Efficient and environmentally friendly synthesis of 2-amino-imidazole

Article abstract of DOI:10.1016/S0040-4039(01)02226-2

A new and efficient method for the preparation of 2-amino-imidazole 3 was developed. Starting from cheap commodities O-methyl-iso-urea sulphate and 2-aminoacetaldehyde-acetales the desired product is isolated through a very simple work-up in a good yield.

Full text of DOI:10.1016/S0040-4039(01)02226-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 593–595
Efficient and environmentally friendly synthesis of
2-amino-imidazole
Hilmar Weinmann,* Michael Harre, Klaus Koenig, Erik Merten and Ulf Tilstam
Schering AG, Process Research, D-13342 Berlin, Germany
Received 30 October 2001; revised 21 November 2001; accepted 22 November 2001
Abstract—A new and efficient method for the preparation of 2-amino-imidazole 3 was developed. Starting from cheap
commodities O-methyl-iso-urea sulphate and 2-aminoacetaldehyde-acetales the desired product is isolated through a very simple
work-up in a good yield. This new procedure overcomes several technical and environmental problems of the traditional
approaches to this molecule and is therefore very attractive for large-scale preparation. © 2002 Elsevier Science Ltd. All rights
reserved.
2-Amino-imidazoles are a very interesting class of hete-
rocyclic compounds as they are found in many pharma-
cologically active substances, e.g. cephalosporin 11 or
a2-receptor agonist 2,2 (Scheme 1) and also in some
natural products like the marine alkaloids Isonaamine
A, Dorimidazole A and Preclathridine A.3 Due to these
interesting biological properties, several methods for
the preparation of unsubstituted 2-amino-imidazole 3
have been described in the literature.
procedure for the preparation of larger amounts of
2-amino-imidazole in the pilot plant. Due to large
waste streams and tedious work-up conditions this pro-
cedure was not acceptable for large-scale manufacture.
Another procedure which is often cited in the literature
is the reaction between cyanamide 4 and 2-amino-acet-
aldehyde-acetales 5 followed by an acid catalysed cycli-
sation which was found by Lawson.5 From a technical
point of view this method also faces several problems as
the guanidine derivative 6 which is formed as an inter-
mediate is obtained as a gum which has to be triturated
with diethyl ether and acetone to purify the material
(Scheme 2). In our hands yields and purity of the
product produced by this method tended to be low.
Preparation of 2-amino-imidazole is a tedious task as it
is not only highly prone to oxidation by air, brown oils
are often produced during the reaction but it is also
very soluble in water. The latter fact makes the work-
up, isolation and purification of this compound
extremely difficult.
A standard procedure for the synthesis of substituted
guanidines is the transformation of S-methyl-isothio-
urea derivatives with amines. This method was used by
Storey, Sullivan and Moyer for the preparation of
2-amino-imidazole-sulfate by reacting S-methyl-isothio-
urea with 2-amino-acetaldehyde-diethylacetal.6 The fol-
lowing acid catalysed cyclisation gave the desired
product. However, the release of equimolar amounts of
badly smelling methyl mercaptan during the course of
the reaction gives rise to significant environmental and
safety problems which make additional technical mea-
sures necessary and therefore adds to the costs of such
a manufacturing process. A similar method was also
described in a Japanese patent by T. Yamamoto.7
The oldest method was described as early as 1919 by
Pyman et al.4 who used the reduction of 2-arylazo-imi-
dazoles to 2-amino-imidazoles. Unfortunately, this pro-
cedure was not viable for us as we had to find a
As all of the described literature procedures have sev-
eral drawbacks we tried to find a new and improved
method for the large-scale preparation of 2-amino-imi-
dazole. Back in 1954, Fearing and Fox had demon-
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02226-2

594
H. Weinmann et al. / Tetrahedron Letters 43 (2002) 593–595
Scheme 2.
Scheme 3.
Experiments to precipitate the salt from the aqueous
solution by adding water-miscible organic solvents like
THF or DMF were not successful. To our great sur-
prise we then found that by slowly (over 1 h) dropping
the reaction mixture at 0–5°C into ice-cold ethanol,
2-amino-imidazole-hemisulfate was obtained as a white
crystalline precipitate in 86% yield.9 This result was
even more surprising as Storey, Sullivan and Moyer
had used ethanol as a solvent in their work-up proce-
dure. Therefore, it seems that the solubility of 2-amino-
imidazole-hemisulfate strongly depends on the
temperature.
strated that amines can be reacted with O-methyl-
isourea-sulfate for the preparation of monosubstituted
guanidines.8 However, to the best of our knowledge,
2-amino-acetaldehyde-acetals have not been used so
far. Surprisingly, we found that at 50°C in an aqueous
solution after 4 h a complete transformation to the
guanidine derivative is achieved (Scheme 3).
The reaction can be performed with 2-amino-acetalde-
hyde diethylacetal as well as with 2-amino-acetaldehyde
dimethylacetal. As the latter is cheaper, we preferred
the dimethylacetal. Both the 2-amino-acetaldehyde-
dimethylacetal and the O-methyl-isourea are cheap
commodities and therefore this process has economic
advantages and is environmentally more friendly as
only methanol is released as a by-product during the
reaction.
In summary we have developed a new procedure for the
preparation of 2-amino-imidazole which besides a very
good yield and quality of the product has several other
advantages related to technical, safety and environmen-
tal aspects. By using the new one-pot procedure not
only a higher yield is obtained but also the work-up is
drastically simplified.
Unfortunately, our attempts to isolate the guanidine
derivative were not successful. Therefore, we developed
a one-pot procedure. The transformation of O-methyl-
isourea to the guanidine is followed immediately by the
sulphuric acid-catalysed cyclisation to 2-amino-imida-
zole-hemisulfate. A pH of 2.5 was found to be optimal
as no deterioration or polymerisation occurred under
these conditions. After 2 h at 100°C a complete trans-
formation was reached. Due to the extremely good
solubility of 2-amino-imidazole in water as a salt or free
base, it was impossible to isolate the product from the
reaction mixture by the usual extraction with organic
solvents. On the other hand, removal of the water
through distillation resulted in partial deterioration of
the product. It was possible to isolate the product by
freeze-drying but, from a technical point of view, this
was not an economical method for isolation. Concen-
tration of the solution and crystallisation attempts were
also unsuccessful.
Acknowledgements
We thank the Schering Spectroscopic and Analytical
Departments for their excellent support.
References
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20°C and 7 ml concentrated sulphuric acid were added
(pH 2 and 5). The mixture was heated to 100°C and
stirred for 2 h at this temperature. TLC control showed
complete transformation. The reaction mixture was
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9. Preparation of 2-amino-imidazole-hemisulfate 3:
88.74 g O-Methyl-isourea-hemisulfate was weighed into
the reaction vessel. Under inert atmosphere (nitrogen)
150 ml deionised water and 109.2 2-amino-acetaldehyde-
diethylacetale were added and the reaction mixture was
stirred for 4 h at 50°C. TLC control showed complete