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Mol Divers<br />
DOI 10.1007/s11030-010-9270-5<br />
FULL-LENGTH PAPER<br />
One-pot microwave-assisted protocol for the synthesis<br />
of substituted 2-amino-1H -imidazoles<br />
D. S. Ermolat’ev · B. Savaliya · A. Shah ·<br />
E. Van der Eycken<br />
Received: 19 May 2010 / Accepted: 7 August 2010<br />
© Springer Science+Business Media B.V. 2010<br />
Abstract An efficient microwave-assisted one-pot two-step<br />
protocol was developed for the construction of disubstituted<br />
2-amino-1H-imidazoles. This process involves the sequential<br />
formation of 2,3-dihydro-2-hydroxyimidazo[1,2-a]pyrimidinium<br />
salts from readily available 2-aminopyrimidines<br />
and α-bromoketones, followed by cleavage of the pyrimidine<br />
ring with hydrazine.<br />
Keywords Heterocycles · 2-Aminoimidazoles ·<br />
Microwave-assisted synthesis · Ring opening ·<br />
Rearrangement<br />
Introduction<br />
The class of 2-aminoimidazoles has recently attracted particular<br />
interest due to various biological properties of these compounds.<br />
2-Aminoimidazole alkaloids and their metabolites,<br />
isolated from the marine sponges Hymeniacidon sp., have<br />
been described as potent antagonists of serotonergic [1] and<br />
histaminergic receptors [2]. Naamine and isonaamine alkaloids<br />
from the marine sponges Leucetta sp. exhibit antiviral<br />
and anticancer activity [3–10]. Because of these interesting<br />
Electronic supplementary material The online version of this<br />
article (doi:10.1007/s11030-010-9270-5) contains supplementary<br />
material, which is available to authorized users.<br />
D. S. Ermolat’ev · B. Savaliya · E. Van der Eycken (B)<br />
Laboratory for Organic and Microwave-Assisted Chemistry<br />
(LOMAC), Department of Chemistry, Katholieke Universiteit<br />
Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium<br />
e-mail: erik.vandereycken@chem.kuleuven.be<br />
B. Savaliya · A. Shah<br />
Department of Chemistry, <strong>Saurashtra</strong> <strong>University</strong>,<br />
Rajkot 360 005, Gujarat, India<br />
N<br />
2<br />
N<br />
N<br />
R 2<br />
R 2<br />
A<br />
R1HN N<br />
B<br />
R1 = H<br />
N<br />
H<br />
1<br />
N<br />
Br<br />
Scheme 1 Synthesis of substituted 2-amino-1H-imidazoles<br />
3<br />
N<br />
N<br />
OH<br />
biological activities, numerous synthetic routes to 1-substituted<br />
and 1-unsubstituted 2-aminoimidazoles have been<br />
reported. Modern synthetic methods for accessing 1-unsubstituted<br />
2-amino-1H-imidazoles can be roughly classified<br />
as heterocyclization of substituted or protected guanidines<br />
with 1,2-dielectrophiles [11,12], heteroaromatic nucleophilic<br />
substitution, and recyclization of 2-aminooxazoles [13].<br />
Although different substituted guanidines are readily available<br />
and can be prepared in situ (e.g., from cyanamides [14]),<br />
the high basicity of guanidines together with non-regioselectivity<br />
often leads to multiple products. Protection by acetyl<br />
[11] and Boc-groups [12] requires, in turn, acidic deprotection<br />
conditions.<br />
Recently, we have described two new approaches to the<br />
synthesis of substituted 2-amino-1H-imidazoles 1. The first<br />
approach is based on the cleavage of imidazo[1,2-a]pyrimidines<br />
[15] 2 with hydrazine (Scheme 1, route A) [16]. In the<br />
second approach, the hydrazinolysis of 2-hydroxy-2,<br />
3-dihydroimidazo[1,2-a]pyrimidinium salts 3 followed<br />
by Dimroth-type rearrangement afforded trisubstituted<br />
2-amino-1H-imidazoles 1 (Scheme 1, route B) [17].<br />
2-Hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidinium salts<br />
3 can be easily prepared from 2-aminopyrimidines 4 with<br />
α-bromoketones 5 under microwave irradiation (Scheme 2).<br />
We found that the outcome of this reaction strongly depends<br />
on the temperature [18]. The microwave-assisted reaction<br />
R 2<br />
R 1<br />
123