Sterically Hindered N-Heterocyclic Salts Utilized as Antimicrobial Agents

Article abstract of DOI:10.1002/jhet.2992

By the adoption of annulated ring systems for their steric bulkiness, a new series of symmetric N-heterocyclic imidazolium and perimidium salts were synthesized. Also, corresponding asymmetric ferrocenyl N-functionalized series were prepared as salts. All

Full text of DOI:10.1002/jhet.2992

Month 2017 Sterically Hindered N-Heterocyclic Salts Utilized as Antimicrobial Agents
*
Slindile N. P. Ndlovu, Halliru Ibrahim, and Muhammad D. Bala
School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X54001, Durban 4000, South Africa
*
E-mail: bala@ukzn.ac.za
Received April 19, 2017
DOI 10.1002/jhet.2992
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
By the adoption of annulated ring systems for their steric bulkiness, a new series of symmetric
N-heterocyclic imidazolium and perimidium salts were synthesized. Also, corresponding asymmetric
ferrocenyl N-functionalized series were prepared as salts. All the reported salts were fully characterized.
The reported X-ray structure of 4,5-diphenyl-1,3-dimethyl-1H-imidazol-3-ium iodide (2a) shows that it
crystallized in the orthorhombic space group P212121. Low to moderate antimicrobial activities were
observed with both sets of salts against important clinical isolates of Staphylococcus aureus, Bacillus
subtilis, and Enterococcus faecalis and Escherichia coli, Pseudomonas aeruginosa, and Salmonella
enterica. The results were benchmarked against meropenem. Both 1,3-propyl-1H-phenanthro[9,10-d]
imidazol-3-ium iodide (3b) and 1-ferrocenyl-3-propyl-1H-perimidin-3-ium iodide (9b) showed high
antimicrobial activities against all tested Gram-positive bacterial strains, with minimum inhibitory
concentration values ranging from 8 to 4 μg/mL (meropenem = 0.5–0.125 μg/mL), while all the salts showed
little or no activity against Gram-negative bacterial strains. In general, the asymmetric ferrocenyl-containing
salts exhibited higher activities than the symmetric ones.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
of research spheres that include catalysis, fine chemical
synthesis, and biological studies [1–4]. A study by Tapu
et al. [5] has shown that in most applications of
imidazolium-based compounds, the stability of the cation
is of utmost importance and is considerably influenced by
the nature of the C4,5 substituents on the imidazolium
ring. With bulky aromatic and annulated groups as 4,5
Because of the ability to easily modify the properties of
the cation, anion, and N-substituents, which allows for
great flexibility in the design and fine-tuning of their
physical, chemical, and biological properties, (imid)
azolium salts have received much interest from a variety
© 2017 Wiley Periodicals, Inc.

S. N. P. Ndlovu, H. Ibrahim, and M. D. Bala
Vol 000
substituents, their rigidity and aromaticity help in
modulating geometrical constraints, while the conjugation
of electron density increases donation of electrons to the
N atoms, leading to improved stability of the imidazolium
ring system. In addition, N-substituent modifications and
functionalization with ferrocenyl groups has been studied
to investigate the effects of the ferrocenyl moiety on
steric and electronic properties. Results obtained have
shown unique influences that include steric bulking,
electronic stabilization, and electrochemical reversibility
of the ferrocene/ferrocenium redox couple on such
products [6]. Hence, a variety of ferrocenylimidazolium
salts have been designed and isolated as symmetric and
asymmetric salts [7,8], which were used as antitumor [9],
antifungal [10], and antimalarial [11] agents. More
recently, Özbek et al. [12] have reported on a series of N,
N-bis(ferrocenylmethyl)imidazolium salts with a wide
range of antimicrobial activities for which they
demonstrated a structure/activity trend that linked the
chemical properties of the salts to the inhibition of
specific bacterial strains. Ultimately, the well-established
biological activity of multisubstituted imidazoles,
combined with added advantages of the incorporation of
modulating 4,5-aryl substituents in their design [13] and
coupled with the stability and nontoxicity of ferrocenium
salts, has contributed to the growing interest in the
development of new derivatives of imidazolium and
especially ferrocenylimidazolium salts. These derivatives
of (imid)azolium salts and compounds with triazole or
quinoline moieties are now widely accepted as potential
antibiotic, antimicrobial, and antitumor agents [9]. Hence,
we report on the prospects of sterically hindered 4,5-aryl-
substituted and ferrocenyl-functionalized imidazolium
salts as antimicrobial agents against important clinically
active bacterial strains, aimed at developing new
pharmacologically active biocides. This is because, to the
best of our knowledge, well-planned systematic studies
on the synthesis and biological activities of such salts are
still relevant but rare.
[16] and imidazolium 3 [5] and perimidinium 4 [17]
salts. Perimidine was added to the study in order to
observe the influence of ring expansion on the
antibacterial properties of the salts [13]. We observed
moderate to excellent isolated yields, which showed
direct correlation to the steric rigidity and steric
hindrance of the 4,5-aryl substituents. Hence, the
phenanthrene-substituted compound 3 was isolated in an
excellent 94% yield, while only a modest yield of 63%
was recorded for compound 2, substituted with the more
flexible diphenyl group. These adopted techniques are
highly efficient at reasonable reaction times based on
readily available starting materials, and the product yields
are moderate to high. We also note that all the
spectroscopic and analytical data collected closely match
those already reported for 1–4. The synthetic pathway
then proceeded in two different fronts to produce the two
sets of salts, that is, the symmetric dialkylated (1a–4b)
and asymmetric (6a–9b) ferrocenyl-functionalized
analogues (Scheme 1).
Symmetric 1,3-dialkylated iodide salts.
The more
popular and viable routes for the alkylation and arylation
of imidazoles to quaternary imidazolium salts include
their reaction with alkyl/aryl halides, aryl boronic acids,
or diaryliodonium salts [18,19]. In this section of the
study, we adopted the easiest of these methods to prepare
the six symmetric imidazolium (1a–3b) and two
perimidinium (4a and 4b) salts by quaternization with
alkyl iodides of which only the two benzimidazolium-
based salts (1a and 1b) [15] and 2a [20] were previously
reported (Scheme 1). At the end of each reaction, we
1
checked for salt formation by H-NMR as indicated by
quaternization of the N atoms. Disappearance of the
downfield broad singlet resonance peak of the N protons
(∼12.5 ppm) and the simultaneous appearance of new
upfield peak(s) of the N,N-dialkyl substituents serve as
confirmation of salt formation.
