In situ palladium/N-heterocyclic carbene complex catalyzed carbonylative cross-coupling reactions of arylboronic acids with 2-bromopyridine under CO pressure: efficient synthesis of unsymmetrical arylpyridine ketones and their antimicrobial activities

Article abstract of DOI:10.1007/s11243-018-00298-9

The carbonylative Suzuki cross-coupling of 2-bromopyridine with various boronic acids to prepare unsymmetrical arylpyridine ketones has been carried out using palladium/N-heterocyclic carbene complexes as catalysts prepared in situ. The selectivity and the rate of these reactions are highly dependent on the conditions, i.e., nature of the palladium catalyst precursor, solvent, temperature and CO pressure. The main side-products arise from direct, non-carbonylative cross-coupling. Under the optimum conditions, arylpyridine ketones are recovered in high yields (60–88%). The antibacterial activities of the corresponding benzimidazole salts 2 were tested against Gram positive and negative bacteria using the agar dilution procedure, and their IC50 values have been determined.

Full text of DOI:10.1007/s11243-018-00298-9

Transition Metal Chemistry
https://doi.org/10.1007/s11243-018-00298-9
In situ palladium/N‑heterocyclic carbene complex catalyzed
carbonylative cross‑coupling reactions of arylboronic acids
with 2‑bromopyridine under CO pressure: efcient synthesis
of unsymmetrical arylpyridine ketones and their antimicrobial
activities
L. Boubakri1 · Abdullah S. Al‑Ayed2 · L. Mansour3 · A. A. Harrath3 · J. Al‑Tamimi3 · I. Özdemir4 · S. Yasar4 · N. Hamdi1,2
Received: 29 September 2018 / Accepted: 6 December 2018
© Springer Nature Switzerland AG 2018
Abstract
The carbonylative Suzuki cross-coupling of 2-bromopyridine with various boronic acids to prepare unsymmetrical arylpyri-
dine ketones has been carried out using palladium/N-heterocyclic carbene complexes as catalysts prepared in situ. The selec-
tivity and the rate of these reactions are highly dependent on the conditions, i.e., nature of the palladium catalyst precursor,
solvent, temperature and CO pressure. The main side-products arise from direct, non-carbonylative cross-coupling. Under
the optimum conditions, arylpyridine ketones are recovered in high yields (60–88%). The antibacterial activities of the cor-
responding benzimidazole salts 2 were tested against Gram positive and negative bacteria using the agar dilution procedure,
and their IC50 values have been determined.
Introduction
properties and straightforward synthesis. Complexes of
NHC ligands have been synthesized for almost every tran-
sition metal [11–13]. Among NHC complexes, the palla-
dium complexes have come to the fore due to their success
as catalysts for cross-coupling reactions [14–17]. Although
excellent progress has been made with mononuclear com-
plexes [18–28], diferent types of NHC-Pd complexes and
their catalytic properties have recently started to attract
attention [29–35]. At present, palladium-catalyzed cross-
coupling reactions represent over 60% of the carbon–car-
bon bond formation reactions used in medicinal chemistry
[36]. In particular, the discovery of palladium-catalyzed
C–C coupling reactions, such as Heck–Mizoroki coupling
[37, 38] in the early 1970s and Suzuki–Miyaura coupling
[39] in the early 1980s, has been exploited in a wide range
of felds, from natural product synthesis to materials sci-
ence, as well as biologically important molecules including
drugs and agrochemicals [40]. A great number of in situ
generated NHC-Pd catalysts have been reported for Suzuki
cross-coupling reactions [47–49]. Herrmann reported
the frst Pd-NHC catalyst for Suzuki cross-coupling in
2002 [50, 51]. Subsequently, Nolan [52–62], Glorious
[63–65], Organ [66–71] and others [40, 72–74] reported
diferent Pd-NHC catalysts for Suzuki–Miyaura cross-
couplings. α-Pyridyl ketones are useful intermediates in
Following Arduengo’s isolation of free N-heterocyclic car-
benes (NHC) [1], NHCs have gained an important place as
ancillary ligands for transition metals, partially as alter-
natives to phosphine ligands [2–7]. Although NHCs and
