Synthesis, characterization and anticancer activity of palladium allyl complexes bearing benzimidazole-based N-heterocyclic carbene (NHC) ligands

Article abstract of DOI:10.1016/j.poly.2021.115381

The synthesis of twelve new palladium allyl complexes bearing benzimidazole-based NHC (NHC = N-heterocyclic carbene) ligands is reported. All the complexes were characterized by NMR and elemental analysis and, in the case of complex 5c, it was possible to confirm the connectivity by single crystal X-ray diffraction. The cationic palladium allyl complexes were tested toward 5 different cancer lines, with IC₅₀ values generally lower than cisplatin and similar antiproliferative activity in the two ovarian cancer cell lines (A2780 and A2780cis), suggesting a different mechanism of action from classical platinum-based anticancer drugs. Compounds equipped with a pyridine arm or with the NHC/PTA combination (PTA = 1,3,5-triaza-7-phosphaadamantane) showed a lower cytotoxicity on normal cells with respect to cancer ones. By comparing the IC₅₀ values of mixed NHC/PTA complexes reported in this work and their trifluoromethyl congeners recently published by our group, it appears evident that they have very similar antiproliferative activity against cancer cells but the absence of the CF₃ group significantly decreases the selectivity toward them.

Full text of DOI:10.1016/j.poly.2021.115381

Polyhedron 207 (2021) 115381
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Synthesis, characterization and anticancer activity of palladium allyl
complexes bearing benzimidazole-based N-heterocyclic carbene
(NHC) ligands
,
,
Thomas Scattolina b, Andrea Piccina, Matteo Mauceria, Flavio Rizzolioa b, Nicola Demitric,
Vincenzo Canzonierib d, Fabiano Visentina
,
a
`
Dipartimento di Scienze Molecolari e Nanosistemi, Universita Ca’ Foscari, Campus Scientifico Via Torino 155, 30174 Venezia-Mestre, Italy
b Pathology Unit, Department of Molecular Biology and Translational Research, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Franco Gallini 2, 33081
Aviano, Italy
c Elettra – Sincrotrone Trieste, S.S. 14 Km 163.5 in Area Science Park, 34149 Basovizza, Trieste, Italy
d
`
Department of Medical, Surgical and Health Sciences, Universita degli Studi di Trieste, Strada di Fiume 447, Trieste, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords:
The synthesis of twelve new palladium allyl complexes bearing benzimidazole-based NHC (NHC = N-hetero-
cyclic carbene) ligands is reported. All the complexes were characterized by NMR and elemental analysis and, in
the case of complex 5c, it was possible to confirm the connectivity by single crystal X-ray diffraction.
The cationic palladium allyl complexes were tested toward 5 different cancer lines, with IC50 values generally
lower than cisplatin and similar antiproliferative activity in the two ovarian cancer cell lines (A2780 and
A2780cis), suggesting a different mechanism of action from classical platinum-based anticancer drugs.
Compounds equipped with a pyridine arm or with the NHC/PTA combination (PTA = 1,3,5-triaza-7-phos-
phaadamantane) showed a lower cytotoxicity on normal cells with respect to cancer ones.
N-heterocyclic carbene ligands
Benzimidazole
Palladium allyl complexes
Anticancer activity
Phosphine ligands
By comparing the IC50 values of mixed NHC/PTA complexes reported in this work and their trifluoromethyl
congeners recently published by our group, it appears evident that they have very similar antiproliferative ac-
tivity against cancer cells but the absence of the CF3 group significantly decreases the selectivity toward them.
1. Introduction
privileged ancillary ligands in homogeneous catalysis [10] could be
exploited for the preparation of benzimidazole-based NHC metal com-
Benzimidazole derivatives are among the most common heterocyclic
compounds in the U.S. FDA-approved pharmaceutical drugs [1]. In
particular, they exhibit a wide range of biological properties such as
anti-inflammatory [2], anti-ulcer [3], antihypertensive [4] and anti-
cancer [5].
plexes with biological properties.
It should be noted that the use of ligands with a biologically active
framework is a well-recognized strategy for the development of new
potential metallodrugs. In fact, in numerous contributions a synergy
between the biologically active ligand and the organometallic fragment
was proved and in the most favourable cases, the ligand has become a
real targeting vector of the metal compound [11].
For instance, Candesartan [6] and omeprazole [7] are used for the
treatment of hypertension and stomach ulcers, respectively, whereas
Nocodazole and Dovotininb are well-established antineoplastic drugs
[8,9].
On this basis, a number of gold, silver and ruthenium complexes
equipped with benzimidazole-based NHCs have been prepared and
tested as potential antibacterial and antitumor agents, showing inter-
esting results [12].
The therapeutic potential of these derivatives has prompted re-
searchers to design and synthesize new organic and organometallic
compounds containing the benzimidazole scaffold for a wide selection of
pharmacological applications.
Among the metal complexes studied as alternative to classical
platinated antineoplastic drugs, palladium organometallic compounds
have received growing interest in the last two decades because of their
remarkable in vitro cytotoxicity toward different cancer cell lines and
In this context, organometallic chemists wondered if the remarkable
advances obtained in the field of N-heterocyclic carbenes (NHCs) as
E-mail addresses: thomas.scattolin@unive.it (T. Scattolin), flavio.rizzolio@unive.it (F. Rizzolio), fvise@unive.it (F. Visentin).
https://doi.org/10.1016/j.poly.2021.115381
Received 25 June 2021; Accepted 16 July 2021
Available online 22 July 2021
0277-5387/© 2021 Elsevier Ltd. All rights reserved.

T. Scattolin et al.
Polyhedron 207 (2021) 115381
their good stability in physiological conditions [13].
2. Results and discussion
In this context, some palladium complexes bearing benzimidazole-
based NHCs, mainly of general formula [Pd(NHC)2X2] or [Pd(NHC)
X2L] (X = I, Br, Cl; L = Py, PR3 etc.), have been previously synthesized
and tested as potential anticancer agents. Unfortunately, only few de-
rivatives have shown a satisfactory cytotoxicity (Scheme 1) [14].
Conversely, a category of organopalladium compounds that has
recently produced some promising results is represented by Pd-allyl
derivatives [15]. These complexes have shown a good/excellent anti-
proliferative activity against different cisplatin-sensitive and cisplatin-
resistant cell lines.
2.1. Synthesis of benzimidazolium and bis-benzimidazolium salts (1a-f)
The benzimidazolium salts 1a-d used as precursors of the mono-
dentate carbene ligands were prepared by alkylation of the N-3 of
methyl-benzimidazole (for 1a-b and 1d) or phenyl-benzimidazole (for
1c) under the operating conditions reported in Scheme 2.
In all 1H NMR spectra of the products it is possible to observe a
considerable increase of the H2 proton chemical shift (Δδ ≈ 2 ppm) with
respect to the starting materials, due to the quaternization of benz-
imidazole nitrogen.
In particular, in our recent study we proved the potent in vitro anti-
cancer activity of palladium-allyl complexes stabilized by tri-
fluoromethyl benzimidazolylidenes and phosphine ligands [14]. The
mixed NHC/PTA (PTA = 1,3,5-triaza-7-phosphaadamantane) palladium
complexes were particularly interesting as they combine excellent
cytotoxicity toward cancer cells with low toxicity toward normal ones.
These results were confirmed on more complex biological systems
such as 3D organoids and tumoroids extracted from real patients.
Moreover, detailed immunofluorescence assays revealed cell death via
mitochondrial disfunction rather than the classical interaction with DNA
observed in cisplatin and its derivatives.
For needs connected to the subsequent synthetic steps, the azolium
salts 1a-c were synthesized in the chloride version, suspending the in-
termediate iodide derivatives in methanol in the presence of the DOWEX
21 K Cl ion-exchange resin.
Bis-benzimidazolium salts 1e-f were synthesized by reacting methyl-
benzimidazole or adamantyl-benzimidazole with dibromomethane in
However, an important question has been left open: is the presence of
the trifluoromethyl group necessary to ensure the uncommon selectivity
of these palladium derivatives toward cancer cells?
As a matter of fact, the importance of fluorinated substituents in the
biological activity of organic molecules is well documented [16] but, at
the best of our knowledge, this issue has been scarcely explored in metal-
based compounds.
With the main goal to address this problem herein we report the
synthesis and anticancer activity of palladium allyl complexes bearing
benzimidazole-based NHCs in which the trifluoromethyl group, present
in these compounds, has been replaced by a methyl substituent.
The easier access to these derivatives compared to their tri-
fluoromethyl congeners makes the latter decidedly less expensive and
rapid to prepare.
Scheme 2. Synthesis of benzimidazolium salts 1a-d.
Scheme 1. Examples of palladium complexes bearing benzimidazole-based NHCs with potent anticancer activity.
2

T. Scattolin et al.
Polyhedron 207 (2021) 115381
tetrahydrofuran or in neat conditions, as reported in Scheme 3. Unfor-
tunately, the bisbenzimidazolium bromides obtained are scarcely solu-
ble and therefore it was necessary to exchange the halide with the
perchlorate anion, in order to facilitate the following synthetic steps.
The metathesis was carried out using AgClO4 as a dehalogenating agent.
The 1H NMR spectra of 1e-f exhibit in addition to the methyl or
adamantyl substituents signals the methylene bridge NCH2N singlets at
7.4–8.5 ppm and the diagnostic peaks of the H2 proton at 9–10 ppm.
2.2. Synthesis of silver-NHC complexes (2a-d)
The classical transmetallation route from silver-NHC precursors was
chosen as the synthetic strategy for the synthesis of the palladium
compounds reported in this work.
Scheme 4. Synthesis of silver-NHC complexes 2a-d.
