Efficient synthesis of imidazoles from aldehydes and 1,2-Diketones under superheating conditions by using a continuous flow microreactor system under pressure

Article abstract of DOI:10.1021/op100058h

A simple and efficient method for the synthesis of 2,4,5-trisubstituted imidazoles has been developed by using a continuous flow microreactor system under pressure; aryl-, alkyl-, and heteroaryl-substituted imidazoles were obtained in high yields within 2 min under superheating conditions.

Full text of DOI:10.1021/op100058h

Organic Process Research & Development 2010, 14, 902–904
Efficient Synthesis of Imidazoles from Aldehydes and 1,2-Diketones under
Superheating Conditions by Using a Continuous Flow Microreactor System under
Pressure
Lingjie Kong, Xiaoming Lv, Qi Lin, Xiaofeng Liu, Yaming Zhou, and Yu Jia*
Chemistry Department, Fudan UniVersity, Shanghai, 200433, P.R. China.
Abstract:
route have focused on the usage of catalysts6 and microwave
irradiation.7 However, preparations of some catalysts require
relatively expensive reagents, harsh reaction conditions, and
sometimes tedious workup using toxic reagents or solvents.6 A
microwave reaction system can provide an environment in
which the reaction mixture can be rapidly dielectrically heated
in sealed vessels at temperatures far above the boiling point of
the solvent under pressure. However, it is difficult to scale up
due to the limited penetration depth of microwave irradiation
into absorbing media.8 Consequently, exploring a simpler,
greener, and easy to scale-up method for the efficient synthesis
of 2,4,5-trisubstituted imidazoles is highly desirable.
Recently, more and more attention has been paid to
performing organic synthesis in continuous flow microreactor
systems.9 Microreactors, compared with the conventional batch
reactors, hold a higher surface area-to-volume ratio,9 which leads
to faster heat and mass transfer. In addition, the continuous flow
microreactor system can be easily scaled up due to its number-
ing-up property.10 As a result, through performing reactions in
continuous microflow systems under pressure, we can achieve
a rapid and evenly superheated (above the boiling point of
solvents) environment similar to that provided by a microwave
reactor, while avoiding the scale-up problem of the latter.11
These advantages have been reflected in improvement of the
multicomponent thermal reactions,12,13 for which the heat and
mass transfer are the key factors. Earlier, we successfully
A simple and efficient method for the synthesis of 2,4,5-trisubsti-
tuted imidazoles has been developed by using a continuous flow
microreactor system under pressure; aryl-, alkyl-, and heteroaryl-
substituted imidazoles were obtained in high yields within 2 min
under superheating conditions.
Introduction
Imidazoles and their derivatives, based on their diverse
biological activities, play important roles in the synthesis of
pharmaceuticals and versatile building blocks for natural prod-
ucts.1 2,4,5-Trisubstituted imidazoles, especially, occur in a
number of biologically active structures, such as modulators
of P-glycoprotein and inhibitors of P38 MAP kinase, etc.2 This
structural motif is also found in diverse therapeutic agents, for
example, antibacterial and anti-inflammatory agents.3 Therefore,
the organic synthesis of these imidazole derivatives has a
significant impact on medicinal chemistry. Many routes to
synthesize 2,4,5-trisubstituted imidazoles have been developed.4
The classic synthesis by a one-pot reaction of aldehydes, benzil,
and ammonium acetate, refluxing in acetic acid for many hours,5
proceeds with low yields. Recent modifications on the synthesis
* Author to whom correspondence should be addressed. E-mail:
yujia@fudan.edu.cn. Fax: 86-21-6564-3925. Telephone: 86-21-6564-2261.
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Vol. 14, No. 4, 2010 / Organic Process Research & Development
10.1021/op100058h  2010 American Chemical Society
Published on Web 06/24/2010