phosphines are considered to be similar as ligands, their
steric and electronic behaviors are rather diferent. The
NHCs have some advantages compared to phosphines,
such as high thermal stability, lower toxicity, resistance to
oxidation [8, 9], strong σ-donor [10] and weak π-acceptor
capability, as well as easily tuneable electronic and steric
* N. Hamdi
naceur.hamdi@isste.rnu.tn
1
Research Laboratory of Environmental Sciences
and Technologies (LR16ES09), Higher Institute
of Environmental Sciences and Technology, University
of Carthage, Hammam-Lif, Tunisia
2
Chemistry Department, College of Science and Arts, Qassim
University, Al-Rass, Saudi Arabia
3
Zoology Department, College of Science, King Saud
University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
4
Department of Chemistry, Faculty of Science and Art, İnönü
University, Malatya, Turkey
Vol.:(0123456789)
1 3

Transition Metal Chemistry
the synthesis of various natural products and drugs [41,
42]. Diferent methodologies have been proposed to access
this important class of products. Many of them are based
on the stoichiometric reaction of a pyridyl organometal-
lic derivative with an electrophile; i.e., selective ortho-
metallation of pyridine with lithiated reagents followed
by reaction with amides [43, 44], anhydrides or aroyl
chlorides to pyridyl Grignard reagents [45, 46], pyridyl-
tellurides [47], pyridyl-zinc [48, 49] or pyridyltrialkylstan-
nyl derivatives [50, 51]. Other routes involve oxidation of
hydroxy-, imino- and benzyl-substituents on pyridyl rings
[52–57], or use multistep procedures [58, 59]. However,
these aforementioned methodologies generally require
expensive and/or toxic reagents (oxidizers), can give poor
yields, and/or are only efective with specifc substrates.
In this regard, to our knowledge, only three examples of
Suzuki carbonylative cross-coupling of 2-pyridine hal-
ides with 3-bromoquinoline have been reported, giving
the expected benzoyl products in up to 66% yield [60–62].
Among the methodologies described in the literature, the
Suzuki reaction is one of the most practical for the forma-
tion of nitrogen-containing heterobiaryls through alterna-
tive cross-coupling paths (Scheme 1) [63–65]. The frst
path involves cross-coupling of a 2-pyridyl boronic acid/
ester or borate with an aryl halide (Scheme 1, path I). In
recent years, a variety of activated boronates have been
reported for the construction of biaryl systems contain-
ing a 2-pyridyl moiety [66]. However, path I is limited by
the accessibility and/or stability of the boron-containing
reagents. Additionally, a phosphine ligand is necessary
for path I [67–71]. Path II uses a 2-halogenated pyridine
as one of the coupling partners. The groups of Buchwald
[72, 73], Fu [74], Plenio [75], and others [76, 77] have
developed ligand-promoted approaches for the formation
of 2-aryl-substituted pyridine derivatives from 2-halopyr-
idines. Recently, ligand-free protocols for the synthesis
of heterobiaryls containing a 2-pyridyl moiety via path
II have attracted attention because they are simpler and
cheaper than their ligand counterparts [78–80]. Unfortu-
nately, the ligand-free Suzuki reaction usually proceeds
with low reactivity with respect to 2-halopyridines.
We have previously obtained results [81] that suggest that
an in situ four-component system consisting of Pd(OAc)2,
1,3-dialkylbenzimidazolium halide and K2CO3 under a
CO atmosphere catalyzes carbonylative cross-coupling of
2-bromopyridine with various boronic acids to give unsym-
metrical arylpyridine ketones. We were therefore interested
to see whether analogous in situ palladium N-heterocyclic
carbene complexes would show good activity in carbon-
ylative cross-coupling reactions of arylboronic acids with
2-bromopyridine under CO. We now report that the proper
choice of reaction conditions enables the easy and selective
transformation of a variety of arylboronic acids to unsym-
metrical arylpyridine ketones. In addition, all of the obtained
compounds were tested for in vitro antibacterial activities
against diferent strains.