Palladium allyl complexes bearing chelating bisNHC ligands (3e-f)
were synthesized by a one-pot procedure. More in detail, the bisimida-
zolium salts 1e-f were reacted with Ag2O for 18–48 h in acetonitrile at
To this end, the silver-NHC complexes 2a-d were prepared in good
yields by reaction between benzimidazolium salts 1a-d and Ag2O. Each
reaction is completed in a few hours at room temperature in dichloro-
methane (Scheme 4).
room temperature and then the dimeric precursor [Pd(
μ
-Cl)(
η
3-allyl)]2
was added, affording the desired complexes 3e-f in good yields and
purity (Scheme 6).
The successful outcome of the reaction is proved by the disappear-
ance of the benzimidazole proton H2 and by the downfield shift of the
corresponding carbon (C2) in the 1H and 13C NMR spectra, respectively,
in addition to a general shift of all other signals with respect to the
starting imidazolium salts. In particular, the C2 carbon resonates at ca.
190 ppm which is typical of a coordinated carbene carbon.
The 1H NMR spectrum of 3e is characterized by three different allyl
protons (Hsyn, Hanti and Hcentral), an AB system at ca. 6.5 ppm and a
singlet at 4 ppm ascribable to methylene protons NCH2N and methyl
substituents, respectively.
In the 13C NMR spectrum, the signal at ca. 60 ppm for the terminal
allyl carbons, the carbene carbon (187 ppm) and the methylene bridge
signal at 57 ppm are particularly worth of mention.
–
2.3. Synthesis of palladium-allyl complexes bearing chelating C N or
–
C
C ligands (3d-f)
The presence of a single set of signals suggests that in solution the
rearrangement of the methylene spacer above and below the main co-
ordination plane (ring inversion of chelating ligand) is free and therefore
the two possible diastereoisomers are not distinguishable at room
temperature.
The first category of palladium-allyl complexes taken into consid-
eration includes those containing picolyl-carbene (3d) and biscarbene
(3e-f) as chelating ligands.
These classes of compounds have recently exhibited a promising in
vitro anticancer activity when classical imidazolylidenes were used as
spectator ligands [15] and for this reason we believe that synthesis and
biological investigations of their benzimidazolylidene congeners could
be interesting.
Conversely, complex 3f, which contains the higher steric demanding
adamantyl wing-type substituents, is present in solution as a mixture of
two atropoisomers (in a 1:2 ratio).
Also in this case, for each isomer the two terminal allyl protons (syn
and anti), the central allyl proton and the AB systems of the NCH2N
methylene protons can be identified in the 1H NMR spectrum.
As illustrated in Scheme 5, complex 3d was synthesized by reacting
the picolyl-NHC silver precursor 2d with [Pd(
μ
-Cl)(
η
3-allyl)]2, in the
presence of NaClO4⋅H2O as the dehalogenating agent.
2.4. Synthesis of neutral palladium-allyl complexes bearing monodentate
The latter is perfectly soluble in these optimal conditions unlike
other alternative dehalogenants (eg. KPF6 or NaBF4) and ensures the
obtainment of products with a high degree of purity and stability both in
the solid state and in solution.
NHC ligands (4a-c)
The neutral allyl complexes of the type [Pd(NHC)Cl(
η
3-allyl)] [17],
which will be used as precursors of the mixed NHC/PR3 derivatives,
The desired complex was obtained in high yield and purity and its
NMR characterization is straightforward.
were synthesized by reaction between [Pd(
μ-Cl)(
η
3-allyl)]2 and the
silver-NHC complexes 2a-c. Each reaction is completed within 30 min,
in which the progressive precipitation of AgCl was observed (Scheme 7).
In the 1H NMR spectra of the final products 4a-c it is possible to
observe, in addition to the signals ascribable to carbene ligand, five
different allyl protons, with those trans to chloride having a lower
chemical shift than those trans to the carbene ligand.
In particular, the coordination of the pyridine arm is confirmed by
the downfield shift of the proton ortho to the pyridine nitrogen (Δδ ≈
0.3 ppm) with respect to the silver precursor and by the presence of an
AB system attributable to the diastereotopic methylene protons N-CH2.
As for the allyl fragment, we can observe that the protons trans to
pyridine are significantly broadened at room temperature, suggesting a
This effect is confirmed in the 13C NMR spectra in which the terminal
allyl carbon trans to chloride resonates at chemical shifts lower than 20
ppm compared to that trans to the carbene.
selective η3
-
η1
-
η
3 fluxionality. By lowering the temperature to 243 K it is
possible to block this fluxional phenomenon and observe five sharp allyl
signals, with those trans to the carbene resonating at higher chemical
shifts due to the greater trans effect of NHC ligands compared to pyri-
dine. For the same reason, the terminal allyl carbon trans-N occurs at 49
ppm whereas that trans-C falls at 75 ppm. In the 13C NMR spectrum the
coordinate carbene carbon peak at 187 ppm is also well recognizable.
In these neutral derivatives the carbene carbon singlet resonates at
ca. 180 ppm.
2.5. Synthesis of mixed NHC/PR3 palladium-allyl complexes (5a-d and
6a-b)
With the aim of indirectly evaluate the importance of the tri-
fluoromethyl group in the antitumor activity of the mixed NHC/PR3
(PR3 = PPh3 and PTA) palladium allyl complexes recently reported by
our group [14], we synthesized their methyl congeners by reaction be-
tween triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane (PTA)
and the neutral palladium allyl complexes 4a-c in the presence of
Scheme 3. Synthesis of bisbenzimidazolium salts 1e-f.
3

T. Scattolin et al.
Polyhedron 207 (2021) 115381
Scheme 5. Synthesis of palladium-allyl complexes bearing a picolyl-NHC ligand (3d).
The 1H NMR spectra display five different allyl signals and, among
them, those attributable to the terminal protons trans to the phosphine
ligand are distinguishable by coupling with the phosphorus nucleus.
The concomitant presence of phosphine and NHC ligands is
confirmed by the 13C NMR spectra, in which the carbene carbon signal
resonates as a doublet (JC-P ≈ 20 Hz) at 180–190 ppm.
As regards the complexes 5c-d, which bear unsymmetrical
benzimidazole-based NHC ligands, the presence of two different atro-
poisomers is observed because of the hindered rotation about the Pd-
Scheme 6. Synthesis of palladium-allyl complexes bearing chelating bisNHC
ligands (3e-f).
CNHC bond. In particular, two singlets at ca. 25 ppm are distinguishable
in the 31P NMR spectra.
Consistently, in the 1H and 13C NMR spectra we also observe the
presence of two sets of signals, one for each atropoisomer.
It should be noted that every attempt at synthesizing complexes 6c-
d led to the formation of significant amounts of bisNHC (3c-d) and
bisPTA complexes, in addition to the desired mixed NHC/PTA species.
This phenomenon had already been observed previously in attempts at
synthesizing Pd(0) olefin complexes bearing one xanthine-based NHC
and one PTA molecule [13].
As a definitive confirmation of the nature of mixed NHC/PR3 com-
plexes, we report the structure of complex 5c obtained by single crystal
X-ray diffraction (Fig. 1).
Scheme 7. Synthesis of neutral palladium-allyl complexes (4a-c).
NaClO4 or, in the case of complex 5d, by addition of triphenylphosphine
to complex 3d bearing the chelate carbene-picolyl ligand (Scheme 8).
It should be noted that, unlike the trifluoromethyl derivatives, the
complexes reported in this work are easier to isolate and purify using
NaClO4 instead of NaBF4 (or AgBF4) as a dehalogenating agent.
Complexes 5a-b and 6a-b, which contain symmetrical
benzimidazole-based NHC ligands, show a single peak at ca. 25 ppm (for
5a-b) and ꢀ 55 ppm (for 6a-b) in 31P NMR spectra, with a remarkable
downfield shift with respect to the uncoordinated PPh3 or PTA.
The crystalline form of 5c contains one crystallographically inde-
pendent palladium complex.
The palladium centers adopt square planar coordination spheres
with bond lengths and angles in agreement with literature structural
data of similar complexes, like CCDC 1,992,549 [14] (Table S2). The
complex bears a positive charge which is balanced by a ClO-4 counterion,
located close to the allyl ligand, which represent the area where the
metal is more exposed (shortest O⋅⋅⋅Pd contacts are 4.530(4) Å in 5c and
3.88(1) Å in CCDC 1992549). The molecular model of 5c is well
Scheme 8. Synthesis of mixed NHC/PR3 palladium-allyl complexes (5a-d and
6a-b).
Fig. 1. Ellipsoid representation of 5c crystal ASU content (ellipsoids radii
corresponding to 50% probability). Atom labels in use are reported.
4

T. Scattolin et al.
Polyhedron 207 (2021) 115381
superimposable with CCDC 1,992,549 (Fig. S2) with minimal shifts of
atoms directly bound to the metal and equivalent benzimidazole and
allyl arrangements. This comparison highlights the phosphine ligand
conformational freedom, which is influenced by crystal packing contacts
and relative bulkiness of benzimidazole substituents.
these few derivatives, compound 3d is the most promising as it is sub-
stantially inactive against normal cells (IC50 > 100 μM).
As already observed in some previous works [14,15], two combi-
nations that seem in general to guarantee a certain selectivity toward
cancer cells are the presence of a pyridine arm on the NHC or the NHC/
PTA motif.
The crystal packing of 5c shows hydrophobic contacts among
neighbour molecules, involving weak intermolecular interactions:
π
⋅⋅⋅
π
Although mixed NHC/PTA complexes 6a-b showed some selectivity
toward cancer cells, their cytotoxicity toward MRC-5 fibroblasts is
significantly higher than mixed NHC/PTA palladium allyl complexes
bearing N-trifluoromethyl benzimidazolylidenes [14], suggesting that
the presence of the CF3 group is crucial for an in vitro selective antitumor
activity.
(i.e. dπ π = 3.710(1) Å with 1.00 Å slippage between benzimidazole ring
⋅⋅⋅
centroids) and CH⋅⋅⋅
π
(i.e. dCH⋅⋅⋅π = 3.477(3) Å with 63◦ between CH and
π
-plane), among the allyl ligand and neighbour aromatic sidechains. The
η
3-allyl instead can adopt two equally probable conformations specular
respect to the Pd coordination plane.
