N-Heterocyclic carbene-Pd(II)-PPh3 complexes as a new highly efficient catalyst system for the Sonogashira cross-coupling reaction: Synthesis, characterization and biological activities

Article abstract of DOI:10.1080/00958972.2018.1430791

A novel series of N-heterocyclic carbene-phosphine palladium(II) complexes has been synthesized and fully characterized by IR, ¹H NMR, ¹³C NMR, and ³¹P NMR spectroscopies, and elemental analysis. The new N-heterocyclic car

Full text of DOI:10.1080/00958972.2018.1430791

Journal of Coordination Chemistry
ISSN: 0095-8972 (Print) 1029-0389 (Online) Journal homepage: http://www.tandfonline.com/loi/gcoo20
N-Heterocyclic carbene-Pd(II)-PPh3 complexes
as a new highly efficient catalyst system for the
Sonogashira cross-coupling reaction: Synthesis,
characterization and biological activities
L. Boubakri, L. Mansour, A.H. Harrath, I. Özdemir, S. Yaşar & N. Hamdi
To cite this article: L. Boubakri, L. Mansour, A.H. Harrath, I. Özdemir, S. Yaşar & N. Hamdi
(2018): N-Heterocyclic carbene-Pd(II)-PPh3 complexes as a new highly efficient catalyst system
for the Sonogashira cross-coupling reaction: Synthesis, characterization and biological activities,
Journal of Coordination Chemistry, DOI: 10.1080/00958972.2018.1430791
To link to this article: https://doi.org/10.1080/00958972.2018.1430791
Accepted author version posted online: 22
Jan 2018.
Submit your article to this journal
Article views: 2
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gcoo20

Publisher: Taylor & Francis
Journal: Journal of Coordination Chemistry
DOI: http://doi.org/10.1080/00958972.2018.1430791
N-Heterocyclic carbene-Pd(II)-PPh3 complexes as a new highly efficient
catalyst system for the Sonogashira cross-coupling reaction: Synthesis,
characterization and biological activities
L. BOUBAKRI1, L. MANSOUR2, A.H. HARRATH2, I. ÖZDEMIR3, S. YAŞAR3 and N. HAMDI*1,4
1Research Laboratory of Environmental Sciences and Technologies (LR16ES09), Higher Institute of Environmental
Sciences and Technology, University of Carthage, Hammam-Lif 2050, Tunisia
2Zoology Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
3İnönü University, Faculty of Science and Art, Department of Chemistry, Malatya 44280, Turkey
4Chemistry Department, College of Science and Arts, Qassim University, Al-Rass, 51921, Kingdom of Saudi Arabia
A novel series of N-heterocyclic carbene-phosphine palladium(II) complexes has been
synthesized and fully characterized by IR, 1H NMR, 13C NMR and 31P NMR spectroscopies, and
elemental analysis. The new N-heterocyclic carbene (NHC)-phosphine palladium(II) complexes
3a-h have been easily prepared by the reaction of the corresponding PEPPSI (pyridine-enhanced
precatalyst preparation stabilization and initiation) complexes 2a-h and triphenylphosphine in
dichloromethane in high yields. These complexes were applied as catalyst precursors which
efficiently catalyzed Sonogashira reactions between aryl bromides and phenylacetylene to afford
the corresponding products in good yields. The bulky NHC-Pd-PPh3 complexes 3 were tested
against Gram-positive and Gram-negative bacteria to study their biological activity. All the
complexes exhibit antibacterial against these organisms. Investigation of the anti-
acetylcholinesterase activity of the studied complexes showed that compounds 3a and 3b
exhibited moderate activity at 100 μg/mL and product 3b is the most active.
Keywords: N-Heterocyclic carbine; Sonogashira reaction; Palladium catalyst; Biological
activities
*Corresponding author. Email: hamdi_naceur@yahoo.fr
1

Br
R1
Y
Y
Cl
Pd
Cl
N
P
N
R2
Cu free
Scheme 1. Sonogashira cross coupling reaction of aryl bromides with phenylacetylene.
1. Introduction
Since the discovery of the first N-heterocyclic metal-carbene complexes in 1968 by the Öfele [1]
and Wanzlick [2] groups, these compounds have aroused great interest in the field of
coordination chemistry, which has been redoubled after the isolation of the first free-NHC in
1991 by Arduengo [3]. Later studies from Herrmann showed that NHC and phosphine have
important similarities in properties, which make them particularly useful ligands for applications
in catalysis [4]. However, NHCs are in general more σ-donating and have lower electronic
parameters than phosphines. This leads to the remarkable stability of the metal-carbene bond.
Different transition metal-NHC complexes have been synthesized [5] and used as catalyst on
various organic transformations [6]. The prominence of metal-NHC complexes is likely due to
their catalytic efficiency and robustness against air, moisture and high temperature. The basis of
this interest lies in the facile modulation of electronic and steric parameters reflected by a strong
σ-donor and weak π-acceptor ability of NHC ligand. Complexes bearing sterically bulky and
electron-rich ligands exhibit enhanced catalytic activity in oxidative addition and reductive
elimination reactions that are key elemental steps of many catalytic reactions [7].
Palladium-catalyzed carbon-carbon bond forming reactions such as the Suzuki Miyaura
[8], Heck [9], and Sonogashira [10] coupling reactions are important synthetic transformations
that are widely employed for the preparation of a great variety of complex organic molecules and
materials such as natural products, fine chemicals, drugs, agrochemicals, and polymers [11]. The
palladium-catalyzed coupling of aryl halides with aryl boronic acids (Suzuki-Miyaura coupling)
or terminal alkynes (Sonogashira-Hagihara coupling) represent the most successful methods for
the preparation of biaryls and internal acetylenes, respectively. These reactions have shown to
2

have widespread applications in the synthesis of natural products, biologically active molecules,
and materials science [12-17]. Many catalytic systems have been developed for the Suzuki-
Miyaura and Sonogashira-Hagihara cross-coupling reactions using different palladium catalysts
such as [Pd(PPh3)4], [Pd(OAc)2], [PdCl2(PPh3)2], and [PdCl2(CH3CN)2] [18-20]. However,
phosphine ligands used in these reactions are sensitive to air oxidation and thus require air-free
conditions which pose significant inconvenience on synthetic applications [21-23].
Phosphine ligands have emerged as some of the most widely utilized ligands in catalysis.
Phosphines are used because of their activation of a metal center towards desired reactivity. In
particular, ligands including trialkylphosphines [24-26] and dialkyl(2-biphenyl)phosphines
[27-29] have emerged as the most widely used. Carbene ligands have been used as well [30-34].
The Sonogashira reaction constitutes an effective and versatile method of generating non-
terminal alkynes from terminal alkynes. It has found wide-spread application in industrial
synthesis, partly because of its functional group compatibility and the nontoxicity and easy
removal of the product [35, 36]. The order of reactivity with respect to the organic halide has
been observed as: vinyl iodide "J vinyl bromide > aryl iodide > vinyl chloride » aryl bromide.
Although there are numerous reports dealing with the palladium-catalyzed Sonogashira
reaction of aryl/vinyl halides (especially iodides and bromides) in the presence of copper
co-catalysts, attention is now turning towards copper-free palladium catalyzed Sonogashira
reactions [37]. It is obvious that copper-free, palladium-catalyzed reactions have advantage over
the traditional Sonogashira reaction, which employed palladium/copper catalyst. Copper-free
reactions are much cleaner and easy to purify than reactions contaminated with copper [38-40].
They are catalytically active, although no thorough study has been published yet concerning their
potential in this domain.
We herein describe the synthesis and characterization of novel N-heterocyclic carbine-
phosphine palladium(II) complexes. Furthermore the antimicrobial activities of complexes 3, as
growth inhibiting agents, have been screened in vitro against different species of bacteria and the
results concluded that the metal complexes are effective drugs against the tested strains.
3

