Imidazo[1,5-a]pyridine-3-ylidenes and dipyridoimidazolinylidenes as ancillary ligands in Palladium allyl complexes with potent in vitro anticancer activity

Article abstract of DOI:10.1016/j.jorganchem.2021.122014

The synthesis and characterization of silver and palladium allyl complexes bearing imidazo[1,5-a]pyridine-3-ylidene and dipyridoimidazolinylidene ligands is reported. NMR analysis of the starting azolium salts revealed the weaker σ-donor character of these NHC ligands compared to the most common imidazol-2-ylidenes and imidazolin-2-ylidenes. All cationic palladium allyl complexes showed remarkable antitumoral activity toward a panel of cisplatin-sensitive and cisplatin-resistant cell lines, with IC₅₀ in the micro- and nano-molar range. Among the tested derivatives, those with a pyridine arm combine good anticancer activity with a poor cytotoxicity against normal cells. Finally, all palladium complexes, especially the bisNHC species, showed good photoluminescence properties, with emission in the blue/green region.

Full text of DOI:10.1016/j.jorganchem.2021.122014

Journal of Organometallic Chemistry 952 (2021) 122014
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Imidazo[1,5-a]pyridine-3-ylidenes and dipyridoimidazolinylidenes as
ancillary ligands in Palladium allyl complexes with potent in vitro
anticancer activity
Thomas Scattolina,∗, Giovanni Andreettaa, Matteo Mauceria, Flavio Rizzolioa,b,∗
,
Nicola Demitric, Vincenzo Canzonierib,d, Fabiano Visentina,∗
a Dipartimento di Scienze Molecolari e Nanosistemi, Università 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, Università 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
Article history:
The synthesis and characterization of silver and palladium allyl complexes bearing imidazo[1,5-
a]pyridine-3-ylidene and dipyridoimidazolinylidene ligands is reported.
Received 25 June 2021
Revised 15 July 2021
Accepted 31 July 2021
Available online 3 August 2021
NMR analysis of the starting azolium salts revealed the weaker σ-donor character of these NHC lig-
ands compared to the most common imidazol-2-ylidenes and imidazolin-2-ylidenes.
All cationic palladium allyl complexes showed remarkable antitumoral activity toward a panel of
cisplatin-sensitive and cisplatin-resistant cell lines, with IC50 in the micro- and nano-molar range.
Among the tested derivatives, those with a pyridine arm combine good anticancer activity with a poor
cytotoxicity against normal cells. Finally, all palladium complexes, especially the bisNHC species, showed
good photoluminescence properties, with emission in the blue/green region.
Keywords:
Palladium complexes
Anticancer activity
imidazo[1,5-a]pyridine and
dipyridoimidazole derivatives
N-heterocyclic carbene ligands
Photoluminescence
© 2021 Published by Elsevier B.V.
1. Introduction
diac stimulants (e.g. Olprinone) [4] and anti-osteoporosis drugs
(e.g. Minodronic acid) [5].
Imidazopyridines are a large family of heterocyclic compounds
commonly divided into four macro-categories, called imidazo[1,2-
a]pyridines, imidazo[1,5-a]pyridines, imidazo[4,5-b]pyridines and
imidazo[4,5-b]pyridines, depending on the mutual positions of the
nitrogen atoms.
The only example of an imidazopyridine derivative that has
been approved and is still used for the treatment of some types
of cancer is Fadrozole, commercialized by Novartis with the
brand name Afema [6]. This molecule belongs to the category of
imidazo[1,5-a]pyridines and is administered orally.
These classes of compounds generally exhibit a marked biolog-
ical activity that has enabled their use in the medical field for the
treatment of a wide range of diseases (Fig. 1).
Imidazo[1,5-a]pyridines have also interesting photophysical
properties and for this reason they have been extensively studied
for the preparation of Organic Light-Emitting Diodes (OLEDs) and
Thin-Layer Field Effect Transistors (TLTFT) [7].
For example, some imidazo[1,2-a]pyridine and imidazo[4,5-
b]pyridine derivatives are employed as non-benzodiazepine anxi-
olytics (e.g. Alpidem, DS-1, Necopidem and Zolpidem) [1], gastro-
protective agents (e.g. Zolimidine, CJ-033466 and Tenatoprazole)
[2], anti-inflammatories (e.g. Miroprofen and Telcagepant) [3], car-
Moreover, this particular class of imidazopyridines has the sig-
nificant advantage of being easily functionalized to form the cor-
responding azolium salts [8]. The latter, in turn, have been ex-
ploited by some research groups to prepare stable N-heterocyclic
carbene complexes with a wide range of transition metals [9]. In
particular, gold, silver, iridium and rhodium complexes have been
mainly studied as homogeneous catalysts, in which it was pos-
sible to modulate the stereoelectronic features of these NHC lig-
ands by acting on the N-2 nitrogen atom substituent [10]. Some of
∗
Corresponding authors.
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.jorganchem.2021.122014
0022-328X/© 2021 Published by Elsevier B.V.

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
Fig. 1. Examples of biological active imidazopyridine derivatives.
these compounds have also been studied as possible chemother-
apeutic agents, showing good antiproliferative activity toward dif-
ferent cancer cell lines [8].
At the best of our knowledge, the only examples of metal-
dipyridoimidazolinylidene complexes were reported by Kunz and
co-workers in 2005 (Fig. 2) [16]. More in detail, the authors de-
scribed the synthesis and characterization of pentacarbonyl com-
plexes of chromium and tungsten, without investigating potential
applications in homogeneous catalysis or medicinal chemistry.
Some examples of palladium complexes bearing imidazo[1,5-
a]pyridine-3-ylidene ligands have recently been prepared and stud-
ied for their catalytic activity in cross-coupling processes [11],
whereas there is no report to date concerning their potential anti-
tumor activity (Fig. 2).
2. Results and discussion
Based on our recent contributions on the promising antitu-
mor activity of palladium N-heterocyclic carbene complexes [12],
we believe that a biological study on palladium complexes with
imidazo[1,5-a]pyridine-3-ylidenes may be of great interest.
In particular, we decided to focus on the synthesis and antitu-
mor activity of Pd-η3-allyl complexes as they are the most versa-
tile and promising category in the panorama of organopalladium
anticancer agents [13].
2.1. Synthesis and characterization of azolium salts (1a-f)
The first step for the synthesis of our palladium complexes
involved the preparation of imidazo[1,5-a]pyridine-3-ylidene and
dipyridoimidazolinylidene precursors.
In particular, by reacting iodomethane, picolyl chloride or
(chloromethyl)methylsulfide with imidazo[1,5-a]pyridine, which
was in turn synthesized according to the protocol reported in the
literature [17], the azolium salts 1a∗, 1c and 1d were obtained
(Scheme 1).
It is worth mentioning that 1a∗, which had already been ob-
tained by Neda and Tamm in 2016 [8a], for reasons connected to
the successive synthetic steps was transformed into its chloride
congener 1a by using the DOWEX 21K Cl ion-exchange resin.
On the contrary, according to the protocol reported by Aron and
Hutt, the mesityl derivative 1b was obtained directly in its chloride
A more limited space will be dedicated to the synthesis and cy-
totoxicity of Pd-η3-allyl complexes bearing dipyridoimidazolinyli-
dene ligands. This class of N-heterocyclic carbenes exhibits a sym-
metrical structure with three condensed rings and are usually ob-
tained by deprotonation of their corresponding azolium salts [14].
The low steric hindrance of dipyridoimidazolinylidenes favours
their dimerization according to the Wanzlick equilibrium and are
therefore generally prepared in situ and immediately reacted with
the metal precursor of interest [15].
2

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
Fig. 2. Examples of metal complexes bearing imidazo[1,5-a]pyridine-3-ylidene (red) and dipyridoimidazolinylidene (blue) ancillary ligands.
version by condensation between formaldehyde, 2,4,6-trimethyl
aniline and picolyl aldehyde in the presence of HCl (Scheme 1)
[8c].
dipyridoimidazolinylidenes compared to imidazo[1,5-a]pyridine-3-
ylidenes (Fig. 3).
In the 1H-NMR spectra (in DMSO-d6) of 1a-d it is possible to
observe the presence of all signals ascribable to the R substituent
(-Me, -Mes, -CH2Py and -CH2SMe) and the azolium proton (H3) at
ca. 10 ppm, with a 1J(C-H) coupling constant, obtained from the
13C satellites, of approximately 229 Hz. The latter, according to the
model recently proposed by Szostak and Nolan [18], suggests that
the corresponding carbenes have σ-donor character similar to IPrCl
but much lower than the most common imidazol-2-ylidene and
imidazolin-2-ylidene ligands (e.g. 1J(C-H) of IPr and SIPr = 223.7
and 206.1 Hz, respectively).
2.2. Synthesis and characterization of silver-NHC complexes (2a-f)
The well-proven synthetic strategy adopted for the preparation
of the final palladium complexes involves the transfer of the car-
bene fragment from a silver-NHC complex to a suitable palladium
precursor (transmetallation route) [9c].
To this end, the silver-NHC complexes 2a-f were synthesized by
reaction between the azolium salts 1a-f and Ag2O under the oper-
ating conditions reported in Scheme 2.
The 1H NMR spectra show a general shift of the signals with
respect to those of the starting azolium salts and above all the dis-
appearance of the peak ascribable to the imidazole proton.
In the 13C NMR spectra, the appearance of the typical signals of
the metal-coordinated carbene carbon at 165-170 ppm (to replace
those of imidazole carbons at 120-130 ppm), represents a further
evidence of the formation of NHC-silver complexes.
Starting from imidazo[1,5-a]pyridine and following the protocol
reported by Kunz and co-workers [8b], the bis-azolium derivative
1f∗ was obtained using diiodomethane as alkylating agent. Also in
this case, the chloride azolium salt 1f was achieved by passing 1f∗
through the DOWEX 21K Cl ion-exchange resin.
In order to complete the series of the azolium salts used as
precursors in this work, we prepared bipyridoimidazolium iodide
ꢀ
1e∗ by reaction between 2,2 -bipyridine and diiodomethane as re-
2.3. Synthesis and characterization of bis-NHC palladium allyl
complexes (3a-f)
ported by Sasse and colleagues [14].
The corresponding chloride derivative 1e was obtained, once
again, by halogen metathesis and, as usually, characterized by 1H
and 13C spectroscopies.
In particular, the 1H NMR spectrum, recorded in DMSO-d6,
shows all aromatic signals in the range 7.5-8.8 ppm and the im-
idazole proton at ca. 9.9 ppm, with a 1J(C-H) coupling constant
of 233.2 Hz. This value certifies the lower σ-donor character of
The first category of η3-allyl palladium complexes is character-
ized by the presence of two carbene ligands (or one chelating bis-
carbene) coordinated to the metal center.
For the synthesis of these compounds, similarly to those
containing the classical imidazol-2-ylidenes [13d], the reac-
tion between the silver-NHC complexes 2a-f and the complex
[Pd(MePyCH2SPh)(η3-allyl)]ClO4 was carried out (Scheme 3). This
3

