Efficient synthesis of 2-imidazol-2-ylacetates

Article abstract of DOI:10.1016/j.tetlet.2006.06.155

A simple method of synthesizing various 2-imidazol-2-ylacetates is described. Condensation of α-aminoketals with imidates, followed by cyclization in refluxing 4 M-HCl/Dioxane, yielded 2-imidazol-2-ylacetates under one-pot and mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2006.06.155

Tetrahedron Letters 47 (2006) 6201–6204
Efficient synthesis of 2-imidazol-2-ylacetates
Jae Du Ha,* Su Jung Lee, So Yeun Nam, Seung Kyu Kang, Seung Yoon Cho,
Jin Hee Ahn and Joong-Kwon Choi
Medicinal Science Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea
Received 26 May 2006; revised 23 June 2006; accepted 29 June 2006
Abstract—A simple method of synthesizing various 2-imidazol-2-ylacetates is described. Condensation of a-aminoketals with imi-
dates, followed by cyclization in refluxing 4 M-HCl/Dioxane, yielded 2-imidazol-2-ylacetates under one-pot and mild reaction
conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
Imidazoles frequently are found in biologically active
natural products or pharmaceutically important drugs.1
Our interest in the search for new receptor tyrosine
kinase inhibitors2 has been focusing on the synthesis
of 2-quinolinone core derivatives 5 with C-3 imidazole
moiety (Fig. 1). The quinolin-2(1H)-one-3-imidazoles 5
were readily prepared by condensing 2-imidazol-2-ylace-
tate 3 with various substituted 2-aminobenzaldehydes 4.3
Several methods for the synthesis of 2-imidazol-2-ylace-
tate derivatives have been described in the literature,
which are mainly based on the elaboration of acetate
functionality from the simple imidazole derivatives4–6
or the condensation of ethylenediamine derivatives with
imidate followed by dehydrogenation.7 However the
existing methods suffer in terms of moderate yields
and availability of starting material with various func-
tional groups. Also, their preparations are difficult in
many cases and took many reaction steps. Thus, we
decided to investigate the synthesis of imidazoles by con-
densation of a-aminoketals with imidates developed by
Lawson.8 Whereas numerous syntheses of substituted
imidazoles by this method are described in the litera-
ture,9 no synthetic study for 2-imidazol-2-ylacetates
has been reported.
Generally, the reaction of imidates and a-aminoketal
yields amidine intermediates, which are then cyclized,
by heating in aqueous hydrochloric acid solution, to
produce imidazoles.10 However, this approach suffers
from the hydrolysis of the ester group that resulted in
low product yields. To overcome this problem, we tested
the cyclization reaction under a non-aqueous solvent
system without isolation of the amidine. In this letter,
we disclose our results for a mild and convenient method
to synthesize 2-imidazol-2-ylacetate from imidate salt
and various a-aminoketal derivatives.
The preparation of various a-aminoketal derivatives
from ketones was carried out following the general route
via Neber rearrangement procedure,11 which consists of
R1
R1
N
R3
R3
R2
CHO
NH2
EtO OEt
N
NH2Cl
OEt
2
N
H
R2
+
NH2
EtO2C
+
EtO2C
R1
R2
1
N
H
N
H
O
4
5
3
Figure 1. Synthetic approach to 2-imidazol-2-ylacetate.
Keywords: 2-Imidazol-2-ylacetates; a-Aminoketals; Neber rearrangement.
*
Corresponding author. Tel.: +82 42 860 7072; fax: +82 42 860 7160; e-mail: jdha@krict.re.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.155