In the spectra of the 1,3-dimethyl salts (1a, 2a, 3a, and
4a), the singlet peak representing the six (2 × CH3)
equivalent methyl protons appeared relatively downfield
(4.50–3.50 ppm) owing to the quaternized N atom they
are directly bonded to, while in the spectra of
corresponding 1,3-dipropyl counterparts (1b, 2b, 3b,
and 4b), the three peaks 0.90–1.01 ppm (t, 6H),
1.60–2.05 ppm (m, 4H), and 3.88–4.85 ppm (t, 4H) are
respectively assigned to equivalent protons bound to
the methyl and two different methylene carbons of
the propyl N-substituents. All the salts also showed
a signal for the characteristic imidazolium (C2) proton
that resonates downfield around 9–11 ppm [21]. In
general, sharp melting points and the clean NMR spectra
(see supporting information) recorded for all the salts
indicated their high purity, which is also further
supported by high-resolution mass spectrometry (HRMS)
RESULTS AND DISCUSSION
This study was planned in such a way that two series of
salts (Scheme 1) were prepared based on a common series
of 4,5-aryl-substituted imidazole (1–3) and perimidine (4)
precursors. Traditionally, the synthesis of imidazole and
its derivative salts revolved around the classical
multifunctional one-pot method [14]. Although, for bulky
and sterically hindered versions of imidazole, the ring
cyclization step in their synthesis tends to be a limitation
of the method. Hence, we adopted a series of multistep
reaction procedures reported for the synthesis of the
sterically hindered imidazolium 1 [15], imidazolium 2
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Sterically Hindered N-heterocyclic Salts Utilized As Antimicrobial Agents
Scheme 1. General synthetic routes to the symmetric and ferrocenyl alkyl-functionalized salts. [Color figure can be viewed at wileyonlinelibrary.com]
results, with experimentally determined m/z values in close
agreement within 99.5% of calculated ones.
For the preparation of the salts (6a–9b), we applied a
solvent-free technique we reported earlier, which is based
on the neat alkylation of neutral imidazoles, in this
instance 6–9 by each of the two alkyl halides [24].
Although no products were isolated in the attempted
synthesis of salts 7b, 8a, and 8b, which we believe is
mainly due to steric constraints associated with, especially,
the bulkier 4,5-phenanthro derivatives (8a and 8b) and
added flexibility of propyl iodide (7b), the yields were low
Asymmetric ferrocenyl-functionalized iodide salts. The
source of the ferrocenyl moiety N,N,N-trimethyl-1-
ferrocenylmethanaminium iodide (5) was easily prepared
in excellent yield by methods reported by Ripert et al.
[22]. Isolated 5 was successfully coupled to imidazoles
1–4 via the procedure of Howarth et al. [23], to
successfully yield the desired neutral ferrocenylmethyl-
4,5-arylimidazoles 6–9, which were positively identified
by spectroscopic analysis. The 1H-NMR data were all
standard with characteristic proton signals ascribable to
imidazole (C2-H), methylene linker (CH2), and the
ferrocenyl (C5H5) moieties confirming isolation of the N-
functionalized ferrocenylmethyl-4,5-arylimidazoles. The
IR spectra of all the products showed standard stretching
frequencies of the key functional groups with the
diagnostic absorption band around 1100 cmÀ1 assigned to
the ferrocenyl moiety.
1
to moderate, and H-NMR was used to confirm identities
1
of the new compounds. When the H-NMR data of the
salts (6a–9b) were compared to those of the starting
neutral compounds (6–9), the resonance positions of the
characteristic C2-H (Scheme 1) of the salts showed
significant far downfield shifts. This is usually accepted as
a clear confirmation of quaternization of an imidazolium
moiety and its acquisition of a formal positive charge,
hence the shift downfield [21]. Also, identities of the
ferrocenyl salts were further confirmed by the appearance
Journal of Heterocyclic Chemistry
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S. N. P. Ndlovu, H. Ibrahim, and M. D. Bala
Vol 000
of new peaks of the 3-alkyl substituents. Hence, for the
N-methyl-substituted salts, a singlet peak was observed
around 3.5–4.0 ppm, which integrated to the expected 3H,
while the N-propyl substituent gave rise to the expected
three peaks that corresponded to the two different
methylene protons [4.15–5.05 ppm (2H, t) and
3.93–3.05 ppm (2H, m)] and the terminal methyl proton
(3H, t) with expected coupling and splitting patterns.
High-resolution mass spectrometry analysis confirmed
successful isolation of the 1-ferrocenylmethyl-3-
methylimidazolium iodide salts. The calculated and found
m/z values of the parent fragment of the salts are in
agreement. The data showed fragmentation peaks due to
the presence of the ferrocenyl group in the form of the
stable (ferrocenylmethyl)+, which was observed as the
base peak ( 199.0292) for all the salts.
Lima and Lovely [20] have reported the spectroscopic
data of 2a, as part of a broader study on method develop-
ment for the oxidation of imidazolium salts. However, its
full structural analysis by single-crystal X-ray diffraction
studies is reported here for the first time. The X-ray diffrac-
tion data show that 2a crystallized in the orthorhombic
crystal system (P212121 space group) with four molecules
in the asymmetric unit. An ORTEP molecular representa-
tion shown in Figure 1 highlights the symmetric distribu-
tion of the phenyl rings (C4,5-substituents) and the
1,3-methyl substituents around an essentially planar
imidazolium core. The phenyl substituents are also planar
as indicated by bond angles that average 120° [118.6(9)–
121.0(9)°], which compare well with those of reported
compounds containing planar phenyl rings. Also, key
indices of bond lengths and angles are all within ranges re-
ported for related imidazolium-based compounds [25–28].
We also isolated and determined the solid-state structure
of 6a by single-crystal X-ray diffraction. All the indices are
similar to those reported by Bildstein and coworkers [29].
The data confirmed the asymmetry imposed on the
molecules by the introduction of the ferrocenyl moiety in
these salts.
Antimicrobial activity. Scarcity of new molecules that
exhibit acceptable antibacterial activity and resistance to
existing antimicrobial agents by a growing list of bacterial
strains are some of the problems currently plaguing studies
in drug development and pharmacology. However, it is
well established that most molecules with proven
antibacterial potency contain at least one heterocyclic
moiety of which azoles and azolium derivatives are more
commonly encountered as active analgesics, anticancer,
antifungal,
and
anti-human-immunodeficiency-virus
molecules [9b,9c,13,30]. In particular, the structural
morphology of imidazole is similar to that of natural
nucleotides, which facilitate interaction with biopolymers
in living systems, thus resulting in extensive biological
activities for imidazole/imidazolium-based compounds,
either independently or complexed to metals as
N-heterocyclic carbene moieties. As compared with
conventional antimicrobial agents, it is much easier to
fine-tune and control the hydrophobic/hydrophilic
properties of imidazole/imidazolium-based compounds by
the modification of the backbone C4,5 functionalities and
the wingtip N,N-substituents [31]. Based on these facts,
we hypothesize that the imidazolium salts reported herein
Figure 1. ORTEP diagram of 2a with thermal ellipsoids drawn at the 50% probability level. Selected interatomic distances (Å) and angles (°): C(1)–N(1)
1.476(14); C(2)–N(2) 1.460(12); C(3)–N(1) 1.334(12); C(3)–H(3) 0.9500; N(1)–C(3)–N(2) 107.7(9); C(3)–N(1)–C(4) 109.2(8); C(3)–N(1)–C(1)
124.4(8); C(3)–N(2)–C(2) 123.0(9). [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Sterically Hindered N-heterocyclic Salts Utilized As Antimicrobial Agents
will serve to extend the scope of development of new
pharmacologically active medicinal compounds. Hence,
the two series of compounds, that is, the 1,3-dialkyl-
4,5-arylimidazolium iodides (1a–4b) and 1-ferrocenyl-3-
alkyl-4,5-arylimidazolium iodides (6a–9b), were tested for
antimicrobial activity against important clinically isolated
bacterial strains. Minimum inhibitory concentration (MIC)
studies were performed in triplicate, and averages of
obtained values (Table 1) are reported. The results
obtained were analyzed, referenced to the efficacy of a
well-established antibiotic (meropenem) as the control
drug. All tests were conducted under similar conditions.
