Synthesis of tetrasubstituted 4,4′-biimidazoles

Article abstract of DOI:10.1021/ol3013414

Highly substituted 4,4′-biimidazoles were synthesized, in good to excellent yields, through a multicomponent imidazole ring synthesis by using imidazol-4-yl-ethane-1,2-diones as starting materials. The obtained compounds were preliminarily tested as chrom

Full text of DOI:10.1021/ol3013414

ORGANIC
LETTERS
Synthesis of Tetrasubstituted 4,40-
Biimidazoles
2012
Vol. 14, No. 13
3240–3243
Annamaria Martorana,† Andrea Pace,† Silvestre Buscemi,†,‡ and Antonio Palumbo
Piccionello*,†,‡
Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari (STEMBIO),
ꢀ
Universita degli Studi di Palermo, Viale delle Scienze - Parco d’Orleans II, Ed. 17,
I-90128 Palermo, Italy, and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Via
U. La Malfa, 153, 90146 Palermo, Italy
antonio.palumbopiccionello@unipa.it
Received March 15, 2012
ABSTRACT
Highly substituted 4,40-biimidazoles were synthesized, in good to excellent yields, through a multicomponent imidazole ring synthesis by using
imidazol-4-yl-ethane-1,2-diones as starting materials. The obtained compounds were preliminarily tested as chromogenic and fluorescent
sensors for heavy metals.
4,40-Biimidazoles have received less attention than more
studied 2,20-isomers, and little has been reported about
their synthesis and properties.1 For instance, the parent
compound 4,40-biimidazole was unknown until 1994.2
Only recently, 4,40-biimidazole and oligo(imidazole)s with
4,40-biimidazole moieties have been considered for their
potential applications as bidentate ligands capable of
multidimensional networks.3 Assembled metal complexes
of 4,40-biimidazole, exhibiting multidirectional hydrogen
bonds, were investigated in Ag, Cu, and Ni complexes,4
while triple-stranded metallo-helicates of quaterimidazole
with Mn(II) or Zn(II) cations gave a prototype of synthetic
electron spin qubits, useful in the field of Quantum Com-
puters (QCs).5 Moreover, charge-transfer salts of proto-
nated cations of 2,20-disubstituted-4,40-biimidazoles with
tetracyano-quinodimethane (TCNQ) wereinvestigatedfor
their semiconducting behavior.6
From a synthetic point of view, to date, obtaining 4,40-
biimidazoles is limited to symmetrically 2,20-disubstituted
compounds and synthetic protocols are based on cross-
coupling reactions with the use of metal catalysts.2,3 Con-
sidering the growing interest on these compounds, we
†
ꢀ
Universita degli Studi di Palermo.
‡ Istituto di Biofisica.
(1) Steel, P. J. Advances in Heterocyclic Chemistry; Academic:
New York, 1997; Vol. 67, pp 1ꢀ117.
(2) Cliff, M. D.; Pyne, S. G. Synthesis 1994, 7, 681–682.
(3) (a) Morita, Y.; Murata, T.; Yamada, S.; Tadokoro, M.; Ichimura,
A.; Nakasuji, K. J. Chem. Soc., Perkin Trans. 1 2002, 2598–2600. (b)
Zhang, W.; Landee, C. P.; Willett, R. D.; Turnbull, M. M. Tetrahedron
2003, 59, 6027–6034. (c) Morita, Y.; Murata, T.; Fukui, K.; Tadokoro,
M.; Sato, K.; Shiomi, D.; Takui, T.; Nakasuji, K. Chem. Lett. 2004, 33,
188–189. (d) Murata, T.; Morita, Y.; Fukui, K.; Yakiyama, Y.; Sato, K.;
Shiomi, D.; Takui, T.; Nakasuji, K. Cryst. Growth Des. 2006, 6, 1043–
1047.
(4) Murata, T.; Yakiyama, Y.; Nakasuji, K.; Morita, Y. Cryst.
Growth Des. 2010, 10, 4898–4905.
(5) Morita, Y.; Yakiyama, Y.; Nakazawa, S.; Murata, T.; Ise, T.;
Hashizume, D.; Shiomi, D.; Sato, K.; Kitagawa, M.; Nakasuji, K.;
Takui, T. J. Am. Chem. Soc. 2010, 132, 6944–6946.
(6) Murata, T.; Morita, Y.; Yakiyama, Y.; Yamamoto, Y.; Yamada,
S.; Nishimura, Y.; Nakasuji, K. Cryst. Growth Des. 2008, 8, 3058–3065.
r
10.1021/ol3013414
Published on Web 06/18/2012
2012 American Chemical Society