Table 1. Optimization of temperature and residence time
for the synthesis of 2,4,5-triphenyl-1H-imidazole
entry
T (°C)
residence time (min)
conversion (%)a
Figure 1. Continuous synthesis of 2,4,5-trisubstituted imidazoles
1
2
3
4
5
6
7
8
120
140
160
180
180
180
180
180
10
10
10
10
5
91
93
using a microreactor system under pressure.
97
98
performed Claisen rearrangement reaction in a continuous flow
microreactor at high temperature.14 On this basis, we report the
development of a more efficient method for the synthesis of
2,4,5-trisubstituted imidazoles by using an optimized system
under pressure.
98
3
98
2
1
98 (93b)
96
a Back pressure of the MR is 75 psi. Conversion determined by LC/MS.
b isolated yield.
Microreactor Fabrication. The continuous flow microre-
actor system (MR) we used for our studies mainly consists of
five parts: microsyringe pumps (flow rate 0.005-36 mL min-1),
microchannels (250 µm in I.D.), a heating bath, a back pressure
unit (75 psi), and collection devices. The microchannel is a 120-
cm long stainless steel pipe with the heating length of 102 cm.
It is acid/base resistant and high-temperature endurable and is
commonly used in high-performance liquid chromatography
(HPLC). The back pressure unit is placed between the heating
bath and the collection devices. The solution of reactants mixture
is injected through the pipe, heated in the oil bath, and finally
the effluent liquid is collected. When the microreactor system
is running, the internal pressure of the microchannels is
maintained at 75 psi by the back pressure valve to give a
superheating environment.
conditions. It was observed that only when the residence time
is g2 min can the conversion be maintained at 98% (isolated
yield: 93%), and further residence time reduction lead to lower
conversion (Table 1).
We believe that the high reaction efficiency primarily
benefits from the excellent heat exchange in the microchannels
under superheating conditions. The reactants can absorb heat
more rapidly under the temperature higher than the boiling point
of the solvent to reach the reaction activation energy. As a result,
the reaction rate increases remarkably compared with the
reaction performed under conventional conditions.
In addition, this procedure is continuous. Thus, this method
has potential to avoid the scale-up problem which occurs in
the microwave reactors. The numbering-up property of the
microreactor is another potential advancement to solve the scale-
up problem.10
Using the optimized conditions (180 °C, 2 min), reactions
with various substrates were examined. Reactions of the o-, m-,
p-substituted aromatic aldehydes with either electron-withdraw-
ing groups or electron-donating groups were effective to give
corresponding imidazole derivatives (Table 2, entries 2-7).
Aromatic heterocyclic aldehydes were also found to be equally
reactive substrates for the system (Table 2, entry 8). In addition,
aliphatic aldehydes with short carbon chains and small car-
bocyclic rings could also be employed in this microreactor
process (Table 2, entries 9-10).
Results and Discussion
Initial efforts focused on optimizing the microreaction
conditions for the synthesis of 2,4,5-triphenyl-1H-imidazole
using acetic acid as the solvent with NH4OAC in the microre-
actor system, based upon previous investigations of conventional
thermal conditions15 (see Figure 1).
Ten equivalents is a classic reactant ratio for ammonium
acetate in the synthesis of 2,4,5-trisubstituted imidazoles using
1,2-diketone (1 equiv) and aldehyde (1 equiv) under conven-
tional conditions. The yield will decrease when the reactant ratio
of ammonium acetate is reduced. Hence, we chose 10 equiv of
ammonium acetate directly in our initial exploration of the
synthesis of 2,4,5-trisubstituted imidazoles in the microreactor
system.
The conversion increased from 91% to 98% as the reaction
temperature rose from 120 to 180 °C when the residence time
is 10 min, and then we reduced the amount of ammonium
acetate to 8 equiv in the microreaction, but the conversion of
the imidazole showed an obvious decrease (92%). As a result
we gave up further exploration on the amount of ammonium
acetate. In addition, we gradually reduced the residence time
from 10 to 1 min at 180 °C to further optimize the reaction
We next expanded our study to various 1,2-diketones.
Benzils were proven to be effective as the candidates in the
preparation of 2,4,5-trisubstituted imidazoles in good to excellent
yields. These substrates include both benzils with electron-
donating groups and those with electron-withdrawing groups
(Table 3, entries 1-3). In addition to benzil-derived substrates,
heteroaromatic (entries 4-5) and aliphatic 1,2-diketones (entry
6) gave corresponding imidazoles with satisfactory yields (Table
3, entries 4-6). The results illustrate the high ability of this
method for the synthesis of 2, 4, 5-trisubstituted imidazoles.
(13) (a) Acke, D. R. J.; Orru, R. V. A.; Stevens, C. V. QSAR Combi. Sci.
2006, 25, 474–483. (b) Richter, T.; Ehrfeld, W.; Hessel, V.; Lowe,
H.; Storz, M.; Wolf, A. Microreaction Technology: Industrial
Prospects: IMRET 3: Proceedings of the Third International Confer-
ence on Microreaction Technology 2000; pp 636-644.
Conclusion
In conclusion, we have developed a new general synthetic
method for the synthesis of 2,4,5-trisubstituted imidazoles by
using a continuous flow microreactor system under pressure.
Aryl-, alkyl-, and heteroaryl-substituted imidazoles were ob-
tained in high yields within 2 min under superheating conditions
(14) Kong, L. J.; Lin, Q.; Lv, X. M.; Yang, Y. T.; Jia, Y.; Zhou, Y. M.
Green Chem. 2009, 11 (8), 1108–1111.
(15) Abrahams, S. L.; Hazen, R. J.; Batson, A. G.; Phillips, A. P.
J. Pharmacol. Exp. Ther. 1989, 249, 359–365.
Vol. 14, No. 4, 2010 / Organic Process Research & Development
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903

