Microwave-assisted synthesis of substituted 2-amino-1H-imidazoles from imidazo[1,2-a]pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2009.06.128

An efficient method for the synthesis of mono- and disubstituted 2-amino-1H-imidazoles via microwave-assisted hydrazinolysis of substituted imidazo[1,2-a]pyrimidines is reported. This protocol avoids strong acidic conditions and is superior to the classic

Full text of DOI:10.1016/j.tetlet.2009.06.128

Tetrahedron Letters 50 (2009) 5218–5220
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted synthesis of substituted 2-amino-1H-imidazoles
from imidazo[1,2-a]pyrimidines
D. S. Ermolat’ev a, E. P. Svidritsky b, E. V. Babaev b, E. Van der Eycken a,
*
a Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
b Chemistry Department, Moscow State University, Moscow 119992, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the synthesis of mono- and disubstituted 2-amino-1H-imidazoles via microwave-
assisted hydrazinolysis of substituted imidazo[1,2-a]pyrimidines is reported. This protocol avoids strong
Received 21 April 2009
Revised 24 June 2009
Accepted 29 June 2009
Available online 3 July 2009
acidic conditions and is superior to the classical cyclocondensation of
acetylguanidine.
a-haloketones with N-
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Imidazo[1,2-a]pyrimidines
Substituted 2-amino-1H-imidazoles
Microwave-assisted reaction
Hydrazinolysis
Ring cleavage
The 2-amino-1H-imidazole motif, which is common in all mem-
bers of the oroidin family of marine sponge alkaloids,1 constitutes
an important class of potent antagonists of serotonergic and hista-
minergic receptors.2 Very recently, it was demonstrated that natu-
rally occurring 2-amino-1H-imidazoles and their synthetic
analogues inhibit and disperse bacterial biofilms through a non-
bactericidal mechanism.3 Because of these interesting biological
properties, numerous synthetic routes to 2-amino-1H-imidazoles
have been reported.4
zoles 1 from readily available N-acetylguanidine (2) and
tones
(Scheme 1, route A).4 Unfortunately, strong acidic
conditions required for the deacetylation of the final products
a-haloke-
3
and limited availability of the starting 1,2-diaryl-a-haloketones
significantly narrow the scope of the method.
Recently, we described the microwave-assisted procedure for
the synthesis of polysubstituted 2-aminoimidazoles 1.11 This pro-
tocol is based on the cyclocondensation of 2-aminopyrimidines
and
a-bromocarbonyl compounds 3 at elevated temperature,
Modern synthetic methods for accessing 1-unsubstituted
2-amino-1H-imidazoles can be classified as heterocyclization of
substituted or protected guanidines with 1,2-dielectrophiles,5 het-
eroaromatic nucleophilic substitution5c,6 and recyclization of
2-aminooxazoles.7 Although different substituted guanidines are
readily available and can be prepared in situ (e.g., from cyanam-
ines8), the high basicity of guanidines together with non-regiose-
lectivity of the reaction often leads to multiple products.9
Protection by acetyl5a and Boc-groups5c requires, in turn, acidic
deprotection conditions. Another procedure is the cyclocondensa-
tion of aldehydes and guanidine nitrate using sodium cyanide
and supported aluminium oxide, which provides 2-aminoimidaz-
oles with identical substituents on positions 4 and 5 of the ring
structure.10
followed by the cleavage of the intermediary imidazo[1,2-a]pyrim-
idin-1-ium salts 4 with excess of hydrazine (Scheme 1, route B). In
this approach to 1-substituted 2-aminoimidazoles we used readily
available substituted 2-aminopyrimidines as the masked guani-
dine function for the construction of the imidazole ring.12
Herein we describe an alternative strategy for the synthesis of
polysubstituted 2-amino-1H-imidazoles 1. Due to the fact that
the bicyclic system of the imidazo[1,2-a]pyrimidines 6 possesses
an electron-poor (
p-deficient) pyrimidine ring and an electron-rich
(p-excessive) imidazole ring, we started our investigations by
choosing imidazo[1,2-a]pyrimidines 6 as templates for the modu-
lar synthesis of 4,5-disubstituted 2-amino-1H-imidazoles (Scheme
2). In our preliminary report13 we developed a new microwave-as-
sisted Pd-catalyzed synthesis of 2,3-disubstituted imidazo[1,2-
An interesting microwave-assisted protocol was developed by
Lam and co-workers for the construction of 2-amino-1H-imida-
a]pyrimidines 5 via a Heck-type arylation of 2-substituted
imidazo[1,2-a]pyrimidines 6. In this Letter, we report a facile and
practical microwave-assisted synthesis of 4(5)-mono- and 4,5-
disubstituted 2-amino-1H-imidazoles from the corresponding
substituted imidazo[1,2-a]pyrimidines 5 and 6.
* Corresponding author. Tel.: +32 16 327406; fax: +32 16 327990.
E-mail address: erik.vandereycken@chem.kuleuven.be (E. Van der Eycken).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.128

