1902
A. K. Bose et al. / Tetrahedron Letters 46 (2005) 1901–1903
In a recent publication9 we have reported observations
on the solvent-free Biginelli reaction when it was initi-
ated by grinding (known as Grindstone Chemistry in
our laboratory). The temperature profile of the reaction
established that this reaction is strongly exothermic. In
connection with a project we became interested in the
preparation of dihydropyrimidinones on several hun-
dred grams scale. The highly exothermic nature of the
reaction therefore presented a problem for which we
have devised a simple green chemistry and energy-effi-
cient solution that is described below.
with acetic anhydride (6), an exothermic reaction ensues
(as shown by the temperature rise of the reaction mix-
ture) and in a matter of minutes the insoluble amide
starts to precipitate. It may be noted that the rate of
hydrolysis of acetic anhydride under these conditions
is quite slow as shown by our reaction temperature pro-
file for a mixture of acetic anhydride and water. In most
cases the amide is of high purity and produced in more
than 90% yield. Successful preparations of substituted
acetanilide (including acetaminophen or tylenol (7a)
and phenacetin (7b)) were conducted on molar (or mul-
tiple molar) quantities of amines. The purity of the
amides was very high without recrystallization (see
Scheme 2).
Water is a medium that is fully compatible with green
chemistry. Also, because of its large specific heat capac-
ity, water is very efficient in removing thermal energy
from reaction mixtures. After some experimentation
with a few widely used reactions, a water-based proce-
dure has been developed in our laboratory that has
proved very convenient for conducting on a large scale
several exothermic reactions involving liquid reagents.
Encouraged by the above findings, the Biginelli reaction
was conducted on 50 mmol scale: benzaldehyde (5.3 g),
ethyl acetoacetate (6.5 g), and urea (100 mmol, 6 g, dis-
solved in 15 mL of water) were mixed together and the
resulting biphasic mixture was stirred vigorously. In
about 5 min a white crystalline solid started to separate.
This solid was collected by filtration, washed with water
and dried. The product was found to be essentially pure
Biginelli product in 93% yield. This protocol was also
applied to several other substituted benzaldehydes (see
Scheme 1). In all cases the corresponding N-heterocycles
(Biginelli products) were obtained in essentially pure
form and in more than 90% yield.
This procedure consists of the following steps: (1) water
immiscible, organic reagents for an exothermic reaction
are added to a large volume of water; (2) an efficient
mechanical stirrer is used next for mixing intimately
these two separate layers; (3) the appropriate (acid or
base) catalyst—if required for the reaction—is added
to this biphasic liquid mixture. As stirring is continued
the temperature of the reaction mixture rises indicating
the start of an exothermic reaction. If the temperature
rise is too rapid, cold water or crushed ice can be added
to keep the temperature of the reaction mixture at the
desired low level (usually 50 °C or lower to minimize
evaporation).
For further testing our protocol, the Biginelli reaction
was conducted successfully starting with 250 g of the
following aldehydes: benzaldehyde, salicylaldehyde, p-
chlorobenzaldehyde, p-nitrobenzaldehyde, and o-chlo-
robenzaldehyde. About 100 mL of water was used for
these reactions. The condensation reaction with separa-
tion of crystalline product appeared to be complete in
less than 30 min (Table 1). Another experiment, with
There are several useful aspects of this water-based bi-
phasic medium for conducting exothermic reactions.
The apparatus required is simple: a large enough reac-
tion vessel and an efficient stirrer are adequate. In our
experience, most reactions take less than 20 min for
completion on a molar scale of reactants. The solid reac-
tion product that separates is usually crystalline and of
high purity. In almost all cases the yield is very high.
All these positive aspects make the reaction very com-
patible with green chemistry requirements. This proce-
dure does not apply to endothermic reactions.
NH2
NHCOCH3
O
O
O
H3C
H3C
water-based
+
biphasic reaction
R
R
6
5
7
(a) Acetaminophen (Tylenol), Yield 90%, mp 171o C
(b) Phenacetin, Yield 88%, mp 135o C
(a) R = OH
(b) R = OCH2CH3
For a test of this procedure the acetylation of various
amines that are immiscible with water was studied. It
may be noted that a standard conventional method for
N-acylation is the Schotten–Baumann reaction, which
may be conducted by the interaction of an acid chloride
and an amino compound that are added to an aqueous
alkali solution and agitated vigorously. Traditionally,
acetylation of amines is also conducted by the treatment
of the solution of an amino compound (in a solvent such
as dichloromethane or ether) with an acid anhydride or
acid chloride in presence of pyridine (or a tertiary amine
such as triethylamine).
Prepared on about a molar scale of anilines
Scheme 2.
Table 1. Synthesis of dihydropyrimidinones derivatives (4a–f) using
water based biphasic green chemistry strategy
Entry
RX
Yield
Mp (°C)
found
Mp (°C)
(%)
reported6
4a
4b
4c
4d
4e
4f
H
O
O
O
O
O
S
91
92
94
90
90
81
210
237–238
200
209–210
236–238
199–201
205–207
210–212
205–206
4OH
4OCH3
4NO2
4Cl
206–207
211
206
In contrast, we have found that when an aqueous mix-
ture of a water immiscible amine (5a–b) (e.g., a substi-
tuted aniline or benzyl amine) is stirred vigorously
H