Synthetic analogue of stilbene containing an imidazole nucleus

Article abstract of DOI:10.3390/50600856

Synthesis of trans-1,2-bis(4-nitro-1-p-methoxybenzylimidazol-5-yl)ethene (1) as an imidazole analogue of stilbene has been reported. In order to confirm the trans geometry of the product using an UV spectral comparison, a mixture of both trans (1) and cis isomer (3) was also prepared. The synthesis involved one-step dimerization of the precursor, 4-nitro-1-p-methoxybenzyl-5-methyl-1H- imidazole (2), using N-chlorosuccinimide catalyzed by potassium t-butoxide.

Full text of DOI:10.3390/50600856

Molecules 2000, 5, 856-863
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthetic Analogue of Stilbene Containing an Imidazole Nucleus
Saika Siddiqui and Ramachandra S. Hosmane*
Laboratory for Drug Design and Synthesis, Department of Chemistry & Biochemistry, University of
Maryland, Baltimore County (UMBC), 1000 Hilltop Circle, Baltimore, Maryland 21250, USA
Tel.: +1-410-455-2520, Fax: +1-410-455-1148, E-mail: hosmane@research.umbc.edu,
URL: http://research.umbc.edu/~hosmane
Received: 24 May 2000 / Accepted: 13 June 2000 / Published: 18 June 2000
Abstract: Synthesis of trans-1,2-bis(4-nitro-1-p-methoxybenzylimidazol-5-yl)ethene (1) as
an imidazole analogue of stilbene has been reported. In order to confirm the trans geometry
of the product using an UV spectral comparison, a mixture of both trans (1) and cis isomer
(3) was also prepared. The synthesis involved one-step dimerization of the precursor, 4-nitro-
1-p-methoxybenzyl-5-methyl-1H-imidazole (2), using N-chlorosuccinimide catalyzed by po-
tassium t-butoxide.
Keywords: Dimerization, heterocycles, biaryls, imidazole, stilbene.
Introduction
Trans-stilbene is an important organic compound carrying a wide variety of useful applications in or-
ganic synthesis [1]. These applications include, but are not limited to, asymmetric dihydroxylation [1a],
photocyclization [1b], photoisomerization [1c], and synthesis of diphenyl acetylenes [1d], bromohydrins
[1e], and benzils [1f]. Heterocyclic analogues of trans-stilbene are of interest not only for exploring
these various applications but also for their inherent potential to serve as key precursors to the synthesis
of a host of novel as well as known heterocycles. We present here the synthesis of trans-1,2-bis(4-nitro-
1-p-methoxybenzylimidazol-5-yl)ethene (1) as an analogue of trans-stilbene containing an imidazole
ring. In order to confirm the trans geometry of 1 using ultraviolet spectroscopy, a mixture of both trans
(1) and cis isomer (3) was also prepared. The comparison of the UV spectrum of 1 with that of the
mixture corroborated the trans geometry of 1.
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

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Molecules 2000, 5
NO2
N
H
R
N
N
R
H
N
O2N
1
Figure 1.
Results and Discussion
The required synthetic precursor, 4-nitro-1-p-methoxybenzyl-5-methyl-1H-imidazole (2), was pre-
pared by alkylation of 5-methyl-4-nitro-1H-imidazole [2] with p-methoxybenzyl chloride in the presence
of potassium carbonate in dimethylformamide (DMF) (Scheme 1). Compound 2 was obtained as a sin-
gle regioisomer as determined from NMR data. The regioisomeric assignment of 2 was based upon (a)
1
comparison of the benzyl absorptions of 2 in its H NMR spectrum with those of several other benzyl-
substituted nitroimidazoles previously synthesized in this laboratory [3-5], and (b) the established fact
that the alkylation of nitroimidazoles predominantly yield substitutions at the nitrogen atom farther away
from the nitro group [6].
NO2
N
CH2-Ph-OCH3 (p)
H
N
H
R
N
H3C
O2N
H3C
O2N
N
R
N
t
NCS, -BuOK
p
Cl-CH2-Ph-OCH3 ( )
H
DMF, K CO
DMF
2
3
N
N
N
O2N
2
1
R = -CH2-Ph-OCH3 (p)
Scheme 1.
The target 1 was prepared by the slow addition of a solution of 2 and potassium t-butoxide in DMF
to a solution of N-chlorosuccinimide (NCS) [7] in DMF.
The energetically less-favored cis isomer (3), required for structural assignment by UV comparison,
was prepared in low yield as a mixture of cis and trans isomers by reversal of the above addition proce-
dure, consisting of a slow addition of a solution of NCS in DMF to a mixture of 2 and potassium t-
butoxide in DMF (Scheme 2). The 1H NMR of the product mixture thus obtained exhibited two sets of
peaks, while the product obtained by the first method showed only a single set of peaks.