D. S. Ermolat’ev et al. / Tetrahedron Letters 50 (2009) 5218–5220
5219
NAc
N
R2
R3
H2N
NH2
R1
HN
N
2
B
A
R1
OH
+
N
Br
N
R1 = H
Br
R3
N
H
R3
R2
1
R2
3
4
O
Scheme 1. Synthesis of substituted 2-amino-1H-imidazoles.
N
N
R1
N
Ref. 13
?
N
H2N
N
N
N
N
H
R2
R2
R1
R1
5
1
6
Scheme 2. Retrosynthetic analysis of the synthesis of 4,5-disubstituted 2-amino-1H-imidazoles.
To optimize the procedure we first studied nucleophilic cleav-
age of 2-phenylimidazo[1,2-a]pyrimidine (6a) under a variety of
conditions and compared microwave and conventional heating
conditions. Hydrazine was found to be the most reactive bis-nucle-
ophile among the cleaving agents, such as hydroxylamine and
alkylamines, giving pyrazole as the only by-product of pyrimidine
ring cleavage.14 A possible mechanism of the cleavage was given in
our previous work.11b In a typical procedure, a mixture of 2-pheny-
limidazo[1,2-a]pyrimidine (6a) and 20% hydrazine hydrate in a
suitable solvent was irradiated in a sealed vial at 150 W maximum
power or heated in an oil bath (Table 1).
First, we tried the cleavage in MeCN under conventional heat-
ing. However, the reaction was found to be sluggish and after
12 h of heating at 80 °C only 38% of 2-amino-1H-4(5)-phenylimi-
dazole (1a) was isolated next to a considerable amount of unre-
acted starting material (Table 1, entry 1). Increasing the
temperature to 140 °C afforded product 1a in 72% yield within
5 h (Table 1, entry 4). Interestingly, the cleavage was found to pro-
ceed faster in ethanol, thus providing the desired product in 83%
yield within only 2 h (Table 1, entry 5). At this point, after the con-
ventional heating attempts, we decided to carry out the cleavage of
2-phenylimidazo[1,2-a]pyrimidine (6a) under focused microwave
irradiation. Unfortunately, irradiating the reaction mixture for 1 h
at 80 °C provided the product in a disappointingly low yield of
13% isolated yield (Table 1, entry 6). However, contrary to the reac-
tion under conventional heating conditions, we found that at
100 °C ceiling temperature the reaction was much faster as moni-
tored by TLC (Table 1, entry 7). A further experiment performed at
120 °C improved substantially the yield of 2-amino-1H-4(5)-phen-
ylimidazole (1a) and the reaction was completed within 30 min
Table 2
Microwave-assisted synthesis of 4(5)-substituted 2-amino-1H-imidazoles 1a–ka
Table 1
Optimization of the conditions for the cleavage of 6a with hydrazinea
N
R1
N
N
Ph
N
20% N2H4/EtOH
MW, 120 °C
H2N
N
N
20% N2H4
Solvent
N
H
H2N
N
N
6b-k
N
H
1b-k
R1
1a
6a
Entry
Product
R1
Time (min)
Yield (%)b
Ph
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
p-MeOPh
p-FPh
p-ClPh
p-BrPh
p-MePh
p-MeSO2Ph
p-NO2Ph
Biphenyl-4-yl
CONHBn
CONHPh
10
25
10
10
10
20
15
15
20
5
89
79
93
88
87
80
88
64
89
87
93
Entry
Conditions
Solvent
Temperature (°C)
Time (h)
Yield (%)c
1
2
3
4
5
6
7
8
9
D
MeCN
MeCN
MeCN
MeCN
EtOH
MeCN
MeCN
MeCN
EtOH
80
100
120
140
140
80
100
120
120
120
12
12
5
5
2
1
1
0.5
0.5
0.5
38
45
69
72
83
13
55
85
91
47
MWb
10
11
1j
1k
5
10
Dioxane
a
All reactions were performed on a 5-mmol scale in 12 mL of solvent. All the
microwave experiments were performed at a ceiling temperature of 120 °C and
150 W maximum power.
a
All reactions were performed on a 0.5-mmol scale in 3 mL of solvent.
All the microwave experiments were performed at 150 W maximum power.
All yields are isolated yields.
b
c
b
All yields are isolated yields.