Analysis of the data is first based on the symmetric set of
salts and then the ferrocenyl-functionalized counterparts.
From Table 1, it is clear that in general, the propyl-
alkylated symmetric salts 2b–4b showed some degree of
activity against all the bacterial strains tested, while
compounds 1a and 1b showed no inhibitory effects at all.
With ionized compounds such as those reported herein, it
is thought that inhibition of bacterial growth might be due
to attraction of the ionic charges of the imidazolium salt to
the bacterial membrane, which contributes to cell
penetration and damage leading to the death of the
bacteria [32]. Imidazolium iodides 3a–3b showed the
highest growth inhibitory concentrations against all Gram-
positive bacteria and Escherichia coli. An exception was
observed with Enterococcus faecalis, a nonmotile, Gram-
positive, spherical bacteria, which showed no inhibitory
response to compounds 1a–4b. This is not quite
unexpected as the microbe has high ability to catabolize
salt and has shown good survival tendency in strongly
alkaline pH conditions [33]. However, their activity
against Gram-negative bacterial strains is generally poor
and limited. The increased difficulty encountered by
biocides in attacking Gram-negative bacteria has been
observed to be due to the microbial structural morphology
that comprises a difficult-to-penetrate double-membrane
(lipopolysaccharide) layer, alongside porins that act to
limit negative interactions of the cytoplasm with potential
antimicrobial agents [34]. Studies have shown that
because the bacterial cell dry mass is made up of around
50% carbon, the degree by which an antimicrobial agent
can partition into the lipid bilayer of the bacterial
membrane is controlled by its hydrophobicity [35,36].
Therefore, a significant increase in the hydrophobicity of
antimicrobial agents translates to more effective
penetration into bacterial cells, resulting in cell membrane
distortion and eventual bacterial death [37]. In
agreement with these observations, we also noted a
direct correlation between the antibacterial activities of
related salts and their hydrophobicity. This is observed
for salts that differ by the type of N,N-dialkyl
substituents, for instance, a comparison of the activities
of 4a and 4b shows a significant decrease in inhibitory
concentration against both Staphylococcus aureus and
Bacillus subtilis and E. coli from 512 to 128 and
64 μg/mL, respectively on increasing the alkyl chain
length from methyl to propyl. The positive effects of
hydrophobic factors toward antimicrobial activities were
also observed in the comparison of the related
compounds 3a and 3b, whereby the MIC values
generally decreased from 32 to 8, 16 to 8, and 8 to
4 μg/mL against S. aureus, B. subtilis, and E. coli,
respectively upon increasing the alkyl chain length from
Table 1
Minimum inhibitory concentration data for the symmetric compounds 1a–4b and the ferrocenyl-substituted compounds 6a–9b against Gram-positive and
Gram-negative bacterial strains.
Gram-positive (μg/mL)
Gram-negative (μg/mL)
Staphylococcus
aureus ATCC
25923
Bacillus
subtilis ATCC
6051
Enterococcus
faecalis ATCC
29212
Escherichia
coli ATCC
25922
Pseudomonas
aeruginosa ATCC
27853
Salmonella
enterica ATCC
10708
Antimicrobial
compound
1a
1b
2a
2b
3a
3b
4a
4b
6a
6b
7a
9a
NI
NI
256
128
32
NI
NI
256
128
16
8
512
64
256
128
16
32
8
NI
NI
NI
NI
NI
NI
NI
NI
128
64
8
NI
NI
256
128
8
4
512
64
NI
NI
128
NI
NI
NI
NI
NI
NI
512
512
128
128
512
512
NI
NI
NI
NI
NI
512
128
128
256
NI
NI
NI
NI
NI
8
512
128
256
128
16
128
8
16
4
NI
NI
9b
Meropenem
0.125
0.03
2
0.03
0.25
0.5
ATCC, American Type Culture Collection; NI, no inhibition.
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S. N. P. Ndlovu, H. Ibrahim, and M. D. Bala
EXPERIMENTAL
Vol 000
3a to 3b (Table 1). It is also clear that in addition to the
observed effects of the N,N-dialkyl substituents, the
ability of the compounds to inhibit the growth of
bacteria also depended upon the nature of the 4,5-aryl
substituents. For example, we observe that as the
bulkiness of the 4,5-substituents increased, activity of
the imidazolium iodides against Gram-positive bacteria
also increased in the order 1a < 4a < 2a < 3a.
Compound 3a, with the bulkiest 4,5-substituent
(phenanthrene), resulted in the highest ability to inhibit
the growth of Gram-positive bacteria when compared to
the other three methylated salts, which could be
attributed to the hydrophobicity and its increased
stability due to the aromatic group bound to positions
4,5 of the azolium ring [32].
General. All air-sensitive reactions were carried out
under a nitrogen atmosphere using standard Schlenk
techniques, and all glassware were dried at 100°C in an
oven. Solvents were dried using standard drying
procedures and were stored over activated molecular
sieves. Double-distilled water was used for reactions that
involved water. Thin-layer chromatography was
performed using Merck silica gel F254 (Darmstadt,
Germany) plates, and the compounds were visualized
under UV light. Column chromatography was performed
on a Merck Kieselgel 60. Benzoin, magnesium sulfate
anhydrous, N,N-dimethylaminomethyl ferrocene, 9,10-
phenanthraquinone, propyl iodide, and triethyl
orthoformate were purchased from Sigma-Aldrich (St.
Louis, MO), while 1,8-diaminonaphthalene, formic acid,
methyl iodide, and 1,2-phenylenediamine were purchased
from Merck. Formamide was purchased from Fluka
(Buchs, Switzerland). All the reagents were used as
received. All of the starting materials (1 [15], 2 [16], 3
[5], 4 [17], and 5 [22]) were prepared by the adaptation
of published procedures. The successful synthesis of
These results also revealed that all the ferrocenyl-
functionalized salts are inactive against Gram-negative
bacteria, although 7a showed
a
slight activity
(MIC = 128 μg/mL) against E. coli. This is attributed to
the bulky 4,5-diaryl substituent in addition to the
1-ferrocenyl group. Despite poor inhibitory effects
exhibited by the ferrocenyl salts against Gram-negative
bacteria, the salts showed low to moderate activities
against Gram-positive bacterial strains, with inhibitory
concentrations in the range 256–8 μg/mL depending on
the composition of the salt. Among this series, salt 7a
(MIC = 16, 16, and 8 μg/mL against S. aureus,
B. subtilis, and E. faecalis, respectively) is also the most
active, further confirming that antimicrobial activity is
most influenced by hydrophobicity and a degree of
structural constraint and stability.
