Novel and convenient to substituted imidazoles

Article abstract of DOI:10.1002/jhet.213

(Chemical Equation Presented) A one-pot synthesis of imidazoles has been established from the addition of azides to 2-amidoacrylates, and this synthetic method demonstrates an efficient synthesis of imidazole-4-carboxylates.

Full text of DOI:10.1002/jhet.213

November 2009
Novel and Convenient to Substituted Imidazoles
Yu-An Changa* and Hsiang Changb
1235
aDepartment of Biotechnology, Chung Chou Institute of Technology, Yuanlin Township,
Changhua County 51003, Taiwan
bDivision of Biotechnology, Taiwan Agricultural Research Institute, Council of Agriculture,
Wufeng Township, Taichung 41357, Taiwan
*E-mail: cya0520@gmail.com
Received March 28, 2009
DOI 10.1002/jhet.213
Published online 6 November 2009 in Wiley InterScience (www.interscience.wiley.com).
A one-pot synthesis of imidazoles has been established from the addition of azides to 2-amidoacry-
lates, and this synthetic method demonstrates an efficient synthesis of imidazole-4-carboxylates.
J. Heterocyclic Chem., 46, 1235 (2009).
INTRODUCTION
article, we have systematically investigated each possi-
ble reaction of various 2-aminoacrylates and presented
the results as follows.
Over the century, the chemical and biochemical prop-
erties of imidazoles in the biological system have been
attracting much interest. Even today, research in imidaz-
ole chemistry continues unabated. Compounds with im-
idazole ring systems have many pharmacological proper-
ties and play important roles in biochemical processes
[1]. Many substituted imidazoles are known as key phar-
macophore in modern drugs [2]. Therefore, the prepara-
tion of imidazoles has gained considerable attention in
recent years [3].
RESULTS AND DISCUSSION
When 2-amidoacrylates 9 were heated with benzyl az-
ide at reflux in toluene, imidazoles 11 were obtained as
the main product in the reaction mixture. The effects of
temperature, azide equivalents, and reaction time on the
yield of imidazoles and byproducts 12 were investigated
(Table 1). It is clear that temperature has a pivotal role
in the reaction, since only trace amounts of imidazoles
were observed under 100ꢀC, and the yield of imidazoles
increased with regard to reaction temperature. Likewise,
we found that required reaction time could be shortened
from 2–4 d to 15 h if reaction temperature increased
from reflexing toluene to 190ꢀC in a sealed tube
(Table 1, entries 4, 6, and 7). Increased equivalents of
benzyl azide appeared to be slightly detrimental to the
yield of imidazoles, and more byproducts were yielded
(Table 1, entries 6 and 7). Optimal yield of imidazoles
was achieved when the reactants were heated in toluene
in a sealed tube at 190ꢀC for 15 h (Table 1, entries 4
and 6).
In 1998, Hadjiantou-Maroulis et al. [4] found the py-
rolysis of 1-aroylamino-4,5-diphenyl-1,2,3-triazoles (I)
yields 2,3-diphenyl-2H-azirine (II) and 2-aryl-4,5-diphe-
nylimidazoles (III) as the major products (Scheme 1).
More recently, great attention has been given to dipo-
lar cycloaddition chemistry using azides, especially az-
ide cycloadditions to alkynes to generate triazoles [5]
(Scheme 2). Addition of azides to a,b-unsaturated car-
bonyl compounds IV has been reported in the literature
[6–10] (Scheme 3). Particularly interesting were the
transformations of 2-amido-3-arylaminoacrylates V and
VII to imidazoles VI and VIII, respectively [11]
(Scheme 4).
According to Hadjiantou-Maroulis et al. [4], we found
a novel synthesis of imidazoles XI from 2-aminoacry-
lates IX and azides X. To our knowledge, no report has
described such a one-pot procedure to synthesize imida-
zoles XI from 2-amidoacrylates IX (Scheme 5). In this
Based on similar imidazole synthesis previously
reported [12] and the chemical properties of organic
azides, we proposed a mechanism (Scheme 6) that
can possibly explain the formation of 2-amido-
C
V
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Y.-A. Chang and H. Chang
Vol 46
Scheme 1
Scheme 3
Methyl 2-benzamidoacrylate (9a). The (S)-Methyl 2-ben-
zamido-3-hydroxypropanoate compound (1.21 g, 5.40 mmol)
was dissolved in 50 mL of dry CH2Cl2 in a flame-dried 100-
mL round-bottomed flask under Ar. EDC HCl (1.24 g, 6.46
mmol) was added to the solution in one portion followed by
CuCl (160.7 mg, 1.62 mmol). The reaction was wrapped in
foil and stirred under Ar at room temperature. After 2 h, TLC
of the reaction (1:1 hexanes/EtOAc) indicated starting material
had been completely consumed, and a new, less polar com-
pound was observed. After 3 h, H2O (100 mL) was added to
the reaction, and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (2 ꢂ 20 mL), and the combined
CH2Cl2 layers were washed with H2O (100 mL), dried over
MgSO4, filtered, and concentrated to yield a yellow oil. The
oil was purified through a plug (30 g) of silica gel using
CH2Cl2 and yielded 9a as a colorless, cloudy liquid (1.06 g,
96% yield). IR: 3300, 3150, 3075, 1740, 1640, 1210, 830, 750
3aminoacrylate byproduct 12 as an intermediate in the
synthesis of imidazole 11. Dipolar cycloaddition of ben-
zyl azide to 2-amidoacrylate 9 should offer the regioiso-
meric triazolines A and B, even previous studies
reported [13] that the formation of triazoline A would
be greatly favored over the regioisomeric triazoline B.