2. Results and discussion
2.1. Synthesis
The PEPPSI Pd-NHC complexes were prepared previously at yields between 85% and 95% by
combining the benzimidazolium salts, PdCl2, K2CO3 and pyridine at 80 °C for 16 h [37]. These
complexes were stable against air, moisture and light at room temperature for a long period
without decomposition.
The PEPPSI Pd-NHC complexes isolated after chromatography were treated with two
equivalents of triphenyl phosphine ligand to give monometallic mixed complexes 3 bearing one
carbene and one triphenylphosphine ligand isolated in 76-87% yield (scheme 2).
The N-heterocyclic carbine-phosphine palladium(II) complexes 3a-h are stable in air and
toward the moisture with good solubility in polar solvents.
The identity of the phosphine complexes 3a-h has been confirmed by elemental analyses,
IR, 1H, 13C, and 31P NMR spectroscopy.
The successful formation of these N-heterocyclic carbine-phosphine palladium(II)
complexes was indicated by the absence of a peak of NCHN proton region of 11.10-11.83 ppm
in their 1H NMR spectra. In the 1H NMR spectra, benzylic proton (NCH2) was resonated at low δ
fields 6.02, 6.20, 5.95, 6.57,5.38,5.30, 6.22 and 6.96 ppm for 3a-h, respectively.
The structure of the expected complexes 3 was further verified with the 13C NMR: the
carbene carbon resonance (for metal-bound carbon atom in 2-position, NCN-Pd) shifted
significantly downfield at δ 172.5, 174.1, 173.2, 172.6, 172.6, 174.5, 172.72 and 172.6 ppm
for 3a-h, respectively. In addition, benzylic carbon (NCH2) was resonated at δ 53.1, 53.3, 53.4,
53.3, 53.5, 54.0, 53.0 and 53.1 ppm for 3a-h, respectively (scheme 2).
The formation of the C-N moiety in the benzimidazole ring correlated with a shift in the
IR(C-N) band by approximately 120-130 cm-1. The IR data for carbene complexes 3 clearly
indicate the presence of the -C-N- group with a ν(C-N) vibration between 1313 and 1330 cm-1 as
expected [42, 43] for 3a-h, respectively.
4

R1
R1
PdCl2
K2CO3
Cl
N
N
X
Pd
N
(X = Cl, Br)
N
N
Pyridine
80 °C
Cl
R2
1a-h
R2
2a-h
P
DCM, 25 °C
R1
Cl
N
Pd
P
N
Cl
3a-h
R2
5

Cl
Cl
Cl
N
N
N
N
N
N
Pd
P
Pd
P
Pd
P
Cl
Cl
Cl
N
3b
3a
3c
Cl
Cl
Cl
N
N
N
N
N
N
Pd
P
Pd
P
Pd
P
Cl
Cl
Cl
3d
3e
3f
Cl
Cl
N
N
N
N
Pd
P
Pd
P
Cl
Cl
3h
3g
Scheme 2. Preparation of mixed NHC-phosphine palladium complexes 3a-h.
In order to demonstrate the utility of these N-heterocyclic carbine-phosphine palladium(II)
complexes, we used them as co-catalysts in Sonogashira reactions of phenylacetylene with aryl
bromides, which are common industry-applicable processes.
6

2.2. 2-Sonogashira reactions of phenylacetylene with aryl bromides
In Sonogashira reaction, despite that numerous other metals catalyzed such reactions [44],
conventional palladium complexes such as [PdCl2(PPh3)2] and [Pd(PPh3)4] often in combination
with copper(I) salts are still the most preferred ones [45, 46]. However, the limitation of the early
catalytic combinations based on phosphine-containing catalysts was the sensitivity to air.
Although, the use of Cu(I)-halide salt as catalyst can result in the formation of some Cu(I)
acetylides which then transmetalate to Pd. It has been also shown that the presence of copper(I)
species had a deleterious effect on catalysis [47, 48], selected examples include participation of
Cu in Glaser-Hay homocoupling of the alkyne product [49], inhibition of Pd catalyst activation
and oxidation of coordinatively unsaturated Pd(0) species to form Pd(I) complexes that promote
alkyne polymerization [50]. These resultant by-products are wasteful and can complicate the
purification of the desired compound. Thus, the method development and optimization is often
necessary to yield adequate overall catalyst performance [51]. In this connection, stable NHC-
palladium(II) complexes with low catalyst loading and copper-free coupling reaction conditions
are still a challenge for Sonogashira reaction.
In order to evaluate and compare the activities of our catalytic systems, Biffis’ work is at
the forefront. Thus Biffis’ [52] reaction conditions were initially selected for the Sonogashira
reaction. In optimization studies, the deactivated 4-bromoanisole (0.6 mmol) was used as test
substrate. To search the best solvent and base, we investigated the Sonogashira coupling reaction
using the [Pd(NHC)(PPh3)] (catalyst loading 1.0 mol%) and phenylacetylene (1.2 mmol) as a
model reaction. The desired product was obtained with moderate-to-high yield after 3 h at
100 °C in the presence of (1.2 mmol) of K2CO3, Cs2CO3, t-BuOK as a base and organic solvents
such as DMF and toluene and protic solvents such as water and ethanol under free copper
conditions [53].
To determine the scope of this method, we examined the coupling reaction of activated
and unactivated aryl bromides with phenylacetylene using 0.5 mol% loading of
[PdCl2(NHC)(PPh3)] 3a-h in the presence of DMF as a solvent and KOtBu as a base. Usually,
electron-withdrawing groups have an effect on increasing the reactivity of substrates. In this
case, the results obtained with unsymmetrically and symmetrically catalysts 3a-h showed that
the catalytic system proved to be the best efficient in Sonogashira cross coupling reaction of
4-bromoacetophenone with phenylacetylene, showing its wide substrate tolerance. The reaction
7

ran very quickly and afforded the catalytic product in 100% conversion in less than 15 min
(table 1, entries 7-12 and table 2, entries 3 and 4). It can be observed that arylbromides
containing electron-neutral substituents such as 4-bromobenzene were completely converted to
the corresponding coupled product in shorter reaction time (table 2, entries 7 and 8). Thus, to
investigate the effects of the new catalytic system with an electron-donating substrate, we
performed the reaction between 4-bromoanisole, 4-bromotoluene and phenylacetylene under
similar reaction conditions. It is surprising to see that the electron-donating groups -OCH3 and
-CH3 gave superior product formation (table 2, entries 1, 2, 9 and 10) compared to the strong
electron-withdrawing groups -CHO (4-bromobenzaldehyde) (table 2, entries 5 and 6) in the
presence of symmetrical catalyst 3g-h within short reaction time. We got a lower yield with
4-bromotoluene (29%) instead of 4-bromoanisole (100%) in 1 h. On the contrary, the desired
product was obtained in a moderate-to-good yield when 4-bromotoluene was used in the
presence of unsymmetrical palladium catalysts (table 1, entries 13-18).
It is important to mention that, in general, ortho- or/and meta-substituted arylbromides
required more reaction time compared to the para-substituted counterparts owing to steric
hindrance put by ortho- or/and meta-substituents. This system also proves to be tolerant of
sterically hindered substrates. We then turned our attention to the prolonging of the reaction time
to 6 h. The reaction proved to be very efficient with all employed catalysts and the desired
product was obtained with good to excellent yields (57-100%). Indeed, 5-bromo-1,2,3-
trimethoxybenzene was transformed completely to the cross-coupling product when the reaction
was catalyzed by 3(b, c, d, f, g) (table 1, entries 26-28 and 30; table 2, entry 15) and a trace
amount of product was detected with 3(a, e, h) (table 1, entries 25 and 29; table 2, entry 16). It is
worth noting that significantly high yields were observed with 2-bromomesitylene (table 1,
entries 31-34 and 36). With the results in hand and in every case studied, the catalyst 3g is more
active than catalyst 3h. We attributed these performance differences to well-balanced electronic
and steric properties imposed by two 4-tertbutyl-substituted benzylic groups of the 3g which
facilitates the oxidative addition step. Also, the steric effect of the catalyst and substrates
facilitates the reductive elimination of the product from the active catalyst. On the other hand,
2-bromo-1,3,5-triisopropylbenzene and 2-bromo-p-xylene react very cleanly with
phenylacetylene in a moderate-to-good yield (table 1, entries 19-24 and 37-41; table 2, entries
11, 12, 17 and 18). Remarkably, the double coupling of 2,6-dibromopyridine as a substrate in
8