3. Conclusions
2.6. Cytotoxicity studies on cationic palladium allyl complexes 3d-f, 5a-
d and 6a-b
In summary, we reported the synthesis and characterization of 12
new palladium allyl complexes bearing benzimidazole-based NHC li-
gands. Compounds 3f and 5c-d appear as a mixture of two atro-
poisomers and for 5c it was possible to unequivocally establish the
connectivity of the atoms by single crystal X-ray diffraction.
The nine cationic compounds were tested as potential anticancer
agents against five different types of tumors (cisplatin-sensitive and
cisplatin-resistant ovarian cancers, lung cancer, colon cancer and glio-
blastoma), exhibiting excellent cytotoxicity in the sub-micromolar
range.
The antiproliferative activity of the cationic palladium(II) de-
rivatives 3d-f, 5a-d and 6a-b was assayed toward MRC-5 normal cells
(human fibroblasts) and five different human tumor cell lines: ovarian
cancer (A2780, with its cisplatin resistant clone A2780cis), lung cancer
(A549), colon cancer (DLD-1) and glioblastoma (U87 cells).
Preliminarily, the stability of all the compounds examined was
checked in 1:1 DMSO‑d6/D2O solution by NMR spectroscopy: after 24 h
at room temperature no noticeable degradation was observed.
The half-inhibitory concentrations (IC50) induced by the palladium
(II) compounds and cisplatin (positive control) are summarized in
Table 1.
In particular, they are generally more active than cisplatin and
showed similar IC50 values in the two of ovarian cancer lines (A2780 and
A2780cis), suggesting a different mechanism of action with respect to
classical platinated chemotherapeutic agents.
The IC50 values display a marked cytotoxicity of all compounds in the
different tumor lines tested. In most cases, the complexes exhibit a
higher antiproliferative activity than cisplatin, which is generally also
maintained in the A2780cis (cisplatin-sensitive) cell line, suggesting a
different mechanism of action compared to cisplatin. In this respect, in
our previous contribution, their trifluoromethyl congeners showed
inducing mitochondrial dysfunction as primary damage [14].
An important result obtained concerns the cytotoxicity of our com-
pounds toward MRC-5 normal cells. In this context, complexes 3d, 3e,
5d, 6a and 6b show IC50 values on average an order of magnitude higher
on normal cells with respect to those obtained on cancer ones. Among
Compounds with a pyridine arm or the NHC/PTA combination
showed a significant selectivity toward cancer cells, in which compound
3d was the most promising by virtue of its poor cytotoxicity against
MRC-5 normal cells.
On comparing the IC50 values of complexes 6a-b and their tri-
fluoromethyl congeners recently published by our group, it appears
evident that they have very similar cytotoxicity toward cancer cells but
the presence of the CF3 group guarantees a greater selective anticancer
activity, with a substantial inactivity toward MRC-5 lung fibroblasts
(IC50 > 100
μM vs approx. 2 μM).
Table 1
4. Experimental section
Cytotoxicity of Pd-complexes toward several cancer and normal cell lines*.
Complex
IC50 (μM)
4.1. Materials and characterization techniques
A2780
A2780cis
A549
DLD-1
U87
MRC-5
All syntheses of complexes were carried out using standard Schlenk
techniques under an atmosphere of dry nitrogen. Solvents were dried
and distilled according to standard methods: CH2Cl2 was firstly treated
with 3 Å molecular sieves and then distilled over P2O5. All other
chemicals were commercially available grade products and were used as
purchased.
CisPt
3d
3e
0.16 ±
0.02
5.8 ± 0.6
5.2 ±
0.8
4 ± 1
31 ± 4
2.4 ±
0.2
0.71 ±
0.03
3.0 ± 0.04
0.9 ± 0.3
3.4 ±
0.2
2.3 ±
0.2
0.57 ±
0.04
>100
0.23 ±
0.03
2.8 ±
0.3
0.5 ±
0.3
1.8 ± 0.4
4.4 ±
0.4
3f
0.035
0.029 ±
0.003
0.015
± 0.003
0.44 ±
0.03
0.04 ±
0.02
0.022 ±
0.001
0.32
± 0.04
0.9 ±
0.3
The palladium(II) precursor 1-methylbenzimidazole [18], 1-phenyl-
benzimidazole [19] and 1-adamantylbenzimidazole [20], were synthe-
sized according to published procedures.
± 0.008
0.16 ±
0.05
5a
0.17 ±
0.02
0.28 ±
0.02
0.19 ±
0.03
5b
5c
0.030
0.18 ±
0.06
0.10 ±
0.02
0.104
± 0.003
0.014
± 0.003
0.13 ±
0.03
0.028 ±
0.009
0.38
± 0.02
0.22
± 0.03
2.3 ±
0.2
The IR and NMR spectra were recorded on a Perkin-Elmer Spectrum
One spectrophotometer and on a Bruker 400 Avance spectrometer,
respectively.
± 0.007
0.026
0.019 ±
0.003
0.035
± 0.003
0.80 ±
0.06
0.0183 ±
0.0004
0.30 ±
0.03
± 0.006
0.13 ±
0.06
5d
6a
1.5 ± 0.4
Elemental analysis was carried out using an Elemental CHN “CUBO
Micro Vario” analyzer.
0.017
0.19 ±
0.03
3.4 ±
0.5
0.32 ±
0.05
0.5 ± 0.1
2.1 ±
0.3
Safety note: Perchlorate salts (eg. NaClO4) are potentially explosive
and should only be handled in small quantities with care.
± 0.002
0.10 ±
0.03
6b
0.25 ±
0.03
0.59 ±
0.07
0.3 ±
0.1
0.36 ±
2.8 ±
0.1
0.06
4.2. Synthesis of the compound 1a
*
Data after 96 h of incubation. Stock solutions in DMSO for all complexes;
stock solutions in H2O for cisplatin. A2780 (cisplatin-sensitive ovarian cancer
cells), A2780cis (cisplatin-resistant ovarian cancer cells), A549 (lung cancer
cells), DLD1 (colon cancer cells), U87 (glioblastoma cells), MRC-5 (normal lung
fibroblasts).
In a 100 mL flask, 1.3 g (10 mmol) of 1-methylbenzimidazole was
solubilized in 15 mL of acetonitrile and 0.87 mL (13.5 mol) of iodo-
methane was added to the resulting solution.
5

T. Scattolin et al.
Polyhedron 207 (2021) 115381
The reaction mixture was kept at 90 ◦C for ca. 8 h and then cooled
repeatedly washed with diethylether and n-pentane and dried under
vacuum.
down to room temperature.
The solvent was removed under vacuum and the iodide azolium salts
was solubilized in 100 mL of methanol. Then, 20 g of DOWEX 21KCl
resin was added. The system was then stirred at room temperature for
24 h. After filtration of the resin, the solvent was removed under vacuum
and the final white product 1a was obtained in excellent yield (1.80 g,
82%).
1H NMR (300 MHz, DMSO‑d6, T = 298 K, ppm) δ: 9.87 (s, 1H,
NCHN), 8.54 – 8.44 (m, 1H, Ar-H), 8.04 (dd, J = 7.0, 1.5 Hz, 1H, Ar-H),
7.98 – 7.85 (m, 2H, Ar-H), 7.75 – 7.58 (m, 2H, Ar-H), 7.38 (dd, J = 6.6,
4.9 Hz, 2H, Ar-H), 5.92 (s, 2H, NCH2N), 4.15 (s, 3H, CH3).
Anal. Calc. for C14H14BrN3: C, 55.28; H, 4.64; N, 13.81. Found: C,
55.16; H, 4.71; N, 13.88%.
1H NMR (300 MHz, DMSO‑d6, T = 298 K, ppm) δ: 9.62 (s, 1H,
NCHN), 8.01 (dt, J = 6.7, 3.4 Hz, 2H, Ar-H), 7.72 (dt, J = 6.2, 3.3 Hz,
2H, Ar-H), 4.08 (s, 6H, CH3).
4.6. Synthesis of compound 1e
Anal. Calc. for C9H11ClN2: C, 59.18; H, 6.07; N, 15.34. Found: C,
59.30; H, 6.00; N, 15.27%.
In a 10 mL flask, 1.5 g (11 mmol) of 1-methylbenzimidazole was
solubilized in 5 mL of tetrahydrofuran and 1.1 g (5 mol) of dibromo-
methane was added to the resulting solution.
4.3. Synthesis of the compound 1b
The reaction mixture was kept at 120 ◦C for ca. 72 h and then cooled
down to room temperature.
In a 100 mL flask, 1.3 g (10 mmol) of 1-methylbenzimidazole was
solubilized in 15 mL of acetonitrile and 2.0 mL (20 mol) of 2-iodopro-
pane was added to the resulting solution.
The solid was filtered off (1.98 g) and suspended in a 250 mL flask
with 150 mL of methanol. Then 1.87 g (9 mmol) of AgClO4 was added
and AgBr was removed by filtration on a millipore membrane filter.
The solution was concentrated and the title compound precipitated
by addition of diethylether.
The reaction mixture was kept at 90 ◦C for ca. 24 h and then cooled
down to room temperature.
The solvent was removed under vacuum and the iodide azolium salts
recrystallized using a 1:2 acetonitrile/methanol mixture. The purified
solid was dissolved in 100 mL of methanol and 20 g of DOWEX 21KCl
resin was added. The system was then stirred at room temperature for
24 h. After filtration of the resin, the solvent was removed under vacuum
and the final white product 1b was obtained in good yield (1.44 g, 68%).
