Convenient synthesis of highly substituted imidazole derivatives

Article abstract of DOI:10.1080/00397911.2011.591957

A one-pot synthesis of the trisubstituted imidazole derivatives from α-acetoxy-α-chloro-β-keto-esters, aldehydes, and ammonium acetate has been developed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.591957

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Convenient Synthesis of Highly
Substituted Imidazole Derivatives
Lai Chun Wong a , Alexander Gehre a , Stephen P. Stanforth a & Brian
Tarbit b
a School of Life Sciences, Northumbria University, Newcastle upon
Tyne, United Kingdom
b Vertellus Specialty Materials, Seal Sands, Middlesbrough, United
Kingdom
Accepted author version posted online: 20 Jan 2012.Version of
record first published: 05 Sep 2012.
To cite this article: Lai Chun Wong, Alexander Gehre, Stephen P. Stanforth & Brian Tarbit (2013):
Convenient Synthesis of Highly Substituted Imidazole Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:1, 80-84
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Synthetic Communications1, 43: 80–84, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.591957
CONVENIENT SYNTHESIS OF HIGHLY
SUBSTITUTED IMIDAZOLE DERIVATIVES
Lai Chun Wong,1 Alexander Gehre,1 Stephen P. Stanforth,1
and Brian Tarbit2
1School of Life Sciences, Northumbria University, Newcastle upon Tyne,
United Kingdom
2Vertellus Specialty Materials, Seal Sands, Middlesbrough, United Kingdom
GRAPHICAL ABSTRACT
Abstract A one-pot synthesis of the trisubstituted imidazole derivatives from a-acetoxy-a-
chloro-b-keto-esters, aldehydes, and ammonium acetate has been developed.
Keywords Imidazoles; tricarbonyl equivalents
INTRODUCTION
We recently described a short and convenient synthetic sequence for the
preparation of a-acetoxy-a-chloro-b-keto-esters 2 from readily available and
inexpensive b-ketoesters.[1–3] A practical advantage of this methodology is that puri-
fication of compounds 2 or their precursors, by either chromatography or distil-
lation, is not required and multigram quantities of material can be prepared. We
subsequently demonstrated that compounds 2 could be used as tricarbonyl equiva-
lents 3 to effect a versatile one-pot synthesis of pyridine, 2,20-bipyridyl and
2,20:60,200-terpyridine derivatives.[1–3] In this article, we describe a synthesis of highly
substituted imidazole derivatives 4 from compounds 2/3. There are relatively few
examples of tricarbonyls 3 being used as building blocks for the synthesis of imida-
zole derivatives. Brackeen and coworkers described the preparation of a range of
imidazoles 4 in good yields from tricarbonyls 3, aldehydes (R2CHO) and ammonium
acetate in boiling acetic acid solution[4] and a patent describes a similar procedure.[5]
The tricarbonyls 3 required in these transformations were obtained from oxidation
of the phosphorane derivatives 1, which produces triphenylphosphine oxide as an
Received May 12, 2011.
Address correspondence to Stephen P. Stanforth, School of Life Sciences, Northumbria University,
Newcastle upon Tyne, NE1 8ST, UK. E-mail: steven.stanforth@northumbria.ac.uk
80

HIGHLY SUBSTITUTED IMIDAZOLE DERIVATIVES
81
Scheme 1. Synthesis of imidazoles 4.
unwanted by-product. Thus, we were interested in examining whether the readily
prepared a-acetoxy-a-chloro-b-keto-esters 2, which as noted can behave as tricarbo-
nyl 3 equivalents, might also provide suitable building blocks for highly substituted
imidazole derivatives 4 (Scheme 1).
RESULTS AND DISCUSSION
Pretreatment of compounds 2 with methylamine (33% in EtOH) has been
described previously as a method for generating the tricarbonyls 3.[1–3] Subsequent
addition of an aromatic aldehyde (R2CHO), and an excess of ammonium acetate
to the mixture afforded the known imidazole derivatives 4a[4,5] (mp 167 ꢀC, lit.[4]
165–167 ꢀC) and 4b[4] (mp decomp. > 140 ꢀC, lit.[4] not reported) and the additional
examples 4c–4f (Table 1, entries 1–6) after heating in acetic acid at 70–80 ꢀC for
2–3 h. The yields of the imidazole products 4 were generally moderate at best, but
in view of the simplicity of the procedure and the availability of compounds 2, the
overall synthesis does provide a convenient method for the preparation of this
important class of heterocyclic compound. Without pretreatment of compound 2
(R2 ¼ Ph) with methylamine, a comparable yield (41%) of the imidazole product
4a was obtained. Imidazole 4g (entry 7) bearing an aliphatic 2-substituent could
not be prepared satisfactorily using this protocol. However, by performing the
Table 1. Structures and yields of imidazole derivatives 4
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
38
65
43
27
37
63
46
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Ph
4-MeOC6H4
4-ClC6H4
4-(O2N)C6H4
2-(O2N)C6H4
Et
4g