5220
D. S. Ermolat’ev et al. / Tetrahedron Letters 50 (2009) 5218–5220
Table 3
Finally, we have applied the optimized protocol for the cleavage
of 2,3-disubstituted imidazo[1,2-a]pyrimidines (Table 3). We sub-
jected 12 compounds 5a–m to the microwave-assisted hydrazinol-
ysis to afford the corresponding 4,5-disubstituted 2-amino-1H-
imidazoles 1l–w. Interestingly, all the reactions were completed
within 10 min providing the products in high yields (Table 3). In
a typical procedure, a mixture of 2,3-disubstituted imidazo[1,2-
a]pyrimidines 5 and hydrazine hydrate in ethanol was irradiated
in a sealed reaction vial at 150 W maximum power for 10 min at
a ceiling temperature of 120 °C. The products were purified by
column chromatography using 5–10% MeOH in CH2Cl2 as the
eluent.
Microwave-assisted synthesis of 4,5-disubstituted 2-amino-1H-imidazoles 1l–w
N
R1
N
20% N2H4/EtOH
N
N
H2N
MW, 110 °C
10 min
N
H
R2
R2
R1
1l-w
5a-m
Entry
Product
R1
R2
Yielda,b (%)
In conclusion, we have developed a simple and practical proce-
dure for the preparation of 4(5)-monosubstituted and 4,5-disubsti-
tuted 2-amino-1H-imidazoles. We have investigated the cleavage
of 2-arylimidazo[1,2-a]pyrimidines by hydrazine hydrate and
found microwave irradiation to be very effective in this regard. A
small library of 4(5)-mono- and 4,5-disubstituted 2-amino-1H-
imidazoles was synthesized for screening for potential antiviral
activity.
1
2
3
4
5
6
7
8
9
1l
Ph
p-ClPh
p-FPh
68
83
95
94
83
89
88
94
88
89
61
84
1m
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
p-ClPh
p-ClPh
p-MePh
Ph
p-FPh
Ph
p-CF3Ph
p-ClPh
p-MeOPh
p-FPh
p-CF3Ph
o-FPh
p-MeSO2Ph
p-CF3Ph
p-FPh
Ph
p-MeOPh
p-MeSO2Ph
CONHPh
CONHBn
10
11
12
Acknowledgements
Ph
a
All reactions were performed on a 0.5-mmol scale in 3–4 mL of solvent. All the
microwave experiments were performed at a ceiling temperature of and 150 W
maximum power.
Support was provided by the Research Fund of the University of
Leuven and by the F.W.O. (Fund for Scientific Research—Flanders
(Belgium)). D.E. is grateful to the University of Leuven for obtaining
a postdoctoral fellowship.
b
All yields are isolated yields.
Supplementary data
(Table 1, entry 8). Switching to ethanol the solvent resulted in an
excellent yield of 91%. Curiously, the cleavage reaction proceeded
comparatively slower in an apolar solvent as 1,4-dioxane giving
the product 1a in only 47% yield (Table 1, entry 10).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.128.
Thus, after optimizing the cleavage of 2-phenylimidazo[1,2-
a]pyrimidine (6a) under microwave irradiation, we extended our
strategy towards a series of 2-substituted imidazo[1,2-a]pyrimi-
dines (6a–k). All reactions were carried out on a 5-mmol scale in
20% hydrazine monohydrate solution in ethanol at a ceiling tem-
perature of 120 °C, applying microwave irradiation at 150 W max-
imum power (Table 2). The reactions proceeded smoothly with a
very low amount of the starting material left and the products
1a–k were purified by column chromatography using 15–20%
MeOH in CH2Cl2 as the eluent. The reaction times varied from 5
to 25 min depending on the nature of substituent R1 (Table 2). It
was found that imidazo[1,2-a]pyrimidines bearing electron-donat-
ing substituents, for example, p-methoxyphenyl and p-tolyl (Table
2, entries 2 and 6), require up to 25 min to drive the cleavage to
completion. On the contrary, the cleavage of the imidazo[1,2-
a]pyrimidines bearing electron-withdrawing substituents was
completed within 5 min (Table 2, entries 10 and 11). Importantly,
the carboxamide function remained intact upon hydrazinolysis of
the imidazo[1,2-a]pyrimidines and we have not observed any trace
of transamination by-products.
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The microwave-assisted cleavage of 2-(p-nitrophenyl)imi-
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