Synthesis, microwave-promoted catalytic activity in Suzuki-Miyaura cross-coupling reactions and antimicrobial properties of novel benzimidazole salts bearing trimethylsilyl group

Article abstract of DOI:10.1002/aoc.1772

A mixture of benzimidazole salts (2-7), Pd(OAc)₂ and K ₂CO₃ in DMF-H₂O catalyzes the Suzuki-Miyaura cross-coupling reactions promoted by microwave irradiation resulting in high yield within a short time. In particular, the yield of the Suzuki-Miyaura reactions with aryl bromides was found to be nearly quantitative. The synthesized benzimidazole salts (2-7) were identified by ¹H- ¹³C, NMR, IR spectroscopic methods and microanalysis. The molecular structure of 1 was determined by X-ray crystallography. The antibacterial and antifungal activities of the novel benzimidazole derivatives (1-7) were also tested against standard strains.

Full text of DOI:10.1002/aoc.1772

Full Paper
Received: 21 September 2010
Revised: 29 November 2010
Accepted: 29 November 2010
Published online in Wiley Online Library: 4 April 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1772
Synthesis, microwave-promoted catalytic
activity in Suzuki–Miyaura cross-coupling
reactions and antimicrobial properties of novel
benzimidazole salts bearing trimethylsilyl
group
a
a∗
b
c
¨
Ulku¨ Yılmaz , Hasan Ku¨c¸u¨kbay , Nihat S¸ireci , Mehmet Akkurt ,
Selami Gu¨nald, Rıza Durmazd and M. Nawaz Tahire
A mixture of benzimidazole salts (2–7), Pd(OAc)2 and K2CO3 in DMF–H2O catalyzes the Suzuki–Miyaura cross-coupling
reactions promoted by microwave irradiation resulting in high yield within a short time. In particular, the yield of the
Suzuki–Miyaura reactions with aryl bromides was found to be nearly quantitative. The synthesized benzimidazole salts (2–7)
were identified by 1H-13C, NMR, IR spectroscopic methods and microanalysis. The molecular structure of 1 was determined by
X-ray crystallography. The antibacterial and antifungal activities of the novel benzimidazole derivatives (1–7) were also tested
c
against standard strains. Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: benzimidazole salt; carbene; palladium catalysis; coupling reaction; Suzuki–Miyaura coupling; microwave; antimicrobial
activity.
Introduction
coupling reactions. Pd(II)–NHC complexes are more attractive as
pre-catalysts because of their stability to air, moisture and heating
and their excellent long-term storage profile.[7] In particular,
Pd(OAc)2 –benzimidazole or imidazole ligands could be very
effective catalytic systems in these reactions.[16–18]
In the past 10 years, heating and driving chemical reactions by
microwave energy has been an increasingly popular theme in the
scientific community. The use of metal catalysts in conjunction
with microwaves may have significant advantages over traditional
heating methods since the inverted temperature gradient under
microwave conditions may lead to an increased lifetime of
catalyst through elimination of wall effects.[19] Although there
are extensive studies on Suzuki-type C–C cross-coupling reaction
The Suzuki–Miyaura cross-coupling reaction of organoboron
compounds and organic halides or pseudohalides can be
considered as one of the most efficient methods for the formation
of carbon–carbon bonds.[1–3] The Suzuki–Miyaura reaction has
become a mainstay of modern synthetic organic chemistry
for the preparation of biaryl compounds. A large number of
synthetic methods have been developed over the year for the
selective construction of carbon–carbon bonds, in particular for
the formation of biaryl derivatives.[4–9]
Metal-catalyzed cross-coupling reactions, notably those per-
mitting C–C bond construction, have witnessed a meteoritic
development and are now routinely employed as a powerful syn-
thetic tool both in the laboratory and in industry. In this context,
palladium is arguably the most studied transition metal, and ter-
tiary phosphines occupy a preponderant place as ancillary ligands.
Seriously challenging this situation, the use of N-heterocyclic
carbenes (NHCs) as alternative ligands in palladium-catalyzed
cross-coupling reactions is rapidly gaining in popularity because
of their superior performance compared with the more traditional
tertiary phosphanes.[10,11]
∗
˙
¨
Correspondence to: Hasan Ku¨c¸u¨kbay, Inonu¨ University, Faculty of Science and
Arts, Department of Chemistry, 44280 Malatya, Turkey.
E-mail: hkucukbay@inonu.edu.tr
˙
¨
a
Inonu¨ University, Faculty of Science and Arts, Department of Chemistry, 44280
Malatya, Turkey
b
c
Adıyaman University, Faculty of Education, 02040 Adıyaman, Turkey
Both NHCs and electron-rich alkenes which can be used as NHCs
source are highly air- and moisture-sensitive and require handling
under strict inert conditions.[12–15] Contrary to cumbersome
preparation and isolation of NHCs and electron-rich alkenes, in situ
preparation of NHCs has more advantages, using a strong base,
diazolium salts and a common palladium source such as PdCl2
or Pd(OAc)2, in a number of catalytic synthesis, particularly C–C
Erciyes University, Faculty of Sciences, Department of Physics, 38039 Kayseri,
Turkey
˙
¨
d
e
Inonu¨ University, Faculty of Medicine, Department of Microbiology, 44280
Malatya, Turkey
University of Sargodha, Department of Physics, Sargodha, Pakistan
c
Appl. Organometal. Chem. 2011, 25, 366–373
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

Microwave-promoted catalytic activity in Suzuki–Miyaura cross-coupling reactions
CH3
H3C
CH3
Si
H3C
N
Si
H
1.KOH/EtOH
CH3
+
Y
CH3
Y
N
N
Y
N
2.(CH3)3 SiCH2Cl
DMF
. X-
R X
+
N
N
R
Y: H, NO2
I) Y: H
1) Y: NO2
2) R X : CH3I, Y: H
3) R X : C2H5I, Y: H
4) R X : (CH3)2CHI, Y: H
5) R X : CH3CH2CH2Br, Y: H
6) R X : CH3CH2CH2CH2Cl, Y: H
7) R X : CH3I, Y: NO2
Scheme 1. Synthesis pathways of the benzimidazole derivatives.