82
L. C. WONG ET AL.
reaction in ethanol at room temperature for 3 days, a reasonable yield of the
required imidazole derivative 4g was obtained.
CONCLUSION
We have demonstrated that the tricarbonyl equivalents 2 can be successfully
used in the synthesis of highly substituted imidazole derivatives 4. This methodology
avoids the production of triphenylphospine oxide as a by-product, which as noted is
formed in current routes to these imidazole derivatives 4.
EXPERIMENTAL
1H NMR spectra (270 MHz) and 13C NMR spectra (68 MHz) were recorded
on a Jeol EX270 instrument. High-resolution mass spectrometry (HRMS) (electro-
spray) was performed by the EPSRC mass spectrometry service. Infrared (IR)
spectra were obtained via a diamond anvil sample cell using a Perkin-Elmer 1000
spectrometer. Melting points are reported uncorrected as determined on a Stuart
SMP 1 melting-point apparatus. Thin-layer chromatography (TLC) was performed
on Merck plastic foil plates precoated with silica gel 60 F254. Merck silica gel 60 was
used for column chromatography.
Typical Procedure Illustrating the Synthesis of Ethyl 2-(4-
Methoxyphenyl)-4-propylimidazole-5-carboxylate 4c
Methylamine (0.49 mL, 33% w=w in ethanol, 3.98 mmol) was added to a stirred
solution of compound 2 (R1 ¼ n-Pr) (500 mg, 1.99 mmol) in ethanol (5 mL) The mix-
ture was stirred (1 h) at room temperature and evaporated. 4-Methoxybenzaldehyde
(543 mg, 3.99 mmol) and a solution of ammonium acetate (1.53 g, 19.8 mmol) in
acetic acid (6 mL) were added to the residue, and the mixture was heated (3 h) at
70 ꢀC. The solvent was evaporated, and the residue was taken up in ethyl acetate
(12 mL). The organic extract was washed sequentially with saturated aqueous
NaHCO3 solution (12 mL), water (12 mL), and brine (12 mL); dried over (MgSO4);
and evaporated, giving the crude product (612 mg) as a brown solid. Purification by
column chromatography over silica gel (eluent; EtOAc–hexane, 1:1) gave imidazole
4c (247 mg, 43%) as a yellow solid, mp 180–181 ꢀC. 1H NMR (CDCl3): d 7.82 (d, 2H,
J ¼ 8.9 Hz), 6.96 (d, 2H, J ¼ 8.9 Hz), 4.37 (q, 2H, J ¼ 7.2 Hz), 3.86 (s, 3H), 2.89 (t,
2H, J ¼ 7.7 Hz), 1.80–1.64 (m, 2H), 1.39 (t, 3H, J ¼ 7.2 Hz), 0.99 (t, 3H, J ¼ 7.4 Hz)
) ppm. The >NH signal was not located; IR (tmax cmꢁ1): 2965, 1705, 1495, 1440,
1313, 1252, 1204, 1187, 1103, 1033, 970, 837, 739; HRMS (ESI) for C16H21N2O3
[M þ H]þ: calculated 289.1547; measured 289.1545.
Ethyl 2-(4-Chlorophenyl)-4-propylimidazole-5-carboxylate 4d
1
Yellow solid, mp 193–196 ꢀC; H NMR (CDCl3): d 7.83 (d, 2H, J ¼ 8.4 Hz),
7.43 (d, 2H, J ¼ 8.4 Hz), 4.38 (q, 2H, J ¼ 6.9 Hz), 2.90 (t, 2H, J ¼ 7.7 Hz),
1.80–1.60 (m, 2H), 1.40 (t, 3H, J ¼ 7.2 Hz), 0.99 (t, 3H, J ¼ 7.4 Hz) ppm. The
>NH signal was not located; IR (tmax cmꢁ1): 2966, 1708, 1480, 1322, 1220, 1112,

HIGHLY SUBSTITUTED IMIDAZOLE DERIVATIVES
83
1093, 972, 852, 736: HRMS (ESI) for C15H18ClN2O2 [M þH]þ: calculated 293.1051;
measured 293.1045.
Ethyl 2-(4-Nitrophenyl)-4-propylimidazole-5-carboxylate 4e
Yellow-orange solid, mp 222–223 ꢀC; 1H NMR (CDCl3): d 8.33 (d, 2H,
J ¼ 9.2 Hz), 8.07 (d, 2H, J ¼ 9.2 Hz), 4.40 (q, 2H, J ¼ 7.2 Hz), 3.10–2.88 (m, 2H),
1.82–1.71 (m, 2H), 1.42 (t, 3H, J ¼ 7.2 Hz), 1.01 (t, 3H, J ¼ 7.4 Hz) ppm. The
>NH signal was not located; IR (tmax cmꢁ1): 2964, 1706, 1517, 1340, 1320, 1309,
1291, 1207, 1100, 857, 711; HRMS (ESI) for C15H18N3O4 [M þ H]þ: calculated
304.1292; measured 304.1291.
Ethyl 2-(2-Nitrophenyl)-4-propylimidazole-5-carboxylate 4f
Tan-colored wax. 1H NMR (CDCl3): (60:40 mixture of tautomers), major tau-
tomer d 10.33–10.13 (br, 1H, NH), 8.02 (dd, 1H, J ¼ 7.9 and 1.2 Hz), 7.94 (d, 1H,
J ¼ 7.9 Hz), 7.74–7.65 (m, 1H), 7.62–7.54 (m, 1H), 4.37 (q, 2H, J ¼ 7.2 Hz), 2.90
(t, 2H, J ¼ 7.7 Hz), 1.81–1.67 (m, 2H), 1.40 (t, 3H, J ¼ 7.2 Hz), 0.99 (t, 3H,
J ¼ 7.4 Hz) ppm, minor tautomer d 10.13–9.97 (br, 1H, NH), 8.19 (dd, 1H, J ¼ 7.9
and 1.0 Hz), 7.94 (d, 1H, J ¼ 7.9 Hz), 7.74–7.65 (m, 1H), 7.62–7.54 (m, 1H), 4.40
(q, 2H, J ¼ 7.2 Hz), 3.03 (t, 2H, J ¼ 7.7 Hz), 1.81–1.67 (m, 2H), 1.40 (t, 3H,
J ¼ 7.2 Hz), 1.02 (t, 3H, 6-H, J ¼ 7.4 Hz) ppm; IR (tmax cmꢁ1): 2964, 1702, 1323,
1215, 1113, 714, 694; HRMS (ESI) for C15H18N3O4 [M þ H]þ: calculated
304.1292; measured 304.1291.
Synthesis of Ethyl 2-Ethyl-4-phenylimidazole-5-carboxylate 4g
Ammonium acetate (9.43 g, 122 mmol) was added to a mixture of compound 2
(R2 ¼ Ph) (3.87 g, 13.6 mmol) and freshly distilled propionaldehyde (0.789 g,
13.6 mmol) in EtOH (120 mL). The reaction mixture was stirred (3 days) at room tem-
perature and evaporated. The residue was dissolved in CH2Cl2 (20 mL) and washed
with H2O (3 ꢂ 20 mL), and the organic fraction was dried (MgSO4) and evaporated.
The resulting crude product was purified by column chromatography over silica gel
(eluent; EtOAc–CH2Cl2, 1:9, increasing polarity to EtOAc–CH2Cl2, 1:1), yielding
the product (Rf ¼ 0.62, EtOAc) as a tan-colored solid (1.54 g, 46%), mp 150–152 ꢀC.
1H NMR (CDCl3): d 7.75–7.67 (m, 2H), 7.38–7.24 (m, 3H), 4.22 (q, 2H, J ¼ 7.2 Hz),
2.61 (q, 2H, J ¼ 7.5 Hz), 1.24–1.12 (m, 6H) ppm. The>NH signal was not located; 13
C
NMR (CDCl3): d 162.0, 151.5, 131.9, 129.3, 128.4, 127.8, 60.6, 21.7, 14.2, 12.6 ppm;
IR (tmax cmꢁ1): 1708, 1538, 1294, 1227, 1126, 1021, 762, 690: HRMS (ESI) for
C14H17N2O2 [M þ H]þ: calculated 245.1285; measured 245.1286.
ACKNOWLEDGMENTS
We thank Vertellus Specialty Materials for generous financial support and the
EPSRC mass spectrometry service (Swansea) for high resolution mass spectra.

84
L. C. WONG ET AL.
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