long reaction time (6 h) afforded the desired product with complete conversion 100% in the
presence of 0.5 mol% of [PdCl2(NHC)(PPh3)] 3a-h which indicate that the catalytic system was
not poisoned by pyridine substrates (table 3, entries 1-8).
We proposed a plausible mechanism for the copper-free Sonogashira cross-coupling
reaction catalyzed by [Pd(NHC)(PPh3)] (3a-h). The Pd(0) species could be generated readily
from the reaction of [Pd(NHC)(PPh3)] with solvents, substrates, etc. [54-56], followed by the
oxidative addition of palladium(0) with arylbromides to form intermediate 1. The
phenylacetylene is not able to deprotonate, therefore, the replacement between intermediate 1
and phenylacetylene occurred to afford intermediate 2. Furthermore, in this catalytic process, the
base KOtBu abstracts the acetylenic proton of the terminal alkyne, thereby enhancing the
coordination of phenylacetylene ligand to the metal and liberation of HBr [57]. Finally, the
reductive elimination of intermediate 3 took place to regenerate the active Pd(0) species and give
the desired product. The suggested mechanism according to the above explanations is shown in
scheme 3.
NHC Pd(0) PPh3
Ph
H
Br
R
Reductive elimination
Oxidative addition
PPh3
PPh3
1
NHC Pd(II)
3
Ph
NHC Pd(II)
R
Br
R
Ph
H
KOtBuH+, Br-
Br
KOtBu
(Ph3P)(NHC) Pd(II)
R
Ph
H
2
Scheme 3. Proposed catalytic mechanism for Sonogashira coupling-reaction catalyzed by
[PdCl2(NHC)(PPh3)] 3a-h under free copper.
9

In summary, the NHC-Pd complex featured with air-insensitivity was proved to be a highly
efficient catalyst for the Suzuki and Sonogashira coupling reactions. In a simple one-pot
procedure free of co-catalyst, this complex is available for a wide range of substrates under mild
conditions with good to excellent product yields and a low catalyst loading.
2.3. Biological activities
2.3.1. Antibacterial activity. The palladium complexes 3 were evaluated for antimicrobial
activity against three Gram-positive bacteria (Micrococcus luteus LB 14110, Staphylococcus
aureus ATCC 6538 and Listeria monocytogenes ATCC 19117) and two Gram-negative bacteria
(Salmonella Typhimurium ATCC 14028 and Pseudomonas aeruginosa ATCC 49189). The
obtained antimicrobial activitiy is presented in table 4. Table 4 shows that all metal complexes 3
exhibit antimicrobial activity in one or more strains. Although complex 3e showed high activity
as antimicrobial activity, complex 3b showed high activity in Gram-positive and Gram-negative
bacteria in high and low concentrations. The outcome of antimicrobial studies showed that the
Pd(II) complexes 3 possessed moderate to significant activities against different bacterial strains.
In parallel, the minimal inhibitory concentrations (MICs) values N-heterocyclic carbine-
phosphine palladium(II) complexes 3a–h were determined against the two Gram-positive
bacteria Micrococcus luteus LB 14110 and Listeria monocytogenes ATCC 19117 and the Gram-
negative bacterium Salmonella Typhimurium ATCC 14028. Ampicillin was used as standard. As
shown in table 5, the MIC values range from 0.0197-0.625 mg/mL for Micrococcus luteus LB
14110, 0.078-1.25 mg/mL for Listeria monocytogenes ATCC 19117 and 1.25-5 mg/mL for
Salmonella Typhimurium ATCC 14028.
The most active compound was 3b which presents against Micrococcus luteus LB 14110
having lower MIC value (0.0186 mg/mL) than the used standard (ampicillin). The lowest MIC
values of 0.024 mg/mL were recorded for the Pd complexes 3c against Micrococcus luteus LB
14110. Complex 3b also has MIC values of 0.076 mg/mL against Listeria monocytogenes ATCC
19117.
2.3.2. Acetylcholinesterase inhibition. The acetylcholinesterase enzyme (AChE) is an attractive
target for the rational drug design and for the discovery of mechanism-based inhibitors because
of its role in the hydrolysis of the neurotransmitter acetylcholine (ACh). AChE inhibitors are the
10

most effective approach to treat the cognitive symptoms of Alzheimer disease (AD) [41, 42] and
other possible therapeutic applications in the treatment of Parkinson′s disease, senile dementia,
and ataxia, among others [58].
The results of AChEI of the synthesized N-heterocyclic carbine-phosphine palladium(II)
complexes 3a-h are presented in table 6. Compounds 3a, 3b and 3e exhibited moderate AChEI
activity at 100 μg/mL. As the antibacterial and antioxidant activities, compound 3b possesses the
highest AChEI activity.
3. Conclusion
We have synthesized a new series of benzimidazole-based NHC-Pd-PPh3 complexes. These
palladium(II) complexes have been employed on the one hand as precatalysts in Sonogashira
cross-coupling reactions and on the other hand as antimicrobial and antiacetylcholinesterase
agents. For the Sonogashira coupling reaction, only complexes 3a-h show productive catalytic
activity under 100 °C using DMF and KOtBu.
In this Sonogashira cross-coupling reaction, we believe that the bulky and electron-donor
NHC ligands associated with triphenylphosphine in complexes 3 provide the synergetic steric
and electronic effects to confer the metal center the appropriate properties to make optimum for
the key-steps of the catalytic cycles.
The outcome of antimicrobial studies showed that Pd(II) complexes 3 possessed
moderate-to-significant activities against different bacterial strains which might be due to
azomethine (–C-N–) linkage and/or phosphor present in these compounds.
4. Experimental
General information
All manipulations were performed using Standard Schlenck techniques under argon atmosphere.
Chemicals were purchased from Sigma Aldrich and used without purification. All solvents were
purified and dried by MBraun SPS 800 solvent purification system. 1H, 31P and 13C NMR spectra
were recorded at 300 MHz and 75 MHz, respectively. Chemical shifts, , are reported in ppm
relative to the internal standard TMS for both 1H and 13C NMR. The products were characterized
by GC (gas chromatography). Quantitative GC analyses were performed with a GC-2010 Plus
gas chromatograph (SHIMADZU).
11

