Ortho-(methylsulfanyl)phenylphosphonates and derivatives: Synthesis and applications as mono- or bidentate ligands for the preparation of platinum complexes

Article abstract of DOI:10.1016/j.jorganchem.2013.07.069

The preparation of six phenylphosphonates (and phosphonic acid derivatives) bearing a sulfur group in ortho position was accomplished via either a [1,3]- or a [1,4]-sigmatropic rearrangement. Their complexation with different platinum sources has been stu

Full text of DOI:10.1016/j.jorganchem.2013.07.069

Journal of Organometallic Chemistry 745-746 (2013) 206e213
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Ortho-(methylsulfanyl)phenylphosphonates and derivatives:
Synthesis and applications as mono- or bidentate ligands
for the preparation of platinum complexes
,
b
,
a
a
,
c
d,e
Matthieu Hamel a , Mathieu Lecinq , Mihaela Gulea , Jirí Kozelka
*
ꢀ
a Laboratoire de Chimie Moléculaire et Thio-organique (UMR CNRS 6507), ENSICAEN e Université de Caen, 6 Boulevard Maréchal Juin, 14050 Caen, France
b CEA, LIST, Laboratoire Capteurs et Architectures Électroniques, CEA Saclay, 91191 Gif-sur-Yvette, France
c Laboratoire d’Innovation Thérapeutique (UMR CNRS 7200), Faculté de Pharmacie, Université de Strasbourg, 74 route du Rhin, 67401 Illkirch, France
d Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (UMR CNRS 8601), Université René Descartes, 45 rue des Saints-Pères,
75270 Paris 06, France
e
ꢀ
Institute of Condensed Matter Physics, Faculty of Science, Masaryk University, Kotlárská 2, 61137 Brno, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of six phenylphosphonates (and phosphonic acid derivatives) bearing a sulfur group in
ortho position was accomplished via either a [1,3]- or a [1,4]-sigmatropic rearrangement. Their
complexation with different platinum sources has been studied and the new platinum complexes ob-
tained were characterized by NMR spectroscopy (1H, 13C, 31P and 195Pt). Three runs of experiments were
performed. The first was the reaction of ligands 1 and 2 bearing one sulfide and a phosphonate diester
functions with potassium tetrachloroplatinate. In the obtained complexes, two molecules of ligand
chelate the metal only by the sulfur atom. We were able to observe by 195Pt and 31P NMR spectroscopy
the trans to cis rearrangement of a dichloro-methyl-(o-phosphorylbenzyl)sulfide platinum(II) complex
upon time, leading to two new species, which are diastereomers of the cis-complex. The second set of
experiments involved ligands 1, 2 and 3 bearing one sulfide or sulfoxide and a phosphonate diester
moieties, cisplatin and one equivalent of silver nitrate. In the resulting complexes the platinum is co-
ordinated by the sulfur atom of one molecule of ligand. In the third run, the reaction between ligands 4,
5, and 6 bearing one sulfide or sulfoxide and one phosphonic acid or one phosphonic monoester group
and the cisplatin diaqua form led to O,SePt chelates.
Received 9 June 2013
Received in revised form
15 July 2013
Accepted 26 July 2013
Keywords:
Platinum complexes
Sigmatropic rearrangement
O,S-Bidentate ligands
Cis/trans isomerization
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
reported the synthesis and the biological activity of cis-dia-
mmineplatinum(II) complexes bearing a monodentate sulfoxide
After the serendipitous discovery of the antitumor properties of
cisplatin by Rosenberg et al. in the 60s [1], several research groups
have focused their attention on the design of new platinum com-
plexes able to overcome the drawbacks of the parent molecule [2].
Among the hundreds of new compounds prepared every year to
this aim, a very few number of them will reach the final tests,
allowing a potential commercialization. The fact that the Pt(II)eS
bond is thermodynamically stable but kinetically labile [3] has
prompted several groups to use sulfanyl or sulfinyl ligands as
leaving groups instead of chloride. For example, Farrell et al. have
and one chloride as leaving groups [4]. A similar sulfide series was
later synthesized and tested by Khokhar and coworkers [5], In the
same time, the group of Pasini has successfully used the methyl-
sulfinyl acetate and benzoate ligands as O,S-leaving groups [6]. The
behavior of these complexes toward DNA seems to be similar to
that of carboplatin, i.e. the direct nucleophilic attack of a guanine
base [7], instead of the preliminary aquation such as in the case of
cisplatin [8].
Bisphosphonates are an important class of osteotropic com-
pounds, thanks to their binding ability to bone or calcified tissues
[9]. This capacity has been extensively used by the group of Keppler
to prepare platinum phosphonate complexes well-designed for
bone malignancies [10]. Hollis et al. have used a phosphoroformiate
which, after decomplexation to platinum, liberates FoscarnetÒ, an
antiherpetic drug [11]. It is therefore of interest to combine the
advantages of sulfureplatinum complexes which could afford a
* Corresponding author. CEA, LIST, Laboratoire Capteurs et Architectures Élec-
troniques, CEA Saclay, 91191 Gif-sur-Yvette, France. Tel.: þ33 1 69 08 33 25; fax: þ33
1 69 08 60 30.
E-mail address: matthieu.hamel@cea.fr (M. Hamel).
0022-328X/$ e see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2013.07.069

M. Hamel et al. / Journal of Organometallic Chemistry 745-746 (2013) 206e213
207
better water solubility and a lower inherent toxicity as compared to
cisplatin with the possibility to target calcified tissues by using
phosphonates. Thus, the group of Natile has described the prepa-
ration of a bidentate ligand {the diethyl (methylsulfinyl)emethyl-
phosphonate} and its complexation with K2PtCl4 [12]. The formed
O,S-chelate was shown to inhibit matrix Metalloproteinase 2, 3, 9
and 12 [13].