6202
J. D. Ha et al. / Tetrahedron Letters 47 (2006) 6201–6204
EtO OEt
O
NOTs
NH2
R1
KOEt, EtOH
1. NH2OH.HCl
2. TsCl, pyrdine
R1
R1
R2
R2
R2
1
6
7
Scheme 1. Synthesis of a-aminoketals via a Neber rearrangement.
EtO OEt
NH2
EtO OEt
EtO OEt
b
a
NHCbz
NH2
R=Br
N
N
9
8
R
R
1
R=NO2
c
EtO OEt
NH2
EtO OEt
d
NHCbz
AcHN
11
AcHN
10
Scheme 2. Reagents and conditions: (a) CbzCl, Et3N/CH2Cl2, 0 °C, 90%; (b) 2-(t-BuP)2biphenyl, Pd2(dba)3, NaOt-Bu, N-methylpiperazine, toluene,
reflux, 92%; (c) (i) Fe, NH4Cl/EtOH–H2O, reflux, (ii) AcCl, Et3N/CH2Cl2, 0 °C, 58%; (d) 10% Pd/C, H2, EtOH, 88%.
the introduction of an amino group at the a-position of
a ketone. As shown in Scheme 1, a-aminoketal deriva-
tives 1 were prepared by a KOEt treatment of oxyme
tosylate 7, which was obtained by reacting various
ketones 6 with hydroxylamine followed by tosylation
of the corresponding oxyme.
by acetylation (Scheme 2). Imidate hydrochloride, an-
other key intermediate, was readily obtained from ethyl
cyanoacetate by treatment with HCl(g)/EtOH.13
The condensation and cyclization reactions were carried
out by a one-pot method. As shown in Table 1, the
a-aminoketals were treated with imidate hydrochloride
in refluxing EtOH for 5 h and then acid solution was
added. Heating the resultant mixture under reflux for
12 h yielded the imidazoles. Initially, we attempted the
cyclization of amidines 6 in refluxing aqueous 2 N-HCl
solution, but the desired imidazole 3a was obtained in
less than 5% yield due to hydrolysis of the ester group
Neber rearrangement of the oxyme tosylates with elec-
tron-rich aryl groups proved to be problematic, owing
to the intrinsic instability of the oxyme tosylates. Thus,
some a-aminoketals 914 and 11 bearing 4-amino phenyl
groups were obtained by Pd-catalyzed amination12 of
bromophenyl or reduction of the nitro group followed
Table 1.
R1
EtO OEt
EtO OEt
H
N
N
NH2Cl
OEt
HCl
NH2
R2
EtOH
reflux
R1
R2
1
EtO2C
EtO2C
+
R1
CO2Et
N
H
R2 NH
reflux
2
6
3
Entry
1
a-Aminoketals
Products
Yield (%)a
EtO OEt
N
NH2
5b
EtO2C
N
H
Br
3a
Br
1a
2
3
1a
3a
3a
48c
61
1a
EtO OEt
N
NH2
EtO2C
4
56
N
H
NO2
3b
O2N
1b
EtO OEt
N
NH2
EtO2C
5
52
N
H
NHAc
3c
AcHN
1c

J. D. Ha et al. / Tetrahedron Letters 47 (2006) 6201–6204
6203
Table 1 (continued)
Entry
a-Aminoketals
Products
Yield (%)a
EtO OEt
N
NH2
EtO2C
N
H
N
6
48
N
3d
N
N
1d
NMs
EtO OEt
N
NH2
7
8
35
42
MsN
N
N
EtO2C
N
H
3e
3f
1e
EtO OEt
H
N
NH2
N
N
H
N
EtO2C
EtO2C
N
H
N
O
O
1f
EtO OEt
N
NH2
9
64
0
N
H
3g
N
N
1g
1h
EtO OEt
N
NH2
EtO2C
EtO2C
10
N
N
H
3h
3i
N
EtO OEt
N
N
NH2
11
72
N
N
H
1i
a All reactions were carried out for 12 h in 25% v/v 4 M-HCl/Dioxane in EtOH unless otherwise stated.
b After removal of EtOH, the reaction was carried out in 2 N-HCl aqueous solution.
c The reaction was carried out in 25% v/v CF3COOH in EtOH.
(entry 1). In order to avoid hydrolysis, the cyclization
was carried out in non-aqueous acids 4 M-HCl/Dioxane
and TFA (entries 2 and 3). Under these reaction condi-
tions, the imidazole 314 was obtained in moderate yields.
A better yield and a cleaner reaction was obtained with
4 M-HCl/Dioxane than with TFA. No significant differ-
ence was observed for the electron-rich (entries 5 and 6)
and electron-deficient (entries 4 and 8) phenyl groups;
the rates and yields of the reactions were comparable.
N-Acyl, N-mesyl and amide groups (entries 5–8) are tol-
erated under these conditions. Those reactions produced
moderate yields (35–56%). Similar treatment of a-amino-
ketals 1g containing a 3-pyridyl group produced imidaz-
ole 3g in a 64% isolated yield. Interestingly, amidine
intermediate of a-aminoketals 1h containing 4-pyridyl
group produced under the same reaction conditions a
complex mixture of product and the desired product
could not be detected. Both prolonged reaction time
and different acid systems resulted in the slow decompo-
sition of amidine. For the formation of the bicyclic ring
system (entry 11), the cyclization into 4,5,6,7-tetra-
hydro-3H-imidazo[4,5-c]pyridine required shorter reaction
times (8 h) and produced slightly higher yields (72%).
Condensation of a-aminoketals with imidates, followed
by cyclization in refluxing 4 M-HCl/Dioxane, provides
rapid access to 2-imidazole-2-ylacetates.
Acknowledgement
We are grateful to the Korea Research Institute of
Chemical Technology (KRICT) for financial support.
References and notes
1. (a) Crimmett, M. R. In Comprehensive Heterocyclic
Chemistry II; Elsevier: Oxford, UK, 1996; Vol. 3, pp 77–
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3. For the reaction between 2-benzoimidazole-2-ylacetate
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R.; Hungate, R. W. U.S. Patent 6479512 B1, 2002.
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273.
In conclusion, we developed a method for the prepara-
tion of a variety of substituted 2-imidazol-2-ylacetates,
which are pharmacologically useful intermediates.

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J. D. Ha et al. / Tetrahedron Letters 47 (2006) 6201–6204
5. For elaboration from imidazole-2-carboxylic acid:
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14. Representative spectroscopic data. Compound 9: 1H
NMR (300 MHz, CDCl3) d 7.40–7.16 (m, 4H), 3.68 (s,
2H), 3.45–3.38 (m, 4H), 3.12 (t, J = 5.1 Hz, 4H), 2.57 (t,
J = 5.1 Hz, 4H), 2.35 (s, 3H), 1.22–1.15 (m, 6H). Com-
pound 3a: 1H NMR (300 MHz, CDCl3) d 7.58 (d, J =
8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 4.25 (q, J = 7.2 Hz,
2H), 3.93 (s, 2H), 1.31 (t, J = 7.2 Hz, 3H). Compound 3b:
1H NMR (300 MHz, CDCl3) d 10.21 (br s, 1H), 8.22 (d,
J = 8.9 Hz, 2H), 7.90 (d, J = 8.9 Hz, 2H), 7.45 (d, J =
1.8 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.96 (s, 1H), 1.33 (t,
J = 7.2 Hz, 3H). Compound 3d: 1H NMR (300 MHz,
CDCl3) d 7.62 (d, J = 8.8 Hz, 2H), 7.15 (s, 1H), 6.93 (d,
J = 8.8 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.92 (s, 2H), 3.23
(t, J = 4.6 Hz, 4H), 2.58 (t, J = 4.6 Hz, 4H), 2.35 (s, 3H),
1.31 (t, J = 7.1 Hz, 3H). Compound 3g: 1H NMR
(300 MHz, CDCl3) d 10.30 (br s, 1H), 8.95 (s, 1H), 8.48–
8.46 (m, 1H), 8.04 (m, 1H), 7.35 (s, 1H), 7.32–7.27 (m, 1H),
4.25 (q, J = 7.2 Hz, 2H), 3.95 (s, 2H), 1.32 (t, J = 7.2 Hz,
9. (a) LaMattina, J. L. J. Hetrocycl. Chem. 1983, 20, 533; (b)
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28, 1628; (d) Reader, V. A. Synlett 1998, 1077.
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amines: (a) Frutos, R. P.; Gallou, I.; Reeves, D.; Xu, Y.;
Krishnamurthy, D.; Senanayake, C. H. Tetrahedron Lett.
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M. Tetrahedron Lett. 1993, 34, 6395.
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1
3H). Compound 3i: H NMR (300 MHz, CDCl3) d 4.19
(q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 3.45 (s, 2H), 2.73–2.67
(m, 4H), 2.48 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).