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Tetrahedron Letters
Metal Free, I2‑Catalyzed [3+1+1] Cycloaddition Reactions to Synthesize
1,2,4-Trisubstituted Imidazoles
Dong Tang, a Xin Guo, a Yu Wang, a Jing Wang, a Jihui Li,b Qiangwei Huang a and Baohua Chen* a
a State Key Laboratory of Applied Organic Chemistry Lanzhou University, Lanzhou 730000, P.R.of China;
b College of Materials and Chemical Engineering, Hainan University, Haikou, 570228, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We have successfully developed an operationally simple and economical one-pot
three-component cycloaddition reaction to synthesize 1,2,4-trisubstituted imidazoles by
employing aldehydes, α-amino carbonyl compounds and ammonium acetate. The transformation
is environmentally friendly and metal free by employing I2 (10 mol %) as a catalyst and EtOH as
a solvent, and a wide range of function groups and heterocyclics are well tolerated resulting in
moderate to good yields.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Iodine catalyzed
Cycloaddition reaction
Imidazoles
Multi-component reactions
Introduction
imidazoles in moderate condition. Hence, the results of I2 ‑
catalyzed α-amino carbonyl compounds,11 aldehyde and
ammonium acetate to synthesize 1,2,4-trisubstituted imidazoles is
reported in the current work.
Imidazole represents an important class of heterocycles found
in many natural products and thereby the structure can exhibit an
array of biology and pharmacological activities.1 In particular,
imidazole, as a privileged structural motif, is a kind of important
2
N-heterocyclic carbene (NHC)
and chiral ligands.3 The
We initiated our studies by using 4-chlorobenzaldehyde (1a)
and 1-phenyl-2-(phenylamino)ethanone (2a) as model substrates
to optimize the reaction conditions. Treatment of 1a with 2a used
an equiv of iodine as the catalyst in ethanol overnight and the
desired product (3-1a) was isolated in 24% yield (Table1, entry1).
Other lewis acids, such as FeCl3, ZnI2 and Cu(OTf)2, did not
show any catalytic activities to this transformation (Table 1,
development of convenient and efficient methods for imidazole
derivatives has attracted considerable attention. To get high
substituted imidazoles, the usual strategy involves 1,2-diketone,
aldehyde, a primary amine and ammonium acetate to afford
multi-substituted imidazoles in one-pot.4 Transition metal
catalyzed N-arylation5 and C-arylation6 of imidazoles are also
versatile tools to construct imidazole derivatives. In recent years,
our groups has reported some works about the synthesis of
multisubstituted imidazoles.7 For example, copper-catalyzed
[3+2] cycloaddition reaction to synthesize multi-substituted
entries
2-4).
Iodine
sources
including
KI
and
tetrabutylammonium iodide (TBAI) were conducted into the
reaction and only 19% and 14% yields were isolated, respectively
(Table 1, entries 5-6). Moreover, reducing the amount of iodine
to 0.1 equiv could significantly increase the yield to 57% (Table
1, 7-8). To our delight, the yield increased to 81% when the
temperature changed into 40 °C (Table 1, entries 9-12). Different
solvents including dioxane, toluene, DMF, DMSO and DCE
were tested (Table 1, entries 13-17), and EtOH proved to be the
best solvent. Therefore, the subsequent reactions were performed
imidazoles8
and
iron
(III)-catalyzed
synthesis
of
1,2,4-trisubstituted imidazoles.9 Since transition metal addition,
high temperature, environmental toxic and scope limitation may
be a restriction of these methods, and an efficient and general
access to imidazole derivatives under mild condition is
anticipated.
o
in the presence of iodine (0.1 equiv) in EtOH under 40 C
The multi-component reactions (MCR) emerged as useful
methods because the combination of components to generate new
products in a single step is energy saving, low waste and
environmentally friendly.10 With the conception in mind, our
continuous research focus on new strategies for multi-substituted
overnight.