Our group has also reported some platinum complexes derived
from difunctionalized phosphorus and sulfur compounds [14,15].
In this paper, we investigate the ability of two structural families
of difunctionalized phosphorus and sulfur compounds [16] to form
platinum complexes. The two structural families are the 2-(sulfa-
nylmethyl)phenylphosphonates and the 2-sulfanyl benzene-
phosphonates, obtained via a s-[1,3] and a s-[1,4] rearrangement,
respectively [17,18]. Their phosphonic monoesters and phosphonic
acids derivatives are also examined.
2. Results and discussion
2.1. Preparation of the ligands
Fig. 2. Preparation of compounds 4e6 from 1.
We have considered the synthesis of both neutral and anionic
ligands so as to determine the differences of complexation function
to the charge of the molecule. Neutral compounds can be resumed
to arylphosphonates and anionic compounds to their acid de-
rivatives. All the ligands are drawn in Fig. 1.
The 2-methylsulfanyl phenylphosphonate 1 was prepared from
the [1,3]-sigmatropic rearrangement of S-phenyl-diisopropylphos-
phorotioate and subsequent methylation of the thiolate interme-
diate [17]. This sulfide was then converted either to its phosphonic
acid derivative 6 by the procedure of McKenna et al. [19], or mono-
hydrolyzed following the conditions of Holý [20]. The resulting
phosphonic acid monoester 4 was finally oxidized with sodium
periodate to afford the isopropyl 2-(methylsulfinyl)-phenyl-
phosphonic acid 5 (Fig. 2).
Starting from 2-iodobenzylsulfanyl diisopropylphosphor-
othioate 8, easily obtained from triethylammonium O,O-diisopro-
pylphosphorothioate 7, we generate by using t-BuLi, via a [1,4]-
sigmatropic rearrangement the corresponding benzylic thiolate
[17], which was quenched by methyl iodide to afford sulfide 2.
Finally, the corresponding sulfoxide 3 was quantitatively obtained
after oxidation of 2 with one equivalent of mCPBA (Fig. 3).
of Natile [12a], examining whether our ligand bearing the bulky
diisopropyl phosphonate functional group could also act as an O,S-
bidentate ligand toward platinum. After one day of reaction in
water at room temperature, a single product was detected by 31P
NMR, which was isolated as a clear yellow powder, albeit in low
3
yield (34%). In the 1H NMR spectrum, a JPtH was clearly visible
between platinum and the hydrogens of the methyl group, indi-
cating the creation of a PteS bond. Meanwhile, no NMR informa-
tion was collected about a plausible existence of a P]OePt bond.
Finally, the HRMS and the elemental analysis proved that the ob-
tained complex corresponded in fact to the formula PtCl2L2, where
L was the compound 1. By adding 2 equivalents of sulfide 1, the
yield could be improved to 61%, and complex 9 was obtained as the
sole reaction product. Ultimately, the 195Pt NMR gave a singlet at
ꢀ3373 ppm, in agreement with a Cl2S2 squareeplanar environment
surrounding platinum [21], and which can be compared to the 195Pt
NMR chemical shift of trans-[PtCl2(PhSMe)2]: ꢀ3385 ppm [21].
Therefore we can assume that our complex 9 has trans geometry. In
the same way, the reaction between K2PtCl4 and two equivalents of
ligand 2 gave the trans-dichlorido(bis-sulfide) complex 10 (Fig. 4).
Reaction of 3 and K2PtCl4 under the same reaction conditions lead
to a mixture of products from which we were not able to obtain a
pure compound.
We next extended our study to another platinum source, and we
tried to prepare complexes according to the procedure described by
Farrell for the synthesis of monodentate sulfoxides [4] and by
Khokhar for monodentate sulfides [5]. Thus, the equimolar reaction
between cisplatin and 1, 2 or 3 in the presence of silver nitrate led to
the formation of the corresponding cationic complexes 11e13,
where the organic moiety was coordinated to platinum by the
sulfur atom (Fig. 5).
2.2. Reactions of bifunctional ligands bearing a sterically hindered
phosphodiester group
At first we investigated the equimolar reaction between 1 and
potassium tetrachloroplatinate in the same conditions of reaction
Fig. 1. Ligands for coordination with Pt(II) discussed in this work.
Fig. 3. Preparation of compounds 2 and 3 from 8.

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M. Hamel et al. / Journal of Organometallic Chemistry 745-746 (2013) 206e213
such a trans elimination, we have replaced in this case cisplatin by
cis-diaqua(ethylenediammine)eplatinum(II). This reaction yielded
the desired chelate complex 16.
In contrast to 14 and 15, complex 16 is extremely stable, even in
aqueous solution: 1H and 31P NMR spectra of its aqueous solution
recorded after several months were identical to those of a freshly
prepared solution. All these bidentate complexes are highly water-
soluble.
Fig. 4. Reaction of potassium tetrachloroplatinate with 1 or 2.
2.5. Characterization of the complexes
The complexes 9e16 were all characterized by NMR spectros-
copy. A comparison of their principal signals, together with those of
the free ligands is shown in Table 1.
