Synthesis of di- and tri-substituted imidazole-4-carboxylates via PBu3-mediated [3+2] cycloaddition

Article abstract of DOI:10.1080/00397911.2011.644846

Some new di- and trisubstituted imidazole-4-carboxylates were prepared from amidoacetic acids 3 in the present report. The key step to establish such imidazole- 4-carboxylates stemmed from the PBu₃-mediated [3+2] cycloaddition between in situ-generated Δ2-oxazolinone 4 and ethyl cyanoformate6. Our results indicated that trisubstituted imidazoles 7-20 were afforded in better yields than those of disubstituted imidazoles 21-27. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications1 to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.644846

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Synthesis of Di- and Tri-Substituted
Imidazole-4-carboxylates via PBu3-
Mediated [3 + 2] Cycloaddition
Mei-Yuan Hsu a , Justin Dietrich b c , Christopher Hulme b c & Arthur
Y. Shaw b c
a Department of Chemistry, Tamkang University, New Taipei City,
Taiwan
b Department of Pharmacology and Toxicology, College of Pharmacy,
University of Arizona, Tucson, Arizona, USA
c BIO5 Oro Valley, University of Arizona, Oro Valley, Arizona, USA
Accepted author version posted online: 14 Mar 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Mei-Yuan Hsu , Justin Dietrich , Christopher Hulme & Arthur Y. Shaw (2013):
Synthesis of Di- and Tri-Substituted Imidazole-4-carboxylates via PBu3-Mediated [3 + 2] Cycloaddition,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 43:11, 1538-1542
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Synthetic Communications1, 43: 1538–1542, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.644846
SYNTHESIS OF DI- AND TRI-SUBSTITUTED
IMIDAZOLE-4-CARBOXYLATES VIA PBu3-MEDIATED
[3 þ 2] CYCLOADDITION
Mei-Yuan Hsu,1 Justin Dietrich,2,3 Christopher Hulme,2,3 and
Arthur Y. Shaw2,3
1Department of Chemistry, Tamkang University, New Taipei City, Taiwan
2Department of Pharmacology and Toxicology, College of Pharmacy,
University of Arizona, Tucson, Arizona, USA
3BIO5 Oro Valley, University of Arizona, Oro Valley, Arizona, USA
GRAPHICAL ABSTRACT
Abstract Some new di- and trisubstituted imidazole-4-carboxylates were prepared from
amidoacetic acids 3 in the present report. The key step to establish such imidazole-
4-carboxylates stemmed from the PBu3-mediated [3 þ 2] cycloaddition between in
situ–generated D2-oxazolinone 4 and ethyl cyanoformate6. Our results indicated that trisub-
stituted imidazoles 7–20 were afforded in better yields than those of disubstituted imidazoles
21–27.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords [3 þ 2] Cycloaddition; cyclo-dehydration; dehydrating agent; imidazole-4-
carboxylate; D2-oxazolinone
INTRODUCTION
Imidazoles are biologically important heterocyclic compounds, and a variety of
useful therapeutic agents bearing the imidazole moiety have been developed.[1–4]
Recently, our group employed a novel [3 þ 2] cycloaddition to develop potent kinase
inhibitors, of which the imidazole scaffold plays a critical role for target selectivity.[5]
To continue our interest in the synthesis of pharmacologically relevant small
molecules, in the present study we aim to synthesize structurally diversified di- and
Received October 30, 2011.
Address correspondence to Arthur Y. Shaw, BIO5 Oro Valley, 1580 E. Hanley Blvd., Oro Valley,
AZ 85737, USA. E-mail: shaw.299@gmail.com
1538

IMIDAZOLE-4-CARBOXYLATES
1539
trisubstituted imidazole-4-carboxylates via a sequential cyclo-dehydration=[3 þ 2]
cycloaddition process.
RESULTS AND DISCUSSION
As shown in Scheme 1, amidoacetic acids 3 were robotically prepared from
amino acids 1 and corresponding acyl chlorides 2 in 10% NaOH aqueous solution
in 60 to 80% isolated yields.[6] In contrast to our early results in which acetic
anhydride was used as a dehydrating agent, herein we intended to employ 1-ethyl-3-
(3-dimeth-ylaminopropyl)-carbodiimide (EDC) as an alternative dehydrating agent
to afford D2-oxazolinones 4 thanks to its friendly workup procedure.
Moreover, we further demonstrated [3 þ 2] cycloaddition with ethyl cyanofor-
mate 6 in the presence of appropriate catalysts with in situ–generated D2-oxazoli-
nes 4 as indicated in Table 1. As shown, 2-benzamidoacetic acid 3a was taken as
our reaction model to examine [3 þ 2] cycloaddition to afford ethyl 2-phenyl-1H-
imidazole-5-carboxylate 7.
Scheme 1. Synthesis of di- and trisubstituted imidazole-4-carboxylates (5).
Table 1. PBu3-catalyzed [3 þ 2] cycloaddition of in situ–generated D2-oxazolinone 4a with
ethyl cyanoformate 6 to synthesize ethyl 2-phenyl-1H-imidazole-5-carboxylate 7
Entry
Catalyst
Time (h)
Yielda (%)
1
2
3
4
5
6
None
6
6
6
6
6
6
NDb
ND
0.5 eq PPh3
0.5 eq TMSCl
0.5 eq AgOAc
0.3 eq PBu3
0.6 eq PBu3
ND
Unknown products
45
57
aYield refers to two-step isolated 7 from amidoacetic acid 3a.
bThe product was not found.

