1,1′-Carbonyldiimidazole mediates the synthesis of N-substituted imidazole derivatives from Morita-Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2013.10.146

In this Letter, we describe a simple and straightforward method for the synthesis of N-substituted imidazole derivatives. 1,1-carbonyldiimidazole mediates the process, which requires no activation group step. We obtained imidazole derivatives in high yiel

Full text of DOI:10.1016/j.tetlet.2013.10.146

Tetrahedron Letters 55 (2014) 180–183
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1,10-Carbonyldiimidazole mediates the synthesis of N-substituted
imidazole derivatives from Morita–Baylis–Hillman adducts
⇑
⇑
Manoel T. Rodrigues Jr. , Marilia S. Santos, Hugo Santos, Fernando Coelho
University of Campinas, Institute of Chemistry, PO Box 6154, 13083-970 Campinas, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, we describe a simple and straightforward method for the synthesis of N-substituted
imidazole derivatives. 1,1-carbonyldiimidazole mediates the process, which requires no activation group
step. We obtained imidazole derivatives in high yields and with short reaction times. To demonstrate the
synthetic significance of the aforementioned compounds, we also describe the synthesis of novel ionic
liquids from these derivatives.
Received 29 September 2013
Revised 28 October 2013
Accepted 29 October 2013
Available online 6 November 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Imidazole
Morita–Baylis–Hillman
Michael reaction
Diastereoselective
Ionic liquids
Introduction
O
O
C
O
N
N
Over the years, the imidazole nucleus has attracted the atten-
tion of the scientific community due to its chemical and biological
properties.1 For example, this nucleus is present in the structures
of several natural products in the form of the essential amino-acid
histidine or in alkaloids exhibiting anti-tumoral and anti-bacterial
activities.2 A great numbers of medicines contain the imidazole
nucleus, including ketoconazole (1), metronidazole (2), and
cimetidine (3), which are used to treat fungal infections, bacterial
infections, and gastric ulcers, respectively (Fig. 1).3
In addition, compounds containing the imidazole nucleus can
be used as ligand, because they can serve as precursors for N-het-
erocyclic carbenes (NHC) and/or catalysts for chemical reactions.
Imidazole-containing compounds are also used as a platform for
the synthesis of various types of ionic liquids.4
N
N
N
C
H2
O
H2
Cl
Ketoconazole (1)
Cl
N
S
N
NO2
N
H
N
N
N
H
HO
H2N
Metronidazole (2)
Cimetidine (3)
Figure 1. Medicines containing imidazole nucleus.
The Morita–Baylis–Hillman reaction is an organocatalyzed
transformation that forms a new
r C–C bond and a new stereogen-
ic center. This reaction allows for easy access to multi-functional-
ized and versatile small molecules, allowing the development of
a rich and diverse chemistry.5–7
Morita–Baylis–Hillman adducts have been used as substrates
for the preparation of N-substituted imidazole derivatives. One
such approach is based on an SN2 reaction between allyl bromides,
prepared from MBH adducts, and imidazole (Scheme 1).7–9
N-substituted imidazole derivatives are multifaceted substrates
that can be utilized as a platform for the synthesis of different
classes of compounds. Because of their importance, there is a
continuing interest in the development of new methods for prepar-
ing them.
In this Letter, we disclose a simple and direct method for the
preparation of N-substituted imidazole derivatives, via the
Morita–Baylis–Hillman reaction. This process does not require an
activation step. To exemplify the synthetic utility of these
compounds, we also synthesized the first ionic liquids derived
from MBH adducts.
⇑
Corresponding authors. Tel.: +55 19 3521 3085; fax: +55 19 3521 3023.
E-mail address: coelho@iqm.unicamp.br (F. Coelho).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.146

M. T. Rodrigues Jr. et al. / Tetrahedron Letters 55 (2014) 180–183
181
Jian et al.8
EWG
Br
mates. However, as far as we know, it has never been tested in
the presence of MBH adducts. We decided to use this reagent
because it can acylate the secondary alcohol, favoring a Michael
addition reaction.11 Initially, we chose to use the mixture of sol-
vents described by Zhang et al.9b and adduct 4 as a model for this
study. Thus, we added adduct 4 to a mixture of THF and water
(5:1), imidazole, and CDI. After 1 h, at room temperature, we
obtained the desired N-substituted imidazole derivative 20 in
70% yield. We then chose to test different solvents to optimize
the yield of this reaction. The results are summarized in Table 2.
Therefore, the suitable reaction condition was: 1.5 equiv of CDI,
2.0 equiv of imidazole, and acetonitrile as the solvent. (Table 2, en-
try 7). After 1 h, we obtained the desired imidazole derivative in
very high yield at room temperature. CDI is crucial for the effi-
ciency of this reaction. We tentatively demonstrated the role of
this reagent by performing two experiments (entries 8 and 9). In
the first experiment, we conducted the reaction in the absence of
imidazole. After 21 h, it was possible to obtain 20 in 53% yield
(Table 2, entry 8). In a second experiment, we removed CDI and
ran the reaction in the presence of imidazole only. Under these
conditions, we observed no product even after 48 h of stirring at
room temperature.
N
EWG
R
R
+
N
H
N
N
Zhang et al.9b
OAc
N
EWG
R
EWG
+
R
N
H
N
N
This work
OH
N
EWG
R
+
EWG
R
N
H
N
N
Scheme 1. Synthesis of N-substituted imidazole derivatives from Morita–Baylis–
Hillman adducts.
Results and discussion
Once we optimized the conditions for this transformation, we
treated adducts 5 to 19 with CDI and imidazole in acetonitrile at
room temperature to give the corresponding N-substituted imidaz-
ole derivatives in good yields and high stereoselectivities. The
results are summarized in Table 3.
We began this work by preparing a set of Morita–Baylis–Hill-
man adducts using a method we have previously reported.10 In this
method, a suitable aldehyde is treated with different acrylates or
cycloenones to provide the corresponding MBH adducts in good
to excellent yields. The results are summarized in Table 1.
We employed the synthesized MBH adducts as substrates for
the next step. We treated them with imidazole and 1,1-carbonyldi-
imidazole (CDI) to obtain the target compounds. CDI is commonly
used in esterification reaction, and in the preparation of carba-
We used 1H NMR, and comparisons with data available in the
literature to determine the double bond configurations of these
compounds (Fig. 2).11
NOE experiments confirmed the E configuration of the double
bond for almost all compounds synthesized. For example, the
allylic hydrogen atoms of imidazole compound 33 (major and
minor diastereoisomers) were irradiated. The results are shown
in Figure 2.
The process we have developed seems to have some advantages
over other processes reported in the literature. The transformation
occurs directly from the MBH adducts, in a single step and does not
require previous protection and/or hydroxyl activation. The
N-substituted imidazole derivative results from an SN20 reaction
and its production is dependent on the presence of CDI.
Table 1
Preparation of MBH adducts
OH
R2
R2
R1
DABCO, ))), rt.
4-17
O
Table 2
O
R1
H
Optimization of reaction conditions
OH
O
O
R1
solvent, rt.,
OH
O
DPI10b, rt.
imidazole, 1h
OMe
N
OMe
18-19
O
N
N
N
Entry
R1
R2
Adducts, yielda (%)
20
4
1
C6H5
CO2Me
4, 85
5, 73
N
N
CDI
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4-OBn-C6H4
4-tBu-C6H4
3,5-F-C6H3
4-NO2-C6H4
Cyclohexyl
n-Propyl
4-OMe-C6H4
3,4,5-OMe-C6H2
2-Thiazolyl
4-Isopropyl-C6H4
2-Cl-Quinoloyl
4-NO2-C6H4
3-OMe-C6H4
3-OMe-C6H4
3-Cl-C6H5
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2tBu
CO2Et
CN
6, 77
7, 91
Entry
Solvent
Conversiona (%)
1
2
3
4
5
6
THF/H2O (5:1)
Diethyl ether
Ethyl acetate
Tetrahydrofuran (THF)
Dichloromethane
Toluene
Acetonitrile
Acetonitrile
Acetonitrile
70
84
72
69
70
80
>95
53
0
8, 90
9, 40
10, 95
11, 71
12, 71
13, 93
14, 52
15, 93
16, 85
17, 87
18, 85
19, 83
7
8b
9c
CN
—
—
Conversion measured by 1H NMR.
The reaction was carried out without the addition of imidazole (1.5 equiv CDI,
rt, 21 h).
The reaction was carried out in the presence of imidazole, but without CDI
(2.0 equiv of imidazole, rt, 48 h).
a
b
c
a
Yields refer to isolated and purified products (by silica gel column
chromatography).