1H NMR (300 MHz, DMSO‑d6, T = 298 K, ppm) δ: 9.80 (s, 1H,
NCHN), 8.18 – 8.07 (m, 1H, Ar-H), 8.07 – 7.98 (m, 1H, Ar-H), 7.76 –
7.65 (m, 2H, Ar-H), 5.06 (p, J = 6.7 Hz, 1H, isopropyl-CH), 4.07 (s, 3H,
N-CH3), 1.62 (d, J = 6.7 Hz, 6H, isopropyl-CH3).
The white product (2.0 g, 80%) was filtered off on a gooch filter,
repeatedly washed with diethylether and n-pentane and dried under
vacuum.
1H NMR (300 MHz, DMSO‑d6, T = 298 K, ppm) δ: 10.28 (s, 1H,
NCHN), 8.39 (dd, J = 6.7, 2.0 Hz, 2H, Ar-H), 7.88 – 7.68 (m, 6H, Ar-H),
7.48 (s, 2H, NCH2N), 4.15 (s, 6H, NCH3).
Anal. Calc. for C17H18Cl2N4O8: C, 42.78; H, 3.80; N, 11.74. Found: C,
42.61; H, 3.86; N, 11.83%.
4.7. Synthesis of compound 1f
Anal. Calc. for C11H15ClN2: C, 62.70; H, 7.18; N, 13.30. Found: C,
62.54; H, 7.28; N, 13.17%.
In a 5 mL vial, 543.1 mg (2.16 mmol) of 1-adamanylbenzimidazole
was suspended in 1.5 mL (21.5 mmol) of dibromomethane.
The reaction mixture was kept at 85 ◦C for ca. 24 h and then cooled
down to room temperature.
4.4. Synthesis of the compound 1c
In a 100 mL flask, 2.2 g (11 mmol) of 1-phenylbenzimidazole was
dissolved in 20 mL of tetrahydrofuran and 1.1 mL (17 mol) of iodo-
methane was added to the resulting solution.
The solid was filtered off (0.6 g) and suspended in a 100 mL flask
with 50 mL of methanol. Then 0.37 g (1.8 mmol) of AgClO4 was added
and AgBr was removed by filtration on a millipore membrane filter.
The solution was concentrated and the title compound precipitated
by addition of diethylether.
The reaction mixture was kept at 90 ◦C for ca. 24 h and then cooled
down to room temperature.
The iodide azolium salts was filtered off and dried under vacuum.
This white intermediate was dissolved in 100 mL of methanol and 20 g
of DOWEX 21KCl resin was added. The system was then stirred at room
temperature for 24 h. After filtration of the resin, the solvent was
removed under vacuum and the final white product 1c was obtained in
good yield (1.81 g, 66%).
The white product (0.66 g, 85%) was filtered off on a gooch filter,
repeatedly washed with diethylether and n-pentane and dried under
vacuum.
1H NMR (300 MHz, CD3CN, T = 298 K, ppm) δ: 12.08 (s, 2H, NCHN),
9.07 (d, J = 8.4 Hz, 2H, Ar-H), 8.52 (s, 2H, NCH2N), 8.06 (d, J = 8.5 Hz,
3H, Ar-H), 7.84 – 7.60 (m, 4H, Ar-H), 2.55 (d, J = 2.7 Hz, 12H, CH2),
2.45 (s broad, 6H, CH), 1.92 (s broad, 12H, CH2).
1H NMR (300 MHz, DMSO‑d6, T = 298 K, ppm) δ: 10.10 (s, 1H,
NCHN), 8.15 (d, J = 7.7 Hz, 1H, Ar-H), 7.95 – 7.60 (m, 8H, Ar-H), 4.17
(s, 3H, CH3).
Anal. Calc. for C35H42Cl2N4O8: C, 58.58; H, 5.90; N, 7.81. Found: C,
58.70; H, 5.81; N, 7.75%.
Anal. Calc. for C14H13ClN2: C, 68.71; H, 5.35; N, 11.45. Found: C,
68.89; H, 5.30; N, 11.38%.
4.8. Synthesis of silver-NHC complexes 2a-d
4.5. Synthesis of compound 1d
4.8.1. Synthesis of complex 2a
0.4012 g (2.2 mmol) of 1a was dissolved in 30 mL of anhydrous
dichloromethane in a two-necked flask and 0.2790 g (1.2 mmol) of Ag2O
was added under inert atmosphere (Ar).
In a 100 mL flask, 1.98 g (15.6 mmol) of 2-chloromethylpyridine was
dissolved in 70 mL of anhydrous acetonitrile. 2.7 g (22 mmol) of 1-meth-
ylbenzimidazole was added to the resulting solution.
The reaction mixture was kept at 90 ◦C for ca. 30 h and then cooled
down to room temperature.
The mixture was stirred for 24 h at RT in the dark and subsequently
transferred to a 250 mL flask with the addition of ca. 100 mL of CH2Cl2.
The solution was filtered on a millipore membrane filter, concentrated
under vacuum and the title complex precipitated by addition of
diethylether.
The solvent was removed under vacuum, the resulting solid resus-
pended in dichloromethane (50 mL) and the mixture was filtered in
order to remove inorganic salts.
The brownish complex was filtered off on a gooch filter, repeatedly
washed with diethylether and n-pentane and dried under vacuum.
0.3994 g of 2a was obtained (yield 60%).
The solution was concentrated and the title compound precipitated
by addition of diethylether.
The red solid (4.12 g, 89%) was filtered off on a gooch filter,
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 7.58 – 7.42 (m, 4H, Ar-
6

T. Scattolin et al.
Polyhedron 207 (2021) 115381
H), 4.06 (s, 6H, NCH3).
filtrate was concentrated under vacuum. Addition of diethylether caused
the precipitation of complex 3d as a white solid which was filtered off on
a gooch and washed with n-pentane. 0.1562 g of 3d was obtained (yield
93%).
13C{1H} (75,5 MHz, CDCl3, ppm): 189.7 (C, carbene), 134.3 (C, Ar-
C), 124.3 (CH, Ar-CH), 111.2 (CH, Ar-CH), 35.8 (CH3, NCH3).
Anal. Calc. for C9H10AgClN2: C, 37.34; H, 3.48; N, 9.68. Found: C,
37.21; H, 3.56; N, 9.61%.
1H NMR (300 MHz, CD3CN, T = 243 K, ppm) δ: 8.96 – 8.85 (m, 1H, 6-
py-H), 8.05 (td, J = 7.7, 1.6 Hz, 1H, 4-py-H), 7.92 (d, J = 7.5 Hz, 1H, Ar-
H), 7.88 – 7.80 (m, 1H, Ar-H), 7.68 – 7.57 (m, 2H, Ar-H), 7.55–7.39 (m,
3H, Ar-H, 3-py-H, 5-pyr-H), 5.88 – 5.70 (m, 1H, central allyl), 5.67 – 5.36
(AB system, J = 15.3 Hz, 2H, NCH2Py), 4.50 (dd, J = 7.7, 1.8 Hz, 1H, syn
allyl-H trans-C), 4.08 (dd, J = 4.9, 1.8 Hz, 1H, syn allyl-H trans-N), 3.97
(s, 3H, NCH3), 3.74 (d, J = 13.7 Hz, 1H, anti allyl-H trans-C), 3.10 (d, J =
12.2 Hz, 1H, anti allyl-H trans-N).
4.8.2. Synthesis of complex 2b
Complex 2b was prepared by a procedure analogous to that
described for 2a starting from 0.4049 g (1.92 mmol) of 1b and 0.2364 g
(1.02 mmol) of Ag2O.
0.5733 g (yield 93%) of 2b was obtained.
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 7.69 – 7.58 (m, 1H, Ar-
H), 7.54 – 7.37 (m, 4H, Ar-H), 5.07 (p, J = 7.0 Hz, 1H, isopropyl-CH),
4.05 (s, 3H, NCH3), 1.74 (d, J = 7.0 Hz, 6H, isopyl-CH3).
13C{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 187,6 (C, carbene), 134.9
(C, Ar-C), 132.4 (C, Ar-C), 124.2 (CH, Ar-CH), 123.8 (CH, Ar-CH), 112.4
(CH, Ar-CH), 111.5 (CH, Ar-CH), 53.7 (CH, isopropyl-CH), 36.1 (NCH3),
22.6 (CH3, isopropyl-CH3).
13C{1H}-NMR (CD3CN, T = 243 K, ppm) δ: 186.66 (C, carbene),
155.7 (C, 2-py-C), 153.4 (CH, 6-py-CH), 140.5 (CH, 4-py-CH), 134.1 (C,
Ar-C), 133.5 (C, Ar-C), 126.2 (CH, Ar-CH), 125.3 (CH, Ar-CH), 124.00
(CH, 3-py-CH), 123.9 (CH, 5-py-CH), 121.2 (CH, central allyl), 111.7
(CH, Ar-CH), 110.9 (CH, Ar-CH), 74.5 (CH2, allyl trans-C), 50.9 (CH2,
NCH2py), 49.2 (CH2, allyl trans-N), 35.0 (CH3, NCH3).
Anal. Calc. for C11H14AgClN2: C, 41.60; H, 4.44; N, 8.82. Found: C,
41.72; H, 4.39; N, 8.75%.
Anal. Calc. for C17H18ClN3O4Pd: C, 43.42; H, 3.86; N, 8.94. Found: C,
43.29; H, 3.92; N, 8.99%.
4.8.3. Synthesis of complex 2c
4.9.2. Synthesis of complex 3e
Complex 2c was prepared by a procedure analogous to that described
for 2a starting from 0.2720 g (1.66 mmol) of 1c and 0.1355 g (0.58
mmol) of Ag2O.
0.0941 g (0.20 mmol) of 1e was dissolved in 20 mL of anhydrous
acetonitrile in a two-necked flask and 0.0550 g (0.24 mmol) of Ag2O was
added under inert atmosphere (Ar).
0.2834 g (yield 72%) of 2c was obtained.
The mixture was stirred for 18 h at RT in the dark and subsequently
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 7.66 – 7.55 (m, 6H, Ar-
H), 7.47 – 7.42 (m, 3H, Ar-H), 4.17 (s, 3H, NCH3).
