Nonsteroidal Anti-inflammatory-Organometallic Anticancer Compounds

Article

pubs.acs.org/IC

Nonsteroidal Anti-inﬂammatoryOrganometallic Anticancer

Compounds

Emilia Paunescu, Sarah McArthur, Mylene Soudani, Rosario Scopelliti, and Paul J. Dyson*

̆

̀

Institut des Sciences et Ingen

́

ierie Chimiques, Ecole Polytechnique Fed

́

er

́

ale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland

S

* Supporting Information

ABSTRACT: Compounds that combine metal-based drugs with

covalently linked targeted organic agents have been shown, in some

instances, to exhibit superior anticancer properties compared to the

individual counterparts. Within this framework, we prepared a series

of organometallic ruthenium(II)- and osmium(II)-p-cymene com-

plexes modiﬁed with the nonsteroidal anti-inﬂammatory drugs

(NSAIDs) indomethacin and diclofenac. The NSAIDs are attached

to the organometallic moieties via monodentate (pyridine/

phosphine) or bidentate (bipyridine) ligands, aﬀording piano-stool

Ru(II) and Os(II) arene complexes of general formula [M(η⁶-p-

cymene)Cl₂(N)], where N is a pyridine-based ligand, {2-(2-(1-(4-

chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-3-

(pyridin-3-yl)propanoate} or {2-(2-(2-((2,6-dichlorophenyl)amino)-

phenyl)acetoxy)ethyl-3-(pyridin-3-yl)propanoate}, [M(η⁶-p-

cymene)Cl₂(P)], where P is a phosphine ligand, {2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-

4-(diphenylphosphanyl)benzoate} or {2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl-4-(diphenylphosphanyl)-

benzoate, and [M(η⁶-p-cymene)Cl(N,N′)][Cl], where N,N′ is a bipyridine-based ligand, (4′-methyl-[2,2′-bipyridin]-4-

yl)methyl-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate), (4′-methyl-[2,2′-bipyridin]-4-yl)methyl-2-(2-

((2,6-dichlorophenyl)amino)phenyl)acetate), (bis(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)-

ethyl)[2,2′-bipyridine]-5,5′-dicarboxylate), or (bis(2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl)[2,2′-bipyridine]-

5,5′-dicarboxylate). The antiproliferative properties of the complexes were assessed in human ovarian cancer cells (A2780 and

A2780cisR, the latter being resistant to cisplatin) and nontumorigenic human embryonic kidney (HEK-293) cells. Some of the

complexes are considerably more cytotoxic than the original drugs and also display signiﬁcant cancer cell selectivity.

been extensively studied. RAPTA-C exerts antimetastatic,^8,9

INTRODUCTION

■

antiangiogenic,¹³and antitumor eﬀects.¹⁰These compounds

have been extensively modiﬁed via derivatization of the η⁶-

arene moiety or with various mono- or bidentate leg ligands.

Related osmium-based compounds, typically showing slower

exchange kinetics than those of ruthenium analogues, have also

been evaluated in vitro¹⁴⁻¹⁹and in vivo.^11,20−22In this context,

bioactive organic compounds tethered to the complexes have

been shown to signiﬁcantly modulate the activity and selectivity

of the organometallic scaﬀold.^20,23−31Indeed, the intra-

molecular combination of a ruthenium(II)-arene moiety with

an organic drug can lead to substantial enhancements in

antiproliferative activity.^{14,23,24,26,32−36}

Metal ions are an important building-block for the generation

of chemical diversity in the search for novel therapeutic and

diagnostic agents, especially anticancer drugs. Following the

remarkable success of platinum-based chemotherapeutics,¹

ruthenium complexes have emerged as an encouraging class

of anticancer agents, and two ruthenium compounds have been

evaluated in the clinic. The compounds evaluated in clinical

trials are imidazolium trans-[tetrachlorido(dimethyl sulfoxide)-

(1H-imidazole)ruthenate(III)] (NAMI-A), which reduces the

number and size of solid metastatic tumors²⁻⁴and which

recently completed a phase II trial in combination with

gemcitabine,³and indazolium trans-[tetrachloridobis(1H-

indazole)ruthenate(III)] (KP1019) or its sodium salt

KP1339, which are active against a number of primary

human tumors (Figure 1).⁵⁻⁷

Nonsteroidal anti-inﬂammatory drugs (NSAIDs) have

recently been shown to exhibit chemo-preventive and

anticancer eﬀects,³⁷⁻⁴⁴and studies have shown that they can

increase the activity of certain anticancer drugs when applied in

combination.⁴⁵⁻⁵²Certain NSAIDS are even moderately

eﬀective against colorectal and ovarian cancers.⁵²⁻⁵⁵

Organometallic ruthenium(II)-arene compounds oﬀer a

versatile platform for the design of novel anticancer agents,

and for example, [Ru(II)(η⁶-p-cymene)(PTA)Cl₂] (PTA =

1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane, RAPTA-C)⁸⁻¹⁰

and [Ru(II)(η⁶-biphenyl)(en)Cl][PF₆] (en = ethylenediamine,

RM175)^11,12(Figure 1) represent lead structures that have

Received: November 23, 2015

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synergistic eﬀects with traditional chemotherapeutics (indome-

thacin and diclofenac are both cyclooxygenase inhibitors).⁶⁶⁻⁶⁸

Since various studies have established a relationship between

inﬂammation and carcinogenesis, the development of new

anticancer chemotherapeutics combining a metal unit with an

anti-inﬂammatory drug represents an attractive approach. In

this context, a cobalt(0) carbonyl complex with a pendant

aspirin moiety shows promising antiproliferative and antiangio-

genic properties^69,70and silver(I) complexes modiﬁed with

naproxen and salicilic acid show higher activity than cisplatin

against leiomyosarcoma and breast cancer cells.^71,72Other

studies combine NSAIDs with essential metal ions such as

Cu(II), Zn(II), and Co(II).⁷³⁻⁷⁸The dinuclear complex

[Cu₂(indomethacin)₄(DMF)₂] was shown to inhibit colorectal

cancer growth in rats with only low levels of observed renal and

gastrointestinal toxicity.^77,79Pt(II) and Pt(IV) complexes with

indomethacin or ibuprofen conjugates were found to overcome

cisplatin resistance in COX-2-expressing triple negative breast

cancer cells and ovarian adenocarcinoma cells (Figure 2).^80,81

Mixed valent Ru₂(II/III)-NSAID (ibuprofen, aspirin, naproxen,

indomethacin, or ketoprofen) paddlewheel complexes have

been reported.⁸²⁻⁸⁴Coordination to the Ru₂(II/III) core

signiﬁcantly increases the inhibition of C6 rat glioma tumor-cell

proliferation compared to the organic compounds alone.

Ruthenium(II)-arene complexes with oxicam-derived ligands

have been recently reported (Figure 2).³⁵In these compounds

the anti-inﬂammatory drug is directly complexed to the

ruthenium(II) center. Based on these studies we decided to

tether NSAID moieties to monodentate or bidentate ligands

and then to coordinate them to ruthenium(II)- or osmium(II)-

p-cymene units, thereby creating conjugates with possible new

modes of action. Herein, we describe the synthesis and

characterization of these compounds and also report on their

promising biological properties.

Figure 1. Structures of the ruthenium complexes NAMI-A, KP1019,

KP1339, RAPTA-C, and RM175.

The anti-inﬂammatory eﬀect of NSAIDs is mainly attributed

to the inhibition of cyclooxygenase (COX)-mediated produc-

tion of prostaglandins, although COX-independent mecha-

nisms have also been considered.^56,57COX-1 is commonly

found in the kidney, stomach, and platelets, where it helps to

maintain normal physiological function, i.e. control of renal

parenchyma, gastric mucosa protection and gastric acid

regulation, and platelet function, whereas COX-2 is mainly

found in macrophages, leukocytes, and ﬁbroblasts, where it

produces the prostaglandins involved in inﬂammation and

mitogenesis. The mechanism of action responsible for the

antitumorigenic eﬀects of NSAIDs remains unclear.^55,58−60

COX-independent mechanisms of cancer chemoprevention by

anti-inﬂammatory drugs have been proposed.⁴¹Nonetheless,

COXs are known to play a role in tumor growth, progression,

migration, and angiogenesis,⁶¹which makes them interesting

anticancer targets. For example, COX-2 is involved in

tumorigenesis (especially of gastrointestinal and colorectal

cancer),^43,62−65and inhibitors of the enzyme are increasingly

used as adjuvant modulators in anticancer therapies due to their

RESULTS AND DISCUSSION

■

The two NSAIDS considered for this study, indomethacin (1,

2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-

indol-3-yl}acetic acid) and diclofenac (2, 2-(2,6-dichloranilino)-

phenylacetic acid) (Figure 2), are eﬃcient inﬂammation

Figure 2. Structures of indomethacin (1), diclofenac (2), indomethacin Pt(II) and Pt(IV) conjugates, and a Ru(II)-p-cymene complex bearing an

oxicam-derived ligand.

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Scheme 1. Synthesis of the Indomethacin-Based Intermediate L1a; Pyridine Complexes 1a, 1b; Phosphine Complexes 3a, 3b

(top); Diclofenac-Based Intermediate L2a; Pyridine Complexes 2a, 2b; and Phosphine Complexes 4a, 4b (bottom)

modulators used to treat painful conditions and are also shown

to exhibit promising anticancer properties.^{54,55,59,85−90}They are

both classiﬁed as phenylalkanoic acids presenting an easy

derivatizable carboxylic group. Previous reports indicate that

modiﬁcation of the carboxylic group does not impair biological

activity.⁹¹⁻⁹³Monodentate pyridine- and phosphine-based

ligands modiﬁed with indomethacin and diclofenac were

prepared as shown in Scheme 1. In the ﬁrst step, indomethacin

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Scheme 2. Synthesis of the Indomethacin Ligand L5 and Complexes 5a, 5b (left) and the Diclofenac Ligand L6 and Complexes

6a, 6b (right)

or diclofenac are reacted with ethylene glycol, leading to

intermediates L1a and L2b, respectively, which are further

coupled with 3-(pyridin-3-yl)propanoic acid or 4-

(diphenylphosphanyl)benzoic to obtain the pyridine ligands

L1 and L2 and the phosphine ligands L3 and L4 in reasonable

overall yields, with the coupling reactions being conducted in

the presence of EDCI (1-ethyl-3-(3-(dimethylamino)propyl)-

carbodiimide) as coupling agent and DMAP ((4-

dimethylamino)pyridine) as catalyst. The ruthenium(II)-p-

cymene complexes 1a, 2a, 3a, and 4a and osmium(II)-p-

cymene complexes 1b, 2b, 3b, and 4b were obtained from the

direct reaction of the appropriate ligands with the metal-dimers

[M(η⁶-p-cymene)Cl]₂Cl₂(M = Ru and Os; Scheme 1). All

corresponding to the p-cymene ligand shifting to lower

frequencies, i.e. Δδ_H≈ 0.3 ppm for 3a, 3b and Δδ_H≈ 0.9

ppm for 4a, 4b. Electrospray ionization mass spectrometry

(ESI-MS) corroborated the spectroscopic data with the ligands

exhibiting molecular ion peaks corresponding to [M + H]⁺ions

and the complexes as [M − Cl]⁺ions. Complexes 3a, 3b and

4a, 4b are stable in DMSO-d₆at r.t. (see Figures S12−S15,

Supporting Information), whereas 1a, 1b and 2a, 2b react over

time, presumably involving substitution of the chloride ligands

and possibly the pyridine ligand by DMSO-d₆. In water, in the

absence of DMSO, the compounds are likely to be more stable.

Indomethacin and diclofenac were also conjugated to a

bipyridine ligand. Ligands L5 and L6 were obtained in a single

step by direct reaction with indomethacin or diclofenac with 4-

hydroxymethyl-4′-methyl-2,2′-bipyridyl in the presence of

EDCI/DMAP (Scheme 2). Ligands L5 and L6 were reacted

with the metal dimers [M(η⁶-p-cymene)Cl]₂Cl₂(M = Ru and

Os), aﬀording complexes 5a, 5b, 6a, and 6b in good yield.

1

compounds were characterized by H, ³¹P (when appropriate),

and ¹³C NMR spectroscopy, mass spectrometry, IR spectros-

copy, and elemental analysis (see Experimental Section for full

details).

The ¹H NMR spectra of ligands L1 and L2 diﬀer from those

of the complexes, with coordination to the ruthenium(II) ion,

leading to the two protons in the α position to the pyridine

nitrogen atom being observed at higher frequencies, by ca. Δδ_H

≈ 0.5 ppm. In the ¹³C NMR spectra of 1a and 2a the

corresponding C atoms α to the pyridine nitrogen are also

observed at higher frequencies than in the ligands, Δδ_C≈ 5

ppm. A similar, but slightly less pronounced eﬀect, is observed

in the ¹H and ¹³C NMR spectra of the osmium(II) derivatives,

1b and 2b (Δδ_H≈ 0.4 ppm and Δδ_C≈ 4 ppm). The phosphine

ligands L3 and L4 exhibit peaks at −4.96 and −5.01 ppm,

respectively. Following coordination of the ruthenium(II) ion,

these peaks are observed at 25.12 ppm for 3a and 24.94 ppm

for 4a, and for the osmium(II) complexes, the corresponding

signals appear at −12.31 ppm for 3b and −12.50 ppm for 4b.

Coordination of the phosphine ligands results in the peaks

1

The compounds were characterized by H and ¹³C NMR

spectroscopy, mass spectrometry, IR spectroscopy, and

elemental analysis (see Experimental Section for full details).

The ¹H NMR spectra of the ligands, L5 and L6, with respect to

the corresponding ruthenium(II) and osmium(II)-p-cymene

complexes, 5a, 5b, 6a, and 6b, show trends similar to the

pyridine complexes described above; that is, the α protons on

the heterocycle shift to higher frequencies (Δδ_H0.7−1.2 ppm),

whereas the two protons in the β position to the N atoms are

1

less aﬀected (Δδ_H≈ 0.4 ppm). The H and ¹³C NMR spectra

of 5a, 6a and 5b, 6b reveal diastereotopic splitting for peaks

corresponding to the p-cymene ring protons as well as to the

iso-propyl group protons, and the corresponding carbon atoms,

due to chirality at the metal center from loss of the 2-fold

symmetry of the M(II)-p-cymene moiety.¹⁸

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Scheme 3. Synthesis of the Indomethacin Ligand L7 and Complexes 7a, 7b (left) and the Diclofenac Ligand L8 and Complexes

8a and 8b (right)

Coordination of nonsymetrical N,N-ligands is accompanied

in the ¹H NMR spectra by diastereotopic splitting of the signals

corresponding to the η⁶-bound p-cymene ring, i.e. four doublets

for the aromatic ring protons and two doublets for the methyl

groups of the iso-propyl moiety.⁹⁴⁻⁹⁶In addition, coordination

of L5 and L6 to the ruthenium center in 5a and 6a is

accompanied by a shift toward slightly higher frequencies with

Δδ_H≈ 0.6−0.7 ppm of the p-cymene ring peaks.

The bis-substituted bipyridine ligands L7 and L8 were also

prepared from the reaction of [2,2′-bipyridine]-5,5′-dicarbox-

ylic acid and the intermediates L1a and L2a (Scheme 3).

Ligands L7 and L8 were subsequently reacted with the dimers

[M(η⁶-p-cymene)Cl]₂Cl₂(M = Ru or Os) to aﬀord 7a, 7b, 8a,

and 8b in high yield.

higher frequency than those observed in the spectra of the

dimer in CDCl₃, Δδ_H≈ 0.5 ppm (in CDCl₃for [Ru(η⁶-p-

cymene)Cl₂]₂, the p-cymene arene protons appear at 5.33 and

5.46 ppm, while, for [Os(η⁶-p-cymene)Cl₂]₂, the equivalent

protons appear at 6.01 and 6.17 ppm). The ESI-MS of L5−L8

contain a parent ion peak attributable to the [M + H]⁺ion and

complexes 5a, 6a, 5b, 6b, 7a, 7b, 8a, and 8b contain a strong

peak corresponding to the [M − Cl]⁺ion. All the bipyridine-

containing complexes are stable in DMSO-d₆at r.t. (see Figures

S16−S19, Supporting Information).

The solid state structure of L4 containing the diclofenac

moiety was established by single crystal X-ray diﬀraction

analysis (Figure 3), conﬁrming the expected molecular

structure. The structure reveals a bifurcated intramolecular H-

bond interaction between the diclofenac secondary amine N−

H and the oxygen atom of the ester group (contact D−H···A

corresponds to N−H···O) and one of the chlorine atoms of the

dichlorophenyl unit (contact D−H···A corresponds to N−H···

Cl) (parameters characterizing these interactions are provided

in Tables 1 and 2).

Similar changes to those described above were observed in

1

the H NMR spectra of L7 and L8 and their corresponding

complexes; that is, the protons in the α positions of the

bipyridine ring system are shifted to higher frequency (Δδ_H≈

0.4−0.5). In keeping with 5a and 6a, the peaks corresponding

to the p-cymene ring protons in 7a and 8a are observed at

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Figure 4. ORTEP representation of L6 (thermal ellipsoids are 50%

equiprobability envelopes, and H atoms are spheres of arbitrary

diameter).

Figure 3. ORTEP representation of L4 (thermal ellipsoids are 50%

equiprobability envelopes, and H atoms are spheres of arbitrary

diameter).

Table 1. Intramolecular H-Bonding Interactions (Contact

D−H···A Corresponds to N−H···O) for Ligands L4, L6, and

L8 and Complex 8a

Distance, Å

Angle, deg

Compound

D−H

H···A

D···A

D−H···A

L4

L6

L8

0.872

0.873

0.893

0.966

0.910

2.212

2.184

2.518

2.428

2.457

2.995

2.958

3.220

3.057

2.977

149.32

147.65

135.93

122.41

116.53

8b

Table 2. Intramolecular H-Bonding Interactions (Contact

D−H···A Corresponds to N−H···Cl) for Ligands L4, L6, and

L8 and Complex 8a

Distance, Å

Angle, deg

Compound

D−H

H···A

D···A

D−H···A

L4

L6

L8

0.872

0.873

0.893

0.966

0.910

2.664

2.578

2.526

2.504

2.335

3.004

2.992

3.005

3.032

3.003

104.50

110.11

114.27

114.26

130.06

Figure 5. ORTEP representations of L8 (top) and 8b (bottom).

Thermal ellipsoids are 50% and 30% equiprobability envelopes,

respectively, for L8 (top) and 8b (bottom), and H atoms are spheres

of arbitrary diameter. In the structure of 8b the chloride counterion

has been omitted for clarity.

8b

The solid state structure of L6 was also determined (Figure

4), conﬁrming the expected molecular structure, and as for L4,

intramolecular H-bonds between the diclofenac secondary

amine N−H and the oxygen atom of the CO ester group are

observed (see Tables 1 and 2). The two pyridine rings are

coplanar (torsion angle N(1)−C−C−N(2) 176.20°) with a

distance between the two nitrogen atoms N(1)···N(2) of 3.623

Å. The bipyridine unit is coplanar with the chloroarene moiety

(Figure S4).

The solid state structures of ligand L8 and its corresponding

osmium complex 8b were established by single crystal X-ray

diﬀraction (Figure 5). In both structures bifurcated intra-

molecular H-bond interactions similar to those observed in L4

and L6 are present (Tables 1 and 2). The two pyridine rings in

L8 are coplanar with a N(1)−C−C−N(2) torsion angle of

180.00°, similar to the topology observed in L6. Complex 8b

adopts the familiar half-sandwich three-legged “piano-stool”

geometry with the η⁶-p-cymene ring forming the seat and the

bipyridine and chloride ligands representing the legs of the

stool. The more representative bond parameters around the

Os-center that characterize 8b in solid state include: the η⁶-

ring-Os centroid of 1.690 Å, and the Os−Cl 2.408(4) Å, Os−N

distances 2.105(11) and 2.129(12) Å. The two rings of the

bidentate ligand are almost coplanar with a distance between

the two nitrogen atoms N(2)···N(3) of 2.601 Å and a torsion

angle N(2)−C−C−N(3) 0(2)°. For all the compounds N−H···

O and N−H···Cl intramolecular hydrogen bonding interactions

are observed (Tables 1 and 2).

In vitro antiproliferative activity. The cytotoxicity of the

ligands L1−L8 and complexes 1a/b−8a/b was assessed in the

human ovarian carcinoma cell lines A2780 and A2780cisR, with

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the latter exhibiting acquired resistance to cisplatin, and human

embryonic kidney (HEK-293) cells, used as a model for normal

cells (Table 3 and Figure 6). The cytotoxicity values of

indomethacin 1, diclofenac 2, and cisplatin were also evaluated

as controls.

Of the monodentate ligands, L1 is slightly cytotoxic to all

three cell lines tested, but L3 shows no appreciable toxicity. On

coordination to the organometallic fragment in complexes 1a/

1b, the selectivity is increased with toxicity toward A2870 also

enhanced, whereas the toxicity toward the other two cell lines

decreases. In contrast, coordination of L3 to aﬀord 3a/3b

increases the cytotoxicity observed in all three cell lines, but

with no selectivity toward the tumor cell lines.

Ligand L2 is more active against A2780 cells compared to the

other two cell lines, and this property is preserved on

coordination to the organometallic fragments, i.e. in complexes

2a and 2b. The cytotoxicity of L4 increases considerably

following coordination to the organometallic unit. Notably, 4a

and 4b, incorporating the diclofenac-modiﬁed phosphine, are

highly cytotoxic to A2780 cells (IC₅₀= 3.1 and 4.8 μM,

respectively), and 4b is also selective, being considerably less

Table 3. IC₅₀Values (μM, 72 h) Determined for

Indomethacin, Diclofenac, L1-L8, 1a/1b−8a/8b, and

Cisplatin toward Human Ovarian A2780 and A2780R

Cancer Cells and Human Embryonic Kidney HEK-293 Cells

a

Using the MTT Assay

Compound

A2780

A2780cisR

HEK-293

1

26.7 1.4

202.3 16.4

79.4 0.8

34.2 2.3

48.7 3.7

36.6 2.6

20.0 0.3

25.1 4.7

>200

112.3 1.1

84.3 2.6

53.8 1.4

110.3 7.1

77.5 1.1

79.5 0.6

79.8 3.5

62.5 2.1

>200

66.8 0.6

186.4 13.7

49.7 0.1

60.7 2.3

89.2 3.5

76.5 0.1

70.9 0.4

53.7 1.4

>200

2

L1

1a

cytotoxic to HEK-293 cells (34.3

3.1 μM), with a similar

1b

L2

2a

cytotoxicity proﬁle to cisplatin.

The monofunctionalized bipyridine ligands L5 and L6 are

reasonably cytotoxic, but they are not selective. Indeed, L5 is at

least an order of magnitude more cytotoxic to the HEK-293 cell

line than the tumorgenic cell lines. When coordinated to the

metal units as in 5a/5b and 6a/6b, the overall cytotoxicity

changes relatively little. However, the relative selectivtiy toward

the nontumorigenic HEK-293 cell line is reduced. For example,

L5 is the most cytotoxic of all the compounds to the

nontumorigenic HEK-293 cells (IC₅₀= 0.3 μM), whereas the

IC₅₀values of 5a are 7.8 and 8.1 μM in the A2780 and

A2780cisR cell lines and 19.9 μM in HEK-293 cells, thus

showing a moderate degree of cancer cell selectivity combined

with a lack of cross resistance on the A2780cisR cell line.

The bis-functionalized bipyridine modiﬁed ligands L7 and L8

are not cytotoxic to any of the cell lines, whereas their

organometallic complexes are highly cytotoxic, with IC₅₀values

ranging from 0.2 to 9.9 μM. Importantly, complex 8a is more

than 20-fold more cytotoxic toward A2870cisR than the HEK-

293 cell line, which is on the same order of selectivity as

cisplatin for the sensitive A2780 cell line and considerably more

eﬀective than cisplatin on A2780cisR cells. It is noteworthy that

although the ligands with two bioactive moieties, i.e. L7 and L8,

are considerably less cytotoxic than the single NSAID

equivalent (L5 and L6, respectively), the organometallic

complexes show the opposite proﬁle, with the increased

cytotoxicity ranging from 2- to 46-fold, with 7a showing the

least enhancement compared to its single NSAID analogue 5a,

whereas 8a shows the largest enhancement compared to 6a.

Cytotoxicity is a multifactorial process, and resistance to

cisplatin in the A2870cisR cell line is attributed to decreased

uptake, increased glutathione and glutathione S-transferase

levels, and increased DNA repair (adduct removal), although

other mechanism cannot be excluded.⁹⁷Uptake may be

correlated with Ctr1 transporter expression, with cisplatin

resistant A2870cisR cells having lower levels compared to

sensitive cell lines.⁹⁸In addition, HEK-293 cells have a

relatively high expression of this transporter which is linked

to the side eﬀect of nephrotoxicity caused by cisplatin

treatment.⁹⁹The toxicity proﬁles of the three most selective

complexes for A2870cisR cells over HEK-293 cells (8a > 8b >

7a) also demonstrate a higher toxicity in A2870cisR cells

compared to A2870 cells and therefore suggest a diﬀerent mode

of uptake compared to cisplatin. It should be noted that certain

COX-2 inhibitors can overcome cross-drug resistance in

multidrug-resistant (MDR) cells.¹⁰⁰It has also been shown

2b

L3

3a

43.5 2.4

60.2 2.3

>200

29.1 3.5

74.5 2.8

>200

22.4 0.6

48.7 1.4

>200

3b

L4

4a

3.1 0.6

4.8 0.8

6.8 2.4

7.8 2.8

15.5 1.2

6.2 1.1

10.2 2.4

13.6 1.1

>200

24.2 1.3

45.1 0.8

13.2 2.4

8.1 3.5

14.6 1.9

22.4 4.9

9.1 1.7

4.3 1.7

34.3 3.1

0.3 0.0

19.9 1.4

20.1 0.5

24.6 1.1

28.2 0.4

23.5 1.5

>200

4b

L5

5a

5b

L6

6a

6b

L7

7a

18.5

1

>200

4.8 1.9

2.1 0.0

>200

1.7 0.1

1.4 0.1

>200

4.0 0.2

4.9 0.3

>200

7b

L8

8a

2.5 0.2

5.8 0.7

0.95 0.3

0.2 0.0

2.2 0.3

11.1 0.5

4.1 0.5

9.9 0.7

16.5 1.2

8b

Cisplatin

a

Values are given as the mean SD.

Compounds 1 and 2 are slightly cytotoxic to the three cell

lines, but do not display clinically useful cancer cell selectivity.

Ligands L3, L4, L7, and L8 are essentially nontoxic to any of

the cell lines tested (>200 μM). However, there is a dramatic

increase in activity when these ligands are coordinated to either

the ruthenium(II)- or osmium(II)-p-cymene fragments (more

than 2 orders of magnitude more cytotoxic in the case of 7a, 7b

and 8a, 8b, reaching low micromolar IC₅₀values in the range of

cisplatin and lower in the A2780cisR resistant cell line). For the

related pairs, 3a/3b and 4a/4b, merely diﬀering in the metal,

i.e. ruthenium versus osmium, the osmium derivatives are the

less cytotoxic of each pair. For these compounds, however,

selectivity to cancerous cells is not observed. Compounds 1, L2,

2a, 2b, 4b, 5a, L6, 6a, and 7b are at least two times more

cytotoxic to A2780 cells relative to nontumorigenic HEK-293

cells, although none display the same extent of selectivity as

cisplatin. In the case of the cisplatin resistant A2780cisR cancer

cells, selectivity relative to nontumorgenic HEK-283 is observed

with 2, 5a, 6a, 7a, 7b, 8a, and 8b, all demonstrating greater

selectivity than cisplatin, with 8a even exceeding the selectivity

of cisplatin for the cisplatin sensitive A2780 cell line.

G

DOI: 10.1021/acs.inorgchem.5b02690

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Inorganic Chemistry

Article

Figure 6. Comparison of the IC₅₀values for indomethacin, diclofenac, L1-L8, 1a/1b−8a/8b, and cisplatin.

1

not essential. H (400.13 MHz), ¹³C (100.62 MHz) and ³¹P (161.97

MHz) NMR spectra were recorded on a Bruker Avance II 400

spectrometer at 298 K. The chemical shifts are reported in parts per

million (ppm) and referenced to deuterated solvent residual peaks for

¹H and ¹³C (CDCl₃: ¹H δ 7.26, ¹³C δ 77.16 ppm, CD₃OD: ¹H δ 3.31,

¹³C δ 49.00 ppm) and coupling constants (J) are reported in Hertz

that platium(II) and platinum(IV) complexes modiﬁed with

aspirin, a potent COX-1 inhibitor, are able to overcome

cisplatin acquired drug resistance via a mechanism involving

COX-1 pathway modulation.^101−104Moreover, 1 has been

shown to increase the cellular accumulation of dyes that are

usually eﬄuxed via multidrug resistant protein, thereby

sensitizing formerly resistant cells to drugs such as vincris-

tine,¹⁰⁵and in other studies 1 has been shown to enhance the

anticancer activity of chlorambucil.^106,107Interestingly, 2 is

suggested to be activated in a process involving glutathione

conjugation,¹⁰⁸also oﬀering a mode of selectivity to the hybrid

complexes.

(Hz).^110,111IR spectra were recorded on a PerkinElmer Spectrum One

FT-IR Spectrometer at room temperature. Electrospray ionization

mass spectra (ESI-MS) were obtained on a Thermo-Finnigan LCQ

Deca XP Plus quadropole ion-trap instrument operated in positive-ion

mode. Elemental analysis was carried out by the microanalytical

laboratory at the Institute of Chemical Sciences and Engineering

(EPFL). Melting points were determined using a SMP3 Stuart Melting

Point Apparatus and are uncorrected. Reactions were monitored by

TLC using Merck TLC silica gel coated aluminum sheets 60 F₂₅₄, and

veriﬁed with a UV lamp at 254 nm and KMnO₄stain. Puriﬁcation of

products was performed by column ﬂash chromatography using silica

gel (60A, 43−60 μm) using the elution systems indicated.

Synthesis of 2-hydroxyethyl 2-(1-(4-chlorobenzoyl)-5-me-

thoxy-2-methyl-1H-indol-3-yl)acetate (L1a). To a solution of

indomethacin (0.702 g, 1 equiv) in CH₂Cl₂(150 mL), EDCI (0.478 g,

1.25 equiv) ethylene glycol (0.44 mL, 4 equiv) and DMAP (0.048 g,

0.2 equiv) were added. The reaction mixture was stirred at r.t. for 24 h.

The mixture was washed with H₂O (150 mL) and isolated organic

phase was washed with brine (150 mL), dried over anhydrous Na₂SO₄,

ﬁltered and concentrated under reduced pressure. Puriﬁcation by ﬂash

column chromatography using Hex/EtOAc elution mixture aﬀorded

the product as a pale-yellow solid (0.532 g, yield 70%). Mp (°C):

CONCLUDING REMARKS

■

Combining organometallic fragments based on metal(II)-p-

cymene (metal = ruthenium and osmium) with anti-

inﬂammatory drug motifs, i.e. indomethacin and diclofenac,

represents a promising strategy to generate cytotoxic, cancer

cell selective compounds, which lack the cross-resistance

problematic in cisplatin treatment. The relative ratio between

the two active units, i.e. the metal fragment versus the bioactive

organic drug moiety, is important, with the bis-functionalized

compounds being the most cytotoxic and selective and also the

most active against the cisplatin resistant A2780cisR cell line,

and demonstrating higher cytotoxicity and selectivity than

cisplatin against the A2870 cell line. Thus, combining

established anti-inﬂammatory (NSAID) drugs with these

organometallic fragments appears to be a promising approach

to overcoming drug resistance mechanisms associated with

cisplatin treatment.

1

104−105; R_f(Hex/EtOAc: 5/5 (v/v)): 0.35; H NMR (CDCl₃) δ_H,

3

4

ppm: 7.66 (2H, m, 2xCl-(Ar)C−CH-CH, J_H,H= 8.7 Hz, J_H,H= 2.3

3

4

Hz), 7.47 (2H, m, 2xCl-(Ar)C−CH-CH, J_H,H= 8.7 Hz, J_H,H= 2.3

Hz), 6.96 (1H, d, CH₃−O-(Ar)C−CH-C, ⁴J_H,H= 2.5 Hz), 6.86 (1H, d,

3

CH₃−O-(Ar)C−CH-CH-C, J_H,H= 8.9 Hz), 6.67 (1H, dd, CH₃−O-

(Ar)C−CH-CH-C, ³J_H,H= 8.9 Hz, ⁴J_H,H= 2.5 Hz), 4.23−4.25 (2H, m,

O−CH₂-CH₂−OH), 3.83 (3H, s, CH₃-O-(Ar)C−CH-C), 3.80−3.82

(2H, m, O−CH₂−CH₂−OH), 3.71 (2H, s, CH₂−O-CH₂-CH₂−OH),

2.39 (3H, s, (Ar)N−C−CH₃); ¹³C NMR (CDCl₃) δ_C, ppm: 171.3

(1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−OH), 168.4 (1C, Cl-(Ar)C−

CH−CH-C-(CO)), 156.2 (1C, CH₃−O-(Ar)C-CH-C), 139.5 (1C,

Cl-(Ar)C-CH−CH), 136.2 (1C, CH₃−O-(Ar)C−CH-C), 134.0 (1C,

CH₃-(Ar)C-N-(CO)), 131.3 (2C, 2xCl-(Ar)C−CH-CH), 131.0

(1C, Cl-(Ar)C−CH−CH-C), 130.7 (1C, CH₃−O-(Ar)C−CH−CH-

C), 129.3 (2C, 2xCl-(Ar)C-CH−CH), 115.2 (1C, CH₃−O-(Ar)C−

CH-CH−C), 112.4 (1C, (Ar)C-CH₂−(CO)-O), 111.8 (1C, CH₃−

O-(Ar)C-CH−CH-C), 101.4 (1C, CH₃−O-(Ar)C-CH−C), 66.7 (1C,

EXPERIMENTAL SECTION

■

General experimental conditions. RuCl₃·3H₂O was obtained

from Precious Metals Online and all other chemicals were purchased

from Aldrich, AlfaAesar, Acros, ABCR Chemicals and Bachem and

used without further puriﬁcation. Reactions were performed under an

inert atmosphere (N₂) using Schlenk techniques with solvents dried

using drying-columns. The dimers [Ru(η⁶-p-cymene)Cl₂]₂and

[Os(η⁶-p-cymene)Cl₂]₂were prepared and puriﬁed according to

literature procedures.¹⁰⁹The complexation reactions were performed

in the absence of light, as a precaution, although exclusion of light is

H

DOI: 10.1021/acs.inorgchem.5b02690

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

(Ar)C−CH₂−(CO)-O−CH₂−CH₂−OH), 61.3 (1C, (Ar)C−CH₂−

(CO)-O-CH₂−CH₂−OH), 55.9 (1C, CH₃−O-(Ar)C), 30.4 (1C,

(Ar)C-CH₂-(CO)-O-(CH₂)₂−OH), 13.5 (1C, (Ar)N−C-CH₃); IR

(ν, cm⁻¹): 3448 (O−H); 2931 (C−H, CH₂, CH₃); 1731 (CO,

ester); 1676 (CO, amide); 1589, 1476, 1355, 1313 (ring skeleton

CC, C−C, CN, C−N); 1218, 1165, 1142 (C−O, ether,

ester);831 (C−H, aromatic); ESI-MS(+): m/z 402.11 [M + H]⁺,

424.09 [M + Na]⁺, 825.18 [2M+Na]⁺calcd. for C₂₁H₂₀ClNO₅401.84,

the isotopic pattern corresponds well to the calculated one; Elemental

analysis (%): calcd. for C₂₁H₂₀ClNO C 62.77, H 5.02, N 3.49; found C

62.87, H 4.89, N 3.44.

the product as colorless solid (0.532 g, yield 66%). Mp (°C): 70−71;

1

R_f(Hex/EtOAc): 3/2 (v/v)): 0.34; H NMR (CDCl₃) δ_H, ppm: 7.34

3

(2H, d, 2xCl-(Ar)C−CH-CH, J_H,H= 8.1 Hz), 7.24 (1H, dd, NH-

3

4

(Ar)C−CH-CH−CH, J_H,H= 7.4 Hz, J_H,H= 1.4 Hz), 7.13 (1H, ddd

overlapped, NH-(Ar)C−CH-CH-CH, ³J_H,H= 8.0 Hz, ⁴J_H,H= 1.6 Hz),

3

7.00 (1H, t, Cl-(Ar)C−CH-CH, J_H,H= 8.1 Hz), 6.96 (1H, ddd

overlapped, NH-(Ar)C−CH−CH-CH, ³J_H,H= 7.4 Hz, ⁴J_H,H= 1.2 Hz),

3

6.84 (1H, s br, NH), 6.56 (1H, dd, NH-(Ar)C−C−CH-CH, J_H,H

=

4

8.0 Hz, J_H,H= 1.0 Hz), 4.28−4.30 (2H, m, (Ar)C−CH₂−(CO)−

O-CH₂-CH₂−OH), 3.87 (2H, s, (Ar)C−CH₂-(CO)-O-(CH₂)₂−

OH), 3.84−3.87 (2H, m, (Ar)C−CH₂−(CO)-O−CH₂−CH₂−

OH); ¹³C NMR (CDCl₃) δ_C, ppm: 172.8 (1C, (Ar)C−CH₂−(C

O)-O-(CH₂)₂−OH), 142.9 (1C, NH-(Ar)C−C-Cl), 137.9 (1C, NH-

(Ar)C-CH−CH−CH), 131.0 (1C, NH-(Ar)C−CH-CH−CH), 129.7

(2C, 2xCl-(Ar)C-CH−CH), 129.0 (2C, 2xCl-(Ar)C-CH−CH), 128.3

(1C, NH-(Ar)C−CH-CH−CH), 124.3 (1C, NH-(Ar)C-C-CH), 124.3

(1C, Cl-(Ar)C−CH-CH), 122.3 (1C, NH-(Ar)C−CH−CH-CH),

118.5 (1C, NH-(Ar)C−C-CH−CH), 67.0 (1C, (Ar)C−CH₂−(C

O)-O-CH₂−CH₂−OH), 61.3 (1C, (Ar)C−CH₂−(CO)-O−CH₂−

CH₂−OH), 38.6 (1C, (Ar)C-CH₂-(CO)-O-(CH₂)₂−OH); IR (ν,

cm⁻¹): 3319 (O−H); 2953 (C−H, CH₂, CH₃); 1717 (CO); 1577,

1503, 1450, (ring skeleton CC, C−C); 1279, 1252, 1147, 1075 (C−

O, ester); 882, 743 (C−H, aromatic); ESI-MS(+): m/z 341.07 [M +

H]⁺, calcd. for C₁₆H₁₅Cl₂NO₃340.20, the isotopic pattern corresponds

well to the calculated one; Elemental analysis (%): calcd. for

C₁₆H₁₅Cl₂NO₃C 56.49, H 4.44, N 4.12; found C 56.57, H 4.39, N

4.11.

Synthesis of 2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-

1H-indol-3-yl)acetoxy)ethyl-3-(pyridin-3-yl)propanoate (L1).

To a suspension of 3-(pyridin-3-yl)propanoic acid (0.186 g, 1.1

equiv) in CH₂Cl₂(100 mL), EDCI (0.263 g, 1.2 equiv), a solution of

L1a (0.435 g, 1 equiv) in CH₂Cl₂(50 mL) and DMAP (0.027 g, 0.2

equiv) were added. The reaction mixture was stirred at 40 °C for 2 h

and then for further 24 h at r.t. The mixture was then washed with

H₂O (100 mL) the isolated organic phase was further washed with

brine (150 mL), dried over anhydrous Na₂SO₄, ﬁltered and

concentrated under reduced pressure. Puriﬁcation by ﬂash column

chromatography using Hex/EtOAc elution mixture aﬀorded the

product as a viscous pale yellow oil (0.463 g, yield 84%). R_f(Hex/

1

EtOAc: 5/5 (v/v)): 0.49; H NMR (CDCl₃) δ_H, ppm: 8.45 (2H, m,

(Py)N−CH-C−CH, (Py)N−CH-CH−CH), 7.64 (2H, m, 2xCl-

3

4

(Ar)C−CH-CH, J_H,H= 8.6 Hz, J_H,H= 2.3 Hz), 7.49 (1H, ddd

overlapped, (Py)N−CH-CH-CH, ³J_H,H= 7.8 Hz, ⁴J_H,H= 1.8 Hz), 7.45

(2H, m, 2xCl-(Ar)C−CH-CH, J_H,H= 8.6 Hz, J_H,H= 2.3 Hz), 7.21

3

4

Synthesis of 2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)-

acetoxy)ethyl-3-(pyridin-3-yl)propanoate (L2). To a suspension

of 3-(pyridin-3-yl)propanoic acid (0.386 g, 1.1 equiv) in CH₂Cl₂(100

mL), EDCI (0.263 g, 1.2 equiv) a solution of L2a (0.435 g, 1 equiv) in

CH₂Cl₂(50 mL) and DMAP (0.027 g, 0.2 equiv) were added. The

reaction mixture was stirred at 40 °C for 2 h and then for further 24 h

at r.t. The mixture was washed with H₂O (100 mL), the isolated

organic phase was further washed with brine (150 mL), dried over

anhydrous Na₂SO₄, ﬁltered and concentrated under reduced pressure.

Puriﬁcation by ﬂash column chromatography using Hex/EtOAc

elution mixture aﬀorded the product as a viscous yellow oil (0.463

g, yield 86%). R_f(CH₂Cl₂/MeOH: 4/1 (v/v)): 0.39; ¹H NMR

(CDCl₃) δ_H, ppm: 8.45−8.46 (2H, m, (Py)N−CH-C−CH, (Py)N−

3

(1H, dd, (Py)N−CH-CH-CH, J_H,H= 7.8 Hz, J_H,H= 4.9 Hz), 6.96

(1H, d, CH₃−O-(Ar)C−CH-C, ⁴J_H,H= 2.5 Hz), 6.84 (1H, d, CH₃−O-

(Ar)C−CH-CH-C, ³J_H,H₄= 9 Hz), 6.64 (1H, dd, CH₃−O-(Ar)C−CH-

3

CH-C, J_H,H= 9 Hz, J_H,H= 2.5 Hz), 4.25−4.30 (4H, m, (Ar)C−

CH₂−(CO)−O-CH₂-CH₂−O, (Ar)C−CH₂−O−CH₂−CH₂-O),

3.80 (3H, s, CH₃-O-(Ar)C−CH-C), 3.67 (2H, s, (Ar)C−CH₂-O-

(CH₂)₂−O), 2.87 (2H, t, (Py)N−CH−C-CH₂-CH₂−(CO), ³J_H,H

=

3

7.6 Hz), 2.55 (2H, t, (Py)N−CH-C−CH₂−CH₂-(CO), J_H,H= 7.6

Hz), 2.38 (3H, s, CH₃-(Ar)C−N-(CO)); ¹³C NMR (CDCl₃) δ_C,

ppm: 172.1 (1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−O), 170.7 (1C,

(Py)N−CH-C-(CH₂)₂−(CO)), 168.4 (1C, Cl-(Ar)C−CH−CH-C-

(CO)), 156.1 (1C, CH₃−O-(Ar)C-CH-C), 149.7 (1C, (Py)N-CH−

C−CH), 147.8 (1C, (Py)N-CH−CH−CH), 139.4 (1C, Cl-(Ar)C-

CH−CH), 136.2 (1C, CH₃−O-(Ar)C−CH-C), 136.1 (1C, (Py)N−

CH-CH-CH,), 135.9 (1C, (Py)N−CH-C-CH), 134.0 (1C, CH₃-(Ar)

C-N-(CO)), 131.3 (2C, 2xCl-(Ar)C−CH-CH), 130.9 (1C, Cl-

(Ar)C−CH−CH-C), 130.7 (1C, CH₃−O-(Ar)C−CH−CH-C), 129.3

(2C, 2xCl-(Ar)C-CH−CH), 123.6 (1C, (Py)N−CH-CH−CH,), 115.0

(1C, CH₃−O-(Ar)C−CH-CH−C), 112.3 (1C, (Ar)C-CH₂−(CO)-

O-(CH₂)₂−O-(Py)C), 111.6 (1C, CH₃−O-(Ar)C-CH−CH-C), 101.6

(1C, CH₃−O-(Ar)C-CH−C), 62.7 (1C, (Ar)C−CH₂−(CO)-O−

CH₂−CH₂−O), 62.3 (1C, (Ar)C−CH₂−(CO)-O-CH₂−CH₂−O),

55.8 (1C, CH₃−O-(Ar)C−CH-C), 35.0 (1C, (Py)N−CH-C-CH₂−

CH₂−(CO)), 30.3 (1C, (Ar)C-CH₂-(CO)-O-(CH₂)₂−O-

(Py)C), 28.0 (1C, (Py)N−CH-C−CH₂−CH₂-(CO)), 13.4 (1C,

CH₃-(Ar)C−N-(CO)); IR (ν, cm⁻¹): 2932 (C−H, CH₂, CH₃);

1733 (CO, ester); 1678 (CO, amide); 1590, 1477, 1355, 1314

(ring skeleton CC, C−C, CN, C−N); 1220, 1140 (C−O, ether,

ester); 832, 802, 754 (C−H aromatic); ESI-MS(⁺): m/z 535.50 [M +

H]⁺, calcd. for C₂₉H₂₇ClN₂O₆534.99, the isotopic pattern corresponds

well to the calculated one; Elemental analysis (%): calcd. for

C₂₉H₂₇ClN₂O₆C 65.11, H 5.09, N 5.24; found C 65.10, H 5.07, N

5.13.

3

CH-CH−CH), 7.48 (1H, ddd overlapped, (Py)N−CH-CH-CH, J_H,H

= 7.9 Hz, ⁴J_H,H= 1.7 Hz), 7.33 (2H, d, 2xCl-(Ar)C−CH-CH, ³J_H,H= 8

3

4

Hz), 7.22 (1H, dd, NH-(Ar)C−CH-CH−CH, J_H,H= 7.5 Hz, J_H,H

=

1.5 Hz), 7.19 (1H, dd, (Py)N−CH-CH-CH, ³J_H,H= 7.9 Hz, ³J_H,H= 4.9

3

Hz), 7.11 (1H, ddd overlapped, NH-(Ar)C−CH-CH-CH, J_H,H= 7.7

4

3

Hz, J_H,H= 1.5 Hz), 6.98 (1H, t, Cl-(Ar)C−CH-CH, J_H,H= 8 Hz),

3

6.94 (1H, ddd overlapped, NH-(Ar)C−CH−CH-CH, J_H,H= 7.4 Hz,

⁴J_H,H= 1.0 Hz), 6.84 (1H, s br, NH), 6.53 (1H, d, NH-(Ar)−C−C-

CH-CH, ³J_H,H= 8 Hz), 4.32−4.34 (2H, m, (Ar)C−CH₂−(CO)−O-

CH₂-CH₂−O), 4.29−4.31 (2H, m, (Ar)C−CH₂−(CO)-O−CH₂−

CH₂-O), 3.83 (2H, s, (Ar)C−CH₂-(CO)-O-(CH₂)₂−O), 2.89 (2H,

3

t, (Py)N−CH-C−CH₂−CH₂-(CO), J_H,H= 7.6 Hz), 2.59 (2H, t,

(Py)N−CH−C-CH₂-CH₂−(CO), J_H,H= 7.6 Hz); ¹³C NMR

3

(CDCl₃) δ_C, ppm: 172.21 (1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−

O), 172.15 (1C, (Py)N−CH-C-(CH₂)₂−(CO)), 150.0 (1C, (Py)N-

CH−C−CH), 148.0 (1C, (Py)N-CH−CH−CH), 142.8 (1C, NH-(Ar)

C−C-Cl), 137.9 (1C, NH-(Ar)C-CH−CH−CH), 135.9 (1C, (Py)N−

CH-CH-CH), 135.8 (1C, (Py)N−CH-C-CH), 131.0 (1C, NH-

(Ar)C−CH-CH−CH), 129.7 (2C, 2xCl-(Ar)C-CH−CH), 129.0

(2C, 2xCl-(Ar)C-CH−CH), 128.2 (1C, NH-(Ar)C−CH-CH−CH),

124.3 (1C, NH-(Ar)C-C-CH−CH), 124.2 (1C, Cl-(Ar)C−CH-CH),

123.5 (1C, (Py)N−CH-CH−CH), 122.2 (1C, NH-(Ar)C−CH−CH-

CH), 118.4 (1C, NH-(Ar)C−C-CH−CH), 62.9 (1C, (Ar)C−CH₂−

(CO)-O-CH₂−CH₂−O), 62.3 (1C, (Ar)C−CH₂−(CO)-O−

CH₂−CH₂−O), 38.5 (1C, (Ar)C-CH₂-(CO)-O-(CH₂)₂−O), 35.2

(1C, (Py)N−CH-C−CH₂−CH₂-(CO)), 28.0 (1C, (Py)N−CH-C-

CH₂−CH₂−(CO)); ESI-MS(+): m/z 474.11 [M + H]⁺, calcd. for

C₂₄H₂₃Cl₂N₂O₄473.35, the isotopic pattern corresponds well to the

calculated one; IR (ν, cm⁻¹): 3315 (N−H); 2958 (C−H, CH₂, CH₃);

1731 (CO, ester); 1503, 1450, 1423 (ring skeleton CC, C−C,

Synthesis of 2-hydroxyethyl-2-(2-((2,6-dichlorophenyl)-

amino)phenyl)acetate (L2a). To a solution of diclofenac (0.702 g,

1 equiv) in CH₂Cl₂(150 mL), EDCI (0.478 g, 1.25 equiv), ethylene

glycol (0.44 mL, 4 equiv) and DMAP (0.048 g, 0.2 equiv) were added.

The reaction mixture was stirred at r.t. for 24 h. and then the mixture

was washed with H₂O (150 mL), the isolated organic phase was

further washed with brine (150 mL), dried over anhydrous Na₂SO₄,

ﬁltered and concentrated under reduced pressure. Puriﬁcation by ﬂash

column chromatography using Hex/EtOAc elution mixture aﬀorded

I

DOI: 10.1021/acs.inorgchem.5b02690

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Inorganic Chemistry

Article

3

4

CN, C−N); 1278, 1251, 1141 (C−O, ester); 772, 745 (C−H

aromatic); Elemental analysis (%): calcd. for C₂₄H₂₃Cl₂N₂O₄C 60.90,

H 4.68, N 5.92; found C 61.01, H 4.70, N 5.88.

CH, J_H,H= 7.5 Hz, J_H,H= 1.4 Hz), 7.02 (1H, ddd overlapped, NH-

3

4

(Ar)C−CH-CH-CH, J_H,H= 7.7 Hz, J_H,H= 1.5 Hz), 6.95 (1H, t, Cl-

(Ar)C−CH-CH, J_H,H= 8 Hz), 6.86 (1H, ddd overlapped, NH-

3

4

Synthesis of 2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-

1H-indol-3-yl)acetoxy)ethyl-4-(diphenylphosphanyl)benzoate

(L3). To a solution of 4-(diphenylphosphanyl)benzoic acid (0.493 g,

1.2 equiv) in CH₂Cl₂(100 mL), EDCI (0.329 g, 1.25 equiv), L1a

(0.520 g, 1.0 equiv) and DMAP (0.042 g, 0.3 equiv) were added. The

reaction mixture was stirred at r.t. for 24 h, then the mixture was

washed with H₂O (150 mL), the isolated organic phase has been

further washed with brine (150 mL), dried over anhydrous Na₂SO₄,

ﬁltered and concentrated under reduced pressure. Puriﬁcation by ﬂash

column chromatography using Hex/EtOAc as elution mixture aﬀorded

the product as a yellow solid (0.886 g, yield 87%). Mp (°C): 114−115;

(Ar)C−CH−CH-CH, J_H,H= 7.5 Hz, J_H,H= 1.1 Hz), 6.86 (1H, s br,

NH), 6.46 (1H, dd, NH-(Ar)C−C−CH-CH, ³J_H,H= 7.9 Hz, ⁴J_H,H= 0.5

Hz), 4.51−4.54 (2H, m, (Ar)C−CH₂−(CO)−O-CH₂-CH₂−O),

4.47−4.50 (2H, m, (Ar)C−CH₂−(CO)-O−CH₂−CH₂-O), 3.84

(2H, s, (Ar)C−CH₂-(CO)-O-(CH₂)₂−O); ³¹P NMR (CDCl₃) δ_P,

ppm: −5.01 (1P); ¹³C NMR (CDCl₃) δ_C, ppm: 172.2 (1C, (Ar)C−

CH₂−(CO)-O−CH₂−CH₂−O), 166.1 (1C, O-(CO)-(Ar)C−

CH−CH−C-P), 144.4 (1C, d, O-(CO)-(Ar)C−CH−CH-C-P, ¹J_C,P

= 14 Hz), 142.8 (1C, NH-(Ar)C−C-Cl), 137.8 (1C, NH-(Ar)C-CH−

1

CH), 136.2 (2C, d, 2xP-(Ar)C-CH−CH−CH, J_C,P= 11 Hz), 134.1

2

(4C, d, 4xP-(Ar)C-CH−CH−CH, J_C,P= 20 Hz), 133.2 (2C, d, 2xO-

1

2

R_f(Hex/EtOAc: 7/3 (v/v)): 0.39; H NMR (CDCl₃) δ_H, ppm: 7.83

(CO)-(Ar)C−CH-CH−C−P, J_C,P= 19 Hz), 130.9 (1C, NH-

3

4

(2H, m, 2xO-(CO)-(Ar)C−CH-CH−C-P, J_H,H= 5.2 Hz, J_H,H

=

(Ar)C−CH-CH−CH), 129.6 (2C, 2xCl-(Ar)C-CH−CH), 129.6 (1C,

O-(CO)-(Ar)C-CH−CH−C-P), 129.5 (2C, d, O-(CO)-(Ar)C-

1.7 Hz), 7.61 (2H, m, 2xCl-(Ar)C−CH-CH, ³J_H,H= 8.6 Hz, ⁴J_H,H= 2.4

3

4

3

Hz), 7.43 (2H, m, 2xCl-(Ar)C−CH-CH, J_H,H= 8.6 Hz, J_H,H= 2.4

Hz), 7.25−7.40 (12H, m, 2xO-(CO)-(Ar)C−CH-CH−C-P, 4xP-

(Ar)C−CH-CH−CH, 4xP-(Ar)C−CH-CH-CH, 2xP-(Ar)C−CH−

CH−CH−C-P, J_C,P= 6 Hz), 129.3 (2C, 2xP-(Ar)C−CH−CH-CH),

129.0 (2C, 2xCl-(Ar)C-CH−CH), 128.8 (4C, d, 4xP-(Ar)C−CH-

CH−CH, ³J_C,P= 7 Hz), 128.1 (1C, NH-(Ar)C−CH-CH−CH), 124.2

(1C, Cl-(Ar)C−CH-CH), 124.1 (1C, NH-(Ar)C-C-CH), 122.1 (1C,

NH-(Ar)C−CH−CH-CH), 118.4 (1C, NH-(Ar)C−C-CH−CH), 62.9

(1C, (Ar)C-(CO)-O-CH₂−CH₂−O), 62.7 (1C, (Ar)C-(CO)-

O−CH₂−CH₂−O), 38.5 (1C, (Ar)C-CH₂-(CO)-O-(CH₂)₂−O);

IR (ν, cm⁻¹): 3327 (N−H); 2960 (C−H, CH₂, CH₃); 1719 (CO,

ester); 1586, 1505, 1450, 1395 (ring skeleton CC, C−C); 1285,

1266, 1232, 1124 (C−O); 743 (C−H aromatic); ESI-MS(+): m/z

629.10 [M + H]⁺, 651.08 [M + Na]⁺, calcd. for C₃₅H₂₈Cl₂NO₄P

628.49, the isotopic pattern corresponds well to the calculated one;

Elemental analysis (%): calcd. for C₃₅H₂₈Cl₂NO₄P C 66.89, H 4.49, N

2.23, found C 66.86, H 4.48, N 2.16;

3

CH-CH), 6.96 (1H, d, CH₃−O-(Ar)C−CH-C, J_H,H= 2.6 Hz), 6.79

3

(1H, d, CH₃−O-(Ar)C−CH-CH-C, J_H,H= 9.0 Hz), 6.55 (1H, dd,

CH₃−O-(Ar)C−CH-CH-C, ³J_H,H= 9.0 Hz, ⁴J_H,H= 2.6 Hz), 4.49−4.52

(2H, m, (Ar)C−CH₂−(CO)-O−CH₂−CH₂-O), 4.43−4.45 (2H, m,

(Ar)C−CH₂−(CO)−O-CH₂-CH₂−O), 3.73 (3H, s, CH₃-O-

(Ar)C−CH-C), 3.70 (2H, s, (Ar)C−CH₂-(CO)-O-(CH₂)₂−O),

2.37 (3H, s, CH₃-(Ar)C−N); ³¹P NMR (CDCl₃) δ_P, ppm: −4.96

(1P); ¹³C NMR (CDCl₃) δ_C, ppm: 170.6 (1C, (Ar)C−CH₂−(CO)-

O-(CH₂)₂−O), 168.2 (1C, Cl-(Ar)C−CH−CH-C-(CO)), 166.0

(1C, O-(CO)-(Ar)C−CH−CH−C-P), 156.1 (1C, CH₃−O-(Ar)C-

1

CH-C), 144.5 (1C, O-(CO)-(Ar)C−CH−CH-C-P, J_C,P= 15 Hz),

139.3 (1C, Cl-(Ar)C-CH−CH), 136.2 (2C, 2xP-(Ar)C-CH−CH−

Synthesis of (4′-methyl-[2,2′-bipyridin]-4-yl)methyl-2-(1-(4-

chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate

(L5). To a solution of indomethacin (0.643 g, 1.2 equiv) in CH₂Cl₂

(100 mL), EDCI (0.493 g, 1.4 equiv), 4′-methyl-[2,2′-bipyridin]-4-

yl)methanol (0.300 g, 1 equiv) and DMAP (0.055 g, 0.3 equiv) were

added. The reaction mixture was stirred at r.t. for 24 h, then the

mixture was washed with H₂O (150 mL), the isolated organic phase

was further washed with brine (150 mL), dried over anhydrous

Na₂SO₄, ﬁltered and concentrated under reduced pressure. Puriﬁcation

by ﬂash chromatography using CH₂Cl₂/MeOH elution mixture

aﬀorded the product as pale yellow solid (0.598 g, yield 74%). Mp

1

CH, J_C−P= 11 Hz), 136.1 (1C, CH₃−O-(Ar)C−CH-C), 134.1 (4C,

2

4xP-(Ar)C-CH−CH−CH, J_C,P= 20 Hz), 133.9 (1C, CH₃₂-(Ar)C-N-

(CO)), 133.2 (2C, O-(CO)-(Ar)C−CH-CH−C−P, J_C,P= 19

Hz), 131.2 (2C, 2xCl-(Ar)C−CH-CH), 130.8 (1C, Cl-(Ar)C−CH−

CH-C), 130.6 (1C, CH₃−O-(Ar)C−CH−CH-C), 129.5 (1C, O-(C

O)-(Ar)C-CH−CH−C-P), 129.3 (2C, O-(CO)-(Ar)C-CH−CH−

3

C-P, J_C−P= 6 Hz), 129.3 (2C, 2xCl-(Ar)C-CH−CH), 129.2 (2C,

2xP-(Ar)C−CH−CH-CH), 128.7 (4C, 4xP-(Ar)C−CH-CH−CH,

³J_C,P= 7 Hz), 114.9 (1C, CH₃−O-(Ar)C−CH-CH−C), 112.3 (1C,

(Ar)C-CH₂−(CO)-O), 111.6 (1C, CH₃−O-(Ar)C-CH−CH-C),

101.3 (1C, CH₃−O-(Ar)C-CH−C), 62.7 (1C, (Ar)C−CH₂−(CO)-

O-CH₂−CH₂−O), 62.6 (1C, (Ar)C−CH₂−(CO)-O−CH₂−CH₂−

O), 55.6 (1C, CH₃−O-(Ar)C−CH-C), 30.3 (1C, (Ar)C-CH₂-(C

O)-O-(CH₂)₂−O), 13.4 (1C, CH₃-(Ar)C−N-(CO)); IR (ν, cm-1):

2931 (C−H, CH₂, CH₃); 1730, (CO, ester); 1714 (CO, ester);

1678 (CO, amide); 1594, 1469, 1353 (ring skeleton CC, C−C,

CN, C−N); 1243, 1144, 1086 (C−O, ether, ester); 857, 745 (C−H

aromatic); ESI-MS(+): m/z 690.42 [M]⁺, calcd. for C₄₀H₃₁ClNO₆P

690.13, the isotopic pattern corresponds well to the calculated one;

Elemental analysis (%): calcd. for C₄₀H₃₁ClNO₆P C 69.62, H 4.82, N

2.03, found C 69.53, H 4.86, N 2.01.

1

(°C): 134.5−135.5; R_f(CH₂Cl₂/MeOH: 9.5/0.5 (v/v)): 0.339; H

NMR (CDCl₃) δ_H, ppm: 8.59 (1H, d, O−CH₂−(Py)C−CH-CH-N,

³J_H,H= 5.0 Hz), 8.48 (1H, d, CH₃-(Py)C−CH-CH-N, ³J_H,H= 4.9 Hz),

8.34 (1H, s, CH₃-(Py)C−CH−C-N), 8.22 (1H, s, O−CH₂−(Py)C−

CH−C-N), 7.61 (2H, m, 2xCl-(Ar)C−CH-CH, ³J_H,H= 8.6 Hz, ⁴J_H,H

=

2.3 Hz), 7.41 (2H, m, 2xCl-(Ar)C−CH-CH, ³J_H,H= 8.6 Hz, ⁴J_H,H= 2.3

3

4

Hz), 7.16 (1H, dd, O−CH₂−(Py)C−CH-CH-N, J_H,H= 5.0 Hz, J_H,H

= 1.5 Hz), 7.11 (1H, dd, CH₃-(Py)C−CH-CH-N, ³J_H,H= 4.9 Hz, ³J_H,H

4

= 1.3 Hz), 6.95 (1H, d, CH₃−O-(Ar)C−CH-C, J_H,H= 2.5 Hz), 6.85

3

(1H, d, CH₃−O-(Ar)C−CH-CH-C, J_H,H= 9 Hz), 6.64 (1H, dd,

CH₃−O-(Ar)C−CH-CH-C, ³J_H,H= 9 Hz, ⁴J_H,H= 2.5 Hz), 5.22 (2H, s,

O−CH₂-(Py)C−CH−CH-N), 3.79 (2H, s, (Ar)C−CH₂-(CO)-O−

CH₂−(Py)C), 3.75 (3H, s, CH₃-O-(Ar)C−CH-C), 2.43 (6H, s, CH₃-

(Ar)C−N-(CO), CH₃-(Py)C−CH−CH-N); ¹³C NMR (CDCl₃)

δ_C, ppm: 170.5 (1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−O), 168.4

(1C, e), Cl-(Ar)C−CH−CH-C-(CO), 156.8 (1C, O−CH₂−

(Py)C−CH-C-N), 156.2 (1C, CH₃−O-(Ar)C-CH-C), 155.5 (1C,

CH₃-(Py)C−CH-C-N), 149.4 (1C, O−CH₂−(Py)C−CH-CH-N),

149.0 (1C, CH₃-(Py)C−CH-CH-N), 148.4 (1C, O−CH₂−(Py)C-

CH−CH-N), 145.8 (1C, CH₃-(Py)C-CH−CH-N), 139.3 (1C, Cl-

(Ar)C-CH−CH), 136.2 (1C, CH₃−O-(Ar)C−CH-C), 134.0 (1C,

CH₃-(Ar)C-N-(CO)), 131.3 (2C, 2xCl-(Ar)C−CH-CH), 130.9

(1C, Cl-(Ar)C−CH−CH-C), 130.6 (1C, CH₃−O-(Ar)C−CH−CH-

C), 129.2 (2C, 2xCl-(Ar)C-CH−CH), 125.0 (1C, CH₃-(Py)C-CH−

CH-N), 122.1 (1C, CH₃-(Py)C-CH−C−N), 121.8 (1C, O−CH₂−

(Py)C-CH−CH-N), 119.4 (1C, O−CH₂−(Py)C-CH−C−N), 115.1

(1C, CH₃−O-(Ar)C−CH-CH−C), 112.2 (1C, (Ar)C-CH₂−(CO)-

O−CH₂−(Py)C), 112.0 (1C, CH₃−O-(Ar)C-CH−CH-C), 101.2 (1C,

Synthesis of 2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)-

acetoxy)ethyl-4-(diphenylphosphanyl)benzoate (L4). To a

solution of 4-(diphenylphosphanyl)benzoic acid (0.972 g, 1.2 equiv)

in CH₂Cl₂(100 mL), EDCI (0.647 g, 1.25 equiv), a solution of L2a

(0.900 g, 1.0 equiv) in CH₂Cl₂(50 mL) and DMAP (0.097 g, 0.3

equiv) were added. The reaction mixture was further stirred for 24 h at

r.t., then the mixture was washed with H₂O (150 mL), the isolated

organic phase was further washed with brine (150 mL), dried over

anhydrous Na₂SO₄, ﬁltered and concentrated under reduced pressure.

Puriﬁcation by ﬂash column chromatography using Hex/EtOAc

elution mixture aﬀorded the product as a white solid (0.784 g, yield

1

47%). Mp (°C): 115−116; R_f(Hex/EtOAc: 9/1 (v/v)): 0.692; H

NMR (CDCl₃) δ_H, ppm: 7.84 (2H, m, 2xO-(CO)-(Ar)C−CH-

3

4

CH−C-P, J_H,H= 8.4 Hz, J_H,H= 1.4 Hz), 7.24−7.38 (12H, m, 2xO-

(CO)-(Ar)C−CH-CH−C-P, 4xP-(Ar)C−CH-CH−CH, 4xP-

(Ar)C−CH-CH-CH, 2xP-(Ar)C−CH−CH-CH), 7.30 (2H, d, 2xCl-

3

(Ar)C−CH-CH, J_H,H= 8 Hz), 7.20 (1H, dd, NH-(Ar)C−CH-CH−

J

DOI: 10.1021/acs.inorgchem.5b02690

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

CH₃−O-(Ar)C-CH−C), 65.1 (1C, O-CH₂-(Py)C−CH−CH-N), 55.7

(1C, CH₃−O-(Ar)C−CH-C), 30.4 (1C, (Ar)C-CH₂-(CO)-O−

CH₂−(Py)C), 21.3 (1C, CH₃-(Py)C−CH-CH-N), 13.5 (1C, CH₃-

(Ar)C−N-(CO)); IR (ν, cm⁻¹): 2927 (C−H, CH₃, CH₂); 1731

(CO, ester); 1670, (CO, amide); 1597, 1458, 1357, (ring

skeleton CC, C−C, CN, C−N); 1214, 1171, 1148 (C−O, ester);

820, 755 (C−H aromatic); ESI-MS(+): m/z 540.20 [M]⁺, calcd. for

C₃₁H₂₆ClN₃O₄540.02, the isotopic pattern corresponds well to the

calculated one; Elemental analysis (%): calcd. for C₃₁H₂₆ClN₃O₄C

68.95, H 4.85, N 7.78; found C 68.97, H 4.81, N 7.74;

¹H NMR (CDCl₃) δ_H, ppm: 9.17 (2H, d, 2xO-(CO)-(Py)C−CH-

4

3

N, J_H,H= 2.1 Hz), 8.48 (2H, d, 2x(Py)N−C−CH-CH-C, J_H,H= 8.3

Hz), 8.24 (2H, dd, 2x(Py)N−C−CH-CH-C, ³J_H,H= 8.3 Hz, ⁴J_H,H= 2.1

3

4

Hz), 7.62 (4H, m, 4xCl-(Ar)C−CH-CH, J_H,H= 8.5 Hz, J_H,H= 2.3

3

4

Hz), 7.42 (4H, m, 4xCl-(Ar)C−CH-CH, J_H,H= 8.5 Hz, J_H,H= 2.3

Hz), 6.96 (2H, d, 2xCH₃−O-(Ar)C−CH-C, ⁴J_H,H= 2.5 Hz), 6.77 (2H,

3

d, 2xCH₃−O-(Ar)C−CH-CH-C, J_H,H= 9 Hz), 6.58 (2H, dd,

3

4

2xCH₃−O-(Ar)C−CH-CH-C, J_H,H= 9 Hz, J_H,H= 2.5 Hz), 4.56−

4.61 (4H, m, 2x(Ar)C−CH₂−(CO)-O−CH₂−CH₂-O), 4.48−4.53

(4H, m, 2x(Ar)C−CH₂−(CO)−O-CH₂-CH₂−O), 3.78 (6H, s,

2xCH₃-O-(Ar)C−CH-C), 3.72 (4H, s, 2x(Ar)C−CH₂-(CO)-O-

(CH₂)₂−O), 2.40 (6H, s, 2xCH₃-(Ar)C−N); ¹³C NMR (CDCl₃) δ_C,

ppm: 170.8 (2C, 2x(Ar)C−CH₂−(CO)-O-(CH₂)₂−O), 168.3 (2C,

2xCl-(Ar)C−CH−CH-C-(CO)), 164.9 (2C, 2x(Py)N−CH-C-

(CO)-O), 158.3 (2C, 2x(Py)N-C-CH−CH-C), 156.2 (2C,

2xCH₃−O-(Ar)C-CH−CH-C), 150.7 (2C, 2x(Py)N−CH-C-(C

O)), 139.4 (2C, 2xCl-(Ar)C-CH−CH), 138.3 (2C, 2x(Py)N−C−

CH-CH-C), 136.3 (2C, 2xCH₃−O-(Ar)C−CH-C), 134.0 (2C,

2xCH₃-(Ar)C-N-(CO)-O), 131.3 (4C, 4xCl-(Ar)C−CH-CH),

130.9 (2C, 2xCl-(Ar)C−CH−CH-C), 130.6 (2C, 2xCH₃−O-

(Ar)C−CH−CH-C), 129.2 (4C, 4xCl-(Ar)C-CH−CH), 126.0 (2C,

2x(Py)N−CH-C-(CO)-O), 121.5 (2C, 2x(Py)N−C−CH-CH-C),

115.1 (2C, 2xCH₃−O-(Ar)C−CH-CH−C), 112.3 (2C, 2x(Ar)C-(C

O)-O−CH₂), 111.6 (2C, 2xCH₃−O-(Ar)C-CH−CH-C), 101.5 (2C,

2xCH₃−O-(Ar)C-CH−C), 63.2 (2C, 2x(Ar)C−CH₂−(CO)-O−

CH₂−CH₂−O), 62.6 (2C, 2x(Ar)C−CH₂−(CO)-O-CH₂−CH₂−

O), 55.8 (2C, 2xCH₃−O-(Ar)C), 30.4 (2C, 2x(Ar)C-CH₂-(CO)-O-

(CH₂)₂−O), 13.5 (2C, 2xCH₃-(Ar)C−N-(CO)); IR (ν, cm⁻¹):

2959 (C−H, CH₂, CH₃); 1722 (CO, ester); 1661 (CO, amide);

1592, 1457, 1363, (ring skeleton CC, C−C, CN, C−N); 1286,

1235 (C−O, ether, ester); 827, 753 (C−H aromatic); ESI-MS(+): m/

z 1011.24 [M + H]⁺, calcd. for C₅₄H₄₄Cl₂N₄O₁₂1011.86, the isotopic

pattern corresponds well to the calculated one; Elemental analysis

(%): calcd. for C₅₄H₄₄Cl₂N₄O₁₂C 64.10, H 4.38, N 5.54; found C

64.25, H 4.39, N 5.44;

Synthesis of (4′-methyl-[2,2′-bipyridin]-4-yl)methyl-2-(2-

((2,6-dichlorophenyl)amino) phenyl)acetate (L6). To a solution

of diclofenac (0.714 g, 1.2 equiv) in CH₂Cl₂(100 mL), EDCI (0.547

g, 1.4 equiv), 4′-methyl-[2,2′-bipyridin]-4-yl)methanol (0.400 g, 1

equiv) and DMAP (0.055 g, 0.3 equiv) were added. The reaction

mixture was stirred at r.t for 24 h, then the mixture was washed with

H₂O (150 mL), the isolated organic phase was further washed with

brine (150 mL), dried over anhydrous Na₂SO₄, ﬁltered and

concentrated under reduced pressure. Puriﬁcation by ﬂash chromatog-

raphy using CH₂Cl₂/MeOH elution mixture aﬀorded the product as

pale pink solid (0.731 g, yield 77%). Mp (°C): 108−109; R_f(CH₂Cl₂/

1

MeOH: 9.5/0.5 (v/v)): 0.51; H NMR (CDCl₃) δ_H, ppm: 8.63 (1H,

3

d, O−CH₂−(Py)C−CH-CH-N, J_H,H= 5.0 Hz), 8.54 (1H, d, CH₃-

(Py)C−CH-CH-N, ³J_H,H= 5.0 Hz), 8.38 (1H, s, CH₃-(Py)C−CH−C-

N), 8.23 (1H, s, O−CH₂−(Py)C−CH−C-N), 7.31 (2H, d, 2xCl-

(Ar)C−CH-CH, ³J_H,H= 8.1 Hz), 7.28 (1H, dd, NH-(Ar)C−CH-CH−

3

4

CH, J_H,H= 7.6 Hz, J_H,H= 1.1 Hz), 7.21 (1H, dd, O−CH₂−(Py)C−

CH-CH-N, ³J_H,H= 5 Hz, ⁴J_H,H= 1.1 Hz), 7.16 (1H, dd, CH₃-(Py)C−

CH-CH-N, J_H,H= 5 Hz, J_H,H= 1.1 Hz), 7.14 (1H, ddd overlapped,

3

4

NH-(Ar)C−CH-CH, J_H,H= 7.5 Hz, J_H,H= 1.3 Hz), 6.97 (1H, ddd

overlapped, NH-(Ar)C−CH−CH-CH, ³J_H,H= 7.1 Hz, ⁴J_H,H= 0.9 Hz),

6.96 (1H, t, Cl-(Ar)C−CH-CH, ³J_H,H= 8.1 Hz), 6.79 (1H, s br, NH),

6.55 (1H, d, NH-(Ar)C−C−CH-CH, ³J_H,H= 8.0 Hz), 5.30 (2H, s, O−

CH₂-(Py)C−CH−CH-N), 3.94 (2H, s, (Ar)C−CH₂-(CO)-O),

2.45 (3H, s, CH₃-(Py)C−CH−CH-N); ¹³C NMR (CDCl₃) δ_C,

ppm: 172.0 (1C, (Ar)C−CH₂−(CO)-O−CH₂−(Py)C), 156.6 (1C,

O−CH₂−(Py)C−CH-C-N), 155.4 (1C, CH₃-(Py)C−CH-C-N), 149.6

(1C, O−CH₂−(Py)C−CH-CH-N), 149.0 (1C, CH₃-(Py)C−CH-CH-

N), 148.6 (1C, O−CH₂−(Py)C-CH−CH-N), 145.8 (1C, CH₃-(Py)C-

CH−CH-N), 142.9 (1C, NH-(Ar)C−C-Cl), 137.9 (1C, NH-(Ar)C-

CH−CH), 131.1 (1C, NH-(Ar)C−CH-CH−CH), 129.6 (2C, 2xCl-

(Ar)C-CH−CH), 129.0 (2C, 2xCl-(Ar)C-CH−CH), 128.3 (1C, NH-

(Ar)C−CH-CH−CH), 125.1 (1C, CH₃-(Py)C−CH-CH-N), 124.2

(2C, NH-(Ar)C-C-CH, Cl-(Ar)C−CH-CH), 122.34 (1C, NH-

(Ar)C−CH−CH-CH), 122.29 (1C, CH₃-(Py)C−CH−C-N), 122.0

(1C, O−CH₂−(Py)C-CH−CH-N), 119.7 (1C, O−CH₂−(Py)C-CH−

C−N), 118.6 (1C, NH-(Ar)C−C-CH−CH), 65.3 (1C, O-CH₂-

(Py)C−CH−CH-N), 38.6 (1C, (Ar)C-CH₂-(CO)-O−CH₂−

(Py)C), 21.4 (1C, CH₃-(Py)C−CH-CH-N); IR (ν, cm⁻¹): 3321

(N−H); 3009, 2923 (C−H, CH₂, CH₃); 1724 (CO, ester); 1676

(CO, ester); 1597, 1502, 1450 (ring skeleton CC, C−C, C−N,

CN, C−N); 1277, 1233, 1142 (C−O); 821, 770, 747 (C−H

aromatic); ESI-MS(+): m/z 478.13 [M + H]⁺, calcd. for

C₂₆H₂₁Cl₂N₃O₂477.10, the isotopic pattern corresponds well to the

calculated one; Elemental analysis (%): calcd. for C₂₆H₂₁Cl₂N₃O₂C

65.28, H 4.42, N 8.78; found C 65.18, H 4.29, N 8.68;

Synthesis of bis(2-(2-(2-((2,6-dichlorophenyl)amino)phenyl)-

acetoxy)ethyl)[2,2′-bipyridine]-5,5′-dicarboxylate (L8). To a

suspension of [2,2′-bipyridine]-5,5′-dicarboxylic acid (0.524 g, 1

equiv) in a mixture of CH₂Cl₂(20 mL) and H(CO)-N(CH₃)₂(40

mL), EDCI (0.987 g, 2.4 equiv), L2a (1.679 g, 2.3 equiv) and DMAP

(0.157 g, 0.6 equiv) were added. The reaction mixture was stirred at

r.t. for 48 h then the mixture was concentrated under reduced pressure

to dryness, and the crude was solubilized in CH₂Cl₂(150 mL) washed

with H₂O (150 mL), then the isolated organic phase organic phase was

further washed with brine (150 mL), dried over anhydrous Na₂SO₄,

ﬁltered and concentrated under reduced pressure. Puriﬁcation by ﬂash

column chromatography using ﬁrst Hex/EtOAc elution mixture

aﬀorded the product as a white solid (1.301 g, yield 68%). Mp

1

(°C): 94−95; R_f(Hex/EtOAc: 6/4 (v/v)): 0.54; H NMR (CDCl₃)

4

δ_H, ppm: 9.22 (2H, d, 2xO-(CO)-(Py)C−CH-N, J_H,H= 2.1 Hz),

3

8.49 (2H, d, 2x(Py)N−C−CH-CH-C, J_H,H= 8.3 Hz), 8.31 (2H, dd,

2x(Py)N−C−CH-CH-C, ³J_H,H= 8.3 Hz, ⁴J_H,H= 2.1 Hz), 7.30 (2H, d,

3

2xCl-(Ar)C−CH-CH, J_H,H= 8.1 Hz), 7.23 (2H, dd, 2xNH-(Ar)C−

3

4

CH-CH−CH, J_H,H= 7.5 Hz, J_H,H= 1.2 Hz), 7.09 (2H, ddd

3

4

overlapped, 2xNH-(Ar)C−CH-CH-CH, J_H,H= 7.8 Hz, J_H,H= 1.4

Hz), 6.93 (2H, t, 2xCl-(Ar)C−CH-CH, ³J_H,H= 8.1 Hz), 6.92 (2H, ddd

3

4

overlapped, 2xNH-(Ar)C−CH−CH-CH, J_H,H= 7.3 Hz, J_H,H= 0.9

Hz), 6.81 (2H, s br, 2xNH), 6.52 (2H, d, 2xNH-(Ar)C−C−CH-CH,

³J_H,H= 8.0 Hz), 4.59−4.64 (4H, m, 2x(Ar)C−CH₂−(CO)−O-CH₂-

CH₂−O), 4.52−4.57 (4H, m, 2x(Ar)C−CH₂−(CO)-O−CH₂−

CH₂-O), 3.87 (4H, s, 2x(Ar)C−CH₂-(CO)-O-(CH₂)₂−O); ¹³C

NMR (CDCl₃) δ_C, ppm: 172.2 (2C, 2x(Ar)C−CH₂−(CO)-O-

(CH₂)₂−O), 165.0 (2C, 2x(Py)N−CH-C-(CO)-O), 158.4 (2C,

2x(Py)N-C-CH−CH-C), 150.8 (2C, 2x(Py)N-CH−C-(CO)), 142.8

(2C, 2xNH-(Ar)C−C-Cl), 138.3 (2C, 2x(Py)N−C−CH-CH−C),

137.9 (2C, 2xNH-(Ar)C-CH−CH), 131.0 (2C, 2xNH-(Ar)C-CH−

CH−CH), 129.6 (4C, 4xCl-(Ar)C-CH−CH), 129.0 (4C, 4xCl-(Ar)C-

CH−CH), 128.4 (2C, 2xNH-(Ar)C−CH-CH−CH), 126.0 (2C,

2x(Py)N−CH-C-(CO)-O), 124.2 (2C, 2xNH-(Ar)C-C-CH),

124.1 (2C, 2xCl-(Ar)C−CH-CH), 122.2 (2C, 2xNH-(Ar)C−CH−

Synthesis of bis(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-

methyl-1H-indol-3-yl)acetoxy)ethyl) [2,2′-bipyridine]-5,5′-di-

carboxylate (L7). To a suspension of [2,2′-bipyridine]-5,5′-

dicarboxylic acid (0.528 g, 1 equiv) in a mixture of CH₂Cl₂(20

mL) and H(CO)-N(CH₃)₂, EDCI (0.996 g, 2.4 equiv), L1a (2.000 g,

2.3 equiv) and DMAP (0.159 g, 0.6 equiv) were added. The reaction

mixture was stirred at r.t. for 48 h, then the mixture was concentrated

under reduced pressure to dryness, the crude was solubilized in

CH₂Cl₂(150 mL) washed with H₂O (150 mL), then the isolated

organic phase was further washed with brine (150 mL), dried over

anhydrous Na₂SO₄, ﬁltered and concentrated under reduced pressure.

Puriﬁcation by ﬂash column chromatography using ﬁrst Hex/EtOAc

elution mixture aﬀorded the product as a pale yellow solid (1.133 g,

yield 52%). Mp (°C): 117−119; R_f(Hex/EtOAc: 4/6 (v/v)): 0.702;

K

DOI: 10.1021/acs.inorgchem.5b02690

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

CH-CH), 121.5 (2C, 2x(Py)N−C−CH-CH-C), 118.5 (2C, 2xNH-

(Ar)C−C-CH−CH), 63.1 (2C, 2x(Ar)C−CH₂−(CO)-O-CH₂−

CH₂−O), 62.8 (2C, 2x(Ar)C−CH₂−(CO)-O−CH₂−CH₂−O),

38.6 (2C, 2x(Ar)C-CH₂-(CO)-O-(CH₂)₂−O); IR (ν, cm⁻¹): 3347

(N−H); 2954 (C−H, CH₂, CH₃); 1719 (CO, ester); 1713 (CO,

ester); 1591, 1511, 1451 (ring skeleton CC, C−C, CN, C−N);

1288, 1242, 1139 (C−O, ester); 854, 742, 734 (C−H aromatic); ESI-

MS(+): m/z 889.12 [M + H]⁺, calcd. for C₄₄H₃₄Cl₄N₄O₈888.58, the

isotopic pattern corresponds well to the calculated one; Elemental

analysis (%): calcd. for C₄₄H₃₄Cl₄N₄O₈·CH₂Cl₂55.52; H, 3.73; N,

5.76; found C 55.44, H 3.79, N 5.58;

the calculated one; Elemental Analysis (%): calcd. for

C₃₉H₄₁Cl₃N₂O₆Ru C 55.69, H 4.91, N 3.33; found C 55.69, H 4.93,

N 3.33.

Synthesis of [Os(η⁶-p-cymene)Cl₂]{(2-(2-(1-(4-chlorobenzo-

yl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-3-(pyri-

din-3-yl)propanoate} (1b). Complex 1b was prepared following the

general procedure starting from [Os(η⁶-p-cymene)Cl]₂Cl₂(0.235 g, 1

equiv) and ligand L1 (0.350 g, 2.2 equiv), to aﬀord a yellow-orange

1

solid (0.297 g, yield 54%). Mp (°C): 83−85; H NMR (CDCl₃) δ,

ppm: 8.78−8.81 (2H, m, (Py)N−CH-C−CH, (Py)N−CH-CH−CH),

3

7.65 (2H, m, 2xCl-(Ar)C−CH-CH, J_H,H= 8.4 Hz), 7.43−7.49 (3H,

3

m, 2xCl-(Ar)C−CH-CH, (Py)N−CH-CH-CH, J_H,H= 8.4 Hz), 7.17

General procedure for the synthesis of the ruthenium(II)-

and osmium(II)-p-cymene complexes. To a solution of the

appropriate dimer, [Ru(η⁶-p-cymene)Cl₂]₂or [Os(η⁶-p-cymene)Cl₂]₂,

in CH₂Cl₂(10 mL) a solution of the appropriate ligand in CH₂Cl₂(25

mL) was added and the resulting mixture was stirred at r.t. in the dark

for 24 h. The solvent was removed under reduced pressure and the

crude was redissolved in CH₂Cl₂(1 mL) and then successively washed

with Et₂O (4 × 50 mL) and then with hexane (2 × 25 mL). The

solvent was removed under reduced pressure and the resulting solid

was dried under high vacuum.

3

(1H, dd, (Py)N−CH-CH-CH, J_H,H= 7.6 Hz, J_H,H= 5.7 Hz), 6.96

(1H, d, CH₃−O-(Ar)C−CH-C, ⁴J_H,H= 2.5 Hz), 6.87 (1H, d, CH₃−O-

(Ar)C−CH-CH-C, ³J_H,H= 9 Hz), 6.65 (1H, dd, CH₃−O-(Ar)C−CH-

CH-C, ³J_H,H= 9 Hz, ⁴J_H,H= 2.5 Hz), 5.80 (2H, d, 2xCH₃-(Ar)C−CH-

CH-C, ³J_H,H= 5.4 Hz), 5.55 (2H, d, 2xCH₃-(Ar)C−CH-CH-C, ³J_H,H

=

5.4 Hz), 4.24−4.32 (4H, m, (Ar)C−CH₂−(CO)−O-CH₂-CH₂−O,

(Ar)C−CH₂−O−CH₂−CH₂-O), 3.81 (3H, s, CH₃-O-(Ar)C−CH-C),

3.68 (2H, s, (Ar)C−CH₂-(CO)-O-(CH₂)₂−O), 2.85 (2H, t,

3

(Py)N−CH-C−CH₂−CH₂-(CO), J_H,H= 7.2 Hz), 2.81 (1H, sept,

(Ar)C−CH−CH−C-CH(CH₃)₂, ³J_H,H= 6.9 Hz), 2.55 (2H, t, (Py)N−

Synthesis of [Ru(η⁶-p-cymene)Cl₂]{(2-(2-(1-(4-chlorobenzo-

yl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-3-(pyri-

din-3-yl)propanoate} (1a). Complex 1a was prepared following the

general procedure starting from [Ru(η⁶-p-cymene)Cl]₂Cl₂(0.123 g, 1

equiv) and ligand L1 (0.237 g, 2.2 equiv)), to aﬀord a yellow-orange

3

CH−C-CH₂-CH₂−(CO), J_H,H= 7.2 Hz), 2.37 (3H, s, CH₃-

(Ar)C−N-(CO)), 2.04 (3H, s, CH₃-(Ar)C−CH−CH-C), 1.28

3

(6H, d, (Ar)C−CH−CH-C−CH(CH₃)₂, J_H,H= 6.9 Hz); ¹³C NMR

(CDCl₃) δ_C, ppm: 171.8 (1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−O),

170.7 (1C, (Py)N−CH-C-(CH₂)₂−(CO)), 168.4 (1C, Cl-(Ar)C−

CH−CH-C-(CO)), 156.2 (1C, CH₃−O-(Ar)C-CH-C), 154.5 (1C,

(Py)N-CH−C−CH), 152.5 (1C, (Py)N-CH−CH−CH), 139.5 (1C,

Cl-(Ar)C-CH−CH), 137.9 (1C, (Py)N−CH-CH-CH), 137.1 (1C,

(Py)N−CH-C-CH₂), 136.2 (1C, CH₃−O-(Ar)C−CH-C), 134.0 (1C,

CH₃-(Ar)C-N-(CO)), 131.3 (2C, 2xCl-(Ar)C−CH-CH), 131.0

(1C, Cl-(Ar)C−CH−CH-C), 130.7 (1C, CH₃−O-(Ar)C−CH−CH-

C), 129.3 (2C, 2xCl-(Ar)C-CH−CH), 124.3 (1C, (Py)N−CH-CH−

CH), 115.1 (1C, CH₃−O-(Ar)C−CH-CH−C), 112.4 (1C, (Ar)C-

CH₂−(CO)-O-(CH₂)₂−O), 111.6 (1C, CH₃−O-(Ar)C-CH−CH-

C), 101.7 (1C, CH₃−O-(Ar)C-CH−C), 93.8 (1C, CH₃-(Ar)C−CH−

CH-C), 88.8 (1C, CH₃-(Ar)C-CH−CH-C), 75.1 (2C, 2xCH₃-(Ar)C−

CH-CH−C), 73.1 (2C, 2xCH₃-(Ar)C-CH−CH-C), 62.6 (1C, (Ar)C−

CH₂−(CO)-O−CH₂−CH₂−O), 62.5 (1C, (Ar)C−CH₂−(CO)-

O-CH₂−CH₂−O), 55.9 (1C, CH₃−O-(Ar)C−CH-C), 34.4 (1C,

(Py)N−CH-C-CH₂−CH₂−(CO)), 31.0 (1C, (Ar)CH−CH-C-CH-

(CH₃)₂), 30.3 (1C, Ar)C-CH₂-(CO)-O-(CH₂)₂−O), 27.7 (1C,

(Py)N−CH-C−CH₂−CH₂-(CO)), 22.7 (2C, (Ar)CH−CH-C−

CH(CH₃)₂), 18.2 (1C, CH₃-(Ar)C−CH−CH), 13.5 (1C, CH₃-

(Ar)C−N-(CO)); IR (ν, cm⁻¹): 2960 (C−H, CH₂, CH₃); 1731

(CO, ester); 1676, (CO, amide); 1590, 1477, 1356, 1317, (ring

skeleton CC, C−C, CN, C−N); 1221, 1142 (C−O, ether, ester);

832, 803, 754 (C−H, aromatic); ESI-MS(+): m/z 894.20 [M-Cl]⁺,

calcd. for C₃₉H₄₁Cl₂N₂O₆Os⁺894.90, the isotopic pattern corresponds

well to the calculated one; Elemental Analysis (%): calcd. for

C₃₉H₄₁Cl₃N₂O₆Os C 50.35, H 4.44, N 3.01; found C 50.32, H 4.43,

N 3.07.

1

solid (0.321 g, yield 86%). Mp (°C): 84−85.5; H NMR (CDCl₃) δ,

4

ppm: 8.90 (1H, d, (Py)N−CH-C−CH, J_H,H= 2 Hz), 8.87 (1H, dd,

3

4

(Py)N−CH-CH−CH, J_H,H= 5.7 Hz, J_H,H= 1 Hz), 7.66 (2H, m,

3

4

2xCl-(Ar)C−CH-CH, J_H,H= 8.5 Hz, J_H,H= 2.3 Hz), 7.49 (1H, ddd

3

4

overlapped, (Py)N−CH-CH-CH, J_H,H= 7.8 Hz, J_H,H= 2 Hz), 7.47

3

4

(2H, m, 2xCl-(Ar)C−CH-CH, J_H,H= 8.5 Hz, J_H,H= 2.3 Hz), 7.20

3

(1H, dd, (Py)N−CH-CH-CH, J_H,H= 7.8 Hz, J_H,H= 5.7 Hz), 6.96

(1H, d, CH₃−O-(Ar)C−CH-C, ⁴J_H,H= 2.5 Hz), 6.86 (1H, d, CH₃−O-

(Ar)C−CH-CH-C, ³J_H,H= 9 Hz), 6.66 (1H, dd, CH₃−O-(Ar)C−CH-

CH-C, ³J_H,H= 9 Hz, ⁴J_H,H= 2.5 Hz), 5.43 (2H, d, 2xCH₃-(Ar)C−CH-

CH-C, ³J_H,H= 6.0 Hz), 5.20 (2H, d, 2xCH₃-(Ar)C−CH-CH-C, ³J_H,H

=

6.0 Hz), 4.25−4.32 (4H, m, (Ar)C−CH₂−(CO)−O-CH₂-CH₂−O,

(Ar)C−CH₂−O−CH₂−CH₂-O), 3.82 (3H, s, CH₃-O-(Ar)C−CH-C),

3.69 (2H, s, (Ar)C−CH₂-O-(CH₂)₂−O), 2.95 (1H, sept, (Ar)C−

CH−CH−C-CH(CH₃)₂, ³J_H,H= 6.9 Hz), 2.88 (2H, t, (Py)N−CH-C−

3

CH₂−CH₂-(CO), J_H,H= 7.2 Hz), 2.55 (2H, t, (Py)N−CH−C-

3

CH₂-CH₂−(CO), J_H,H= 7.2 Hz), 2.38 (3H, s, CH₃-(Ar)C−N),

2.07 (3H, s, CH₃-(Ar)C−CH−CH-C), 1.29 (6H, d, (Ar)C−CH−CH-

3

C−CH(CH₃)₂, J_H,H= 6.9 Hz); ¹³C NMR (CDCl₃) δ_C, ppm: 171.8

(1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−O), 170.7 (1C, (Py)N−CH-

C-(CH₂)₂−(CO)), 168.4 (1C, Cl-(Ar)C−CH−CH-C-(CO)),

156.2 (1C, CH₃−O-(Ar)C-CH-C), 155.1 (1C, (Py)N-CH−C−CH),

153.0 (1C, (Py)N-CH−CH−CH), 139.5 (1C, Cl-(Ar)C-CH−CH),

137.7 (1C, (Py)N−CH-CH-CH), 137.1 (1C, (Py)N−CH-C-CH),

136.2 (1C, CH₃−O-(Ar)C−CH-C), 134.0 (1C, CH₃-(Ar)C-N-(C

O)), 131.3 (2C, 2xCl-(Ar)C−CH-CH), 131.0 (1C, Cl-(Ar)C−CH−

CH-C), 130.7 (1C, CH₃−O-(Ar)C−CH−CH-C), 129.3 (2C, 2xCl-

(Ar)C-CH−CH), 124.2 (1C, (Py)N−CH-CH−CH,), 115.1 (1C,

CH₃−O-(Ar)C−CH-CH−C), 112.4 (1C, (Ar)C-CH₂−(CO)-O-

(CH₂)₂−O), 111.6 (1C, CH₃−O-(Ar)C-CH−CH-C), 103.6 (1C,

CH₃-(Ar)C−CH−CH-C), 101.6 (1C, CH₃−O-(Ar)C-CH−C), 97.2

(1C, CH₃-(Ar)C-CH−CH-C), 83.0 (2C, 2xCH₃-(Ar)C−CH-CH−C),

82.3 (2C, 2xCH₃-(Ar)C-CH−CH-C), 62.6 (1C, (Ar)C−CH₂−(C

O)-O−CH₂−CH₂−O), 62.5 (1C, (Ar)C−CH₂−(CO)-O-CH₂−

CH₂−O), 55.9 (1C, CH₃−O-(Ar)C−CH-C), 34.5 (1C, (Py)N−CH-

C-CH₂−CH₂−(CO)), 30.8 (1C, (Ar)CH−CH-C-CH(CH₃)₂), 30.3

(1C, (Ar)C-CH₂-(CO)-O-(CH₂)₂−O, 27.7 (1C, (Py)N−CH-C−

CH₂−CH₂-(CO)), 22.4 (2C, (Ar)CH−CH-C−CH(CH₃)₂), 18.3

(1C, CH₃-(Ar)C−CH−CH), 13.5 (1C, CH₃-(Ar)C−N-(CO)); IR

(ν, cm⁻¹): 2925 (C−H, CH₂, CH₃); 1733 (CO, ester); 1676, (C

O, amide); 1589, 1476, 1356, 1317 (ring skeleton CC, C−C, CN,

C−N); 1221, 1141, (C−O, ether, ester); 834, 803, 754 (C−H,

aromatic); ESI-MS(+): m/z 805.14 [M-Cl]⁺, calcd. for

C₃₉H₄₁Cl₂N₂O₆Ru⁺805.73, the isotopic pattern corresponds well to

Synthesis of [Ru(η⁶-p-cymene)Cl₂]{2-(2-(2-((2,6-

dichlorophenyl)amino)phenyl)acetoxy)ethyl-3-(pyridin-3-yl)-

propanoate} (2a). Complex 2a was prepared following the general

procedure starting from [Ru(η⁶-p-cymene)Cl]₂Cl₂(0.206 g, 1 equiv)

and ligand L2 (0.350 g, 2.2 equiv), to aﬀord an orange solid (0.413 g,

1

yield80%). Mp (°C): 89.5−90.5; H NMR (CDCl₃) δ_H, ppm: 8.90

4

(1H, d, (Py)N−CH-C−CH, J_H,H= 1.9 Hz), 8.88 (1H, dd, (Py)N−

3

4

CH-CH−CH, J_H,H= 5.6 Hz, J_H,H= 1.1 Hz), 7.52 (1H, ddd

overlapped, (Py)N−CH-CH-CH, ³J_H,H= 7.8 Hz, ⁴J_H,H= 1.8 Hz), 7.34

3

(2H, d, 2xCl-(Ar)C−CH-CH, J_H,H= 8 Hz), 7.23 (1H, dd, NH-

3

4

(Ar)C−CH-CH−CH, J_H,H= 7.5 Hz, J_H,H= 1.4 Hz), 7.20 (1H, dd,

3

(Py)N−CH-CH-CH, J_H,H= 7.8 Hz, J_H,H= 5.6 Hz), 7.12 (1H, ddd

overlapped, NH-(Ar)C−CH-CH-CH, ³J_H,H= 7.7 Hz, ⁴J_H,H= 1.5 Hz),

3

6.98 (1H, t, Cl-(Ar)C−CH-CH, J_H,H= 8 Hz), 6.95 (1H, ddd

overlapped, NH-(Ar)C−CH−CH-CH, ³J_H,H= 7.4 Hz, ⁴J_H,H= 0.9 Hz),

6.82 (1H, s br, NH), 6.53 (1H, d, NH-(Ar)−C−C-CH-CH, ³J_H,H= 8.0

Hz), 5.43 (2H, d, 2xCH₃-(Ar)C−CH-CH-C, ³J_H,H= 6 Hz), 5.20 (2H,

L

DOI: 10.1021/acs.inorgchem.5b02690

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

3

d, 2xCH₃-(Ar)C−CH-CH-C, J_H,H= 6 Hz), 4.33−4.37 (2H, m,

(Ar)C−CH₂−(CO)−O-CH₂-CH₂−O), 4.28−4.32 (2H, m,

(Ar)C−CH₂−(CO)-O−CH₂−CH₂-O), 3.84 (2H, s, (Ar)C−CH₂-

(CO)-O-(CH₂)₂−O), 2.97 (1H, sept, (Ar)C−CH−CH−C-

(1C, (Ar)C−CH₂−(CO)-O−CH₂−CH₂−O), 38.5 (1C, (Ar)C-

CH₂-(CO)-O-(CH₂)₂−O), 34.5 (1C, (Py)N−CH-C-CH₂−CH₂−

(CO)), 31.0 (1C, (Ar)CH−CH-C-CH(CH₃)₂), 27.7 (1C, (Py)N−

CH-C−CH₂−CH₂-(CO)), 22.8 (2C, (Ar)CH−CH-C−CH-

(CH₃)₂), 18.2 (1C, CH₃-(Ar)C−CH−CH); IR (ν, cm⁻¹): 3322

(N−H); 3066, 2960 (C−H, CH₃, CH₂); 1729 (CO, ester); 1506,

1450 (ring skeleton CC, C−C, C−N, CN); 1144 (C−O, ester);

774, 745 (C−H, aromatic); ESI-MS(+): m/z 833.13 [M-Cl]⁺, calcd.

for C₃₄H₃₆Cl₃N₂O₄Os⁺833.25, the isotopic pattern corresponds well

to the calculated one; Elemental analysis (%): calcd. for

C₃₄H₃₆Cl₄N₂O₄Os C 47.01, H 4.18, N 3.22; found C 47.03, H 4.22,

N 3.28.

3

CH(CH₃)₂, J_H,H= 6.9 Hz), 2.89 (2H, t, (Py)N−CH-C−CH₂−CH₂-

3

(CO), J_H,H= 7.2 Hz), 2.60 (2H, t, (Py)N−CH−C-CH₂-CH₂−

(CO), ³J_H,H= 7.2 Hz), 2.06 (3H, s, CH₃-(Ar)C−CH−CH-C), 1.29

(6H, d, (Ar)C−CH−CH-C−CH(CH₃)₂, J_H,H= 6.9 Hz); ¹³C NMR

3

(CDCl₃) δ, ppm: 172.2 (1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−O),

171.8 (1C, (Py)N−CH-C-(CH₂)₂−(CO)), 155.1 (1C, (Py)N-CH−

C−CH), 153.0 (1C, (Py)N-CH−CH−CH), 142.8 (1C, NH-(Ar)C−

C-Cl), 137.8 (1C, NH-(Ar)C-CH−CH−CH), 137.7 (1C, (Py)N−

CH-CH-CH), 137.0 (1C, (Py)N−CH-C-CH), 131.0 (1C, NH-

(Ar)C−CH-CH−CH), 129.6 (2C, 2xCl-(Ar)C-CH−CH), 129.0

(2C, 2xCl-(Ar)C-CH−CH), 128.2 (1C, NH-(Ar)C−CH-CH−CH),

124.3 (1C, NH-(Ar)C-C-CH−CH), 124.2 (1C, Cl-(Ar)C−CH-CH),

124.2 (1C, (Py)N−CH-CH−CH), 122.2 (1C, NH-(Ar)C−CH−CH-

CH), 118.4 (1C, NH-(Ar)C−C-CH−CH), 103.5 (1C, CH₃-(Ar)C−

CH−CH-C), 97.2 (1C, CH₃-(Ar)C-CH−CH-C), 83.0 (2C, 2xCH₃-

(Ar)C−CH-CH−C), 82.3 (2C, 2xCH₃-(Ar)C-CH−CH-C), 62.9 (1C,

(Ar)C−CH₂−(CO)-O-CH₂−CH₂−O), 62.5 (1C, (Ar)C−CH₂−

(CO)-O−CH₂−CH₂−O), 38.5 (1C, (Ar)C-CH₂-(CO)-O-

(CH₂)₂−O), 34.6 (1C, (Py)N−CH-C-CH₂−CH₂−(CO)), 30.7

(1C, (Ar)CH−CH-C-CH(CH₃)₂), 27.7 (1C, (Py)N−CH-C−CH₂−

CH₂-(CO)), 22.4 (2C, (Ar)CH−CH-C−CH(CH₃)₂), 18.2 (1C,

CH₃-(Ar)C−CH−CH); IR (ν, cm⁻¹): 3317 (N−H); 2959 (C−H,

CH₂, CH₃); 1729 (CO, ester); 1501, 1450 (ring skeleton CC,

C−C, C−N, CN); 1145 (C−O, ester); 776, 746 (C−H aromatic);

ESI-MS(+): m/z 744.08 [M-Cl]⁺, calcd. for C₃₄H₃₆Cl₃N₂O₄Ru⁺

744.09, the isotopic pattern corresponds well to the calculated one;

Elemental analysis (%): calcd. for C₃₄H₃₆Cl₄N₂O₄Ru C 52.39, H 4.66,

N 3.59; found C 52.31, H 4.65, N 3.50.

Synthesis of [Ru(η⁶-p-cymene)Cl₂]{2-(2-(1-(4-chlorobenzoyl)-

5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-4-

(diphenylphosphanyl)benzoate} (3a). Complex 3a was prepared

following the general procedure strating from [Ru(η⁶-p-cymene)-

Cl]₂Cl₂(0.133 g, 1 equiv) and ligand L3 (0.300 g, 2 equiv), to aﬀord

an orange solid (0.267 g, yield 98%).

1

Mp (°C): 107−108; H NMR (CDCl₃) δ_H, ppm: 7.79−7.90 (8H,

m, 2xO-(CO)-(Ar)C−CH-CH−C-P, 2xO-(CO)-(Ar)C−CH-

CH−C-P, 4xP-(Ar)C−CH-CH−CH), 7.62 (2H, m, 2xCl-(Ar)C−

3

4

CH-CH, J_H,H= 8.6 Hz, J_H,H= 2.3 Hz), 7.44 (2H, m, 2xCl-(Ar)C−

3

4

CH-CH, J_H,H= 8.6 Hz, J_H,H= 2.3 Hz), 7.37−7.47 (6H, m, 4xP-

(Ar)C−CH-CH-CH, 2xP-(Ar)C−CH−CH-CH), 6.94 (1H, d, CH₃−

3

O-(Ar)C−CH-C, J_H,H= 2.5 Hz), 6.81 (1H, d, CH₃−O-(Ar)C−CH-

3

CH-C, J_H,H= 9.0 Hz), 6.54 (1H, dd, CH₃−O-(Ar)C−CH-CH-C,

³J_H,H= 9.0 Hz, J_H,H= 2.5 Hz), 5.22 (2H, d, 2xCH₃-(Ar)C−CH-CH-

4

C, ³J_H,H= 6.2 Hz), 4.98 (2H, d, 2xCH₃-(Ar)C−CH-CH-C, ³J_H,H= 6.2

Hz), 4.45−4.49 (2H, m, (Ar)C−CH₂−(CO)-O−CH₂−CH₂-O),

4.38−4.42 (2H, m, (Ar)C−CH₂−(CO)−O-CH₂-CH₂−O), 3.72

(3H, s, CH₃-O-(Ar)C−CH-C), 3.68 (2H, s, (Ar)C−CH₂-(CO)-O-

3

(CH₂)₂−O), 2.86 (1H, sept, (Ar)C−CH−CH−C-CH(CH₃)₂, J_H,H

=

Synthesis of [Os(η⁶-p-cymene)Cl₂]{2-(2-(2-((2,6-

dichlorophenyl)amino)phenyl)acetoxy)ethyl-3-(pyridin-3-yl)-

propanoate} (2b). Complex 2b was prepared following the general

procedure starting from [Os(η⁶-p-cymene)Cl]₂Cl₂(0.266 g, 1 equiv)

and ligand L2 (0.350 g, 2.2 equiv), to aﬀord an orange solid (0.316 g,

yield 54%).

6.9 Hz), 2.34 (3H, s, CH₃-(Ar)C−N-(CO)), 1.85 (3H, s, CH₃-

(Ar)C−CH−CH-C), 1.11 (6H, d, (Ar)C−CH−CH-C−CH(CH₃)₂,

³J_H,H= 6.9 Hz); ³¹P NMR (CDCl₃) δ_P, ppm: 25.12 (1P); ¹³C NMR

(CDCl₃) δ_C, ppm: 170.7 (1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−O),

168.3 (1C, Cl-(Ar)C−CH−CH-C-(CO)), 165.9 (1C, O-(CO)-

(Ar)C−CH−CH−C-P), 156.2 (1C, CH₃−O-(Ar)C-CH-C), 139.5

(1C, O-(CO)-(Ar)C−CH−CH-C-P, ¹J_C,P= 44 Hz), 139.3 (1C, Cl-

(Ar)C-CH−CH), 136.1 (1C, CH₃−O-(Ar)C−CH-C), 134.6 (2C, O-

(CO)-(Ar)C−CH-CH−C−P, ²J_C,P= 9 Hz), 134.4 (4C, 4xP-(Ar)C-

Mp (°C): 74−76; ¹H NMR (CDCl₃) δ_H, ppm: 8.81 (1H, d,

4

(Py)N−CH-C−CH, J_H,H= 1.6 Hz), 8.79 (1H, dd, (Py)N−CH-CH−

3

4

CH, J_H,H= 5.8 Hz, J_H,H= 1.2 Hz), 7.47 (1H, ddd overlapped,

3

4

2

(Py)N−CH-CH-CH, J_H,H= 7.8 Hz, J_H,H= 1.6 Hz), 7.33 (2H, d,

CH−CH−CH, J_C,P= 10 Hz), 134.0 (1C, CH₃-(Ar)C-N-(CO)),

2xCl-(Ar)C−CH-CH, ³J_H,H= 8.1 Hz), 7.23 (1H, dd, NH-(Ar)C−CH-

133.5 (2C, 2xP-(Ar)C-CH−CH−CH, ¹J_C,P= 45 Hz), 131.3 (2C, 2xCl-

(Ar)C−CH-CH), 130.9 (1C, Cl-(Ar)C−CH−CH-C), 130.8 (1C,

CH₃−O-(Ar)C−CH−CH-C), 130.7 (2C, 2xP-(Ar)C−CH−CH-CH,

⁴J_C,P= 2 Hz), 130.7 (1C, O-(CO)-(Ar)C-CH−CH−C-P), 129.2

(2C, 2xCl-(Ar)C-CH−CH), 128.7 (2C, O-(CO)-(Ar)C-CH−CH−

3

4

CH−CH, J_H,H= 7.5 Hz, J_H,H= 1.3 Hz), 7.16(1H, dd, (Py)N−CH-

3

CH-CH, J_H,H= 7.8 Hz, J_H,H= 5.8 Hz), 7.12 (1H, ddd overlapped,

NH-(Ar)C−CH-CH-CH, ³J_H,H= 7.6 Hz, ⁴J_H,H= 1.4 Hz), 6.98 (1H, t,

3

Cl-(Ar)C−CH-CH, J_H,H= 8.1 Hz), 6.95 (1H, ddd overlapped, NH-

3

4

3

(Ar)C−CH−CH-CH, J_H,H= 7.4 Hz, J_H,H= 1.1 Hz), 6.82 (1H, s br,

C-P, J_C,P= 10 Hz), 128.3 (4C, 4xP-(Ar)C−CH-CH−CH, J_C,P= 10

Hz), 115.0 (1C, CH₃−O-(Ar)C−CH-CH−C), 112.4 (1C, O-(C

O)−CH₂−(Ar)C), 111.8 (1C, CH₃−O-(Ar)C-CH−CH-C), 111.6,

111.7 (1C, CH₃-(Ar)C−CH−CH-C), 101.4 (1C, CH₃−O-(Ar)C-

CH−C), 96.4 (1C, CH₃-(Ar)C-CH−CH-C), 89.03 (1C, CH₃-(Ar)C−

CH-CH−C), 89.0 (1C, CH₃-(Ar)C−CH-CH−C), 87.52 (1C, CH₃-

(Ar)C-CH−CH-C), 87.47 (1C, CH₃-(Ar)C-CH−CH-C), 62.9 (1C,

(Ar)C−CH₂−(CO)-O-CH₂−CH₂−O), 62.8 (1C, (Ar)C−CH₂−

(CO)-O−CH₂−CH₂−O), 55.8 (1C, CH₃−O-(Ar)C−CH-C), 30.4

(1C, O-(CO)-CH₂-(Ar)C), 30.3 (1C, (Ar)CH−CH-C-CH(CH₃)₂),

22.0 (2C, (Ar)CH−CH-C−CH(CH₃)₂), 17.9 (1C, CH₃-(Ar)C−CH−

CH), 13.5 (1C, CH₃-(Ar)C−N-(CO)); IR (ν, cm⁻¹): 2961 (C−H,

CH₂, CH₃); 1721 (CO, ester); 1679 (CO, amide); 1597, 1476,

1434, 1356 (ring skeleton CC, C−C, CN, C−N); 1259, 1221,

1086 (C−O, ether, ester); 799, 752 (C−H aromatic); ESI-MS(+): m/

z 1035.09 [M+K]⁺, 960.15 [M-Cl]⁺, calcd. for C₅₀H₄₇Cl₃NO₆PRu

996.32, calcd. for C₅₀H₄₇Cl₂NO₆PRu⁺960.87, the isotopic pattern

corresponds well to the calculated one; Elemental analysis (%): calcd.

for C₅₀H₄₇Cl₃NO₆PRu C 60.28; H 4.76; N 1.41; O; found C 60.38, H

4.83, N 1.36.

3

NH), 6.53 (1H, d, NH-(Ar)−C−C-CH-CH, J_H,H= 8.0 Hz), 5.80

3

(2H, d, 2xCH₃-(Ar)C−CH-CH-C, J_H,H= 5.6 Hz), 5.55 (2H, d,

3

2xCH₃-(Ar)C−CH-CH-C, J_H,H= 5.6 Hz), 4.33−4.37 (2H, m,

(Ar)C−CH₂−(CO)−O-CH₂-CH₂), 4.28−4.32 (2H, m, (Ar)C−

CH₂−(CO)-O−CH₂−CH₂), 3.83 (2H, s, (Ar)C−CH₂-(CO)-O-

(CH₂)₂−O), 2.87 (2H, t, (Py)N−CH-C−CH₂−CH₂-(CO), ³J_H,H

=

3

7.3 Hz), 2.80 (1H, sept, (Ar)C−CH−CH−C-CH(CH₃)₂, J_H,H= 6.9

Hz), 2.59 (2H, t, (Py)N−CH−C-CH₂-CH₂−(CO), ³J_H,H= 7.3 Hz),

2.04 (3H, s, CH₃-(Ar)C−CH−CH-C), 1.29 (6H, d, (Ar)C−CH−CH-

C−CH(CH₃)₂, J_H,H= 6.9 Hz); ¹³C NMR (CDCl₃) δ, ppm: 172.2

3

(1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−O), 171.8 (1C, (Py)N−CH-

C-(CH₂)₂−(CO)), 154.5 (1C, (Py)N-CH−C−CH), 152.5 (1C,

(Py)N-CH−CH−CH), 142.8 (1C, NH-(Ar)C−C-Cl), 137.9 (2C,

NH-(Ar)C-CH−CH, (Py)N−CH-C-CH), 137.2 (1C, (Py)N−CH-

CH-CH), 131.0 (1C, NH-(Ar)C−CH-CH−CH), 129.6 (2C, 2xCl-

(Ar)C-CH−CH), 129.1 (2C, 2xCl-(Ar)C-CH−CH), 128.3 (1C, NH-

(Ar)C−CH-CH−CH), 124.3 (2C, Cl-(Ar)C−CH-CH, NH-(Ar)C-C-

CH−CH), 124.2 (1C, (Py)N−CH-CH−CH), 122.2 (1C, NH-

(Ar)C−CH−CH-CH), 118.5 (1C, NH-(Ar)C−C-CH−CH), 93.8

(1C, CH₃-(Ar)C−CH−CH-C), 88.8 (1C, CH₃-(Ar)C-CH−CH-C),

75.1 (2C, 2xCH₃-(Ar)C−CH-CH−C), 73.1 (2C, 2xCH₃-(Ar)C-CH−

CH-C), 62.9 (1C, (Ar)C−CH₂−(CO)-O-CH₂−CH₂−O), 62.5

Synthesis of [Os(η⁶-p-cymene)Cl₂]{2-(2-(1-(4-chlorobenzoyl)-

5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl-4-

(diphenylphosphanyl)benzoate} (3b). Complex 3b was prepared

M

DOI: 10.1021/acs.inorgchem.5b02690

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

following the general procedure starting from [Os(η⁶-p-cymene)-

Cl]₂Cl₂(0.444 g, 1 equiv) and ligand L3 (1.370 g, 3.5 equiv) to aﬀord

CH₂−O), 4.43−4.47 (2H, m, (Ar)C−CH₂−(CO)-O−CH₂−CH₂-

O), 3.83 (2H, s, (Ar)C−CH₂-(CO)-O-(CH₂)₂−O), 2.86 (1H, sept,

1

3

an orange solid (1.430 g, yield 65%). Mp (°C): 115−116; H NMR

(Ar)C−CH−CH−C-CH(CH₃)₂, J_H,H= 6.9 Hz), 1.85 (3H, s, CH₃-

(CDCl₃) δ_H, ppm: 7.84−7.86 (4H, m, 2xO-(CO)-(Ar)C−CH-

(Ar)C−CH−CH-C), 1.11 (6H, d, (Ar)C−CH−CH-C−CH(CH₃)₂,

³J_H,H= 6.9 Hz); ³¹P NMR (CDCl₃) δ_P, ppm: 24.94 (1P); ¹³C NMR

(CDCl₃) δ_C, ppm: 172.2 (1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−O),

165.7 (1C, O-(CO)-(Ar)C−CH−CH−C-P), 142.6 (1C, NH-(Ar)

CH−C-P, 2xO-(CO)-(Ar)C−CH-CH−C-P), 7.71−7.76 (4H, m,

3

4xP-(Ar)C−CH-CH−CH), 7.62 (2H, m, 2xCl-(Ar)C−CH-CH, J_H,H

= 8.6 Hz, ⁴J_H,H= 2.1 Hz), 7.45 (2H, m, 2xCl-(Ar)C−CH-CH, ³J_H,H

=

4

1

8.6 Hz, J_H,H= 2.1 Hz), 7.38−7.46 (6H, m, 4xP-(Ar)C−CH-CH-CH,

C−C-Cl), 139.4 (1C, d, O-(CO)-(Ar)C−CH−CH-C-P, J_C,P= 45

2xP-(Ar)C−CH−CH-CH), 6.94 (1H, d, CH₃−O-(Ar)C−CH-C, ³J_H,H

Hz), 137.7 (1C, NH-(Ar)C-CH−CH), 134.4 (2C, d, 2xO-(CO)-

3

2

= 2.5 Hz), 6.81 (1H, d, CH₃−O-(Ar)C−CH-CH-C, J_H,H= 9.0 Hz),

(Ar)C−CH-CH−C−P, J_C,P= 8 Hz), 134.3 (4C, d, 4xP-(Ar)C-CH−

3

4

2

6.54 (1H, dd, CH₃−O-(Ar)C−CH-CH-C, J_H,H= 9.0 Hz, J_H,H= 2.5

CH−CH, J_C,P= 10 Hz), 133.4 (2C, d, 2xP-(Ar)C-CH−CH−CH,

3

¹J_C,P= 45 Hz), 130.9 (1C, NH-(Ar)C−CH-CH), 130.8 (1C, d, O-

Hz), 5.42 (2H, d, 2xCH₃-(Ar)C−CH-CH-C, J_H,H= 5.8 Hz), 5.15

(2H, d, 2xCH₃-(Ar)C−CH-CH-C, ³J_H,H= 5.8 Hz), 4.46−4.50 (2H, m,

(Ar)C−CH₂−(CO)-O−CH₂−CH₂-O), 4.39−4.44 (2H, m,

(Ar)C−CH₂−(CO)−O-CH₂-CH₂−O), 3.72 (3H, s, CH₃-O-

(Ar)C−CH-C), 3.68 (2H, s, (Ar)C−CH₂-(CO)-O-(CH₂)₂−O),

2.75 (1H, sept, (Ar)C−CH−CH−C-CH(CH₃)₂, ³J_H,H= 6.9 Hz), 2.34

(3H, s, CH₃-(Ar)C−N), 1.96 (3H, s, CH₃-(Ar)C−CH−CH-C), 1.16

4

(CO)-(Ar)C-CH−CH−C-P, J_C,P= 2 Hz), 130.6 (2C, d, 2xP-

4

(Ar)C−CH−CH-CH, J_C,P= 2 Hz), 129.5 (2C, 2xCl-(Ar)C-CH−

CH), 128.9 (2C, 2xCl-(Ar)C-CH−CH), 128.7 (2C, d, 2xO-(CO)-

(Ar)C-CH−CH−C-P, ³J_C,P= 10 Hz), 128.2 (4C, d, 4xP-(Ar)C- CH−

3

CH−CH, J_C,P= 10 Hz), 128.1 (1C, NH-(Ar)C−CH-CH−CH),

124.1 (1C, Cl-(Ar)C−CH-CH), 124.0 (1C, NH-(Ar)C-C-CH), 122.1

(1C, NH-(Ar)C−CH−CH-CH), 118.2 (1C, NH-(Ar)C−C-CH−

CH), 111.5, 111.6 (1C, CH₃-(Ar)C−CH−CH-C), 96.3 (1C, CH₃-

(Ar)C-CH−CH-C), 89.99 (1C, CH₃-(Ar)C−CH-CH−C), 88.96 (1C,

CH₃-(Ar)C−CH-CH−C), 87.4 (1C, CH₃-(Ar)C-CH−CH-C), 87.3

(1C, CH₃-(Ar)C-CH−CH-C), 62.8 (1C, (Ar)C-(CO)-O-CH₂−

CH₂−O), 62.7 (1C, (Ar)C-(CO)-O−CH₂−CH₂−O), 38.4 (1C,

(Ar)C-CH₂-(CO)-O-(CH₂)₂−O), 30.3 (1C, (Ar)CH−CH-C-CH-

(CH₃)₂), 21.9 (2C, (Ar)CH−CH-C−CH(CH₃)₂), 17.8 (1C, CH₃-

(Ar)C−CH−CH); IR (ν, cm⁻¹): 3322 (N−H); 2960 (C−H, CH₃,

CH₂); 1717 (CO, ester); 1588, 1502, 1450, 1395 (ring skeleton

CC, C−C); 1285, 1272, 1229 (C−O); 853, 745 (C−H aromatic);

ESI-MS(+): m/z 899.10 [M-Cl]⁺, calcd. for C₄₅H₄₂Cl₃NO₄PRu⁺

899.23, the isotopic pattern coresponds well to the calculated one;

Elemental analysis (%): calcd. for C₄₅H₄₂Cl₄NO₄PRu C 57.83, H 4.53,

N 1.50, found C 57.73, H 4.62, N 1.42.

(6H, d, (Ar)C−CH−CH-C−CH(CH₃)₂, J_H,H= 6.9 Hz); ³¹P NMR

3

(CDCl₃) δ_P, ppm: −12.31 (1P); ¹³C NMR (CDCl₃) δ_C, ppm: 170.7

(1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−O), 168.3 (1C, Cl-(Ar)C−

CH−CH-C-(CO)), 165.9 (1C, O-(CO)-(Ar)C−CH−CH−C-

P), 156.1 (1C, CH₃−O-(Ar)C-CH-C), 139.3 (1C, Cl-(Ar)C-CH−

1

CH), 139.2 (1C, O-(CO)-(Ar)C−CH−CH-C-P, J_C,P= 50 Hz),

136.1 (1C, CH₃−O-(Ar)C−CH-C), 134.8 (2C, O-(CO)-(Ar)C−

2

CH-CH−C−P, J_C,P= 11 Hz), 134.6 (4C, 4xP-(Ar)C-CH−CH−CH,

²J_C,P= 10 Hz), 134.0 (1C, CH₃-(Ar)C-N-(CO)), 132.9 (2C, 2xP-

1

(Ar)C-CH−CH−CH, J_C,P= 52 Hz), 131.3 (2C, 2xCl-(Ar)C−CH-

CH), 130.8 (2C, Cl-(Ar)C−CH−CH-C, CH₃−O-(Ar)C−CH−CH-

4

C,), 130.7 (2C, 2xP-(Ar)C−CH−CH-CH, J_C,P= 2 Hz), 130.8 (1C,

O-(CO)-(Ar)C-CH−CH−C-P), 129.2 (2C, 2xCl-(Ar)C-CH−CH),

3

128.6 (2C, 2xO-(CO)-(Ar)C-CH−CH−C-P, J_C,P= 10 Hz), 128.2

3

(4C, 4xP-(Ar)C−CH-CH−CH, J_C,P= 10 Hz), 115.0 (1C, CH₃−O-

Synthesis of [Os(η⁶-p-cymene)Cl₂]{2-(2-(2-((2,6-

d i c h l o r o p h e n y l ) a m i n o ) p h e n y l ) ac e t o x y ) e t h y l - 4 -

(diphenylphosphanyl)benzoate} (4b). Complex 4b was prepared

following the general procedures starting from [Os(η⁶-p-cymene)-

Cl]₂Cl₂(0.220 g, 1 equiv) and ligand L4 (0.461 g, 3.5 equiv) to aﬀord

an orange solid (0.126 g, yield 33%).

(Ar)C−CH-CH−C), 112.4 (1C, (Ar)C-CH₂−(CO)-O), 111.8 (1C,

CH₃−O-(Ar)C-CH−CH-C), 103.95, 103.99 (1C, CH₃-(Ar)C−CH−

CH-C), 101.3 (1C, CH₃−O-(Ar)C-CH−C,), 89.0 (1C, CH₃-(Ar)C-

CH−CH-C), 80.44 (1C, CH₃-(Ar)C−CH-CH−C), 80.41 (1C, CH₃-

(Ar)C−CH-CH−C), 80.30 (1C, CH₃-(Ar)C-CH−CH-C), 80.25 (1C,

CH₃-(Ar)C-CH−CH-C), 62.9 (1C, (Ar)C−CH₂−(CO)-O-CH₂−

CH₂−O), 62.8 (1C, (Ar)C−CH₂−(CO)-O−CH₂−CH₂−O), 55.8

(1C, CH₃−O-(Ar)C−CH-C), 30.3 (1C, (Ar)CH−CH-C-CH(CH₃)₂),

30.2 (1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−O), 22.3 (2C, (Ar)CH−

CH-C−CH(CH₃)₂), 18.0 (1C, CH₃-(Ar)C−CH−CH), 13.5 (1C,

CH₃-(Ar)C−N-(CO)); IR (ν, cm⁻¹): 2960 (C−H, CH₂, CH₃);

1719 (CO, ester); 1680 (CO, amide); 1597, 1476, 1356, 1315

(ring skeleton CC, C−C, CN, C−N); 1259, 1222, 1086 (C−O,

ester, ether); 799, 753 (C−H aromatic); ESI-MS(+): m/z m/z

1124.14 [M+K]⁺, 1050.21 [M-Cl]⁺, calcd. for C₅₀H₄₇Cl₃NO₆OsP

1085.48, calcd. for C₅₀H₄₇Cl₂NO₆OsP⁺1050.03, the isotopic pattern

corresponds well to the calculated one; Elemental analysis (%): calcd.

for C₅₀H₄₇Cl₃NO₆OsP C 55.33, H 4.36, N 1.29; found C 55.29, H

4.36, N 1.24.

1

Mp (°C): 108−109; H NMR (CDCl₃) δ_H, ppm: 7.80−7.88 (4H,

m, 2xO-(CO)-(Ar)C−CH-CH−C-P, 2xO-(CO)-(Ar)C−CH-

CH−C-P), 7.70−7.76 (4H, m, 4xP-(Ar)C−CH-CH−CH), 7.37−

7.44 (6H, m, 4xP-(Ar)C−CH-CH-CH, 2xP-(Ar)C−CH−CH-CH),

3

7.29 (2H, d, 2xCl-(Ar)C−CH-CH, J_H₄_,H= 8 Hz), 7.20 (1H, dd, NH-

3

(Ar)C−CH-CH−CH, J_H,H= 7.5 Hz, J_H,H= 1.4 Hz), 7.02 (1H, ddd

overlapped, NH-(Ar)C−CH-CH-CH, ³J_H,H= 7.7 Hz, ⁴J_H,H= 1.4 Hz),

3

6.95 (1H, t, Cl-(Ar)C−CH-CH, J_H,H= 8 Hz), 6.87 (1H, ddd

3

4

overlapped, NH-(Ar)C−CH−CH-CH, J_H,H= 7.4 Hz, J_H,H= 1 Hz),

3

6.84 (1H, s br, NH), 6.45 (1H, dd, NH-(Ar)C−C−CH-CH, J_H,H

=

8.0 Hz), 5.40 (2H, d, 2xCH₃-(Ar)C−CH-CH-C, ³J_H,H= 5.8 Hz), 5.15

(2H, d, 2xCH₃-(Ar)C−CH-CH-C, ³J_H,H= 5.8 Hz), 4.89−4.53 (2H, m,

(Ar)C−CH₂−(CO)−O-CH₂-CH₂−O), 4.44−4.48 (2H, m,

(Ar)C−CH₂−(CO)-O−CH₂−CH₂-O), 3.83 (2H, s, (Ar)C−CH₂-

(CO)-O-(CH₂)₂−O), 2.75 (1H, sept, (Ar)C−CH−CH−C-

Synthesis of [Ru(η⁶-p-cymene)Cl₂]{2-(2-(2-((2,6-

d i c h l o r o p h e n y l ) a m i n o ) p h e n y l ) a c e t o x y ) e t h y l - 4 -

(diphenylphosphanyl)benzoate} (4a). Complex 4a was prepared

following the general procedure starting from [Ru(η⁶-p-cymene)-

Cl]₂Cl₂(0.098 g, 1 equiv) and ligand L4_(0.200 g, 2 equiv) to aﬀord

an orange solid (0.096 g, yield 59%).

3

CH(CH₃)₂, J_H,H= 6.9 Hz), 1.96 (3H, s, CH₃-(Ar)C−CH−CH-C),

1.16 (6H, d, (Ar)C−CH−CH-C−CH(CH₃)₂, J_H,H= 6.9 Hz); ³¹P

3

NMR (CDCl₃) δ, ppm: −12.50 (1P); ¹³C NMR (CDCl₃) δ_C, ppm:

172.3 (1C, (Ar)C−CH₂−(CO)-O-(CH₂)₂−O), 165.8 (1C, O-(C

O)-(Ar)C−CH−CH−C-P), 142.7 (1C, NH-(Ar)C−C-Cl), 139.3

1

Mp (°C): 92−93; H NMR (CDCl₃) δ_H, ppm: 7.77−7.89 (8H, m,

1

(1C, d, O-(CO)-(Ar)C−CH−CH-C-P, J_C,P= 49 Hz), 137.8 (1C,

2xO-(CO)-(Ar)C−CH-CH−C-P, 2xO-(CO)-(Ar)C−CH-CH−

C-P, 4xP-(Ar)C−CH-CH−CH), 7.36−7.49 (6H, m, 4xP-(Ar)C−CH-

CH-CH, 2xP-(Ar)C−CH−CH-CH), 7.29 (2H, d, 2xCl-(Ar)C−CH-

NH-(Ar)C-CH−CH), 134.7 (2C, d, 2xO-(CO)-(Ar)C−CH-CH−

C−P, ²J_C,P= 9 Hz), 134.6 (4C, d, 4xP-(Ar)C-CH−CH−CH, ²J_C,P= 9

1

3

Hz), 133.0 (2C, d, 2xP-(Ar)C-CH−CH−CH, J_C,P= 52 Hz), 131.0

CH, J_H,₄_H= 8 Hz), 7.20 (1H, dd, NH-(Ar)C−CH-CH−CH, J_H,H

=

(1C, NH-(Ar)C−CH-CH−CH), 130.9 (1C, d, O-(CO)-(Ar)C-

CH−CH−C-P, ⁴J_C,P= 2 Hz), 130.7 (2C, d, 2xP-(Ar)C−CH−CH-CH,

⁴J_C,P= 2 Hz), 129.6 (2C, 2xCl-(Ar)C-CH−CH), 129.0 (2C, 2xCl-

(Ar)C-CH−CH), 128.7 (2C, d, O-(CO)-(Ar)C-CH−CH−C-P,

³J_C,P= 10 Hz), 128.3 (4C, d, 4xP-(Ar)C−CH-CH−CH, ³J_C,P= 10 Hz),

128.2 (1C, NH-(Ar)C−CH-CH−CH), 124.2 (1C, Cl-(Ar)C−CH-

CH), 124.1 (1C, NH-(Ar)C-C-CH), 122.2 (1C, NH-(Ar)C−CH−

7.7 Hz, J_H,H= 1.3 Hz), 7.02 (1H, ddd overlapped, NH-(Ar)C−CH-

3

4

CH-CH, J_H,H= 7.8 Hz, J_H,H= 1.4 Hz), 6.94 (1H, t, Cl-(Ar)C−CH-

3

CH, J_H,H= 8 Hz), 6.87 (1H, ddd overlapped, NH-(Ar)C−CH−CH-

CH, ³J_H,H= 7.4 Hz, ⁴J_H,H= 1.1 Hz), 6.83 (1H, s br, NH), 6.45 (1H, dd,

NH-(Ar)C−C−CH-CH, ³J_H,H= 8.0 Hz), 5.21 (2H, d, 2xCH₃-(Ar)C−

3

CH-CH-C, J_H,H= 6.1 Hz), 4.97 (2H, d, 2xCH₃-(Ar)C−CH-CH-C,

³J_H,H= 6.1 Hz), 4.86−4.54 (2H, m, (Ar)C−CH₂−(CO)−O-CH₂-

N

DOI: 10.1021/acs.inorgchem.5b02690

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

CH-CH), 118.3 (1C, NH-(Ar)C−C-CH−CH), 103.9, 114.0 (1C,

CH₃-(Ar)C−CH−CH-C), 89.0 (1C, CH₃-(Ar)C-CH−CH-C), 80.51

(1C, CH₃-(Ar)C−CH-CH−C), 80.48 (1C, CH₃-(Ar)C−CH-CH−C),

80.3 (1C, CH₃-(Ar)C-CH−CH-C), 80.2 (1C, CH₃-(Ar)C-CH−CH-

C), 62.9 (1C, (Ar)C−CH₂−(CO)-O-CH₂−CH₂), 62.8 (1C,

(Ar)C−CH₂−(CO)-O−CH₂−CH₂), 38.5 (1C, (Ar)C-CH₂-(C

O)-O-(CH₂)₂−O), 30.2 (1C, (Ar)CH−CH-C-CH(CH₃)₂), 22.3 (2C,

(Ar)CH−CH-C−CH(CH₃)₂), 18.0 (1C, CH₃-(Ar)C−CH−CH); IR

(ν, cm⁻¹): 3315 (N−H); 2960 (C−H, CH₂, CH₃); 1719 (CO,

ester); 1588, 1503, 1451, 1395 (ring skeleton CC, C−C); 1272

(C−O, ester); 855, 743 (C−H aromatic); ESI-MS(+): m/z 1046.11

[M + Na]⁺, 988.15 [M-Cl]⁺, calcd. for C₄₅H₄₂Cl₃NO₄POs⁺988.39,

calcd. for C₄₅H₄₂Cl₄NO₄POs 1023.84, the isotopic pattern corre-

sponds well to the calculated one; Elemental analysis (%): calcd. for

C₄₅H₄₂Cl₄NO₄POs C 52.79, H 4.14, N 1.37; found C 52.69, H 4.02, N

1.30.

C₄₁H₄₀Cl₃N₃O₄Ru C 58.20, H 4.76, N 4.97; found C, 58.08, H,

4.81, N, 4.84.

Synthesis of {[Os(η⁶-p-cymene)Cl](4′-methyl-[2,2′-bipyri-

din]-4-yl)methylene-2-(1-(4-chlorobenzoyl)-5-methoxy-2-

methyl-1H-indol-3-yl)acetate)}Cl (5b). Complex 5b was prepared

following the general procedure starting from [Os(η⁶-p-cymene)-

Cl]₂Cl₂(0.200 g, 1 equiv) and ligand L5 (0.273 g, 2 equiv), to aﬀord a

yellow-orange solid (0.188 g, yield 79%). Mp (°C): 174.5−175.5 with

decomp.; ¹H NMR (CDCl₃) δ_H, ppm: 9.61 (1H, d, O−CH₂−(Py)C−

3

CH-CH-N, J_H,H= 4.8 Hz), 9.40 (1H, d, CH₃-(Py)C−CH-CH-N,

³J_H,H= 5.3 Hz), 8.41 (1H, s, O−CH₂−(Py)C−CH−C-N), 8.23 (1H, s,

3

CH₃-(Py)C−CH−C-N), 7.64 (2H, d, 2xCl-(Ar)C−CH-CH, J_H,H

=

3

8.4 Hz), 7.54 (1H, d, O−CH₂−(Py)C−CH-CH-N, J_H,H= 4.8 Hz),

7.45−7.47 (2H, m, CH₃-(Py)C−CH-CH-N, 2xCl-(Ar)C−CH-CH,

³J_H,H= 8.4 Hz), 6.97 (1H, d, CH₃−O-(Ar)C−CH-C, J_H,H= 2.2 Hz),

4

6.91 (1H, d, CH₃−O-(Ar)C−CH-CH-C, ³J_H,H= 9 Hz), 6.66 (1H, dd,

CH₃−O-(Ar)C−CH-CH-C, ³J_H,H= 9 Hz, ⁴J_H,H= 2.2 Hz), 6.37 (1H, d,

CH₃-(Ar)C−CH-CH-C, ³J_H,H= 5 Hz), 6.32 (1H, d, CH₃-(Ar)C−CH-

Synthesis of {[Ru(η⁶-p-cymene)Cl](4′-methyl-[2,2′-bipyri-

din]-4-yl)methyl-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-

1H-indol-3-yl)acetate)}Cl (5a). Complex 5a was prepared following

the general procedures starting from [Ru(η⁶-p-cymene)Cl]₂Cl₂(0.198

g, 1 equiv) and ligand L5 (0.350 g, 2 equiv), to aﬀord an orange solid

3

CH-C, J_H,H= 5 Hz), 6.15 (1H, d, CH₃-(Ar)C−CH-CH-C, J_H,H= 5

Hz), 6.09 (1H, d, CH₃-(Ar)C−CH-CH-C, ³J_H,H= 5 Hz), 5.38 (2H, s,

O−CH₂-(Py)C−CH−CH-N), 3.84 (2H, s, (Ar)C−CH₂-(CO)-O−

CH₂−(Py)C), 3.78 (3H, s, CH₃-O-(Ar)C−CH-C), 2.61 (3H, s, CH₃-

(Py)C−CH−CH-N), 2.49 (1H, sept, (Ar)C−CH−CH−C-

1

(0.485 g, yield 88%). Mp (°C): 133−134 with decomp.; H NMR

3

(CDCl₃) δ_H, ppm: 9.75 (1H, d, O−CH₂−(Py)C−CH-CH-N, J_H,H

=

3

5.7 Hz), 9. 55 (1H, d, CH₃-(Py)C−CH-CH-N, J_H,H= 5.7 Hz), 8.23

CH(CH₃)₂, J_H,H= 6.8 Hz), 2.37 (3H, s, CH₃-(Ar)C−N-(CO)),

(1H, s, O−CH₂−(Py)C−CH−C-N), 8.04 (1H, s, CH₃-(Py)C−CH−

2.29 (3H, s, CH₃-(Ar)C−CH−CH-C), 0.96 (6H, d, (Ar)C−CH−CH-

3

C−CH(CH₃)₂, J_H,H= 6.8 Hz); ¹³C NMR (CDCl₃) δ_C, ppm: 170.3

3

C-N), 7.62 (2H, m, 2xCl-(Ar)C−CH-CH, J_H,H= 8.4 Hz), 7.59 (1H,

3

d, O−CH₂−(Py)C−CH-CH-N, J_H,H= 5.7 Hz), 7.50 (1H, d, CH₃-

(1C, (Ar)C−CH₂−(CO)-O−CH₂−(Py)C), 168.4 (1C, Cl-(Ar)C−

CH−CH-C-(CO)), 156.5 (1C, O−CH₂−(Py)C−CH-C-N), 156.2

(1C, CH₃−O-(Ar)C-CH-C), 155.7 (1C, CH₃-(Py)C−CH-C-N),

155.6 (1C, O−CH₂−(Py)C−CH-CH-N), 154.7 (1C, CH₃-(Py)C−

CH-CH-N), 152.4 (1C, O−CH₂−(Py)C-CH−CH-N), 149.3 (1C,

CH₃-(Py)C-CH−CH-N), 139.5 (1C, Cl-(Ar)C-CH−CH), 136.2 (1C,

CH₃−O-(Ar)C−CH-C), 133.7 (1C, CH₃-(Ar)C-N-(CO)), 131.2

(2C, 2xCl-(Ar)C−CH-CH), 130.9 (1C, Cl-(Ar)C−CH−CH-C),

130.6 (1C, CH₃−O-(Ar)C−CH−CH-C), 129.8 (1C, CH₃-(Py)C−

CH-CH-N), 129.3 (2C, 2xCl-(Ar)C-CH−CH), 126.7 (1C, CH₃-

(Py)C−CH−C-N), 124.8 (1C, O−CH₂−(Py)C-CH−CH-N), 121.7

(1C, O−CH₂−(Py)C-CH−C−N), 115.1 (1C, CH₃−O-(Ar)C−CH-

CH−C), 112.0 (1C, (Ar)C-CH₂−(CO)-O−CH₂−(Py)C), 111.9

(1C, CH₃−O-(Ar)C-CH−CH-C), 101.5 (1C, CH₃−O-(Ar)C-CH−

C), 97.5 (1C, CH₃-(Ar)C−CH−CH-C), 95.5 (1C, CH₃-(Ar)C-CH−

CH-C), 78.7 (1C, CH₃-(Ar)C−CH-CH-C), 78.6 (1C, CH₃-(Ar)C−

CH-CH-C), 74.6 (1C, CH₃-(Ar)C−CH-CH-C), 74.3 (1C, CH₃-

(Ar)C−CH-CH-C), 63.9 (1C, O-CH₂-(Py)C−CH−CH-N), 56.0 (1C,

CH₃−O-(Ar)C−CH-C), 31.3 (1C, (Ar)CH−CH-C-CH(CH₃)₂), 30.2

(1C, (Ar)C−C-CH₂-(CO)-O−CH₂), 22.6 (1C, (Ar)CH−CH-C−

CH-CH₃), 22.5 (1C, (Ar)CH−CH-C−CH-CH₃), 21.5 (1C, CH₃-

(Py)C−CH−CH-N), 19.0 (1C, CH₃-(Ar)C−CH−CH), 13.6 (1C,

CH₃-(Ar)C−N-(CO)); IR (ν, cm⁻¹): 2963 (C−H, CH₂, CH₃);

1739 (CO, ester); 1676 (CO, amide); 1621, 1589, 1476, 1356,

1314 (ring skeleton CC, C−C, CN, C−N); 1220, 1140 (C−O,

ether, ester); 828 (C−H aromatic); ESI-MS(+): m/z 899.19 [M-Cl]⁺,

calcd. for C₄₁H₄₀Cl₂N₃O₄Os⁺899.92; the isotopic pattern corresponds

well to the calculated one; Elemental analysis (%): calcd. for

C₄₁H₄₀Cl₃N₃O₄Os C 54.72, H 4.48, N 4.67; found C 54.83, H 4.67,

N 4.57;

3

(Py)C−CH-CH-N, J_H,H= 5.7 Hz), 7.44 (2H, m, 2xCl-(Ar)C−CH-

3

4

CH, J_H,H= 8.4 Hz), 6.95 (1H, d, CH₃−O-(Ar)C−CH-C, J_H,H= 2.4

3

Hz), 6.88 (1H, d, CH₃−O-(Ar)C−CH-CH-C, J_H,H= 9 Hz), 6.63

3

4

(1H, dd, CH₃−O-(Ar)C−CH-CH-C, J_H,H= 9 Hz, J_H,H= 2.4 Hz),

3

6.19 (1H, m, CH₃-(Ar)C−CH-CH-C, J_H,H= 6.1 Hz), 6.17 (1H, m,

3

CH₃-(Ar)C−CH-CH-C, J_H,H= 6.1 Hz), 6.05 (1H, m, CH₃-(Ar)C−

3

CH-CH-C, J_H,H= 6.1 Hz), 6.01 (1H, m, CH₃-(Ar)C−CH-CH-C,

³J_H,H= 6.1 Hz), 5.29 (2H, s, O−CH₂-(Py)C−CH−CH-N), 3.81 (2H,

s, (Ar)C−CH₂-(CO)-O−CH₂−(Py)C), 3.73 (3H, s, CH₃-O-

(Ar)C−CH-C), 2.63 (1H, sept, (Ar)C−CH−CH−C-CH(CH₃)₂,

³J_H,H= 6.8 Hz), 2.51 (3H, s, CH₃-(Py)C−CH−CH-N), 2.35 (3H, s,

CH₃-(Ar)C−N-(CO)), 2.22 (3H, s, CH₃-(Ar)C−CH−CH-C), 1.01

3

(3H, d, (Ar)C−CH−CH-C−CH-CH₃, J_H,H= 6.8 Hz), 0.99 (3H, d,

(Ar)C−CH−CH-C−CH-CH₃, J_H,H= 6.8 Hz); ¹³C NMR (CDCl₃)

3

δ_C, ppm: 170.3 (1C, (Ar)C−CH₂−(CO)-O−CH₂−(Py)C), 168.4

(1C, Cl-(Ar)C−CH−CH-C-(CO)), 156.8 (1C, O−CH₂−(Py)C−

CH-C-N), 156.2 (1C, CH₃−O-(Ar)C-CH-C), 155.8 (1C, CH₃-

(Py)C−CH-C-N), 154.7 (1C, O−CH₂−(Py)C−CH-CH−N), 153.9

(1C, CH₃-(Py)C−CH-CH−N), 152.2 (1C, O−CH₂−(Py)C-CH−

CH-N), 149.1 (1C, CH₃-(Py)C-CH−CH-N), 139.6 (1C, Cl-(Ar)C-

CH−CH), 136.2 (1C, CH₃−O-(Ar)C−CH-C), 133.7 (1C, CH₃-(Ar)

C-N-(CO)), 131.3 (2C, 2xCl-(Ar)C−CH-CH), 130.9 (1C, Cl-

(Ar)C−CH−CH-C), 130.6 (1C, CH₃−O-(Ar)C−CH−CH-C), 129.3

(2C, 2xCl-(Ar)C-CH−CH), 129.2 (1C, CH₃-(Py)C−CH-CH-N),

126.0 (1C, CH₃-(Py)C−CH−C-N), 124.5 (1C, O−CH₂−(Py)C-

CH−CH-N), 121.3 (1C, O−CH₂−(Py)C-CH−C−N), 115.1 (1C,

CH₃−O-(Ar)C−CH-CH−C), 112.0 (1C, (Ar)C-CH₂−(CO)-O−

CH₂−(Py)C), 111.9 (1C, CH₃−O-(Ar)C-CH−CH-C), 104.7 (1C,

CH₃-(Ar)C−CH−CH-C), 104.2 (1C, CH₃-(Ar)C-CH−CH-C), 101.5

(1C, CH₃−O-(Ar)C-CH−C), 87.3 (1C, CH₃-(Ar)C−CH-CH-C),

87.2 (1C, CH₃-(Ar)C−CH-CH-C), 84.6 (1C, CH₃-(Ar)C−CH-CH-

C), 84.4 (1C, CH₃-(Ar)C−CH-CH-C), 64.0 (1C, O-CH₂-(Py)C−

CH−CH-N), 56.0 (1C, CH₃−O-(Ar)C−CH-C), 31.2 (1C, (Ar)CH−

CH-C-CH(CH₃)₂), 30.2 (1C, (Ar)C-CH₂-(CO)-O−CH₂−(Py)C),

22.31 (1C, (Ar)CH−CH-C−CH-CH₃), 22.25 (1C, (Ar)CH−CH-C−

CH-CH₃), 21.5 (1C, CH₃-(Py)C−CH−CH-N), 19.1 (1C, CH₃-

(Ar)C−CH−CH), 13.6 (1C, CH₃-(Ar)C−N-(CO)); IR (ν,

cm⁻¹): 2963 (C−H, CH₃, CH₂); 1737 (CO, ester); 1676 (CO,

amide); 1618, 1476, 1456, 1356, 1316 (ring skeleton CC, C−C,

CN); 1218, 1140, 1086 (C−O, ester, ether); 828, 803, 754 (C−H

aromatic); ESI-MS(+): m/z 810.13 [M-Cl]⁺, calcd. for

C₄₁H₄₀Cl₂N₃O₄Ru⁺810.76, the isotopic pattern corresponds well to

the calculated one; Elemental analysis (%): calcd. for

Synthesis of {[Ru(η⁶-p-cymene)Cl](4′-methyl-[2,2′-bipyri-

din]-4-yl)methyl-2-(2-((2,6-dichlorophenyl)amino)phenyl)-

acetate)}Cl (6a). Complex 6a was prepared following the general

procedure starting from [Ru(η⁶-p-cymene)Cl]₂Cl₂(0.141 g, 1 equiv)

and ligand L6 (0.221 g, 2 equiv), to aﬀord a yellow-orange solid (0.237

g, yield 65%). Mp (°C): 199−200.5 with decomp.; ¹H NMR

3

(CD₃OD) δ_H, ppm: 9.35 (1H, d, O−CH₂−(Py)C−CH-CH-N, J_H,H

= 5.9 Hz), 9.25 (1H, d, CH₃-(Py)C−CH-CH-N, ³J_H,H= 5.8 Hz), 8.29

(1H, s, CH₃-(Py)C−CH−C-N), 8.16 (1H, s, O−CH₂−(Py)C−CH−

C-N), 7.64 (1H, dd, O−CH₂−(Py)C−CH-CH-N, ³J_H,H= 5.9 Hz, ⁴J_H,H

= 1.4 Hz), 7.58 (1H, dd, CH₃-(Py)C−CH-CH-N, ³J_H,H= 5.8 Hz, ³J_H,H

3

= 1.1 Hz), 7.38 (2H, d, 2xCl-(Ar)C−CH-CH, J_H,H= 8.1 Hz), 7.32

3

4

(1H, dd, NH-(Ar)C−CH-CH−CH, J_H,H= 7.5 Hz, J_H,H= 1.2 Hz),

3

7.11 (1H, ddd overlapped, NH-(Ar)C−CH-CH-CH, J_H,H= 7.7 Hz,

O

DOI: 10.1021/acs.inorgchem.5b02690

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

⁴J_H,H= 1.4 Hz), 7.09 (1H, t, Cl-(Ar)C−CH-CH, ³J_H,H= 8.1 Hz), 6.96

(Ar)C−C-Cl), 138.9 (1C, NH-(Ar)C-CH−CH), 132.2 (1C, NH-

(Ar)C-CH−CH−CH), 131.6 (2C, 2xCl-(Ar)C-CH−CH), 130.5 (1C,

NH-(Ar)C−CH-CH−CH), 130.1 (2C, 2xCl-(Ar)C-CH−CH), 129.3

(1C, CH₃-(Py)C−CH-CH-N), 127.2 (1C, NH-(Ar)C-C-CH), 126.3

(2C, Cl-(Ar)C−CH-CH), 125.7 (1C, NH-(Ar)C−CH−CH-CH),

125.0 (1C, CH₃-(Py)C−CH−C-N), 122.9 (1C, O−CH₂−(Py)C-

CH−CH-N), 122.4 (1C, O−CH₂−(Py)C-CH−C−N), 118.4 (1C,

NH-(Ar)C−C-CH−CH), 98.7 (1C, CH₃-(Ar)C−CH−CH-C), 96.6

(1C, CH₃-(Ar)C-CH−CH-C), 79.49 (1C, CH₃-(Ar)C−CH-CH-C),

79.45 (1C, CH₃-(Ar)C−CH-CH-C), 75.4 (1C, CH₃-(Ar)C−CH-CH-

C), 75.2 (1C, CH₃-(Ar)C−CH-CH-C), 65.0 (1C, O-CH₂-(Py)C−

CH−CH-N), 38.6 (1C, (Ar)C-CH₂-(CO)-O−CH₂−(Py)C), 32.5

(1C, (Ar)CH−CH-C-CH(CH₃)₂), 22.7 (1C, (Ar)CH−CH-C−CH-

CH₃), 22.6 (1C, (Ar)CH−CH-C−CH-CH₃), 21.3 (1C, CH₃-(Py)C−

CH−CH-N), 18.9 (1C, CH₃-(Ar)C−CH−CH); IR (ν, cm⁻¹): 2968−

3004 (C−H, CH₂, CH₃); 1742 (CO, ester); 1622, 1511, 1450 (ring

skeleton CC, C−C, C−N, CN); 1143 (C−O, ester); 779, 750

(C−H aromatic); ESI-MS(+): m/z 838.16 [M-Cl]⁺, calcd. for

C₃₆H₃₅Cl₃N₃O₂Os⁺838.28, the isotopic pattern coresponds well to

the calculated one; Elemental analysis (%): calcd. for

C₃₆H₃₅Cl₄N₃O₂Os C 49.49, H 4.04, N 4.81; found C 49.56, H 3.93,

N 4.70.

3

4

(1H, ddd overlapped, NH-(Ar)C−CH−CH-CH, J_H,H= 7.4 Hz, J_H,H

= 1.2 Hz), 6.39 (1H, d, NH-(Ar)C−C−CH-CH, ³J_H,H= 8.0 Hz), 6.06

3

(1H, m, CH₃-(Ar)C−CH-CH-C, J_H,H= 7.2 Hz), 6.04 (1H, m, CH₃-

3

(Ar)C−CH-CH-C, J_H,H= 7.2 Hz), 5.82 (1H, m, CH₃-(Ar)C−CH-

3

CH-C, J_H,H= 7.2 Hz), 5.80 (1H, m, CH₃-(Ar)C−CH-CH-C, J_H,H

=

7.2 Hz), 5.46 (2H, s, O−CH₂-(Py)C−CH−CH-N), 4.03 (2H, s,

(Ar)C−CH₂-(CO)-O), 2.59 (1H, sept, (Ar)C−CH−CH−C-

3

CH(CH₃)₂, J_H,H= 6.9 Hz), 2.59 (3H, s, CH₃-(Py)C−CH−CH-N),

2.25 (3H, s, CH₃-(Ar)C−CH−CH), 1.03 (3H, d, (Ar)C−CH−CH-

3

C−CH-CH₃, J_H,H= 6.9 Hz), 1.01 (3H, d, (Ar)C−CH−CH-C−CH-

CH₃, J_H,H= 6.9 Hz); ¹³C NMR (CD₃OD) δ_C, ppm: 173.0 (1C,

3

(Ar)C−CH₂−(CO)-O−CH₂−(Py)C), 156.53 (1C, O−CH₂−

(Py)C−CH-CH−N), 156.46 (1C, O−CH₂−(Py)C−CH-C-N), 156.0

(1C, CH₃-(Py)C−CH-CH−N), 155.5 (1C, CH₃-(Py)C−CH-C-N),

154.1 (1C, O−CH₂−(Py)C-CH−CH-N), 151.8 (1C, CH₃-(Py)C-

CH−CH-N), 144.2 (1C, NH-(Ar)C−C-Cl), 138.9 (1C, NH-(Ar)C-

CH−CH), 132.2 (1C, NH-(Ar)C-CH−CH−CH), 131.6 (2C, 2xCl-

(Ar)C-CH−CH), 130.1 (2C, 2xCl-(Ar)C-CH−CH), 129.8 (1C, NH-

(Ar)C−CH-CH−CH), 129.3 (1C, CH₃-(Py)C−CH-CH-N), 126.4

(1C, NH-(Ar)C-C-CH), 126.2 (2C, Cl-(Ar)C−CH-CH), 125.6 (1C,

NH-(Ar)C−CH−CH-CH), 125.0 (1C, CH₃-(Py)C−CH−C-N),

122.8 (1C, O−CH₂−(Py)C-CH−CH-N), 122.3 (1C, O−CH₂−

(Py)C-CH−C−N), 118.4 (1C, NH-(Ar)C−C-CH−CH), 105.8 (1C,

CH₃-(Ar)C−CH−CH-C), 105.6 (1C, CH₃-(Ar)C-CH−CH-C), 88.03

(1C, CH₃-(Ar)C−CH-CH-C), 87.97 (1C, CH₃-(Ar)C−CH-CH-C),

85.4 (1C, CH₃-(Ar)C−CH-CH-C), 85.3 (1C, CH₃-(Ar)C−CH-CH-

C), 65.0 (1C, O-CH₂-(Py)C−CH−CH-N), 38.6 (1C, (Ar)C-CH₂-

(CO)-O−CH₂−(Py)C), 32.3 (1C, (Ar)CH−CH-C-CH(CH₃)₂),

22.3 (1C, (Ar)CH−CH-C−CH-CH₃), 22.2 (1C, (Ar)CH−CH-C−

CH-CH₃),21.3 (1C, CH₃-(Py)C−CH−CH-N), 19.0 (1C, CH₃-

(Ar)C−CH−CH); IR (ν, cm⁻¹): 3228 (N−H); 3047−2921 (C−H,

CH₂, CH₃); 1741 (CO, ester); 1619, 1511, 1450 (ring skeleton C

C, C−C, CN, C−N); 1143 (C−O, ester); 775, 751 (C−H

aromatic); ESI-MS(+): m/z 750.08 [M-Cl]⁺, calcd. for

C₃₆H₃₅Cl₃N₃O₂Ru⁺749.12, the isotopic pattern coresponds well to

the calculated one; Elemental analysis (%): calcd. for

C₃₆H₃₅Cl₄N₃O₂Ru C 55.11, H 4.50, N 5.36, found C 55.07, H 4.51,

N 5.26;

Synthesis of {[Ru(η⁶-p-cymene)Cl](bis(2-(2-(1-(4-chloroben-

zoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl) [2,2′-

bipyridine]-5,5′-dicarboxylate)}Cl (7a). Complex 7a was prepared

following the general procedure starting from [Ru(η⁶-p-cymene)-

Cl]₂Cl₂(0.064 g, 1 equiv) and ligand L7 (0.210 g, 2 equiv), to aﬀord

yellow solid (0.258 g, yield 94%). Mp (°C): 119−121 with decomp.;

¹H NMR (CDCl₃) δ_H, ppm: 9.69 (2H, s, 2xO-(CO)-(Py)C−CH-

3

N), 9.15 (2H, d, 2x(Py)N−C−CH-CH-C, J_H,H= 7.3 Hz), 8.54 (2H,

3

d, 2x(Py)N−C−CH-CH-C, J_H,H= 7.3 Hz), 7.63 (4H, m, 4xCl-

3

4

(Ar)C−CH-CH, J_H,H= 8.5 Hz, J_H,H= 2.1 Hz), 7.45 (4H, m, 4xCl-

(Ar)C−CH-CH, ³J_H,H= 8.5 Hz, ⁴J_H,H= 2.1 Hz), 6.96 (2H, d, 2xCH₃−

4

O-(Ar)C−CH-C, J_H,H= 2.4 Hz), 6.86 (2H, d, 2xCH₃−O-(Ar)C−

3

CH-CH-C, J_H,H= 9 Hz), 6.62 (2H, dd, 2xCH₃−O-(Ar)C−CH-CH-

C, ³J_H,H= 9 Hz, ⁴J_H,H= 2.4 Hz), 5.95 (2H, d, 2xCH₃-(Ar)C−CH-CH-

C, ³J_H,H= 5.1 Hz), 5.84 (2H, d, 2xCH₃-(Ar)C−CH-CH-C, ³J_H,H= 5.1

Hz), 4.50−4.72 (8H, m, 2x(Ar)C−CH₂−(CO)-O−CH₂−CH₂-O,

2x(Ar)C−CH₂−(CO)−O-CH₂-CH₂−O), 3.79 (6H, s, 2xCH₃-O-

(Ar)C−CH-C), 3.77 (4H, s, 2x(Ar)C−CH₂-(CO)-O-(CH₂)₂−O),

2.82 (1H, sept, (Ar)C−CH−CH−C-CH(CH₃)₂, ³J_H,H= 6.9 Hz), 2.37

(6H, s, 2xCH₃-(Ar)C−N), 2.17 (3H, s, CH₃-(Ar)C−CH−CH-C),

Synthesis of {[Os(η⁶-p-cymene)Cl](4′-methyl-[2,2′-bipyri-

din]-4-yl)methyl-2-(2-((2,6-dichlorophenyl)amino)phenyl) ace-

tate)}Cl (6b). Complex 6b was prepared following the general

procedure starting from [Os(η⁶-p-cymene)Cl]₂Cl₂(0.241 g, 1 equiv)

and ligand L6 (0.200 g, 2 equiv), to aﬀord a yellow-orange solid (0.351

g, yield 80%). Mp (°C): 203−204.5 with decomp.; ¹H NMR

3

1.19 (6H, d, (Ar)C−CH−CH-C−CH(CH₃)₂, J_H,H= 6.9 Hz);

¹³C NMR (CDCl₃) δ_C, ppm: 171.1 (2C, 2x(Ar)C−CH₂−(CO)-

O-(CH₂)₂−O), 168.4 (2C, 2xCl-(Ar)C−CH−CH-C-(CO)), 162.3

(2C, 2x(Py)N−CH-C-(CO)-O), 157.2 (2C, 2x(Py)N-C-CH−CH-

C), 156.2 (2C, 2xCH₃−O-(Ar)C-CH−CH-C), 155.9 (2C, 2x(Py)N−

CH-C-(CO)),140.9 (2C, 2x(Py)N−C−CH-CH-C), 139.5 (2C,

2xCl-(Ar)C-CH−CH), 136.2 (2C, 2xCH₃−O-(Ar)C−CH-C), 133.8

(2C, 2xCH₃-(Ar)C-N-(CO)-O), 131.3 (4C, 4xCl-(Ar)C−CH-CH),

130.9 (2C, 2xCl-(Ar)C−CH−CH-C), 130.6 (2C, 2xCH₃−O-(Ar)C−

CH−CH-C), 129.4 (2C, 2x(Py)N−C−CH-CH-C), 129.3 (4C, 4xCl-

(Ar)C-CH−CH), 126.9 (2C, 2x(Py)N−CH-C-(CO)-O), 115.1

(2C, 2xCH₃−O-(Ar)C−CH-CH−C), 112.2 (2C, (Ar)C-(CO)-

O−CH₂), 111.6 (2C, 2xCH₃−O-(Ar)C-CH−CH-C), 106.3 (1C,

CH₃-(Ar)C−CH−CH-C), 102.5 (1C, CH₃-(Ar)C-CH−CH-C),

101.8 (2C, 2xCH₃−O-(Ar)C-CH−C), 87.2 (2C, 2xCH₃-(Ar)C−CH-

CH-C), 85.5 (2C, 2xCH₃-(Ar)C−CH-CH-C), 64.9 (2C, 2x(Ar)C−

CH₂−(CO)-O−CH₂−CH₂−O), 62.4 (2C, 2x(Ar)C−CH₂−(C

O)-O-CH₂−CH₂−O), 56.1 (2C, 2xCH₃−O-(Ar)C), 31.3 (1C,

(Ar)CH−CH-C-CH(CH₃)₂), 30.5 (2C, 2x(Ar)C-CH₂-(CO)-O-

(CH₂)₂−O), 22.3 (2C, (Ar)CH−CH-C−CH(CH₃)₂), 18.8 (1C,

CH₃-(Ar)C−CH−CH), 13.6 (2C, 2xCH₃-(Ar)C−N-(CO)); IR

(ν, cm⁻¹): 2960 (C−H, CH₂, CH₃); 1728 (CO, ester); 1676 (C

O, amide); 1589, 1477, 1356 (ring skeleton CC, C−C, CN, C−

N); 1285, 1219, 1133, (C−O, ether, ester); 830, 753 (C−H aromatic);

ESI-MS(+): m/z 1282.22 [M-Cl]⁺, calcd. for C₆₄H₅₈Cl₃N₄O₁₂Ru⁺

1282.60, the isotopic pattern corresponds well to the calculated one;

Elemental analysis (%): calcd. for C₆₄H₅₈Cl₄N₄O₁₂Ru C 58.32, H 4.44,

N 4.25; found C 58.29, H 4.47, N 4.13;

3

(CD₃OD) δ_H, ppm: 9.31 (1H, d, O−CH₂−(Py)C−CH-CH-N, J_H,H

3

= 6 Hz), 9.20 (1H, d, CH₃-(Py)C−CH-CH-N, J_H,H= 6 Hz), 8.37

(1H, s, O−CH₂−(Py)C−CH−C-N), 8.24 (1H, s, CH₃-(Py)C−CH−

3

4

C-N), 7.60 (1H, dd, O−CH₂−(Py)C−CH-CH-N, J_H,H= 6 Hz, J_H,H

= 1.6 Hz), 7.53 (1H, dd, CH₃-(Py)C−CH-CH-N, ³J_H,H= 6 Hz, ³J_H,H

1.2 Hz), 7.37 (2H, d, 2xCl-(Ar)C−CH-CH, ³J_H,H= 8.1 Hz), 7.32 (1H,

=

3

4

dd, NH-(Ar)C−CH-CH−CH, J_H,H= 7.5 Hz, J_H,H= 1.3 Hz), 7.09

(1H, ddd overlapped, NH-(Ar)C−CH-CH-CH, ³J_H,H= 7.8 Hz, ⁴J_H,H

=

3

1.5 Hz), 7.07 (1H, t, Cl-(Ar)C−CH-CH, J_H,H= 8.1 Hz), 6.95 (1H,

ddd overlapped, NH-(Ar)C−CH−CH-CH, ³J_H,H= 7.4 Hz, ⁴J_H,H= 1.1

Hz), 6.39 (1H, dd, NH-(Ar)C−C−CH-CH, ³J_H,H= 8.0 Hz, ⁴J_H,H= 0.9

Hz), 6.28 (1H, m, CH₃-(Ar)C−CH-CH-C), 6.26 (1H, m, CH₃-

(Ar)C−CH-CH-C), 5.98 (1H, m, CH₃-(Ar)C−CH-CH-C), 5.97 (1H,

m, CH₃-(Ar)C−CH-CH-C), 5.50 (2H, s, O−CH₂-(Py)C−CH−CH-

1

N), 4.04 (1H, d, (Ar)C−CH-(CO)-O−CH₂−(Py)C, J_H,H= 15.0

1

Hz), 4.01 (1H, d, (Ar)C−CH-(CO)-O−CH₂−(Py)C, J_H,H= 15.0

Hz), 2.63 (3H, s, CH₃-(Py)C−CH−CH-N), 2.45 (1H, sept, (Ar)C−

3

CH−CH−C-CH(CH₃)₂, J_H,H= 6.9 Hz), 2.31 (3H, s, CH₃-(Ar)C−

3

CH−CH-C), 0.94 (3H, d, (Ar)C−CH−CH-C−CH-CH₃, J_H,H= 6.9

Hz), 0.96 (3H, d, (Ar)C−CH−CH-C−CH-CH₃, ³J_H,H= 6.9 Hz); ¹³

C

NMR (CD₃OD) δ_C, ppm: 173.0 (1C, (Ar)C−CH₂−(CO)-O−

CH₂−(Py)C), 157.2 (1C, O−CH₂−(Py)C−CH-CH−N), 156.5 (1C,

O−CH₂−(Py)C−CH-C-N), 156.2 (1C, CH₃-(Py)C−CH-CH−N),

156.0 (1C, CH₃-(Py)C−CH-C-N), 154.2 (1C, O−CH₂−(Py)C-

CH−CH-N), 151.7 (1C, CH₃-(Py)C-CH−CH-N), 144.2 (1C, NH-

P

DOI: 10.1021/acs.inorgchem.5b02690

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

Synthesis of {[Os(η⁶-p-cymene)Cl](bis(2-(2-(1-(4-chloroben-

zoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetoxy)ethyl)[2,2′-

bipyridine]-5,5′-dicarboxylate)}Cl (7b). Complex 7b was prepared

following the general procedure starting from [Os(η⁶-p-cymene)-

Cl]₂Cl₂(0.093 g, 1 equiv) and ligand L7 (0.250 g, 2.1 equiv), to aﬀord

a red solid (0.300 g, yield 90%). Mp (°C): 94−96; ¹H NMR (CDCl₃)

δ_H, ppm: 9.58 (4H, m, 2xO-(CO)-(Py)C−CH-N, 2x(Py)N−C−

CH-CH-C), 8.56 (2H, m, 2x(Py)N−C−CH-CH-C), 7.62 (4H, m,

4xCl-(Ar)C−CH-CH, ³J_H,H= 8.3 Hz), 7.44 (4H, m, 4xCl-(Ar)C−CH-

2x(Py)N−CH-C-(CO)-O), 157.3 (2C, 2x(Py)N-C-CH−CH-C),

155.8 (2C, 2x(Py)N-CH−C-(CO)), 142.8 (2C, 2xNH-(Ar)C−C-

Cl), 141.0 (2C, 2x(Py)N−C−CH-CH−C), 137.8 (2C, 2xNH-(Ar)C-

CH−CH), 131.2 (2C, 2xNH-(Ar)C-CH−CH−CH), 129.6 (4C, 4xCl-

(Ar)C-CH−CH), 129.5 (2C, 2x(Py)N−C-CH−CH-C), 129.1 (4C,

4xCl-(Ar)C-CH−CH), 128.4 (2C, 2xNH-(Ar)C−CH-CH−CH),

127.1 (2C, 2x(Py)N−CH-C-(CO)-O), 124.4 (2C, 2xCl-(Ar)C−

CH-CH), 124.2 (2C, 2xNH-(Ar)C-C-CH), 122.5 (2C, 2xNH-(Ar)C−

CH−CH-CH), 118.5 (2C, 2xNH-(Ar)C−C-CH−CH), 106.1 (1C,

CH₃-(Ar)C−CH−CH-C), 102.9 (1C, CH₃-(Ar)C-CH−CH-C), 87.4

(2C, 2xCH₃-(Ar)C−CH-CH−C), 85.2 (2C, 2xCH₃-(Ar)C-CH−CH-

C), 64.9 (2C, 2x(Ar)C−CH₂−(CO)-O-CH₂−CH₂−O), 62.5 (2C,

2x(Ar)C−CH₂−(CO)-O−CH₂−CH₂−O), 38.7 (2C, 2x(Ar)C-

CH₂-(CO)-O-(CH₂)₂−O), 31.4 (1C, (Ar)CH−CH-C-CH(CH₃)₂),

22.4 (2C, (Ar)CH−CH-C−CH(CH₃)₂), 19.0 (1C, CH₃-(Ar)C−CH−

CH); IR (ν, cm⁻¹): 3335 (N−H); 2963 (C−H, CH₂, CH₃); 1725

(CO, ester); 1667 (CO, ester); 1503, 1450 (ring skeleton CC,

C−C, CN, C−N); 1283, 1253, 1134 (C−O); 863, 774, 753 (C−H

aromatic); ESI-MS(+): m/z 1159.10 [M-Cl]⁺, calcd. for

C₅₄H₄₈Cl₅N₄O₈Ru⁺1159.32, the isotopic pattern corresponds well

to the calculated one; Elemental analysis (%): calcd. for

C₅₄H₄₈Cl₆N₄O₈Ru C 54.29, H 4.05, N 4.69; found C 54.35, H 4.11,

N 4.82;

3

4

CH, J_H,H= 8.3 Hz), 6.93 (2H, d, 2xCH₃−O-(Ar)C−CH-C, J_H,H

=

3

1.8 Hz), 6.85 (2H, d, 2xCH₃−O-(Ar)C−CH-CH-C, J_H,H= 9 Hz),

3

4

6.61 (2H, dd, 2xCH₃−O-(Ar)C−CH-CH-C, J_H,H= 9 Hz, J_H,H= 1.8

Hz), 6.10 (2H, m, 2xCH₃-(Ar)C−CH-CH-C), 5.93 (2H, m, 2xCH₃-

(Ar)C−CH-CH-C), 4.46−4.68 (8H, m, 2x(Ar)C−CH₂−(CO)-O−

CH₂−CH₂-O, 2x(Ar)C−CH₂−(CO)−O-CH₂-CH₂−O), 3.77 (6H,

s, 2xCH₃-O-(Ar)C−CH-C), 3.75 (4H, s, 2x(Ar)C−CH₂-O-(CH₂)₂−

O), 2.56−2.67 (1H, m, (Ar)C−CH−CH−C-CH(CH₃)₂), 2.35 (6H, s,

2xCH₃-(Ar)C−N), 2.21 (3H, s, CH₃-(Ar)C−CH−CH-C), 1.08 (6H,

3

d, (Ar)C−CH−CH-C−CH(CH₃)₂, J_H,H= 5.4 Hz); ¹³C NMR

(CDCl₃) δ_C, ppm: 171.0 (2C, 2x(Ar)C−CH₂−(CO)-O-(CH₂)₂−

O), 168.4 (2C, 2xCl-(Ar)C−CH−CH-C-(CO)), 162.1 (2C,

2x(Py)N−CH-C-(CO)-O), 158.0 (2C, 2x(Py)N-C-CH−CH-C),

156.2 (2C, 2xCH₃−O-(Ar)C-CH−CH-C), 155.6 (2C, 2x(Py)N−

CH-C-(CO)), 140.9 (2C, 2x(Py)N−C−CH-CH-C), 139.5 (2C,

2xCl-(Ar)C-CH−CH), 136.2 (2C, 2xCH₃−O-(Ar)C−CH-C), 133.9

(2C, 2xCH₃-(Ar)C-N-(CO)-O), 131.3 (4C, 4xCl-(Ar)C−CH-CH),

130.9 (2C, 2xCl-(Ar)C−CH−CH-C), 130.6 (2C, 2xCH₃−O-(Ar)C−

CH−CH-C), 130.0 (2C, 2x(Py)N−C−CH-CH-C), 129.3 (4C, 4xCl-

(Ar)C-CH−CH), 127.3 (2C, 2x(Py)N−CH-C-(CO)-O), 115.1

(2C, 2xCH₃−O-(Ar)C−CH-CH−C), 112.2 (2C, 2x(Ar)C-CH₂−

(CO)-O), 111.6 (2C, 2xCH₃−O-(Ar)C-CH−CH-C), 101.8 (2C,

2xCH₃−O-(Ar)C-CH−C), 97.1 (1C, CH₃-(Ar)C−CH−CH-C), 95.4

(1C, CH₃-(Ar)C-CH−CH-C), 78.7 (2C, 2xCH₃-(Ar)C−CH-CH-C),

75.8 (2C, 2xCH₃-(Ar)C−CH-CH-C), 64.9 (2C, 2x(Ar)C−CH₂−

(CO)-O−CH₂−CH₂-O), 62.3 (2C, 2x(Ar)C−CH₂−(CO)−O-

CH₂-CH₂−O), 56.0 (2C, 2xCH₃−O-(Ar)C), 31.4 (1C, (Ar)CH−CH-

C-CH(CH₃)₂), 30.4 (2C, 2x(Ar)C-CH₂-(CO)-O-(CH₂)₂−O), 22.5

(2C, (Ar)CH−CH-C−CH(CH₃)₂), 18.7 (1C, CH₃-(Ar)C−CH−

CH), 13.6 (2C, 2xCH₃-(Ar)C−N-(CO)); ESI-MS(+): m/z

1371.27 [M-Cl]⁺, calcd. for C₆₄H₅₈Cl₃N₄O₁₂Os⁺1371.76, the isotopic

pattern corresponds well to the calculated one; IR (ν, cm⁻¹): 2961

(C−H, CH₂, CH₃); 1729 (CO, ester); 1677 (CO, amide); 1589,

1476, 1356 (ring skeleton CC, C−C, CN); 1286, 1134 (C−O,

ether, ester); 833, 753 (C−H, aromatic); Elemental analysis (%):

calcd. for C₆₄H₅₈Cl₄N₄O₁₂Os ·3CH₂Cl₂C, 48.42; H, 3.88; N, 3.37;

found C 48.49, H 3.78, N 3.31;

Synthesis of {[Os(η⁶-p-cymene)Cl](bis(2-(2-(2-((2,6-

dichlorophenyl)amino)phenyl) acetoxy)ethyl)[2,2′-bipyri-

dine]-5,5′-dicarboxylate)}Cl (8b). Complex 8b was prepared

following the general procedure starting from [Os(η⁶-p-cymene)-

Cl]₂Cl₂(0.093 g, 1 equiv) and ligand L8 (0.210 g, 2 equiv), to aﬀord a

1

red solid (0.284 g, yield 94%). Mp (°C): 112−114 with decomp.; H

3

NMR (CDCl₃) δ_H, ppm: 9.77 (2H, d, 2x(Py)N−C−CH-CH-C, J_H,H

= 6.9 Hz), 9.56 (2H, s, 2xO-(C = O)-(Py)C−CH-N), 8.64 (2H, d,

3

2x(Py)N−C−CH-CH-C, J_H,H= 6.9 Hz), 7.32 (2H, d, 2xCl-(Ar)C−

3

CH-CH, J_H,H= 8 Hz), 7.24 (2H, m, 2xNH-(Ar)C−CH-CH−CH),

7.10 (2H, dd overlapped, 2xNH-(Ar)C−CH-CH-CH, ³J_H,H= 7.3 Hz),

3

6.98 (2H, t, 2xCl-(Ar)C−CH-CH, J_H,H= 8 Hz), 6.92 (2H, dd

3

overlapped, 2xNH-(Ar)C−CH−CH-CH, J_H,H= 6.8 Hz), 6.67 (2H, s

br, 2xNH), 6.52 (2H, d, NH-(Ar)C−C−CH-CH, ³J_H,H= 7.8 Hz), 6.05

3

(2H, d, 2xCH₃-(Ar)C−CH-CH-C, J_H,H= 3.8 Hz), 5.98 (2H, d,

3

2xCH₃-(Ar)C−CH-CH-C, J_H,H= 3.8 Hz), 4.54−4.77 (8H, m,

2x(Ar)C−CH₂−(CO)−O-CH₂-CH₂−O, 2x(Ar)C−CH₂−(CO)-

O−CH₂−CH₂-O), 3.93 (2H, d, 2x(Ar)C−CH-(CO)-O-(CH₂)₂−

1

O, J_H,H= 14.8 Hz), 3.88 (2H, d, 2x(Ar)C−CH-(CO)-O-(CH₂)₂−

1

O, J_H,H= 14.8 Hz), 2.59 (1H, sept, (Ar)C−CH−CH−C-CH(CH₃)₂,

³J_H,H= 5.9 Hz), 2.24 (3H, s, CH₃-(Ar)C−CH−CH-C), 1.06 (6H, d,

(Ar)C−CH−CH-C−CH(CH₃)₂, ³J_H,H= 5.9 Hz); ¹³C NMR (CDCl₃)

δ_C, ppm: 172.5 (2C, 2x(Ar)C−CH₂−(CO)-O-(CH₂)₂−O), 162.1

(2C, 2x(Py)N−CH-C-(CO)-O), 158.1 (2C, 2x(Py)N-C-CH−CH-

C), 155.5 (2C, 2x(Py)N-CH−C-(CO)), 142.8 (2C, 2xNH-(Ar)C−

C-Cl), 141.2 (2C, 2x(Py)N−C−CH-CH−C), 137.8 (2C, 2xNH-(Ar)

C-CH−CH), 131.2 (2C, 2xNH-(Ar)C-CH−CH−CH), 130.0 (2C,

2x(Py)N−C-CH−CH-C), 129.5 (4C, 4xCl-(Ar)C-CH−CH), 129.1

(4C, 4xCl-(Ar)C-CH−CH), 128.4 (2C, 2xNH-(Ar)C−CH-CH−CH),

127.7 (2C, 2x(Py)N−CH-C-(CO)-O), 124.4 (2C, 2xCl-(Ar)C−

CH-CH), 124.1 (2C, 2xNH-(Ar)C-C-CH), 122.5 (2C, 2xNH-(Ar)C−

CH−CH-CH), 118.5 (2C, 2xNH-(Ar)C−C-CH−CH), 96.8 (1C,

CH₃-(Ar)C−CH−CH-C), 96.1 (1C, CH₃-(Ar)C-CH−CH-C), 78.9

(2C, 2xCH₃-(Ar)C−CH-CH−C), 75.3 (2C, 2xCH₃-(Ar)C-CH−CH-

C), 64.9 (2C, 2x(Ar)C−CH₂−(CO)-O-CH₂−CH₂−O), 62.5 (2C,

2x(Ar)C−CH₂−(CO)-O−CH₂−CH₂−O), 38.7 (2C, 2x(Ar)C-

CH₂-(CO)-O-(CH₂)₂−O), 31.4 (1C, (Ar)CH−CH-C-CH(CH₃)₂),

22.6 (2C, (Ar)CH−CH-C−CH(CH₃)₂), 18.9 (1C, CH₃-(Ar)C−CH−

CH); IR (ν, cm⁻¹): 3334 (N−H); 2960 (C−H, CH₂, CH₃); 1725

(CO, ester); 1503, 1450 (ring skeleton CC, C−C, CN, C−N);

1284, 1134 (C−O); 863, 775, 753 (C−H aromatic); ESI-MS(+): m/z

1248.15 [M-Cl]⁺, calcd. for C₅₄H₄₈Cl₅N₄O₈Os⁺1248.48, the isotopic

pattern corresponds well to the calculated one; Elemental analysis

(%): calcd. for C₅₄H₄₈Cl₆N₄O₈Os C 50.52, H 3.77, N 4.36; found C

50.46, H 3.70, N 4.39.

Synthesis of {[Ru(η⁶-p-cymene)Cl](bis(2-(2-(2-((2,6-

dichlorophenyl)amino)phenyl) acetoxy)ethyl)[2,2′-bipyri-

dine]-5,5′-dicarboxylate)}Cl (8a). Complex 8a was prepared

following the bgeneral procedure starting from [Ru(η⁶-p-cymene)-

Cl]₂Cl₂(0.083 g, 1equiv) and ligand L8 (0.240 g, 2 equiv), to aﬀord a

yellow solid (0.302 g, yield 94%). Mp (°C): 107−109 with decomp;

¹H NMR (CDCl₃) δ_H, ppm: 9.69 (2H, s, 2xO-(CO)-(Py)C−CH-

3

N), 9.22 (2H, d, 2x(Py)N−C−CH-CH-C, J_H,H= 7.4 Hz), 8.61 (2H,

3

d, 2x(Py)N−C−CH-CH-C, J_H,H= 7.4 Hz), 7.32 (2H, d, 2xCl-

3

(Ar)C−CH-CH, J_H,H= 8.1 Hz), 7.25 (2H, dd, 2xNH-(Ar)C−CH-

3

4

CH−CH, J_H,H= 7.4 Hz, J_H,H= 1.1 Hz), 7.09 (2H, ddd overlapped,

2xNH-(Ar)C−CH-CH-CH, ³J_H,H= 7.7 Hz, ⁴J_H,H= 1.2 Hz), 6.97 (2H,

3

t, 2xCl-(Ar)C−CH-CH, J_H,H= 8.1 Hz), 6.92 (2H, ddd overlapped,

3

2xNH-(Ar)C−CH−CH-CH, J_H,H= 7.4 Hz), 6.69 (2H, s br, 2xNH),

3

6.51 (2H, d, NH-(Ar)C−C−CH-CH, J_H,H= 8.0 Hz), 5.94 (2H, d,

3

2xCH₃-(Ar)C−CH-CH-C, J_H,H= 5.1 Hz), 5.83 (2H, d, 2xCH₃-

3

(Ar)C−CH-CH-C, J_H,H= 5.1 Hz), 4.59−4.74 (8H, m, 2x(Ar)C−

CH₂−(CO)−O-CH₂-CH₂−O, 2x(Ar)C−CH₂−(CO)-O−CH₂−

1

CH₂-O), 3.92 (2H, d, 2x(Ar)C−CH-(CO)-O-(CH₂)₂−O, J_H,H

=

1

15.1 Hz), 3.88 (2H, d, 2x(Ar)C−CH-(CO)-O-(CH₂)₂−O, J_H,H

15.1 Hz), 2.80 (1H, sept, (Ar)C−CH−CH−C-CH(CH₃)₂, ³J_H,H= 6.9

Hz), 2.18 (3H, s, CH₃-(Ar)C−CH−CH-C), 1.18 (6H, d, (Ar)C−

CH−CH-C−CH(CH₃)₂, J_H,H= 6.9 Hz); ¹³C NMR (CDCl₃) δ_C,

X-ray structure determination for L4, L6, L8, and 8b.

Diﬀraction data of L4, L6, L8, and 8b were measured at 100(2) K

3

ppm: 172.6 (2C, 2x(Ar)C−CH₂−(CO)-O-(CH₂)₂−O), 162.3 (2C,

Q

DOI: 10.1021/acs.inorgchem.5b02690

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

a

Table 4. Crystal Data and Structure Reﬁnement for L4, L6, L8, and 8b

L4

L6

L8

8b

C₃₅H₂₈Cl₂NO₄P

C₂₆H₂₁Cl₂N₃O₂

C₄₄H₃₄Cl₄N₄O₈

C₅₄H₄₈Cl₆N₄O₈Os·C₆H₅Cl·H₂O

F.W. (g·mol⁻¹

)

628.45

478.36

100(2)

888.55

100(2)

1414.43

100(2)

Temperature (K)

Wavelength (Å)

Crystal system

Space group

Unit cell dimensions

a (Å)

100(2)

0.71073

Triclinic

0.71073

Monoclinic

P2₁/n

0.71073

Monoclinic

P2₁/c

0.71073

Monoclinic

P2₁/c

P1

̅

11.1554(11)

11.5216(12)

12.7533(11)

94.419(9)

90.632(8)

110.452(7)

1530.0(3)

2

7.7313(4)

19.2204(19)

15.4838(14)

90

22.264(2)

26.219(9)

b (Å)

4.6639(4)

13.193(7)

c (Å)

23.386(2)

20.409(8)

α (deg)

90

β (deg)

92.174(6)

90

93.066(7)

112.12(3)

γ (deg)

V (Å³)

90

2299.2(3)

4

2424.9(4)

6540(5)

Z

2

4

D_calcd(g·cm³)

1.364

1.382

1.217

1.437

μ (mm⁻¹

)

0.305

0.312

0.295

2.290

F(000)

652

992

916

2840

Crystal size

0.43 × 0.34 × 0.29

1.60 to 33.50

0.31 × 0.28 × 0.22

1.69 to 31.10

0.553 × 0.179 × 0.112

1.744 to 26.395

0.277 × 0.217 × 0.122

1.996 to 24.097

Θ range for data collection

(deg)

Index ranges

h

−17/17

−11/10

−27/27

−30/30

k

−17/17

−27/27

−5/5

−14/15

l

−19/19

−22/22

−29/29

−20/23

Measd. reﬂns.

Independent reﬂns

Completeness to Θ (%)

36699

38402

24310

66063

11782 [R(int) = 0.0167]

98.20

7317 [R(int) = 0.0310]

98.90

4856 [R(int) = 0.0602]

98.10

10315 [R(int) = 0.1431]

99.30

(Θ = 33.50°)

(Θ = 31.10°)

(Θ = 25.242°)

(Θ = 24.097°)

Absorption correction

Semiempirical from

equivalents

Semiempirical from

equivalents

Semiempirical from

equivalents

Semiempirical from equivalents

Max. and min transmission

0.7466 and 0.6988

0.7462 and 0.6807

0.7454 and 0.5493

0.6211 and 0.2755

Full-matrix least-squares on F²

Reﬁnement method

Full-matrix least-squares on

F²

Full-matrix least-squares on

F²

Full-matrix least-squares on

F²

Data/restraints/parameters

GooF²

11782/0/392

1.109

7317/0/303

1.107

4856/1/275

1.048

10315/0/739

1.111

R1 [I > 2σ(I)]

wR2

0.0334

0.0366,

0.0649

0.0913

0.0825

0.0809

0.1294

0.2037

R1 (all data)

wR2

0.0455

0.0533

0.1160

0.1481

0.0918

0.0914

0.1565

0.2400

Largest diﬀ. peak and hole

0.481 and −0.248 e

0.436 and −0.247 e

0.334 and −0.365 e

2.638 and −2.737 e

(Å⁻³

)

a

R₁= ∑||F_o| − |F_c||/∑|F_o|, wR₂= {∑[w(F_o²− F_c²)²]/∑[w(F_o²)²]}^1/2; GooF = {∑[w(F_o²− F_c²)²]/n − p}^1/2, where n is the number of data and p is

the number of parameters reﬁned.

using Mo Kα radiation on a Bruker APEX II CCD diﬀractometer

equipped with a kappa geometry goniometer (Table 4). The data sets

were reduced by EvalCCD¹¹¹and then corrected for absorption.¹¹²

The solutions and reﬁnements were performed with SHELX.¹¹³The

crystal structures were reﬁned using full-matrix least-squares based on

F²with all non-hydrogen atoms anisotropically deﬁned. Hydrogen

atoms were placed in calculated positions by means of the “riding”

model. Additional electron density found in the diﬀerence Fourier map

of compound L6 and 8b was treated using the SQUEEZE algorithm of

PLATON.¹¹⁴

Cell culture. Human A2780 and A2780cisR ovarian carcinoma

cells were obtained from the European Centre of Cell Cultures

(ECACC, UK). The resistance of the A2780cisR cells was maintained

by a monthly treatment with cisplatin (2 μM/one 4 days passage).

Nontumorigenic HEK-293 cells were provided by the Institute of

Pathology, CHUV, Lausanne, Switzerland. A2780 and A2780cisR were

grown in RPMI 1640 medium supplemented with GlutaMAX (Gibco)

and HEK-293 cells were grown in DMEM medium, all containing

heat-inactivated fetal calf serum (FCS, Sigma, USA) (10%) and

antibiotics (Penicillin (100 U/mL): Streptomycin (100 μg/mL),

working concentration 1:100, Life Technologies, Gibco) at 37 °C and

CO₂(5%).

Antiproliferative activity in vitro. Cytotoxicity was determined

using the MTT assay (MTT = 3-(4,5-dimethyl-2-thiazolyl)-2,5-

diphenyl-2H-tetrazolium bromide). Cells were seeded in 96-well

plates as monolayers with 100 μL of cell solution per well and

preincubated for 24 h in the cell medium. Compounds were freshly

prepared as DMSO solution that were rapidly dissolved in the culture

medium and serially diluted to the appropriate concentration to give a

ﬁnal DMSO concentration of 0.5% (all compounds were soluble at the

concentrations employed). 100 μL of the drug solution was added to

each well and the plates were incubated for another 72 h.

Subsequently, MTT (5 mg/mL solution) was added to the cells and

the plates were incubated for further 4 h. The culture medium was

aspirated, and the purple formazan crystals formed by the

mitochondrial dehydrogenase activity of vital cells were dissolved in

R

DOI: 10.1021/acs.inorgchem.5b02690

Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry

Article

DMSO. The optical density, directly proportional to the number of

surviving cells, was quantiﬁed at 590 nm using a multiwell plate reader

and the fraction of surviving cells was calculated from the absorbance

of untreated control cells. Evaluation is based on means from two

independent experiments, each comprising four microcultures per

concentration level.

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Chen, H.; Sadler, P. J.; Jodrell, D. I. Br. J. Cancer 2002, 86, 1652−1657.

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Med. Chem. 2011, 54, 3895−3902.

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Jakupec, M. A.; Galanski, M.; Berger, W.; Arion, V. B.; Keppler, B. K. J.

Med. Chem. 2007, 50, 6343−6355.

ASSOCIATED CONTENT

* Supporting Information

■

(15) Kilpin, K. J.; Crot, S.; Riedel, T.; Kitchen, J. A.; Dyson, P. J.

Dalton Trans. 2014, 43, 1443−1448.

S

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.inorg-

chem.5b02690.

(16) Peacock, A. F. A.; Parsons, S.; Sadler, P. J. J. Am. Chem. Soc.

2007, 129, 3348−3357.

(17) Romero-Canelon, I.; Salassa, L.; Sadler, P. J. J. Med. Chem. 2013,

56, 1291−1300.

Packing diagrams of the X-ray structures with relevant

bond parameters, and ¹H and ³¹P spectra (when

appropriate) NMR spectra of the complexes and ligands

in DMSO-d₆at r.t. Full crystallographic information is

available free of charge via the Internet on the ACS

Publications Web site http://pubs.acs.org/journal/inocaj

and on the Cambridge Crystallographic Data Centre

Web site under the deposition numbers CCDC

1450285-1450288. (PDF)

(18) Fu, Y.; Habtemariam, A.; Pizarro, A. M.; van Rijt, S. H.; Healey,

D. J.; Cooper, P. A.; Shnyder, S. D.; Clarkson, G. J.; Sadler, P. J. J. Med.

Chem. 2010, 53, 8192−8196.

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Clarkson, G. J.; Parsons, S.; McGowan, P. C.; Sadler, P. J. J. Med.

Chem. 2009, 52, 7753−7764.

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Jakupec, M. A.; Keppler, B. K.; Berger, W.; Arion, V. B. Organometallics

2013, 32, 903−914.

(21) Shnyder, S. D.; Fu, Y.; Habtemariam, A.; van Rijt, S. H.; Cooper,

P. A.; Loadman, P. M.; Sadler, P. J. MedChemComm 2011, 2, 666−668.

(22) Hanif, M.; Babak, M. V.; Hartinger, C. G. Drug Discovery Today

2014, 19, 1640−1648.

(23) Kurzwernhart, A.; Kandioller, W.; Bachler, S.; Bartel, C.; Martic,

S.; Buczkowska, M.; Muhlgassner, G.; Jakupec, M. A.; Kraatz, H. B.;

Bednarski, P. J.; Arion, V. B.; Marko, D.; Keppler, B. K.; Hartinger, C.

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Henke, H.; Keppler, B. K.; Hartinger, C. G. J. Organomet. Chem. 2011,

696, 999−1010.

Cif data for L4 C₃₅H₂₈Cl₂NO₄P (CIF)

Cif data for L6 C₂₆H₂₁Cl₂N₃O₂(CIF)

Cif data for L8 C₄₄H₃₄Cl₄N₄O₈(CIF)

Cif data for L8b C₆₀H₅₅Cl₇N₄O₉Os (CIF)

AUTHOR INFORMATION

Corresponding Author

*Phone: +41-21-6939854. Fax: +41-21-6939853. E-mail: paul.

dyson@ep ﬂ .ch.

■

Notes

The authors declare no competing ﬁnancial interest.

(26) Kurzwernhart, A.; Kandioller, W.; Bartel, C.; Bachler, S.; Trondl,

R.; Muhlgassner, G.; Jakupec, M. A.; Arion, V. B.; Marko, D.; Keppler,

B. K.; Hartinger, C. G. Chem. Commun. 2012, 48, 4839−4841.

(27) Ang, W. H.; Parker, L. J.; De Luca, A.; Juillerat-Jeanneret, L.;

Morton, C. J.; Lo Bello, M.; Parker, M. W.; Dyson, P. J. Angew. Chem.,

Int. Ed. 2009, 48, 3854−3857.

ACKNOWLEDGMENTS

■

We thank the Swiss National Science Foundation and EPFL for

ﬁnancial support and Dr. Euro Solari (EPFL) for the elemental

analysis and assistance with the crystal structure determinations.

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