Table 2. Synthesis of 2,4,5-trisubstituted imidazoles with
benzil and various aldehydes
Table 3. Synthesis of 2,4,5-trisubstituted imidazoles with
various 1,2-dione and aldehydes
a Isolated yields.
a Isolated yields.
rated and purified by column chromatography on silica gel
(300-400 mesh) using ethyl acetate/petroleum ether mixture
(1:10, v/v) as eluent to afford pure 2,4,5-triphenylimidazole as
a bright, white solid (275 mg, 93%).
For entries 1-2, Table 3, the amount of HOAc is increased
to 10 mL when the 1,2-dione is 1.0 mmol.
in this system. In addition to efficiency and simplicity, this
platform provides a very fast, green, and easy scale-up procedure
for the synthesis of 2,4,5-trisubstituted imidazoles.
Experimental Section
Reagents and solvents were obtained from commercial
sources and used as received.
For entry 3, Table 3, the solvent is changed to the mixture
of acetic acid and dimethylbenzene (1:1, v/v), and the mount
of the solvent is 20 mL when the 1,2-dione is 1.0 mmol.
Typical Procedure for the Preparation of 2,4,5-
Trisubstituted Imidazoles Using Microreactor under
Pressure.
Acknowledgment
We are grateful for National Research Program of China
(973 Program) 2007CB714504.
(2,4,5-Triphenylimidazole, Table 2, entry 1): benzil (0.2 M),
aldehyde (0.2 M), and ammonium acetate (2 M) were dissolved
in HOAc at room temperature. The solution was injected
through the microchannel (1.5 mL min-1), heated in an oil bath,
and finally collected from the other end of the microchannel.
The residence time is 2 min. The internal pressure of the
microreactor is provided by the back pressure valve (75 psi).
The crude product was added dropwise to a 0 °C concentrated
NH4OH solution. The mixture was extracted with ethyl acetate
(3 × 30 mL). The combined organic phases were dried over
sodium sulfate and then concentrated. The product was sepa-
Supporting Information Available
Detailed experimental procedures and compound character-
ization data, including NMR spectra for all described com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org/.
Received for review February 24, 2010.
OP100058H
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Vol. 14, No. 4, 2010 / Organic Process Research & Development