General preparation of benzimidazolium salts 1a-h
The known N-heterocyclic carbene ligands 1a-h were synthesized according to literature
procedure and characterized by spectroscopic techniques. Results are consistent with the
literature [59, 60].
General preparation of [PdCl2(NHC)(pyridine)] 2a-h
The known PEPPSI complexes 2a-h were synthesized according to literature procedure and
characterized by spectroscopic techniques. Results are consistent with the literature [59-61].
General preparation of [PdCl2(NHC)(PPh3)] 3a-h
A Schlenk was charged with PEPSSI complex 2a-h (1 mmol), PPh3 (2 mmol) and a stir bar
under argon atmosphere. Anhydrous DCM was added as a solvent. The mixture was stirred for
2 days at 25 °C. The resultant solution was filtered and the solvent was then removed under
reduced pressure. The residue was washed thoroughly with diethylether and hexane to remove
excess PPh3 and then dried under vacuum. The solid obtained was characterized by NMR
spectroscopy. Further purification was done using recrystallization (DCM - hexane) to get pure
complexes for analysis and catalysis.
Dichloro[1-(3,5-dimethylbenzyl)-3-(2,3,4,5,6-pentamethylbenzyl)-5,6-dimethylbenzimidazole-
2-ylidene](triphenylphosphine)palladium(II) (3a)
m.p: 260 °C. Yield: 75%. 1H NMR (CDCl3, 300 MHz)  (ppm): 7.56 (m, 6H, H12,14,12’,14’,12”,14”
,
arom. CH); 7.40 (m, 3H, H13,13’,13”, arom. CH); 7.23 (m, 6H, H11,15,11’,15’,11”,15”, arom. CH); 7.13
(s, 2H, H3’,7’, arom. CH); 6.84 (s, 1H, H5’, arom. CH); 6.55 (s, 2H, H4,7, arom. CH); 6.02 (s, 2H,
H1’, CH2); 5.97 (s, 2H, H1”, CH2); 2.31 (s, 3H, Hg, CH3); 2.22 (s, 6H, Hc,d, 2CH3); 2.20 (s, 6H,
Hf,h, 2CH3); 2.06 (s, 3H, He, CH3); 1.98 (s, 6H, Ha,b, 2CH3); 1.85 (s, 3H, Hi, CH3). 13C NMR
(CDCl3, 75 MHz) ( (ppm)): 172.54 (C2, NCN); 138.38 (C8,9, arom.Cq); 136.46 (C4’,6’, arom.
Cq); 134.18 (C10,10’,10’’, arom. Cq); 134.03 (C11,15,11’,15’,11”,15”, arom. CH); 133.15 (C2’, arom. Cq);
131.93 (C2”, arom. Cq); 131.65 (C5”, arom. Cq); 131.26 (C4”,6”, arom. Cq); 130.00(C5’, arom.
CH); 128.64-128.57 (C12,13,14,12’,13’,14’,12”,13”,14”, arom. CH); 127.28 (C3’,7’, arom. CH); 126.22
(C3”,7”, arom. Cq); 112.14 (C5,6, arom. Cq); 111.50 (C4,7, arom. CH); 53.14 (C1’, CH2); 51.82
12

(C1”, CH2); 21.39 (Cc,d, 2CH3); 20.57 (Cg, CH3); 20.28 (Cf, h, 2CH3); 17.37-17.18 (Ce,i,
2CH3); 16.98 (Ca,b, 2CH3). 31P NMR (300 MHz, CDCl3, 25 °C):  = 27.24 ppm. Calcd for
C48H52Cl2N2PPd: C, 66.6%; H, 3.4%; N, 3.2%. Found: C, 66.5; H, 3.3; N, 3.2.
Dichloro[1-(3,5-dimethylbenzyl)-3-(4-cyanolbenzyl)-5,6-dimethylbenzimidazole-2-
ylidene](triphenylphosphine)palladium(II) (3b)
m.p: 272 °C. Yield: 82%. FT-IR (KBr) ν, cm-1: 3026 (C-H arom.); 1330 (C-N). 1H NMR
(CDCl3, 300 MHz)  (ppm): 7.60 (m, 4H, H4”,6”, arom. CH); 7.50 (m, 6H, H12,14,12’,14’,12”,14”
,
arom. CH); 7.30 (m, 3H, H13,13’,13”, arom. CH); 7.22 (m, 6H, H11,15,11’,15’,11”,15”, arom. CH); 7.13
(s, 2H, H3”,7”, arom. CH); 6.87 (s, 1H, H5’, arom. CH); 6.67 (s, 2H, H3’,7’, arom. CH); 6.56 (s, 2H,
H4,7, arom. CH); 6.20 (s, 2H, H1’, CH2); 6.01 (s, 2H, H1”, CH2); 2.24 (s, 6H, Hc,d, 2CH3); 2.16
(s, 6H, Ha,b, 2CH3). 13C NMR (CDCl3, 75 MHz) ( (ppm)): 174.15 (C2, NCN); 139.78 (C2”,
arom. Cq); 138.58 (C8,9, arom. Cq); 134.37 (C4’,6’, arom. Cq); 134.23 (C10,10’,10’’, arom. Cq);
133.85 (C2’, arom. Cq); 133.21 (C11,15,11’,15’,11”,15”, arom. CH); 132.70 (C4”,6”, arom. CH); 131.41
(C5’, arom. CH); 130.28 (C3”,7”, arom. CH); 130.07 (C13,13’,13”, arom. CH); 129.10
(C12,14,12’,14’,12”,14”, arom. CH); 128.69 (C3’,7’, arom. CH); 128.54 (C5,6, arom. Cq); 126.19 CN;
112.35 (C4,7, arom. CH); 111.18 (C5”, arom. Cq); 53.37 (C1’, CH2); 52.47 (C1”, CH2); 21.40 (Cc,d,
2CH3); 20.46 (Ca,b, 2CH3). 31P NMR (300 MHz, CDCl3, 25 °C):  = 26.72 ppm. Calcd for
C44H41Cl2N3PPd: C, 64.4%; H, 5.0%; N, 5.1%. Found: C, 64.5; H, 5.2; N, 5.2.
Dichloro[1-(3,5-dimethylbenzyl)-3-(2-methylbenzyl)-5,6-dimethylbenzimidazole-2-
ylidene](triphenylphosphine)palladium(II) (3c)
m.p: 270 °C. Yield: 85%. FT-IR (KBr) ν, cm-1: 3013 (C-H arom.); 1317 (C-N). 1H NMR
(CDCl3, 300 MHz)  (ppm): 7.44 (m, 6H, H12,14,12’,14’,12”,14”, arom. CH); 7.29 (m, 3H, H13,13’,13”
,
arom. CH); 7.17 (s, 2H, H6”,7”, arom. CH); 7.12 (m, 6H, H11,15,11’,15’,11”,15”, arom. CH); 7.04 (m,
3H, H4”,5’,5”, arom. CH); 6.88 (s, 2H, H3’,7’, arom. CH); 6.76 (s, 1H, H4, arom. CH); 6.57 (s, 1H,
H7, arom. CH); 5.95 (s, 2H, H1’, CH2); 5.21 (s, 2H, H1”, CH2); 2.29 (s, 3H, He, CH3); 2.14 (s, 6H,
Hc,d, 2CH3); 2.04 (s, 6H, Ha,b, 2CH3). 13C NMR (CDCl3, 75 MHz) ( (ppm)): 173.24 (C2,
NCN); 138.31 (C8,9, arom. Cq); 134.92 (C4’,6’, arom. Cq); 134.27 (C10,10’,10’’, arom. Cq); 134.04
(C11,15,11’,15’,11”,15”, arom. CH); 133.66 (C2’, arom. Cq); 133.42 (C3”, arom. Cq); 132.39 (C2”, arom.
Cq); 132.14 (C4”, arom. CH); 131.07 (C5’, arom. CH); 130.30 (C13,13’,13”, arom. CH); 129.98
13