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
Fig. 3. 1J(C-H) of azolium salts 1a-e and other NHC precursors (in DMSO-d6).
palladium-precursor contains a labile pyridyl-thioether ligand that
can be easily replaced by strong ligands such as phosphines and
N-heterocyclic carbenes.
Each reaction was carried out in dichloromethane at room tem-
perature with a reaction time of 0.5-2 h. The driving force of the
process is the precipitation of AgCl or AgBr which, after being re-
moved by filtration, allow the obtainment of bisNHC palladium
complexes in good yields and purity.
In this context, the only exception is represented by the com-
plex with an alkylsulfide arm (3d), which could not be obtained in
a pure form, despite several purification attempts.
The 1H NMR spectra of complexes 3a-c show three sets of allyl
signals, in addition to the proton signals of the R substituents. This
is the consequence of the presence of two equivalent ligands and
of free rotation about the Pd-CNHC bond.
However, in the spectrum of 3b the mesityl proton peaks are
broad as a result of an only partial block of the rotation about the
CMes-NIm bond. By lowering the temperature to 233K it is possi-
ble to completely stop this rotation and differentiate the mesityl
proton signals.
Fig. 4. Ellipsoid representation of 4c crystal ASU content (50% probability). Atom
labels in use for Pd coordination sphere are reported.
The proton spectrum of the palladium derivative bearing two
dipyridoimidazolinylidenes (3e) exhibits, in addition to the aro-
matic protons, two doublets at 3.3 and 4.2 ppm (J = 13.3 and 7.4
Hz) attributable to anti and syn allyl protons, respectively, and a
multiplet at 5.9 ppm ascribable to the central allyl proton.
In contrast to what observed in previous studies in which pal-
ladium allyl complexes bearing chelating bisNHC ligands with high
steric demanding substituents appear as couples of diastereoiso-
mers [13d], the 1H NMR spectrum of complex 3f recorded at RT
is characterised by only one set of signals. This spectral feature
proves that in this case a rapid conformational inversion of the
chelate ring is active.
The 13C NMR spectra of 3a-c and 3e-f show the diagnostic sig-
nals of the carbene carbon at 167-168 ppm (3a-c and 3f) or 155
ppm (3e), the central allyl carbon at ca. 120 ppm and the terminal
allyl carbons at 60-65 ppm.
Fig. 5. Emission of complexes 3e (green) and 3b (blue).
More in detail, 1H NMR spectra show the presence of five dif-
ferent allyl protons, the methylene protons NCH2Py or NCH2S as
AB systems at ca. 5.5 ppm. In the case of complex 4c, the coordi-
nation of pyridine is proved by the increase in the chemical shift
of the proton adjacent to the pyridine nitrogen (H2’) with respect
to both the starting silver complex 2c and the biscarbene complex
3c.
2.4. Synthesis and characterization of palladium complexes bearing
C-N and C-S chelating ligands (4c-d)
The second category of cationic palladium complexes that has
been examined is represented by the allyl complexes bearing
chelating C-N and C-S ligands 4c-d (Scheme 4).
These compounds were obtained in high yields and purity by
reaction between the silver complexes 2c-d and the [Pd(μ-Cl)(η3-
allyl)]2 precursor in the presence of NaClO4 as a dehalogenating
agent.
In the 13C NMR spectra it is possible to find the characteristic
signals of the allyl carbon trans to carbene and trans to pyridine (or
to the thioether substituent), at 71-74 and 47-59 ppm, respectively,
and of the carbene carbon at 167-172 ppm.
Both reactions proceed at room temperature and the final prod-
ucts have been exhaustively characterized by NMR spectroscopy.
To further confirm the nature of complex 4c, its structure was
obtained by single crystal X-ray diffraction (Fig. 4).
4

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
Scheme 1. Synthesis of azolium salts 1a-f.
Scheme 2. Synthesis of silver-NHC complexes 2a-f.
5

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
Scheme 3. Synthesis of bisNHC palladium complexes 3a-c and 3e-f.
Scheme 4. Synthesis of palladium complexes 4c-d bearing C-N and C-S chelating ligands.
The crystalline form of 4c contains one crystallographically
independent palladium complex. The palladium center adopts a
square planar coordination sphere. Bond lengths and angles are
in agreement with literature structural data of similar Pd-(η3-allyl)
complexes: the Pd-(η 3-allyl) fragment found in the CSD database
Unfortunately, the complex containing the thioether substituent
(4d) is unstable in solution and therefore was not taken into con-
sideration for the anticancer activity studies.
˚
˚
(version 5.42) shows average dPd-C = 2.15(5) A, dC=C = 1.37(5) A
distances and ꢀC-Pd-C = 68(1)°, ꢀC=C=C = 120(4)° angles, match-
ing the 4c values. Palladium core of 4c is well superimposable with
CCDC 1970548 bearing a similar picolyl-N-heterocyclic carbene lig-
and [19].
2.5. Synthesis and characterization of neutral NHC/Cl and mixed
NHC/PPh3 palladium allyl complexes (5-6)
A class of compounds that has recently shown promising anti-
tumor activity, in some cases accompanied by a lower cytotoxicity
toward normal cells, is represented by the mixed NHC/phosphine
palladium allyl complexes [13].
The complex bears a positive charge which is balanced by a
−
ClO4 counterion, located close to the allyl ligand, which repre-
sents the area where the metal is more exposed (shortest O•••Pd
Inspired by these encouraging results, we first synthesized the
neutral NHC/Cl palladium derivatives 5a-b and 5e by transmetal-
lation reaction between the silver complexes 2a-b and 2e and the
[Pd(μ-Cl)(η3-allyl)]2 precursor. This process takes place within 1
hour in dichloromethane at room temperature (Scheme 5).
The obtained complexes were successfully characterized by 1H
and 13C NMR spectroscopies.
˚
contact is 4.36(2) A in 4c). Crystal packing of 4c shows hydropho-
˚
bic intermolecular π•••π contacts (e.g. d
= 3.623(4) A with
π•••
π
˚
0.81 A slippage between facing picolyl ring centroids) giving rise
to layers of stacked molecules where perchlorate and allyl moieties
are intercalated. No solvent molecules have been found in the crys-
tal packing.
6

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
Scheme 5. Synthesis of neutral NHC/Cl palladium complexes 5a-b and 5e.
Scheme 6. Synthesis of mixed NHC/PPh3 palladium complexes 6a-c and 6e.
In the 1H NMR spectra recorded at room temperature, five dif-
ferent allyl protons can be observed (Hcentral, Hsyn t-C, Hsyn t-Cl,
Hanti t-C and Hanti t-Cl) in addition to the signals of the carbene
ligands used.
Starting from 5a-b and 5e, by addition of triphenylphosphine
and in the presence of NaClO4, the mixed NHC/PPh3 palladium
complexes 6a-b and 6e were obtained in good yields and purity
(Scheme 6).
Complex 6c was instead prepared by addition of triphenylphos-
phine directly to derivative 4c (through opening of the picolyl
arm).
Moreover, the signals of the two different terminal allyl carbons
can be easily identify at ca. 73 (CH2 trans-C) and ca. 49 ppm (CH2
trans-Cl) in the 13C NMR spectra, whereas the coordination of NHC
ligand to the palladium centre is proved by the presence of the
peaks of carbene carbon at 171 ppm (5a-b) or 159 ppm (5e) [20].
With the same approach, starting from 4d, it was not possible
to selectively open the thioether arm. As a matter of fact, the cor-
responding mixed NHC/PPh3 complex 5d presents several impu-
7

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
Table 1
idazolinylidenes derivatives), with a Stoke-shift of ca. 20-40 nm
(Fig. 5).
Photophysical properties of palladium complexes 3-6 in comparison with an-
thracene and imidazo[1,5-a]pyridine.
The quantum yields obtained are lower than those of the start-
ing imidazo[1,5-a]pyridine and anthracene (Ф = 56 and 27%, re-
spectively) [21].
Category
Compound
λabs
(nm)
Logε
λem
(nm)
Ф (%)
Reference
Precursor
Monodentate
bisNHCs
Anthracene
366
3.03
2.59
2.36
2.12
3.15
2.97
2.44
2.21
2.40
2.63
2.40
2.96
2.77
2.30
2.22
2.59
397
414
399
399
404
492
412
/
27
56
15
19
1
However, among the investigated derivatives, the bisNHC com-
plexes 3a-c and 3e-f showed the best performances confirming
that their photoluminescence is attributable to the imidazo[1,5-
a]pyridine or dipyridoimidazole fragment. In particular, complexes
3a and 3b exhibit quantum yields of 15 and 19%, respectively.
Imidazo[1,5a]pyridine 367
3a
3b
3c
3e
376
376
370
445
366
367
370
376
376
445
367
372
374
446
2
Chelating C-C, C-S 3f
3.2
/
and C-N
4c
4d
5a
5b
5e
6a
6b
6c
6e
2.7. Anticancer activity
complexes
Neutral NHC/Cl
complexes
422
400
399
489
419
423
420
484
0.4
4
The antiproliferative activity of the cationic palladium(II)
derivatives 3a-c, 3e-f, 4c, 6a-c and 6e 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 glioblas-
toma (U87 cells).
0.8
0.3
3.3
3.5
0.9
0.6
Mixed NHC/PPh3
complexes
Preliminarily, the stability of all the compounds examined was
checked in 1:1 DMSO-d6/D2O solution by NMR spectroscopy: af-
ter 24 hours at room temperature no noticeable degradation was
observed.
rities which are difficult to identify and impossible to remove by
recrystallization.
Complexes 6a-c and 6e are stable in solution and their identi-
ties can be established as usual by NMR spectroscopy. Remarkably,
the spectra of compounds 6a-c showed the presence of the signals
of two different atropoisomers originated from the blocked rota-
tion about the Pd-CNHC bond. In the 31P NMR spectra the peaks of
the two isomers occur at very close chemical shifts, in the range
23-26 ppm and at ca. 30 ppm downfield from that of the free PPh3.
In contrast, compound 6e, which contains the symmetrical
dipyridoimidazolinylidene ligand, exhibits a single signal at 27
ppm.
In the 1H NMR spectra of 6a-c and 6e, four different termi-
nal allyl proton signals can be observed for each isomer and those
trans to phosphine ligand appear as doublets of doublets due to
the coupling with the phosphorus nucleus.
The half-inhibitory concentrations (IC50) induced by the palla-
dium(II) compounds and cisplatin (positive control) are summa-
rized in Table 2.
The data shown in Table 2 indicate that all the complexes tested
exhibit a high antiproliferative activity against all the tumor lines
examined, with IC50 in the micro- and nano-molar range. The cy-
totoxicity of our palladium complexes is generally higher than that
of cisplatin, in some cases by 2-3 orders of magnitude.
Intriguingly, most of the complexes show very similar IC50
values
in the cisplatin-sensitive (A2780) and cisplatin-resistant
(A2780cis) cell lines, suggesting a different mode of action com-
pared to cisplatin and its derivatives.
The results obtained by compounds 3c and 4c are particularly
interesting, as they combine a high antiproliferative activity toward
cancer cells with a poor cytotoxicity against MRC-5 normal cells
(IC50 > 100 μM). This selectivity, which needs to be confirmed by
further in vivo studies, appears to be attributable to the presence of
the pyridine arm in both compounds. A similar result has recently
been obtained with palladium allyl complexes bearing classical im-
idazolylidene ligands [13d].
A further confirmation of the nature of these complexes was
obtained from 13C NMR spectra, where the allyl carbon trans to
phosphine at 66-67 ppm as doublet (JC-P ≈ 30 Hz), allyl carbon
trans to carbene at 68-69 ppm (singlet), central allyl carbon at 121-
122 ppm, and carbene carbon (a doublet with JC-P ≈ 20 Hz) at 166
ppm (6a-c) or 153 ppm (6e), are particularly noteworthy.
It should be noted that the replacement of PPh3 with 1,3,5-
triaza-7-phosphaadamantane (PTA) has a different outcome. Al-
though the main product consists of the desired mixed NHC/PTA
complex, the signals ascribable to bisNHC and bisPTA complexes
are also well evident. The poor stability of bisPTA derivatives
also leads to the formation of decomposition products. This phe-
nomenon had already been observed previously during the syn-
thesis of mixed Pd(0) olefin complexes bearing one xanthine-based
NHC and one PTA molecule [12c].
3. Conclusions
In this contribution we have described the synthesis and char-
acterization of new silver and palladium allyl complexes bear-
ing imidazo[1,5-a]pyridine-3-ylidene and dipyridoimidazolinyli-
dene ancillary ligands.
NMR analysis of the corresponding azolium salts has high-
lighted the lower electron-donor ability of dipyridoimidazolinyli-
denes compared to imidazo[1,5-a]pyridine-3-ylidenes, which are in
turn less σ-donors than the most common imidazolylidenes (e.g.
IPr, SIPr and IMes).
2.6. Emission spectra of palladium complexes 3-6
The synthesized cationic palladium allyl complexes were tested
toward five different tumor lines, exhibiting excellent antitumor
activity, which in most cases is significantly higher than cisplatin.
Remarkably, compounds 3c and 4c, which contain a pyridine
arm, showed poor in vitro cytotoxicity toward MRC-5 normal cells.
These truly encouraging results need to be confirmed by further in
vivo studies and it will also be of great interest to investigate their
mechanism of action, in the hope of explaining their selectivity to-
ward cancer cells.
The palladium allyl complexes 3-6 have been subjected to a
photophysical investigation in solution at room temperature. The
absorption profiles in ethanol solution are centred in the UV-vis
spectral window (360-450 nm).
The absorption/emission wavelengths (λabs and λem) and quan-
tum yield (Ф) of each synthesized complex, imidazo[1,5-a]pyridine
and anthracene as reference compound are reported in Table 1.
All palladium complexes, except 4c, showed photoluminescence
properties, with an emission band at 399-423 nm (for imidazo[1,5-
a]pyridine-3-ylidene derivatives) or 484-492 nm (for dipyridoim-
Finally, all synthesized palladium compounds, especially bisNHC
derivatives 3a-c and 3e-f, showed good photoluminescence prop-
8

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Journal of Organometallic Chemistry 952 (2021) 122014
Table 2
Cytotoxicity of Pd-complexes toward several cancer and normal cell lines∗.
IC50 (μM)
Complex
A2780
A2780cis
27
A549
5.2
DLD-1
1.4
U87
16
MRC-5
2.6 0.7
CisPt
3a
3b
3c
0.43
0.04
6
0.8
0.3
2
0.9 0.1
1.5 0.1
3.8 0.8
1.9 0.5
2.6 0.3
8
1
0.024 0.008
0.3 0.1
0.034 0.008
4.0 0.2
0.018 0.003
0.64 0.02
3.1 0.3
0.04 0.01
2.2 0.1
0.029 0.001
4.2 0.2
0.038 0.001
>100
3e
3f
5.04 0.03
0.13 0.07
0.62 0.08
0.019 0.001
0.034 0.007
0.05 0.02
0.21 0.05
3.5 0.3
2.48 0.01
1.2 0.4
3.1 0.4
5.13 0.04
4.9 0.1
>100
0.48 0.06
3.7 0.5
0.15 0.02
2.6 0.2
0.29 0.05
0.8 0.2
4c
3 1
6a
6b
6c
0.33 0.02
0.10 0.01
1.7 0.3
1.3 0.2
0.47 0.07
0.16 0.02
0.32 0.04
0.30 0.06
0.297 0.008
0.28 0.02
0.31 0.05
0.169 0.007
3.2 0.4
0.36 0.05
2.8 0.3
1.3 0.2
0.027 0.002
0.8 0.1
6e
0.29 0.03
0.43 0.02
∗
Data after 96h 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).
H8), 8.24 (s, 1H, H1), 8.71 (dd, 1H, J = 8.0, 1.1 Hz, H5), 9.88 (d, 1H,
erties, with emission in the blue (for imidazo[1,5-a]pyridine-
J = 1.1 Hz, H3).
3-ylidenes) and green (for dipyridoimidazolinylidenes) regions,
13C{1H}-NMR (DMSO-d6, T=298K, ppm) δ: 37.5 (CH3, NCH3),
which are attributable to the fascinating photophysical properties
115.0 (CH, CH1), 117.7 (CH, CH7), 118.5 (CH, CH8), 124.6 (CH, CH5),
of their organic starting materials (e.g. imidazo[1,5-a]pyridine).
124.9 (CH, CH6), 127.6 (CH, CH3), 129.6 (C, C9).
Anal. Calc. for C8H9ClN2: C, 56.98; H, 5.38; N, 16.61. Found: C,
4. Experimental section
57.11; H, 5.45; N, 16.50%.
4.1. Materials and characterization techniques
4.3. Synthesis of compound 1c
All syntheses of complexes were carried out using standard
Schlenk techniques under argon. Solvents were dried and distilled
In a 100 mL flask, 3.02 g (0.025 mol) of imidazo[1,5-a]pyridine
˚
according to standard methods: CH2Cl2 was firstly treated with 3A
was dissolved in 50 mL of acetonitrile. 4.14 g (0.032 mol) of picolyl
chloride and 4.105 g (0.034 mol) of potassium bromide were added
to the resulting solution. The reaction mixture was stirred at room
temperature for 48 hours and then inorganic salts were removed
by filtration. The solvent was removed under vacuum and the solid
residue was washed several times with diethyl ether, affording 3.58
g (yield = 48%) of the desired product 1c (red powder).
1H-NMR (300 MHz, DMSO-d6, T = 298K, ppm) δ: 5.93 (s, 2H,
NCH2), 7.20 (m, 1H, H7), 7.28 (m, 1H, H6), 7.42 (m, 1H, H3’), 7.59
(dt, 1H, J = 7.8, 1.1 Hz, H5’), 7.86-7.94 (2H, H8, H4’), 8.31 (s, 1H, H1),
8.55 (ddd, 1H, J = 4.8, 1.8, 0.9 Hz, H2’), 8.71 (dq, 1H, J = 7.0, 1.0 Hz,
H5), 9.88 (d, 1H, J = 1.0 Hz, H3).
molecular sieves and then distilled over P2O5. All other chemicals
were commercially available grade products and were used as pur-
chased.
The palladium(II) precursor [Pd(MePyCH2SPh)(η3-allyl)]ClO4
[22], imidazo[1,5-a]pyridine [17] and the azolium salt 1b [8c], were
synthesized according to published procedures.
The NMR spectra were recorded on a Bruker 300 Avance spec-
trometer.
Absorption and emission spectra were recorded with Perkin-
Elmer lambda 35 and Jasco FP-750 spectrometers, respectively. For
luminescence experiments, the samples in ethanol solution were
placed in fluorimetric 1-cm path cuvettes. Corrected spectra were
obtained via a calibration curve supplied with the instrument. Lu-
minescence quantum yields (ꢁ) in solution obtained from spectra
on a wavelength scale (nm) were measured according to a previ-
ously published protocol [23] using anthracene in ethanol solution
(ꢁ = 0.27) as standard [21].
13C{1H}-NMR (DMSO-d6, T = 298K, ppm) δ: 54.6 (CH2, NCH2),
114.6 (CH, CH1), 118.0 (CH, CH7), 118.7 (CH, CH8), 123.2 (CH, CH5’),
124.3 (CH, CH3’), 124.8 (CH, CH5), 125.1 (CH, CH6), 127.6 (CH, CH3),
129.7 (C, C9), 138.1 (C, C4’),150.1 (CH, CH2’), 153.9 (C, C6’).
Anal. Calc. for C13H12BrN3: C, 53.81; H, 4.17; N, 14.48. Found: C,
53.68; H, 4.22; N, 14.60%.
The elemental analysis was carried out using an Elemental CHN
"CUBO Micro Vario" analyzer.
4.3. Synthesis of compound 1d
4.2. Synthesis of compound 1a
In a 100 mL flask, 1.51 g (0.0128 mol) of imidazo[1,5-a]pyridine,
1.674 g (0.0141 mol) of potassium bromide and 0.98 mL (0.0120
mol) of chloromethyl methyl sulfide were suspended in 25 mL of
anhydrous acetonitrile. The reaction mixture was stirred at room
temperature for 5 hours and then inorganic salts were removed by
filtration. Then, 2 mL of triisobutyl amine was added and the sol-
vent was removed under vacuum affording a solid residue which
was washed several times with diethyl ether.
In a 100 mL flask, 3.02 g (0.025 mol) of imidazo[1,5-a]pyridine
was dissolved in 25 mL of tetrahydrofuran and 8.00 mL (0.128 mol)
of iodomethane was added to the resulting solution.
The reaction mixture was kept at 80°C for ca. 4 hours and then
cooled down to room temperature. Compound 1a∗ was filtered off
on a gooch filter, affording 6.58 g of a green powder.
Subsequently, 1a∗ was dissolved in 200 mL of methanol and 30
g of DOWEX 21KCl resin was added. The system was then stirred
at room temperature for 24 hours. After filtration of the resin, the
solvent was removed under vacuum and the final green product 1a
was obtained in excellent yield (4.22 g, 98%).
1.68 g of the desired product 1d (purple powder, yield = 48%)
was obtained.
1H-NMR (300 MHz, DMSO-d6, T = 298K, ppm) δ: 2.20 (s, 3H,
SCH3), 5.74 (s, 2H, NCH2), 7.20 (m, 1H, H7), 7.29 (m, 1H, H6), 7.88
(d, 1H, J = 9.4 Hz, H8), 8.33 (s, 1H, H1), 8.65 (d, 1H, J = 6.8 Hz,
H5), 9.90 (s, 1H, H3).
1H-NMR (300 MHz, DMSO-d6, T = 298K, ppm) δ: 4.19 (s, 3H,
NCH3), 7.17 (m, 1H, H7), 7.26 (m, 1H, H6), 7.86 (d, 1H, J = 9.2 Hz,
9

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
13C{1H}-NMR (DMSO-d6, T = 298K, ppm) δ: 14.7 (CH3, SCH3),
53.4 (CH2, NCH2), 113.6 (CH, CH1), 118.0 (CH, CH7), 118.8 (CH, CH8),
124.9 (CH, CH5), 125.3 (CH, CH6), 127.0 (CH, CH3), 130.1 (C, C9).
Anal. Calc. for C9H11 BrN2S: C, 41.71; H, 4.28; N, 10.81. Found: C,
41.84; H, 4.20; N, 10.71%.
The brownish complex was filtered off on a gooch filter, repeat-
edly washed with diethylether and n-pentane and dried under vac-
uum.
0.2720 g of 2a was obtained (yield 78%).
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 4.13 (s, 3H,
NCH3), 6.69 (m, 1H, H7), 6.99 (m, 1H, H6), 7.33 (s, 1H, H1), 7.36
(dt, 1H, J = 9.3, 1.3 Hz, H8), 8.28 (dd, 1H, J = 7.3, 1.1 Hz, H5)
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 40.1 (CH3, NCH3), 112.1
(CH, CH1), 114.2 (CH, CH7), 117.2 (CH, CH8), 123.4 (CH, CH6), 128.2
(CH, CH5), 131.4 (C, C9), 171.8 (C, carbene).
4.4. Synthesis of compound 1e
ꢀ
In a 100 mL flask, 1.02 g (0.0065 mol) of 2,2 -bipyridine and
0.265 mL (0.0033 mol) of diiodomethane were dissolved in 20 mL
of anhydrous acetonitrile under argon atmosphere. The reaction
mixture was stirred at 100°C for 5 days. The solvent was then re-
moved under vacuum and 0.11 g of a dark green solid was obtained
(compound 1e∗).
Anal. Calc. for C8H8AgClN2: C, 34.88; H, 2.93; N, 10.17. Found:
C, 35.01; H, 2.87; N, 10.09%.
4.6.2. Synthesis of complex 2b
Subsequently, 1e∗ was dissolved in 20 mL of methanol and 3
g of DOWEX 21KCl resin was added. The system was then stirred
at room temperature for 24 hours. After filtration of the resin, the
solvent was removed under vacuum and the final green product 1e
was obtained in 12% yield (0.076 g).
Complex 2b was prepared by a procedure analogous to that de-
scribed for 2a starting from 0.2008 g (0.7 mmol) of 1b and 0.0938
g (0.4 mmol) of Ag2O.
0.2438 g (yield 87%) of 2b was obtained.
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 1.94 (s, 6H, 2 o-
aryl-CH3), 2.38 (s, 3H, p-aryl-CH3), 6.79 (m, 1H, H7), 6.99 (m, 1H,
H6), 7.00 (s, 2H, 2 m-aryl-H), 7.26 (s, 1H, H1), 7.45 (d, 1H, J = 9.2
Hz, H8), 8.62 (bs, 1H, H5).
1H-NMR (300 MHz, DMSO-d6, T = 298K, ppm) δ: 7.50-7.63 (4H,
H4, H5, H4’, H5’), 8.69 (d, 2H, J = 8.9 Hz, H3, H3’), 9.06 (d, 2H,
J = 7.4 Hz, H6, H6’), 10.41 (s, 1H, NCHN).
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 17.6 (CH3, o-mesityl),
21.1 (CH3, p- mesityl), 112.4 (CH, CH1), 114.5 (CH, CH7), 117.5 (CH,
CH8), 123.6 (CH, CH6), 128.7 (CH, CH5), 129.4 (CH, m-aryl-CH),
131.1 (C, C9), 134.3 (C, o-mesityl), 135.8 (C, i-mesityl), 139.8 (C, p-
mesityl), 171.6 (C, carbene).
13C{1H}-NMR (DMSO-d6, T = 298K, ppm) δ: 116.6 (CH, NCHN),
119.2 (CH, CH3, CH3’), 120.9 (CH, CH4, CH4’), 122.3 (C, C2, C2’), 123.2
(CH, CH5, CH5’), 123.9 (CH, CH6, CH6’).
Anal. Calc. for C11 H9ClN2: C, 64.56; H, 4.43; N, 13.69. Found: C,
64.71; H, 4.38; N, 13.58%.
Anal. Calc. for C16 H16 AgClN2: C, 50.62; H, 4.25; N, 7.38. Found:
C, 50.73; H, 4.18; N, 7.30%.
4.5. Synthesis of compound 1f
4.6.3. Synthesis of complex 2c
In a 100 mL flask, 4.07 g (0.034 mol) of imidazo[1,5-a]pyridine
was dissolved in 40 mL of toluene and 1.4 mL (0.017 mol) of di-
iodomethane were then added. The reaction mixture was subse-
quently stirred at 120°C for 24 hours and then cooled down to
room temperature. The solid formed was filtered off on a gooch
filter and washed with three portions of diethyl ether. 4.53 g of
1f∗ was obtained as a brownish powder.
Complex 2c was prepared by a procedure analogous to that de-
scribed for 2a starting from 0.4168 g (1.4 mmol) of 1c and 0.1849
g (0.8 mmol) of Ag2O.
0.4050 g (yield 71%) of 2c was obtained.
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 5.71 (s, 2H,
NCH2), 6.67 (m, 1H, H7), 6.91 (m, 1H, H6), 7.28 (m, 1H, H3’), 7.35
(dt, J = 9.3, 1.2 Hz, H8), 7.47 (dt, J = 7.8, 1.1 Hz, H5’), 7.53 (d, J = 1.0
Hz, H1) 7.72 (td, J = 7.7, 1.8 Hz, H4’) 8.39 (dq, 1H, J = 7.3, 1.1 Hz,
H5), 8.61 (ddd, 1H, J = 4.8, 1.8, 0.9 Hz, H2’).
The latter was dissolved in 800 mL of methanol and 15 g of
DOWEX 21KCl resin was added. The system was then stirred at
room temperature for 24 hours. After filtration of the resin, the sol-
vent was removed under vacuum affording a solid residue which
was washed with dichloromethane (10 mL) and several times with
diethyl ether.
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 58.3 (CH2, NCH2), 111.7
(CH, CH1), 114.2 (CH, CH7), 117.5 (CH, CH8), 123.1 (CH, CH5’), 123.3
(CH, CH3’), 123.6 (CH, CH6), 128.6 (CH, CH5), 131.4 (C, C9), 137.5 (C,
C4’),149.9 (CH, CH2’), 154.8 (C, C6’), 173.3 (C, carbene).
Anal. Calc. for C13H11 AgBrN3: C, 39.33; H, 2.79; N, 10.58. Found:
C, 39.46; H, 2.71; N, 10.68%.
The desired product 1f was obtained as a greenish powder (2.87
g, yield = 52%).
1H-NMR (300 MHz, DMSO-d6, T = 298K, ppm) δ: 7.22-7.33 (4H,
2H6, 2H7), 7.49 (s, 2H, NCH2N), 7.93 (d, 2H, J = 9.1 Hz, 2H8), 8.71
(s, 2H, 2H1), 8.57 (d, 2H, J = 6.1, 2H5), 9.95 (d, 2H, J = 1.6 Hz, 2H3).
13C{1H}-NMR (DMSO-d6, T = 298K, ppm) δ: 60.0 (CH2, NCH2N),
113.9 (CH, CH1), 118.7 (CH, CH7), 119.0 (CH, CH8), 125.0 (CH, CH5),
125.6 (CH, CH6), 128.4 (CH, CH3), 129.8 (C, C9).
4.6.4. Synthesis of complex 2d
Complex 2d was prepared by a procedure analogous to that de-
scribed for 2a starting from 0.2190 g (0.8 mmol) of 1d and 0.1077
g (0.4 mmol) of Ag2O.
0.2247 g (yield 73%) of 2d was obtained.
Anal. Calc. for C15H14 Cl2N4: C, 56.09; H, 4.39; N, 17.44. Found:
C, 55.92; H, 4.46; N, 17.50%.
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 2.15 (s, 3H,
SCH3), 5.43 (s, 2H, NCH2), 6.69 (m, 1H, H7), 6.96 (m, 1H, H6), 7.38
(d, 1H, J = 9.3 Hz, H8), 7.59 (s, 1H, H1), 8.65 (dq, 1H, J = 7.4, 1.2
Hz, H5).
4.6. Synthesis of silver-NHC complexes 2a-e
4.6.1. Synthesis of complex 2a
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 14.7 (CH3, SCH3), 56.0
(CH2, SCH2), 110.2 (CH, CH1), 114.2 (CH, CH7), 117.4 (CH, CH8),
123.6 (CH, CH6), 128.6 (CH, CH5), 131.9 (C, C9), 173.2 (C, carbene).
Anal. Calc. for C9H10AgBrN2: C, 29.53; H, 2.75; N, 7.65. Found:
C, 29.65; H, 2.68; N, 7.59%.
0.2148
g (1.3 mmol) of 1a was dissolved in 30 mL of a
dichloromethane/methanol (10:1) solution in a two-necked flask
and 0.1630 g (0.7 mmol) of Ag2O was added under inert atmo-
sphere (Ar).
The mixture was stirred for 24 hours at RT in the dark and sub-
sequently 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 precipi-
tated by addition of diethylether.
4.6.5. Synthesis of complex 2e
Complex 2e was prepared by a procedure analogous to that de-
scribed for 2a starting from 0.2316 g (1.1 mmol) of 1e and 0.1511 g
(0.6 mmol) of Ag2O.
10

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
0.2180 g (yield 62%) of 2e was obtained.
3.84 (d, 2H, J = 7.3 Hz, syn allyl-H), 5.32 (m, 1H, central allyl-H),
6.39 (m, 2H, 2H7), 6.88 (bs, 6H, 4 m-aryl-H, 2H5), 6.98 (m, 2H,
2H6), 7.32 (s, 2H, 2H1), 7.46 (dt, 2H, J = 9.4, 1.3 Hz, 2H8).
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 17.2 (CH3, o-mesityl),
21.1 (CH3, p-mesityl), 60.5 (CH2, allyl), 113.8 (CH, CH1), 114.1 (CH,
CH7), 117.7 (CH, CH8), 119.7 (CH, central allyl), 123.2 (CH, CH6),
127.3 (CH, m-aryl-CH), 130.1 (CH, CH5), 132.0 (C, C9), 134.2 (C, o-
mesityl), 135.3 (C, i-mesityl), 139.5 (C, p-mesityl), 168.6 (C, car-
bene).
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 7.07-7.14 (4H, H4,
H5, H4’, H5’), 7.93 (m, 2H, H3, H3’), 8.59 (m, 2H, H6, H6’).
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 117.6 (CH, CH3, CH3’),
117.7 (CH, CH4, CH4’), 120.5 (CH, CH5, CH5’), 123.0 (C, C2, C2’), 127.1
(CH, CH6, CH6’), 161.1 (C, carbene).
Anal. Calc. for C11 H8AgClN2: C, 42.41; H, 2.59; N, 8.99. Found:
C, 42.27; H, 2.66; N, 9.05%.
Anal. Calc. for C35H37ClN4O4Pd: C, 58.42; H, 5.18; N, 7.79.
Found: C, 58.30; H, 5.25; N, 7.87%.
4.7. Synthesis of dinuclear silver-NHC complex 2f
0.1010 g (0.3 mmol) of 1f was dissolved in 14 mL of methanol
in a two-necked flask and 0.0743 g (0.3 mmol) of Ag2O was added
under inert atmosphere (Ar).
4.8.3. Synthesis of complex 3c
Complex 3c was prepared by a procedure analogous to that
described for 3a starting from 0.0820 g (0.2 mmol) of [Pd(Me-
PyCH2SPh)(η3-allyl)]ClO4 and 0.1414 g (0.4 mmol) of 2c.
0.0816 g (yield 69%) of 3c was obtained.
The mixture was stirred for 3 hours at RT in the dark and sub-
sequently 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 precipi-
tated by addition of diethylether.
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 2.82 (d, 2H,
J = 13.3 Hz, 2 allyl-H), 3.88 (d, 1H, J = 7.3 Hz, 2 syn allyl-H), 5.49
(s, 4H, 2NCH2), 5.50 (m, 1H, central allyl-H), 6.61 (t, 2H, J = 7.1 Hz,
2H7), 6.78 (dd, 2H, J = 9.3, 7.1 H, 2H6), 6.89 (d, 2H, J = 7.8 Hz,
2H8), 7.06 (dd, 2H, J = 7.5, 4.9 Hz, 2H3’), 7.22 (d, 2H, J = 9.2 Hz,
2H5’), 7.43 (s, 2H, 2H1), 7.48 (td, 2H, J = 7.8, 1.7 Hz, 2H4’), 8.17 (d,
2H, J = 7.3 Hz, 2H5), 8.28 (dd, 2H, J = 5.0, 1.7 Hz, 2H2’).
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 56.9 (CH2, NCH2), 60.4
(CH2, allyl), 113.2 (CH, CH1), 114.2 (CH, CH7), 117.7 (CH, CH8), 121.6
(CH, central allyl), 122.6 (CH, CH5’), 122.8 (CH, CH3’), 127.2 (CH,
CH6), 127.3 (CH, CH5), 132.0 (C, C9), 136.9 (C, C4’), 148.9 (CH, CH6’),
154.8 (C, C2’), 168.2 (C, carbene).
The brownish complex was filtered off on a gooch filter, repeat-
edly washed with diethylether and n-pentane and dried under vac-
uum.
0.1580 g of 2f was obtained (yield 94%).
1H-NMR (300 MHz, DMSO-d6, T = 298K, ppm) δ: 6.83 (t, 2H,
J = 6.4 Hz, 2H7), 7.06 (dd, 2H, J = 9.3, 6.4 Hz, 2H6), 7.31 (s, 2H,
NCH2N), 7.67 (d, 2H, J = 9.3 Hz, 2H8), 8.33 (s, 2H, 2H1), 8.56 (d,
2H, J = 6.4, 2H5).
13C{1H}-NMR (DMSO-d6, T = 298K, ppm) δ: 55.3 (CH2, NCH2N),
112.7(CH, CH1), 118.2 (CH, CH7), 119.4 (CH, CH8), 119.7 (CH, CH5),
123.6 (CH, CH6), 128.7 (C, C9), 162.4 (C, carbene).
Anal. Calc. for C15H12Ag2Cl2N4: C, 33.68; H, 2.26; N, 10.47.
Found: C, 33.81; H, 2.19; N, 10.40%.
Anal. Calc. for C29H27ClN6O4Pd: C, 52.34; H, 4.09; N, 12.63.
Found: C, 52.47; H, 4.01; N, 12.50%.
4.8.4. Synthesis of complex 3e
4.8. Synthesis of bisNHC palladium allyl complexes
Complex 3e was prepared by a procedure analogous to that
described for 3a starting from 0.0409 g (0.1 mmol) of [Pd(Me-
PyCH2SPh)(η3-allyl)]ClO4 and 0.0552 g (0.2 mmol) of 2e.
0.0416 g (yield 81%) of 3e was obtained.
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 3.27 (d, 2H,
J = 13.3 Hz, 2 anti allyl-H), 4.19 (d, 2H, J = 7.4 Hz, 2 syn allyl-H),
5.87 (m, 1H, central allyl-H), 6.98-7.15 (8H, 2H4, 2H5, 2H4’, 2H5’),
7.85 (dt, 4H, J = 9.0, 1.3 Hz, 2H3, 2H3’), 8.61(dt, 4H, J = 7.2, 1.1 Hz,
2H6, 2H6’).
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 61.1 (CH2, allyl), 117.6
(CH, CH3, CH3’), 117.6 (CH, CH4, CH4’), 119.8 (CH, CH5, CH5’), 123.2
(CH, central allyl), 123.2 (CH, CH6, CH6’), 127.3 (C, C2, C2’), 154.8 (C,
carbene).
4.8.1. Synthesis of complex 3a
0.0830 g (0.2 mmol) of the precursor [Pd(Me-PyCH2SPh)(η3-
allyl)]ClO4 was dissolved in 15 mL of anhydrous dichloromethane
in a 50 mL two-necked flask under inert atmosphere (Ar). Subse-
quently, 0.0991 g (0.4 mmol) of the silver complex 2a previously
dissolved in ca. 5 mL of CH2Cl2 was added. The mixture was stirred
at room temperature for 1 hour and the precipitated AgCl was re-
moved by filtration on a millipore membrane filter.
The solvent was reduced under vacuum and the brownish solid
was precipitated by addition of diethylether and filtered off on a
gooch filter.
0.0758 g of 3a was obtained (yield 83%).
Anal. Calc. for C25H21ClN4O4Pd: C, 51.48; H, 3.63; N, 9.60.
Found: C, 51.64; H, 3.55; N, 9.53%.
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 2.98 (dt, 2H,
J = 13.3, 1.1 Hz, 2 anti allyl-H), 3.90 (s, 6H, 2 NCH3), 4.04 (dt, 2H,
J = 7.4, 1.1 Hz, 2 syn allyl-H), 5.62 (m, 1H, central allyl-H), 6.67 (m,
2H, 2 H7), 6.82 (m, 2H, 2 H6), 7.31 (m, 2H, 2 H8), 7.46 (s, 2H, 2 H1),
8.08 (dq, 1H, J = 7.3, 1.1 Hz, H5).
4.8.5. Synthesis of complex 3f
Complex 3f was prepared by a procedure analogous to that
described for 3a starting from 0.1743 g (0.4 mmol) of [Pd(Me-
PyCH2SPh)(η3-allyl)]ClO4 and 0.2013 g (0.4 mmol) of 2f.
0.1756 g (yield 94%) of 3f was obtained.
1H-NMR (300 MHz, CD3CN, T = 298K, ppm) δ: 3.12 (dt, 2H,
J = 13.3, 0.8 Hz, 2 anti allyl-H), 4.04 (dt, 2H, J = 7.4, 0.8 Hz, 2
syn allyl-H), 5.49 (m, 1H, central allyl-H), 6.45-6.63 (AB system, 2H,
J = 13.3 Hz, NCH2N), 6.82 (m, 2H, 2H7), 7.01 (m, 2H, 2H6), 7.53 (m,
2H, 2H8), 7.90 (s, 2H, 2H1), 8.25 (m, 2H, 2H5).
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 39.4 (CH3, NCH3), 60.3
(CH2, allyl), 113.8 (CH, CH1), 114.1 (CH, CH7), 117.8 (CH, CH8), 119.8
(CH, central allyl), 122.5 (CH, CH6), 127.0 (CH, CH5), 131.9 (C, C9),
167.2 (C, carbene).
Anal. Calc. for C19 H21ClN4O4Pd: C, 44.64; H, 4.14; N, 10.96.
Found: C, 44.77; H, 4.09; N, 10.90%.
4.8.2. Synthesis of complex 3b
Complex 3b was prepared by a procedure analogous to that
described for 3a starting from 0.0807 g (0.2 mmol) of [Pd(Me-
PyCH2SPh)(η3-allyl)]ClO4 and 0.1321 g (0.4 mmol) of 2b.
0.0758 g (yield 83%) of 3b was obtained.
13C{1H}-NMR (CD3CN, T = 298K, ppm) δ: 58.3 (CH2, NCH2N),
64.6 (CH2, allyl), 112.6 (CH, CH1), 114.8 (CH, CH7), 118.1 (CH, CH8),
119.6 (CH, central allyl), 123.4 (CH, CH6), 128.0 (CH, CH5), 130.7 (C,
C9), 166.9 (C, carbene).
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 1.49 (bs, 12H, 4
Anal. Calc. for C18 H17 ClN4O4Pd: C, 43.66; H, 3.46; N, 11.31.
Found: C, 43.80; H, 3.39; N, 11.26%.
o-aryl-CH3), 2.60 (bs, 2H, anti allyl-H), 2.41 (s, 6H, 2 p-aryl-CH3),
11

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
4.9. Synthesis of palladium complexes bearing C-N and C-S chelating
ligands (4c-d)
The precipitated AgCl was filtered off on a Celite filter and re-
peatedly washed with CH2Cl2, whereas the filtrate was concen-
trated under vacuum. Addition of diethylether caused the precip-
itation of complex 5a as a green solid which was filtered off on a
gooch and washed with n-pentane.
4.9.1. Synthesis of complex 4c
0.0852 g (0.2 mmol) of [Pd(μ-Cl)(η3-allyl)]2 was dissolved in ca.
10 mL of anhydrous CH2Cl2. 0.1857 g (0.4 mmol) of the silver com-
plex 2c dissolved in ca. 5 mL of CH2Cl2 was added and the mix-
ture was stirred at room temperature for ca. 1 hour in a 50 mL
two-necked flask under inert atmosphere (Ar).
0.1256 g of 5a was obtained (yield 86%).
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 2.58 (d, 1H,
J = 11.9 Hz, anti allyl-H trans-Cl), 3.43 (d, 1H, J = 13.6 Hz, anti
allyl-H trans-C), 3.53 (d, 1H, J = 6.5 Hz, syn allyl-H trans-Cl), 4.14
(s, 3H, NCH3), 4.41 (d, 1H, J = 7.6 Hz, syn allyl-H trans-C), 5.46 (m,
1H, central allyl-H), 6.54 (m, 1H, H7), 6.81 (m, 1H, H6), 7.23 (m, 1H,
H8), 7.26 (s, 1H, H1), 8.43 (dq, 1H, J = 7.3, 1.1 Hz, H5).
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 39.4 (CH3, NCH3), 48.7
(CH2, allyl trans-Cl), 73.5 (CH2, allyl trans-C), 112.1 (CH, CH1), 112.6
(CH, CH7), 115.1 (CH, central allyl), 116.9 (CH, CH8), 122.5 (CH, CH6),
128.6 (CH, CH5), 131.6 (C, C9), 170.7 (C, carbene).
The precipitated AgBr was removed by filtration on a millipore
membrane filter and 0.1430 g (1.0 mmol) of NaClO4 H O, dissolved
•
2
in 5 mL of methanol, was added to the filtrate which was left aside
for ca. 20 min.
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. Ad-
dition of diethylether caused the precipitation of the complex 4c as
a white solid which was filtered off on a gooch and washed with
n-pentane. 0.1820 g of 4c was obtained (yield 85%).
Anal. Calc. for C11 H13ClN2Pd: C, 41.93; H, 4.16; N, 8.89. Found:
C, 42.06; H, 4.10; N, 8.79%.
4.10.2. Synthesis of complex 5b
1H-NMR (300 MHz, CD3CN, T = 298K, ppm) δ: 3.11 (d, 1H,
J = 11.9 Hz, anti allyl-H trans-N), 3.75 (d, 1H, J = 13.7 Hz, anti allyl-
H trans-C), 4.11 (bs, 1H, syn allyl-H trans-N), 4.51 (d, 1H, J = 7.7 Hz,
syn allyl-H trans-C), 5.54 (m, 2H, NCH2), 5.77 (m, 1H, central allyl-
H), 6.79 (t, 1H, J = 6.9 Hz, H7), 6.90 (dd, 1H, J = 9.3, 6.9 H, H6),
7.28-7.35 (m, 2H, H8, H3’), 7.77 (d, J = 1.0 Hz, H1), 7.84 (d, J = 7.8
Hz, H5’), 8.07 (td, J = 7.8, 1.7 Hz, H4’), 8.19 (d, 1H, J = 7.3 Hz, H5),
8.93 (d, 1H, J = 5.3 Hz, H2’).
Complex 5b was prepared by a procedure analogous to that de-
scribed for 5a starting from 0.0867 g (0.2 mmol) of [Pd(μ-Cl)(η3-
allyl)]2 and 0.1804 g (0.4 mmol) of 2b.
0.1852 g (yield 93%) of 5b was obtained.
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 1.81 (d, 1H,
J = 12.0 Hz, anti allyl-H trans-Cl), 2.04 (s, 3H, o-aryl-CH3), 2.19
(s, 3H, o-aryl-CH3), 2.38 (s, 3H, p-aryl-CH3), 3.12 (d, 1H, J = 13.6
Hz, anti allyl-H trans-C), 3.15 (m, 1H, syn allyl-H trans-Cl), 4.18 (dd,
1H, J = 7.6, 2.3 Hz, syn allyl-H trans-C), 5.10 (m, 1H, central allyl-
H), 6.62 (m, 1H, H7), 6.90 (m, 1H, H6), 6.99 (s, 1H, m-aryl-H), 7.02
(s, 1H, m-aryl-H), 7.23 (s, 1H, H1), 7.32 (m, 1H, H8), 8.85 (dq, 1H,
J = 7.3, 1.1 Hz, H5).
13C{1H}-NMR (CD3CN, T = 298K, ppm) δ: 47.8 (CH2, allyl trans-
N), 55.6 (CH2, NCH2), 74.2 (CH2, allyl trans-C), 112.0 (CH, CH1),
114.5 (CH, CH7), 117.9 (CH, CH8), 120.0 (CH, central allyl), 123.0 (CH,
CH5’), 123.3 (CH, CH3’), 126.3 (CH, CH6), 127.5 (CH, CH5), 130.7 (C,
C9), 140.4 (C, C4’), 153.9 (CH, CH6’), 155.9 (C, C2’), 167.2 (C, car-
bene).
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 18.0 (CH3, o-mesityl),
18.4 (CH3, o-mesityl), 21.1 (CH3, p- mesityl), 49.5 (CH2, allyl trans-
Cl), 72.8 (CH2, allyl trans-C), 112.0 (CH, CH1), 112.5 (CH, CH7), 114.9
(CH, central allyl), 117.0 (CH, CH8), 123.2 (CH, CH6), 128.7 (CH, m-
aryl-CH), 129.1 (CH, m-aryl-CH), 129.8 (CH, CH5), 131.6 (C, C9),
134.7 (C, o- mesityl), 135.6 (C, o- mesityl), 136.8 (C, i- mesityl),
139.1 (C, p- mesityl), 172.5 (C, carbene).
Anal. Calc. for C16 H16 ClN3O4Pd: C, 42.13; H, 3.54; N, 9.21.
Found: C, 42.02; H, 3.59; N, 9.27%.
4.9.2. Synthesis of complex 4d
Complex 4d was prepared by a procedure analogous to that de-
scribed for 4c starting from 0.0860 g (0.2 mmol) of [Pd(μ-Cl)(η3-
allyl)]2 and 0.1739 g (0.4 mmol) of 2d.
Anal. Calc. for C19 H21ClN2Pd: C, 54.43; H, 5.05; N, 6.68. Found:
C, 54.29; H, 5.14; N, 6.79%.
0.1767 g (yield 88%) of 4d was obtained.
1H-NMR (300 MHz, CD3CN, T = 298K, ppm) δ: 2.53 (s, 3H,
SCH3), 3.27-3.36 (2H, anti allyl-H trans-S, anti allyl-H trans-C), 4.64
(d, 1H, J = 7.5 Hz, syn allyl-H trans-S), 4.75 (d, 1H, J = 7.0 Hz,
syn allyl-H trans-C), 5.38-5.50 (AB system, 2H, J = 12.1 Hz, NCH2),
5.57(m, 1H, central allyl-H), 6.83 (m, 1H, H7), 7.02 (m, 1H, H6), 7.52
(m, 1H, H8), 7.82 (d, J = 1.0 Hz, H1), 8.23 (dd, 1H, J = 7.3, 1.1 Hz,
H5).
13C{1H}-NMR (CD3CN, T = 298K, ppm) δ: 21.0 (CH3, SCH3),
57.5 (CH2, NCH2), 58.5 (CH2, allyl trans-S), 70.8 (CH2, allyl trans-C),
112.0 (CH, CH1), 115.8 (CH, CH7), 118.7(CH, CH8), 119.3 (CH, cen-
tral allyl), 124.3 (CH, CH6), 129.5 (CH, CH5), 132.9 (C, C9), 171.7 (C,
carbene).
4.10.3. Synthesis of complex 5e
Complex 5e was prepared by a procedure analogous to that de-
scribed for 5a starting from 0.0807 g (0.2 mmol) of [Pd(μ-Cl)(η3-
allyl)]2 and 0.1377 g (0.4 mmol) of 2e.
0.1425 g (yield 92%) of 5e was obtained.
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 2.70 (d, 1H,
J = 11.9 Hz, anti allyl-H trans-Cl), 3.52 (d, 1H, J = 13.5 Hz, anti allyl-
H trans-C), 3.61 (bs, 1H, syn allyl-H trans-Cl), 4.49 (d, 1H, J = 7.5
Hz, syn allyl-H trans-C), 5.54 (m, 1H, central allyl-H), 6.93-7.02 (4H,
H4, H5, H4’, H5’), 7.87 (m, 2H, H3, H3’), 8.81(m, 2H, H6, H6’).
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 49.2 (CH2, allyl trans-
Cl), 73.8 (CH2, allyl trans-C), 115.1 (CH, central allyl), 116.1 (CH, CH3,
CH3’), 117.4 (CH, CH4, CH4’), 119.4 (CH, CH5, CH5’), 123.2 (C, C2, C2’),
127.3 (CH, CH6, CH6’), 159.3 (C, carbene).
Anal. Calc. for C12H15ClN2O4PdS: C, 33.90; H, 3.56; N, 6.59.
Found: C, 34.02; H, 3.50; N, 6.49%.
Anal. Calc. for C14 H13ClN2Pd: C, 47.89; H, 3.73; N, 7.98. Found:
C, 48.03; H, 3.61; N, 8.07%.
4.10. Synthesis of neutral palladium complexes (5a-b and 5e)
4.10.1. Synthesis of complex 5a
4.11. Synthesis of mixed NHC/PPh3 palladium complexes
0.0853 g (0.2 mmol) of [Pd(μ-Cl)(η3-allyl)]2 was dissolved in ca.
25 mL of anhydrous CH2Cl2. 0.1285 g (0.4 mmol) of the silver com-
plex 2a was added and the mixture was stirred at room tempera-
ture for ca. 1 hour in a 50 mL two necked flask under inert atmo-
sphere (Ar).
4.11.1. Synthesis of complex 6a
0.0890 g (0.3 mmol) of 5a was dissolved in ca. 12 mL of CH2Cl2
and 0.0752 g (0.3 mmol) of PPh3 was added. Subsequently, 0.0982
g (0.7 mmol) of NaClO4 H O, dissolved in 4 mL of methanol, was
•
2
12

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
added and the mixture was stirred at room temperature for ca. 30
min in a 50 mL flask.
Anal. Calc. for C37H36ClN2O4PPd: C, 59.61; H, 4.87; N, 3.76.
Found: C, 59.73; H, 4.81; N, 3.72%.
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. Ad-
dition of diethylether caused the precipitation of the complex 6a as
a white solid which was filtered off on a gooch and washed with
n-pentane. 0.1062 g of 6a was obtained (yield 59%).
Isomer 1 (50%):
4.11.3. Synthesis of complex 6c
Complex 6c was prepared by a procedure analogous to that de-
scribed for 6a (no further addition of NaClO4 H O was necessary)
•
2
starting from 0.1007 g (0.2 mmol) of 4c and 0.0594 g (0.2 mmol)
of PPh3.
0.1248 g (yield 79%) of 6c was obtained.
Most abundant isomer (ca. 55%):
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 3.20 (d, 1H,
J = 13.6 Hz, anti allyl-H trans-C), 3.44 (m, 1H, anti allyl-H trans-
P), 3.56 (s, 3H, NCH3), 4.14 (m, 1H, syn allyl-H trans-P), 4.45 (d, 1H,
J = 7.0 Hz, syn allyl-H trans-C), 5.88 (m, 1H, central allyl-H), 6.49
(m, 1H, H7), 6.73 (m, 1H, H6), 6.60-7.94 (18H, Ph, H1, H5, H8).
31P{1H}-NMR (CDCl3, T=298K, ppm) δ: 26.1
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 3.31 (m, 1H, anti
allyl-H trans-P), 3.09 (d, 1H, J = 13.7 Hz, anti allyl-H trans-C), 4.01
(m, 1H, syn allyl-H trans-P), 4.13 (d, 1H, J = 7.7 Hz, syn allyl-H
trans-C), 5.03 (s, 2H, NCH2), 5.60 (m, 1H, central allyl-H), 6.49 (m,
1H, H7), 6.73 (m, 1H, H6), 7.11-7.64 (20H, Ph, H3’, H4’, H5’, H1, H8).
7.87 (d, 1H, J = 7.2 Hz, H5), 8.32 (m, 1H, H2’).
13C{1H}-NMR (CDCl3, T=298K, ppm) δ: 38.8 (CH3, NCH3), 67.3
(d, CH2, JCP = 32.0 Hz, allyl trans-P), 69.0 (CH2, allyl trans-C), 121.7
(d, CH, JCP = 5.0 Hz, central allyl), 114.0-133.9 (CH1, CH5, CH6, CH7,
CH8), 165.6 (d, C, JCP = 20.1 Hz, carbene).
31P{1H}-NMR (CDCl3, T = 298K, ppm) δ: 26.4
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 56.8 (CH2, NCH2), 67.6
(d, CH2, JCP = 30.4 Hz, allyl trans-P), 68.8 (CH2, allyl trans-C), 121.7
(d, CH, JCP = 4.9 Hz, central allyl), 114.0-154.6 (Py-C, CH1, CH5, CH6,
CH7, CH8), 166.2 (d, C, JCP = 19.7 Hz, carbene).
Isomer 2 (50%):
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 3.20 (d, 1H,
J = 13.6 Hz, anti allyl-H trans-C), 3.44 (m, 1H, anti allyl-H trans-
P), 3.72 (s, 3H, NCH3), 4.14 (m, 1H, syn allyl-H trans-P), 4.45 (d, 1H,
J = 7.0 Hz, syn allyl-H trans-C), 5.88 (m, 1H, central allyl-H), 6.49
(m, 1H, H7), 6.73 (m, 1H, H6), 6.60-7.94 (18H, Ph, H1, H5, H8).
31P{1H}-NMR (CDCl3, T = 298K, ppm) δ: 26.2
Less abundant isomer (ca. 45%):
1H-NMR (300 MHz, CDCl3, T = 298K, ppm) δ: 2.75 (m, 1H, anti
allyl-H trans-P), 3.08 (d, 1H, J = 13.5 Hz, anti allyl-H trans-C), 4.15
(d, 1H, J = 7.6 Hz, syn allyl-H trans-C), 4.31 (m, 1H, syn allyl-H
trans-P), 5.12 (AB system, 2H, J = 15.0 Hz, NCH2), 5.87 (m, 1H, cen-
tral allyl-H), 6.49 (m, 1H, H7), 6.73 (m, 1H, H6), 7.11-7.64 (21H, Ph,
H3’, H4’, H5’, H1, H5, H8). 8.32 (m, 1H, H2’).
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 38.9 (CH3, NCH3), 67.0
(d, CH2, JCP = 30.5 Hz, allyl trans-P), 69.1 (CH2, allyl trans-C), 121.9
(d, CH, JCP = 4.9 Hz, central allyl), 114.0-133.9 (CH1, CH5, CH6, CH7,
CH8), 165.8 (d, C, JCP = 19.8 Hz, carbene).
31P{1H}-NMR (CDCl3, T = 298K, ppm) δ: 25.8
13C{1H}-NMR (CDCl3, T = 298K, ppm) δ: 56.9 (CH2, NCH2), 67.7
(d, CH2, JCP = 30.3 Hz, allyl trans-P), 68.6 (CH2, allyl trans-C), 121.7
(d, CH, JCP = 4.9 Hz, central allyl), 114.0-154.6 (Py-C, CH1, CH5, CH6,
CH7, CH8), 166.1 (d, C, JCP = 19.7 Hz, carbene).
Anal. Calc. for C29H28ClN2O4PPd: C, 54.31; H, 4.40; N, 4.37.
Found: C, 54.49; H, 4.32; N, 4.47%.
Anal. Calc. for C34H31ClN3O4PPd: C, 56.84; H, 4.35; N, 5.85.
Found: C, 56.70; H, 4.39; N, 5.93%.
4.11.2. Synthesis of complex 6b
Complex 6b was prepared by a procedure analogous to that de-
scribed for 6a starting from 0.0499 g (0.1 mmol) of 5b and 0.0317
g (0.1 mmol) of PPh3.
4.11.4. Synthesis of complex 6e
Complex 6e was prepared by a procedure analogous to that de-
scribed for 6a starting from 0.0546 g (0.2 mmol) of 5e and 0.0421
g (0.2 mmol) of PPh3.
0.0816 g (yield 92%) of 6b was obtained.
Most abundant isomer (ca. 65%):
0.1043 g (yield 99%) of 6e was obtained.
1H-NMR (300 MHz, CD3CN, T = 298K, ppm) δ: 3.27 (d, 1H,
J = 13.5 Hz, anti allyl-H trans-C), 3.45 (m, 1H, anti allyl-H trans-
P), 4.27 (d, 1H, J = 7.4 Hz, syn allyl-H trans-C), 4.49 (m, 1H, syn
allyl-H trans-P), 5.95 (m, 1H, central allyl-H), 6.61-8.29 (23H, Ph,
H4’, H4, H5, H5’, H3, H3’, H6, H6’).
1H-NMR (300 MHz, CDCl3, T = 233K, ppm) δ: 1.90 (s, 3H, o-
aryl-CH3), 1.92 (s, 3H, o-aryl-CH3), 2.39 (s, 3H, p-aryl-CH3), 2.84
(d, 1H, J = 13.3 Hz, anti allyl-H trans-C), 3.47 (m, 1H, anti allyl-H
trans-P), 3.69 (d, 1H, J = 6.4 Hz, syn allyl-H trans-C), 4.39 (m, 1H,
syn allyl-H trans-P), 5.83 (m, 1H, central allyl-H), 6.19-8.10 (22H,
Ar-H).
31P{1H}-NMR (CD3CN, T = 298K, ppm) δ: 27.0
13C{1H}-NMR (CD3CN,
T
=
298K, ppm) δ: 66.5 (d, CH2,
31P{1H}-NMR (CDCl3, T = 233K, ppm) δ: 23.3
13C{1H}-NMR (CDCl3, T = 233K, ppm) δ: 17.9 (CH3, o-mesityl),
18.0 (CH3, o-mesityl), 21.5 (CH3, p- mesityl), 67.4 (d, CH2, JCP = 31.0
Hz, allyl trans-P), 68.9 (CH2, allyl trans-C), 121.7 (d, CH, JCP = 5.0
Hz, central allyl), 114.1-144.1 (Ar-C), 167.7 (d, C, JCP = 20.4 Hz, car-
bene).
JCP = 30.3 Hz, allyl trans-P), 67.8 (CH2, allyl trans-C), 122.0 (d, CH,
JCP = 5.6 Hz, central allyl), 118.1-133.1 (Ph, CH3, CH3’, CH4, CH4’,
CH5, CH5’, C2, C2’, CH6, CH6’), 153.2 (d, C, JCP = 21.3 Hz, carbene).
Anal. Calc. for C32H28ClN2O4PPd: C, 56.74; H, 4.17; N, 4.14.
Found: C, 56.88; H, 4.24; N, 4.04%.
Less abundant isomer (ca. 35%):
1H-NMR (300 MHz, CDCl3, T = 233K, ppm) δ: 1.48 (bs, 6H,
2 o-aryl-CH3), 1.88 (s, 3H, p-aryl-CH3), 2.74 (d, 1H, J = 13.3 Hz,
anti allyl-H trans-C), 3.47 (m, 1H, anti allyl-H trans-P), 4.86 (d, 1H,
J = 6.5 Hz, syn allyl-H trans-C), 4.12 (m, 1H, syn allyl-H trans-P),
5.03 (m, 1H, central allyl-H), 6.19-8.10 (22H, Ar-H).
4.12. Cell viability assays
Cells were grown in accordance with the supplier and main-
tained at 37°C in a humidified atmosphere of 5% carbon dioxide.
Five hundred cells were placed in 96 wells and treated with six
different concentrations (0.001, 0.01, 0.1, 1, 10 and 100μM) of palla-
dium(II) compounds. After 96 hours from the treatment cell viabil-
ity was measured with a CellTiter glow assay (Promega, Madison,
WI, USA) with a Tecan M1000 instrument. IC50 values were calcu-
lated from logistical dose response curves. Averages were obtained
from triplicates and error bars are standard deviations.
31P{1H}-NMR (CDCl3, T = 233K, ppm) δ: 24.0
13C{1H}-NMR (CDCl3, T = 233K, ppm) δ: 18.1 (CH3, o-mesityl),
18.2 (CH3, o-mesityl), 21.4 (CH3, p- mesityl), 67.1 (d, CH2, JCP = 30.1
Hz, allyl trans-P), 68.8 (CH2, allyl trans-C), 121.8 (d, CH, JCP = 5.1
Hz, central allyl), 114.1-144.1 (Ar-C), 167.8 (d, C, JCP = 19.9 Hz, car-
bene).
13

T. Scattolin, G. Andreetta, M. Mauceri et al.
Journal of Organometallic Chemistry 952 (2021) 122014
4.13. Crystal structure determination
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The 4c crystal data were collected at 150K at the XRD2
beamline of the Elettra Synchrotron, Trieste (Italy) [24], using a
˚
monochromatic wavelength of 0.620 A. The data sets were inte-
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in Table S1. Pictures were prepared using Ortep3 [31] and Pymol
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Crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition num-
ber CCDC 2091478. These data can be obtained free of charge via
https://www.ccdc.cam.ac.uk/structures.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
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Acknowledgements
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(2020) 5684–5694.
The authors are grateful to the Associazione Italiana per la
Ricerca sul Cancro-AIRC IG grant (No. 23566 to F. R.).
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