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DOI 10.1007/s11030-010-9270-5
FULL-LENGTH PAPER
One-pot microwave-assisted protocol for the synthesis
of substituted 2-amino-1H -imidazoles
D. S. Ermolat’ev · B. Savaliya · A. Shah ·
E. Van der Eycken
Received: 19 May 2010 / Accepted: 7 August 2010
© Springer Science+Business Media B.V. 2010
Abstract An efficient microwave-assisted one-pot two-step
protocol was developed for the construction of disubstituted
2-amino-1H-imidazoles. This process involves the sequential
formation of 2,3-dihydro-2-hydroxyimidazo[1,2-a]pyrimidinium
salts from readily available 2-aminopyrimidines
and α-bromoketones, followed by cleavage of the pyrimidine
ring with hydrazine.
Keywords Heterocycles · 2-Aminoimidazoles ·
Microwave-assisted synthesis · Ring opening ·
Rearrangement
Introduction
The class of 2-aminoimidazoles has recently attracted particular
interest due to various biological properties of these compounds.
2-Aminoimidazole alkaloids and their metabolites,
isolated from the marine sponges Hymeniacidon sp., have
been described as potent antagonists of serotonergic [1] and
histaminergic receptors [2]. Naamine and isonaamine alkaloids
from the marine sponges Leucetta sp. exhibit antiviral
and anticancer activity [3–10]. Because of these interesting
Electronic supplementary material The online version of this
article (doi:10.1007/s11030-010-9270-5) contains supplementary
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D. S. Ermolat’ev · B. Savaliya · E. Van der Eycken (B)
Laboratory for Organic and Microwave-Assisted Chemistry
(LOMAC), Department of Chemistry, Katholieke Universiteit
Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
e-mail: erik.vandereycken@chem.kuleuven.be
B. Savaliya · A. Shah
Department of Chemistry, Saurashtra University,
Rajkot 360 005, Gujarat, India
N
2
N
N
R 2
R 2
A
R1HN N
B
R1 = H
N
H
1
N
Br
Scheme 1 Synthesis of substituted 2-amino-1H-imidazoles
3
N
N
OH
biological activities, numerous synthetic routes to 1-substituted
and 1-unsubstituted 2-aminoimidazoles have been
reported. Modern synthetic methods for accessing 1-unsubstituted
2-amino-1H-imidazoles can be roughly classified
as heterocyclization of substituted or protected guanidines
with 1,2-dielectrophiles [11,12], heteroaromatic nucleophilic
substitution, and recyclization of 2-aminooxazoles [13].
Although different substituted guanidines are readily available
and can be prepared in situ (e.g., from cyanamides [14]),
the high basicity of guanidines together with non-regioselectivity
often leads to multiple products. Protection by acetyl
[11] and Boc-groups [12] requires, in turn, acidic deprotection
conditions.
Recently, we have described two new approaches to the
synthesis of substituted 2-amino-1H-imidazoles 1. The first
approach is based on the cleavage of imidazo[1,2-a]pyrimidines
[15] 2 with hydrazine (Scheme 1, route A) [16]. In the
second approach, the hydrazinolysis of 2-hydroxy-2,
3-dihydroimidazo[1,2-a]pyrimidinium salts 3 followed
by Dimroth-type rearrangement afforded trisubstituted
2-amino-1H-imidazoles 1 (Scheme 1, route B) [17].
2-Hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidinium salts
3 can be easily prepared from 2-aminopyrimidines 4 with
α-bromoketones 5 under microwave irradiation (Scheme 2).
We found that the outcome of this reaction strongly depends
on the temperature [18]. The microwave-assisted reaction
R 2
R 1
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