Results and discussion
Synthesis and characterization of benzimidazolium
salts 2a–e
The N,N-disubstituted benzimidazolium salts 2a–e
(Scheme 2) were synthesized in two steps. The frst involves
the introduction of an N-alkyl/group aryl to the benzimida-
zole, enhancing the reactivity of the other the nitrogen atom.
Addition of the other alkylating agent to the remaining nitro-
gen atom gives the desired N,N-disubstituted benzimidazo-
lium salt45. Benzimidazolium salts 2a–e were prepared in
good yields of 89–96% by treatment of the N,N-substituted
benzimidazoles (A), with appropriate substituted benzyl hal-
ides in DMF at 70 °C for 48 h, as previously described [82].
The benzimidazolium salts 2a–e are stable to air and
moisture, both in the solid state and in solution. They were
Scheme 1 Alternative synthetic
Ar-X
paths for 2-aryl-substituted pyri-
GF
dine derivatives
Path I
N
(B)
GF
N
Ar
GF
Ar-(B)
Path II
N
X
(B)= boronic acid, boronate ester, borate
1 3

Transition Metal Chemistry
R1
Scheme 2 General preparation
and structure formulae of benzi-
midazolium salts 2a–e
R1
R2
H
N
N
N
X
DMF
70 °C
X
N
N
R1
EtOH, KOH
reflux
+
X
N
A: R1 = 3, 5- dimethyl
B: R1 = 4- methyl
2
R2
C: R1 = 4- ter-butyl
N
N
N
Br
Cl
Br
N
N
N
2a
2b
2c
N
N
Br
Br
N
N
2d
2e
characterized by 1H-NMR, 13C{1H} NMR, IR and elemental
analysis techniques.
agreement with previously reported values for benzimida-
zolium salts [83]. The benzylic –CH2– proton signals H1′,1″
for the benzimidazolium salt 2e as representative were
observed at 5.67 and 5.76 ppm, respectively, while the aro-
matic protons appeared at δ between 6.97 and 7.37 ppm.
The carbene carbon signals of the salt 2e were observed
at δ 141.6 ppm in the 13C NMR spectrum, while the C1′,1″
carbon signals were at δ 51.1 ppm. The mass spectrum of
salt 2e gave the most prominent peak at m/z = 253; this
can be explained by the fragmentation pattern shown in
Scheme 3.
The 1H-NMR spectra of salts 2a–e showed the NCHN
protons as singlets at 11.58, 11.17, 11.54, 11.63 and
11.57 ppm, respectively. In the 13C{1H} NMR spectra,
the NCHN carbon of benzimidazolium salts is usually
observed at around 142 4 [82]. For the salts 2a–e, it was
observed at 152.1, 142.9, 141.8, 163.0 and 141.6 ppm,
respectively. In the IR spectra, the ν(C=N) bands for
salts 2a–e were observed at 1566, 1547, 1566, 1670
and 1599 cm−1, respectively. These values are in good
m/z = 253
Scheme 3 Mechanism of frag-
mentation of 2e leading to the
m/z=253 peak
CH2
N
CH2
N
Br-
N
Br-
Br-
)
N
N
N
CH2
m/z = 344
m/z = 435
m/z = 253
1 3

Transition Metal Chemistry
Table 1 Optimization of
reaction conditions for the
carbonylative cross-coupling
reaction of 2-bromopyridine
with phenyl boronic acid
Entry
Ligand
(mol%)
Base
Temperature
(°C)
Pressure of CO Solvent
Yield
(bar)
1
2
3
4
5
6
7
8
3
3
3
3
3
3
3
3
3
5
5
6
K2CO3
K2CO3
K2CO3
t-BuOK
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
100
100
100
100
100
100
100
110
120
110
120
110
20
20
20
20
20
10
40
20
20
20
20
20
DMF
1,4-dioxane
THF
THF
THF
THF
THF
THF
THF
–
55%
65%
50
70%
55%
60%
70%
65%
85%
70%
85%
9
10
11
12
THF
THF
THF
Conditions: 2-Br-Py (1 mmol), Pd(OAc)2, base (2 mmol), benzimidazole 2e, PhB(OH)2 (1.1 mmol), CO,
solvent (10 mL), T°, overnight
Scheme 4 Carbonylative
cross-coupling reaction of
2-bromopyridine with phe-
nylboronic acid
R
R
B(OH)2
N
N
Br
O
Palladium catalysts based on N-heterocyclic carbene
ligands have previously been exploited for the efective car-
bonylative coupling of diferent chloropyridines with phe-
nylboronic acid [84]. However, the results to date suggest
that commercial Pd-based catalysts are not efective for this
transformation, probably because of poisoning by CO [85].