(C12,14,12’,14’,12”,14”, arom. CH); 128.37 (C5”, arom. CH); 127.84 (C3’,7’, arom. CH); 127.72 (C7”,
arom. CH); 126.16 (C5,6, arom. Cq); 112.00 (C6”, arom. CH); 111.61 (C4,7, arom. CH); 53.49
(C1’, CH2); 50.44 (C1”, CH2); 21.28 (Ce, CH3); 20.34 (Cc,d, 2CH3); 19.80 (Ca,b, 2CH3).
31P NMR (300 MHz, CDCl3, 25 °C):  = 27.11 ppm. Calcd for C44H44Cl2N2PPd: C, 65.3%; H,
5.4%; N, 3.4%. Found: C, 65.5; H, 5.6; N, 3.2.
Dichloro[1-(3,5-dimethylbenzyl)-3-(4-tertbutylbenzyl)-5,6-dimethylbenzimidazole-2-
ylidene](triphenylphosphine)palladium(II) (3d)
m.p: 280 °C. Yield: 86%. FT-IR (KBr) ν, cm-1: 3013 (C-H arom); 1317 (C-N). 1H NMR (CDCl3,
300 MHz)  (ppm): 7.50 (m, 6H, H12,14,12’,14’,12”,14”, arom. CH); 7.41 (m, 3H, H13,13’,13”, arom.
CH); 7.35 (m, 4H, H3”,4”,6”,7”, arom. CH); 7.26 (s, 2H, H3’,7’, arom. CH); 7.20 (m, 6H,
H11,15,11’,15’,11”,15”, arom. CH); 7.11 (s, 2H, H4,7, arom. CH); 6.85 (s, 1H, H5’, arom. CH); 6.57 (s,
2H, H1’, CH2); 6.03 (s, 2H, H1”, CH2); 2.23 (s, 6H, Hc,d, 2CH3); 2.15-2.12 (s, 6H, Ha,b, 2CH3);
1.59 (s, 3H, Hg, CH3); 1.24 (s, 6H, He,f, 2CH3). 13C NMR (CDCl3, 75 MHz) ( (ppm)): 172.69
(C2, NCN); 151.32 (C8,9, arom. Cq); 138.36 (C4’,6’, arom. Cq); 134.45 (C10,10’,10’’, arom. Cq);
134.31 (C5”, arom. Cq); 132.28 (C11,15,11’,15’,11”,15”, arom. CH); 132.15 (C2’, arom. Cq); 131.12
(C2”, arom. Cq); 130.37 (C5’, arom. CH); 130.02 (C3”,7”, arom. CH); 128.71 (C4”,6”, arom. CH);
128.55 (C13,13’,13”, arom. CH); 128.40 (C12,14,12’,14’,12”,14”, arom. CH); 126.16 (C3’ 7’, arom. CH);
125.66 (C5,6, arom. Cq); 111.93 (C4,7, arom. CH); 53.30 (C1’, CH2); 53.14 (C1”, CH2); 34.64 (Cc,d,
2CH3); 31.37 (Cg, CH3); 21.34 (Ca,b, 2CH3); 20.38 (Ce,f, 2CH3). 31P NMR (300 MHz, CDCl3,
25 °C):  = 26.85 ppm. Calcd for C47H50Cl2N2PPd: C, 66.3%; H, 5.91%; N, 3.2%. Found: C,
66.5; H, 5.8; N, 3.2.
Dichloro[1-(3,5-dimethylbenzyl)-3-(2,3,5,6-tetramethylbenzyl)-5,6-dimethyl benzimidazole-2-
ylidene](triphenylphosphine)palladium(II) (3e)
m.p: 268 °C. Yield: 77%. 1H NMR (CDCl3, 300 MHz)  (ppm):7.55 (m, 6H, H12,14,12’,14’,12”,14”
,
arom. CH); 7.40 (m, 3H, H13,13’,13”, arom. CH); 7.23 (m, 6H, H11,15,11’,15’,11”,15”, arom. CH); 7.13
(s, 2H, H3’,7’, arom. CH); 7.07 (s, 1H, H5’, arom. CH); 6.84 (s, 1H, H5”, arom. CH); 6.55 (s, 2H,
H4,7, arom. CH); 5.38 (s, 2H, H1’, CH2); 5.30 (s, 2H, H1”, CH2); 2.22 (s, 12H, Hc,d,g,h, 4CH3);
2.06 (s, 3H, He, CH3); 1.94 (s, 6H, Ha,b, 2CH3); 1.87 (s, 3H, Hf, CH3). 13C NMR (CDCl3,
14

75 MHz) ( (ppm)): 172.65 (C2, NCN); 138.38 (C8,9, arom. Cq); 134.36 (C2”, arom. Cq); 134.14
(C4’,6’, arom. Cq); 133.92 (C10,10’,10’’, arom. Cq); 133.11 (C2’, arom. Cq); 132.78
(C11,15,11’,15’,11”,15”, arom. CH); 132.02 (C4”,6”, arom. Cq); 131.72 (C3”,7”, arom.) 130.03 (C5”, arom.
CH); 129.88 (C13,13’,13”, arom. CH); 128.64 (C12,14,12’,14’,12”,14”, arom. CH); 126.20 (C3’,7’, arom.
CH); 112.02 (C5,6, arom. Cq); 111.46 (C4,7, arom. CH); 53.58 (C1’, CH2); 53.13 (C1”, CH2); 21.38
(Cc,d,g,h, 4CH3); 20.60 (Ca,b,e,f, 4CH3). 31P NMR (300 MHz, CDCl3, 25 °C):  = 27.18 ppm.
Calcd for C47H50Cl2N2PPd: C, 66.3%; H, 5.1%; N, 3.2%. Found: C, 66.4; H, 5.7; N, 3.3.
Dichloro[1-(3,5-dimethylbenzyl)-3-(4-methylbenzyl)-5,6-dimethylbenzimidazole-2-
ylidene](triphenylphosphine)palladium(II) (3f)
m.p: 279 °C. Yield: 87%. FT-IR (KBr) ν, cm-1: 3013 (C-H arom); 1317 (C-N). 1H NMR (CDCl3,
300 MHz)  (ppm): 7.48 (m, 6H, H12,14,12’,14’,12”,14”, arom. CH); 7.35 (m, 3H, H13,13’,13”, arom.
CH); 7.26 (s, 2H, H3”,7”, arom. CH); 7.20 (m, 6H, H11,15,11’,15’,11”,15”, arom. CH); 7.11 (s, 2H,
H4”,6”, arom. CH); 6.96 (m, 2H, H3’,7’, arom. CH); 6.85 (s, 1H, H5’, arom. CH); 6.07 (s, 2H, H4,7,
arom. CH); 5.30 (s, 4H, H1’,1”, 2CH2); 2.23 (s, 9H, Hc,d,e, 3CH3); 2.13 (s, 6H, Ha,b, 2CH3).
13C NMR (CDCl3, 75 MHz) ( (ppm)): 174.59 (C2, NCN); 138.81 (C8,9, arom. Cq); 138.47
(C4’,6’, arom. Cq); 135.00 (C10,10’,10’’, arom. Cq); 134.89 (C5”, arom. Cq); 134.75
(C11,15,11’,15’,11”,15”, arom. CH); 134.75 (C2’, arom. Cq); 131.56 (C2”, arom. Cq); 130.48 (C5’, arom.
CH); 129.91 (C3”,7”, arom. CH); 129.09 (C4”,6”, arom. CH); 129.00 (C12,13,14,12’,13’,14’,12”,13”,14”
,
arom. CH); 128.86 (C3’,7’, arom. CH); 126.62 (C5,6, arom. Cq); 112.41 (C4,7, arom. CH); 54.00
(C1’, CH2); 53.70 (C1”, CH2); 21.79 (Cc,d,e, 3CH3); 20.84 (Ca,b, 2CH3). 31P NMR (300 MHz,
CDCl3, 25 °C):  = 27.07 ppm. Calcd for C44H44Cl2N2PPd: C, 65.3%; H, 5.4%; N, 3.4%. Found:
C, 65.4; H, 5.7; N, 3.3.
Dichloro[1,3-bis-(4-tert-butylbenzyl)-5,6-dimethylbenzimidazole-2-
ylidene](triphenylphosphine)palladium(II) (3g)
m.p: 281 °C. Yield: 85%. FT-IR (KBr) ν, cm-1: 3026 (C-H arom.); 1324 (C-N). 1H NMR
(CDCl3, 300 MHz)  (ppm): 7.50 (m, 9H, H12,13,14,12’,13’,14’,12”,13”,14”, arom. CH); 7.42-7.35 (m,
6H, H11,15,11’,15’,11”,15”, arom. CH); 7.26 (s, 2H, H4,7, arom. CH); 7.22 (m, 8H, H3’,4’,6’,7’,3”,4”,6”,7”
,
arom. CH); 6.22 (m, 4H, H1’1”, 2CH2); 2.13 (s, 6H, Hd,g, 2CH3); 1.24 (s, 18H, Ha,b,c,e,f,h
,
6CH3). 13C NMR (CDCl3, 75 MHz) ( (ppm)): 172.72 (C2, NCN); 151.32 (C8,9, arom. Cq);
15