Thermal decomposition of triazolines A and B would
provide compounds C and D, on extrusion of nitrogen,
which would yield either aziridine E or imine F. Tauto-
merization of imine F would provide E-enamine G or
the observed Z-enamine 12, which on intramolecular cy-
clization would provide imidazole 11 after dehydration
of tetrahedral intermediate H.
On the basis of proposed mechanism, we suggest that
byproduct 12 appeared to be an intermediate contribut-
ing to the production of imidazole 11. We found that
enamine 12 was accumulated exclusively only in the
sealed reaction conditions where water was confined in
reaction system, otherwise imidazole 11 was observed
(Table 2) [14].
cmꢁ1 1H NMR (deuteriochloroform): d 8.49 (br-s, 1H), 7.75
;
(dd, J ¼ 7.1, 1.9 Hz, 2H), 7.43 (m, 1H), 7.37 (m, 2H), 6.71
(d, J ¼ 1.6 Hz, 1H), 5.90 (d, J ¼ 1.6 Hz, 1H), 3.76 (s, 3H).
13C NMR: d 165.3, 164.3, 133.9, 131.7, 130.8, 128.4, 126.6,
108.5, 52.7. HRMS (FAB): m/z [MþH]þ calcd for
C11H12NOþ3 , 206.0817; found, 206.0818.
Benzyl 2-benzamidoacrylate (9b). Compound 9b was pre-
pared following a similar procedure for 9a. The (S)-Benzyl 2-
benzamido-3-hydroxypropanoate compound (1.51 g, 5.03
mmol), EDC HCl (1.17 g, 6.12 mmol), and CuCl (0.15 g, 1.51
mmol) provided an oil. Chromatography through silica gel
using CH2Cl2 yielded 9b as a white solid (1.45 g, 99% yield);
mp 51–52ꢀC. IR (KBr): 3310, 3140, 3010, 1735, 1630, 1210,
A one-pot synthesis of imidazoles 11 has been devel-
oped from adding azides to 2-amidoacrylates 9, and this
synthetic method represents an efficient synthesis for
imidazole-4-carboxylates 11.
1
840, 730 cmꢁ1; H NMR: d 8.56 (br-s, 1H), 7.84 (dd, J ¼ 7.0,
EXPERIMENTAL
1.5 Hz, 2H), 7.55 (m, 1H), 7.47 (m, 2H), 7.41–7.36 (m, 5H),
All reactions were performed under an atmosphere of dry
nitrogen unless noted otherwise. 1H and 13C NMR spectra
were recorded on a Varian 300 MHz or 500 MHz spectrometer
using CDCl3 as solvent under ambient temperatures unless oth-
erwise noted. Infrared spectra were recorded using an FT-IR
spectrometer and are reported in cmꢁ1. Mass spectra were
obtained as specified. Low-resolution mass and high-resolution
mass spectra were measured with a Hitachi M-52-Instrument
or Bruker APEX II mass spectrometer. Melting points were
uncorrected and were determined either using recrystallized
samples or samples, which crystallized during concentration of
the chromatography eluents.
Scheme 4
Scheme 2
Journal of Heterocyclic Chemistry
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November 2009
Novel and Convenient to Substituted Imidazoles
1237
Scheme 5
Scheme 6. Proposed formation mechanism of imidazole.
6.82 (d, J ¼ 2.0 Hz, 1H), 6.06 (d, J ¼ 2.0 Hz, 1H), 5.32 (s,
2H). 13C NMR: d 165.7, 164.2, 135.0, 134.2, 132.0, 131.0,
128.8, 128.7, 128.6, 128.2, 126.9, 109.1, 67.9. HRMS (FAB):
m/z [MþH]þ calcd for C17H16NOþ3 , 282.1130; found,
282.1140.