On comparison of the asymmetric series against the
symmetric series, it is clear that introduction of the
ferrocenyl group as an N-substituent further increased
the antimicrobial activity of the salts. This might be
because the ferrocenyl group behaves like an added
electroactive aromatic center that enhanced the efficacy
of the main heterocyclic imidazolium ring through
electronic resonance contribution and stabilization.
1
compounds 1–5 was checked by H-NMR and 13C-NMR
spectroscopies, with spectra acquired at ambient tempera-
ture on a Bruker (Billerica, MA) 400-MHz spectrometer
in deuterated solvents. Chemical shifts are reported in parts
per million, relative to tetramethylsilane as the internal
standard. HRMS analyses were conducted on a Bruker
micrOTOF-Q using electron spray ionization (ESI), with
a sample concentration of approximately 5.0 ppm. Infrared
spectra were recorded on a Fourier transform IR
PerkinElmer (Waltham, MA) spectrometer model 100
equipped with a universal attenuated total reflection
(ATR), and functional group bands reported in per centi-
meter [38]. Uncorrected melting point ranges, recorded in
degrees Celsius, were obtained from a Bibby Stuart Scien-
tific (Stone, UK) apparatus model SMP3.
General procedure for the synthesis of symmetric salts
(1a–4b).
The symmetric imidazolium and perimidium
salts were synthesized by amendment of literature
procedures [11]. A typical and generic procedure is
described. Spectroscopic and analytical data obtained are
presented accordingly. Into a stirred solution of NaH
(1 equiv) was added dropwise a dry dimethylformamide
solution of the required imidazole derivative (1 equiv,
10 mL). The resultant mixture was stirred at room
temperature for 1 h, after which the alkyl halide
(3.5 equiv) was added dropwise and the resultant mixture
heated under reflux for 12 h. At the expiration of the
reaction time, the mixture was diluted with double-
distilled water and extracted with CHCl3 (5 × 10 mL).
Combined organic layers were dried over a bed of
anhydrous MgSO4 and filtered. All volatiles were
CONCLUSION
Two series of (imid)azolium salts comprising symmetric
1,3-dialkyl-substituted and asymmetric ferrocenyl-
substituted derivatives were synthesized from four
precursors bearing sterically bulky C4,5 ring substituents.
Both series of salts were screened for antimicrobial
activity, for which low to moderate activities were
observed. It is thus concluded that the antibacterial
activity of these sets of salts is influenced by the nature
of the 4,5-aryl and the two 1,3-alkyl substituents, with
the asymmetric salts showing higher activities for
Gram-positive bacterial strains.
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Sterically Hindered N-heterocyclic Salts Utilized As Antimicrobial Agents
removed under reduced pressure, and the crude product was
purified by column chromatography, where elution with
MeOH afforded pure products [24].
1,3-Dimethyl-1H-benzo[d]imidazol-3-ium iodide (1a).
This compound was prepared from 1H-benzo[d]imidazole
(4.2 mmol, 0.50 g), NaH (6.4 mmol, 0.15 g), and methyl
iodide (12.7 mmol, 1.80 g, 0.8 mL). The product was
obtained as a white solid: 0.99 g, yield 84%, mp
193–194°C. All other characterization data correspond to
(3.4 mmol, 0.08 g), and propyl iodide (6.9 mmol, 1.17 g,
0.7 mL). The product was obtained as an orange solid:
0.69 g, yield 71%, mp 211–213°C; IR (ATR, cmÀ1):
3463 (C=N aromatic), 3041, 2957 (CH aliphatic), 1581
1
(N–C–N), 1438 (C–C). H-NMR [(CD3)2SO, 400 MHz]:
δ 9.80 (s, 1H, CH), 8.99 (d, 2H, J = 8 Hz, Ar–H), 8.45
(d, 2H, J = 8 Hz, Ar–H), 7.88–7.81 (m, 4H, 2 × CH2),
4.84 (t, 4H, J = 7 Hz, 2 × CH2), 2.07–1.99 (m, 4H,
2 × CH2), 1.01 (t, 6H, J = 7 Hz, 2 × CH3). 13C-NMR
[(CD3)2SO, 400 MHz]: δ 140.9, 129.1, 128.6, 128.0,
125.6, 124.5, 122.2, 120.2, 51.5, 21.8, 10.4. HRMS (ESI)
[M+ À IÀ] calculated for C21H23N2: 303.1861, found:
303.1868.
those previously reported [15].
1,3-Dipropyl-1H-benzo[d]imidazol-3-ium iodide (1b). This
compound was prepared from 1H-benzo[d]imidazole
(4.2 mmol, 0.50 g), NaH (6.4 mmol, 0.15 g), and propyl
iodide (12.7 mmol, 2.16 g, 1.3 mL). The product was
obtained as a white solid: 0.79 g, yield 57%, mp
108–109°C. All other characterization data correspond to
1,3-Dimethyl-1H-perimidin-3-ium iodide (4a).
This
compound was prepared from 1H-perimidine (3.0 mmol,
0.50 g), NaH (4.5 mmol, 0.12 g), and methyl iodide
(8.9 mmol, 1.26 g, 0.6 mL). The product was obtained as a
white solid: 0.89 g, yield 93%, mp 276–277°C; IR (ATR,
cmÀ1): 3887, 3507 (C=N aromatic), 3056, 2789 (CH
aliphatic), 1595, 1571 (N–C–N), 1463, 1448 (C–C).
1H-NMR [(CD3)2SO, 400 MHz]: δ 8.99 (s, 1H, CH), 7.62
(d, 2H, J = 8 Hz, Ar–H), 7.51 (t, 2H, J = 8 Hz, Ar–H),
7.00 (d, 2H, J = 8 Hz, Ar–H), 3.50 (s, 6H, 2 × CH3).
13C-NMR [(CD3)2SO, 400 MHz] δ 153.1, 133.8, 132.7,
128.3, 123.4, 120.2, 107.6, 38.7. HRMS (ESI) [M+ À IÀ]
calculated for C13H13N2: 197.1079, found: 197.1073.
those previously reported [15].
4.5-Diphenyl-1,3-dimethyl-1H-imidazol-3-ium iodide (2a).
This compound was prepared from 4,5-diphenyl-1H-
imidazole (2.3 mmol, 0.50 g), NaH (3.4 mmol, 0.08 g),
and methyl iodide (6.8 mmol, 0.97 g, 0.6 mL). The
product was obtained as a yellow solid: 0.42 g, yield
49%, mp 203–206°C. Other spectroscopic and analytical
data correspond to those reported by Lima et al. [20].
4.5-Diphenyl-1,3-dipropyl-1H-imidazol-3-ium iodide (2b).
