A simplified green chemistry approach to the Biginelli reaction using 'Grindstone Chemistry'

Article abstract of DOI:10.1016/j.tetlet.2004.09.064

Solvent-free reactions that are complete in a few minutes. Grindstone Chemistry - a greatly evolved version of Toda's method of grinding solids together for solvent-free chemical reactions - has been described and its usefulness illustrated by the success

Full text of DOI:10.1016/j.tetlet.2004.09.064

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8351–8353
A simplified green chemistry approach to the Biginelli reaction using
ꢀGrindstone Chemistryꢁ
Ajay K. Bose,a,* Suhas Pednekar,a Subhendu N. Ganguly,a Goutam Chakrabortyb and
Maghar S. Manhasa
aGeorge Barasch Bioorganic Research Laboratory, Department of Chemistry and Chemical Biology, Stevens Institute of Technology,
Hoboken, NJ 07030, USA
bDepartment of Chemistry and Biochemistry, Montclair State University, Montclair, NJ 07043, USA
Received 18 August 2004; revised 3 September 2004; accepted 8 September 2004
Available online 25 September 2004
Abstract—Grindstone Chemistry––a greatly evolved version of Todaꢁs method of grinding solids together for solvent-free chemical
reactions––has been described and its usefulness illustrated by the successful application of this technique to a simplified process for
conducting the multi-component Biginelli reaction for the synthesis of physiologically active tetrahydropyrimidinones.
Ó 2004 Published by Elsevier Ltd.
Green chemistry is destined to be a national goal in the
near future. In this context, a convenient and rapid syn-
thetic procedure that is energy efficient is highly desira-
ble. To be of practical value, such a procedure should be
suitable for large-scale operation also. We wish to
describe here a technique with the descriptive title of
Grindstone Chemistry that is useful for desktop synthe-
sis as well as kilogram scale operation.
make the grinding process more efficient it is convenient
to add to the reaction mixture some amount of crystal-
line MgSO4Æ7H2O, a very common, inexpensive, and
water soluble chemical (available even in drug stores).
The addition of this friction-enhancing solid has given
very satisfactory result in promoting the reaction be-
tween liquid reagents by the grinding method. If the
reaction products are water soluble, the work-up of
the reaction mixture with magnesium sulfate added
may be inconvenient. In such a case, sand may be used
in place of magnesium sulfate; during work up the sand
can be easily removed by filtration.
The groundbreaking work of Toda et al. has shown that
many reactions (but not all) can be conducted in high
yield by just grinding solids together.1 Usually these
reactions were carried out on a very small scale in an
agate mortar and pestle. It has been of interest to us
to extend this approach to chemical reactions on a large
scale without being restricted to interactions between
solids only. This modified approach has been given the
name of ꢀGrindstone Chemistryꢁ in our laboratory. We
wish to describe here some significant aspects of this
type of synthesis that is also suitable for the large-scale
preparation of pharmaceuticals and their intermediates.
To conduct Grindstone Chemistry on a large scale a
simple and inexpensive expedient is to use a hand held
electric food mixer with stainless steel rotors for grind-
ing together the reagents in a large glass or porcelain
bowl.
For obtaining a better understanding of the energetics of
reactions, a thermocouple connected to a computer was
used for recording the ꢀReaction Temperature Profileꢁ
(change in the reaction temperature with the progression
of time) during and after the grinding. Data from several
of the successful reactions by grinding described by
Tanaka2 led us to generalize that these reactions are
all exothermic. We have concluded that after the reac-
tion is initiated by grinding with the transfer of very
small amounts of energy through friction, the reaction
proceeds by itself if it is exothermic in nature;
We have devised techniques for using reagent pairs that
may be solid/solid, solid/liquid, or even liquid/liquid. To
Keywords: Tetrahydropyrimidinone; Reaction by grinding; Solvent-
free reaction; p-TSA as an acid catalyst.
*
Corresponding author. Tel.: +1 201 216 5547; fax: +1 201 216
8420; e-mail: abose@stevens.edu
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.09.064