As revealed in Table 1, complexation to platinum moves the 1
H
NMR signals corresponding to the methyl and to the methylene
groups to the lower fields, with an average relative shift of
z0.4 ppm, indicating a decrease of the electronic density around
the H nuclei. This effect is also accompanied by the appearance of a
coupling constant between these protons and platinum (the J value
for complex 13 could not be determined due to interferences with
the solvent residual peak). It is noteworthy that in the case of
complex 12, where platinum is coordinated by benzyl methyl sul-
fide 2, the 1H NMR spectrum reveals a differentiation between the
two CH2 protons, showing their diastereotopic character due to the
formation of a stereogenic center at the sulfur atom by its coordi-
nation to the platinum. This effect is less marked in compound 10,
since only a broadening of the signal is observed. For the sulfoxide
ligands 3 and 5 and their corresponding platinum complexes 13
and 15, the diastereotopic character of the two CH2 protons is
clearly revealed by NMR spectroscopy. In the cases of trans-com-
plexes 9 and 10 no diastereomeric forms are observed, probably
because of their rapid exchange [22]. All the signals in 31P NMR are
shifted to the upper fields upon Pt coordination, by an amount
ranging from 1 up to 7 ppm. Finally, the 195Pt NMR reveals the
important electronic difference between sulfide and sulfoxides as
ligands toward platinum. Indeed, in each case the chemical shift is
lower for the sulfoxideeplatinum complexes, with Dd ranging from
200 to nearly 500 ppm (complex 12 compared to 13, 14 and 15).
There is a considerable difference in physical properties between
the dichlorido complexes 9 and 10 and the diammine complexes
Fig. 5. Reaction of Cisplatin with 1, 2 or 3, affording 11, 12 and 13.
2.3. Reactions of bifunctional ligands bearing a deprotonated
monoester group
After the failure to observe coordination by the bulky diiso-
propyl phosphonate group (see reactions with K2PtCl4, Section 2.2),
we investigated the reactions of ligands in which the phosphonate
has been partially hydrolyzed to the corresponding phosphonic
acid monoester. Thus, the reaction of the ligands 4 and 5 with the
diaqua form of cisplatin in the presence of KOH at room tempera-
ture gave the chelate complexes 14 and 15 (Fig. 6). The complexes
14 and 15 were isolated with modest yields (ranging from 29 to
58%) after crystallization, probably because of their relative insta-
bility, however, we could characterize them by NMR spectroscopy.
2.4. Reaction of a bifunctional ligand bearing a deprotonated
phosphonic acid group
Earlier work from our laboratory had shown that a reaction of 6
with cisplatin did not yield a bidentate complex but a dinuclear
product, due to the elimination of an NH3 group [14]. So as to avoid
Fig. 6. Preparation of complexes 14e16.

M. Hamel et al. / Journal of Organometallic Chemistry 745-746 (2013) 206e213
209
Table 1
11e16, since the former are completely insoluble in water and the
latter are highly soluble in water and methanol.
Comparison between characteristic signals of the ligands 1e6 and the complexes 9e
16.
Ligand/
complex nꢁ
Chemical shift in ppm and (3JPtH
)
2.6. Pyramidal configuration at S centers gives rise to
diastereomers. Transecis isomerization of complex 10
CH3eS (1H)
CH2eS (1H)
31P
195Pt
1a
2.49
2.71 (26)
2.95 (17)
e
e
e
15.8
12.5
12.1
e
9b
ꢀ3373
ꢀ2925
11c
Interestingly, we observed an isomerization of complex 10 to its
cis derivative. Thus, when we recorded the 195Pt NMR spectrum of a
one-month old solution of trans-10 in CDCl3, we observed, in
addition to the expected singlet at ꢀ3383 ppm, two more signals in
the area of ꢀ3540 ppm (Fig. 7). The chemical shift indicates that the
coordination remained PtCl2S2, and a plausible explanation is a
trans-to-cis isomerization. This isomerization may be catalyzed by
traces of free chloride anions contained in non-distilled CDCl3. It is
noteworthy that this isomerization has not been observed for
complex 9.
2a
2.08
2.44 (25)
2.45 (25)
4.10
4.70 (br)
4.38 (d) and 4.94 (d)
17.7
15.8
14.9
e
10b
12c
ꢀ3383
ꢀ2966
3b
2.63
3.34
4.12 (d) and 4.70 (d)
5.43 (d) and 5.62 (d)
16.0
15.2
e
13c
ꢀ3143
4a
2.47
2.54
e
e
19.4
12.0
e
14d
ꢀ1902
5b
2.72
3.10
e
e
11.2
9.3
e
15d
ꢀ2390
The difference of chemical shift between the two isomers
6d
2.52
2.39
e
e
14.0
10.0
e
(Dd z 160 ppm) is perfectly in agreement with those reported in the
16e
ꢀ2793
literature for similar PtCl2S2 systems (cis-[PtCl2(PhSMe)2] and trans-
[PtCl2(PhSMe)2] displaying chemical shifts at ꢀ3385 and ꢀ3488 ppm,
respectively [23]). Isomerization of trans-platinum complexes to their
cis derivatives is a well-known phenomenon [24], the latter being the
a
Recorded at 250 MHz in CDCl3.
Recorded at 400 MHz in CDCl3.
Recorded at 400 MHz in MeOD.
Recorded at 250 MHz in D2O.
Recorded at 400 MHz in D2O.
b
c
d
e
Fig. 7. 195Pt NMR spectrum of an aged solution of 10 (1 month in CDCl3 at 278 K, recorded at 298 K) showing the signals of the trans (left) and cis (right) isomers.

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M. Hamel et al. / Journal of Organometallic Chemistry 745-746 (2013) 206e213
Fig. 8. 31P NMR spectrum of an aged solution of 10 (1 month in CDCl3 at 278 K) recorded at 296 and 318 K, respectively.
thermodynamically-favored product, even if the ligands are sterically
hindered.
fact that only one peak is observed for the trans-isomer of 10 in
Figs. 7 and 8 is in agreement with considerably faster intercon-
version at S-centers systematically observed for trans-[PtCl2(dialkyl
sulfide)2] complexes as compared with cis-complexes [22].
In Fig. 7, the cis-complex 10 shows up as two peaks with a ratio
of integrals of z60:40. Two reasons could explain the presence of
two signals. First, the presence of two diastereomers due to the two
stereogenic centers at both sulfur atoms, and second, the steric
hindrance of the benzylic sulfide phosphorylated in the ortho po-
sition, which can produce rotamers.