This compound was prepared from 4,5-diphenyl-1H-
imidazole (2.3 mmol, 0.50 g), NaH (3.4 mmol, 0.08 g),
and propyl iodide (6.8 mmol, 1.16 g, 0.7 mL). The
product was obtained as a dark yellow gel-like solid:
0.32 g, yield 32%; IR (ATR, cmÀ1): 3452 (C=N
aromatic), 3057, 2956, 2873 (CH aliphatic), 1593, 1573
1,3-Dipropyl-1H-perimidin-3-ium iodide (4b).
This
compound was prepared from 1H-perimidine (3.0 mmol,
0.50 g), NaH (4.5 mmol, 0.11 g), and propyl iodide
(8.9 mmol, 1.52 g, 0.9 mL). The product was obtained as
a green solid: 1.03 g, yield 92%, mp 136–137°C; IR
(ATR, cmÀ1): 3500 (C=N aromatic), 3059, 1945 (CH
1
(N–C–N), 1443 (C–C). H-NMR [(CD3)2SO, 400 MHz]:
δ 9.53 (s, 1H, CH), 7.39–7.34 (m, 10H, 2 × Ar–H), 3.99
(t, 4H, J = 7 Hz, 2 × CH2), 1.61–1.52 (m, 4H, 2 × CH2),
0.71 (t, 6H, J = 7 Hz, 2 × CH3). 13C-NMR [(CD3)2SO,
400 MHz]: δ 135.5, 131.3, 130.7, 130.0, 128.8, 125.2,
48.7, 22.1, 10.4. HRMS (ESI) [M+ À IÀ] calculated for
1
aliphatic), 1592, 1574 (N–C–N), 1450 (C–C). H-NMR
[(CD3)2SO, 400 MHz]: δ 8.99 (s, 1H, CH), 7.52 (d, 2H,
J = 8 Hz, Ar–H), 7.40 (t, 2H, J = 8 Hz, Ar–H), 7.05 (d,
2H, J = 8 Hz, Ar–H), 3.88 (t, 4H, J = 7 Hz, 2 × CH2),
1.78–1.69 (m, 4H, 2 × CH2), 0.92 (t, 6H, J = 7 Hz,
2 × CH3). 13C-NMR [(CD3)2SO, 400 MHz]: δ 152.5,
134.4, 131.6, 128.3, 123.5, 121.2, 107.9, 52.5, 19.1,
10.3. HRMS (ESI) [M+ À IÀ] calculated for C17H21N2:
253.1705, found: 253.1695.
C21H25N2: 305.2018, found: 305.2012.
1,3-Dimethyl-1H-phenanthro[9,10-d]imidazol-3-ium iodide
(3a).
This compound was prepared from 1H-
phenanthro[9,10-d]imidazole (2.3 mmol, 0.50 g), NaH
(3.4 mmol, 0.08 g), and methyl iodide (6.87 mmol,
0.98 g, 20.4 mL). The product was obtained as a light
orange solid: 0.79 g, yield 93%, mp 228–229°C; IR
(ATR, cmÀ1): 3502, 3448 (C=N aromatic), 3059, 2954
(CH aliphatic), 1574 (N–C–N), 1450 (C–C). 1H-NMR
[(CD3)2SO, 400 MHz]: δ 9.56 (s, 1H, CH), 8.89 (d, 2H,
J = 3 Hz, Ar–H), 8.47 (d, 2H, J = 3 Hz, Ar–H), 7.80–
7.78 (m, 4H, Ar–H), 4.39 (s. 6H, 2 × CH3). 13C-NMR
[(CD3)2SO, 400 MHz]: δ 141.4, 128.8, 128.2, 127.8,
General
procedure
for
the
synthesis
of
N-ferrocenylferrocenylmethyl-4,5-aryl imidazoles (6–9).
Typically, the required compounds 1–4 (1 equiv) and
K2CO3 (1.5 equiv) were dissolved in dry acetonitrile and
refluxed at 70°C for 1 h under a nitrogen atmosphere. N,N,
N-Trimethyl-1-ferrocenylmethanaminium
iodide
5
(1 equiv) was added, and the resultant mixture further
refluxed at 70°C for 2 days, after which the mixture was
concentrated under reduced pressure. The crude product
obtained was purified by column chromatography (Merck
Kieselgel 60), and the corresponding pure N-
ferrocenylmethyl-4,5-aryl-substituted neutral compound
(6–9) was obtained as an eluent of ethyl acetate.
125.3, 124.2, 122.0, 120.3, 38.0. HRMS (ESI) [M+ À IÀ]
calculated for C17H15N2: 247.1235, found: 247.1235.
1,3-Dipropyl-1H-phenanthro[9,10-d]imidazol-3-ium iodide
(3b).
This compound was prepared from 1H-
phenanthro[9,10-d]imidazole (2.3 mmol, 0.50 g), NaH
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. N. P. Ndlovu, H. Ibrahim, and M. D. Bala
Vol 000
N-Ferrocenylmethyl-1H-benzo[d]imidazole (6).
This
ferrocenylmethylimidazolium iodides 6a–9b. Typically,
the corresponding N-ferrocenylmethyl-4,5-arylimidazoles
6–9 (1 equiv) and excess alkyl iodide were mixed neat
under a nitrogen atmosphere and heated at 50°C for 24 h.
The resulting mixture was allowed to cool to room
temperature, and a minimal amount of diethyl ether was
added to precipitate out the salt, which was then filtered,
further washed with diethyl ether (5 × 10 mL), and dried
in vacuo.
compound was prepared from 1 (6.9 mmol, 0.77 g),
K2CO3 (9.7 mmol, 1.34 g), and 5 (6.48 mmol, 2.50 g).
The product was obtained as a yellowish orange powder:
0.75 g, yield 70%, mp 128–130°C; IR (ATR, cmÀ1):
3076 (CH aliphatic), 1733 (C=C), 1612 (N–C–N), 1489
1
(C–C). H-NMR (CDCl3, 400 MHz): δ 7.86 (s, 1H, CH),
7.79–7.77 (m, 1H, Ar–H), 7.45–7.43 (m, 1H, Ar–H),
7.31–7.24 (m, 2H, Ar–H), 5.07 (s, 2H, CH2), 4.25 (t, 2H,
J = 2 Hz, C5H4), 4.18–4.17 (m, 7H overlapping, C5H4
and C5H5). 13C-NMR (CDCl3, 400 MHz): δ 143.7,
142.4, 133.7, 122.8, 122.0, 120.3, 109.7, 82.1, 68.8, 44.7.
N-Ferrocenylmethyl-4,5-diphenyl-1H-imidazole (7). This
compound was prepared from 3 (5.2 mmol, 1.14 g),
K2CO3 (7.8 mmol, 1.07 g), and 5 (5.2 mmol, 2.00 g). The
product was obtained as a yellow solid: 0.19 g, yield 8%,
mp 155–159°C; IR (ATR, cmÀ1): 3067 (CH aliphatic),
1508 (N–C–N), 1476, 1443 (C–C). 1H-NMR (CDCl3,
400 MHz): δ 7.56 (s, 1H, CH), 7.47–7.42 (m, 5H, C6H5),
7.31–7.29 (m, 2H, Ar–H), 7.17–7.07 (m, 3H, Ar–H), 4.68
(s, 2H, CH2), 4.07 (t, 2H, J = 2 Hz, C5H4), 4.05 (s, 5H,
C5H5), 3.93 (t, 2H, J = 2 Hz, C5H4). 13C-NMR (CDCl3,
400 MHz): δ 134.6, 131.1, 130.8, 128.9, 128.6, 128.1,
128.0, 126.5, 126.2, 82.6, 68.7, 68.7, 68.2, 44.9.