Thus, we have studied the behavior of benzimidazole salt 2e
as a ligand in the presence of Pd(OAc)2 for the carbonylative
cross-coupling of 2-bromo pyridine with diferent boronic
acids.
of 65% (entry 3). Use of alkali carbonates such as K2CO3
and CsCO3 as base gave good yields (entries 3, 5). On vary-
ing the reaction temperature, the best yield was obtained
at 110 °C (entry 8). Increasing the temperature to 120 °C
resulted in a decrease in the yield to 65% (entry 9). We there-
fore selected 110 °C as the optimum temperature.
Based on these results, the optimized reaction condi-
tions were determined as: 2-bromopyridine (1.0 mmol),
arylboronic acid (1.1 mmol), benzimidazole 2e (5 mol %),
Pd(OAc)2 (0.025 mmol) and K2CO3 (2.0 mmol) in THF at
110 °C under a CO atmosphere (20 bar).
The reaction of 2-bromopyridine with phenyl boronic
acid was chosen as a model system in order to optimize the
reaction conditions (Scheme 3, Table 1) under diferent CO
pressures at 110 °C, using various solvents and bases with
Pd(OAc)2 and two equivalents of 2e. The results are summa-
rized in Table 1. Direct non-carbonylative cross-coupling is
the major side reaction, and 2-bromopyridine was recovered
with a good fnal selectivity (entry 12), Scheme 4.
To further investigate the scope and limitations of
this methodology, we carried out cross-couplings of
2-bromopyridine with various aryl boronic acids under the
optimized conditions. As shown in Table 2, the coupling
of phenylboronic acid with 2-bromopyridine gave exclu-
sively phenyl(pyridin-2-yl)methanone in 75% yield, show-
ing high efciency and good selectivity (Table 2, entry 1).
Using 4-methylphenyl boronic acid instead of phenylbo-
ronic acid, the cross-coupling was completed in 67% yield
(Table 2, entry 2). The cross-coupling of 2-bromo pyridine
with (4-formylphenyl) boronic acid proceeded well to give
the expected product in excellent yield (entry 4), while
4-boronobenzoic acid also aforded a satisfactory 88% (entry
5). Scheme 5.
Selected results are shown in Table 1. Conditions; benzi-
midazolium salt 2e, CO, base, Pd(OAc)2 for Table 1, R=H.
First, DMF, 1.4-dioxane and THF were used as solvents,
(Table 1, entries 1–3). No reaction was observed in DMF
(Table 1, entry 1). Use of 1,4-dioxane also gave unsatisfac-
tory results in this case in terms of the selectivity for the
product (Table 1, entry 2). However, when the reaction was
carried out in tetrahydrofuran, the selectivity was markedly
increased and the desired product was obtained with a yield
The chemical structures of the arylpyridine ketones were
established by FTIR, 1HNMR and 13C-NMR.
