An efficient route to unsymmetrical bis(azolium) salts: CCC-NHC pincer ligand complex precursors

Article abstract of DOI:10.1016/j.tet.2017.02.020

The coupling of N-heterocyclic azoles (imidazoles, benzimidazoles, triazoles) to bromobenzenes (1,2-; 1,3-; or 1,4) in a step-wise, sequential manner was accomplished by manipulation of reaction time and stoichiometry, which provided straight-forward acce

Full text of DOI:10.1016/j.tet.2017.02.020

Accepted Manuscript
An efficient route to unsymmetrical bis(azolium) salts: CCC-NHC pincer ligand
complex precursors
Hannah K. Box, Tyler O. Howell, William E. Kennon, Griffin A. Burk, Henry U. Valle,
T. Keith Hollis
PII:
S0040-4020(17)30145-X
10.1016/j.tet.2017.02.020
TET 28461
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 September 2016
Revised Date: 1 February 2017
Accepted Date: 8 February 2017
Please cite this article as: Box HK, Howell TO, Kennon WE, Burk GA, Valle HU, Hollis TK, An efficient
route to unsymmetrical bis(azolium) salts: CCC-NHC pincer ligand complex precursors, Tetrahedron
(2017), doi: 10.1016/j.tet.2017.02.020.
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Graphical Abstract
An Efficient Route to Unsymmetrical Bis(azolium) Salts: CCC-NHC Pincer Ligand Complex Precursors
Hannah K. Box, Tyler O. Howell, William E. Kennon, Griffin A. Burk, Henry U. Valle, T. Keith Hollis*
Department of Chemistry, Mississippi State University, MS State, Mississippi 39762
khollis@chemistry.msstate.edu