General procedure for the preparation of imidazoles
from 2-amidoacrylates and azides. Methyl 1-benzyl-2-phe-
nyl-1H-imidazole-4-carboxylate (11a). Compound 9a (116.2
mg, 0.57 mmol) and benzyl azide (0.11 mL, 0.87 mmol) were
dissolved in 5 mL of toluene in a sealed pyrex tube fitted with
a stir bar. The tube was heated in an oil bath maintained at
190ꢀC. After 1 h, the colorless solution turned yellow in color,
and gradually, the color became brown. After 15 h, the reac-
tion was cooled to RT and concentrated. The crude brown oil
was purified through 25 g of silica gel using a solvent gradient
from CH2Cl2 to 80% CH2Cl2/EtOAc and yielded pure 12a
(26.5 mg, 15.1% yield), pure 11a as an amber oil (84.1 mg,
50.8% yield), and a mixture of 12a and 11a (26.1 mg). Total
yield of 11a isolated as amber oil was 90.1 mg (54%). 11a
was recrystallized from EtOAc/hexanes to produce light yel-
low crystals. Rf ¼ 0.14 (1:1 hexanes/EtOAc). IR (KBr): 3010,
(Z)-Methyl 2-benzamido-3-(benzylamino)acrylate (12a). Com-
pound 12a was isolated as amber oil. Total yield isolated was
46.6 mg (27%). Compound 12a was recrystallized from 70%
EtOH/H2O to yield colorless crystals. Rf ¼ 0.26 (1:1 hexanes/
EtOAc). IR (KBr): 3270, 3140, 3010, 2400, 1750, 1630, 840,
1
1735, 1590, 1320, 1210, 840, 730 cmꢁ1; H NMR: d 7.69 (s,
1
730 cmꢁ1; H NMR: d 8.00 (br, 1H), 7.84 (m, 2H), 7.51 (m,
1H), 7.60 (m, 2H), 7.44–7.40 (m, 3H), 7.37–7.32 (m, 3H),
7.09 (m, 2H), 5.23 (s, 2H), 3.90 (s, 3H). 13C NMR: d 163.0,
148.8, 135.4, 132.5, 129.2, 129.0, 128.8, 128.7, 128.2, 127.9,
126.9, 126.5, 51.3, 50.5. HRMS (FAB): m/z [MþH]þ calcd
for C18H17N2Oþ2 , 293.1290; found, 293.1293.
1H), 7.44 (m, 2H), 7.37–7.26 (m, 6H), 6.50 (br, 1H), 4.42 (d,
J ¼ 6.0 Hz, 2H), 3.73 (s, 3H). 13C NMR: d 166.5, 164.8,
140.1, 138.5, 134.0, 131.6, 131.3, 128.73, 128.69, 128.6,
128.51, 128.46, 127.2, 127.1, 127.0, 126.9, 52.5, 51.6. HRMS
Table 1
Investigation of reaction conditions for the addition of benzyl azide to 2-amidoacrylates.
Result/yield (%)
Entry
R
BnN3 (equiv)
Solvent
Temp (ꢀC)
Time
11a/11b
12a/12b
1
2
3
4
5
6
7
Me
Me
Me
Me
Bn
Bn
Bn
1.5
1.5
1.3
1.5
1.5
1.5
3.0
Toluene
Toluene
Xylene
110
110
150
190a
110
190a
190a
2 d
4 d
26 h
15 h
4 d
29
33
52
54
39
63
54
7
4
13
27
10
18
25
Toluene
Toluene
Toluene
Toluene
15 h
15 h
a Reaction was performed in a sealed pyrex tube and heated in an oil bath.
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Y.-A. Chang and H. Chang
Vol 46
REFERENCES AND NOTES
Table 2
Thermal cyclization of methyl 2-benzamido-3-(benzylamino)
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190b
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40
No reaction
35
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Benzyl 1-benzyl-2-phenyl-1H-imidazole-4-carboxylate (11b). Com-
pound 11b was prepared following the general procedure for
the synthesis of imidazoles from acrylates and azides. Acrylate
9b (0.14 g, 0.51 mmol) and benzyl azide (0.10 mL, 0.79
mmol) were heated in toluene (5 mL) in a sealed pyrex tube
for 15 h in a 190ꢀC oil bath. Chromatography through 25 g of
silica gel using a solvent gradient from CH2Cl2 to 90%
CH2Cl2/EtOAc yielded pure 12b, 11b, and a mixture of 11b
and 12b as amber oils. Total yield of 11b was 120 mg (63%).
IR (KBr): 3010, 1735, 1667, 1590, 1310, 1160, 820, 730
cmꢁ1 1H NMR: d 7.65 (s, 1H), 7.56 (m, 2H), 7.44 (m, 2H),
;
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129.4, 129.3, 129.1, 129.0, 128.44, 128.36, 128.3, 128.2,
128.0, 127.2, 126.7, 66.0, 50.7. HRMS (FAB): m/z [MþH]þ
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1
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(0.01 mol) and toluene (6 mL) were heated under reflux for
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Acknowledgment. The authors thank the financial support from
Chung Chou Institute of Technology.
[14] The thermal cyclization of enamine compound is reversible
reaction, so no reaction was observed in the sealed pyrex tube.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet