Versatile reagents: ferrocenyl azolium compounds as auxiliary ligands for the Heck reaction and potential antifungal agents

Article abstract of DOI:10.1016/j.tetlet.2006.11.179

We report the synthesis, catalytic, and biological properties of new bridged and cyclic ferrocenyl azolium compounds.

Full text of DOI:10.1016/j.tetlet.2006.11.179

Tetrahedron Letters 48 (2007) 1017–1021
Versatile reagents: ferrocenyl azolium compounds as auxiliary
ligands for the Heck reaction and potential antifungal agents
Andrea Dallas,a Henry Kuhtz,a Alan Farrell,b Brid Quiltyb and Kieran Nolana,c,
*
aSchool of Chemical Sciences, Dublin City University, Glasnevin D9, Dublin, Ireland
bNational Center for Sensor Research, School of Biotechnology, Dublin City University, Glasnevin D9, Dublin, Ireland
cNational Institute of Cellular Biotechnology, School of Biotechnology, Dublin City University, Glasnevin D9, Dublin, Ireland
Received 22 September 2006; revised 17 November 2006; accepted 30 November 2006
Available online 22 December 2006
Abstract—We report the synthesis, catalytic, and biological properties of new bridged and cyclic ferrocenyl azolium compounds.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The azole system arguably represents one of the most
ubiquitous classes of heterocyclic species. Their many
wide-ranging applications vary from medicinal use as
pharmaceuticals to being some of the building blocks
necessary for life. They are also used in numerous more
technical applications, such as electrolytes, components
in supramolecular structures, and in polymers.1 One
particular area in which the application of azoles, in par-
ticular imidazoles, has been expanding is that of transi-
tion-metal catalysis, as imidazolium salts are becoming
increasingly recognized as stable alternatives to triaryl-
phosphines as auxiliary ligands.2
X
N
N
R
N
N
Fe
Fe
R=CH3, X=I
Im
1
Im
Bzim
3
4
Bzim 2
+
N
I
N
Fe
Fe
Studies by us into the application and derivatization of
azolium salts focused on their ability to act as potential
anion receptors3 and their biological activity.4 The ionic
azolium structure has been introduced into ferrocene,
tripodal, and cyclophane imidazole systems, which have
then been evaluated as anion receptors and antimicro-
bial agents. Previously prepared compounds include
the ferrocenyl azoles 1 and 2 and ferrocenyl azolium
salts, for example, 3–6 (Im = imidazolium, Bzim = benz-
imidazolium).3,4
Im
5
Bzim 6
of a new generation of ferrocenyl azolium systems 7 and
8 containing two azolium and four centers, respectively.
Such compounds could be potentially used as both car-
bene ligands and anion receptors. Compounds 7 and 8
contain a cavity, which we believe would aid the pre-
organization of the imidazolium groups to enhance
anion binding selectivity.5 The acyclic ferrocenyl
azolium system may have the potential to form a cleft
with a specific geometry and topology to offer greater
selectivity for anion recognition.
Herein, we report on the synthesis of a new series of acy-
clic and cyclic ferrocenyl azole/azolium compounds and
their application as auxiliary ligands in transition-metal
catalysis, anion receptors, and bioactive agents. Follow-
ing our previous studies, we focused on the preparation
Outlined in Scheme 1 is the synthetic strategy employed
to prepare 7. A facile way of introducing two azolium
centers was to link two monosubstituted ferrocenyl
*
Corresponding author. Tel.: +353 1 7005913; e-mail: kieran.nolan@
dcu.ie
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.179