134.49 (C10,10’,10’’, arom. Cq); 134.35 (C5’,5”, arom. Cq); 133.43 (C11,15,11’,15’,11”,15”, arom. CH);
133.17 (C2’,2”, arom. Cq); 132.43-132.21 (C3’,7’,3”,7”, arom. CH); 131.13 (C4’,6’,4”,6”, arom. CH);
128.60 (C13,13’,13”, arom. CH); 128.45, 128.30, 128.22 (C12,14,12’,14’,12”,14”, arom. CH); 125.70 (C5,6,
arom. Cq); 111.91 (C4,7, arom. CH); 53.04 (C1’,1”, 2CH2); 34.66 (Cd,g, 2CH3); 31.39 (Cc,e,f,h
4CH3); 20.34 (Ca,b, 2CH3). 31P NMR (300 MHz, CDCl3, 25 °C):  = 27.34 ppm. Calcd for
C49H54Cl2N2PPd: C, 66.9%; H, 6.1%; N, 3.1%. Found: C, 67.2; H, 6.3; N, 3.2.
,
Dichloro[1,3-bis-(4-methylbenzyl)-5,6-dimethylbenzimidazole-2-
ylidene](triphenylphosphine)palladium(II) (3h)
m.p: 279 °C. Yield: 73%. 1H NMR (CDCl3, 300 MHz)  (ppm): 7.41 (m, 9H,
H12,13,14,12’,13’,14’,12”,13”,14”, arom. CH); 7.28 (m, 6H, H11,15,11’,15’,11”,15”, arom. CH); 7.19 (s, 2H, H4,7,
arom. CH); 7.12 (m, 8H, H3’,4’,6’,7’,3”,4”,6”,7”, arom. CH); 6.96-6.90 (m, 4H, H1’,1”, 2CH2); 2.18 (s,
6H, Hc,d, 2CH3); 2.06 (s, 6H, Ha,b, 2CH3). 13C NMR (CDCl3, 75 MHz) ( (ppm)): 172.61 (C2,
NCN); 138.08 (C8,9, arom. Cq); 134.46 (C10,10’,10’’, arom. Cq); 134.32 (C5’,5”, arom. Cq); 133.47
(C11,15,11’,15’,11”,15”, arom. CH); 132.32 (C2’,2”, arom. Cq); 131.37 (C3’,7’,3”,7”, arom. CH); 131.31
(C4’,6’,4”,6”, arom. CH); 131.14 (C13,13’,13”, arom. CH); 129.50 (C12,14,12’,14’,12”,14”, arom. CH);
128.57 (C5,6, arom. Cq); 111.89 (C4,7, arom. CH); 53.15 (C1’,1”, 2CH2); 21.32 (Cc,d, 2CH3);
20.40 (Ca,b, 2CH3). 31P NMR (300 MHz, CDCl3, 25 °C):  = 27.02 ppm. Calcd for
C43H42Cl2N2PPd: C, 64.9%; H, 5.3%; N, 3.5%. Found: C, 65.2; H, 5.6; N, 3.8.
General procedure for the Sonogashira reaction
Under argon atmosphere, arylbromides (0.6 mmol), palladium catalyst (0.5 mol %), KOtBu
(0.6 mmol) and DMF (5 mL) were added to a schlenck containing a magnetic stir bar, followed
by (0.6 mmol) of phenylacetylene. The resulting mixture was placed in an oil bath preheated to
100 °C and stirred vigorously for the indicated time. Upon completion, the mixture was cooled to
room temperature, was partitioned between 30 mL of water and 20 mL of diethylether or ethyl
acetate and the combined organic layer was further washed with 220 mL of diethylether or
ethyl acetate and was dried over MgSO4. The extraction was done with DCM when
2,6-dibromopyridine was used as a substrate. The filtrate was sampled at intervals for GC
analysis to check the purity and the conversions are based on arylbromides.
16

Antimicrobial activities
The in vitro evaluation of antimicrobial activity was studied as previously [62].
Acknowledgements
The authors would like to extend their sincere appreciation to the Deanship of Scientific
Research at King Saud University for its funding this research group No. (RG-1435-023).
References
[1]
[2]
[3]
[4]
[5]
K. Öfele, M. Herberhold. Angew. Chem., 82, 775 (1970).
H.W. Wanzlick, H.J. Schönherr. Angew. Chem., 80, 154 (1968).
A.J. Arduengo III, R.L. Harlow, M. Kline. J. Am. Chem. Soc., 113, 361 (1991).
D. Pugh, A.A. Danopoulos. Coord. Chem. Rev., 251, 610 (2007).
(a) S. Diez-Gonzalez, N. Marion, S.P. Nolan. Chem. Rev., 109, 3612 (2009). (b) E.L.
Kolychev, A.F. Asachenko, P.B. Dzhevakov, A.A. Bush, V.V. Shuntikov, V.N.
Khrustalev, M.S. Nechaev. Dalton Trans., 42, 6859 (2013).
[6]
[7]
E. Colacino, J. Martinez, F. Lamaty. Coord. Chem. Rev., 251, 726 (2007).
E.Ö. Karaca, M. Akkoç, E. Öz, S. Altin, V. Dorcet, T. Roisnel, N. Gürbüz, Ö. Çelik, A.
Bayri, C. Bruneau, S. Yaşar, I. Özdemir. J. Coord. Chem., 70, 1270 (2017).
N. Miyaura, A. Suzuki. J. Chem. Soc., Chem. Commun., 19, 866 (1979).
R.F. Heck, “Palladium-Catalyzed Vinylation of Organic Halides,” Organic Reactions,
Vol. 27 (1982), pp. 345-390.
[8]
[9]
[10] (a) K. Sonogashira. J. Organomet. Chem., 653, 46 (2002). (b) R. Chinchilla, C. Nájera.
Chem. Soc. Rev., 40, 5084 (2011).
[11] (a) H.U. Blaser, A. Indolese, F. Naud, U. Nettekoven, A. Schnyder. Adv. Synth. Catal.,
346, 1583 (2004). (b) K.C. Nicolaou, P.G. Bulger, D. Sarlah. Angew. Chem., 117, 4516
(2005); Angew. Chem. Int. Ed., 44, 4442 (2005). (c) C. Torborg, M. Beller. Adv. Synth.
Catal., 351, 3027 (2009).
[12] H. Doucet, J.-C. Hierso. Angew. Chem., 119, 850 (2007); Angew. Chem. Int. Ed., 46, 834
(2007).
[13] K.C. Nicolaou, E.J. Sorensen, Classics in Total Synthesis, Wiley-VCH, Weinheim
(1996), pp. 582-586.
17

[14] E.I. Negishi, A. de Meijere, Handbook of Organopalladium Chemistry for Organic
Synthesis, Wiley-VCH, Weinheim, Germany (2002).
[15] I. Paterson, R.D.M. Davies, R. Marquez. Angew. Chem. Int. Ed., 40, 603 (2001).
[16] A. de Meijere, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH,
Weinheim (2004), Vol. 2.
[17] L. Ackermann, Modern Arylation Methods, Wiley-VCH, Weinheim (2009).
[18] A. Bahl, W. Grahn, S. Stadler, F. Feiner, G. Bourhill, C. Bräuchle, A. Reisner, P.G.
Jones. Angew. Chem., Int. Ed. Engl., 34, 1485 (1995).
[19] M.B. Goldfinger, K.B. Crawford, T.M. Swager. J. Am. Chem. Soc., 119, 4578 (1997).
[20] J.F. Hartwig, M. Kawatsura, S.I. Hauck, K.H. Shaughnessy, L.M. Alcazar-Roman.
J. Org. Chem., 64, 5575 (1999).
[21] L.L. Hill, J.M. Smith, W.S. Brown, L.R. Moore, P. Guevara, E.S. Pair, J. Porter, J. Chou,
C.J. Woltermann, R. Craciun, D.A. Dixon, K.H. Shaughnessy. Tetrahedron, 64, 6920
(2008).
[22] L.L. Hill, L.R. Moore, R. Huang, R. Craciun, A.J. Vincent, D.A. Dixon, J. Chou, C.J.
Woltermann, K.H. Shaughnessy. J. Org. Chem., 71, 5117 (2006).
[23] A.F. Littke, L. Schwarz, G.C. Fu. J. Am. Chem. Soc., 124, 6343 (2002).
[24] A.F. Littke, G.C. Fu. Angew. Chem., Int. Ed., 41, 4176 (2002).
[25] A.F. Littke, G.C. Fu. J. Am. Chem. Soc., 123, 6989 (2001).
[26] T. Hundertmark, A.F. Littke, S.L. Buchwald, G.C. Fu. Org. Lett., 2, 1729 (2000).
[27] A. Brennführer, H. Neumann, S. Klaus, T. Riermeier, J. Almena, M. Beller. Tetrahedron,
63, 6252 (2007).
[28] K.W. Anderson, R.E. Tundel, T. Ikawa, R.A. Altman, S.L. Buchwald. Angew. Chem., Int.
Ed., 45, 6523 (2006).
[29] S.-i. Kuwabe, K.E. Torraca, S.L. Buchwald. J. Am. Chem. Soc., 123, 12202 (2001).
[30] J.P. Wolfe, H. Tomori, J.P. Sadighi, J. Yin, S.L. Buchwald. J. Org. Chem., 65, 1158
(2000).
[31] S. Harkal, K. Kumar, D. Michalik, A. Zapf, R. Jackstell, F. Rataboul, T. Riermeier, A.
Monsees, M. Beller. Tetrahedron Lett., 46, 3237 (2005).
[32] F. Rataboul, A. Zapf, R. Jackstell, S. Harkal, T. Reiermeier, A. Monsees, U.
Dingerdissen, M. Beller. Chem. Eur. J., 10, 2983 (2004).
18

[33] E.A.B. Kantchev, C.J. O'Brien, M.G. Organ. Angew. Chem., Int. Ed., 46, 2768 (2007).
[34] K. Sonogashira, Y. Tohda, N. Hagihara. Tetrahedron Lett., 4467 (1995).
[35] H.A. Dieck, R.F. Heck. J. Organomet. Chem., 93, 259 (1975).
[36] E. Negishi, L. Anastasia. Chem. Rev., 103, 1979 (2003).
[37] A.F. Littke, L. Schwartz, G.C. Fu. J. Am. Chem. Soc., 124, 6343 (2002).
[38] V.P.W. Bohm, W.A. Herrmann. Eur. J. Org. Chem., 22, 3679 (2000).
[39] W.A. Herrmann, C. Köcher, L.J. Gooßen, G.R.J. Artus. Chem. Eur. J., 2, 1627 (1996).
[40] E. Bappert, G. Helmchen. Synlett, 1789 (2004).
[41] B. Lamia, A. Chakchouk-Mtibaa, B. Hallouma, S. Yasser, I. Ozdemir, L. Mansour, L.
Mellouli, N. Hamdi. Molecules, 22, 420 (2017).
[42] S. Demir, I. Özdemir, B. Çetinkaya. J. Organomet. Chem., 694, 4025 (2009).
[43] S. Demir, I. Özdemir, O. Sahin, B. Çetinkaya, O. Büyükgüngör. Synlett, 3, 496 (2010).
[44] (a) H. Plenio. Angew. Chem., Int. Ed., 47, 6954 (2008). (b) T. Lauterbach, M. Livendahl,
A. Rosellón, P. Espinet, A.M. Echavarren. Org. Lett., 12, 3006 (2010). (c) Z. Gonda,
G.L. Tolnai, Z. Novák. Chem. Eur. J., 16, 11822 (2010).
[45] K. Sonogashira, Y. Tohda, N. Hagihara. Tetrahedron Lett., 16, 4467 (1975).
[46] Y. Liang, Y.X. Xie, J.H. Li. J. Org. Chem., 71, 379 (2006).
[47] X. Pu, H. Li, T.J. Colacot. J. Org. Chem., 78, 568 (2013).
[48] T. Ljungdahl, K. Pettersson, B. Albinsson, J. Martensson. J. Org. Chem., 71, 1677
(2006).
[49] M. Aufiero, F. Proutiere, F. Schoenebeck. Angew. Chem., Int. Ed., 51, 7226 (2012).
[50] M. Bandini, R. Luque, V. Budarin, D.J. Macquarrie. Tetrahedron, 61, 9860 (2005).
[51] N.E. Leadbeater. Nature Chem., 2, 1007 (2010).
[52] A. Marchenko, G. Koidan, A.N. Hurieva, Y. Vlasenko, A. Kostyuk, A. Biffis.
Organometallics, 35, 762 (2016).
[53] L. Boubakri, S. Yaşar, V. Dorcet, T. Roisnel, C. Bruneau, N. Hamdi, İ. Ozdemir. New J.
Chem., 41, 5105 (2017).
[54] A.F. Littke, G.C. Fu. Angew. Chem., Int. Ed., 41, 4176 (2002).
[55] Y. Liang, Y.X. Xie, J.H. Li. J. Org. Chem., 71, 379 (2006).
[56] A. Kamal, V. Srinivasulu, B.N. Seshadri, N. Narkandeya, A. Alarifi, N. Shankaraiah.
Green Chem., 14, 2513 (2012).
19