13C{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 188,2 (C, carbene), 137.6
(C, Ar-C), 134.4 (C, Ar-C), 134.2 (C, Ar-C), 130.2 (CH, Ar-CH), 129.6
(CH, Ar-CH), 129.5 (CH, Ar-CH), 126.0(CH, Ar-CH), 124.7 (CH, Ar-CH),
112.2 (CH, Ar-CH), 111.4 (CH, Ar-CH), 36.1 (CH3, NCH3).
Anal. Calc. for C14H12AgClN2: C, 47.83; H, 3.44; N, 7.97. Found: C,
47.96; H, 3.39; N, 7.88%.
0.0361 g (0.10 mmol) of the precursor [Pd(
μ-Cl)(
η
3-allyl)]2 was added.
After 30 min at RT, the solution was filtered on a millipore membrane
filter, concentrated under vacuum and the title complex precipitated by
addition of diethylether.
The brownish complex was filtered off on a gooch filter, repeatedly
washed with dichloromethane (2x0.5 mL), diethylether (2x3mL) and n-
pentane (2x3mL) and dried under vacuum.
0.0771 g of 2a was obtained (yield 75%).
1H NMR (300 MHz, CD3CN, T = 298 K, ppm) δ: 7.98 (dt, J = 8.5, 0.8
Hz, 2H, Ar-H), 7.69 – 7.65 (m, 2H, Ar-H), 6.55 (AB system, J = 13.9 Hz,
2H, NCH2N), 5.64 – 5.49 (m, 1H, central allyl-H), 4.46 (d, J = 7.4 Hz, 2H,
syn allyl-H), 4.02 (s, 6H, NCH3) , 3.15 (d, J = 13.4 Hz, 2H, anti allyl-H).
13C{1H}-NMR (CD3CN, T = 298 K, ppm) δ: 186.8 (C, carbene), 134.3
(C, Ar-C), 133.4 (C, Ar-C), 124.3 (CH, Ar-CH) 124.1 (CH, Ar-CH), 120.6
(CH, central allyl), 111.7 (CH, Ar-CH), 110.5 (CH, Ar-CH), 60.0 (CH2,
terminal allyl), 56.8 (CH2, NCH2), 35.4 (CH3, NCH3).
4.8.4. Synthesis of complex 2d
Complex 2d was prepared by a procedure analogous to that
described for 2a starting from 0.3997 g (1.31 mmol) of 1d and 0.1658 g
(0.715 mmol) of Ag2O.
0.4222 g (yield 79%) of 2d was obtained.
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 8.58 (m, 1H, 6-py-H),
7.66 (td, J = 7.7, 1.8 Hz, 1H, 4-py-H), 7.57 – 7.31 (m, 6H, Ar-H, 5-pyr-H)
7.24 (dd, J = 7.0, 5.4 Hz, 1H, 3-pyr-H), 5.75 (s, 2H, NCH2), 4.11 (s, 3H,
NCH3).
Anal. Calc. for C20H21ClN4O4Pd: C, 45.91; H, 4.05; N, 10.71. Found:
C, 46.07; H, 3.98; N, 10.60%.
13C{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 191.2 (C, carbene), 154.84
(C, 2-pyr-C), 149.8 (CH, 6-pyr-CH), 137.3 (CH, 4-pyr-CH), 134.5 (C, Ar-
C), 133.9 (C, Ar-C), 124.3 (CH, 3-pyr-CH), 124.2 (CH, Ar-CH), 123.3
(CH, Ar-CH), 122.2 (CH, 5-pyr-CH), 112.3 (CH, Ar-CH), 111.1 (CH, Ar-
CH), 54,9 (s, NCH2), 35.9 (s, NCH3).
4.9.3. Synthesis of complex 3f
Complex 3f was prepared by a procedure analogous to that described
for 3e starting from 0.1006 g (0.14 mmol) of 1e, 0.0354 mg (0.15 mmol)
of Ag2O and 0.0231 g (0.07 mmol) of [Pd(
Reaction time: 48 h.
μ-Cl)(
η
3-allyl)]2.
Anal. Calc. for C14H13AgBrN3: C, 40.91; H, 3.19; N, 10.22. Found: C,
41.06; H, 3.11; N, 10.17%.
0.1019 g (yield 95%) of 3f was obtained.
Isomer A/isomer B ≈ 1: 2.
1H NMR (300 MHz, CD3CN, T = 298 K, ppm) δ: 8.03, 7.96, 7.89 (d, J
= 8.4, Hz, 2H, Ar-H), 7.47 – 7.32 (m, 2H, Ar-H), 6.94, 6.79 (d, J = 14.3
Hz, 1H, NCH2N), 6.51, 6.22 (d, J = 14.3 Hz, 1H, NCH2N), 6.00, 5.51 (m,
1H, central allyl-H), 4.32,4.04 (d, J = 7.2 Hz, 2H, syn allyl-H), 3.08, 2.88
(d, J = 13.3 Hz, 2H, anti allyl-H), 2.28–2.67 (m, 16H, Adamantyl-H),
1.84–1.90 (m, 12H, Adamantyl-H).
–
4.9. Synthesis of palladium allyl complexes bearing chelating C C and
–
C
N ligands
4.9.1. Synthesis of complex 3d
0.0653 g (0.17 mmol) of the precursor [Pd(
μ-Cl)(
η
3-allyl)]2 was
dissolved in 15 mL of anhydrous dichloromethane in a 50 mL two-
necked flask under inert atmosphere (Ar) and 0.1471 g (0.35 mmol)
of the silver complex 2d was added to this solution.
13C{1H}-NMR (CD3CN, T = 298 K, ppm) δ: 188.1 (C, carbene), 187.8
(C, carbene), 134.9 (C, Ar-C), 134.7 (C, Ar-C), 133.4 (C, Ar-C), 133.3 (C,
Ar-C), 123.9 (CH, Ar-CH), 123.8 (CH, Ar-CH), 122.9 (CH, Ar-CH), 122.8
(CH, Ar-CH), 119.1 (CH, central allyl), 117.5 (CH, central allyl), 116.2
(CH, Ar-CH), 116.1 (CH, Ar-CH), 110.4(CH, Ar-CH), 110.3 (CH, Ar-CH),
62.8 (CH2, terminal allyl), 62.6 (CH2, terminal allyl), 61.2 (C, Adamantyl-
C), 61.1 (C, Adamantyl-C), 58.2 (CH2, NCH2), 57.9 (CH2, NCH2), 42.5
(CH2, Adamantyl-CH2), 42.3 (CH2, Adamantyl-CH2), 35.6 (CH2,
Subsequently, 0.1000 g (0.70 mmol) of NaClO4⋅H2O, dissolved in 4
mL of methanol, was added and the mixture was stirred at room tem-
perature for ca. 1 h.
Then the solvent was removed under vacuum and the residue was
suspended in dichloromethane (15 mL). The inorganic salts were filtered
off on a Celite filter and repeatedly washed with CH2Cl2, whereas the
7

T. Scattolin et al.
Polyhedron 207 (2021) 115381
Adamantyl-CH2), 35.5 (CH2, Adamantyl-CH2), 29.3 (CH, Adamantyl-
CH), 29.3 (CH, Adamantyl-CH).
52.08; H, 4.43; N, 7.27%.
Anal. Calc. for C38H45ClN4O4Pd: C, 59.77; H, 5.94; N, 7.34. Found: C,
59.61; H, 6.02; N, 7.40%.
4.11. Synthesis of mixed NHC/PPh3 palladium complexes
4.11.1. Synthesis of complex 5a
4.10. Synthesis of neutral palladium complexes (4a-c)
4.10.1. Synthesis of complex 4a
0.0509 g (0.15 mmol) of 4a was dissolved in ca. 12 mL of anhydrous
CH2Cl2 and 0.0405 g (0.15 mmol) of PPh3 was added. Subsequently,
0.0450 g (0.32 mmol) of NaClO4⋅H2O, dissolved in 4 mL of methanol,
was added and the mixture was stirred at room temperature for ca. 30
min in a 50 mL two necked flask under inert atmosphere (Ar).
Then the solvent was removed under vacuum and the residue was
suspended in dichloromethane (15 mL). The inorganic salts were filtered
off on a Celite filter and repeatedly washed with CH2Cl2, whereas the
filtrate was concentrated under vacuum. Addition of diethylether caused
the precipitation of the complex 5a as a yellow solid which was filtered
off on a gooch and washed with n-pentane. 0.0990 g of 5a was obtained
(yield 98%).
0.0597 g (0.16 mmol) of [Pd(µ-Cl)(
η
3-allyl)]2 was dissolved in ca. 15
mL of anhydrous CH2Cl2. 0.0934 g (0.32 mmol) of the silver complex 2a
was added and the mixture was stirred at room temperature for ca. 30
min in a 50 mL two necked flask under inert atmosphere (Ar).
The precipitated AgCl was filtered off on a Celite filter and repeat-
edly washed with CH2Cl2, whereas the filtrate was concentrated under
vacuum. Addition of diethylether caused the precipitation of complex 4a
as a white solid which was filtered off on a gooch and washed with n-
pentane.
0.0898 g of 4a was obtained (yield 85%).
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 7.49 – 7.14 (m, 33H,
Ar-H), 5.92 (tt, J = 13.5, 7.3 Hz, 1H, central-allyl-H), 4.54 (m, 1H, syn
allyl-H trans-P), 4.15 (d, J = 7.3 Hz, 1H, syn allyl-H trans-P), 3.65 (s, 3H,
NCH3), 3.49 (s, 3H, CH3), 3.48 (m, 1H, syn allyl-H trans-P), 3.29 (d, J =
13.5 Hz, 1H, syn allyl-H trans-C).
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 7.37 (dtd, J = 13.0,
6.7, 3.4 Hz, 4H, Ar-H), 5.47 (tt, J = 13.8, 7.4 Hz, 1H, central allyl-H),
4.43 (dd, J = 7.9, 1.7 Hz, 1H, syn allyl-H trans-C), 4.06 (s, 6H, NCH3),
3.53 (d, J = 6.5 Hz, 1H, syn allyl-H tran-Cl), 3.45 (d, J = 13.7 Hz, 1H, anti
allyl-H trans-C), 2.58 (d, J = 11.9 Hz, 1H, anti allyl-H trans-Cl).