envisaged the use of imidazol-4-yl-ethane-1,2-diones 2 as
synthons for the obtainment of highly substituted 4,40-
biimidazoles 1, through classical multicomponent imida-
zole ring synthesis7 (Figure 1).
In turn, imines 49 were obtained, in two steps, from a
clay-catalyzed nonreductive transamination10 of 5-phenyl-
3-benzoyl-isoxazole 3 and condensation of the resulting
amine with the appropriate aldehyde in AcOH.
The so-obtained imidazolyl-diones 2 were reacted with
different (hetero)aromatic and alphatic aldehydes (2 equiv)
in the presence of ammonium acetate (2 equiv) in refluxing
acetic acid, giving 2,20,5,50-tetrasubtituted 4,40-bimidazoles
1 in good to excellent yields (Table 1).
Table 1. Results for the Synthesis of 4,40-Biimidazoles 1
Figure 1. Retrosynthetic analysis for the obtainment of com-
pounds 1.
Starting compounds 2 were easily obtained through a
novel one-pot tandem BoultonꢀKatritzky Rearrange-
ment (BKR)ꢀoxidation reaction of isoxazolyl-imine 4
under basic conditions. Alternatively, compounds 2 could
be obtained through a two-step procedure, from oxidation
with air, under basic conditions, of imidazoles 5, obtained
from the BKR8 of isoxazoles 4 (Scheme 1).9
time
(h)
yield
(%)a
entry
Ar
R
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2
4
4
1
2
1
3
6
5
3
2
2
4
4
2
5
1
2
1a 94
1b 82
1c 86
1d 92
1e 80
1f 88
1g 87
1h 92
1i 96
1j 65b
1k 96
1l 75
2
4-CH3OPhenyl
4-CH3Phenyl
4-NO2Phenyl
4-ClPhenyl
4-CF3Phenyl
3-CH3Phenyl
2-CH3Phenyl
2-Thienyl
2-Furanyl
4-Pyridyl
Et
3
4
5
6
7
Scheme 1. Synthesis of Imidazoles 2
8
9
10
11
12
13
14
15
16
17
18
n-Pr
1m 78
1n 83
1b 89
1o 71
1p 87
1f 83
Cyclohexyl
Ph
4-CH3OPhenyl
4-CH3OPhenyl
4-CH3OPhenyl
4-CF3Phenyl
4-CH3OPhenyl
4-NO2Phenyl
Ph
a Isolated yields. b 22% recovered 2a.
In all cases the reaction proceeded smoothly and al-
lowed, for the first time, the obtainment of asymmetrically
2,20-disubstituted compounds (see entries 2ꢀ15, 17, 18).
Interestingly, reaction times were dependent on the elec-
tronic demand of the aldehyde substituents. For example,
a comparison of entries 1, 2, and 6 confirms the expected
higher reactivity of electron-withdrawing substituted alde-
hydes. This finding is particularly useful for the choice of
optimal conditions in the preparation of compounds 1b
and 1f. The former is obtained, in comparable high yields,
through two alternative reagent combinationssummarized
by entries 2 and 15, the latter of which being more favor-
able in terms of reaction times.
(7) (a) Grimmett, M. R. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; Vol. 5. (b)
Grimmett, M. R. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: New York, 1996; Vol. 3.
(8) As recent examples of the BoultonꢀKatritzky rearrangement,
see: (a) Pace, A.; Pibiri, I.; Palumbo Piccionello, A.; Buscemi, S.;
Vivona, N.; Barone, G. J. Org. Chem. 2007, 72, 7656–7666. (b) Palumbo
Piccionello, A.; Pace, A.; Buscemi, S.; Vivona, N.; Pani, M. Tetrahedron
2008, 64, 4004–4010. (c) Pace, A.; Pierro, P. Org. Biomol. Chem. 2009, 7,
4337–4348. (d) Palumbo Piccionello, A.; Pace, A.; Buscemi, S.; Vivona,
N. Org. Lett. 2009, 11, 4018–4020. (e) D’Anna, F.; Frenna, V.; Zaira
Lanza, C.; Macaluso, G.; Marullo, S.; Spinelli, D.; Spisani, R.; Petrillo,
G. Tetrahedron 2010, 66, 5442–5450. (f) D’Anna, F.; Frenna, V.; Ghelfi,
F.; Marullo, S.; Spinelli, D. J. Org. Chem. 2011, 76, 2672–2679.
(9) Martorana, A.; Palumbo Piccionello, A.; Buscemi, S.; Giorgi, G.;
Pace, A. Org. Biomol. Chem. 2011, 9, 491–496.
(10) Palumbo Piccionello, A.; Pace, A.; Buscemi, S.; Vivona, N. Org.
Lett. 2010, 12, 3491–3493.
Org. Lett., Vol. 14, No. 13, 2012
3241

The UV/vis spectrum of 1a recorded in acetonitrile
shows a strong absorption band centered at 305 nm (ε =
24500 Mꢀ1 cmꢀ1) with a shoulder around 280 nm (Figure 2).
From the UV/vis spectra of 1a(10 μM) in acetonitrile upon
addition of 10 equiv of various perchlorate salts of metal
Scheme 2. Synthesis of Terimidazole 7
ions, such as Hg2þ, Pb2þ, Cu2þ, Zn2þ, Ca2þ, Co2þ, Mg2þ
,
Naþ, Kþ, and Agþ, a metal-dependent behavior was
observed (Figure 1, and Supporting Information (SI)).
With Ca2þ, Mg2þ, Naþ, Kþ, and Agþ, no relevant spectral
changes were observed (see SI). With other heavy
metals a hypochromic shift was observed; particularly,
in the presence of Pb2þ absorption the maximum was
broadened and blue-shifted to 300 nm, while, with
Hg2þ, Zn2þ, and Co2þ, absorption spectra were char-
acterized by the presence of two maxima (around 300
and 255 nm) (Figure 2). More interestingly, in the
presence of Cu2þ, an absorption maximum centered
at 293 nm was accompanied by a band in the visible
region (λmax= 490 nm), responsible for the pale orange
coloration of the solution (Figure 2, lower). The latter
feature allows visual detection of Cu2þ under ambient
light, configuring compound 1a as a potential sensor
for the naked-eye detection of copper ions. Similar
results were obtained with compounds 1b,f, bearing
an electron-donating and -withdrawing group on the
2-aryl moiety, respectively (see SI).
Similar considerations pointed out entry 6 as an optimal
reagent combination for obtaining 1f. In order to expand
the potential application of compounds 2 to the synthesis
of oligo-imidazoles, we also tested the reactivity of repre-
sentative compound 2a in the presence of imidazolyl-
aldehyde 6,9 under the same conditions reported above,
allowing the obtainment of the pentaphenyl-substituted
4,40-20,400-terimidazole 7 in good yield (Scheme 2). Con-
sidering the great amount of interest in 4,40-biimidazoles as
a ligand for metal complexes,4,5 we preliminarily studied
representative compounds 1a,b,f and their photophysical
behavior in the presence of various metal ions, such as
Hg2þ, Pb2þ, Cu2þ, Zn2þ, Ca2þ, Co2þ, Mg2þ, Naþ, Kþ,
and Agþ, through UV/vis and fluorescence spectroscopy.
Figure 2. UV/visꢀabsorption spectra of 1a (10 μM) and upon
addition of ClO4 salts of Hg2þ, Pb2þ, Cu2þ, Zn2þ, and Co2þ
(10 equiv, each) in CH3CN (upper). Visual appearance of solutions
of 1a with the above metals, under ambient light (lower).
Figure 3. Fluorescence spectra of 1a (10 μM) and upon addition of
ClO4ꢀ salts of Hg2þ, Pb2þ, Cu2þ, Zn2þ, and Co2þ (10 equiv, each)
in CH3CN with an excitation at 305 nm (upper). Visual appearance
of solutions of 1a with the above metals, under UV-light (lower).
3242
Org. Lett., Vol. 14, No. 13, 2012

The fluorescence emission spectrum of compound 1a in
CH3CN (λex = 305 nm) showed an unstructured band
centered at 429 nm (Figure 3). On the other hand, by
measuring the fluorescence emission spectra of 1a (10 μM
in CH3CN, λex = 305 nm) in the presence of 10 equiv of
tested metal salts, again metal-dependent behavior was
observed (Figure 3, and SI). As previously observed from
UV/vis experiments, with Ca2þ, Mg2þ, Naþ, Kþ, and Agþ,
no relevant spectral changes were observed (see SI). With
other heavy metals, fluorescence was quenched in all the
cases with respect to 1a; in particular, fluorescence quench-
ingwas partial, withemission maximaslightly blue-shifted,
in the presence of Zn2þ (λem = 407 nm), Cu2þ (λem
=
421 nm), and Co2þ (λem = 421 nm), while with Hg2þ com-
plete fluorescence quenching was reached under these con-
ditions (Figure 3). More interestingly, in the presence of
Pb2þ, fluorescence emission was broadened and red-
shifted with respect to 1a (λem = 501 nm), giving the
solution a greenish coloration detectable under UV-light
(Figure 3, lower). This fluorescence change allows naked-
eye detection of Pb2þ, configuring compound 1a as a
potential fluorescent sensor for leadcations. Similar results
were obtained with compounds 1b,f (see SI). Moreover, in
order to evaluate the practical applicability of the sensor in
aqueous media, the sensing ability of compound 1a was
tested in H2O/CH3CN mixtures (20%v/v), in the presence
of Cu2þ and Pb2þ, at pH = 7 and 13. Under neutral
conditions, the sensing ability was lost, particularly for the
UV/vis detection of copper ions (see SI). In contrast, under
basic conditions, compound 1a continues to show a band
in the visible region (λmax = 440 nm), maintaining the
ability to detect Cu2þ ions (Figure 4, upper). More inter-
estingly, emission spectra underbasic conditions evidenced
a red shift of the emission of compound1a(λem = 514 nm).
The fluorescence was quenched in the presence of lead
cations and unexpectedly enhanced in the presence of
copper ions (Figure 4, lower). In general, the observed
metal-dependent behavior, from UV and fluorescence
experiments, suggests the use of compounds 1 as multi-
modal sensors for the discrimination of different heavy
metals.
Figure 4. UV/vis absorption spectra (upper) and fluorescence spectra
(lower) of 1a (10 μM) and upon addition of ClO4ꢀ salts of Pb2þ and
Cu2þ (10 equiv, each) in H2O/CH3CN (20% v/v, pH = 13).
compound 1a, the potential application of 4,40-biimida-
zoles as multimodal sensors for heavy metal cations has
been envisaged.
Acknowledgment. Financial support through the Uni-
versity of Palermo is gratefully acknowledged. 400 MHz
NMR experimental data were provided by Centro Grandi
ꢀ
Apparecchiature - UniNetLab - Universita di Palermo
funded by POR Sicilia 2000-2006, Misura 3.15 Quota
Regionale.
In conclusion, a new method for the synthesis of 4,40-
biimidazoles 1 was achieved by using classical multicom-
ponent imidazole ring synthesis. The proposed methodol-
ogy allowed obtaining, for the first time, tetrasubstituted
substrates and the linkage of different moieties at the
2,20-positions, producing asymmetrically substituted com-
pounds. This synthetic strategy opens the way to obtaining
new compounds with potential use in the material science
field. In particular, from preliminary experiments with
Supporting Information Available. Synthetic details,
13
characterization data, 1Hꢀ C NMR spectra of new
compounds, UV/vis and fluorescence spectra. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3243