[57] C.I. Ezugwu, B. Mousavi, Md. A. Asrafa, A. Mehta, H. Vardhan, F. Verpoort. Catal. Sci.
Technol., 6, 2050 (2016).
[58] W. Ahmad, B. Ahmad, M. Ahmad, Z. Iqbal, M. Nisar, M. Ahmad. J. Biol. Sci., 11, 1046
(2003).
[59] L. Boubakri, A.C. Mtibaa, H. Bilel, L. Mansour, L. Mellouli, L. Mellouli, I. Özdemir, S.
Yaşar, N. Hamdi. Molecules, 22, 420 (2017).
[60] N. Hamdi, unpublished results.
[61] (a) S. Yaşar, K.J. Cavell, B.D. Ward, B. Kariuki. Appl. Organomet. Chem., 25, 374
(2011). (b) S. Yaşar, S. Çekirdek, İ. Özdemir. J. Coord. Chem., 67, 1236 (2014).
[62] Atta-ur-Rahman, Atia-Tul-Wahab, S.A. Nawaz, M.I. Choudhary. Chem. Pharm. Bull.,
52, 802 (2004).
Graphical abstract
Y
Br
R1
Y
Cl
N
Pd P
N
Cl
R2
Cu free
20

Table 1. Sonogashira reactions of phenylacetylene with arylbromides catalyzed by
unsymmetrical palladium complexes [PdCl2(NHC)(PPh3)] 3a-f.a
[PdCl2(NHC)(PPh3)] (0.5 mol % )
Br
+
R
KOtBu, DMF
100 °C
R
Entry
Ar-Br
[PdCl2(NHC)(PPh3)] Time (h)
Conversion (%)
1
3a
3b
3c
3d
3e
3f
1
0
2
1
18
3
1
33
Br
O
4
1
37
5
1
22
6
1
12
7
3a
3b
3c
3d
3e
3f
15 min
100
100
100
100
100
100
10
8
15 min
O
9
15 min
Br
10
11
12
13
14
15
16
17
18
19
20
21
15 min
15 min
15 min
3a
3b
3c
3d
3e
3f
1
1
1
1
1
1
6
6
6
48
86
Br
100
67
100
85
3a
3b
3c
77
80
21

22
23
24
3d
3e
3f
6
6
6
79
20
63
Br
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
3a
3b
3c
3d
3e
3f
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
27
O
O
100
100
100
0
O
Br
100
100
91
3a
3b
3c
3d
3e
3f
71
81
Br
29
82
3b
3c
3d
3e
3f
9
100
34
Br
100
100
a Reaction conditions: arylbromide (0.3 mmol), phenylacetylene (0.6 mmol),
[PdCl2(NHC)(PPh3)] (0.5 mol %), KOtBu (0.6 mmol), 5 ml DMF. 100 °C, under argon.
Conversions were determined by GC.
22

Table 2. Sonogashira reactions of phenylacetylene with arylbromides catalyzed by symmetrical
palladium complexes [PdCl2(NHC)(PPh3)] 3g-h.a
[PdCl2(NHC)(PPh3)] (0.5 mol % )
Br
+
R
KOtBu, DMF
100 °C
R
Entry
Ar-Br
[PdCl2(NHC)(PPh3)] Time (h)
Conversion (%)
1
3g
3h
3g
3h
3g
3h
3g
3h
3g
3h
3g
3h
1
100
Br
O
2
1
9
O
3
15 min
100
100
0
Br
4
15 min
O
5
15 min
Br
Br
6
H
15 min
0
7
1
1
1
1
6
6
100
100
29
29
8
8
9
Br
Br
10
11
12
100
13
14
3g
3h
6
6
67
0
Br
O
15
16
3g
3h
6
6
98
0
O
Br
O
17
18
3g
3h
6
6
57
12
Br
23

a Reaction conditions: arylbromide (0.3 mmol), phenylacetylene (0.6 mmol),
[PdCl2(NHC)(PPh3)] (0.5 mol %), KOtBu (0.6 mmol), 5 ml DMF. 100 °C, under argon.
Conversions were determined by GC.
Table 3. Sonogashira reactions of phenylacetylene with 2,6-dibromopyridine catalyzed by
palladium complexes [PdCl2(NHC)(PPh3)] 3(a-h).a
[PdCl2(NHC)(PPh3)] (1mol % )
KOtBu, DMF
Br
+
N
N
Br
Br
6h, 100 °C
Entry
[PdCl2(NHC)(PPh3)]
3a
Conversion (%)
1
100
2
3
4
5
6
7
8
3b
3c
3d
3e
3f
100
100
100
100
100
100
100
3g
3h
a Reaction conditions: 2,6-dibromopyridine (0.3 mmol), phenylacetylene (1.2 mmol), 10 ml
DMF, [PdCl2(NHC)(PPh3)] (1 mol %), KOtBu (1.2 mmol). 100 °C, Ar. Conversions were
determined by GC.
24

Table 4. Antibacterial activity (inhibition zone in mm) of the synthesized N-heterocyclic carbine-
phosphine palladium(II) complexes 3a-h.
Micrococcus Staphylococcus Listeria
Salmonella
Pseudomonas
aeruginosa
Compound luteus
LB 14110
aureus
monocytogenes typhimurium
ATCC 6538
ATCC 19117
ATCC 14028 ATCC 49189
3a
3b
3c
3d
3e
3f
17 ± 0.4
20 ± 0.1
22 ± 0.2
20 ± 0.2
31 ± 0.5
24 ± 0.4
16 ± 0.3
26 ± 0.3
17 ± 1.2
18 ± 0.4
16 ± 0.2
17 ± 0.2
15 ± 0.4
27 ± 0.2
28 ± 0.4
26 ± 0.3
22 ± 0.3
15 ± 1.4
22 ± 0.4
18 ± 0.4
22 ± 0.3
19 ± 0.5
23 ± 0.2
22± 0.4
17 ± 0.3
22 ± 0.5
24 ± 0.1
23 ± 0.3
24 ± 0.4
13 ± 0.5
23 ± 0.5
22 ± 0.5
24 ± 0.4
17 ± 0.2
23 ± 0.5
22 ± 0.3
25 ± 0.5
27 ± 0.5
23 ± 0.2
24 ± 0.1
3g
3h
Table 5. Minimum Inhibitory Concentrations (MICs) expressed in mg/mL of N-heterocyclic
carbine-phosphine palladium(II) complexes 3a-h.
Micrococcusluteus Listeria monocytogenes
Salmonella Typhimurium
Compound
LB 14110
ATCC 19117
ATCC14028
3a
3b
3c
3d
3e
3f
0.042
0.0186
0.024
0.323
0.049
0.425
0.525
0.723
1.23
0.076
1.35
2.4
2.3
1.32
2.3
2.4
2.2
5
0.42
1.34
1.20
1.34
0.039
3g
3h
3
1.4
0.625
Ampicillin 0.0195
25

Table 6. Acetylcholinesterase inhibitory activity (AChEI,
%) of N-heterocyclic carbine-phosphine palladium(II)
complexes 3a-h.
Compound
(AChEI) (%)
3a
3b
3c
3d
3e
3f
37.2
39.25
—
33.15
34.70
33.2
32.5
31.5
3g
3h
26