incorporating microwave irradiation with high yield in a short
time,[20–27] there is no study on Suzuki–Miyaura cross-coupling
reactionincludingtrimethylsilylmethyl-substitutedbenzimidazole
derivatives in the literature. The nature, size and electronic
properties of the substituents on the nitrogen atom(s) of
the benzimidazole may play a crucial role in tuning the
catalytic activity. In order to find a more efficient palladium
catalyst, we synthesized a series of new benzimidazole salts,
1–7 (Scheme 1), containing trimethylsilylmethyl moiety, and we
aimed to investigate the activity of in-situ Pd-carbene-based
catalytic systems for the Suzuki cross-coupling reactions. Some
alkylsilyl substituted benzimidazole derivatives have also been
reported to possess important antitumor activity.[28,29] Since
benzimidazole compounds have been found to have a broad
range of pharmacological activity, many research groups as well
as our group have been interested in these types of heterocyclic
compounds.[30–40]
1-Substitutebenzimidazoles, I used in this work as starting com-
pounds were prepared according to the literature procedure.[41]
GC-MS Analysis
GC-MS spectra were recorded on an Agilient 6890 N GC and
5973 Mass Selective Detector using with an HP-Innowax column
of 60 m length, 0.25 mm diameter and 0.25 µm film thickness.
GC-MS parameters for both Suzuki and Heck coupling reactions
were as follows: initial temperature 60 ◦C; initial time, 5 min;
temperature ramp 1, 30 ◦C/min; final temperature, 200 ◦C; ramp 2,
20 ◦C/min; final temperature 250 ◦C; run time 30.17 min; injector
port temperature 250 ◦C; detector temperature 250 ◦C, injection
volume, 1.0 µl; carrier gas, helium; mass range between m/z 50
and 550.
1-(Trimethylsilyl)methyl-6-nitrobenzimidazole, 1
Herein, we report on the microwave-assisted catalytic activity
of Pd(OAc)2/trimethylsilylmethyl substituted benzimidazole cat-
alytic system in Suzuki cross-coupling reactions. The other aim of
this study was to investigate in vitro antimicrobial and antifungal
activities of the novel trimethylsilylmethyl-substituted benzimi-
dazole derivatives. X-ray structural analysis of compound 1 was
also determined to clarify the nitro group position 5 or 6 for the
tautomerization of starting 5(6)-nitrobenzimidazole.
(Chloromethyl)trimethylsilane (1.8 cm3, 12.90 mmol) was added
to a mixture of 5(6)-nitrobenzimidazole (2.00 g; 12.26 mmol) and
KOH (0.70 g, 12.5 mmol) in EtOH (20 cm3). The mixture was heated
under reflux for 4 h, then cooled, and the precipitating potassium
chloride was filtered off and washed with a little EtOH. The
solvent was then removed from the filtrate in vacuo. The residue
was washed with water (25 cm3) twice and crystallized from
EtOH–DMF (2 : 1). Yield, 1.96 g, (64%); m.p., 162–163 ◦C. Anal.
found: C, 52.91; H, 5.97; N, 16.74. Calcd for C11H15N3O2Si: C, 52.99;
H, 6.06; N, 16.85. Found: IR: υ(C N): 1490 cm−1.1H-NMR (DMSO-
d6): δ = 8.54 (s, 1H, N CH–N); 8.17 and 7.85 (m, 3H, Ar–H); 4.02
(s, 2H, CH2Si); 0.01 ppm [s, 9H, Si (CH3)3]. 13C-NMR (DMSO-d6):
δ = 148.58 (N CH–N); 142.86, 142.54, 139.20, 118.08, 116.12,
111.77 (C6H4); 36.25 (N–CH2 –Si); −2.06 ppm (CH3 –Si).
Experimental
All preparations were carried out in an atmosphere of purified
argon using standard Schlenk techniques. Starting materials
and reagents used in reactions were supplied commercially
from Aldrich or Merck Chemical Co. Solvents were dried with
standard methods and freshly distilled prior to use. All catalytic
activity experiments were carried out in a microwave oven
system manufactured by Milestone (Milestone Start S Microwave
Labstation for Synthesis) under aerobic conditions. 1H-NMR
(300 MHz) and 13C-NMR (75 MHz) spectra were recorded using
a Bruker DPX-300 high-performance digital FT NMR spectrometer.
Infrared spectra were recorded as KBr pellets in the range
4000–400 cm−1 on a Perkin-Elmer FT-IR spectrophotometer.
Elemental analyses were performed by LECO CHNS-932 elemental
analyzer. Melting points were recorded using an electrothermal-
9200 melting point apparatus, and are uncorrected.
Synthesis of 1-(trimethylsilyl)methyl-3-methylbenzimidazolium
iodide, 2
A mixture of 1-trimethylsilylmethylbenzimidazole (1.02 g, 5 mmol)
and iodomethane (0.40 cm3, 6.43 mmol) in dimethylformamide
(5 ml) was refluxed for 3 h. The mixture was then cooled and the
volatileswereremovedundervacuum.Theresiduewascrystallized
from a dimethylformamide–ethanol (1 : 1). White crystals of the
title compound 2 (1.51 g, 87%) were obtained, m.p., 236–237 ◦C;
υ(CN) = 1488 cm−1. Anal. found: C 41.60, H 5.53, N 8.05. Calculated
for C12H19N2ISi: C 41.62, H 5.53, N 8.09. 1H NMR (δ, DMSO-d6): 9.60
c
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U. Yılmaz et al.
(s, 1H, NCHN), 8.13–7.70 (m, 4H, C6H4), 4.24 (s, 2H, CH2Si), 4.11 (s,
3H, CH3) and 0.12 [s, 9H, (CH3)3Si]. 13C NMR (δ, DMSO-d6): 141.9
(NCHN), 132.2, 126.8, 126.6, 114.3 and 113.9 (C6H4), 38.3 (CH2Si),
33.8 (CH3) and −2.2 [(CH3)3Si].