1-Ferrocenylmethyl-3-methyl-1H-benzo[d]imidazol-3-ium
iodide (6a).
This compound was prepared from 6
(1.6 mmol, 0.50 g) and excess of methyl iodide
(68.0 mmol, 9.65 g, 4.2 mL). The salt was obtained as a
bright yellow solid: 0.77 g, yield 99%, mp 150–151°C
(decompose); IR (ATR, cmÀ1): 3438 (C=N), 3039 (CH
aliphatic), 1562 (N–C–N), 1448 (C–C). 1H-NMR
(CDCl3, 400 MHz): δ 10.91 (s, 1H, CH), 7.77–7.74 (m,
1H, Ar–H), 7.63–7.59 (m, 3H, Ar–H), 5.60 (s, 2H, CH2),
4.59 (t, 2H, J = 2 Hz, C5H4), 4.28 (s, 5H, C5H5), 4.21 (t,
2H, J = 2 Hz, C5H4), 4.18 (s, 3H, CH3). 13C-NMR
(CDCl3, 400 MHz): δ 141.7, 131.9, 130.8, 127.2, 127.2,
113.3, 112.7, 78.7, 69.8, 69.7, 69.3, 47.7, 33.9. HRMS
(ESI) [M+ À IÀ] calculated for C19H19FeN2: 331.0892,
found: 331.1125.
N-Ferrocenylmethyl-1H-phenanthro[9,10-d]imidazole (8).
This compound was prepared from 4 (5.2 mmol, 1.13 g),
K2CO3 (7.8 mmol, 1.07 g), and 5 (5.2 mmol, 2.00 g).
The product was obtained as a light orange solid: 0.56 g,
yield 26%, mp 148–150°C (decompose); IR (ATR,
cmÀ1): 3038, 2970 (CH aliphatic), 1526 (N–C–N), 1352
1-Ferrocenylmethyl-3-propyl-1H-benzo[d]imidazol-3-ium
iodide (6b).
This compound was prepared from 6
(0.9 mmol, 0.30 g) and excess of propyl iodide
(40.8 mmol, 6.94 g, 4.1 mL). The product was
obtained as a yellow solid: 0.36 g, yield 74%, mp
155–156°C (decompose); IR (ATR, cmÀ1): 3054, 2965
(CH aliphatic), 1554 (N–C–N), 1453 (C–C), 998, 823
(Ar). 1H-NMR [(CD3)2SO, 400 MHz]: δ 9.80 (s, 1H,
CH), 8.20–8.07 (m, 2H, Ar–H), 7.71–7.65 (m, 2H, Ar–
H), 5.52 (s, 2H, CH2), 4.56 (s, 2H, C5H4), 4.45 (t, 2H,
J = 8 Hz, CH2), 4.28 (s, 5H, C5H5), 4.24 (s, 2H,
C5H4), 1.95–1.89 (m, 2H, CH2), 0.90 (t, 3H, J = 8 Hz,
CH3). 13C-NMR [(CD3)2SO, 400 MHz]: δ 141.5, 131.1,
130.6, 126.6, 126.5, 124.8, 114.7, 113.9, 113.7, 80.1,
69.4, 68.9, 68.7, 58.9, 48.1, 46.4, 22.0, 10.7. HRMS
(ESI) [M+ À IÀ] calculated for C21H23FeN2: 359.1205,
found: 359.1450.
1
(C–C), 822 (Ar). H-NMR (CDCl3, 400 MHz): δ 7.56 (s,
1H, CH), 7.46–7.43 (m, 4H, Ar–H), 7.31–7.29 (m, 2H,
Ar–H), 7.17–7.14 (m, 2H, Ar–H), 4.68 (s, 2H, CH2),
4.07 (t, 2H, J = 2 Hz, C5H4), 4.05 (s, 5H, C5H5), 3.93 (t,
2H, J = 2 Hz, C5H4). 13C-NMR (CDCl3, 400 MHz): δ
136.4, 134.6, 131.1, 130.8, 128.9, 128.6, 128.1, 128.0,
126.5, 126.2, 82.6, 68.7, 68.7, 68.5, 44.9.
N-Ferrocenylmethyl-1H-perimidine (9). This compound
was prepared from 2 (6.5 mmol, 1.59 g), K2CO3
(9.7 mmol, 1.34 g), and 5 (6.5 mmol, 2.50 g). The
product was obtained as an orange solid: 1.03 g, yield
43%, mp 160–161°C (decompose); IR (ATR, cmÀ1):
3049 (CH aliphatic), 1583 (N–C–N), 1401 (C–C), 821,
763 (Ar). 1H-NMR (CDCl3, 400 MHz): δ 7.29 (s,
1H, CH), 7.20 (d, 1H, J = 7 Hz, Ar–H), 7.13–7.11 (m,
1H, Ar–H), 7.08 (t, 2H, J = 3 Hz, Ar–H), 6.80 (dd, 1H,
J = 3 Hz, Ar–H), 6.21 (dd, 1H, J = 3 Hz, Ar–H), 4.25 (t,
2H, J = 2 Hz, C5H4), 4.18 (s, 5H, C5H5), 4.16 (t, 2H,
J = 1.8 Hz, C5H4). 13C-NMR (CDCl3, 400 MHz): δ
147.9, 143.2, 137.8, 135.5, 128.7, 127.2, 123.0, 120.4,
119.5, 115.1, 100.9, 81.4, 68.8, 68.7, 68.6, 48.4.
1-Ferrocenylmethyl-3-methyl-4,5-diphenyl-1H-imidazol-3-
ium iodide (7a). This compound was prepared from 7
(1.2 mmol, 0.30 g) and excess of methyl iodide
(12.0 mmol, 1.69 g, 0.7 mL). The product was
obtained as an orange wool-like solid: 0.36 g, yield
51%, mp 179–181°C (decompose); IR (ATR, cmÀ1):
3044, 2943 (CH aliphatic), 1572, 1558 (N–C–N),
1437 (C–C), 826, 804 (Ar). 1H-NMR [(CD3)2SO,
400 MHz]: δ 9.36 (s, 1H, CH), 7.55–7.39 (m, 10H,
2 × C6H5), 5.15 (s, 2H, CH2), 4.17 (s, 7H, C5H5 and
C5H4), 4.03 (s, 2H, C5H4), 3.73 (s, 3H, CH3). 13C-
NMR [(CD3)2SO, 400 MHz]: δ 135.8, 131.7, 130.9,
130.6, 130.5, 130.2, 130.0, 129.0, 128.9, 125.2, 124.9,
General procedure for the preparation of the ferrocenyl
methylimidazolium salts.