1540
M.-Y. HSU ET AL.
As indicated, the cyclization did not take place in the absence of catalyst (entry
1, Table 1), and both triphenylphosphine (PPh3) and trimethlysilyl chloride (TMSCl)
displayed such poor catalysis that no desired product was obtained. Upon treatment
of 0.5 eq of silver acetate (AgOAc), the unidentified products were found. We thus
turned our attention to tributylphosphine (PBu3), which was employed in our pre-
vious study.[5] As a result, our study revealed that the optimized [3 þ 2] cycloaddition
reaction was carried out at room temperature in the presence of 0.6 eq of PBu3 in 57%
isolated yield. With the satisfactory results in hand (entry 6, Table 1), a series of
di- and trisubstituted imidazole-4-carboxylates were synthesized without further
modifications.
As indicated in Table 2, most desired products were obtained in moderate to
good yields of 31 to 63%. It is worthwhile to notice that trisubstituted imidazole-4-
carboxylates 7–20 were afforded in greater yields than those of disubstituted analogs
21–27. Moreover, except for 10 with 60% isolated yield, the methoxy group at
4-position of benzene ring dramatically reduced the reactivity as shown in 18 and
24 in yields of 31 and 0%, respectively. This finding might be attributed to the stab-
ility of intermediate D2-oxazolinone, which prevented further cycloaddition.[5] The
Table 2. Structure and physical property of synthesized di- and trisubstituted
imidazole-4-carboxylates 7–27
No.
R
R0
Mp (ꢀC)
Yielda (%)
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
H
H
4-Cl
163
191
169
185
166
165
144
197
221
238
184
210
162
182
188
204
214
—
57
59
60
60
62
58
63
58
50
59
61
31
58
54
40
35
36
—
37
36
33
9
4-CF3
4-OMe
4-Me
3-OMe
3-F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
H
4-F
4-Br
4-CF3
4-OMe
4-OCF3
3-OMe
H
H
4-F
H
4-CF3
4-OMe
3-OMe
3-F
H
H
144
158
107
H
H
2-Cl, 4-F
aOne-pot, two-step isolated yield.

IMIDAZOLE-4-CARBOXYLATES
1541
Figure 1. X-ray crystal structure of compound 11.
chemical structure of imidazole-4-carboxylate 11 was further confirmed by the x-ray
crystal structure characterization as shown in Fig. 1.
CONCLUSION
In summary, amidoacetic acids 3 were practically used as starting materials to
undergo a sequential cyclo-dehydration = [3 þ 2] cycloaddition process that afforded
a series of imidazole-4-carboxylates. This one-pot, two-step synthetic route provides
a facile method to carry out a parallel synthesis to benefit a high-throughput drug
screening course.
EXPERIMENTAL
Chemical reagents and organic solvents were purchased from TCI and Alfa
Aesar unless otherwise mentioned. Melting points were determined by Fargo
MP-2D. Nuclear magnetic resonance spectra (1H and 13C NMR) were measured on
Bruker AC-300 and Bruker 600 Ultrashield instruments. Chemical shifts (d) are
reported in parts per million (ppm) relative to the tetramethylsilane (TMS) peak. Mass
spectra were obtained by fast atom bombardment (FAB) on a Jeol JMS-700 instru-
ment. Flash column chromatography was performed with silica gel (230–400 mesh).
Elemental analysis was carried out on a Heraeus Vario EL-III C, H, N analyzer.
1-Ethyl-3-(3-dimeth-ylaminopropyl)-carbodiimide (EDC, 0.43 g, 2.2 mmol) was
added to a mixture of 2-benzamido-2-phenylacetic acid 3a (0.51 g, 2.0 mmol) in DCM
(5 mL). The resulting mixture was stirred at room temperature and monitored by
thin-layer chromatographic (TLC) plate until the complete consumption of starting
material and formation of D2-oxazolinones 4a. Ethyl cyanoformate 6 (0.22 g,
2.2 mmol) was added to the solution, followed by the addition of tributylphosphine
(PBu3, 0.24 g, 1.2 mmol), and the reaction mixture was stirred at room temperature
for another 6 h. The reaction solution was washed with NaHCO3 (5 mL) and brine
(5 mL) and dried over MgSO4, followed by reduced pressure evaporation to obtain

1542
M.-Y. HSU ET AL.
the residue. The crude product was purified with silica-gel flash column (eluent,
hexanes = ethyl acetate ¼ 9=1 to 1=1) to afford ethyl 2,4-diphenyl-1H-imidazole-5-
1
carboxylate 7 (0.33 g, 57%). Mp 163 ꢀC. H NMR (300 MHz, MeOH-d4) d 1.25
(t, J ¼ 7.1 Hz, 3 H), 4.26 (q, J ¼ 7.1 Hz, 2 H), 7.40–7.50 (m, 6 H), 7.69 (br, 1 H), 8.0
(d, J ¼ 8.1 Hz, 3 H) ppm. 13C NMR (150 MHz, DMSO-d6) d 14.54, 60.08, 60.66,
119.69, 121.39, 121.69, 128.16, 128.82, 129.83, 133.89, 138.9, 145.14, 146.99, 149.2,
160.21, 163.09 ppm. HRMS calcd. for C18H16N2O2 (M)þ 292.1212; found
292.1211. Anal. calcd. for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C,
74.04; H, 5.56; N, 9.44.
ACKNOWLEDGMENT
Financial support from the National Science Council of the Republic of China
to A. Y. S. is gratefully acknowledged.
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