(δ, DMSO-d6): 146.0 (NCHN), 136.0, 132.0, 121.9, 115.3 and 111.5
(C6H3), 38.9 (CH2Si), 34.4 (CH3) and −2.4 [(CH3)3Si].
Single-crystal X-ray Diffraction Analysis of 1-
Trimethylsilylmethyl-6-nitrobenzimidazole, 1
Similarly, 1-(trimethylsilyl)methyl-3-ethylbenzimidazolium io-
dide,
3 was synthesized from 1-(trimethylsilyl)methylbenz-
The X-ray data were collected on an Bruker X8 Prospector
diffractometer at room temperature with an highly sensitive APEX
II area detector using an IµS (microfocus source) with multilayer
mirrors, that give an intense monochromatic Cu Kα radiation
(λ = 1.54178 Å). An empirical absorption correction was applied
using SADABS.[42] The structures were solved by direct methods
using the SIR-97 program[43] and refined on F2 by full matrix least-
squares using the SHELXL-97 program.[44] The hydrogen atoms
were placed in calculated positions (C–H = 0.95–0.99 Å) and
included in the refinement using the riding model, with Uiso(H) =
1.2 or 1.5 Ueq (C). A summary of the crystal data, experimental
details and refinement results for 1 is given in Table 1. The
hydrogen bond and molecular packing geometry of compound 1
were calculated with PLATON.[45] The graphical representations of
the structure were made with ORTEP.[46]
imidazole and iodoethane. Yield, 1.46 g (yellow crystals), 81%;
m.p., 126–127 ◦C; υ(CN) = 1478 cm−1. Anal. found: C 43.26, H 5.79,
N 7.56. Calcd for C13H21N2ISi: C 43.33, H 5.87, N 7.77. 1H NMR (δ,
DMSO-d6): 9.70 (s, 1H, NCHN), 8.13 −7.66 (m, 4H, C6H4), 4.55 (q,
2H, CH2 ethyl, J = 7.2 Hz), 4.24 (s, 2H, CH2Si), 1.54 (t, 3H, CH3 ethyl,
J = 7.2 Hz) and 0.11 [s, 9H, (CH3)3Si]. 13C NMR (δ, DMSO-d6): 141.1
(NCHN), 132.3, 131.2, 126.9, 126.7, 114.5 and 114.0 (C6H4), 42.5
(CH2 ethyl), 38.4 (CH2Si), 14.9 (CH3 ethyl) and −2.2 [(CH3)3Si].
Similarly, 1-(trimethylsilyl)methyl-3-isopropylbenzimidazolium
iodide, 4 was synthesized from 1-(trimethylsilyl)methylbenz-
imidazole and 2-iodopropane. Yield, 1.41 g (yellow crystals), 75%;
m.p., 96–98 ◦C; υ(CN) = 1486 cm−1. Anal. found: C 44.88, H 6.18,
N 7.43. Calcd for C14H23N2ISi: C 44.92, H 6.19, N 7.48. 1H NMR
(δ, DMSO-d6): 9.82 (s, 1H, NCHN), 8.18–7.61 (m, 4H, C6H4), 5.10
(sept, 1H, CH isopropyl, J = 6.6 Hz), 4.24 (s, 2H, CH2Si), 1.64 (d,
6H, CH3 isopropyl, J = 6.6 Hz) and 0.10 [s, 9H, (CH3)3Si]. 13C NMR
(δ, DMSO-d6): 139.9 (NCHN), 132.3, 130.8, 126.8, 126.3, 114.4 and
113.8 (C6H4), 50.9 (CH isopropyl), 38.6 (CH2Si), 22.3 (CH3 isopropyl)
and −2.1 [(CH3)3Si].
General Procedure for the Suzuki Reactions
Pd(OAc)2 (1 mmol%), benzimidazolium halides (2–7; 2 mmol%),
aryl halide (1 mmol), phenylboronic acid (1.2 mmol), K2CO3
Similarly,
1-(trimethylsilyl)methyl-3-propylbenzimidazolium
bromide, 5 was synthesized from 1-(trimethylsilyl)methylbenz-
imidazole and 1-bromopropane. Yield, 1.44 g (white crystals),
88%; m.p., 86–87 ◦C; υ(CN) = 1481 cm−1. Anal. found: C 51.35, H
7.08, N 8.49. Calculated for C14H23N2BrSi: C 51.37, H 7.08, N 8.56.
1H NMR (δ, DMSO-d6): 9.78 (s, 1H, NCHN), 8.14–7.61 (m, 4H, C6H4),
4.51 (t, 2H, CH2 propyl, J = 7.2 Hz), 4.25 (s, 2H, CH2Si), 1.92 (sextet,
2H, CH2 propyl, J = 7.2 Hz), 0.91 (t, 3H, CH3 propyl, J = 7.2 Hz) and
0.10 [s, 9H, (CH3)3Si]. 13C NMR (δ, DMSO-d6): 141.5 (NCHN), 132.3,
131.4, 126.9, 126.7, 114.5 and 114.1 (C6H4), 48.4 (CH2 propyl), 38.4
(CH2Si), 22.6 (CH2 propyl), 11.1 (CH3 propyl) and −2.2 [(CH3)3Si].
Table 1. The crystal data, data collection and refinement values of
compound 1
Crystal data
C
11H15N3O2Si
Z = 12
Mr = 249.35
Dx = 1.298 mg m−3
Cu Kα radiation
µ = 1.60 mm−1
T = 100 K
Monoclinic, P21/c
a = 6.6049 (2) Å
b = 10.0291 (3) Å
c = 57.7965 (15) Å
β = 91.599 (1)◦
Similarly,
3-nbutyl-1-(trimethylsilyl)methylbenzimidazolium
Crystal shape needle, colorless
Crystal dimensions:
chloride, 6 was synthesized from 1-(trimethylsilyl)methylbenz-
imidazole and 1-chlorobutane. Yield, 1.06 g (white crystals), 71%;
m.p., 125–126 ◦C; υ(CN) = 1488 cm−1. Anal. found: C 60.63, H 8.48,
0.05 × 0.05 × 0.20 mm3
V = 3827.02 (19) Å3
1
N 9.36. Calcd for C15H25N2ClSi: C 60.68, H 8.49, N 9.43. H NMR
Data collection
Bruker X8 Prospector
diffractomer
θmax = 62.1◦
(δ, DMSO-d6): 9.95 (s, 1H, NCHN), 8.15–7.66 (m, 4H, C6H4), 4.55 (t,
2H, CH2 butyl, J = 7.2 Hz), 4.26 (s, 2H, CH2Si), 1.89 (quint, 2H, CH2
butyl, J = 7.2 Hz), 1.31 (sextet, 2H, CH2 butyl, J = 7.2 Hz), 0.92
(t, 3H, CH3 butyl, J = 7.2 Hz) and 0.09 [s, 9H, (CH3)3Si]. 13C NMR
(δ, DMSO-d6): 141.6 (NCHN), 132.2, 131.4, 126.9, 126.7, 114.5 and
114.1 (C6H4), 46.8 (CH2 butyl), 38.3 (CH2Si), 31.1 (CH2 butyl), 19.5
(CH2 butyl), 13.8 (CH3 butyl) and −2.2 [(CH3)3Si].
ω and φ scans
h = −7 → 7
Absorption correction:
multi-scan (based
k = −11 → 11
on symmetry-related
measurements)
l = −65 → 62
Tmin = 0.740, Tmax = 0.740
34 644 measured reflections
5995 independent reflections
5950 reflections with I > 2σ(I)
Rint = 0.043
Synthesis of 3-methyl-1-(trimethylsilyl)methyl-6-nitrobenzimida-
zolium iodide, 7
A mixture of 1-(trimethylsilyl)methyl-6-nitrobenzimidazole (1.1 g,
4.41 mmol) and iodomethane (0.30 ml, 4.80 mmol) in dimethyl-
formamide (5 ml) was refluxed for 3 h. The mixture was then
cooled and the volatiles were removed under vacuum. The residue
was crystallized from a dimethylformamide–ethanol (1 : 1). Yellow
crystals of the title compound 7 (1.54 g, 89%) were obtained, m.p.
206–208 ◦C; υ(CN) = 1474 cm−1. Anal. found: C 36.72, H 4.63, N
10.61. Calcd for C12H18N3O2ISi: C 36.84, H 4.64, N 10.74. 1H NMR
(δ, DMSO-d6): 9.84 (s, 1H, NCHN), 9.19–8.27 (m, 3H, C6H3), 4.37
(s, 2H, CH2Si), 4.15 (s, 3H, CH3), 0.14 [s, 9H, (CH3)3Si]. 13C NMR
Refinement
Refinement on F2
R[F2 > 2σ(F2)] = 0.048
H atoms constrained to parent site
Calculated weights w =
1/[σ2(Fo2) + (0.071P)2 + 3.3398P]
2
where P = (Fo + 2Fc2)/3
wR(F2) = 0.126
S = 1.12
(ꢀ/σ)max < 0.0001
ꢀρmax = 0.81 e Å−1
5995 reflections
469 parameters
ꢀρmin = −0.28 e Å−1
Extinction correction: none
c
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Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 366–373

Microwave-promoted catalytic activity in Suzuki–Miyaura cross-coupling reactions
(2 mmol), water (3 ml) and DMF (3 ml) were added to microwave
apparatusandthemixturewasheatedat120 ◦C(300 W)for10 min.
It was carried out ramp time 3 min to reach 120 ◦C. At the end of
the reaction, the mixture was cooled, the product extracted with
ethylacetate–n-hexane(1 : 5)andchromatographedonasilicagel
column. The purity of coupling products was checked by NMR and
GC-MS, and yields are based on aryl halide. The coupling products
were confirmed by increasing the peaks on gas chromatograms
and mass values from MS spectrums. All coupling products were
also isolated and characterized by 1H-NMR or MS before the serial
catalytic work up each time.
of the tested compounds were 800, 400, 200, 100, 50, 25, 12.5, 6.25
and 3.12 µg ml−1. Ampicilin and fluconazole from FAKO (Istanbul,
Turkey) were used as a reference compound for the experimental
conditions. A loopful (0.01 ml) of the standardized inoculum of the
bacteria and yeasts (106 CFUs ml−1) was spread over the surface
of agar plates. All of the inoculated plates were incubated at 35 ◦C
andresultswereevaluatedafter16–20 hofincubationforbacteria
and 48 h for yeasts. The lowest concentration of the compounds
that prevented visible growth was considered to be the minimal
inhibitory concentration (MIC).
The Suzuki coupling yields between phenylboronic acid and
4-bromoacetophenone were also determined as a isolated yield
for the comparison purposes with the GC-based yields (Table 3
entries, 6–11). The isolated yields were determined as follows: at
the end of the Suzuki coupling reaction, the mixture was cooled
to room temperature, the contents of the reaction vessel were
poured into a separatory funnel. Water (3 ml) and ethyl acetate
(5 ml) were added, and the coupling product was extracted and
removed. After further extraction of the aqueous phase with ethyl
acetate (5 ml) and combining the extracts, the ethyl acetate was
removed in vacuo, leaving the p-acetylbiphenyl product as a pale
white solid, which was characterized by comparison of NMR data
with that in the literature.
Results and Discussion
1-(Trimethylsilyl)methyl-6-nitrobenzimidazole, 1, was synthesized
from 5(6)-nitrobenzimidazole and KOH in refluxing EtOH in
moderate yield of 64%. The molecular structure of compound
1 was confirmed by single crystal X-ray diffraction to clarify the
nitro group position 5 or 6 for the tautomerization of starting 5(6)-
nitrobenzimidazole compound. Its molecular structure is depicted
in Figure 2.
The compound 1, C11H15N3O2Si, crystallizes in the monoclinic
P 21/c space group by three crystallographically independent
formula units in the asymmetric cell. Intermolecular C–H N and
· · ·
· · ·
C–H O interactions contribute to the stability of the molecular
structure. The π –π interaction involves the two benzene rings
in the same asymmetric unit whose centroids are separated by
3.4157 (11) Å.
Biological Activity: Methods of Antimicrobial Testing
Antimicrobial activities of the compounds were determined by us-
ing agar dilution procedure outlined by the National Committee
for Clinical Laboratory standards.[47,48] Minimal inhibitory concen-
trations for each compound were investigated against standard
bacterial strains: Staphylococcus aureus ATCC 29213, Enterococcus
faecalis ATCC 29212, Escherichia coli ATCC 25922, Pseudomonas
aeruginosaATCC27853andtheyeastsCandidaalbicansandC.trop-
icalis obtained from the Department of Microbiology, Faculty of
Medicine, Ege University (Turkey). The stock solutions of the com-
pounds were prepared in dimethylsulfoxide (DMSO), which had
noeffectonthemicro-organismsintheconcentrationsstudied. All
of the dilutions were done with distilled water. The concentrations
In the asymmetric unit of the compound 1 (Fig. 1), the three
benzimidazole ring systems A(N1/N2/C1–C7), B(N4/N5/C12–C18)
and C(N7/N8/C23–C29) are almost planar, with maximum devi-
ations of −0.022(2) for C6, 0.013(2) for C12 and −0.014(2) for
C25. The dihedral angles between them are A/B = 0.68(6)◦, A/C
= 46.34(6)◦ and B/C = 46.85(6)◦. The silicon atoms have a dis-
torted tetrahedral geometry with angles ranging from 106.02(18)
to 113.60(17)◦. The crystal data, data collection and refinement
values of the compound 1 are given in Table 1.
· · ·
· · ·
The crystal structure is stabilized by C–H N and C–H
hydrogen-bonding interactions (Fig. 2 and Table 2) and π –π
O
Figure 1. The three independent molecules in the asymmetric unit showing the atom-labeling scheme of 1. The probability level for the anisotropic
displacement parameters is at 50%.
c
Appl. Organometal. Chem. 2011, 25, 366–373
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
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¨
U. Yılmaz et al.
Figure 2. Packing view of the title compound in the unitcell. Hydrogen bonds are indicated as dashed lines.
The Suzuki–Miyaura Coupling Reactions
Table 2. Hydrogen-bond parameters (Å, deg)
The Suzuki–Miyaura reaction is one of the most versatile and
utilized reactions for the selective construction of carbon–carbon
bonds, in particular for the formation of biaryl and heterobiaryl
derivatives.[2,24] The catalytic yield of the coupling is dependent
on a variety of parameters such as temperature, solvent, base and
nature of catalyst loading. We recently reported the optimum re-
action conditions for the Suzuki/Heck coupling reaction, including
some benzimidazolium or bis-benzimidazolium salts–Pd(OAc)2
and base as a catalyst system under microwave and conven-
tional heating conditions.[27,53,54] In the present report, a series
of aryl chloride and aryl bromide were used for coupling partner
with phenylboronic acid. Since relatively less reactive aryl chlo-
ride was used, the recently reported optimum parameters were
slightly modified for temperature (120 ◦C/300 W) and reaction
time (10 min) after test reactions using phenylboronic acid and
4-bromoacetophenone (Table 3 entries 1–5). Finally, we found
that the use of 1% Pd(OAc)2, 2% mol of 2–7 and 2% mol K2CO3
in DMF–H2O (1 : 1) at 120 ◦C/300 W microwave heating led to the
best conversation within 10 min.
· · ·
· · ·
· · ·
D–H
H
A
D
A
D–H
A
i
· · ·
C2–H2 O2
0.95
0.99
0.98
0.95
0.99
0.99
0.98
0.98
2.59
3.174 (3)
3.525 (2)
3.324 (3)
3.320 (3)
3.554 (2)
3.318 (3)
3.361 (3)
3.523 (3)
120
ii
· · ·
C8–H8B N1
2.59
2.46
2.38
2.61
2.53
2.55
2.59
157
147
169
160
137
140
158
iii
i
· · ·
C10–H10B O3
ii
· · ·
C18–H18 N7
· · ·
C19–H19A N4
· · ·
C30–H30A O1
· · ·
C32–H32B O1
iv
· · ·
C33–H33B O5
Symmetry codes: (i) −1 + x, y, z; (ii) 1 + x, y, z; (iii) 1 − x, −1/2 + y,
1/2 − z; (iv) -x, 2 − y, −z.
interactions between the benzene rings of the adjacent molecules
in the same asymmetric unit whose centroids are separated by
3.4157(11) Å (Table 2).
Benzimidazolium salts containing trimethylsilyl moiety,
2–7, were prepared by treatment of 1-(trimethylsilyl)methyl-
benzimidazole or 5-nitro-1-(trimethylsilyl)methylbenzimidazole
with appropriate alkyl halides in refluxing DMF with good yields
of 71–89%. The synthesis of the benzimidazolium salts 2–7 is
summarized in Scheme 1. The benzimidazolium salts are air- and
moisture-stable both in the solid state and in solution. The eight
new benzimidazole derivatives were characterized by 1H NMR,
After having established the optimized coupling reaction con-
ditions, the scope of the reaction and efficiencies of the benzimi-
dazolium salts were evaluated by investigating the coupling of the
phenylboronic acid with various p-substituted aryl halides. Under
the optimized conditions, reaction of p-bromoacetophenone, p-
chloronitrobenzene, p-chlorobenzaldehyde and p-chlorotoluene
with phenylboronic acid gave almost as high a yield using a
catalytic system consisting of 2 mol% benzimidazole salts (2–7),
1 mol% Pd(OAc)2 and 2 equiv. K2CO3 in DMF–H2O (1 : 1) at 120 ◦C
by microwave irradiation (300 W) within 10 min. On the other
hand, strong electron donating groups on the aryl chlorides such
as p-chloroanisole, p-chloroaniline and p-chlorothioanisole gave a
low or moderate yield using the optimized conditions. It is note-
worthy that aryl chlorides are arguably the most useful substrates
because of their lower cost and the wide range of commercially
available compounds.[6] We also tested the catalytic yields using
conventional heating system in a preheated oil bath at 10 min at
120 ◦C, but we obtained only 13% yield using benzimidazole salt,
2, and p-bromoacetophenone in optimized conditions (Table 3,
entry 5). Control experiments showed that the Suzuki coupling
reaction did not occur in the absence of 2–7 in 10 min under mi-
crowave heating. The results obtained from optimum conditions
for the Suzuki reactions are given in Table 3. Of the seven differ-
ent aryl halides used in the Suzuki coupling with phenylboronic
acid, those with electron-withdrawing substituents were found to
give the highest yield (Table 3, entries 6–23). Benzimidazole salt
bearing an electron-withdrawing nitro substituent (7) was found
to be the least effective of the salts examined in Suzuki cou-
pling reactions (Table 3, entries 17, 23, 30, 36, 42 and 48). On the
1
13C { H} NMR, IR and elemental analysis techniques which sup-
1
port the proposed structures. The value of δ[13C{ H}], NCHN in
benzimidazolium salts is usually around 142 4.[40] For benz-
imidazolium salts 2–7 it was found to be 141.9, 141.1, 139.9,
141.5, 141.6 and 146.0 ppm, respectively. These values are in
good agreement with the previously reported results.[27,49] In the
1H NMR spectrum of 1-(trimethylsilyl)methylbenzimidazole,I and
1-(trimethylsilyl)methyl-6-nitrobenzimidazole, 1 compounds for
NCHN proton were observed as singlets at 8.10 and 8.54 ppm,
respectively.
The NCHN proton signals for the benzimidazolium salts were
observed as singlets at 9.60, 9.70, 9.82, 9.78, 9.95 and 9.84 ppm,
respectively. As expected, the NCHN proton signals were shifted
downfield about 1.06–1.85 ppm. These chemical shift values
are also typical for NCHN protons of benzimidazolium salts for
increasing the acidity of the NCHN proton.[27,50–52]
The carbon–nitrogen band frequencies, ν(C
for benzimida-
N)
zole compounds I[41] and 1 were observed at 1489–1490 cm−1
,
respectively. These bands were observed at 1474–1488 cm−1 for
the benzimidazolium salts, 2–7. The π-electron delocalization on
the imidazolium ring may be responsible for the slight red shift.
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 366–373

Microwave-promoted catalytic activity in Suzuki–Miyaura cross-coupling reactions
other hand, benzimidazole salts bearing electron-donating alkyl
Table 3. The Suzuki–Miyaura coupling reactions of aryl halides with
group are beneficial for better catalytic activity in Suzuki coupling
reactions. Similar catalytic results for the Suzuki cross-coupling re-
actions have also been obtained from Pd(OAc)2 or PdCl2, base and
benzimidazole or imidazole catalytic systems which bear different
aryl, substituted aryl, alky and substituted alkyl on benzimidazole
or imidazole ligands.[8,9,16,17,55]
phenylboronic acid
Pd(OAc)2 (1 mol %)
2-7 (2 mol %), mw(300 W)
B(OH)2
R
X
R
+
DMF/ H2O (1:1),120 °C, 10min
K2CO3 (2 equiv)
Entry
R
X
Salt
Yield (%)
Itisimportanttonotethattheendpointoftheallthesereactions
was clearly observed black particles in the reaction mixture, which
probably derived from palladium nanoparticles. As can be seen in
Table 3, a high yield of C–C coupling product was obtained from
reaction of aryl bromides with phenylboronic acid, as expected.
1
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
NO2
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
no
2
2
3
4
5
6
7
7
2
3
4
5
6
7
2
3
4
5
6
7
2
3
4
5
6
7
2
3
4
5
6
7
2
3
4
5
6
7
2
3
4
5
6
7
69a
74b
87c
ndd
13e
99 93f
99 94f
99 93f
99 95f
99 96f
99 94f
99
2
3
4
5
Antimicrobial Activity
6
7
The antimicrobial and antifungal activity results (MIC) are given in
Tables 2 and 3, respectively. Tables 4 and 5 also contain results for
ampicillin and fluconazole as reference compounds.
8
9
10
11
11
12
13
14
15
16
17
18
19
20
21
22
23
24
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
Trimethylsilyl substituted benzimidazole derivatives were syn-
thesized and tested against standard strains of Gram-positive (E.
faecalis and S. aureus) and Gram-negative (E. coli and P. aerug-
inosa) bacteria and yeasts (C. albicans and C. tropicalis). As can
be seen in Table 4, all tested compounds in this work showed
some antibacterial activity against both Gram-positive and Gram-
83
NO2
87
NO2
82
negative bacteria with MICs between 6.25 and 400 µg ml−1
.
NO2
94
NO2
90
Among the tested compounds I showed the highest activity
against both Gram-positive and Gram-negative bacteria with MIC
value 6.25 µg ml−1. The compounds 2 and 4 also exhibited high
NO2
77
CHO
79
CHO
82
CHO
73
CHO
91
Table 4. The Minimum antibacterial inhibitory concentrations (µg
cm−3) of the tested compounds
CHO
80
CHO
64
Tested microorganisms
CH3
75
CH3
86
Compound no.
E. faecalis
S. aureus
E. coli
P. aeruginosa
CH3
81
Ampicillin
0.78
6.25
400
50
0.39
12.5
400
50
3.12
200
800
400
400
400
400
400
800
>75
400
800
400
400
400
400
400
800
CH3
80
I
CH3
84
1
2
3
4
5
6
7
CH3
69
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
NH2
57
200
50
200
50
65
59
200
400
400
200
400
400
70
74
40
54
NH2
55
NH2
51
Table 5. The minimum antifungal inhibitory concentrations
(µg cm−3) of the tested compounds
NH2
77
NH2
68
Tested organism
NH2
38
SCH3
SCH3
SCH3
SCH3
SCH3
SCH3
56
Compound no.