A solvent-free method we
reported [21,24] was used for the synthesis of the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Sterically Hindered N-heterocyclic Salts Utilized As Antimicrobial Agents
79.7, 69.1, 68.7, 46.8, 34.5. HRMS (ESI) [M+ À IÀ]
Microplate alamarBlue assay for minimum inhibitory
concentration determination.
The MIC was determined
calculated for C27H25FeN2: 433.1362, found: 433.1654.
1-Ferrocenylmethyl-3-methyl-1H-perimidin-3-ium
iodide
by the microplate alamarBlue assay method. Nutrient
agar medium was used to culture bacterial strains at 37°C
for 24 h. The inocula of microorganisms (1.5 × 108 cfu/
mL) were prepared from 24-h cultures. Microbial
suspensions were adjusted to 0.5 McFarland standard
turbidity. The imidazolium salts were dissolved with
autoclaved distilled water up to 1 mL, to obtain a
concentration of 5120 μg/mL as stock solution. Twofold
dilutions of the drugs were prepared external to the
plates, with approved antibiotic (meropenem) diluted
5120 to 0.07 μg/mL as a standard antimicrobial drug and
synthesized compounds diluted 5120 to 0.07 μg/mL as
well. Mueller-Hinton broth was used as a medium for
bacterial growth in microliter plates. Uniform volumes
(20 μL) for each concentration of the synthesized
compounds and the standard drug were distributed in the
96-well microtiter plates with the exception of those
wells acting as growth control (contained microorganisms
and Mueller-Hinton broth culture media only) and
positive control (contained microorganisms, culture
media, and standard antibiotic) and negative control
(contained only culture media). After the addition of
inocula of bacteria (20 μL) to the 96 wells with the
exception of the wells acting as negative control, the final
volume in each well became 200 μL. The final
concentrations of the tested compounds were
512–0.007 μg/mL, and the final concentration of inocula
was 1.5 × 104 cfu/mL for bacteria. Plates were covered
and sealed with parafilm and incubated for 24 h at 37°C.
After the 24-h period, 20 μL of alamarBlue dye was
added to all 96 wells, and the plates were shaken gently
and incubated for 3 h at 37°C in the dark. The MIC was
defined as the lowest concentration, which prevented a
color change from blue to pink.
(9a). This compound was prepared from 9 (0.8 mmol,
0.30 g) and excess of methyl iodide (8.2 mmol, 1.16 g,
0.5 mL). The product was obtained as a yellow solid:
0.36 g, yield 82%, mp 138–139°C (decompose); IR
(ATR, cmÀ1): 3058, 2930 (CH aliphatic), 1604 (N–C–N),
1
1493 (C–C). H-NMR [(CD3)2SO, 400 MHz]: δ 9.07 (s,
1H, CH), 7.58–7.56 (m, 2H, Ar–H), 7.49–7.44 (m, 2H,
Ar–H), 7.24 (d, 1H, J = 8 Hz, Ar–H), 6.97 (d, 1H,
J = 8 Hz, Ar–H), 5.01 (s, 2H, CH2), 4.64 (s, 2H, C5H4),
4.29 (s, 5H, C5H5), 4.23 (s, 2H, C5H4), 3.51 (s, 3H,
CH3). 13C-NMR [(CD3)2SO, 400 MHz]: δ 152.6, 134.1,
132.7, 131.4, 128.3, 128.2, 123.7, 123.5, 120.7, 108.4,
107.8, 78.9, 69.9, 68.9, 68.7, 50.9, 38.9. HRMS (ESI)
[M+ À IÀ] calculated for C23H21FeN2: 381.1049, found:
381.1317.
1-Ferrocenylmethyl-3-propyl-1H-perimidin-3-ium
iodide
(9b). This compound was prepared from 9 (0.8 mmol,
0.30 g) and excess of propyl iodide (35.2 mmol, 5.99 g,
3.4 mL). The product was obtained as a yellow solid:
0.24 g, yield 50%, mp 166–167°C (decompose); IR
(ATR, cmÀ1): 3067, 2940 (CH aliphatic), 1589 (N–C–N),
1457 (C–C), 819, 762 (Ar). 1H-NMR [(CD3)2SO,
400 MHz]: δ 9.10 (s, 1H, CH), 7.57 (d, 2H, J = 8 Hz,
Ar–H), 7.47 (t, 2H, J = 8 Hz, Ar–H), 7.24 (d, 1H,
J = 8 Hz, Ar–H), 7.12 (d, 1H, J = 8 Hz, Ar–H), 5.02 (s,
2H, CH2), 4.63 (s, 2H, C5H4), 4.29 (s, 7H, overlapping
of C5H5 and C5H4), 7.57 (t, 2H, J = 8 Hz, CH2), 1.84–
1.76 (m, 2H, CH2), 1.01 (t, 3H, J = 7 Hz, CH3). 13C-
NMR [(CD3)2SO, 400 MHz]: δ 152.5, 134.5, 131.4,
131.3, 128.4, 128.2, 123.7, 121.2, 108.4, 108.1, 79.0,
78.7, 69.8, 68.9, 68.7, 52.8, 51.0, 19.1, 10.4. HRMS
(ESI) [M+ À IÀ] calculated for C25H25FeN2: 409.1362,
found: 409.1650.
Biological evaluation. Materials.
The MIC of the
X-ray structure determination.
Single crystals were
tested compounds was determined by microdilution,
using the alamarBlue assay, against six strains of bacteria
following a broth microdilution MIC method. Three
Gram-positive bacteria and three Gram-negative bacteria
obtained from the American Type Culture Collection
(ATCC) were tested: S. aureus ATCC 25923, B. subtilis
ATCC 6051, and E. faecalis ATCC 29212 and E. coli
ATCC 25922, Pseudomonas aeruginosa ATCC 27853,
and Salmonella enterica ATCC 10708, respectively.
Nutrient agar and Mueller Hinton broth were purchased
from Merck for the culture of the microorganisms.
alamarBlue reagent was aliquoted and stored at À80°C.
Prior to each experiment, the alamarBlue was brought to
room temperature and vortexed. The exposure to light
was minimized throughout the experiments. Assays were
performed in Greiner 96-well flat-bottom, clear
polystyrene sterile plates.
selected and glued onto the tip of a glass fiber, mounted in
a stream of cold nitrogen at 173 K and centered in the
X-ray beam using a video camera. Intensity data were
collected on a Bruker APEX II charged coupling device
area detector diffractometer with graphite monochromated
Mo Kα radiation (50 kV, 30 mA) using the APEX 2 data
collection software. The collection method involved ω
scans of width 0.5° and 512 × 512-bit data frames. Data
reduction was carried out using the program SAINT+,
while face indexed and multiscan absorption corrections
were made using SADABS. The structures were solved by
direct methods using SHELXS. Nonhydrogen atoms were
first refined isotropically, followed by anisotropic
refinement by full matrix least-squares calculations based
on F2 using SHELXS. Hydrogen atoms were first located
in the difference map and then positioned geometrically
and allowed to ride on their respective parent atoms.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. N. P. Ndlovu, H. Ibrahim, and M. D. Bala
Vol 000
[14] Arduengo, A. J Acc Chem Res 1999, 32, 913.