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A. Dallas et al. / Tetrahedron Letters 48 (2007) 1017–1021
The preparation of the macrocyclic structure 8 with
2 X
four azolium centers linking two ferrocene units was
successfully carried out by using the same synthetic
route as that for the preparation of the linear bridged
bisazolium ferrocenyl salts 10 and 12 (Scheme 2). 1,4-
Diiodobutane was reacted with 1,10-bis(1-methylbenz-
imidazole)ferrocene 13, obtained from the reaction of
benzimidazole with a disubstituted ferrocenyl quater-
nary ammonium salt,6 to yield the intermediate benz-
imidazolium diiodide 14. Reaction of this compound
with a further aliquot of 13 gave the final macrocycle
15 in 60% yield.
+
+
N
N
N
N
(CH2)n
Fe
Fe
7
4 X
N
N
+
N
N
(CH2)n
(CH2)n
+
Fe
Fe
+
+
N
N
N
N
Both the intermediate 13 and the product 15 were insol-
uble in most solvents, being only sparingly soluble in
DMSO and dimethylformamide (DMF), so further
purification by column chromatography or crystalliza-
tion was not possible. However, 15 could be reprecipi-
tated from DMF/CHCl3 and was characterized by
NMR spectroscopy and elemental analysis (see Supple-
mentary data for details).
8
azole systems3 to create a [1-(1-ferrocenylmethyl)-3-
alkylazolium]-3-(1-ferrocenylmethyl) azolium salt with
a four-atom spacer as the linker group. Precursors 1
and 2 were treated with 1,4-diidobutane to obtain the
corresponding azolium iodide salt. A further aliquot of
the ferrocenyl azole yielded the bridged bisazolium ferro-
cenyl iodide salt systems 10 and 12. In this way, both the
imidazolium and benzimidazolium analogues were
prepared.
Modeling experiments show that 15 may exist as differ-
ent rotameric isomers. There are several possible rota-
tomers of this compound, in which the contortion of
the benzimidazolium moieties and the butyl spacer
groups leads to different cavity shapes. MM+ and
PM3 optimizations predicted two different projected
geometries (Fig. 1) for 8, and a space-filling computer
modeling projection shows four possible rotatomers
The syntheses were facile and moderately high yielding;
for the imidazolium derivatives, the overall yields were
50% for 10 and 55% for 12. However, it should be noted
that purification of these compounds proved to be more
difficult than for the intermediate monosubstituted ferro-
cenyl azolium salts. Both 10 and 12 proved to be spar-
ingly soluble in dimethyl sulfoxide (DMSO) and
insoluble in dichloromethane, chloroform, methanol,
and acetonitrile. Thus, they could not be purified by
column chromatography. However, they were charac-
terized and shown to be sufficiently pure by NMR
spectroscopic and elemental analysis.
1
(Fig. 2). We believe the poorly resolved H NMR spec-
trum of 12 confirms the presence of rotational isomers
(see the Supplementary data).
Further derivatives of these compounds were prepared.
Reaction of 13 with methyl iodide or n-butyl iodide pro-
vided bisbenzimidazolium salts 16 and 17 in yields of
60% and 75%, respectively (Scheme 3). Compound 18
was prepared by the treatment of 1,10-ferrocenyldimeth-
anol with CDI7 in 71% yield (Scheme 4).
I
N
N
MeCN
I
+
N
N
Fe
(CH2)4I2
Fe
Im
Bzim
1
2
Im
9
Bimz 11
1/2
MeCN
2 I
+
+
N
N
N
N
(CH2)4
Fe
Fe
Im
10
Bimz 12
Scheme 1. The synthetic strategy to introduce two azolium centers.

A. Dallas et al. / Tetrahedron Letters 48 (2007) 1017–1021
1019
+
N
N
N
(CH3)3 I
NH
N
Fe
Fe
+
N
N
N
(CH3)3 I
MeCN,
K2CO3
13
I2(CH2)4
MeCN
4 I
2 I
I
I
N
N
N
+
N
+
N
N
N
N
N
(CH2)4
(CH2)4
13
+
Fe
Fe
Fe
+
N
+
MeCN
+
N
N
14
15
Scheme 2. The synthetic strategy to introduce four azolium centers for the preparation of cyclophane 15.
˚
Figure 1. (a) MM+ optimization of a model of the structure of 8. The Fe atoms are removed, showing the Cp rings to be constrained 3.32 A apart.
˚
The cavity is asymmetric; ca. 5.5 · 8.5 A (aspect ratio 1:1.55). (b) PM3 optimization of 8 (starting at MM+ opt geometry; using no constraints)
˚
showing an asymmetric cavity; ca. 8.5 · 10.5 A (aspect ratio 1:1.24).
To investigate the catalytic properties of the ferrocenyl
azolium salts, a simple Heck reaction system was chosen
and a range of salts were employed as auxiliary ligands;
a mixture of the monosubstituted and disubstituted imid-
azolium/benzimidazolium salts was used. As shown
previously, preparation of the carbene metal complex
beforehand was unnecessary.8 Therefore, the active
complex should form in situ from an azolium salt/palla-
dium system. We tested our new compounds in the reac-
tion of ethyl acrylate with 4-nitrobromobenzene at
120 ꢁC under nitrogen for 24 h with sodium acetate as
the base (1.25 equiv), DMF as the solvent, and
Pd(OAc)2 (1 mol %) as the catalyst precursor (Table 1).
These compounds successfully aided catalysis of this
Heck reaction with the product being formed in very
high yields in some cases. This result adds to the grow-
ing, albeit still small, evidence of benzimidazolium salts
acting as effective ligands in such reactions.9 Therefore,
there is considerable potential in the application of these
compounds in transition-metal catalysis. Further deriv-
atization should build on this performance so that sub-
strate scope and increased yields can be obtained and so
that they can be applied to other transition-metal catal-
ysis reactions.
The performance of 15 as an anion receptor was evalu-
1
ated by H NMR titration experiments in DMSO-d6 by
monitoring the change in chemical shift of the H-2 pro-
ton of the imidazolium groups. We were limited to
DMSO as the solvent due to the poor solubility of 15
in organic solvents. Preliminary results indicated that
15 binds with acetate, chloride and fluoride, however,
the chemical shift continued to increase even after the
addition of 5 M equiv of anion. These results indicate
that 15 does not behave as a typical receptor.10
Figure 2. Computer modeling projections of the four predicted
rotamers of 8 using PM3 optimization.

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A. Dallas et al. / Tetrahedron Letters 48 (2007) 1017–1021
2 I
+
N
N
N
N
R
RI
Fe
Fe
+
N
N
R
N
N
13
R
CH3 16
C4H9 17
Scheme 3. Preparation of ferrocenyl bisbenzimidazolium salts through alkylation.
O
for bioactivity. Perhaps the ferrocene groups are playing
an electrochemical role, as has been observed with ferro-
cenyl antimalarials.4 To better understand the bioactiv-
ity of both 5 and 12, a series of structural modifications
are currently being developed from which a new phar-
macophore can be generated.
N
N
N
N
OH
OH
MeCN
+
N
N
N
N
Fe
Fe
18
Scheme 4. The preparation of ferrocenyl bisimidazole analogue 18.
In summary, a series of acyclic and cyclic linked ferro-
cene and azolium units have been prepared that show
much promise in transition-metal catalysis and as anti-
fungal agents. Further derivatization of these structures
would aid the development of highly efficient reagents.
Table 1. The use of ferrocenyl azolium salts as the auxiliary ligand in
the Heck reaction
CO2Et
DMF, 120 oC
Br
N2, NaOAc
Acknowledgements
CO2Et
+
We wish to thank The Irish Research Council for Sci-
ence, Engineering and Technology for financial support
(Grant No. SC/02/331). We also wish to thank Dr. Der-
mot Brougham for his help with the molecular modeling
studies.
Pd(OAc)2, ligand
NO2
NO2
Compound
Yield (%)
3
74
89
91
94
85
36
78
91
20
4
5
10
Supplementary data
12
15
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/
j.tetlet.2006.11.179.
16
17
No auxiliary ligand
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