C. albicans
C. tropicalis
34
Fulconazole
1.25
6.25
400
50
1.25
6.25
200
25
45
I
44
1
2
3
4
5
6
7
45
39
100
50
100
25
Yields are based on aryl halide. Reactio◦ns were monitored by GC-MS.
Conditions: temperature ramped to 90◦ C (3 min) and held for a 5 and
b 10 min. Temperature ramped to 120 C (3 min) and held for c 5 min.
Temperature ramped to 120 ◦C (3 min) and held for d 10 min without
salt (2). On preheated oil bath, e 10 min with thermal heating. f Isolated
yields. n.d., Not detected.
100
100
400
100
100
400
c
Appl. Organometal. Chem. 2011, 25, 366–373
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

¨
U. Yılmaz et al.
activity against Gram-positive bacteria with MIC value 50 µg ml−1
Compound I also showed the highest activity against Gram-
negative bacteria E. coli with MIC value 200 µg ml−1
.
[7] E. A. B. Kantchev, C. J. O’Brien, M. G. Organ, Angew. Chem. Int. Ed.
2007, 46, 2768.
[8] C. S. Linninger, E. Herdtweck, S. D. Hoffmann, W. A. Herrmann,
J. Mol. Struct. 2008, 890, 192.
.
As can be seen from Table 5, all compounds were found to be
effective against C. tropicalis, with a range of MICs between 25
and 50 µg ml−1. Among the tested compounds, I also showed the
highest antifungal activity against C. albicans and C. tropicalis with
MIC values of 6.25 µg ml−1. Compounds 2 and 4 also exhibited
significant antifungal activity against C. albicans and C. tropicalis
with a range of MICs between 25 and 50 µg ml−1. From the data
obtained in this work, it is suggested that increased hydrophobic
character of the benzimidazole derivatives may play some role in
the antimicrobial activities.
[9] R. Singh, M. S. Viciu, N. Kramareva, O. Navarro, S. P. Nolan, Org. Lett.
2005, 7, 1829.
[10] N. Marion, S. P. Nolan, Accounts Chem. Res. 2008, 41, 1440.
[11] F. E. Hahn, M. C. Jahnke, T. Pape, Organometallics 2006, 25, 5927.
[12] E. C¸etinkaya, P. B. Hitchock, H. Ku¨c¸u¨kbay, M. F. Lappert, S. Al-Juaid,
J. Organomet. Chem. 1994, 481, 89.
[13] H. Ku¨c¸u¨kbay,B. C¸etinkaya,S. Guesmi,P. H. Dixneuf, Organometallics
1996, 5, 2434.
[14] B. C¸etinkaya,
E. C¸etinkaya,
J. A. Chamizo,
P. H. Hitchcock,
H. A. Jasim, H. Ku¨c¸u¨kbay, M. F. Lappert, J. Chem. Soc., Perkin
Trans. 1 1998, 2047.
[15] H. Ku¨c¸u¨kbay, E. C¸etinkaya, B. C¸etinkaya and M. F. Lappert, Synth.
Commun. 1997, 27, 4059.
¨
[16] Y. Go¨k, N. Gu¨rbu¨z, Y. Ozdemir, B. C¸etinkaya, E. C¸etinkaya, Appl.
Organomet. Chem. 2005, 19, 870.
Conclusion
¨
[17] S. Demir, I. Ozdemir, B. C¸etinkaya, Appl.Organomet.Chem. 2006, 20,
254.
We prepared one 1-substituted benzimidazole (1) and six
benzimidazole salts containing trimethylsilylmethyl substituent
(2–7). The use of the palladium catalyst system including
benzimidazolium salts in Suzuki coupling reaction gives better
yield under microwave-assisted conditions and short reaction
times compared with those given in literature.
The Suzuki coupling reactions were carried out using 300 W
power microwave irradiation at 120 ◦C in 10 min. The precatalysts
used in this work were prepared from the corresponding
benzimidazole salts (2–7) directly, thereby avoiding the handling
of an isolated highly moisture- and air-sensitive carbene. It can be
concluded that Suzuki reaction may be accelerated by microwave
irradiation even using aryl chlorides particularly bearing electron-
withdrawing substituents. To confirm position of NO2 group
in compound 1, crystal structural analysis was also performed
and the position of NO2 was determined as the 6 position of
the benzimidazole ring. Compounds I and 2–4 were found to
be effective in inhibiting the growth of Gram-positive bacteria
(E. faecalis and S. aureus) and yeast-like fungi (C. albicans and
C. tropicalis)
˙
¨
[18] I. Ozdemir, M. Yigˇit, E. C¸etinkaya, B. C¸etinkaya, Appl. Organomet.
Chem. 2006, 20, 187.
[19] C. O. Kappe, Angew. Chem. Int. Ed. 2004, 43, 6250.
[20] H. Prokopvova, J. Ramirez, E. Fernandez, C.O. Kappe, Tetrahedron
Lett. 2008, 49, 4831.
[21] T. N. Glasnov, S. Findenig, C.O. Kappe, Chem. Eur. J. 2009, 15, 1001.
[22] N. E. Leadbeater, M. Marco, Org.Lett. 2002, 4, 2973.
[23] K. B. Avery, W. G. Devine, C. M. Kormos, N. E. Leadbeater, Tetrahe-
dron Lett. 2009, 50, 2851.
[24] F. Chanthavong, N. E. Leadbeater, Tetrahedron Lett. 2006, 47, 1909.
[25] R. K. Arvela, N. E. Leadbeater, Org. Lett. 2005, 7, 2101.
[26] P. Appukkuttan, E. Van der Eycken, Eur. J. Org. Chem. 2008, 1133.
¨
[27] U. Yılmaz, N. S¸ireci, S. Deniz, H. Ku¨c¸u¨kbay, Appl. Organomet. Chem.
2006, 20, 254.
[28] E. Lukevics, P. Arsenyan, I. Shestakova, I. Domracheva, A. Nesterova,
O. Pudova, Eur. J. Med. Chem. 2001, 36, 507.
[29] L. Ignatovich, V. Muravenko, I. Shestakova, I. Domrachova,
J. Popelis, E. Lukevics, Appl. Organomet. Chem. 2010, 24, 158.
[30] A.K. Singh, J.W. Lown, Anti-Cancer Drug Des. 2000, 15, 265.