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An Efficient Route to Unsymmetrical Bis(azolium) Salts: CCC-NHC Pincer Ligand Complex
Precursors
Hannah K. Box, Tyler O. Howell, William E. Kennon, Griffin A. Burk, Henry U. Valle, T. Keith
Hollis*
Department of Chemistry, Mississippi State University, MS State, Mississippi 39762
khollis@chemistry.msstate.edu
Abstract
The coupling of N-heterocyclic azoles (imidazoles, benzimidazoles, triazoles) to
bromobenzenes (1,2-; 1,3-; or 1,4) in a step-wise, sequential manner was accomplished by
manipulation of reaction time and stoichiometry, which provided straight-forward access to
unsymmetrical bis(azolium) salts in only three isolation steps from commercially-available
starting
materials.
Eight
mono(azole)
substituted
bromobenzenes,
four
mono(azolium)bromobenzene salts, twelve unsymmetrical bis(azole)benzenes, and fourteen
unsymmetrical bis(azolium) salts, which are precursors for pincer ligand complexes, are
reported.
Introduction
Heterocycles are of immense importance biologically and industrially. The
pharmaceutical industry has exploited this characteristic to the point where more than 90% of
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new drugs contain a heterocycle.1 Two important five-membered nitrogen heterocycles are
imidazole and triazole (azoles).
Azolium salts have found widespread use as ionic liquids2 and have shown biological
activity including antitumor,3 antibacterial,4 antimicrobial activities,5 and interaction with DNA.6
They have been used in the design of GalTs inhibitors,7 anion receptors,8 OLED materials,9 and as
ligand precursors for transition metal complexes, which commonly feature improved stability,
catalytic reactivity, and selectivity.10
Figure 1. Examples of azolium or azolylidene complexes in biological and materials applications
Carbenes have a long history as reactive intermediates in organic chemistry,11 and over
the last two decades many stable carbenes have been isolated11-12 and characterized, which has
provided chemists with new reagents.13 The many variants of N-heterocyclic carbenes (NHCs),
the most popular and widely applied version, have become common as ligands coordinated to
transition metals in the field of organometallic chemistry. Because of their strong σ-donating
ability, limited dissociation, and neutral charge, NHCs have exceeded phosphine ligands as a
means of generating more durable catalysts. As the synthetic utility of NHCs has developed;
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research has expanded from the typical imidazolium-derived NHCs to include triazole, abnormal
NHC (aNHC) ligands (C4 or C5 bound), acyclic and numerous other examples.14 Further
investigations, experimental and theoretical, have found aNHC ligands to be stronger donors
and in some cases their complexes were found to have greater reactivity than their C–2
coordinated equivalents.14c
While pincer ligands have found widespread use due to the ease of varying the lateral
donor groups, which provides an effective way to alter the properties of the chelated metal
center, the development of pincer ligand complexes featuring NHC moieties has suffered from a
lack of synthetic methodologies allowing for new and diverse architectures. In 2012 while
attempting to synthesize a normal CCC-NHC pincer complex, Braunstein reported that among a
mixture of products a pincer complex was isolated containing one "normally-coordinated" NHC
and one "abnormally-coordinated" NHC.15 We had begun development of an approach to
prepare unsymmetrical complexes strategically. The previously reported efficient one pot
synthesis of 1,3-bis(azole)benzenes employing a CuO-catalyzed aryl amination reaction of 1,3-
dibromobenzene followed by alkylation yielding symmetrical bis(azolium) salts provided
symmetrical CCC–NHC ligand precursors for the generation of transition metal complexes.16
Previously reported synthetic methodologies for the preparation of NHC pincer ligand
precursors does not directly allow for the expansion of architectural diversity, thus making a
methodology for the direct, efficient synthesis of unsymmetrical bis(azolium) salts a necessity.
Reported herein a synthetic methodology for preparing unsymmetrical salts. This methodology
allows for the architectural diversity of compounds featuring unsymmetrical diazoles to be
expanded and may prove useful in the synthesis of a variety of compounds for a diverse array of
applications.
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Results and Discussion
Synthesis of the unsymmetrical bis(azolium) salts began by reacting imidazole (2), 2-
methylimidazole (3), 2-phenylimidazole (4), 1,2,4-triazole (5), benzimidazole (6), or 5,6-
dimethylbenzimidazole (7) with dibromobenzene (1) to generate mono-azole arenes 8 - 15
(Scheme 1). While after 24 h no starting material was present in the synthesis of 8-9 and 11-15,
the sterically congested 2-phenylimidazole derivative, 10, required a longer reaction time of 72
h. Monitoring the preparation of 9 via thin layer chromatography (TLC) provided further insight
into the rate of conversion. The formation of 1,3-bis(2-methylimidazole)benzene was found to
become competitive with the formation of the mono-product 9 after 24 h. This information
aided in the acquisition of higher yields of the remaining compounds. All future syntheses of
mono(azole) substituted benzenes were worked up before product competition began. There
was a clear trend showing the effect of steric congestion at the imidazole C–2 position on yield
(8 > 9 > 10). A decrease in yield was noted when comparing an unsubstituted imidazole (8) to
benzimidazole derivatives (12 and 13). Due to potential biological investigations, the
methodology was extended to include examples of 1,2- and 1,4-substituted arenes.
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Scheme 1. Synthesis of mono(azole)benzenes
The potential applications for this methodology was extended by the alkylation of
several of the mono(azole)benzenes (Scheme 2). Excellent yields were achieved in the alkylation
of 8 or 11 with butyl halides (Cl, Br, and I). It was interesting to note that the iodide salt 16 was
obtained as a room temperature ionic liquid.
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Scheme 2. Alkylation of select mono(azole)benzenes.
Subsequent reactions for the synthesis of unsymmetrical bis(azole)benzenes were
conducted primarily with 8 or 11 with a triazole, benzimidazole, or imidazole (Scheme 3). All
products were obtained in moderate to good yield on a multigram scale. As in the mono(azole)
substituted benzene case, there was a similar trend in yield as seen between the substitution
patterns (1,4 > 1,3 > 1,2). The reaction of 8 and 11 with imidazole derivatives substituted at the
C–2 position yielded compounds featuring a potential for mixed NHC/aNHC ligand (20, 21, 25,
26, 27), when bound to a metal. Many of the compounds (22, 25-31) feature a 1,2,4-triazole as
one lateral donor group, providing potentially diverse donor properties.
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Scheme 3. Synthesis of unsymmetrical bis(azole)benzenes
.
X-ray quality crystals of compounds 20 were obtained by slow vapor diffusion of Et2O
into a CH2Cl2 solution. An ORTEP illustration of the molecular structure of compound 20 was
shown in Figure 2. In the absence of a transition metal, the structure is C1 symmetric. The C-2
substituted heterocyclic substituent was twisted out of the plane of the phenylene bridge (20:
C1-C2-N3-C11, 56.72(13)°) in the opposite direction of the unsubstituted imidazole substituent.
This twist was due to the steric bulk of the methyl substituent at C-2. The crystal of 20 was
found to be in a chiral space group (P212121) and contains only one enantiomer in the single
crystal by spontaneous chiral resolution. Presumably the mixture contains an equal number of
the alternate enantiomer.
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Figure 2. X-ray molecular structure of 20. Hydrogen atoms are omitted for clarity. Thermal
ellipsoids are shown at 50% probability.
The final step in the synthesis of these unsymmetrical precursors was the alkylation to
give bis(azolium) salts (Scheme 4). At a 1 g scale, all salts were isolated in high yield. As
mentioned before, one compound (21) was reacted with several butyl halides (Cl, Br, I) to give
33-35 with varying halogen counter ions. While all of the halide salts of 21 were isolated in high
yield, the iodide salt provided a 95% yield in 16 h whereas the bromide and chloride salts
required longer reaction times and higher temperatures. The isolation of the iodide derivative
was also much easier than that of the bromide and chloride due to its tendency to precipitate
out of the reaction mixture. All iodide salts were isolated as light yellow crystalline solids, which
are of sufficient quality for further elaboration. If removal of any remaining iodine was
necessary, the solid was dissolved in CH2Cl2 and washed with a saturated aqueous solution of
sodium thiosulfate to obtain a white solid with minimal loss in yield.
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Scheme 4. Synthesis of unsymmetrical bis(azolium) salts.
X-ray quality crystals of compound 37 were obtained by slow vapor diffusion of Et2O
into a CH2Cl2 solution. The ORTEP diagram in Figure 4 shows the salt twisted, minimizing the
steric interactions between arene and the heterocycles. The benzimidazolium donor group was
twisted out of the plane of the phenylene bridge (C1-C6-N3-C10, 40.8(2)°) and in opposite
direction from the imidazolium donor group (C1-C2-N1-C8, -33.2(3)°).
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Figure 4. X-ray molecular structure of 37. Hydrogen atoms are omitted for clarity. Thermal
ellipsoids are shown at 50% probability.
Conclusions
The reported methodology efficiently yielded unsymmetrical bis(azolium) salts in only
three isolation steps. Furthermore, it has been shown that this methodology was not limited to
imidazolium systems, but was applicable to triazolium and benzimidazolium systems. This
method will allow for greater diversity in the design of transition metal ligands, antibacterial
agents, ionic liquids, and many other systems exploiting azolium salts.
Acknowledgements
The National Science Foundation (OIA-1539035) and Mississippi State University
Department of Chemistry and the Office of Research and Economic Development and are
gratefully acknowledged for financial support. H.K.B. also acknowledges the Department of
Education (GAANN-P200A120066) for fellowship support.
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Supporting Information
Full experimental details, characterization data and selected spectral data for all new
compounds. CIF files for 20 (CCDC# 1501474), and 37 (CCDC# 1501475) are available or may be
accessed at Cambridge Crystallographic Data Centre.
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