. Chem. Res. 2000, 33, 879-888.
(5) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360-413.
10.1021/op0255478 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002
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Table 1. Synthesis of dihydropyrimidinones without any
Scheme 1
solvent and catalyst
that under identical reaction conditions (without an acid
catalyst) the reaction did not progress at all in refluxing
dichloromethane, dichloroethane, THF, and toluene during
1 h, although refluxing for 5 h in toluene furnished 15-
20% yields. This indicates the special advantage of the
solventless reaction and the negative role of solvent at least
in this case.
A broad range of structurally diverse 1,3-dicarbonyl
compounds, aldehydes, and urea are subjected under this
procedure to produce the corresponding dihydropyrimidi-
nones. The results are reported in Table 1. A wide variation
of alkyl groups in 1,3-dicarbonyl compound as well as in
aldehyde are tolerated in this procedure to provide a library
of dihydropyrimidinones with a variety of substituents.
Thiourea also works well to give the corresponding thio-
derivatives which are also of much interest with regard to
biological activity.4
In general, the reactions are very clean, and no side
product was obtained in any run. In fact, the crude products
obtained are of high purity (>95% by 1H NMR) and do not
require any chromatographic separation. Recrystallization
from hot ethanol provides analytically pure sample. Most
significantly, the whole operation does not involve any
organic solvent7 at any stage and can be scaled up to the
level producing 1 kg of product in the laboratory (not
optimized) without any problem. In addition, the reaction
condition is mild enough to tolerate a variety of sensitive
functionalities such as NO2, Cl, OH, OMe, conjugated C-C
double bond, and heterocyclic moieties.
In conclusion, the present procedure of the synthesis of
dihydropyrimidin-2(1H)-ones by a solvent-free and catalyst-
free condensation of 1,3-dicarbonyl compound, aldehyde, and
urea provides a simple, efficient, cost-effective, and 100%
green modification of the Biginelli’s reaction. Most signifi-
cantly, this solvent-free and catalyst-free process of three-
component condensation throws a challenge to the existing
procedures4,6 which use volatile and hazardous solvents and
toxic catalysts, and in general, leads to a new direction in
organic synthesis. We believe this will find useful applica-
tions as a practical alternative for the synthesis of dihdro-
pyrimidinones to cater the need of industry as well as
acedmia.
Acknowledgment
This investigation has enjoyed the financial support from
a grant [No. 02(1739)/02] from CSIR, New Delhi. A.H. and
S.S.D. are also thankful to CSIR for their fellowships.
a Yields refer to those of recrystallized pure products characterized by mp
and spectral data (IR, 1H, and 13C NMR).
100-105 °C in neat without any solvent or catalyst. The
reactions are complete by an hour, and the solid products
were filtered and recrystallized. It has also been observed
Received for review May 8, 2002.
OP0255478
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