1 3

Transition Metal Chemistry
Table 2 Results of carbonylative cross-coupling reaction of
Table 3 Antibacterial activity of the benzimidazolium salts 2a–e
2-bromopyridine with arylboronic acids
Microorganism indicator
Compound Inhibition
zone (mm)
Entry
Boronic acid
Yield (%)
1
2
3
4
5
R=H
75
67
65
90
88
Micrococcus luteus LB 14110
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
15 0.4
16 0.3
14 0.2
17 0.4
13 0.4
13 0.4
14 0.3
14 0.2
13 0.2
12 0.3
15 0.4
16 0.3
14 0.2
13 0.4
14 0.5
18 0.5
20 0.2
18 0.1
19 0.3
18 0.5
17 0.5
18 0.2
17 0.1
19 0.3
18 0.5
R=CH3
R=OCH3
R=CHO
R=COOH
Staphylococcus aureus ATCC 6538
Listeria monocytogenes ATCC 19117
Salmonella typhimurium ATCC 14028
Conditions: 2-Br-Py (1 mmol), Pd(OAc)2 (0.025 mmol), K2CO3
(2 mmol), benzimidazolium salt 2e (5 mol%), arylboronic acid
(1.1 mmol), CO (20 bars), 110 °C, THF (10 mL), one night
Antibacterial activities
The benzimidazolium salts 2a–e were evaluated for antimi-
crobial activity against three Gram-positive bacteria, namely
Micrococcus luteus LB 14110, Staphylococcus aureus
ATCC 6538 and Listeria monocytogenes ATCC 19117,
plus two Gram-negative bacteria (Salmonella Typhimurium
ATCC 14028 and Pseudomonas aeruginosa ATCC 49189).
The results of these experiments are presented in Table 3.
All of these benzimidazole salts exhibit antimicrobial activ-
ity against one or more strain of bacteria. Although salt 2e
showed high antimicrobial activity, salt 2b showed high
activity against Gram-positive and Gram-negative bacteria
in high and low concentrations.
Pseudomonas aeruginosa ATCC 49189 2a
2b
2c
2d
2e
In parallel, minimal inhibitory concentration (MIC) val-
ues of the benzimidazole salts were determined against M.
luteus and L. monocytogenes and the Gram-negative bac-
terium S. typhimurium. Ampicillin was used as a positive
control. As shown in Table 4, the MIC values range from
1.5 to 1.8 mg/mL against M. luteus; 1.8–2.4 mg/mL for L.
monocytogenes and 2.1–2.6 mg/mL for S. typhimurium.
addition, the benzimidazolium salts 2a–e showed signifcant
antimicrobial activity compared with a standard antibiotic.
Experimental section
Materials and methods
Conclusion
All manipulations were performed using standard Schlenk
techniques under an argon atmosphere. Chemicals were pur-
chased from Sigma–Aldrich and used without further purif-
cation. All solvents were purifed and dried with an MBraun
SPS 800 solvent purifcation system. Column chromatog-
raphy was performed using silica gel 60 (70–230 mesh).
1H and 13C NMR spectra were recorded on an AC-300
In this study, we have shown that the carbonylative Suzuki
cross-coupling of 2-bromopyridine and arylboronic acids
catalyzed by our palladium complexes provides an efcient
and general route to a variety of unsymmetrical arylpyri-
dine ketones. Further development of this chemistry using
2-chloropyridine substrates will be reported in due course. In
Scheme 5 Carbonylative
20 bars CO,
R
cross-coupling reaction of
K CO , Pd(OAc)
2
3
2
R
B(OH)2
2-bromopyridine with arylbo-
THF, 110°C, one night
Benzimidazole salt 2e
ronic acids. The results are
summarized in Table 2
N
N
Br
O
1 3

Transition Metal Chemistry
Table 4 Minimum inhibitory concentrations (MICs) for benzimida-
zolium salts 2a–e
luteus, and L. monocytogenes and at 37 °C for S. aureus,
S. typhimurium and P. aeruginosa ATCC 49189, and then
diluted 1:100 in LB medium and incubated for 5 h under
constant agitation (200 rpm) at the appropriate temperature.