8352
A. K. Bose et al. / Tetrahedron Letters 45 (2004) 8351–8353
conversely, if the reaction is endothermic, grinding will
not make the reaction go forward.
32
31
30
29
28
27
26
25
24
23
In the course of studies on green chemistry one of our
goals has been to redesign conventional and time-
honored synthetic methods and make them more
eco-friendly and consistent with higher atom economy
(i.e., less chemical waste). We have now come to the con-
clusion that the traditional procedures for many reac-
tions are inefficient and involve unnecessary steps.
Heating under reflux for several hours is logical for
endothermic reactions. For exothermic reactions, how-
ever, such energy input would be superfluous.
0
10
20
30
40
Reaction Time (min)
Figure 1. Reaction temperature profile (RTP) of Biginelli reaction
using Grindstone Chemistry.
The convenience and the time saving that results from
the use of Grindstone Chemistry––for small scale as well
as large scale reactions––is illustrated here by describing
the successful application of this technique to the multi-
component Biginelli reaction.
reaction. We have found that p-toluenesulfonic acid
(p-TSA), an inexpensive and common organic chemical,
is an efficient catalyst for this reaction.
The Biginelli reaction,3 first described in 1893, has
attracted an unprecedented amount of attention in recent
years from synthetic and medicinal chemists.4 Tetra-
hydropyrimidinones (4), prepared by this reaction involv-
ing an aldehyde (1), a b-keto ester (2), and urea (3) (or
thiourea) and catalyzed by a strong acid have potential
use against a number of pathological conditions.
A test experiment was conducted by grinding together
equivalent amounts of benzaldehyde, ethyl acetoacetate,
urea, and a small amount of p-toluenesulfonic acid (as
an acid catalyst). Grinding for about 3–5min led to a
light yellow colored solid mass that proved to be mostly
X
O
R
O
p-TSA
R
EtO
+
+
H2N
NH2
EtO
H3C
NH
CHO
CH3
O
3
N
H
X
1
2
X = O or S
4
This reaction has been conducted in recent years by
heating the reagents or submitting them to microwave
irradiation, in presence of a suitable catalyst, in a sol-
vent such as alcohol, glycol, and polyphosphate esters.5
Many research groups have tried to improve the yield
of this reaction by using various acid catalysts such
as indium bromide, trifluoroacetic acid, boric acid,
potassium hydrogensulfate,6 zinc chloride,7 etc.
the target tetrahydropyrimidinone. The reaction temper-
ature profile as monitored by a thermocouple is shown
in Figure 1. It is quite obvious that the Biginelli reaction
is exothermic. The crude product was washed with cold
water to remove the color; final purification was
achieved by crystallization from acetone–EtOH, mp
208–210°C; yield 94%.
For obtaining larger quantities of the tetrahydropyri-
midinone, the reaction was conducted on 0.5M scale
with reagents placed in a large porcelain bowl. Grinding
We wish to report here a simplified and rapid synthetic
procedure with high atom economy for the Biginelli
Table 1. Synthesis of tetrahydropyrimidinone derivatives (4) using Grindstone Chemistry
Entry
R
X
Yield (%)
Mp (°C) found
Mp (°C) reported
4a
4b
4c
4d
4e
4f
H
O
O
O
O
O
S
93
95
96
94
83
71
208–210
236–238
208–209a
207–208
210–211
205–206
209–2107
236–2387
199–2018
205–2078
210–2129
205–2068
4-OH
4-OCH3
4-NO2
4-Cl
H
a Melting point of 4c synthesized by us is higher than that of the corresponding reported.

A. K. Bose et al. / Tetrahedron Letters 45 (2004) 8351–8353
8353
Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.;
OꢁReilly, B. C. J. Med. Chem. 1991, 34, 806.
5. Kappe, O.; Kumar, D.; Varma, R. S. Synthesis 1999,
1799.
6. Tu, S.; Fang, F.; Zhu, S.; Li, T.; Zhang, X.; Zhuang, Q.
Synlett 2004, 537.
was conducted with the help of a hand-held electric food
mixer with stainless steel rotors. The reaction was com-
plete in less than 15min. The pale yellow colored prod-
uct was worked up as before to give 119g (94% yield), of
the desired heterocyclic product. This procedure was
used for the efficient preparation of a number of tetra-
hydropyrimidinones (see Table 1).10
7. Sun, Q.; Wang, Y. Q.; Ge, Z.; Cheng, T.; Li, R. Synthesis
2004, 1047.
8. Shaabani, A.; Bazgir, A.; Teimouri, F. Tetrahedron Lett.
2003, 44, 857.
9. Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000,
65, 3864.
10. Typical procedure for the preparation of tetrahydropyri-
midinones:
This procedure is much simpler and faster than the pro-
tocols published to date. It is also consistent with a
green chemistry approach since no solvent is needed
(except for recrystallization). The catalyst used in an
inexpensive chemical that is commonly found in most
organic laboratories. Another useful aspect is that this
procedure is energy efficient. This reaction can be easily
adapted for use as an interesting experiment in an
organic chemistry teaching laboratory.
(i) A mixture of an aromatic aldehyde (25mmol), ethyl
acetoacetate (25mmol), urea (50mmol), and p-TSA
(200mg) was ground for 2–3min using a mortar and
pestle of appropriate size. The initial syrupy reaction
mixture solidified within 4–15min. The solid was washed
with cold water and recrystallized from ethanol. The yield
and mpꢁs are reported in Table 1.
Acknowledgements
(ii) The same reactions were also carried out by dissolving
urea in minimum amount of water and mixing it with
other reactants (in the same proportions as mentioned
above). The mixture was then ground for 2–3min by
adding 1g of sand. The mixture solidified within 5–15min
giving clean white product that was washed with water
and crystallized from ethanol when sand was also removed
at the same time. The yields of the products were the same
as obtained by the above method.
We are grateful to the Dreyfus Foundation and the
Technogenesis Program of Stevens Institute of Technol-
ogy for financial support. We thank Hoang Dang,11
William He,12 and Jeffery Speck for valuable technical
assistance and Prof. F. T. Jones and dean R. Gilman
for their encouragement and support.
(iii) The large scale preparation of 4a was carried out by
grinding benzaldehyde (1.06kg, 10mol), ethyl acetoacetate
(1.30kg, 10mol), urea (1.20kg, 20mol) and p-TSA (80g)
for 3min using kitchen Aid Mixture. The usual work up of
the reaction as stated above gave 4a with 93% yield.All the
products were characterized by 1H NMR spectroscopy
and by comparison of their physical characteristics with
those of the authentic samples.
References and notes
1. Toda, F.; Tanaka, K.; Sekikawa, A. J. Chem. Soc., Chem.
Commun. 1987, 279.
2. Tanaka, K. Solvent-free Organic Synthesis; Wiley-VCH:
Weinheim, 2003.
3. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
4. (a) Ronyar, G. C.; Kinball, S. D.; Beyer, B.; Cucinotta,
G.; Dimarco, J. D.; Gougoutas, J.; Hedberg, A.; Malley,
M.; McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med.
Chem. 1995, 38, 119; (b) Atwal, K. S.; Swanson, B. N.;
11. Undergraduate participant in the Technogenesis program
of Stevens Institute of Technology.
12. Undergraduate participant in the MERCK–SURF program
of Merck Company.