182
M. T. Rodrigues Jr. et al. / Tetrahedron Letters 55 (2014) 180–183
Table 3
Synthesis of N-substituted imidazole derivatives
O
(E)
(E)
R2
N
OH
OH
O
R1
R1
N
Acetonitrile, rt.,
imidazole, 1h
R2
or
or
R1
R1
N
O
N
18-19
N
N
4-17
20-33
34-35
N
N
CDI
Entry
R1
R2
Products, yielda (%)
1
2
3
4
5
6
7
8
C6H5
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2tBu
CO2Et
CN
20, 83
21, 90
22, 80
23, 83
24, 70
25, 68
26, 75
27, 91
28, 73
29, 69
30, 85
31, 95
4-BnO-C6H4
4-tBu-C6H4
3,5-F-C6H4
4- NO2-C6H4
Cyclohexyl
n-Propyl
4-MeO-C6H4
3,4,5-MeO-C6H2
2-Thiazolyl
4-Isopropyl-C6H4
2-Cl-Quinoloyl
4-NO2-C6H4
3-MeO-C6H4
3-MeO-C6H4
3-Cl-C6H4
9
10
11
12
13
14
15
16
32, 95 (E/Z; 4:1)b
33, 89 (E/Z; 3:1)b
34, 72
CN
—
—
35, 75
a
Yields refer to isolated and purified products (by silica gel column chromatography).
In these cases, we also observed the presence of the Z diastereoisomer. The reason for this result is unclear.
b
Table 4
Ionic liquids prepared from N-substituted imidazole derivatives
1.46%
Irradiated at
4.90 ppm
H
H
H
R2
N
R2
N
CH3CN
reflux
MeO
H
CN
N
R1
Irradiated at
4.84 ppm
R1
N
Br
+
CN
N
H
36
N
Br
N
OMe
N
33(Z)
33(E)
37-41
0.54-0.85%
R1
n-Propyl (26)
3,4,5-MeO-C6H2 (28)
Thiazolyl (29)
4-Isopropyl-C6H4 (30)
4-NO2-C6H4 (32)
R2
Products, yielda (%)
Figure 2. Confirming the E double bond configuration.
Entry
1
2
3
4
5
CO2Me
37, >95
38, >95
39, >95
40, >95
41, 45
CO2Me
CO2Me
CO2tBu
CN
O
N
N
Nucleophilic
attack
N
N
O
O
a
Yields refer to isolated and purified compounds.
N
N
N
R2
OH
N
R1
CDI
R2
R1
On the basis of the above results (Table 2 entries 7 and 8), we
tetrahedral intermediate
N
proposed the following mechanism for this transformation: the
secondary hydroxyl group attacks the central carbonyl group of
CDI, forming a tetrahedral intermediate, which results in the elim-
ination of a molecule of imidazole. This sequence is responsible for
transferring an acyl group to the hydroxyl group. The free imidaz-
ole can then participate in a Michael addition reaction, which leads
to the elimination of the acyl group and the formation of the
desired N-substituted imidazole derivative with high diastereose-
lectivity (Scheme 2).
N
Elimination
Michael
addition/SN2'
O
R2
N
R1
N
O
R2
N
R1
To exemplify the synthetic versatility of these imidazole deriv-
atives, we decided to transform a subset of them into ionic liquids.
Then, we refluxed the imidazole compounds with n-bromobutane
(36) in acetonitrile for 24 h to afford the corresponding ionic
liquids in high yields. The results are summarized in Table 4.
All compounds tested with the exception of the cyano deriva-
tive (Table 4, entry 5) were obtained in excellent yields. We fully
N
O
N-substituted
imidazole derivatives
O
N
HN
N
N
Scheme 2. Proposed mechanism for the preparation of N-substituted imidazole
compounds with CDI.

M. T. Rodrigues Jr. et al. / Tetrahedron Letters 55 (2014) 180–183
183
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Conclusion
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In summary, we report a simple and expeditious method for
the synthesis of N-substituted imidazole derivatives from
Morita–Baylis–Hillman adducts. In contrast to other approaches
reported in the literature, no previous activation of the secondary
hydroxyl group is necessary using our method. We obtained the
imidazole derivatives in high yields and with good
stereoselectivity.
We demonstrated the synthetic potential of these imidazole
compounds by using them to prepare new ionic liquids. To the best
of our knowledge, this was the first application of MBH adducts as
a platform for the preparation of ionic liquids. A study aiming at
the asymmetric synthesis of these new ionic liquids is ongoing
and the results will be disclosed in due time.
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Acknowledgments
The authors thank the São Paulo State Science Foundation
(FAPESP) and the Brazilian Council for Scientific and Technological
Development (CNPq) for financial support. M.T.R.Jr. thanks CNPq
for
a post-doctoral fellowship. M.S.S. thanks FAPESP for a
fellowship.
Supplementary data
Supplementary data (the spectra of all compounds prepared)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2013.10.146.
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