[31] S-T. Huang, I-J. Hsei, C. Chen, Bioorg. Med. Chem. 2006, 14, 6106.
[32] P.R. Turner, W. A. Denny, Mutation Res. 1996, 355, 141.
[33] S.A. Galal, K.H. Hegab, A.S. Kassab, M.L. Rodriguez, S. M. Kerwin,
A-M. A. El-Khamry, H.I. E. Divani, Eur. J. Med. Chem. 2009, 44, 1500.
[34] E. Carlsson, P. Lindberg, S. Unge, Chem. Britain 2002, 5, 42.
[35] S.K. Kotovskaya, Z.M. Basakova, V.N. Charushin, O.N. Chupakhin,
E. F. Belanov, N.I. Bormotov, S.M. Balakhnin, O.A. Serova, Pharm.
Chem. J. 2005, 39, 574.
Supporting Information
Supporting information can be found in the online version
of this article. CCDC holds the supplementary crystallographic
data 794 108. These data can be obtained free of charge
via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; Fax (+44) 1223-336-033; or email de-
posit@ccdc.cam.ac.uk.
[36] B. C¸etinkaya, E. C¸etinkaya, H. Ku¨c¸u¨kbay, R. Durmaz, Arzneim.
Forsch/Drug Res. 1996, 46, 1154.
[37] B. C¸etinkaya, E. C¸etinkaya, H. Ku¨c¸u¨kbay, R. Durmaz, Arzneim.
Forsch/Drug Res. 1996, 46, 821.
[38] H. Ku¨c¸u¨kbay, E. C¸etinkaya, R. Durmaz, Arzneim. Forsch/Drug Res.
1995, 45, 1331.
[39] H. Ku¨c¸u¨kbay, B. Durmaz, Arzneim. Forsch/Drug Res. 1997, 47, 667.
[40] H. Ku¨c¸u¨kbay, R. Durmaz, N. Okuyucu, S. Gu¨nal, C. Kazaz, Arzneim.
Forsch/Drug Res. 2004, 54, 64.
[41] N. S¸ireci, H. Ku¨c¸u¨kbay, M. Akkurt, S¸. P. Yalc¸ın, M. N. Tahir, H. Ott,
Acknowledgment
J. Coord. Chem. 2010, 63, 3218.
[42] SADABS: G. M. Sheldrick, 2008/1, Go¨ttingen, 2008.
[43] SIR97: A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano,
We thank Dr Holger Ott (Bruker AXS GmbH, Karlsruhe, Germany)
˙
for the data collection. We wish to thank Ino¨nu¨ University Research
C. Giacovazzo, A. Guagliardi,
A. G. G. Moliterni, G. Polidori,
Fund (BAPB-2010/124) for financial support of this study.
R. Spagna, J. Appl. Cryst. 1999, 32, 115.
[44] SHELX: G. M. Sheldrick. Acta Crystallogr. 2008, A64, 112.
[45] PLATON: A. L. Spek, J. Appl. Crystallogr. 2003, 36, 7.
[46] ORTEP-3: L. J. Farrugia, J. Appl. Crystallogr. 1997, 30, 565.
[47] National Committee for Clinical Laboratory Standards (NCCLS),
Methods for dilution antimicrobial susceptibility tests for bacteria
that grow aerobically, Approved Standard M7-A2, NCCLS Villanova,
PA, 1997.
References
[1] A. Suzuki, Pure Appl. Chem. 1985, 57, 1749.
[2] N. Miyaura, A Suzuki, Chem. Rev. 1995, 95, 2457.
[3] F. Alonso, I. P. Beletskaya, M. Yus, Tetrahedron 2008, 64, 3047.
[4] L. Yin, J. Liebscher, Chem. Rev. 2007, 107, 133.
[5] A. Tudose, L. Delaude, B. Andre, A. Demonceau, Tetrahedron Lett.
2006, 47, 8529.
[48] NCCLS, Reference method for broth dilution antifungal
susceptibilitytestingofyeasts. ProposedStandard. DocumentM27-
P. NCCLS, Villanova, PA, 1992.
¨
[49] I. Ozdemir, Y. Go¨k, N. Gu¨rbu¨z, E. C¸etinkaya, B. C¸etinkaya, Synth.
[6] L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem. Int. Ed. 2009,
48, 9792.
Commun. 2004, 34, 4135.
c
wileyonlinelibrary.com/journal/aoc
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 366–373

Microwave-promoted catalytic activity in Suzuki–Miyaura cross-coupling reactions
¨
¨
[50] M. Akkurt, S. Tu¨rktekin, H. Ku¨c¸u¨kbay, U. Yılmaz, O. Bu¨yu¨kgu¨ngo¨r,
[53] N. S¸ireci, U. Yılmaz, H. Ku¨c¸u¨kbay, Asian J. Chem. 2010, 22, 7153.
¨
Acta Cryst. E. 2005, 61, o166.
[54] H. Ku¨c¸u¨kbay, N. S¸ireci, U. Yılmaz, M. Akkurt, S¸.P. Yalc¸ın, M.N. Tahir,
[51] H. Ku¨c¸u¨kbay, R. Durmaz, M. Gu¨ven, S. Gu¨nal, Arzneim.-Forsch./Drug
Res. 2001, 51, 420.
[52] M. Akkurt, S.O. Yıldırım, H. Ku¨c¸u¨kbay, U. Yılmaz, O. Bu¨yu¨kgu¨ngo¨r,
H. Ott, Appl. Organomet. Chem. 2011, 25, DOI 10.1002/aoc.175.
[55] W. Huang, J. Guo, Y. Xiao, M. Zhu, G. Zou, J. Tang, Tetrahedron 2005,
61, 9783.
¨
¨
Acta Cryst. E. 2005, 61, o301.
c
Appl. Organometal. Chem. 2011, 25, 366–373
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
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