[15] Fortenberry, C.; Nammalwar, B.; Bunce, R. A. Org Prep
Proced Int 2013, 45, 57.
[16] Liu, W.; Bensdorf, K.; Proetto, M.; Abram, U.; Hagenbach, A.;
Gust, R. J Med Chem 2011, 54, 8605.
[17] Gahlon, H. L.; Schweizer, W. B.; Sturla, S. J J Am Chem Soc
2013, 135, 6384.
[18] Li, S.; Yang, F.; Lv, T.; Lan, J.; Gao, G.; You, J. Chem
Commun 2014, 50, 3941.
[19] Lv, T.; Wang, Z.; You, J.; Lan, J.; Gao, G. J Org Chem 2013,
78, 5723.
[20] Lima, H. M.; Lovely, C. J Org Lett 2011, 13, 5736.
[21] Ibrahim, H.; Bala, M. D. New J Chem 2016, 40, 6986.
[22] Ripert, M.; Farre, C.; Chaix, C. Electrochim Acta 2013, 91, 82.
[23] Howarth, J.; Thomas, J. L.; Hanlon, K.; McGuirk, D. Synth
Commun 2000, 30, 1865.
[24] Ibrahim, H.; Bala, M. D. Tetrahedron Lett 2014, 55, 6351.
[25] Betz, R.; McCleland, C.; Hosten, E. Acta Crystallogr Sect E:
Struct Rep Online 2011, 67, o1199.
Diagrams were generated using SHELXTL, PLATON [39],
and ORTEP-3 [40]. *Crystallographic data for the
structure in this article have been deposited with the
Cambridge Crystallographic Data Centre 1522045 for 2a.
The data can be obtained free of charge at http://www.
ccdc.cam.ac.uk/conts/retrieving.html
(or
from
the
Cambridge Crystallographic Data Centre, 12 Union Road
Cambridge CB2 1EZ, UK; Fax: +44-1223/336-033;
E-mail: deposit@ccdc.cam.ac.uk).
Acknowledgments. We are grateful to the National Research
Foundation of South Africa (NRF) and University of KwaZulu-
Natal for financial support. H. I. thanks TET-Fund and FCET
Gusau for a fellowship.
[26] Tian, C.; Nie, W.; Borzov, M. V. Acta Crystallogr Sect E:
Struct Rep Online 2013, 69, 1218.
[27] Smith, G.; Wermuth, U. D. Acta Crystallogr Sect E: Struct Rep
Online 2010, 66, o2399.
REFERENCES AND NOTES
[28] Berger, M.; Auner, N.; Bolte, M. Acta Crystallogr Sect E:
Struct Rep Online 2014, 70, o1193.
[1] Arduengo, A. J.; Harlow, R. L.; Kline, M. J Am Chem Soc
1991, 113, 361.
[29] Bildstein, B.; Malaun, M.; Kopacka, H.; Ongania, K.-H.;
Wurst, K. J Organomet Chem 1998, 552, 45.
[30] Verma, A.; Joshi, S.; Singh, D. J Chem 2013 2013.
[31] Alptüzün, V.; Parlar, S.; Taşlı, H.; Erciyas, E. Molecules 2009,
14, 5203.
[32] Reinhardt, A.; Horn, M.; Schmauck, J. P. g.; Bröhl, A.;
Giernoth, R.; Oelkrug, C.; Schubert, A.; Neundorf, I. Bioconjug Chem
2014, 25, 2166.
[33] Stuart, C. H.; Schwartz, S. A.; Beeson, T. J.; Owatz, C. B. J
Endod 2006, 32, 93.
[34] Denyer, S. P.; Stewart, G. Int Biodeterior Biodegrad 1998,
41, 261.
[2] Herrmann, W. A. Angew Chem Int Ed 2002, 41, 1290.
[3] Marion, N.; Nolan, S. P. Acc Chem Res 2008, 41, 1440.
[4] Gnanamgari, D.; Moores, A.; Rajaseelan, E.; Crabtree, R. H.
Organometallics 2007, 26, 1226.
[5] Tapu, D.; Owens, C.; VanDerveer, D.; Gwaltney, K.
Organometallics 2008, 28, 270.
[6] Bildstein, B.; Malaun, M.; Kopacka, H.; Wurst, K.;
Mitterböck, M.; Ongania, K.-H.; Opromolla, G.; Zanello, P.
Organometallics 1999, 18, 4325.
[7] Arduengo, A. J.; Krafczyk, R.; Schmutzler, R.; Craig, H. A.;
Goerlich, J. R.; Marshall, W. J.; Unverzagt, M. Tetrahedron 1999,
55, 14523.
[35] Pernak, J.; Skrzypczak, A.; Lota, G.; Frackowiak, E. Eur J
Chem 2007, 13, 3106.
[36] He, B.; Ou, G.; Zhou, C.; Wang, M.; Chen, S. J Chem
2013, 2013.
[37] Khodarahmi, G.; Khajouei, M. R.; Hakimelahi, G.; Abedi, D.;
Jafari, E.; Hassanzadeh, F. Res Pharm Sci 2012, 7, 151.
[38] Morgan, K. J Chem Soc 1961 2343.
[8] Bildstein, B. J Organomet Chem 2001, 617–618, 28.
[9] (a) Ornelas, C. New J Chem 2011, 35, 1973; (b) Shaikh, M.
H.; Subhedar, D. D.; Kalam Khan, F. A.; Sangshetti, J. N.; Nawale, L.;
Arkile, M.; Sarkar, D.; Shingate, B. B. J Het Chem 2017, 54, 413; (c)
Mohamed, M. I.; Kandile, N. G.; Zaky, H. T. J Het Chem 2017, 54, 35.
[10] Dallas, A.; Kuhtz, H.; Farrell, A.; Quilty, B.; Nolan, K.
Tetrahedron Lett 2007, 48, 1017.
[39] Spek, A. L. J Appl Cryst 2003, 36, 7.
[40] Farrugia, L. J Appl Crystallogr 1997, 30, 565.
[11] Howarth, J.; Hanlon, K. Tetrahedron Lett 2001, 42, 751.
[12] Özbek, H.; Avcı; Aktas, P.; Sözen; Daran, J.-C.; Oskay, M.;
Demirhan, F.; Çetinkaya, B. Inorg Chim Acta 2014, 423, 435.
[13] (a) Krishnanjaneyulu, I. S.; Saravanan, G.; Vamsi, J.; Supriya,
P.; Bhavana, J. U.; Sunil Kumar, M. V. J Adv Pharm Technol Res 2014, 5,
21. (b) Azam, M.; Warad, I.; Al-Resayes, S. I.; Alzaqri, N.; Khan, M. R.;
Pallepogu, R.; Dwivedi, S.; Musarrat, J.; Shakir, M. J Mol Struct 2013,
1047, 48; (c) Chan, A. H.; Wereszczynski, J.; Amer, B. R.; Yi, S. W.;
Jung, M. E.; McCammon, J. A.; Clubb, R. T. Chem Biol Drug Des
2013, 82, 418.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet