Non-classical N-metallated Pd(II) pincer complexes featuring amino acid pendant arms: Synthesis and biological activity

Article abstract of DOI:10.1016/j.poly.2017.08.019

A series of non-classical pincer ligands with the secondary amide central unit and amino acid pendant arms was obtained from 2-diphenylphosphanyl- and 2-methylsulfanylbenzoic acids and a range of amino acid derivatives (S-methyl-L-cysteine, L-methionine, and L-histidine methyl esters). In addition, the reactions of amino acid-functionalized chloroacetamides with in situ generated Ph₂PSK afforded their counterparts with an aliphatic ligand backbone. All the compounds obtained smoothly underwent direct cyclopalladation upon interaction with PdCl₂(NCPh)₂ under mild reaction conditions, resulting in N-metallated pincer complexes with 5,6- and 6,6-membered fused metallocycles. The realization of κ³-S,N,S-, S,N,N- and S,N,P-coordination was unambiguously confirmed based on the IR and NMR spectroscopic data. In the case of the methionine-based thiophosphorylacetamide derivative, the unexpected selectivity in the formation of one complex diastereomer was observed in solution. The solid-state structures of some of the complexes obtained were also elucidated by X-ray crystallography. The preliminary investigations on cytotoxicity of the resulting palladocycles against HCT116, MCF7, and PC3 human cancer cell lines as well as HEK293 normal cells gave some insight into the structure–activity relationships for this relatively new type of potential anticancer agents. Some of the complexes demonstrated promising cytotoxic effects.

Full text of DOI:10.1016/j.poly.2017.08.019

Accepted Manuscript
Non-classical N-Metallated Pd(II) Pincer Complexes Featuring Amino Acid
Pendant Arms: Synthesis and Biological Activity
Svetlana G. Churusova, Diana V. Aleksanyan, Ekaterina Yu. Rybalkina, Yulia
V. Nelyubina, Alexander S. Peregudov, Zinaida S. Klemenkova, Vladimir A.
Kozlov
PII:
S0277-5387(17)30550-8
DOI:
http://dx.doi.org/10.1016/j.poly.2017.08.019
POLY 12783
Reference:
Polyhedron
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 June 2017
14 August 2017
18 August 2017
Please cite this article as: S.G. Churusova, D.V. Aleksanyan, E. Yu. Rybalkina, Y.V. Nelyubina, A.S. Peregudov,
Z.S. Klemenkova, V.A. Kozlov, Non-classical N-Metallated Pd(II) Pincer Complexes Featuring Amino Acid
Pendant Arms: Synthesis and Biological Activity, Polyhedron (2017), doi: http://dx.doi.org/10.1016/j.poly.
2017.08.019
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1
Non-classical N-Metallated Pd(II) Pincer Complexes Featuring Amino Acid
Pendant Arms: Synthesis and Biological Activity
Svetlana G. Churusova,a Diana V. Aleksanyan,*a Ekaterina Yu. Rybalkina,b Yulia V.
Nelyubina,a,c Alexander S. Peregudov,a Zinaida S. Klemenkova,a Vladimir A. Kozlova
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul.
Vavilova 28, Moscow, 119991 Russia
bInstitute of Carcinogenesis, N. N. Blokhin Russian Cancer Research Center, Kashirskoe sh. 24,
Moscow, 115478 Russia
cKurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
Leninskii pr. 31, Moscow, 117901 Russia
corresponding author: aleksanyan.diana@ineos.ac.ru
Abstract
A series of non-classical pincer ligands with the secondary amide central unit and amino
acid pendant arms was obtained from 2-diphenylphosphanyl- and 2-methylsulfanylbenzoic acids
and a range of amino acid derivatives (S-methyl-L-cysteine, L-methionine, and L-histidine methyl
esters). In addition, the reactions of amino acid-functionalized chloroacetamides with in situ
generated Ph2PSK afforded their counterparts with an aliphatic ligand backbone. All the
compounds obtained smoothly underwent direct cyclopalladation upon interaction with
PdCl2(NCPh)2 under mild reaction conditions, resulting in N-metallated pincer complexes with
5,6- and 6,6-membered fused metallocycles. The realization of κ3-S,N,S-, S,N,N- and S,N,P-
coordination was unambiguously confirmed based on the IR and NMR spectroscopic data. In the
case of the methionine-based thiophosphorylacetamide derivative, the unexpected selectivity in
the formation of one complex diastereomer was observed in solution. The solid-state structures
of some of the complexes obtained were also elucidated by X-ray crystallography. The
preliminary investigations on cytotoxicity of the resulting palladocycles against HCT116, MCF7,
and PC3 human cancer cell lines as well as HEK293 normal cells gave some insight into the
structure–activity relationships for this relatively new type of potential anticancer agents. Some
of the complexes demonstrated promising cytotoxic effects.
Key words: pincer complexes, palladium, functionalized amides, amino acids, cytotoxicity

2
1. Introduction
Nowadays pincer complexes featuring a specific tridentate monoanionic framework with
multiple options for directed structural modifications comprise one of the most actively studied
classes of organometallic and metal-organic compounds.1,2 They attract continuous interest of
researchers owing to enormous potential for use in organic synthesis, catalysis, materials science,
and medicinal chemistry. The rapid development of pincer chemistry, especially, in recent years
gave rise to a variety of non-classical structural scaffolds, which open up new horizons for
investigations. One of these types of non-classical pincer ligands is formed by multidentate
derivatives with the central secondary amide unit, furnishing upon metalation the covalent
metal–nitrogen, in particular, Pd–N bond.3 These ligands can be synthesized by modular
assembling of readily available building blocks – functionalized amines and acids. Furthermore,
their cyclopalladated complexes have been already recommended as efficient (pre)catalysts for
different chemical reactions, including, the Suzuki and Heck cross-coupling, asymmetric allylic
alkylation, etc.4 Palladocycles based on functionalized carboxamides were also found to play a
significant role as intermediates in various Pd-catalyzed C–H functionalization processes.5
Recently, Pd(II) pincer complexes of carboxamides with amino acid residues showed promising
inhibition activity against several human cancer cell lines (Fig. 1). Thus, N,N,X-palladocycles (X
= S, N) derived from 8-aminoquinoline and L-alanine or L-methionine (I, II) exhibited
significant in vitro cytotoxicity against human cervical (HeLa), breast (MCF7), and lung (A549)
cancer.6 Their counterparts based on picolinamides with L-cysteine and L- and D-methionine
residues demonstrated pronounced cytotoxic effects on human colon (HCT116), breast (MCF7),
and prostate (PC3) cancer cell lines, with IC50 values falling in the low micromolar range.7
Noteworthy, complexes I and III with ancillary S-donor groups were found to be much more
active than the reference – cisplatin. In general, cyclometallated complexes (including
cyclopalladated derivatives) are very promising antitumor agents.8,9
Me
Cl
Pd
N
Cl
Pd
N
Cl
Pd
N
Me
S
N
N
NH2
Me
N
S
( )n
∗
X
NH
O
O
O
O
OMe
O
OtBu
X = H, Cl; n = 1, 2
II
III
I
Fig. 1. Cytotoxic Pd(II) pincer complexes based on the amide ligands with amino acid pendant
arms.

3
In continuation of these studies, it seemed interesting to broaden the range of Pd(II) pincer
complexes based on amino acid-functionalized carboxamides in order to evaluate their potential
as anticancer agents. Herein, we report on the synthesis of several new non-classical pincer
ligands with the central amide unit featuring amino acid pendant arms and their cyclopalladated
complexes, which were tested for in vitro cytotoxic activity.
2. Results and Discussion
The preliminary evaluation of cytotoxic properties of picolinamide derivatives III towards
several human cancer and normal cell lines allowed us to outline some structure–activity
regularities, which would be interesting to check for new representatives of this type of potential
anticancer agents. Therefore, upon development of novel pincer ligands with the secondary
amide central unit and amino acid pendant arms, it seemed reasonable to vary the structural
parameters, such as rigidity of the ligand backbone, which would affect the conformational
stability of the resulting complexes, and nature of auxiliary coordination sites (soft and/or hard
donor centers), which would define their kinetic and thermodynamic stability.
Convenient key precursors for the synthesis of novel pincer ligands with the aliphatic
backbone were chloroacetamide derivatives 1a,b, readily available from chloroacetyl chloride
and cysteine or methionine methyl esters, in situ generated from the corresponding
hydrochlorides (Scheme 1). Treatment of 1a,b with Ph2PSK afforded thiophosphoryl-
functionalized carboxamides 2a,b in good yields (Scheme 1). Note that the application of chiral
amino acid predecessors allowed us to obtain the target ligands in enantiomerically pure forms.
H
N
Ph
Ph
S
P
S
O
O
O
Ph2PSH/tBuOK,
THF, 60oC, 2h
L
-MeCysOMe or L-MetOMe,
Et3N, CH2Cl2, 0-5oC, 1 h
H
N
72% (2a)
Cl
( )n
Cl
S
Cl
O
O
H
N
O
O
S
Ph
P
S
Ph
n = 1 (1a), 2 (1b)
O
O
O
70% (2b)
Scheme 1. Synthesis of thiophosphorylacetamide ligands 2a,b.
Functionalized carboxamide ligands with the more rigid backbone were derived from 2-
methylthiosalicyl chloride and amino acids bearing ancillary N- and S-donor groups (S-methyl-L-
cysteine, L-methionine, and L-histidine) (compounds 3a–c, Scheme 2). Interestingly, in the case
of L-histidine derivative, the reaction was complicated by further interaction of ligand 3c with 2-

4
methylthiosalicyl chloride, giving rise to double acylation product 4, which was isolated and
fully characterized by spectroscopic methods and X-ray diffraction (Fig. 2).
SMe
C(O)Cl
L
-MeCysOMe,
L-MetOMe or L-HisOMe
Et3N, CH2Cl2, 0-5oC, 1 h
H
N
H
N
H
N
N
S
S
HN
O
S
O
S
O
S
O
O
O
O
O
O
67% (3a)
81% (3b)
65% (3c)
Scheme 2. Synthesis of methylthiosalicylamide ligands 3a–c.
Fig. 2. General view of compound 4 in representation of atoms via thermal ellipsoids at 50%
probability level.
Counterparts of ligands 3a,b with an ancillary phosphine donor group were synthesized by
the reaction of 2-diphenylphosphanylbenzoic acid with the corresponding amino acid
hydrochlorides upon heating in pyridine using P(OPh)3 as a coupling agent (compounds 5a,b,
Scheme 3).

5
PPh2
COOH
L
-MeCysOMe HCl
or
L-MetOMe HCl,
P(OPh)3, Py, 100oC, 6 h
H
N
H
N
S
S
O
PPh2
O
PPh2
O
O
O
O
40% (5a)
34% (5b)
Scheme 3. Synthesis of diphenylphosphanylbenzamide ligands 5a,b.
Independently of the length of coordination arms and nature of the ancillary donor groups,
all the ligands derived readily underwent direct cyclopalladation upon interaction with
PdCl2(NCPh)2 in dichloromethane solution at room temperature, giving rise to 5,6- and 6,6-
membered pincer complexes 6–8 (Schemes 4–6). In some cases the reactions were found to
proceed more efficiently in the presence of Et3N, which obviates the adverse effect of HCl
liberated upon metalation.
2a,b
PdCl2(NCPh)2,
CH2Cl2, rt, 5 h
Cl
Pd
N
Cl
Pd
N
S
Ph
Ph
S
S
Ph
Ph
S
P
P
O
O
O
O
O
O
72% (6b)
65% (6a)
Scheme 4. Synthesis of complexes 6a,b.
3a-c
PdCl2(NCPh)2, Et3N (in the case of 3c),
CH2Cl2, rt, 5 h
HN
Cl
Pd
N
Cl
Cl
S
S
S
N
S
S
Pd
N
Pd
N
O
O
O
O
O
O
O
O
O
65% (7a)
86% (7b)
94% (7c)
Scheme 5. Synthesis of complexes 7a–c.

6
5a,b
PdCl2(NCPh)2,
Et3N, CH2Cl2, rt, 5 h
Ph
P
Ph
P
Cl
Cl
S
Pd
Ph
Ph
S
Pd
N
N
O
O
O
O
O
O
75% (8b)
95% (8a)
Scheme 6. Synthesis of complexes 8a,b.
Complexes 6–8 are moisture- and air-resistant brightly colored crystalline solids. The
realization of κ3-S,N,S-, S,N,N- and S,N,P-coordination was unambiguously confirmed based on
the IR and NMR spectroscopic data. Thus, the 1H NMR spectra of all the complexes obtained
lack the signals of the amide NH protons. Their IR spectra also did not show the absorption
bands characteristic for the stretching and bending vibrations of the amide NH moiety.
Furthermore, the C=O bond stretching vibrations of the amide group are strongly shifted to the
lower frequencies relative to the corresponding absorption bands of the free ligands (∆ν = 36–
122 cm–1). All this clearly indicates the occurrence of metalation at the central secondary amide
unit. The coordination of the ancillary sulfide donor groups in all the palladocycles under
consideration (either in the acid or in the amine part of the ligands) is evident from the downfield
shifts of the signals of SMe hydrogen and carbon nuclei in the 1H and 13C NMR spectra
compared to those of the free ligands (∆δH = 0.26–0.68 ppm, ∆δC = 2.45–11.35 ppm). The
complexation of the imidazole moiety in compound 7c is supported by strong downfield shifts of
the NH proton signal and the signal of H(C9) proton, situated between two nitrogen centers (∆δH
~ 4.2 and 0.4 ppm, respectively). The coordination of the phosphorus-containing donor groups in
complexes 6a,b and 8a,b is confirmed by downfield shifts of the phosphorus resonances in the
31P NMR spectra relative to the spectra of the corresponding ligands, which comprise ~2.7–4.0
ppm in the case of thiophosphoryl-containing derivatives and reach up to 36.3 ppm for the
phosphine-substituted counterparts. In addition, the coordination of the thiophosphoryl group in
complexes 6a,b is supported by a strong low-frequency displacement of the P=S stretching
vibrations in the IR spectra (∆ν = 109 and 123 cm–1 for complexes 6a and 6b, respectively).
An important feature of the complexes under consideration, which merits special
discussion, is their possibility to exist in different diastereomeric forms, which arises from the
presence of the chiral carbon center and the coordinated thioether group. Earlier we have
observed the formation of such diastereomers in solutions of the related picolinamide derivatives
(complexes III in Fig. 1), which was expressed in a double set of signals in the 1H and 13C NMR

7
spectra.7 The additional ROESY experiment confirmed that the isomers differed in the
disposition of the methyl substituent at the sulfur atom and the substituents at the chiral carbon
center relative to the main molecular plane. Similarly, the 1H and 13C NMR spectra of histidine-
based S,N,N-complex 7c also showed a double set of signals (well-resolved already at room
temperature), which correspond to two diastereomers in approximately 3:1 ratio (see
Experimental section). In the case of its S,N,S-counterparts 7a,b, which have two different
coordinated SMe groups, the expected spectral patterns must be essentially complicated due to
possibility of the existence of four diastereomeric forms. While the 1H NMR spectrum of 5,6-
membered complex 7a in CDCl3 at room temperature contained broadened unresolved signals
(Fig. S1 in Supplementary data), cooling to –30 °C indeed resulted in the resolution of the
signals of all four possible isomers. Figure 3 presents the extended fragment of the 1H NMR
spectrum of 7a at the lower temperature in the region of SMe proton signals of the amino acid
pendant arm, which shows four distinct singlet signals of the isomers designated as A, B, C, and
D. Figures S2–S10 in Supplementary data demonstrates the 1H, 13C, and HMQC NMR spectra of
palladocycle 7a in CDCl3 at –30 °C. For 6,6-membered complex 7b based on the methionine
derivative, having more conformationally flexible structure, even cooling to –30 °C does not
afford full resolution of the spectrum. Figure 4 depicts the extended fragment of the 1H NMR
spectrum of 7b at –30 °C in the region of H(C6) proton signals (the signals of the proton situated
in the ortho-position relative to the C(O)N moiety). It is obvious that only one of four
diastereomers affords a resolved doublet signal. Therefore, the 1H and 13C NMR spectra of 7b
cannot be reliably assigned (see Figs. S11–S19 in Supplementary data). As for S,N,P-complex
8b, the 1H and 13C NMR spectra at room temperature show one set of distinct, well-resolved
signals, which testifies that the interconversion between its isomers is rapid on the NMR time
scale at room temperature. In the case of its cysteine-based counterpart 8a, such a dynamic
transformation is slower, which is evident, for example, from the significantly broadened signals
of the CH2 protons, falling under the signals of SMe and OMe protons (Fig. S20 in
Supplementary data). Furthermore, its 13C NMR spectrum showed mainly the signals of the
aromatic carbon nuclei, while most of the aliphatic carbon resonances (except for OMe group
signal) were not observed (Fig. S21). The variable-temperature 1H NMR studies in CDCl3
revealed that heating to 50 °C essentially facilitates the interconversion of the isomers, but the
resolution of the CH2 proton signals is still limited (Fig. S22). In contrast, cooling to –30 °C
afforded fully resolved signals of two diastereomers, which ratio composed ~3:2 (Figs. S23 and
S24). Figures S25–S33 present the 1H, 13C, COSY, and HMQC NMR spectra of complex 8a in
CDCl3 at –30 °C. The most interesting behavior was observed in the case of thiophosphoryl-
functionalized complexes 6a,b. Both of the complexes demonstrated two signals in the 31P NMR

8
spectra in CDCl3 at room temperature, however, only cysteine-based derivative 6a afforded
resolved signals in the 1H and 13C NMR spectrum (for the 31P and 1H NMR spectra of complex
6b in CDCl3 at room temperature see Fig. S34 in Supplementary data). Cooling of a solution of
6b in CDCl3 to –30 °C unexpectedly disclosed that the content of the minor component
composes only 8% (Fig. S35), thus suggesting the preferential formation of one of the
diastereomers. This property of Pd(II) pincer complexes based on functionalized carboxamide
ligands can be further used in catalysis.
Fig. 3. Extended fragment of the 1H NMR spectrum of complex 7a in CDCl3 at –30°C
(AlkSMe proton region).

9
Fig. 4. Extended fragment of the 1H NMR spectrum of complex 7b in CDCl3 at –30 °C
(H(C6) proton region).
The structures of complexes 6b, 7a, 7b, 8a, and 8b were also ascertained by X-ray
diffraction analysis of their single crystals (Figs. 5a–e). Note that compound 8b (Fig. 5e) actually
represents a crystallosolvate with water, having two symmetry-independent molecules of the
complex. According to the results obtained, the coordination environment of the palladium atom
is almost square-planar in the phosphorus-containing derivatives 6b and 8a,b. At the same time,
in S,N,S-complexes 7a and 7b there is a slight bent along the S(1)…S(2) line with the
corresponding angles being equal to 170.2 and 167.3°, respectively. This is likely to be explained
by the less flexible structure of the six-membered metallocycle involving the thiosalicylamide
fragment (in 7a,b) compared to that formed by the thiophosphorylacetamide moiety (in 6b), on
the one hand, and the shorter length of the C(2)–S(2) bond in 7a,b compared to the length of the
C(2)–P(1) bond in complexes 8a,b, on the other hand. The differences in the degree of flexibility
of the ligand backbones are also reflected in conformations of the resulting metallocycles. In
complexes 7a,b and 8a,b, the six-membered palladocycles formed by the aromatic acid
components adopt twist conformations in all cases, although the atoms deviating the most differ
depending on the ancillary donor atom (S vs P): S(2) (1.28–1.84 Å) and C(2) (0.41–0.86 Å) in
7a,b and Pd(1) (up to 1.65 Å) and N(1) (0.31–0.50 Å) in 8a,b. At the same time, the
corresponding metal-containing ring in complex 6b (involving CH2P(S) unit) adopts a boat
conformation with the deviation of Pd(1) and C(1) atoms by 1.12 and 0.76 Å, respectively. The
conformation of the second metallocycle, formed by the amino acid pendant arm, depends on its
size and varies from an envelope (in the case of five-membered rings in 7a and 8a with atoms
C(8) or N(1) deviating by 0.56 or 0.70 Å, respectively) to a twist (in the case of six-membered
rings in complexes 6b, 7b, and 8b). For the latter, the following pairs of atoms deviate the most:
N(1) (0.79 Å) and C(9) (0.80 Å) in 7b, N(1) (0.73 Å) and C(4)/C(5) (0.83/0.60 Å) in 6b
(depending on whether major or minor component of MeS(CH2)2COOMe disordered moiety is
considered), and S(1) (0.69–0.78 Å) and C(8)/C(10) (1.25–1.87 Å) in 8b (the data for two
symmetry-independent complex molecules featuring slightly different geometries).

10
a
b
c
d
e
Fig. 5. General views of complexes 6b (a), 7a (b), 7b (c), 8a (d), and 8b (e) in representation of
atoms via thermal ellipsoids at 50% probability level.
The antiproliferative activity of the complexes obtained was tested against several human
cancer cell lines as well as normal human embryonic kidney cells (HEK293) using the
conventional method based on MTT reduction. Cisplatin from a commercial source served as a
positive control. Table 1 presents the concentrations of the compounds required to inhibit the
cellular survival fraction to 50% (IC50) after exposure for 48 h. As can be seen, thiophosphoryl-
functionalized complexes 6a,b did not exhibit cytotoxic effects even at the concentration of 100

11
µM (Table 1, entries 1–2). Thiosalicylamide derivative 7c based on L-histidine was also nontoxic
at such a high concentration (entry 5). At the same time, its S,N,S-counterparts 7a,b displayed
moderate activity against HCT116 and PC3 cancer cells, exceeding in efficiency the reference
(cisplatin). The differences observed in the activities of complexes 7a,b and 7c are in good
agreement with our earlier assumption about a crucial role of amino acids bearing S-donor
ancillary groups in the cytotoxicity of the related Pd(II) pincer complexes based on picolinamide
derivatives (compounds III in Fig. 1). However, complexes 7a,b demonstrated only low
cytotoxicity towards MCF7 cancer lineage and markedly affected normal HEK293 cells. As for
κ3-S,N,P-palladocycles with the phosphine ancillary donor group, both of the complexes
exhibited pronounced cytotoxic effects on all the cancer cell lines under consideration (Table 1,
entries 6, 7). The values of IC50 achieved with these compounds fall within the low micromolar
range, which make them commensurable with most of picolinamide derivatives III. In addition,
these complexes essentially outperformed in activity the clinically used drug – cisplatin.
Interestingly, the structure–activity relationships observed for palladocycles III were generally
reproduced in the case of complexes 8a,b. Thus, the latter also displayed higher cytotoxicity
against colon cancer cells, indicating their selectivity towards this particular cancer lineage. As
well as in the case of complexes III, a reduction in the size of one of the fused metallocycles
(cysteine vs methionine derivatives) negatively influenced the cytotoxic activity against MCF7
and PC3 cancer cell lines, although had no effect on HCT116 cancer cells. It is also noteworthy
that complexes 8a,b were less toxic to normal cells (HEK293) than to HCT116 and PC3 cancer
cell lines. Thus, S,N,P-complexes 8a,b as well as their picolinamide counterparts III have
potential value as anticancer agents. In summary it can be concluded that the nature of an acid
component in the ligand backbone is of particular importance for the cytotoxic activity of Pd(II)
pincer complexes based on carboxamides with amino acid pendant arms.
Table 1. Cytotoxic effects of the cyclopalladated complexes under consideration
on some human cell lines (IC50/µM)
Cancer cell lines
HCT116
>100
>100
30 4.2
Normal cell line
HEK293
>100
>100
45 7
Entry Compound
MCF7
PC3
>100
>100
26
46
>100
5 1.5
13.5 1.5
120.0
>100
>100
90
1
2
3
4
5
6
7
8
6a
6b
7a
7b
7c
8a
8b
Cisplatin
4
2
40
6
100
55 5
>100
>100
2 1
2 0.5
400.0
>100
16 4
30 8
25.0
8
1
25 5
28.0

12
3. Conclusions
To summarize the results presented, a series of non-classical pincer ligands based on
functionalized carboxamides with amino acid pendant arms were prepared from readily available
precursors. The direct cyclopalladation of the ligands obtained was accomplished under mild
reaction conditions, leading to new representatives of N-metallated Pd(II) pincer complexes,
featuring 5,6- and 6,6-membered fused metallocycles and ancillary P-, N- and S-donor groups. In
the case of the methionine-based thiophosphorylacetamide derivative, the unexpected
diastereoselectivity was observed in solution. The preliminary evaluation of cytotoxicity of the
resulting complexes against several human cancer cell lines allowed us to confirm some
structure–activity relationships observed previously for the related picolinamide derivatives with
amino acid pendant arms. Some of the palladocycles from this study showed an appreciable level
of cytotoxic efficiency. Therefore, further search for anticancer agents among this type of non-
classical N-metallated Pd(II) pincer complexes seems to be reasonable.
4. Experimental
4.1. General remarks
Unless otherwise mentioned, all manipulations were carried out without taking precautions
to exclude air and moisture. Dichloromethane was distilled over P2O5. Tetrahydrofuran was
distilled over sodium benzophenone ketyl. S-Methyl-L-cysteine methyl ester hydrochloride was
obtained from L-cysteine methyl ester hydrochloride via sequential treatment with di-tert-butyl
dicarbonate,10 methyl iodide,11 and acetyl chloride.12 L-Methionine methyl ester hydrochloride
was prepared by the esterification of L-methionine under action of dimethylsulfite, in situ
generated by the reaction of SOCl2 with an excess of methanol at low temperature.13 N-
Chloroacetyl-L-methionine methyl ester 1b was synthesized by the reaction of sodium salt of L-
methionine with ClCH2C(O)Cl14 followed by the esterification with methanol using a catalytic
amount of hydrochloric acid.15 2-(Methylsulfanyl)benzoyl chloride was derived from
thiosalicylic acid via methylation with MeI16 followed by treatment with SOCl2.17 2-
(Diphenylphosphanyl)benzoic acid was synthesized from 2-chlorobenzoic acid, PPh3, and
sodium.18 All other chemicals and solvents were used as purchased.
NMR spectra were recorded on Bruker AV-300, AV-400 and AV-600 spectrometers, and
the chemical shifts (δ) were referenced internally by the residual solvent signals relative to
tetramethylsilane (1H, 13C) or externally to H3PO4 (31P). In most cases, 13C{1H} NMR spectra
were registered using the JMODECHO mode; the signals for the C nuclei bearing odd and even
numbers of protons have opposite polarities. The assignment of the NMR spectra of the

13
compounds obtained was carried out based on 1H, 13C{1H}, 1H–1H-COSY and HMQC
experiments and the data obtained previously for the related compounds.4a,7
IR spectra were recorded on a Nicolet Magna-IR750 FT-spectrometer, resolution 2 cm–1,
128 scans. The assignment of absorption bands in the IR spectra was made according to Ref.19
Column chromatography was carried out using Macherey-Nagel silica gel 60 (MN Kieselgel 60,
70–230 mesh). Melting points were determined with an MPA 120 EZ-Melt Automated Melting
Point Apparatus (Stanford Research Systems).
4.2. Syntheses
4.2.1. Methyl (2R)-2-[(chloroacetyl)amino]-3-(methylsulfanyl)propanoate 1a
H
N
S
Cl
O
O
O
A solution of triethylamine (3.50 mL, 0.025 mol) in CH2Cl2 (6 mL) was added dropwise to
a stirred suspension of S-methyl-L-cysteine methyl ester hydrochloride (1.86 g, 0.010 mol) in
CH2Cl2 (25 mL) at –5 °С under an argon atmosphere. The reaction mixture was stirred for 30
min. Then, a solution of ClCH2C(O)Cl (1.35 g, 0.012 mol) in CH2Cl2 (5 mL) was added
dropwise. The resulting mixture was stirred at 0–5 °С for 1 h and poured into distilled water (75
mL). The organic layer was separated, sequentially washed with a dilute aqueous solution of
hydrochloric acid, saturated aqueous solution of NaHCO3, and water, and dried over anhydrous
Na2SO4. The solvent was removed under vacuum. The resulting residue was purified by column
chromatography on silica gel (eluent CHCl3–MeOH (75:1)) to give 2.13 g of compound 1a as a
white crystalline solid. Yield: 94%. Mp: 65–67 °С. 1Н NMR (300.13 MHz, CDCl3): δ 2.15 (s,
3Н, SMe), 3.01–3.04 (m, 2H, CH2S), 3.81 (s, 3H, OMe), 4.13 (s, 2H, CH2Cl), 4.82–4.88 (m, 1H,
CH), 7.42 (br s, 1H, NH) ppm. Anal. Calcd for C7H12ClNO3S: C, 37.25; H, 5.36; N, 6.21. Found:
С, 37.35; Н, 5.40; N, 6.14%.
4.2.2. General procedure for the synthesis of ligands 2a,b
A solution of Ph2P(S)H (0.50 g, 2.29 mmol) in THF (10 mL) was added dropwise to a
stirred suspension of tBuOK (0.28 g, 2.50 mmol) in THF (10 mL) under an argon atmosphere. In
30 min, the reaction mixture was cooled to 10 °С, and then a solution of the corresponding
chloroacetamide 1a,b (2.29 mmol) in THF (10 mL) was added dropwise. The reaction mixture
was stirred at 60 °С for 2 h. After cooling to room temperature, the resulting mixture was poured
into distilled water (50 mL). The desired product was extracted with chloroform. The organic
layer was separated, dried over anhydrous Na2SO4, and evaporated to dryness. The resulting
residue was purified by column chromatography on silica gel (eluent: CHCl3–MeOH (100:1)

14
(2a), CH2Cl2 (2b)) to give the desired ligands as pinkish (2a) or white (2b) crystalline solids.
Note that an analytically pure sample of compound 2a was obtained after additional purification
by thin-layer chromatography on silica gel plates (eluent Et2O).
4.2.2.1. Methyl (2R)-2-{[(diphenylthiophosphoryl)acetyl]amino}-3-(methylsulfanyl)propanoate
2a
H
N
Ph
Ph
S
P
S
O
O
O
Yield: 0.67 g (72%). Mp: 100–102 °С. 31P{1H} NMR (121.49 MHz, CDCl3): δ 37.56 ppm.
1Н NMR (300.13 MHz, CDCl3): δ 2.07 (s, 3Н, SMe), 2.88 (d, 2H, CH2S, 3JHH = 5.8 Hz), 3.60–
3.65 (m, 2H, CH2P(S)), 3.71 (s, 3H, OMe), 4.75 (dt, 1H, CH, 3JHH = 7.3 Hz, 3JHH = 5.8 Hz),
7.52–7.60 (m, 6H, HAr), 7.87–7.96 (m, 4H, HAr), 8.05 (br d, 1H, NH, 3JHH = 7.3 Hz) ppm.
13C{1H} NMR (100.61 MHz, CDCl3): δ 15.79 (s, SMe), 35.70 (s, CH2S), 41.54 (d, CH2P(S), 1JCP
= 46.2 Hz), 51.90 and 52.05 (both s, OMe and CH), 128.51 (d, m-C in P(S)Ph2, 3JCP = 12.8 Hz),
130.81 (d, o-C in P(S)Ph, 2JCP = 11.0 Hz), 130.97 (d, o-C in P(S)Ph, 2JCP = 10.6 Hz), 131.71 (d,
p-C in P(S)Ph, 4JCP = 3.3), 131.76 (d, p-C in P(S)Ph, 4JCP = 3.3 Hz), 164.03 (d, C(O)NH, 2JCP
=
4.0 Hz), 170.32 (s, C(O)OMe) ppm (the signals of ipso-С nuclei in P(S)Ph2 were not observed).
IR (KBr, ν/cm–1): 445(vw), 485(w), 496(w), 577(w), 614(w), 628(w), 668(w), 693(m), 706(m)
(νP=S), 736(w), 746(w), 805(w), 829(vw), 859(w), 897(vw), 974(vw), 1027(vw), 1107(m),
1139(w), 1168(w), 1213(m), 1250(vw), 1340(w), 1412(w), 1437(m), 1540(br, m) (C(O)NH),
1645(s) (νC=O in C(O)NH), 1738(m) (νC=O in C(O)OMe), 2907(vw), 2954(vw), 3052(vw),
3271(br, m) (νNH). Anal. Calcd for C19H22NO3PS2: C, 56.00; H, 5.44; N, 3.44. Found: С, 56.30;
Н, 5.41; N, 3.46%.
4.2.2.2. Methyl (2S)-2-{[(diphenylthiophosphoryl)acetyl]amino}-4-(methylsulfanyl)butanoate 2b
H
S
N
O
Ph
Ph
P
S
O
O
Yield: 0.68 g (70%). Mp: 98–100 °С. 31P{1H} (121.49 MHz, CDCl3): δ 37.91 ppm. 1Н
NMR (300.13 MHz, CDCl3): δ 1.93–2.09 (m, 2Н, СН2), 2.03 (s, 3Н, SMe), 2.34 (t, 2H, CH2S,
3JHH = 7.5 Hz), 3.51–3.69 (m, 2H, CH2P(S)), 3.72 (s, 3H, OMe), 4.64–4.71 (m, 1H, CH), 7.51–
7.61 (m, 6H, HAr), 7.83–7.99 (m, 5H, NH + HAr) ppm. 13C{1H} (75.47 MHz, CDCl3): δ 15.16 (s,
SMe), 29.50 (s, CH2), 31.28 (s, CH2S), 41.56 (d, CH2P(S), 1JCP = 45.6 Hz), 51.66 and 52.29
(both s, OMe and CH), 128.78 (d, m-C in P(S)Ph2, 3JCP = 12.6 Hz), 130.75 (d, o-С in P(S)Ph,
2JCP = 11.0 Hz), 131.17 (d, o-С in P(S)Ph, 2JCP = 11.0 Hz), 131.94 (d, p-С in P(S)Ph, 4JCP = 2.7
Hz), 132.13 (d, p-C in P(S)Ph, 4JCP = 2.7 Hz), 163.92 (d, C(O)NH, 2JCP = 3.8 Hz), 171.50 (s,

15
C(O)OMe) ppm (the signals of ipso-С nuclei in P(S)Ph2 were not observed). IR (KBr, ν/cm–1):
487(w), 588(vw), 609(vw), 688(w), 707(m) (νP=S), 744(w), 802(vw), 844(w), 935(vw), 991(w),
1073(vw), 1104(w), 1140(w), 1172(w), 1196(w), 1213(m), 1353(m), 1406(w), 1435(m),
1556(br, m) (C(O)NH), 1636(s) (νC=O in C(O)NH), 1738(m) (νC=O in C(O)OMe), 2944(vw),
3055(vw), 3270(br, m) (νNH). Anal. Calcd for C20H24NO3PS2: C, 56.99; H, 5.74; N, 3.32.
Found: С, 56.95; Н, 5.55; N, 3.40%.
4.2.3. General procedure for the synthesis of ligands 3a–c
A solution of triethylamine (1.60 mL, 11.50 mmol) in CH2Cl2 (5 mL) was added dropwise
to a stirred suspension of the corresponding amino acid methyl ester hydrochloride (3.75 mmol)
in CH2Cl2 (10 mL) at –5 °С under an argon atmosphere. The reaction mixture was stirred for 30
min. Then, a solution of 2-(methylsulfanyl)benzoyl chloride (0.70 g, 3.75 mmol) in CH2Cl2 (10
mL) was added dropwise. The resulting mixture was stirred at 0–5 °С for 1 h and poured into
distilled water (75 mL). The organic layer was separated, sequentially washed with a dilute
aqueous solution of hydrochloric acid, saturated aqueous solution of NaHCO3, and water, and
dried over anhydrous Na2SO4. The solvent was removed under vacuum. The resulting residue
was purified by column chromatography on silica gel (eluent: CH2Cl2–MeOH (100:1) (3a,b),
EtOAc–acetone (1:2) (3c)) to give ligands 3a–c as white crystalline solids. In the case of
histidine derivative 3c, the product of double acylation (compound 4) was also isolated.
4.2.3.1. Methyl (2R)-3-(methylsulfanyl)-2-{[2-(methylsulfanyl)benzoyl]amino}propanoate 3a
5
4
3
6
1
H
N
S
2
O
S
O
O
Yield: 0.75 g (67%). Mp: 75–77 °С. 1Н NMR (400.13 MHz, CDCl3): δ 2.16 (s, 3Н,
AlkSMe), 2.49 (s, 3H, ArSMe), 3.04–3.18 (m, 2H, CH2S), 3.81 (s, 3H, OMe), 5.03–5.08 (m, 1H,
CH), 7.22 (dt, 1H, Н(C4), 3JHH = 7.4 Hz, 4JHH = 1.0 Hz), 7.30 (br d, 1H, NH, 3JHH = 6.8 Hz),
7.34 (d, 1H, Н(C3), 3JHH = 7.4 Hz), 7.40–7.44 (m, 1H, Н(C5)), 7.65 (dd, 1H, Н(C6), 3JHH = 7.6
Hz, 4JHH = 1.2 Hz) ppm. 13C{1H} NMR (100.61 MHz, CDCl3): δ 16.19 and 16.63 (both s,
AlkSMe and ArSMe), 36.29 (s, CH2S), 52.04 and 52.53 (both s, OMe and СН), 125.01 (s, C5),
127.19 (s, С3), 128.54 (s, С6), 130.96 (s, C4), 133.60 (s, С1), 137.61 (s, С2), 167.38 (s,
C(O)NH), 171.13 (s, C(O)OMe) ppm. IR (KBr, ν/cm–1): 466(vw), 507(vw), 554(vw), 630(w),
697(w), 740(m), 915(w), 966(vw), 1000(w), 1044(vw), 1066(vw), 1110(vw), 1180(w), 1228(w),
1251(m), 1298(m), 1335(w), 1420(w), 1435(m), 1466(w), 1534(br, m) (C(O)NH), 1570(w),
1586(w), 1650(s) (νC=O in C(O)NH), 1728(sh, m) and 1737(s) (both νC=O in C(O)OMe),

16
2916(w), 3281(br, m) (νNH). Anal. Calcd for C13H17NO3S2: C, 52.15; H, 5.72; N, 4.68. Found:
С, 52.25; Н, 5.84; N, 4.70%.
4.2.3.2. Methyl (2S)-4-(methylsulfanyl)-2-{[2-(methylsulfanyl)benzoyl]amino}butanoate 3b
5
4
3
6
1
H
N
S
2
O
S
O
O
Yield: 0.95 g (81%). Mp: 86–88 °С. 1Н NMR (400.13 MHz, CDCl3): δ 2.07–2.16 (m, 1H,
CH2), 2.12 (s, 3Н, AlkSMe), 2.27–2.36 (m, 1H, CH2), 2.48 (s, 3H, ArSMe), 2.58–2.69 (m, 2H,
CH2S), 3.79 (s, 3H, OMe), 4.91–4.96 (m, 1H, CH), 7.12 (br d, 1H, NH, 3JHH = 7.2 Hz), 7.21 (dt,
1H, Н(C4), 3JHH = 7.6 Hz, 4JHH = 1.0 Hz), 7.32 (d, 1H, Н(C3), 3JHH = 7.6 Hz), 7.39–7.43 (m, 1H,
Н(C5)), 7.60 (d, 1H, Н(C6), 3JHH = 7.6 Hz) ppm. 13C{1H} (100.61 MHz, CDCl3): δ 15.32 and
16.54 (both s, AlkSMe and ArSMe), 29.84 (s, CH2), 31.64 (s, CH2S), 51.86 and 52.42 (both s,
OMe and СН), 125.00 (s, C5), 126.98 (s, С3), 128.48 (s, С6), 130.84 (s, C4), 133.94 (s, С1),
137.15 (s, С2), 167.42 (s, C(O)NH), 172.14 (s, C(O)OMe) ppm. IR (KBr, ν/cm–1): 469(vw),
546(vw), 658(w), 709(vw), 736(w), 784(vw), 888(vw), 928(vw), 958(vw), 1017(w), 1044(w),
1066(vw), 1155(w), 1218(w), 1235(m), 1259(w), 1296(w), 1313(w), 1332(m), 1352(vw),
1433(m), 1443(sh, w), 1464(vw), 1529(br, s) (C(O)NH), 1568(vw), 1585(w), 1633(s) (νC=O in
C(O)NH), 1739(s) (νC=O in C(O)OMe), 2841(vw), 2916(w), 2947(w), 2972(w), 3301(br, m)
(νNH). Anal. Calcd for C14H19NO3S2: C, 53.65; H, 6.11; N, 4.47. Found: С, 53.59; Н, 6.14; N,
4.44%.
4.2.3.3. Methyl (2S)-3-(1H-imidazol-4-yl)-2-{[2-(methylsulfanyl)benzoyl]amino}propanoate 3c
5
4
3
6
1
H
N
N
7
9
2
HN
O
S
8
O
O
Yield: 0.78 g (65%). Mp: 122–124 °С (EtOAc). 1Н NMR (300.13 MHz, CDCl3): δ 2.44 (s,
3Н, SMe), 3.25 (d, 2H, CH2, 3JHH = 5.1 Hz), 3.74 (s, 3H, OMe), 4.99–5.05 (m, 1H, CH), 6.84 (s,
1H, Н(C8)), 7.16–7.21 (m, 1H, Н(C4)), 7.29–7.32 (m, 2H, Н(C3) + NH), 7.40 (t, 1H, Н(C5),
3JHH = 7.7 Hz), 7.53 (s, 1H, Н(C9)), 7.57 (d, 1H, Н(C6), 3JHH = 7.7 Hz), 7.74 (br d, 1H, NHC(O),
3JHH = 7.7 Hz) ppm. 13C{1H} (75.47 MHz, CDCl3): δ 16.28 (s, SMe), 29.03 (s, CH2), 52.39 and
52.77 (both s, OMe and CH), 116.38 (s, C8), 124.73 (s, C5), 126.46 (s, C3), 128.12 (s, С6),
130.84 (s, C4), 133.66 (s, C1 + C7), 135.00 (s, С9), 138.10 (s, С2), 167.98 (s, C(O)NH), 171.75
(s, C(O)OMe) ppm. IR (KBr, ν/cm–1): 520(vw), 545(vw), 625(m), 647(w), 747(m), 757(w),

17
810(w), 920(vw), 985(vw), 1033(w), 1064(w), 1172(m), 1219(m), 1256(m), 1290(w), 1317(w),
1351(w), 1433(m), 1467(w), 1528(br, s) (C(O)NH), 1569(vw), 1586(w), 1648(s) (νC=O in
C(O)NH), 1743(s) (νC=O in C(O)OMe), 2915(w), 3102(w), 3313(s) (νNH). Anal. Cacld for
C15H17N3O3S: C, 56.41; H, 5.37; N, 13.16. Found: С, 56.62; Н, 5.30; N, 13.24%.
4.2.3.4. Methyl (2S)-2-{[2-(methylsulfanyl)benzoyl]amino}-3-{1-[2-(methylsulfanyl)benzoyl]-
1H-imidazol-4-yl}propanoate 4
5
4
3
6
1
14
H
N
N
13
12
15
10
9
2
7
N
O
S
11
8
O
O
S
O
Yield: 0.18 g (20%). Mp: 160–162 °С (CHCl3–Et2O). 1Н NMR (300.13 MHz, CDCl3): δ
2.49 and 2.50 (both s, 3Н + 3H, SMe), 3.31 (d, 2H, CH2, 3JHH = 5.0 Hz), 3.83 (s, 3H, OMe), 5.16
(dt, 1H, CH, 3JHH = 7.5 Hz, 3JHH = 5.0 Hz), 7.24 (t, 1H, НAr), 7.30–7.37 (m, 2H, НAr), 7.43–7.49
(m, 3H, HAr + H(C8)), 7.57–7.66 (m, 4H, HAr + NH), 7.86 (s, 1H, Н(C9)) ppm. 13C{1H} (100.61
MHz, CDCl3): δ 16.34 and 16.54 (both s, SMe), 29.65 (s, CH2), 52.06 and 52.36 (both s, OMe
and CH), 114.90 (s, C8), 124.65 and 124.98 (both s, C5 and C14), 126.57 and 127.69 (both s, C3
and C12), 128.16 and 128.70 (both s, С6 and C15), 130.67 (s, C4), 131.72 (s, С1 or C10), 132.10
(s, C13), 133.82 (s, С10 or C1), 138.01 and 138.83 (both s, C2 and C11), 139.51 (s, C7), 164.79
(s, C(O)N), 167.48 (s, C(O)NH), 171.45 (s, C(O)OMe) ppm (the signal of C9 carbon nucleus
was not observed). IR (KBr, ν/cm–1): 465(vw), 646(vw), 715(vw), 742(w), 754(m), 867(vw),
901(m), 969(w), 1021(w), 1065(vw), 1100(vw), 1135(w), 1179(w), 1218(m), 1241(m), 1286(m),
1309(w), 1362(w), 1383(m), 1435(m), 1464(w), 1488(w), 1544(br, m) (C(O)NH), 1586(m),
1657(s) (νC=O in C(O)N and C(O)NH), 1715(s) and 1747(s) (both νC=O in C(O)OMe),
2843(vw), 2921(vw), 3047(vw), 3130(w), 3233(br, w) (νNH). Anal. Calcd for C23H23N3O4S2: C,
58.83; H, 4.94; N, 8.95. Found: С, 58.58; Н, 4.74; N, 8.86%.
4.2.4. General procedure for the synthesis of ligands 5a,b
Triphenylphosphite (2.25 g, 7.25 mmol) was added portionwise to a stirred mixture of the
corresponding amino acid methyl ester hydrochloride (7.15 mmol), 2-
(diphenylphosphanyl)benzoic acid (2.19 g, 7.15 mmol), and pyridine (30 mL) at 100 °С under an
argon atmosphere. The reaction mixture was stirred at this temperature for 6 h. The excess of
pyridine was removed under vacuum. The resulting residue was dissolved in chloroform, washed
with water (3 times), saturated aqueous solution of NaHCO3 (3 times), and again with water (2
times). The organic layer was separated, dried over anhydrous Na2SO4, and evaporated to

18
dryness. The resulting residue was purified by column chromatography on silica gel (eluent
EtOAc–hexane (1:2)) to give ligands 5a,b as white crystalline solid.
4.2.4.1. Methyl (2R)-2-{[2-(diphenylphosphanyl)benzoyl]amino}-3-(methylsulfanyl)propanoate
5a
5
4
3
6
1
H
N
S
2
O
PPh2
O
O
Yield: 1.25 g (40%). Mp: 105–108 °С. 31P{1H} (121.49 MHz, CDCl3): δ –9.31 ppm. 1Н
NMR (400.13 MHz, CDCl3): δ 2.11 (s, 3Н, SMe), 2.93 (d, 2H, CH2, 3JHH = 5.0 Hz), 3.79 (s, 3H,
OMe), 4.92 (dt, 1H, CH, 3JHH = 7.6 Hz, 3JHH = 5.0 Hz), 6.87 (br d, 1H, NH, 3JHH = 7.6 Hz), 7.02
(ddd, 1H, H(C3), 3JHH = 7.7 Hz, 3JHP = 4.0 Hz, 4JHH = 0.8 Hz), 7.29–7.39 (m, 11H, HAr), 7.43 (dt,
1H, H(C5), 3JHH = 7.5 Hz, 4JHH = 1.2 Hz), 7.70 (ddd, 1H, Н(C6), 3JHH = 7.5 Hz, 4JHP = 3.8 Hz,
4JHH = 1.2 Hz) ppm. 13C{1H} NMR (100.61 MHz, CDCl3): δ 16.33 (s, SMe), 36.45 (s, CH2S),
52.04 and 52.64 (both s, OMe and CH), 127.66 (d, C3, 2JCP = 4.6 Hz), 128.53 (d, m-C in PPh,
3JCP = 6.9 Hz), 128.58 (d, m-C in PPh, 3JCP = 6.8 Hz), 128.62 (s, C4 or C5), 128.75 and 128.78
(both s, p-C in PPh2), 130.60 (s, C5 or C4), 133.79 (d, o-C in PPh, 2JCP = 3.8 Hz), 133.99 (d, o-C
in PPh, 2JCP = 3.7 Hz), 134.45 (s, C6), 137.09 (d, C2, 1JCP = 22.2 Hz), 137.28 (d, ipso-C in PPh,
1JCP = 11.3 Hz), 137.33 (d, ipso-C in PPh, 1JCP = 11.0 Hz), 140.15 (d, C1, 2JCP = 24.3 Hz),
168.37 (s, C(O)NH), 171.26 (s, C(O)OMe) ppm. IR (KBr, ν/cm–1): 498(w), 518(w), 697(m),
749(s), 999(vw), 1027(vw), 1090(w), 1126(vw), 1159(w), 1176(w), 1214(m), 1258(w), 1311(w),
1434(m), 1459(w), 1479(w), 1520(br, m) (C(O)NH), 1560(vw), 1584(w), 1649(s) (νC=O in
C(O)NH), 1744(s) (νC=O in C(O)OMe), 2850(vw), 2917(w), 2950(w), 3051(w), 3295(br, w)
(νNH). Anal. Calcd for C24H24NO3PS: C, 65.89; H, 5.53; N, 3.20. Found: С, 66.03; Н, 5.49; N,
3.14%.
4.2.4.2. Methyl (2S)-2-{[2-(diphenylphosphanyl)benzoyl]amino}-4-(methylsulfanyl)butanoate 5b
5
4
3
6
1
H
N
S
2
O
PPh2
O
O
Yield: 1.10 g (34%). Mp: 74–75 °С (Et2O). 31P{1H} NMR (121.49 MHz, CDCl3): δ –9.89
ppm. 1Н NMR (300.13 MHz, CDCl3): δ 1.89–2.02 (m, 1Н, CH2), 2.12 (s, 3H, SMe), 2.12–2.22
(m, 1H, CH2), 2.46–2.56 (m, 2H, CH2S), 3.79 (s, 3H, OMe), 4.81–4.87 (m, 1H, CH), 6.74 (d,
1H, NH, 3JHH = 7.3 Hz), 7.03 (ddd, 1H, H(C3), 3JHH = 7.5 Hz, 3JHP = 4.0 Hz, 4JHH = 1.0 Hz),

19
7.29–7.48 (m, 12H, HAr), 7.71 (ddd, 1H, H(C6), 3JHH = 7.4 Hz, 4JHP = 3.6 Hz, 4JHH = 1.3 Hz)
ppm. 13C{1H} (100.61 MHz, CDCl3): δ 15.37 (s, SMe), 29.81 (s, CH2), 31.79 (s, CH2S), 51.91
and 52.44 (both s, OMe and СН), 127.85 (d, C3, 2JCP = 4.8 Hz), 128.47 (d, m-C in PPh, 3JСP =
7.0 Hz), 128.61 (d, m-C in PPh, 3JСP = 7.0 Hz), 128.69 and 128.72 (both s, p-C in PPh2), 128.85
and 130.40 (both s, C4 and C5), 133.66 (d, o-C in PPh, 2JCP = 4.0 Hz), 133.86 (d, o-C in PPh,
2JCP = 4.0 Hz), 134.20 (s, C6), 136.12 (d, С2, 1JCP = 21.3 Hz), 136.81 (d, ipso-C in PPh, 1JCP =
11.0 Hz), 136.90 (d, ipso-C in PPh, 1JCP = 11.0 Hz), 140.51 (d, C1, 2JCP = 25.3 Hz), 168.46 (s,
C(O)NH), 172.12 (s, C(O)OMe) ppm. IR (KBr, ν/cm–1): 501(w), 698(m), 746(m), 857(vw),
998(vw), 1027(vw), 1069(vw), 1092(w), 1171(m), 1215(m), 1306(w), 1338(w), 1434(s),
1478(w), 1539(br, m) (C(O)NH), 1584(w), 1638(s) and 1654(sh, m) (both νC=O in C(O)NH),
1741(s) (νC=O in C(O)OMe), 2916(w), 2949(w), 3053(w), 3294(br, m) (νNH). Anal. Calcd for
C25H26NO3PS: C, 66.50; H, 5.80; N, 3.10. Found: С, 66.57; Н, 5.84; N, 3.09%.
4.2.5. General procedure for the synthesis of Pd(II) complexes 6–8
A solution of PdCl2(NCPh)2 (71 mg, 0.185 mmol) in CH2Cl2 (5 mL) was added dropwise
to a solution of the corresponding ligand (0.185 mmol) and, in the case of ligands 3c, 5a,b,
triethylamine (26 µL, 0.185 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred at room
temperature for 5 h and then purified by column chromatography on silica gel (eluent CH2Cl2–
MeOH (50:1)) to give complexes 6–8 as yellow crystalline solids.
4.2.5.1. Complex [κ3-S,N,S-(L)Pd(II)Cl] 6a
Cl
S
Ph
Ph
S
Pd
N
P
O
O
O
Yield: 66 mg (65%). Mp: >200 °С (dec.). 31P{1H} NMR (121.49 MHz, CDCl3, major
isomer (M) 65%, minor isomer (m) 35%): δ 40.84 (m), 41.49 (M) ppm. 1Н NMR (300.13 MHz,
CDCl3): δ 2.32 (dd, 1Н, СН2S (m), 2JHH = 11.4 Hz, 3JHH = 5.3 Hz), 2.67 (s, 3H, SMe (m)), 2.75
(s, 3Н, SMe (M)), 2.79 (dd, 1H, СН2S (M), 2JHH = 13.6 Hz, 3JHH = 5.8 Hz), 2.95 (d, 1H, СН2S
(M), 2JHH = 13.6 Hz), 3.19 (d, 1Н, СН2S (m), 2JHH = 11.4 Hz), 3.33 (s, 3H, OMe (m)), 3.38 (s,
3H, OMe (M)), 3.76 (dd, 1H, CH2P(S) (M), 2JHH = 14.7 Hz, 2JHP = 8.5 Hz), 3.84 (dd, 1H,
CH2P(S) (m), 2JHH = 15.0 Hz, 2JHP = 8.8 Hz), 4.09 (dd, 1H, CH2P(S) (M), 2JHH = 14.7 Hz, 2JHP
19.1 Hz), 4.13 (dd, 1H, CH2P(S) (m), 2JHH = 15.0 Hz, 2JHP = 18.5 Hz), 5.51 (d, 1Н, CH (m), 3JHH
= 5.3 Hz), 5.56 (d, 1Н, CH (M), 3JHH = 5.8 Hz), 7.51–7.57 (m, 2H, HAr (M) + 2H, HAr (m)),
7.62–7.76 (m, 6H, HAr (M) + 6H, HAr (m)), 8.02–8.13 (m, 2H, HAr (M) + 2H, HAr (m)) ppm.
13C{1H} NMR (75.47 MHz, CDCl3): δ 22.78 (s, SMe (M)), 24.66 (s, SMe (m)), 37.69 (s, CH2S
=

20
(M)), 40.86 (s, CH2S (m)), 44.21 (d, CH2P(S) (m), 1JCP = 45.7 Hz), 44.48 (d, CH2P(S) (M), 1JCP
= 44.7 Hz), 52.33 (s, OMe (m)), 52.42 (s, OMe (M)), 64.55 (s, CH (m)), 67.17 (s, CH (M)),
125.47 (d, ipso-С in P(S)Ph2 (M+m), 1JCP = 82.2 Hz), 127.28 (d, ipso-С in P(S)Ph2 (M+m), 1JCP
= 81.9 Hz), 128.98 (d, m-C in P(S)Ph (M+m), 3JCP = 13.3 Hz), 129.25 (d, m-C in P(S)Ph (M+m),
3JCP = 12.8 Hz), 131.23 (d, o-С in P(S)Ph (M+m), 2JCP = 10.6 Hz), 132.03 (d, o-С in P(S)Ph (m),
2JCP = 9.4 z), 132.16 (d, o-C in P(S)Ph (M), 2JCP = 10.5 Hz), 133.08 (d, p-С in P(S)Ph (M+m),
4JCP = 2.6 Hz), 133.17 (d, p-С in P(S)Ph (M+m), 4JCP = 2.6 Hz), 165.96 (d, C(O)N (M), 2JCP =
6.2 Hz), 166.25 (d, C(O)N (m), 2JCP = 6.2 Hz), 171.18 (s, C(O)OMe (m)), 172.28 (s, C(O)OMe
(M)) ppm. IR (KBr, ν/cm–1): 413(vw), 451(vw), 480(vw), 511(m), 570(vw), 597(w) (νP=S),
620(vw), 691(m), 724(w), 748(m), 788(vw), 811(vw), 856(w), 998(vw), 1026(w), 1107(m),
1170(w), 1214(m), 1265(w), 1314(vw), 1369(m), 1437(s), 1484(vw), 1593(br, s) (νC=O in
C(O)N), 1725(s) (νC=O in C(O)OMe), 2923(w). Anal. Calcd for C19H21ClNO3PPdS2: C, 41.62;
H, 3.86; N, 2.55. Found: С, 41.80; Н, 4.15; N, 2.39%.
4.2.5.2. Complex [κ3-S,N,S-(L)Pd(II)Cl] 6b
Cl
S
S
Ph
Ph
Pd
N
P
O
O
O
Yield: 75 mg (72%). Mp: >195 °С (dec.). 31P{1H} NMR (161.98 MHz, CDCl3, major
isomer (M) 84%, minor isomer (m) 16%): δ 40.56 (m), 41.20 (М) ppm. 1Н NMR (600.22 MHz,
CDCl3, 243 K, major isomer):1 δ 2.52–2.57 (m, 1H, CH2 + 1H, CH2S), 2.60 (s, 3Н, SMe), 2.62–
2.68 (m, 1H, CH2 + 1H, CH2S), 3.52(s, 3H, OMe), 3.90–3.94 (m, 1H, CH2P(S)), 4.39–4.44 (m,
1H, CH2P(S)), 4.79 (dd, 1H, CH, 3JHH = 9.9 Hz, 3JHH = 5.8 Hz), 7.57–7.60 (m, 2H, HAr), 7.64–
7.68 (m, 3H, HAr), 7.72–7.74 (m 1H, HAr), 7.90 (dd, 2H, o-H in P(S)Ph, 3JHP = 13.7 Hz, 3JHH
7.6 Hz), 8.00 (dd, 2H, o-H in P(S)Ph, 3JHP = 14.0 Hz, 3JHH = 7.6 Hz) ppm. 13C{1H} NMR
=
(100.61 MHz, CDCl3, 243 K, major isomer): δ 21.17 (s, SMe), 29.80 (s, CH2), 31.80 (s, CH2S),
48.49 (d, CH2P(S), 1JCP = 43.9 Hz), 52.33 (s, OMe), 53.18 (s, CH), 126.95 (d, ipso-C in P(S)Ph,
1JCP = 82.8 Hz), 127.88 (d, ipso-C in P(S)Ph, 1JCP = 82.5 Hz), 129.46 (d, m-C in P(S)Ph, 3JCP =
13.1 Hz), 129.67 (d, m-C in P(S)Ph, 3JCP = 13.1 Hz), 132.08 (d, o-C in P(S)Ph, 2JCP = 11.2 Hz),
132.20 (d, o-C in P(S)Ph, 2JCP = 11.3 Hz), 133.39 (s, p-C in P(S)Ph), 133.63 (s, p-C in P(S)Ph),
167.23 (d, C(O)N, 2JCP = 6.2 Hz), 172.71 (s, C(O)OMe) ppm. IR (KBr, ν/cm–1): 464(vw),
1 The content of the minor isomer at 243 K composes only 8%; therefore, only the signals of the
major isomer were reliably assigned.

21
485(m), 562(w), 584(m) (νP=S), 691(m), 744(m), 752(m), 797(vw), 834(w), 997(w), 1012(w),
1034(w), 1106(m), 1125(w), 1166(w), 1203(m), 1251(w), 1279(w), 1320(w), 1353(m), 1373(m),
1437(m), 1481(vw), 1600(br, s) (νC=O in C(O)N), 1737(s) (νC=O in C(O)Me), 2911(w),
2951(vw), 3052(vw). Anal. Calcd for C20H23ClNO3PPdS2: C, 42.71; H, 4.12; N, 2.49. Found: С,
42.26; Н, 4.41; N, 2.05.
4.2.5.3. Complex [κ3-S,N,S-(L)Pd(II)Cl] 7a
Cl
3
S
4
S
Pd
N
2
5
1
6
O
O
O
Yield: 53 mg (65%). Mp: 135–138 °С (dec.). 1H NMR (600.22 MHz, CDCl3, 243 K,
content of the isomers: 53% (A), 27% (B), 14% (C), 6% (D)): δ 2.27 (dd, 1H, CH2S (D), 2JHH
11.5 Hz, 3JHH = 5.5 Hz), 2.36 (dd, 1H, CH2S (B), 2JHH = 11.5 Hz, 3JHH = 5.5 Hz), 2.55 (s, 3H,
=
AlkSMe (D)), 2.61 (s, 3H, AlkSMe (B)), 2.66 (s, 3H, AlkSMe (A)), 2.71 (s, 3H, AlkSMe (C)),
2.78 (dd, 1H, CH2S (C), 2JHH = 14.0 Hz, 3JHH = 6.0 Hz), 2.82–2.85 (m, 1H, CH2S (A) + 3H,
ArSMe (B)), 2.88 (br s, 3H, ArSMe (A) + 3H, ArSMe (C) + 3H, ArSMe (D)), 3.06 (br d, 1H,
CH2S (A) +1H, CH2S (C), 2JHH = 14.0 Hz), 3.35 (d, 1H, CH2S (D), 2JHH = 11.5 Hz), 3.42 (d, 1H,
CH2S (B), 2JHH = 11.5 Hz), 5.96–6.00 (m, 1H, CH (A) + 1H, CH (B) + 1H, CH (C) + 1H, CH
(D)), 3.80 (s, 3H, OMe (B)), 3.83 (s, 3H, OMe (D)), 3.85 (s, 3H, OMe (A)), 3.89 (s, 3H, OMe
(C)), 7.26 (d, 1H, H(C3) (C), 3JHH = 7.9 Hz), 7.43–7.54 (m, 1H, HAr (A) + 2H, HAr (B) + 1H, HAr
(C)), 7.59–7.65 (m, 2H, HAr (A) + 1H, HAr (B) + 1H, HAr (C) + 3H, HAr (D)), 8.08 (d, 1H, H(C6)
(C), 3JHH = 7.6 Hz), 8.19–8.21 (m, 1H, H(C6) (A) + 1H, H(C6) (D)), 8.31 (d, 1H, H(C6) (B),
3JHH = 7.8 Hz) ppm. 13C{1H} NMR (150.93 MHz, CDCl3, 243K):2 δ 21.71 (s, AlkSMe (A)),
23.80 (s, AlkSMe (B)), 27.48 (s, ArSMe (A)), 27.98 (s, ArSMe (B)), 37.14 (s, CH2S (A)), 39.81
(s, CH2S (B)), 53.18 (s, OMe (A)), 53.22 (s, OMe (B)), 65.48 (s, CH (B)), 67.90 (s, CH (A)),
125.55 (s, C2 (B)), 125.70 (s, C2 (A)), 130.70 (s, C3 (A)), 130.84 (s, C3 (B)), 131.89–131.91 (m,
overlapping signals of C4 (A), C5 (A), and C4 (B) or C5 (B)), 132.18 (s, C4 or C5 (B)), 134.00
(s, C6 (A)), 134.24 (s, C6 (B)), 140.26 (s, C1 (B)), 140.46 (s, C1 (A)), 165.78 (s, C(O)N (B)),
166.29 (s, C(O)N (A)), 171.30 (s, C(O)OMe (B)), 172.54 (s, C(O)OMe (A)) ppm. IR (KBr,
ν/cm–1): 504(vw), 695(w), 749(m), 787(w), 837(vw), 871(vw), 968(w), 1020(w), 1092(w),
1171(m), 1211(m), 1252(w), 1315(w), 1366(m), 1418(w), 1435(w), 1462(w), 1550(s) (νC=O in
2
The signals of C and D isomers were observed only for several carbon nuclei and cannot be
reliably assigned (see Figs. S5–S10 in Supplementary data).

22
C(O)N), 1584(s), 1735(m) (νC=O in C(O)OMe), 2853(vw), 2925(w), 2948(w), 3000(vw),
3059(vw). Anal. Calcd for C13H16ClNO3PdS2: C, 35.46; H, 3.66; N, 3.18. Found: С, 35.41; Н,
3.89; N, 3.00%.
4.2.5.4. Complex [κ3-S,N,S-(L)Pd(II)Cl] 7b
Cl
3
S
S
4
5
Pd
N
2
1
6
O
O
O
Yield: 72 mg (86%). Mp: 195–200 °С (dec).3 IR (KBr, ν/cm–1): 524(vw), 582(vw), 691(w),
742(m), 770(w), 816(w), 901(vw), 976(w), 1046(w), 1066(w), 1107(m), 1173(m), 1198(m),
1225(w), 1286(w), 1320(m), 1368(m), 1418(w), 1442(m), 1559(m) (νC=O in C(O)N), 1583(s),
1591(s), 1655(w), 1735(s) (νC=O in C(O)OMe), 2922(w). Anal. Cacld for C14H18ClNO3PdS2: C,
37.01; H, 3.99; N, 3.08. Found: С, 37.25; Н, 4.03; N, 2.92%.
4.2.5.5. Complex [κ3-S,N,N-(L)Pd(II)Cl] 7c
9
HN
Cl
3
8
N
S
4
5
Pd
N
2
7
1
6
O
O
O
Yield: 80 mg (94%). Mp: 225–230 °С (dec.). 1Н NMR (400.13 MHz, CDCl3, major isomer
(M) 77%, minor isomer (m) 23%): 2.70 (s, 3H, SMe (m)), 2.87 (s, 3H, SMe (M)), 3.13 (dd, 1H,
СН2 (M), 2JHH = 15.0 Hz, 3JHH = 3.4 Hz), 3.24 (dd, 1H, СН2 (m), 2JHH =15.1 Hz, 3JHH = 3.6 Hz),
3.34–3.43 (m, 1H, CH2 (M) + 1H, CH2 (m)), 3.75 (s, 3H, OMe (m)), 3.77 (s, 3H, OMe (M)),
4.42 (dd, 1H, СН (m), 3JHH = 9.7 Hz, 3JHH = 3.6 Hz), 4.54 (dd, 1Н, CH (M), 3JHH = 9.9 Hz, 3JHH
= 3.4 Hz), 6.86 (br s, 1H, H(C8) (m)), 6.88 (br s, 1H, Н(C8) (M)), 7.27–7.29 (m, 1H, H(C4)
(m)), 7.38 (dt, 1H, HC(4) (M), 3JHH = 7.6 Hz, 4JHH = 1.4 Hz), 7.41–7.44 (m, 2H, H(C3) + H(C5)
(m)), 7.51–7.58 (m, 2H, H(C3) + H(C5) (M)), 7.87 (br s, 1H, H(C9) (m)), 7.90–7.93 (m, 1H,
H(C6) (m)), 7.93 (br s, 1H, Н(C9) (M)), 8.06 (dd, 1H, Н(C6) (M), 3JHH = 7.8 Hz, 4JHH = 1.2 Hz),
11.51 (br s, 1H, NH (M+m)) ppm. 13C{1H} NMR (100.61 MHz, CDCl3): δ 18.73 (s, SMe (m)),
24.43 (s, SMe (M)), 29.50 (s, CH2 (m)), 29.84 (s, CH2 (M)), 52.01 (s, OMe (M)), 52.14 (s, OMe
(m)), 57.16 (s, CH (M+m)), 112.78 (s, C8 (M)), 113.00 (s, C8 (m)), 125.27 (s, C2 (M)), 127.17
(s, C2 (m)), 128.97 (s, C3 (m)), 130.23 (s, C3 (M)), 130.42 (s, C4 (M)), 130.98 (s, C4 (m)),
3 1H, 13C{1H} and HMQC NMR spectra of complex 7b in CDCl3 at –30 °C are presented in
Supplementary data (Figs. S11–19).

23
131.31 (s, C5 (M)), 131.92 (s, C5 (m)), 133.06 (s, C6 (M+m)), 133.50 (s, C7 (M)), 133.79 (s, C7
(m)), 138.45 (s, C1 (m)), 140.85 (s, C1 (M)), 166.74 (s, C(O)N (M)), 167.04 (s, C(O)N (m)),
172.84 (s, C(O)OMe (m)), 173.46 (s, C(O)OMe (M)) ppm (the signal of C9 carbon nucleus was
not observed). IR (KBr, ν/cm–1): 455(w), 629(w), 704(vw), 757(m), 783(w), 827(w), 895(vw),
980(w), 1040(w), 1093(w), 1174(m), 1197(m), 1239(w), 1275(w), 1349(w), 1385(m), 1433(w),
1506(m), 1526(s) (νC=O in C(O)N), 1574(m), 1729(m)/1735(m) (both νC=O in C(O)OMe),
2662(w), 2753(w), 2852(w), 3030(w), 3138(w) (νNH). Anal. Calcd for C15H16ClN3O3PdS: C,
39.14; H, 3.50; N, 9.13. Found: С, 39.39; Н, 3.78; N, 8.90%.
4.2.5.6. Complex [κ3-S,N,P-(L)Pd(II)Cl] 8a
Ph
Cl
Ph
3
6
P
4
5
S
Pd
N
2
1
O
O
O
Yield: 102 mg (95%). Mp: >180 °С (dec.). 31P{1H} NMR (121.49 MHz, CDCl3): δ 26.99
ppm. 1Н NMR (600.22 MHz, CDCl3, 243 K, major isomer (M) 61%, minor isomer (m) 39%): δ
2.19 (dd, 1Н, CH2S (m), 2JHH = 11.6 Hz, 3JHH = 4.6 Hz), 2.62 (d, 3H, SMe (m), 4JHP = 4.4 Hz),
2.66 (d, 3H, SMe (M), 4JHP = 4.3 Hz), 2.70 (dd, 1H, CH2S (M), 2JHH = 14.2 Hz, 3JHH = 5.6 Hz),
2.96 (s, 3H, OMe (M)), 3.00 (s, 3H, OMe (m)), 3.11 (dd, 1H, CH2S (M), 2JHH = 14.2 Hz, 3JHH
=
3.1 Hz), 3.42 (dd, 1H, CH2S (m), 2JHH = 11.6 Hz, 3JHH = 6.2 Hz), 6.19–6.21 (m, 1H, CH (M) +
1H, CH (m)), 6.71 (dd, 1H, H(C3) (M), 3JHP = 11.3 Hz, 3JHH = 8.0 Hz), 6.77 (dd, 1H, H(C3) (m),
3JHP = 11.6 Hz, 3JHH = 7.9 Hz), 7.37–7.63 (m, 11H, HAr (M) + 11H, HAr (m)), 7.66–7.71 (m, 1H,
H(C5) (M) + 1H, H(C5) (m)), 8.47 (dd, 1H, Н(C6) (M), 3JHH = 7.8 Hz, 4JHP = 3.9 Hz), 8.56 (dd,
1H, Н(C6) (m), 3JHH = 7.7 Hz, 3JHP = 3.9 Hz) ppm. 13C{1H} NMR (150.93 MHz, CDCl3, 243 K):
δ 20.50 (s, SMe (M)), 22.83 (s, SMe (m)), 34.16 (s, CH2S (M)), 37.57 (s, CH2S (m)), 52.70 (s,
OMe (m)), 52.80 (s, OMe (M)), 65.76 (s, CH (m)), 68.63 (s, CH (M)), 122.62 (d, C2 (M), 1JCP =
51.9 Hz), 122.65 (d, C2 (m), 1JCP = 51.6 Hz), 125.99 (d, ipso-C in PPh (m), 1JCP = 60.2 Hz),
127.09 (d, ipso-C in PPh (M), 1JCP = 60.5 Hz), 127.42 (d, ipso-C in PPh (M), 1JCP = 55.5 Hz),
127.56 (d, ipso-C in PPh (m), 1JCP = 56.4 Hz), 128.60–128.76 (m, m-C in PPh (M+m)), 129.33–
129.46 (m, m-C in PPh (M+m)), 130.32 (d, C4 (M), 3JCP = 8.2 Hz), 130.40 (d, C4 (m), 3JCP = 9.1
Hz), 131.86 (s, p-C in PPh (M+m)), 132.11 (s, p-C in PPh (M+m)), 132.45 (s, C5 (M+m)),
132.86–132.94 (m, C3 (M+m) + C6 (M)), 133.14 (d, C6 (m), 3JCP = 11.4 Hz), 133.33 (d, o-C in
PPh (M), 2JCP = 11.5 Hz), 133.52 (d, o-C in PPh (m), 2JCP = 12.0 Hz), 134.61 (d, o-C in PPh (m),
2JCP = 10.0 Hz), 134.65 (d, o-C in PPh (M), 2JCP = 10.6 Hz), 142.47 (d, C1 (m), 2JCP = 14.0 Hz),
142.74 (d, C1 (M), 2JCP = 14.4 Hz), 166.43 (d, C(O)N (m), 3JCP = 9.3 Hz), 166.95 (d, C(O)N,

24
3JCP = 9.2 Hz), 171.98 (s, C(O)OMe (m)), 173.04 (s, C(O)OMe (M)) ppm. IR (KBr, ν/cm–1):
438(vw), 510(m), 551(m), 693(m), 714(w), 737(w), 750(m), 791(vw), 865(vw), 970(vw),
998(vw), 1026(w), 1101(m), 1126(w), 1170(w), 1184(w), 1209(w), 1252(w), 1287(w), 1314(w),
1360(br, m), 1436(m), 1461(vw), 1482(w), 1548(s) (νC=O in C(O)N), 1579(s), 1593(m),
1724(m) (νC=O in C(O)OMe), 2854(vw), 2926(w), 2952(w), 3055(w). Anal. Calcd for
C24H23ClNO3PPdS: C, 49.84; H, 4.01; N, 2.42. Found: С, 49.84; Н, 4.03; N, 2.38%.
4.2.5.7. Complex [κ3-S,N,P-(L)Pd(II)Cl] 8b
Ph
Cl
Ph
3
S
P
4
5
Pd
N
2
1
6
O
O
O
Yield: 82 mg (75%). Mp: >170 °С (dec.). 31P{1H} NMR (121.49 MHz, CDCl3): δ 25.00
ppm. 1Н NMR (400.13 MHz, CDCl3): δ 2.30–2.36 (m, 1Н, CH2), 2.46 (d, 3H, SMe, 4JHP = 4.2
Hz), 2.63–2.69 (m, 1H, CH2), 2.84–2.88 (m, 1Н, CH2S), 2.93–2.99 (m, 1Н, CH2S), 3.15 (s, 3H,
OMe), 4.24–4.27 (m, 1H, CH), 6.76 (dd, 1H, H(C3), 3JHP = 11.4 Hz, 3JHH = 7.7 Hz,), 7.32 (t, 1H,
HAr, 3JHH = 7.5 Hz), 7.41–7.47 and 7.51–7.64 (both m, 6H + 5H, HAr), 8.29 (dd, 1H, H(C6), 3JHH
= 7.5 Hz, 4JHP = 3.8 Hz) ppm. 13C{1H} NMR (100.61 MHz, CDCl3): δ 19.07 (s, SMe), 26.77 (s,
CH2), 32.59 (s, CH2S), 51.58 (s, OMe), 57.88 (s, CH), 123.20 (d, C2, 1JCP = 53.5 Hz), 125.33 (d,
ipso-C in PPh, 1JСP = 55.7 Hz), 127.23 (d, ipso-C in PPh, 1JСP = 59.1 Hz), 128.34 (d, m-C in PPh,
3JСP = 11.7 Hz), 128.53 (d, m-C in PPh, 3JСP = 12.1 Hz), 129.95 (d, C4, 3JСP = 8.8 Hz), 131.36
(d, C3, 2JСP = 4.4 Hz), 131.46 (d, p-C in PPh, 4JСP = 2.6 Hz), 131.59 (d, p-C in PPh, 4JСP = 2.9
Hz), 131.99 (d, C5, 4JСP = 2.6 Hz), 132.16 (d, C6, 3JСP = 10.3 Hz), 134.13 (d, o-C in PPh, 2JСP =
11.4 Hz), 134.37 (d, o-C in PPh, 2JСP = 11.0 Hz), 142.28 (d, С1, 2JСP = 12.8 Hz), 165.78 (d,
C(O)N, 3JСP = 9.2 Hz), 171.88 (s, C(O)OMe) ppm. IR (KBr, ν/cm–1): 439(w), 515(m), 549(m),
693(m), 713(w), 759(w), 802(w), 964(w), 998(w), 1048(w), 1103(m), 1126(w), 1162(m),
1170(m), 1286(w), 1332(m), 1355(m), 1366(m), 1435(m), 1481(w), 1552(s) (νC=O in C(O)N),
1575(m), 1590(m), 1739(s) (νC=O in C(O)OMe), 2917(w), 3057(w). Anal. Calcd for
C25H25ClNO3PPdS: C, 50.69; H, 4.25; N, 2.36. Found: С, 50.64; Н, 4.19; N, 2.34%.
4.3. X-ray diffraction
Single crystals of compounds 4, 6b, 7a,b, and 8a,b suitable for X-ray diffraction analysis
were obtained by slow recrystallization from CHCl3–CH2Cl2–hexane (4), CH2Cl2–hexane (6b),
CHCl3–hexane (7a,b), Et2O (8a), and MeCN–Et2O–hexane (b). X-ray diffraction experiments
were carried out with a Bruker APEX2 CCD diffractometer (for 4 and 8a,b) and with a Bruker

25
APEX2 DUO CCD diffractometer (for 6b and 7a,b), using the graphite monochromated Mo-Kα
radiation (λ = 0.71073 Å, ω-scans) at 120 K. The structures were solved by direct method and
refined by full-matrix least-squares techniques against F2 in anisotropic approximation for non-
hydrogen atoms. Hydrogen atom of the NH group in 4 was located from difference Fourier
synthesis; the positions of the H(C) atoms were calculated. All hydrogen atoms were then refined
in isotropic approximation in a riding model. Crystal data and structure refinement parameters
for the compounds explored are given in Table 2. All calculations were performed using the
SHELXTL software.20
Table 2. Crystal data and structure refinement parameters for 4, 6b, 7a,b, and 8a,b.
4
6b
7a
7b
8a
8b
Empirical
formula
C20H23ClNO3P C13H16ClNO3 C14H18ClNO3 C24H23ClNO3 C100H106Cl4N4
C23H23N3O4S2
PdS2
PdS2
PdS2
PPdS
O15P4Pd4S4
2423.40
Formula weight 469.56
562.33
440.24
454.26
578.31
Crystal system
orthorhombic
P212121
orthorhombic
P212121
orthorhombic orthorhombic Monoclinic
P212121 P212121 P21
monoclinic
P21
Space group
Z
4
4
4
4
2
1
a, Å
9.3848(6)
11.9291(7)
20.7382(14)
90
9.4734(7)
14.0294(10)
16.5481(12)
90
5.9307(5)
13.0337(11)
20.3502(17)
90
8.5526(6)
8.6465(5)
21.8056(14)
90
9.3913(4)
10.2354(4)
12.6889(5)
103.897(1)
1184.00(8)
1.622
8.9345(5)
10.0505(6)
27.8717(18)
93.4040(10)
2498.4(3)
1.611
b, Å
c, Å
β, °
V, Å3
Dcalc (g cm−1)
2321.7(3)
1.343
2199.3(3)
1.698
1573.0(2)
1.859
1612.53(18)
1.871
Linear
absorption,
2.64
12.5
16.22
15.85
10.79
10.29
µ (cm−1)
F(000)
984
1136
58
880
912
584
1230
58
58
56
58
58
2Θmax, °
Reflections
measured
18382
26962
12160
13346
23849
20148
Independent
reflections
Observed
6139
5073
5846
5621
3796
3160
4275
4034
6284
6224
12603
11344
reflections
[I > 2σ(I)]
Parameters
R1
292
284
193
202
291
617
0.0464
0.1006
0.0191
0.0473
0.0388
0.0726
0.0260
0.0589
0.0143
0.0369
0.0459
0.0884
wR2
Goodness-of-fit
(GOF)
1.042
1.009
1.004
1.003
0.996
1.038
∆ρmax/∆ρmin
0.281/–0.291
0.488/–0.403
0.692/–0.709
0.890/–0.774 0.295/–0.178 0.544/–1.058
(e Å−3)

26
4.4. Cytotoxicity assays
The cytotoxicities of Pd(II) complexes 6–8 were tested against human colon cancer cell
line HCT116, human breast cancer cell line MCF7, human prostate cancer cell line PC3, and
normal human embryonic kidney cells HEK293. RPMI-1640 and DMEM media were obtained
from Gibco. Fetal bovine serum (FBS) was purchased from HyClone. Cells were cultured in
RPMI-1640 (in the case of PC3) or DMEM (in the other cases) media supplemented with 10%
FBS, 100 units/L penicillin, and 100 µg/mL streptomycin in a humidified incubator with 5% CO2
atmosphere. The effect of the compounds on cell viability was evaluated by the standard MTT
assay (ICN Biomedicals, Germany). Cells were seeded in triplicate at a cell density of
5×103/well in 96-well plates in 100 µL complete medium and preincubated for 24 h. The tested
compounds were initially dissolved in DMSO. Then the compounds at various concentrations
were added to the media. The well plates were incubated for 48 h followed by addition of MTT
solution (Sigma) (20 µL, 5 mg/mL). The cells were incubated at 37 °C for further 3 h; then the
culture medium was removed, and formazan crystals were dissolved in DMSO (70 µL). The
absorbance of the resulting solutions was measured on a multi-well plate reader (Uniplan, Picon,
Russia) at 590 nm to determine the percentage of surviving cells. The reported values of IC50 are
the averages of three independent experiments (Table 1). Cisplatin from a commercial source
was used as a positive control.
Acknowledgements
This work was supported by the Russian Foundation for Basic Research, project no. 16-03-
00695.
The X-ray diffraction data were obtained using the equipment of Center for molecule
composition studies of INEOS RAS.
Appendix A. Supplementary data
CCDC 1557198 (for 8a), 1557199 (for 7a), 1557200 (for 4), 1557201 (for 6b), 1557202
(for 8b), and 1557203 (for 7b) contain the supplementary crystallographic data. These data can
be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44)
1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
Appendix B. Supplementary data
1H, 13C{1H}, 1H–1H COSY and HMQC spectra of complexes 6b, 7a,b, and 8a in CDCl3 at
different temperatures.

27
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