The agar well difusion method was employed for deter-
mination of the antibacterial activities of the compounds,
using the published method [86]. Briefy, the test compounds
were allowed to difuse out into LB agar medium on a plate
freshly seeded with a suspension of the required microor-
ganism (0.1 mL of 108 cells per mL). Each compound was
dissolved in DMSO/water (1/9; v/v) to a fnal concentration
of 20 mg/mL, and then, 100 µL of the solution was placed
into the corresponding well. The plate was incubated at the
appropriate temperature for each microorganism, keeping
it at 4 °C for 2 h. The antibacterial activity was assayed
by measuring, in millimeters, the diameter of the inhibition
zone formed around the well. This determination was done
in triplicate, and the reported diameter of inhibition is the
average of the three tests.
Microorganism indicator
Compounds
MIC (mg/mL)
Micrococcus luteus
2a
1.8
1.7
1.5
1.6
1.8
0.0195
2.2
2.3
2.4
1.8
1.9
0.039
2.6
2.3
2.2
2.1
2.4
0.625
2b
2c
2d
2e
Ampicillin
Listeria monocytogenes
Salmonella typhimurium
2a
2b
2c
2d
2e
Ampicillin
2a
2b
2c
2d
The antimicrobial activities of the compounds were also
assayed by their minimum inhibitory concentrations (MICs)
in accordance with NCCLS guidelines M7-A6 and M38-P
[87]. Tests were performed in sterile 96-well microplates
with a fnal volume in each well of 100 µL. The test com-
pounds (20 mg/mL) were dissolved in DMSO/water (1/9;
v/v). These solutions were transferred to the wells in order to
obtain twofold serial dilutions and to produce the concentra-
tion range of 0.0048–20 mg/mL.
2e
Ampicillin
Bruker spectrometer at 300 MHz and 75 MHz, respectively.
Chemical shifts, δ, are reported in ppm relative to the inter-
nal standard TMS for both 1H and 13C NMR. The products
were characterized by GC. Quantitative GC analyses were
performed with a Shimadzu GC-2010 Plus gas chromatogra-
phy. NMR multiplicities are abbreviated as follows: s=sin-
glet, d=doublet, t=triplet, m=multiplet. IR spectra were
recorded on a 398 spectrophotometer (Perkin-Elmer, King
Saud University, Riyadh, Saudi Arabia). Mass spectra were
recorded on a ((DART-TOF–MS) instrument at King Saud
University. Microanalyses were obtained on an Elementar
Vario El III Carlo Erba 1108 elemental analyzer (King Saud
University), and the obtained values were within 0.3% of
the theoretical values. Melting points were determined with
a Kofer bench instrument at Isste of Borj cedria (Hammam
Lif, University of Carthage, Borj Cedria, Tunisia).
To each test well, 10 µL of cell suspension was added
to give fnal inoculum concentrations of 106 CFU/mL for
each microorganism. Positive growth control wells consisted
of the microorganisms only in the medium. Ampicillin was
used as a positive control. The plates were covered with
sterile plate covers and incubated at the appropriate tem-
perature for each microorganism. The MIC was defned as
the lowest concentration of the test compound at which the
microorganism showed no visible growth after incubation.
As an aid to visualization of microorganism growth, 25 µL
of thiazolyl blue tetrazolium Bromide (MTT), indicator solu-
tion (0.5 mg/mL) dissolved in sterile water was added to the
wells and incubated at room temperature for 30 min.
The N-substituted benzimidazoles (A–B) and the benzi-
midazolium salts 2a–e were prepared according the reported
procedures [82].
Acknowledgements The authors would like to extend their sincere
appreciation to the Deanship of Scientifc Research at King Saud Uni-
versity for funding this research group No (RG-1435-023).
Antibacterial activities were determined according the
reported procedures [82].
Gram-positive bacteria: Micrococcus luteus LB 14110,
Staphylococcus aureus ATCC 6538 and Listeria monocy-
togenes ATCC 19117, and Gram-negative bacteria: Salmo-
nella Typhimurium ATCC 14028 and Pseudomonas aerugi-
nosa ATCC 49189. Bacterial cultures were grown overnight
in Luria-Bertani (LB) agar medium composed of (g/L): pep-
tone 10; yeast extract 5; and NaCl 5 at pH 7.2 under aerobic
conditions and constant agitation (200 rpm) at 30 °C for M.
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