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Molecules 2000, 5
H
H
R
N
R
N
Addition of NCS
to 2 + KOt-Bu
1
N
N
O2N
R
O2N
H3C
N
3
NCS, tBuOK
DMF
N
NO2
O2N
N
H
2
R
N
N
R
R = -CH2-Ph-OCH3 (p)
Addition of 2 + KOt-Bu
to NCS
H
N
1
O2N
Scheme 2.
The structural distinction between the two geometric isomers was achieved by comparing the UV
absorbance data of the mixture 1 and 3 with that of 1 alone. The UV absorbance spectra of a mixture of
1 and 3, depicted in Figure 2, showed two peaks above 300 nm, one at 8max 310 nm and 370 nm.
Figure 2. The UV absorbance spectrum of the mixture of 1 and 3 in chloroform: 8max: 1: 370; 2: 310; 3:
242; 4: 210 nm.

859
Molecules 2000, 5
The UV absorbance spectrum of 1 in Figure 3, on the other hand, showed only one peak at 8max 370
nm. The energetically less-favored cis isomer 3, with its two-charged nitro groups in close spatial
proximity, is anticipated to absorb at a lower wave number (higher energy) than the trans isomer 1.
Thus 3 and 1 were assigned the cis and trans configurations, respectively. The mass spectrometric and
microanalytical data were consistent with the dimeric structures of 1 and 3.
Figure 3. UV absorbance spectrum of 1 in chloroform. 8max: 1: 370; 2: 242 nm.
A tentative reaction pathway for the formation of 1 and 3 from 2 is outlined in Scheme 3. It appears
that the key intermediate is the monochloro dimer 8, which might be formed via a couple of different
routes, including the nucleophilic displacement reaction of the carbanion 6 on the initially formed
monochloro species 5 (Path A) or by the attack of carbanion 4 on the dichloro species 7 (Path B). The
intermediate 8 undergoes further dehydrohalogenation in the presence of potassium t-butoxide to yield
the observed cis and trans dimers 3 and 1, respectively.

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Molecules 2000, 5
H
C
R
N
H
R
N
O
O
H3C
O2N
tBuOK
O
N
Cl
N
N
4
O2N
N
Cl
2
R = -CH -Ph-OCH ( )
p
2
3
O
Path A
H
C
H
Cl
C
R
N
H
R
N
O
O
Path B
Cl
Cl
tBuOK
N
N
N
O2N
O2N
6
5
Path B
Path A
R
N
Cl2HC
O2N
N
t-BuO
4
7
R
N
H
H
C
Cl
R
N
H
C
N
N
NO2
O2N
8
NO2
N
H
H
H
R
R
N
R
N
N
R
N
H
N
N
N
O2N
NO2
O2N
1
3
Scheme 3.

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Molecules 2000, 5
Experimental
General
1H NMR spectra were recorded on a General Electric QE-300 (300 MHz) or Varian (200 MHz)
NMR instrument. The reported spectral data are in the following format: chemical shift (all relative to
MeSi4 as an internal reference standard unless otherwise indicated), multiplicity (abbreviations: s = sin-
glet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet, b = broad and app =
apparent), integration, coupling constants, exchangeability after D2O addition, and assignment of reso-
13
nance. C NMR spectra were recorded on a General Electric QE-300 (300 MHz) instrument, using
DMSO-d6 as the reference standard. Atlantic Microlab, Inc., Norcross Georgia, performed elemental
microanalyses. The mass spectra were recorded at the Mass Spectral Facility, Department of Biochem-
istry, Michigan State University. Ultraviolet spectra were recorded on a Jasco V-570 UV/VIS/NIR
spectrophotometer. Thin layer chromatography was performed on Merck Kieselgel 60 GF254 plates (0.2
mm thickness). Melting points were determined on a Thomas-Hoover capillary melting point apparatus
and are uncorrected. Anhydrous THF was freshly distilled from sodium. Anhydrous solvents DMF,
pyridine, and chloroform were purchased from Aldrich Chemical Co. and were used without further pu-
rification.
4-Nitro-1-p-methoxybenzyl-5-methylimidazole (2)
To 1.00 g of 5-methyl-4-nitro-1H-imidazole [2] (7.86 mmol) in a 100 mL three-neck round bottom
flask equipped with a thermometer, N2 inlet, and a magnetic stirring bar, was added potassium carbon-
ate (0.868 gm, 6.29 mmol), DMF (10.0 mL) and p-methoxybenzyl chloride (1.17 mL, 8.65 mmol) in
one portion. The mixture was heated at 130oC overnight. The mixture was then cooled to room tem-
perature and then further cooled in an ice bath. The resulting salts were collected under vacuum and
washed with chloroform. The chloroform was then evaporated to yield a dark slurry (as a last step in
evaporation process, toluene was added and the mixture evaporated again to get all the DMF out). The
dark mixture was then triturated with cold ether to yield brown crystals. The crystals collected had m.p.
98-106oC, and were recrystallized in toluene to yield a light brown solid, m.p. 103-106oC, 42% yield. 1H
NMR. (DMSO-d6) d 7.91(s, 1H, 2-H imidazole), 7.21 (d, J=8.7Hz, 2H, m-Ph), 6.94 (d, J=8.4Hz, 2H,
o-Ph), 5.24 (s, 2H, CH2Ar), 3.74 (s, 3H, OCH3); MS (FAB) m/z 248 (MH+).
Anal. Calcd. for C12H13N3O3 : C, 58.29; H, 5.29; N, 16.99. Found C, 58.43; H, 5.40; N, 15.91.
Mixture of cis-1,2-bis(3-nitro-1-p-methoxybenzylimidazol-2-yl)ethene (3) and trans-1,2-bis(3-nitro- 1-
p-methoxybenzyl imidazol-2-yl)ethene (1)
Compound 2 (0.200 g, 0.81 mmol) in (10.0 mL) DMF was added dropwise over 30 minutes to a
stirred solution of potassium-tert butoxide (0.363 g, 3.24 mmol) in a three-neck round bottom flask,

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Molecules 2000, 5
under nitrogen at 0oC. The reaction mixture was allowed to stand another 30 minutes at 0oC and then
N-chlorosuccinimide (NCS) (0.216 g, 1.618 mmol) in dry THF (10.0 mL) was added to the flask. The
reaction temperature was brought to room temperature, followed by refluxing for 5 hours. TLC (100:1
CHCl3 / MeOH) showed no starting material. The mixture was then rotary evaporated and neutralized
to pH 7 with dil. HCl. The mixture was extracted with chloroform (3 x 50 mL). The organic layers were
combined and dried over anhydrous MgSO4. The chloroform extract was mixed with silica gel and the
mixture was evaporated to dryness. The residue was suspended in a minimum amount of chloroform
and the resulting slurry was loaded onto a silica gel column and the column was eluted with a mixture of
100:1 (CHCl3 / MeOH). Pooling and evaporation of the appropriate eluent fractions under reduced
pressure afforded an oil, which was triturated with cold ethanol to give a mixture of dimers 1 and 3,
1
m.p. 205-210oC. H NMR (300 MHz, DMSO-d6) d 8.05 & 7.87(s, 2x1, 1H, 2-H imidazole), 7.41 (s,
1H, C=C), 7.17 (d, J=8.7Hz, 2H, m-Ph), 7.04 (d, J=8.4Hz, 2H, m-Ph) 6.91 (d, J=8.7Hz, 2H, o-Ph),
6.88 (s, 1H, C=C), 6.86 (d, J=8.7Hz, 2H, o-Ph), 5.26 & 5.18 (s, 2x1, 2H, CH2Ar), 3.70 & 3.67 (s, 2x1,
3H, OCH3); MS (FAB) m/z 491 (MH+). Anal. Calcd. for C24H22N6O6·¼ H O: C, 58.24; H, 4.58; N,
2
16.98. Found C, 58.22; H, 4.70; N, 16.72.
Trans-1,2-bis(3-nitro-1-p-methoxybenzylimidazol-2-yl)ethene (1)
To a vigorously stirred mixture of N-chlorosuccinimide (NCS) (0.216 g, 1.618 mmol) in DMF at
room temperature was added dropwise a well-stirred (see below) mixture of potassium tert-butoxide
(0.272 g, 2.427 mmol) and 2 (0.20 g, 0.809 mmol) in DMF via syringe. Before the addition, the mixture
of potassium tert-butoxide and 2 was stirred for 2.0 hrs at room temperature under nitrogen. After the
addition, the reaction mixture was refluxed overnight. The TLC (100:1 CHCl3 / MeOH) showed one
UV-absorbing, yellow spot. The reaction mixture was evaporated and neutralized to pH 7 with 0.5 N
HCl and water. The mixture was extracted with chloroform (4 x 50 mL). The organic layers were com-
bined and dried over anhydrous MgSO4. The chloroform extract was mixed with silica gel and the mix-
ture was evaporated to dryness. The residue was suspended in a minimum amount of chloroform and
the resulting slurry was loaded onto a silica gel column and the column was eluted with a mixture of
100:1 (CHCl3 / MeOH). Pooling and evaporation of the appropriate eluent fractions under reduced
pressure afforded an oil which was triturated with cold ethanol to give the dimer 1 (0.100 g, 39%), m.p.
220-223oC 1H NMR (DMSO-d6) d 8.06 (s, 1H, 2-H imidazole), 7.41 (s, 1H, C=C), 7.04 (d, J=8.7Hz,
2H, m-Ph), 6.86 (d, J=8.7Hz, 2H, o-Ph), 5.26 (s, 2H, CH2Ar), 3.67 (s, 3H, OCH3); MS (FAB) m/z 491
(MH+). Anal. Calcd. for C24H22N6O6·1½ H2O: C, 55.70; H, 4.83; N, 16.24. Found C, 55.77; H, 4.75; N,
15.44.
Acknowledgement: This work was supported by a grant (# RO1 CA71079) from the National Institutes
of Health.

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Molecules 2000, 5
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