13C{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 192.6 (C, carbene), 135.1
(C, Ar-C), 123.0 (CH, Ar-CH), 115.6 (CH, central allyl), 110.0 (CH, Ar-
CH), 74.1 (CH2, allyl trans-C), 48.4 (CH2, allyl trans-Cl), 35.0 (CH3
NCH3).
31P{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 25.9.
13C{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 189.6 (d, JCP = 19.1 Hz,
carbene), 135.2 (C, Ar-C), 135.2 (C, Ar-C), 123.4 (CH, Ar-CH), 123.4
(CH, Ar-CH), 122.2 (d, JCP = 5.3 Hz, CH, central allyl), 110.1 (CH, Ar-
CH), 110.0 (CH, Ar-CH), 70.2 (d, J = 2.0 Hz, CH2, allyl trans-C), 67.1
(d, , JCP = 27.1 Hz, CH2, allyl trans-P), 34.8 (CH3, NCH3), 34.5 (CH3,
NCH3).
Anal. Calc. for C12H15ClN2Pd: C, 43.79; H, 4.59; N, 8.51. Found: C,
43.92; H, 4.50; N, 8.57%.
Anal. Calc. for C30H30ClN2O4PPd: C, 54.98; H, 4.61; N, 4.27. Found:
C, 55.12; H, 4.54; N, 4.21%.
4.10.2. Synthesis of complex 4b
Complex 4b was prepared by a procedure analogous to that
described for 4a starting from 0.0531 g (0.15 mmol) of [Pd(µ-Cl)(η3
allyl)]2 and 0.0922 g (0.30 mmol) of 2b.
-
4.11.2. Synthesis of complex 5b
Complex 5b was prepared by a procedure analogous to that
described for 5a starting from 0.0885 g (0.25 mmol) of 4b, 0.0649 g
(0.25 mmol) of PPh3 and 0.0700 g (0.50 mmol) of NaClO4⋅H2O.
0.1437 g (yield 84%) of 5b was obtained.
0.1032 g (yield 99%) of 4b was obtained.
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 7.57 (dd, J = 6.1, 2.6
Hz, 1H, Ar-H), 7.43 – 7.20 (m, 3H, Ar-H), 5.66–5.32 (m, 2H, isopropyl-
CH e central-allyl-H), 4.40 (d, J = 7.6 Hz, syn allyl-H trans-C), 4.04 (s, 3H,
NCH3), 3.49 (d, J = 5.3 Hz, 1H, syn allyl-H trans-Cl), 3.44 (d, J = 13.7
Hz, 1H, anti allyl-H trans-C), 2.52 (d, J = 11.8 Hz, 1H, anti allyl-H trans-
Cl), 1.70 (d, J = 6.8 Hz, 6H, isopropyl-CH3).
Isomer A/isomer B ≈ 1: 1.25.
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 7.85 – 7.08 (m, 19H,
Ar-H), 6.08 – 5.78 (m, H, central allyl-H), 5.08 and 4.77 (sept, J = 7.0 Hz,
1H, isopropyl-H), 4.52 and 4.44 (d, J = 6.3 Hz, 1H, syn allyl-H trans-C),
4.10 and 4.00 (dd con JHP, J = 8.3 Hz, 1H, syn allyl-H trans-P), 3.45 –
3.20 (m, 2H, anti allyl-H trans-C and anti allyl-H trans-P), 3.47 and 3.26
(s, 3H, NCH3), 1.62 and 1.55 (d, J = 7.0 Hz, 3H, isopropyl-CH3), 1.15
and 1.08 (d, J = 7.0 Hz, 3H, isopropyl-CH3).
13C{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 190.5 (C, carbene), 136.2
(C, Ar-C), 132.7 (C, Ar-C), 122.8 (CH, Ar-CH), 122.5 (CH, Ar-CH), 115.3
(CH, central allyl), 112.0 (CH, Ar-CH), 110.4 (CH, Ar-CH), 73.7 (CH2,
allyl trans-C), 53.9 (CH, isopropyl-CH), 48.1 (CH2, allyl trans-Cl), 34.9
(CH3, NCH3), 21.6 (CH3 , isopropyl-CH3).
31P{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 25.1 and 25.0
13C{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 187.8 (C, JCP = 18.8 Hz,
carbene), 187.7 (C, JCP = 18.7 Hz, carbene), 136.6 (C, Ar-C), 136.5 (C,
Ar-C), 132.7 (C, Ar-C), 132.5 (C, Ar-C), 128.4 (CH, Ar-CH), 128.3 (CH,
Ar-CH), 123.1 (CH, Ar-CH), 123.0 (CH, Ar-CH), 123.3 (d, JCP = 5.2 Hz,
CH, central allyl), 112.2 (CH, Ar-CH), 112.1 (CH, benzyl-CH), 110.7 (CH,
Ar-CH), 110.6 (CH, Ar-CH), 71.8 (d, JCP = 2.8 Hz, CH2, allyl trans-C),
70.3 (d, JCP = 2.8 Hz, CH2, allyl trans-C), 66.6 (d, JCP = 28.6 Hz, CH2,
allyl trans-P), 66.1 (d, JCP = 27.1 Hz, CH2, allyl trans-P), 55.6 (CH,
isopropyl-CH), 54.2 (CH, isopropyl-CH), 34.5 (CH3, NCH3), 34.2 (CH3,
NCH3), 21.7 (CH3, isopropyl-CH3), 21.5 (CH3, isopropyl-CH3), 20.3
(CH3, isopropyl-CH3), 20.3 (CH3, isopropyl-CH3).
Anal. Calc. for C14H19ClN2Pd: C, 47.08; H, 5.36; N, 7.84. Found: C,
47.20; H, 5.29; N, 7.77%.
4.10.3. Synthesis of complex 4c
Complex 4c was prepared by a procedure analogous to that described
for 4a starting from 0.0605 g (0.16 mmol) of [Pd(µ-Cl)(
0.1165 g (0.33 mmol) of 2c.
η
3-allyl)]2 and
0.1060 g (yield 81%) of 4c was obtained.
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 7.82 (d, J = 7.4 Hz,
2H, Ar-H), 7.67 – 7.44 (m, 4H, Ar-H and Ar-H), 7.43 – 7.24 (m, 3H, Ar-
H), 5.06 (tt, J = 13.7, 7.4 Hz, 1H, central-allyl-H), 4.26 (d, J = 1.7 Hz,
1H, syn allyl-H trans-C), 4.24 (s, 3H, NCH3), 3.18 (d, J = 13.6 Hz, 1H, syn
allyl-H trans-Cl), 3.02 (d, J = 6.4 Hz, 1H, anti allyl-H trans-C), 1.84 (d, J
= 11.9 Hz, 1H, anti allyl-H trans-Cl).
Anal. Calc. for C32H34ClN2O4PPd: C, 56.23; H, 5.01; N, 4.10. Found:
C, 56.09; H, 5.08; N, 4.15%.
13C{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 192.2 (C, carbene), 138.4
(C, Ar-C), 135.3 (C, Ar-C), 134.8 (C, Ar-C), 129.3 (CH, Ar-CH), 126.8
(CH, Ar-CH), 123.6 (CH, Ar-CH), 123.5 (CH, Ar-CH), 117.2 (CH, Ar-CH),
115.1 (CH, central allyl), 111.1 (CH, Ar-CH), 110.4 (CH, Ar-CH), 72.7
(CH2, allyl trans-C), 49.5 (s CH2, allyl trans-Cl), 35.1 (CH3, NCH3).
Anal. Calc. for C17H17ClN2Pd: C, 52.19; H, 4.38; N, 7.16. Found: C,
4.11.3. Synthesis of complex 5c
Complex 5c was prepared by a procedure analogous to that described
for 5a starting from 0.0397 g (0.10 mmol) of 4c, 0.0286 g (0.10 mmol)
of PPh3 and 0.0306 g (0.21 mmol) of NaClO4⋅H2O.
0.0653 g (yield 86%) of 5c was obtained.
Isomer A/isomer B ≈ 1: 1.
8

T. Scattolin et al.
Polyhedron 207 (2021) 115381
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 7.78 – 7.12 (m, 12H,
JCP = 27.4 Hz, CH2, allyl trans-P), 63.00 (CH2, allyl trans-C), 52.8 (d, JCP
= 12.4 Hz, NCH2N), 35.1 (CH3, NCH3), 34.8 (CH3, NCH3).
Anal. Calc. for C18H27ClN5O4PPd: C, 39.29; H, 4.95; N, 12.73 Found:
C, 39.44; H, 4.87; N, 12.64%.
PPh3, Ar-H), 7.08 – 6.83 (m, 12H, Ar-H), 6.08 and 5.29 (m, 1H, central
allyl-H), 4.78 and 4.46 (dd, JHH = JHP 5.2 Hz, 1H, syn allyl-H trans-P),
4.01 and 3.72 (d, J = 6.3 Hz, 1H, syn allyl-H trans-C), 3.87 and 3.78 (s,
3H, NCH3), 3.72 and 3.25 (d, J = 13.5 Hz, 1H, anti allyl-H trans-C), 2.88
and 2.51 (dd, JHH = 13.0, JHP = 10.0 Hz, 1H, anti allyl-H trans-P)).
31P{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 25.2, 25.1.
4.11.6. Synthesis of complex 6b
Complex 6b was prepared by a procedure analogous to that
described for 6a starting from 0.0547 g (0.15 mmol) of 4b, 0.0242 g
(0.15 mmol) of 1,3,5-triaza-7-phosphaadamantane (PTA) and 0.0460 g
(0.30 mmol) of NaClO4⋅H2O.
13C{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 188.9.0, (C, carbene, from
HMBC), 189.8 (C, carbene, from HMBC), 137.2 (C, Ar-C), 137.0 (C, Ar-
C), 135.3 (C, Ar-C), 135.3 (C, Ar-C), 124.2 (C, Ar-C), 124.1 (CH, Ar-CH),
124.0 (CH, Ar-CH), 123.9 (CH, Ar-CH), 122.3 (d, JCP = 4.8 Hz, CH,
central allyl), 121.3 (CH, d, JCP = 5.3 Hz, central allyl), 110.8 (CH, Ar-
CH), 110.8 (CH, Ar-CH), 110.7 (CH, Ar-CH), 69.4 (CH2, d, JCP = 27.8,
allyl trans-P), 69.3 (CH2, allyl trans-C), 69.2 (CH2, allyl trans-C), , 68.0
(d, JCP = 28.8, CH2, allyl trans-P), 35.4 (CH3, NCH3), 35.4 (CH3, NCH3).
Anal. Calc. for C35H32ClN2O4PPd: C, 58.59; H, 4.50; N, 3.90 Found:
C, 58.77; H, 4.42; N, 3.95%.
0.0786 g (yield 89%) of 6b was obtained.
Isomer A/isomer B ≈ 1: 1.
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 7.73 – 7.30 (m, 4H, Ar-
H), 5.68–5.41 (m, 1H, central allyl-H), 5.06 (sept, J = 6.9 Hz, 1H,
isopropyl-H), 4.83 – 4.66 (m, 1H, isopropyl-H), 4.68 – 4.46 (m, 6H,
PCH2N), 4.40–4.30 (m, 2H, syn allyl-H trans-P, syn allyl-H trans-C), 4.31
(s, 6H, NCH2N), 4.01 and 3.79 (s, 3H, NCH3), 3.25 – 3.00 (m, 2H, anti
allyl-H trans-P, anti allyl-H trans-C), 1.83 and 1.71 (d, J = 7.0 Hz, 3H,
isopropyl-CH3), 1.62 and 1.55 (d, J = 6.9 Hz, 3H, isopropyl-CH3).
31P{1H}-NMR (CDCl3, T = 298 K, ppm) δ: ꢀ 56.3, ꢀ 56.6.
13C{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 186.2 (C, carbene, from
HMBC), 186.1 (C, carbene, from HMBC), 136.6 (C, Ar-C), 136.4 (C, Ar-
C), 132.9 (C, Ar-C), 132.7 (C, Ar-C), 123.6 (CH, Ar-CH), 123.5 (CH, Ar-
CH), 123.4 (CH, Ar-CH), 121.8 (d, JCP = 5.1 Hz, CH, central allyl), 121.5
(d, JCP = 5.2 Hz, CH, central allyl), 112.6 (CH, Ar-CH), 112.2 (CH, Ar-
CH), 111.0 (CH, Ar-CH), 110.9 (CH, Ar-CH), 73.1 (d, JCP = 7.1 Hz,
4.11.4. Synthesis of complex 5d
Complex 5d was prepared by a procedure analogous to that
described for 5a (no further addition of NaClO4⋅H2O was necessary)
starting from 0.0550 g (0.12 mmol) of 3d and 0.0315 g (0.12 mmol) of
PPh3.
0.0740 g (yield 86%) of 5d was obtained.
Isomer A/isomer B = 1: 1.25.
1H NMR (300 MHz, CDCl3, T = 243 K, ppm) δ: 8.27 and 8.16 (d, J =
4.1 Hz, 1H, m, 1H, 6-py-H), 7.69 – 7.08 (m, 22H, PPh3, 4-py-H, 5-py-H,
3-py-H and Ar-H), 5.81 and 5.59 (m, 1H, central allyl-H), 5.39 (AB
system, J = 16.2 Hz, 1H, NCH2Py) and 5.19 (AB system, J = 16.2 Hz, 1H,
NCH2Py), 5.17 (s, 2H, NCH2Py), 4.44 (dd, JHH = JHP = 5.8 Hz, syn allyl-
H trans-P), 4.18 (d, J = 7.3 Hz, syn allyl-H trans-C), 4.16 – 4.06 (m, syn
allyl-H trans-P, syn allyl-H trans-C), 3.47 and 3.35 (s, 3H, NCH3), 3.26
and 2.94 (dd, JHH = 13.4, JHP = 9.6 Hz, 1H, CH anti allyl-H trans-P), 3.14
and 2.98 (d, J = 13.4 Hz, 1H, anti allyl-H trans-C).
CH2, NCH2N), 67.9 (d, JCP = 5.3 Hz, CH2, allyl trans-P), 67.6 (d, JCP
=
5.5 Hz, CH2, allyl trans-P), 63.2 (CH2, allyl trans-C), 63.0 (CH2, allyl
trans-C), 54.8 (CH, isopropyl-CH), 54.1 (CH, isopropyl-CH), 53.0 (d, JCP
= 12.2 Hz, PCH2N), 35.2 (CH3, NCH3), 34.8 (CH3, NCH3), 21.7 (CH3,
isopropyl-CH3), 21.7 (CH3, isopropyl-CH3), 21.6 (CH3, isopropyl-CH3),
21.5 (CH3, isopropyl-CH3).
Anal. Calc. for C20H31ClN5O4PPd: C, 41.54; H, 5.40; N, 12.11 Found:
C, 41.69; H, 5.28; N, 12.03%.
31P{1H}-NMR (CDCl3, T = 243 K, ppm) δ: 26.4, 26.2
13C{1H}-NMR (CDCl3, T = 243 K, ppm) δ: 191.1 (d, JCP = 8.0 Hz, C,
carbene), 190.0 (d, JCP = 8.0 Hz, C, carbene), 155.0 (C, 2-py-C), 154.9
(C, 2-py-C), 149.3 (CH, 6-py-CH), 149.2 (CH, 6-py-CH), 137.2 (CH, 4-py-
CH), 137.2 (CH, 4-py-CH), 135.4 (C, Ar-C), 135.2 (C, Ar-C), 135.1 (C, Ar-
C), 134.7(C, Ar-C), 131.7 (CH, 3-py-CH), 131.6 (CH, 3-py-CH), 131.2
(CH, 5-py-CH), 131.0 (CH, 5-py-CH), 123.2 (CH, Ar-CH), 122.2 (CH, Ar-
CH), 123.9 (CH, Ar-CH), 122.1 (d, CH, JCP = 4.5 Hz, central allyl),
110.98 (CH, Ar-CH), 110.86 (CH, Ar-CH), 110.58 (CH, Ar-CH), 110.49
(CH, Ar-CH), 68.87 (CH2, allyl trans-C), 68.10 (CH2, allyl trans-C), 67.14
(d, JCP = 23.0 Hz, CH2, allyl trans-P), 66.75 (d, JCP = 23.0 Hz, CH2, allyl
trans-P), 52.96 (CH2, NCH2), 52.70 (CH2, NCH2), 34.38 (CH3, NCH3),
34.27 (CH3, NCH3).
4.12. Cell viability assays
Cells were grown in accordance with the supplier and maintained at
37 ◦C in a humidified atmosphere of 5% carbon dioxide. Five hundred
cells were placed in 96 wells and treated with six different concentra-
tions (0.001, 0.01, 0.1, 1, 10 and 100 µM) of palladium(II) compounds.
After 96 h from the treatment cell viability was measured with a Cell-
Titer glow assay (Promega, Madison, WI, USA) with a Tecan M1000
instrument. IC50 values were calculated from logistical dose response
curves. Averages were obtained from triplicates and error bars are
standard deviations.
Anal. Calc. for C35H33ClN3O4PPd: C, 57.39; H, 4.54; N, 5.74 Found:
C, 57.22; H, 4.48; N, 5.80%.
4.13. Crystal structure determination
The 5c crystal data were collected at 100 K at the XRD2 beamline of
the Elettra Synchrotron, Trieste (Italy) [21], using a monochromatic
wavelength of 0.620 Å. The data sets were integrated and corrected for
Lorentz, absorption and polarization effects using XDS package [22].
The structures were solved by direct methods using SHELXT program
[23] and refined using full-matrix least-squares implemented in
SHELXL–2018/3 [24].
4.11.5. Synthesis of complex 6a
Complex 6a was prepared by a procedure analogous to that
described for 5a starting from 0.0561 g (0.17 mmol) of 4a, 0.0270 g
(0.17 mmol) of 1,3,5-triaza-7-phosphaadamantane (PTA) and 0.0490 g
(0.34 mmol) of NaClO4⋅H2O.
0.0778 g (yield 82%) of 6a was obtained.
1H NMR (300 MHz, CDCl3, T = 298 K, ppm) δ: 7.59 – 7.40 (m, 4H, Ar-
H), 5.55 (ddd, J = 21.0, 13.6, 7.5 Hz, 1H, central-allyl-H), 4.67 – 4.43 (m,
6H, PCH2N), 4.42–4.30 (m, 2H, syn allyl-H trans-C and syn allyl-H trans-
P), 4.27 (s, 6H, NCH2N), 4.01 (s, 3H, NCH3), 3.81 (s, 3H, NCH3),
3.21–3.02 (m, 2H, anti allyl-H trans-C and anti allyl-H trans-P).
31P{1H}-NMR (CDCl3, T = 298 K, ppm) δ: ꢀ 55.7.
Thermal motions for all non-hydrogen atoms have been treated
anisotropically and hydrogens have been included on calculated posi-
tions, riding on their carrier atoms. Geometric restrains (SAME) have
been applied to disordered ClO-4 counterions. No solvent molecules have
been found in the crystal packing. The Coot program was used for
structure building [25]. The crystal data are given in Table S1. Pictures
were prepared using Ortep3 [26] and Pymol [27] softwares.
13C{1H}-NMR (CDCl3, T = 298 K, ppm) δ: 187.8 (d, C, JCP = 20.6 Hz,
carbene), 135.4 (C, Ar-C), 135.3 (C, Ar-C), 123.8 (CH, Ar-CH), 123.8
(CH, Ar-CH), 121.7 (d, JCP = 5.3 Hz, CH, central allyl), 110.5 (CH, Ar-
CH), 110.4 (CH, Ar-CH), 73.1 (d, JCP = 7.2 Hz, CH2, PCH2N), 67.7 (d,
Crystallographic data has been deposited at the Cambridge Crystal-
lographic Data Centre and allocated the deposition number CCDC
2091479. These data can be obtained free of charge via https://www.
9

T. Scattolin et al.
Polyhedron 207 (2021) 115381
[9] B. B. Hasinoff, X. Wu, J. L. Nitiss, R. Kanagasabai, J. C. Yalowich.
ccdc.cam.ac.uk/structures.
[10] Biochem. Pharmacol. 84 (2012) 1617–1626.
[11] (a) T. Scattolin, S.P. Nolan, Trends Chem. 2 (2020) 721–736;
5. Authorship statement
´
(b) S. Díez-Gonzalez, N. Marion, S.P. Nolan, Chem. Rev. 109 (2009) 3612–3676;
(c) K.V.S. Ranganath, S. Onitsuka, A.K. Kumar, J. Inanaga, Catal. Sci. Technol. 3
(2013) 2161–2181.
Manuscript title: Synthesis, characterization and anticancer activity
of Palladium allyl complexes bearing benzimidazole-based N-heterocy-
clic carbene (NHC) ligands
[12] (a) A. Valentini, F. Conforti, A. Crispini, A. De Martino, R. Condello, C. Stellitano,
G. Rotillo, M. Ghedini, G. Federici, S. Bernardini, D. Pucci, J. Med. Chem. 52
(2009) 484–491;
(b) A. Monney, M. Albrecht, Coord. Chem. Rev. 257 (2013) 2420–2433;
(c) M. Tanaka, H. Kataoka, S. Yano, H. Ohi, K. Kawamoto, T. Shibahara,
T. Mizoshita, Y. Mori, S. Tanida, T. Kamiya, T. Joh, BMC Cancer 13 (2013)
237–245.
• Conception and design of study: Thomas Scattolin, Fabiano Visentin
and Flavio Rizzolio
[13] (a) P.N. Muskawar, P. Karthikeyan, S.A. Aswar, P.R. Bhagat, S.S. Kumar, Arab. J.
Chem. 9 (2016) S1765–S1778;
• Acquisition of data: Thomas Scattolin, Andrea Piccin, Matteo Mau-
ceri, Nicola Demitri
(b) U.F.M. Haziz, R.A. Haque, A.-A.-A. Abdullah, M.R. Razali, J. Coord. Chem. 73
(2020) 2698–2717;
• Analysis and/or interpretation of data: Thomas Scattolin, Andrea
Piccin, Matteo Mauceri, Nicola Demitri, Flavio Rizzolio and Fabiano
Visentin
(c) T.A.C.A. Bayrakdar, T. Scattolin, X. Ma, S.P. Nolan, Chem. Soc. Rev. 49 (2020)
7044–7100.
[14] (a) T. Scattolin, V.A. Voloshkin, F. Visentin, S.P. Nolan, Cell Rep. Phys. Sci.
(2021), https://doi.org/10.1016/j.xcrp.2021.100446;
• Drafting the manuscript: Thomas Scattolin
• Revising the manuscript critically for important intellectual content:
Fabiano Visentin and Flavio Rizzolio
(b) T. Scattolin, E. Bortolamiol, S. Palazzolo, I. Caligiuri, T. Perin, V. Canzonieri,
N. Demitri, F. Rizzolio, L. Cavallo, B. Dereli, M.V. Mane, S.P. Nolan, F. Visentin,
Chem. Commun. 56 (2020) 12238–12241;
(c) T. Scattolin, N. Pangerc, I. Lampronti, C. Tupini, R. Gambari, L. Marvelli,
F. Rizzolio, N. Demitri, L. Canovese, F. Visentin, J. Organomet. Chem. 899 (2019),
120857;
Declaration of Competing Interest
(d) T. Scattolin, S. Giust, P. Bergamini, I. Caligiuri, L. Canovese, N. Demitri,
R. Gambari, I. Lampronti, F. Rizzolio, F. Visentin, Appl. Organomet. Chem. 33
(2019), e4902;
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
(e) T. Scattolin, I. Caligiuri, N. Mouawad, M. El Boustani, N. Demitri, F. Rizzolio,
F. Visentin, Eur. J. Med. Chem. 179 (2019) 325–334.
¨
[15] (a) I. Al Nasr, N. Touj, W. Koko, T. Khan, I. Ozdemir, S. Yasar, N. Hamdi, Catalysts
Acknowledgments
10 (2020), 1190; (b) M. A. Bernd, E. B. Bauer, J. Oberkofler, A. Bauer, R. M. Reich,
F. E. Kühn, Dalton Trans. 49 (2020) 14106–14114; (c) T. Scattolin, E. Bortolamiol,
F. Visentin, S. Palazzolo, I. Caligiuri, T. Perin, V. Canzonieri, N. Demitri, F.
Rizzolio, A. Togni, Chem. Eur. J. 26 (2020) 11868–11876.
The authors are grateful to the Associazione Italiana per la Ricerca
sul Cancro-AIRC IG grant (No. 23566 to F. R.).
[16] (a) T. Scattolin, I. Caligiuri, L. Canovese, N. Demitri, R. Gambari, I. Lampronti,
F. Rizzolio, C. Santo, F. Visentin, Dalton Trans. 47 (2018) 13616–13630;
(b) T. Scattolin, E. Bortolamiol, F. Rizzolio, N. Demitri, F. Visentin, Appl.
Organomet. Chem. 34 (2020), e5876;
Appendix A. Supplementary data
(c) T. Scattolin, E. Bortolamiol, I. Caligiuri, F. Rizzolio, N. Demitri, F. Visentin,
Polyhedron 186 (2020), 114607.
Crystallographic data has been deposited at the Cambridge Crystal-
lographic Data Centre and allocated the deposition number CCDC
2091479. These data can be obtained free of charge via https://www.
ccdc.cam.ac.uk/structures. Supplementary data to this article can be
found online at https://doi.org/10.1016/j.poly.2021.115381.
[17] (a) N.A. Meanwell, J. Med. Chem. 54 (2010) 2529–2591;
´
´
˜
(b) J. Wang, M. Sanchez-Rosello, J.L. Acena, E. Al, Chem. Rev. 114 (2014) (2014)
2432–2506;
(c) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008)
320–330.
´
[18] A. Simoens, T. Scattolin, T. Cauwenbergh, G. Pisano, C.S.J. Cazin, C.V. Stevens, S.
P. Nolan, Chem. Eur. J. 27 (2021) 5653–5657.
References
[19] M.J. Saif, K.R. Flower, Transit. Met. Chem. 38 (2013) 113–118.
[20] M. Takashi, H. Yoshikazu, S. Hiroaki, S. Masami, F. Tsutomu, Synlett. 4 (2008)
614–620.
[1] E. Vitaku, D.T. Smith, J.T. Njardarson, J. Med. Chem. 57 (2014) 10257–10274.
[2] M. Gaba, S. Singh, C. Mohan, Eur. J. Med. Chem. 76 (2014) 494–505.
[3] A.M. Ganie, A.M. Dar, F.A. Khan, B.A. Dar, Mini-Rev. Med. Chem. 19 (2019)
1292–1297.
[21] G.F. Raenko, N.I. Korotkikh, T.M. Pekhtereva, O.P. Shvaika, Russ. J. Org. Chem. 37
(2001) 1153–1157.
[22] A. Lausi, M. Polentarutti, S. Onesti, J. R. Plaisier, E. Busetto, G. Bais, L. Barba, A.
Cassetta, G. Campi, D. Lamba, A. Pifferi, S. C. Mande, D. D. Sarma, S. M. Sharma, G.
Paolucci, Eur. Phys. J. Plus 130 (2015) 1–8.
[4] U.J. Ries, G. Mihm, B. Narr, K.M. Hasselbach, H. Wittneben, M. Entzeroth, J.C. van
Meel, W. Wienen, N.H. Hauel, J. Med. Chem. 36 (1993) 4040–4051.
[5] M.J. Akhtar, Y.M. Shahar, V.K. Sharma, A.A. Khan, Z. Ali, M.R. Haider, A. Pathak,
Curr. Med. Chem. 27 (2020) 5970–6014.
[23] W. Kabsch, XDS, Acta Crystallographica Section D 66 (2010) 125–132.
[24] G.M. Sheldrick, Acta Crystallogr. Section A 71 (2015) 3–8.
[25] P. Emsley, B. Lohkamp, W. Scott, K. Cowtan, Acta Crystallogr. Section D 66 (2010)
486–501.
[6] D.J. Carini, J.V. Duncia, P.E. Aldrich, A.T. Chiu, A.L. Johnson, M.E. Pierce, W.
A. Price, J.B. Santella III, G.J. Wells, R.R. Wexler, P.C. Wong, S.-E. Yoo, P.B.M.W.
M. Timmermans, J. Med. Chem. 34 (1991) 2525–2547.
[26] L. Farrugia, J. Appl. Crystallogr. 45 (4) (2012) 849+854.
[27] L. Schrodinger, The PyMOL Molecular Graphics System (2015), http://www.
pymol.org.
[7] D.S. Strand, D. Kim, D.A. Peura, Gut Liver 11 (2017) 27–37.
[8] J. Li, X. Chen, X. Ding, Y. Cheng, B. Zhao, Z.-C. Lai, K. Al Hezaimi, R. Hakem, K.-
L. Guan, C.-Y. Wang, Cell Rep. 5 (2013) 1650–1663.
10