3. Conclusion
In conclusion, we have demonstrated the ability of ortho-
phosphorylphenyl and benzyl sulfides and sulfoxides to act as li-
gands for platinum(II). These types of aromatic phosphorus and
sulfur difunctionalized ligands are readily obtained either via the
anionic [1,3] or [1,4] rearrangement, and can be produced on a
multi-gram scale. In the presence of a platinum source, the com-
pounds bearing a bulky diisopropyl phosphonate group behave as
monodentate ligands and bind the metal only via the sulfur atom,
while the phosphonic monoester or phosphonic acid derivatives act
as bidentate O,S-ligands. The fair water solubility of the cationic
monodentate complexes 11e13 bearing a dialkyl phosphonate
group, and the excellent water solubility of the chelate complexes
14e16 makes them good candidates for tests as potential anti-
tumor drugs. An interesting aspect of sulfide and sulfoxide com-
plexes is the inversion of configuration at asymmetric sulfur atoms.
For the bis-dialkylsulfide complex cis-10, we observed duplicated
31P and 195Pt NMR peaks due to the two diastereomers below 318 K,
and were able to confirm the interconversion rate earlier reported
for similar platinum complexes by Haake and Turley [22].
Haake and Turley [22,25] thoroughly investigated a series of
bis(dialkyl sulfide) cis-complexes of Pt(II), and observed by analysis
of NMR 1H spectra two peaks indicating two isomers, as well as
their coalescence at higher temperature. The authors concluded
that this is due to the inversion of configuration at the stereogenic
pyramidal sulfur coordinating atoms occurring without decom-
plexation from the metal. No evidence for hindered rotation about
the PteS bonds was found. It is very likely that the same phe-
nomenon is observed in our case. Indeed, the splitting of the signal
observed in the 195Pt NMR spectra of the cis-isomer of 10 also
appeared in the 31P NMR spectra (Fig. 8). Performing 31P NMR ex-
periments at different temperatures, we observed coalescence of
the two signals at 318 K, which allowed us to estimate the rates of
interconversion, k1 and kꢀ1. Eq. 6.5c [26] relates the lifetime sc at
the coalescence temperature with the difference in resonance fre-
quencies Dn, where pA and pB are the mole fractions of the two
interconverting conformations. From the 31P chemical shift differ-
ence of 0.14 ppm (Fig. 8), we calculate, with the frequency of
161.976 MHz used for 31P by our 400 MHz spectrometer,
Dn ¼ 22.677 sꢀ1. Since the approximate mole fractions pA and pB
are 0.4 and 0.6, respectively, we obtain, from this equation,
X z 1.888 and sc z 0.13 s. The rates of interconversion between
4. Experimental
4.1. General data
the diastereomers are thus k1 z 3.1 sꢀ1 and k
z 4.6 sꢀ1 at
ꢀ1
318 K. These rate constants are comparable to that observed for
the interconversion between the two diastereomers of cis-
[PtCl2{C6H5CH2)2S}2], 10.3 sꢀ1 at 307.5 K [22], which supports our
surmise that the same isomerization mechanism is operating. The
The quality of the solvents used was either RPE or RS. Tetrahy-
drofuran (THF) and toluene were purified with a PURESOLVÔ
apparatus developed by Innovative Technology Inc. Ultra deionized
water was obtained with a Milli-Q plus apparatus. DMF was

M. Hamel et al. / Journal of Organometallic Chemistry 745-746 (2013) 206e213
211
distilled over CaH2 and conserved under nitrogen atmosphere.
K2PtCl4 was purchased from Strem Chemicals. Cisplatin and cis-
dichloro(ethylenediammine)eplatinum were obtained from W. C.
Heraeus GmbH. NMR spectra were recorded on Brüker DPX 250 or
DRX 400 instruments. Chemical shifts are referenced to the
following: TMS for 1H, the solvent residual peak for 13C, 85% H3PO4
for 31P and 0.1 M K2PtCl4 in D2O (relative to Na2PtCl6) for 195Pt.
Coupling constants (J) are expressed in Hz. Mass spectra were ob-
tained on a GC/MS Saturn 2000 (EI or CI, 70 eV) or on a Waters
QTOF micro apparatus. Elemental analyses were obtained from a
THERMOQUEST NA 2500 instrument. IR spectra were recorded
with a Perkin Elmer 16 PC FT-IR instrument, or a Perkin Elmer ATR
universal FT-IR instrument. Compounds 1 and 6 were prepared
according to Ref. [17], 7 and 8 from Ref. [18].
1236; 981; 475. HRMS for C14H23O4NaPS (M þ Na): calculated
341.0952; found 341.0927.
4.4. Isopropyl 2-(methylsulfanyl)phenylphosphonic acid 4
Diisopropyl 2-(methylsulfanyl)phenylphosphonate 1 (1.318 g, 1
equiv, 4.57 mmol) and sodium azide (1.758 g; 8 equiv, 36.5 mmol)
were dissolved in DMF and heated to reflux for three days. The
obtained solid was filtered, washed several times with acetone, and
dissolved in a few quantity of methanol. The product was acidified
using Amberlyst 15 resin, and was further crystallized from acetone
to give a white solid.
Yield 61%; MP: 112 ꢁC (acetone). 1H NMR (250 MHz, CDCl3):
3
3
d
1.35 (d, 6H, JHH ¼ 6.2); 2.47 (s, 3H); 4.74 (dsept, 2H, JHH ¼ 6.2,
3JHP ¼ 1.5); 7.15 (dt, 1H, JHH ¼ 7.4, JHP ¼ 3.4); 7.26e7.33 (m, 1H);
3 4
7.44 (t, 1H, 3JHH ¼ 7.4); 7.92 (dd, 1H, 3JHP ¼ 14.8, 3JHH ¼ 7.6); 11.31 (s,
4.2. Diisopropyl 2-(methylsulfanylmethyl)phenylphosphonate 2
1H). 31P NMR (101 MHz, CDCl3): 19.4. 13C NMR (62.9 MHz, CDCl3):
d
d
17.2; 24.3 (d, 3JCP ¼ 5.0); 71.7 (d, 2JCP ¼ 6.3); 124.7 (d, 3JCP ¼ 14.5);
In a round-bottom flask filled with nitrogen, O,O-diisopropyl-(2-
iodobenzyl)-S-phosphorothioate 8 (508 mg, 1 equiv, 1.2 mmol) was
added to a solution of t-BuLi (1.4 mL, 2 equiv, 1.7 M in hexanes,
2.4 mmol) in 20 mL of THF at ꢀ78 ꢁC. After 2 h of stirring at ꢀ78 ꢁC,
MeI (3 equiv) was added, and the solution was stirred for another
2 h. The reaction was then quenched at ꢀ10 ꢁC with 10 mL of an
acidic saturated solution of NH4Cl. The aqueous phase was extrac-
ted with diethyl ether. The extracts were unified, washed with
brine, dried, filtered and concentrated to give a yellow oil, which
was further purified on silica gel chromatography (pentane/ethyl
acetate 70:30, Rf: 0.32).
127.2 (d, JCP ¼ 13.8); 128.5 (d, 1JCP ¼ 196.9); 132.8 (d, JCP ¼ 2.5);
3
4
2
2
134.4 (d, JCP ¼ 9.4); 143.2 (d, JCP ¼ 8.8). MSMS m/z (%): 269
(M þ Na; 100); 227 (70); 209 (40). IR (KBr) cmꢀ1: 1199; 1007; 910;
736. HRMS for C10H16O3PS (M þ H): calculated 247.0558; found
247.0555.
4.5. Isopropyl (2-methylsulfinyl)phenylphosphonic acid 5
To a solution of the sulfide 5 (250 mg, 1 equiv, 1.015 mmol) in
acetone (12 mL) was added dropwise an aqueous solution of so-
dium metaperiodate (239 mg, 1.1 equiv, 1.117 mmol, in 5 mL H2O) at
0 ꢁC. After complete addition the flask was conserved in the fridge
overnight. The precipitate was then filtered, and the residue was
crystallized from acetone/diethyl ether 1:1.
Yield 65%; colorless liquid. 1H NMR (250 MHz, CDCl3):
d 1.27 (d,
3
3
6H, JHH ¼ 6.2); 1.38 (d, 6H, JHH ¼ 6.2); 2.08 (s, 3H); 4.10 (s, 2H);
3
3
3
4.75 (dsept, 2H, JHP ¼ 12.4, JHH ¼ 6.2); 7.31 (dt, 1H, JHH ¼ 7.5,
4JHH ¼ 1.3); 7.31 (dt, 1H, 3JHH ¼ 7.6, 4JHH ¼ 1.4); 7.56e7.62 (m, 1H);
Yield: 61%; white solid. 1H NMR (400 MHz, CDCl3):
d
1.14 (d, 3H,
7.92 (ddd, 1H, JHP ¼ 14.3, JHH ¼ 6.9, JHH ¼ 0.7 Hz). 31P NMR
3
3
4
3
3JHH ¼ 6.0); 1.19 (d, 3H, JHH ¼ 6.4); 2.72 (s, 3H); 4.53 (sept, 1H,
(101.2 MHz, CDCl3):
d d 15.9; 24.2
17.7. 13C NMR (62.9 MHz, CDCl3):
3JHH ¼ 6.0); 7.45 (ddt, 1H, 3JHH ¼ 7.2, 4JHH ¼ 2.8, 4JHP ¼ 0.8); 7.66 (m,
3
3
3
(d, JCP ¼ 4.4); 24.4 (d, JCP ¼ 4.4); 36.4 (d, JCP ¼ 3.8 Hz); 71.3
3
3
3
1H, JHH ¼ 7.6); 7.80 (dd, 1H, JHP ¼ 13.6, JHH ¼ 7.2); 8.11 (m, 1H);
(d, JCP ¼ 5.7); 126.8 (d, JCP ¼ 14.5); 128.8 (d, 1JCP ¼ 185.2); 130.6
2
3
8.48 (s, 1H). 31P NMR (160 MHz, CDCl3):
d
11.2. 13C NMR (100.6 MHz,
3
4
2
(d, JCP ¼ 13.8); 132.6 (d, JCP ¼ 2.5); 13.2 (d, JCP ¼ 9.4); 142.4 (d,
2JCP ¼ 10.0). GC/MS m/z (%): 334 (M þ 1; 100); 256 (17); 201 (5); 172
(29); 41 (4). IR (NaCl) cmꢀ1: 2977; 1244; 979. Analysis for
C14H23O3PS: calculated (C: 55.61; H: 7.67; S: 10.60); found: (C:
55.34; H: 7.68; S: 10.86).
3
3
CDCl3):
d
23.7 (d, JCP ¼ 4.1); 23.9 (d, JCP ¼ 4.3); 44.1; 71.0 (d,
2JCP ¼ 5.9); 123.4 (d, JCP ¼ 11.8); 128.4 (d, 1JCP ¼ 188.6); 132.6 (d,
3
3JCP ¼ 13.0); 132.8 (d, JCP ¼ 8.4); 132.9; 149.0 (d, JCP ¼ 9.8).
2
2
4.6. Trans-dichlorido-bis-{2-(diisopropylphosphoryl)phenyl methyl
sulfide}platinum (II) 9
4.3. Diisopropyl 2-(methylsulfinylmethyl)phenylphosphonate 3
To 1.5 mL of an aqueous solution of potassium tetra-
chloroplatinate (128 mg, 1 equiv, 0.308 mmol) was added dropwise
a solution of the sulfide (168 mg, 1.9 equiv, 0.586 mmol) diluted in
3 mL of water. The reaction was stirred for one day. The resulting
precipitate was filtered, washed with 3 mL of water and dried. It
was crystallized from a mixture THF/pentane 1:2 to afford a clear
yellow solid. The complex can also be purified on silica gel chro-
matography (CHCl3/EtOH 98:2, Rf: 0.3).
To a solution of 2 (411 mg, 1 equiv, 1.36 mmol) in dichloro-
methane (6 mL) at ꢀ78 ꢁC was added dropwise a solution of mCPBA
(305 mg, 1 equiv, 77% purity, 1.36 mmol) in dichloromethane. The
solution was stirred during 1 h and an aqueous solution of sodium
hydrogen carbonate was added. After 30 min at room temperature,
the aqueous layer was extracted. The organic phase was washed
with water, dried on magnesium sulfate, filtered and evaporated to
give light yellow oil. The purification on silica gel chromatography
(ethyl acetate/ethanol 75:25, Rf: 0.3) afforded a colorless oil.
Yield 61%. MP ¼ 188 ꢁC (dec.). 1H NMR (400 MHz, CDCl3):
d 1.34
(d, 6H, 3JHH ¼ 6.2); 1.44 (d, 6H, 3JHH ¼ 6.0); 2.71 (t, 3H, 3JPtH ¼ 26.0);
4.70e4.85 (m, 2H); 7.53 (dt, 1H, 3JHH ¼ 7.4, 4JHH ¼ 2.9); 7.67 (t, 1H,
Yield 99%. 1H NMR (400 MHz, CDCl3):
d
1.24 (d, 3H, 3JHH ¼ 6.2);
3
3
1.26 (d, 3H, JHH ¼ 6.2); 1.36 (d, 3H, JHH ¼ 6.2); 1.37 (d, 3H,
3JHH ¼ 7.5); 7.99 (ddd, 1H, 3JHP ¼ 14.1, 3JHH ¼ 6.5, 4JHH ¼ 0.7); 8.77 (t,
2
3
3JHH ¼ 6.2); 2.63 (s, 3H); 4.12 (d, 1H, JHH ¼ 12.6); 4.68e4.79 (m,
1H, JHH ¼ 7.2). 31P NMR (161 MHz, CDCl3):
d
12.5. 13C NMR
24.4 (d, JCP ¼ 4.1); 24.5 (d, JCP ¼ 4.3); 25.9;
3
3
3H); 7.40e7.48 (m, 1H); 7.50e7.58 (m, 2H); 7.89 (ddd, 1H,
(101 MHz, CDCl3):
d
3
4
3JHP ¼ 14.0, 3JHH ¼ 7.6, 4JHH ¼ 1.1). 31P NMR (160 MHz, CDCl3):
d
16.0.
72.7; 130.6 (d, JCP ¼ 13.7); 133.2 (d, JCP ¼ 2.5); 133.2 (d,
13C NMR (100.6 MHz, CDCl3):
d
24.2 (d, JCP3
¼
4.9); 24.3
1JCP ¼ 190.8); 134.5 (d, JCP ¼ 8.6); 135.9 (d, JCP ¼ 6.6); 138.1 (d,
3
2 2
3
3
(d, JCP ¼ 4.6); 24.5 (d, JCP ¼ 4.7); 38.8; 59.8 (d, JCP ¼ 3.5); 71.7
3JCP ¼ 11.5). 195Pt NMR (85.7 MHz, CDCl3):
d
ꢀ3373. IR (KBr) cmꢀ1
:
(d, 2JCP ¼ 5.9); 128.4 (d, 3JCP ¼ 14.2); 129.5 (d, 1JCP ¼ 184.2); 132.6 (d,
2978; 1453; 1239; 987. MSMS m/z (%): 341 (M þ Na ꢀ 1 ligand; 28);
299 (35); 278 (91); 263 (100); 257 (29); 236 (27); 147 (17). Analysis
for C26H42Cl2O6P2PtS2: calculated (C: 37.06; H: 5.02; S: 7.61); found
(C: 37.32; H: 5.22; S: 7.64).
4
2
3JCP ¼ 14.1); 132.9 (d, JCP ¼ 2.8); 134.2 (d, JCP ¼ 8.2); 135.2 (d,
2JCP ¼ 10.0). MSMS m/z (%): 341 (M þ Na; 28); 299 (35); 278 (91);
263 (100); 257 (29); 236 (27); 147 (17). IR (NaCl) cmꢀ1: 2979; 2932;

212
M. Hamel et al. / Journal of Organometallic Chemistry 745-746 (2013) 206e213
3
2
4.7. Trans-dichlorido-bis-{2-(diisopropylphosphoryl)benzyl methyl
sulfide}platinum (II) 10
3JHP ¼ 8.0, JHH ¼ 6.4); 5.43 (d, 1H, JHH ¼ 13.6); 5.62 (d, 1H,
2JHH ¼ 14.0); 7.68e7.75 (m, 3H); 7.87 (dd,1H, 3JHP ¼ 14.0, 3JHH ¼ 7.2).
31P NMR (161 MHz, CD3OD):
d
15.2. 13C NMR (101 MHz, CD3OD):
This complex was prepared according to the procedure
described for complex 9 from sulfide 2.
d
23.1 (d, 3JCP ¼ 5.3); 23.2 (d, 3JCP ¼ 5.8); 23.3 (d, 3JCP ¼ 5.6); 23.4 (d,
3JCP ¼ 4.1); 41.2; 62.0; 72.5 (d, 2JCP ¼ 6.0); 72.6 (d, 2JCP ¼ 6.0); 129.8
(d, 3JCP ¼ 13.4); 130.4 (d, 1JCP ¼ 185.4); 130.8 (d, 2JCP ¼ 13.1); 134.5
(d, 4JCP ¼ 2.7); 133.4 (d, 3JCP ¼ 14.1); 134.3 (d, 2JCP ¼ 6.9). 195Pt NMR
Yield 53%; yellow solid; MP: 140e142 ꢁC. 1H NMR (400 MHz,
CDCl3):
d
1.26 (d, 6H, 3JHH ¼ 6.0); 1.42 (d, 6H, 3JHH ¼ 6.0); 2.45 (t, 3H,
3
3JPtH ¼ 25.3 Hz); 4.70 (br s, 2H); 4.77 (dsept, 2H, JHP ¼ 12.4,
(85.7 MHz, CD3OD):
1360 (NO2); 1222; 1139
d
ꢀ3143. IR (Neat) cmꢀ1: 3165 (
n NeH); 2979;
3JHH ¼ 6.0); 7.42 (ddt, 1H, 3JHH ¼ 7.6, 4JHH ¼ 3.6, 4JHP ¼ 0.8); 7.55 (t,
(n
SeO); 983. Analysis for
3
1H, JHH ¼ 7.6); 7.88e7.96 (m, 2H). 31P NMR (161 MHz, CDCl3):
C
14H29ClN3O7PPtS: calculated (C: 26.73; H: 4.65; N: 6.68; S: 5.10);
found (C: 26.47; H: 4.92; N: 7.05; S: 5.16). HRMS for
14H29ClN2O4PPtS (M þ H): calculated 582.0922; found 582.0914.
d
15.8. 13C NMR (101 MHz, CDCl3):
d
20.4; 24.3 (d, 3JCP ¼ 4.7); 24.5
3
3
3
(d, JCP ¼ 4.0); 39.7 (d, JCP ¼ 3.1); 71.9 (d, JCP ¼ 5.9); 128.3 (d,
C
3JCP ¼ 14.2); 130.2 (d, 1JCP ¼ 184.6); 132.4 (d, 3JCP ¼ 13.8); 132.8 (d,
4JCP ¼ 2.9); 134.3 (d, JCP ¼ 8.9); 137.3 (d, JCP ¼ 9.6). 195Pt NMR
4.11. Cis-diammine-{isopropyl 2-(methylsulfanyl)
phenylphosphonato}platinum (II) nitrate 14
2
2
(85.7 MHz, CDCl3):
d
ꢀ3383. IR (neat) cmꢀ1: 2978; 1427; 1234; 971.
MSMS m/z (%): 870 (MHþ; 35); 835 (MeCl; 100); 799 (eCl; 17); 756
(5). HRMS for C28H47Cl2O6P2PtS2 (M þ H): calculated 870.1314;
found 870.1301.
Cis-diamminedichloroplatinum (300 mg, 1 mmol, 1.00 equiv)
and silver nitrate (334 mg, 1.99 mmol, 1.99 equiv) were dissolved
in distilled water. The solution was stirred during 24 h at room
temperature. The solution was then filtered in order to obtain a
4.8. Cis-diammine-chlorido-{2-(diisopropylphosphoryl)phenyl
methyl sulfide}platinum (II) nitrate 11
colorless solution of cis-[Pt(NH3)2(H2O)2](NO3)2. In a round-
bottom flask, the sulfide 4 (1 mmol) was dissolved in water. Po-
tassium hydroxide (1 mmol, 1 equiv) was added to the solution.
The mixture was stirred for 10 min and the solution of cis-
[Pt(NH3)2(H2O)2](NO3)2 was added. The reaction was stirred for
5 h at 65 ꢁC. After filtration, the solution was left in the fridge for
crystallization. The obtained solid was filtered off, washed with
Et2O and dried under vacuum. This procedure was repeated for the
synthesis of complexes 15 and 16.
To a slurry methanolic solution of cisplatin (40 mg, 1 equiv,
0.133 mmol) and the sulfide 1 (38 mg, 1 equiv, 0.133 mmol) was
added AgNO3 (22 mg, 1 equiv, 0.133 mmol) dissolved in boiling
MeOH. The mixture was stirred for one day in the dark and the
precipitated AgCl was filtered off. The crude complex was washed
several times with diethyl ether to afford a clear yellow powder.
This procedure has been extended to the synthesis of the com-
plexes 12 and 13.
Yield 47%; white solid. 1H NMR (250 MHz, D2O):
d 1.22 (d, 3H,
Yield: 60%. 1H NMR (400 MHz, CD3OD):
d
1.41 (d, 12H,
3JHH ¼ 6.2); 1.30 (d, 3H, 3JHH ¼ 5.8); 2.54 (s, 3H); 4.20e4.39 (m, 1H);
3JHH ¼ 6.4); 2.95 (t, 3H, JPtH ¼ 17.0 Hz); 4.80e4.95 (m, 2H); 7.72
7.14 (t, 1H, 3JHH ¼ 7.0); 7.33e7.53 (m, 2H); 7.81 (dd, 1H, 3JHP ¼ 14.0,
3
(ddt, 1H, 3JHH ¼ 7.6, 4JHH ¼ 3.2, 4JHP ¼ 1.2); 7.85e7.97 (m, 2H); 8.21e
3JHH ¼ 7.1). 31P NMR (161 MHz, D2O):
d
12.0. 195Pt NMR (53.7 MHz,
8.26 (m,1H). 31P NMR (161 MHz, CD3OD):
d
12.1. 13C NMR (101 MHz,
D2O):
d
ꢀ1902.
CD3OD):
d
22.1; 23.1 (d, 3JCP ¼ 5.0); 23.3 (d, 3JCP ¼ 3.4); 73.5; 130.9
(d, 1JCP ¼ 192.5); 130.9 (d, 3JCP ¼ 13.2); 132.8 (d, 3JCP ¼ 12.0); 133.1
4.12. Cis-diammine-{isopropyl 2-(methylsulfinyl)
phenylphosphonato}platinum (II) nitrate 15
(d, 2JCP ¼ 8.4); 134.1 (d, 2JCP ¼ 7.4); 134.5 (d, 4JCP ¼ 2.6). 195Pt NMR
(85.7 MHz, CD3OD):
d
ꢀ2925.
Yield 29%; Aspect: white solid. 1H NMR (250 MHz, D2O):
d 1.30
4.9. Cis-diammino-chlorido-{2-(diisopropylphosphoryl)benzyl
methyl sulfide}platinum (II) nitrate 12
(d, 3H, 3JHH ¼ 6.2); 1.40 (d, 3H, 3JHH ¼ 6.2); 3.10 (s, 3H); 4.60 (dsept,
3
3
1H, JHP ¼ 8.4, JHH ¼ 6.2); 7.75e7.85 (m, 1H); 7.92e8.11 (m, 2H);
8.12e8.17 (m, 1H). 31P NMR (101 MHz, D2O):
(53.7 MHz, D2O):
ꢀ2390.
d
9.3. 195Pt NMR
Yield 89%; white solid. MP: 222e224 ꢁC. 1H NMR (400 MHz,
d
3
3
CD3OD):
d
1.30 (d, 6H, JHH ¼ 6.0); 1.30 (d, 6H, JHH ¼ 6.4); 2.42 (t,
3H, 3JPtH ¼ 25.1); 4.41 (d, 1H, 2JHH ¼ 12.8); 4.67e4.79 (m, 2H); 4.95
4.13. Cis-ethylenediammine-{2-(methylsulfanyl)
phenylphosphonato}platinum (II) nitrate 16
2
(d, 1H, JHH ¼ 12.4); 7.57e7.62 (m, 2H); 7.67e7.71 (m, 1H); 7.87
3
3
4
(ddd, 1H, JHP ¼ 14.0, JHH ¼ 8.4, JHH ¼ 2.0). 31P NMR (161 MHz,
CD3OD):
d
14.8. 13C NMR (101 MHz, CD3OD):
d
17.5; 23.1 (d,
Yield 58%; white solid. MP: 204e206 ꢁC (decomp.). 1H NMR
(400 MHz, D2O): d 2.39 (s, 3H); 7.11e7.19 (m, 1H); 7.30e7.45 (m,
3
3
3JCP ¼ 4.7); 23.2 (d, JCP ¼ 8.0); 42.7 (d, JCP ¼ 3.4); 72.3 (d,
2
1
3
3
4
2JCP ¼ 5.9); 73.4 (d, JCP ¼ 5.8); 128.9 (d, JCP ¼ 185.5); 129.1 (d,
2H); 7.66 (ddd, 1H, JHP ¼ 14.2, JHH ¼ 7.6, JHH ¼ 1.3). 31P NMR
3JCP ¼ 13.6); 132.1 (d, JCP ¼ 14.5); 133.3 (d, JCP ¼ 2.8); 134.5 (d,
(161 MHz, D2O): d d 26.8; 46.1;
10.0. 13C NMR (100.6 MHz, D2O):
3
4
2JCP ¼ 7.2); 137.0 (d, JCP ¼ 11.5). 195Pt NMR (85.7 MHz, CD3OD):
49.6; 130.2 (d, 2JCP ¼ 5.5); 131.4 (d, 3JCP ¼ 12.1); 131.9 (d, 4JCP ¼ 2.1);
2
d
ꢀ2966. IR (Neat) cmꢀ1: 3159 (
n NeH); 2977; 1350 (NO2); 1218;
133.1 (d, 3JCP ¼ 9.3); 133.9 (d, 2JCP ¼ 7.0); 138.2 (d, 1JCP ¼ 170.9). 195Pt
979. MSMS m/z (%): 567 (MHþ; 40); 550 (MeNH3; 100); 508 (33);
466 (10). Analysis for C14H29ClN3O6PPtS: calculated (C: 26.07; H:
4.53; N: 6.52; S: 4.97); found (C: 25.87; H: 4.44; N: 6.85; S: 5.51).
HRMS for C14H29ClN2O3PPtS (Mþ): calculated 566.0973; found
566.0965.
NMR (53.7 MHz, D2O):
d
ꢀ2793. IR (neat) cmꢀ1: 3157; 2263; 1368;
1123; 1042. MSMS m/z (%): 459 (MHþeNO3; 100); 411 (42); 379
(80). HRMS for C9H17N2O3PPtS (M þ H): calculated 459.0345; found
459.0338.
Acknowledgments
4.10. Cis-diammine-chlorido-{2-(diisopropylphosphoryl)benzyl
methyl sulfoxide}platinum (II) nitrate 13
M.H. gratefully acknowledges the “ Ministère de la Recherche et
des Nouvelles Technologies” for the grant and the “région Basse-
Normandie” and the European Union (FEDER funding), for financial
support. We thank W.C. Heraeus GmbH for a generous gift of pre-
cursor platinum complexes.
Yield 73%; white solid. MP: 172e174 ꢁC. 1H NMR (400 MHz,
CD3OD):
d
1.29 (d, 6H, 3JHH ¼ 6.0); 1.30 (d, 6H, 3JHH ¼ 6.4); 1.34 (d,
3H, 3JHH ¼ 6.0); 1.41 (d, 3H, 3JHH ¼ 6.0); 3.34 (s, 3H); 4.77 (dsept, 2H,

M. Hamel et al. / Journal of Organometallic Chemistry 745-746 (2013) 206e213
213
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