[RuCl2(η6-p-cymene)(P*)] and [RuCl 2(κ-P-η6-arene)] complexes containing p -stereogenic phosphines. activity in transfer hydrogenation and interactions with DNA

Article

pubs.acs.org/Organometallics

[RuCl₂(η⁶‑p‑cymene)(P*)] and [RuCl₂(κ-P*‑η⁶‑arene)] Complexes

Containing P‑Stereogenic Phosphines. Activity in Transfer

Hydrogenation and Interactions with DNA

Rosario Aznar,^†Arnald Grabulosa,^†Alberto Mannu,^†,‡Guillermo Muller,*^,†Daniel Sainz,^†

Virtudes Moreno,^†Merce Font-Bardia,^§Teresa Calvet,^§and Julia Lorenzo^∥

̀

†

́

Departament de Quımica Inorgan

̀

ica, Universitat de Barcelona, Martí i Franques

̀

1-11, E-08028 Barcelona, Spain

^‡Istituto di Chimica Biomolecolare, CNR, trav. La Crucca 3, 07100, Sassari, Italy

^§Departament de Crystal·lograﬁa, Mineralogia i Dipos

Spain

^∥Institut de Biotecnologia i de Biomedicina, Universitat Auton

́

̀

its Minerals, Universitat de Barcelona, Martı i Franques

̀

s/n, E-08028 Barcelona,

̀

oma de Barcelona, 08193 Bellaterra, Barcelona, Spain

S

* Supporting Information

ABSTRACT: The preparation of a series of half-sandwich

ruthenium complexes, [RuCl₂(η⁶-p-cymene)(P*)] (P* = S-

PMeRR′) and [RuCl₂(κ-P*-η⁶-arene)], containing P-stereo-

genic phosphines is reported. The borane-protected P-

stereogenic phosphines have been obtained by addition of

the (H₃B)PMe₂R (R = t-Bu (1), Cy (2), Fc (3))/sec-BuLi/

(−)-sparteine adduct to benzyl halides, carbonyl functions, and

epoxides with yields between 40 and 90% and ee values in the

70−99% range. Those containing an aryl secondary function

have been used in the preparation of [RuCl₂(η⁶-p-cymene)-

(P*)] complexes. Borane deprotection has been performed

using HBF₄, except for (H₃B)PRMe(CH₂SiMe₂Ph) phosphines, where DABCO was used to avoid partial cleavage of the CH₂−

Si bond. In the case of (H₃B)P(t-Bu)Me(CH₂C(OH)Ph₂) (1l) the dehydrated phosphine was obtained. The tethered complexes

were obtained by p-cymene substitution in chlorobenzene at 120 °C, except for ferrocenyl-containing complexes, which

decomposed upon heating. The presence of substituents in the aryl arm of some of the phosphines introduces new chiral

elements in the tethered [RuCl₂(κ-P*-η⁶-arene)] compounds. Full characterization of all compounds both in solution and in the

solid state has been carried out. Crystal structure determinations of four phosphine−borane molecules conﬁrm the S

conﬁguration at the phosphorus atom (1a,e,l and 2d). Moreover, the crystal structure of one p-cymene complex (5i) and four

tethered complexes reveal the strain of the compounds with two atoms in the tether (7c,g,l and 8i). Tethering has a marked

eﬀect on the catalytic performance transfer hydrogenation of acetophenone and on the nature of hydridic species originating

during the activation period. The chiral induction attains 58% ee with complexes with the bulkiest substituents in the pendant

arm of the phosphine. Three of the prepared complexes can interact with DNA and present a reasonable cytotoxicity toward

cancer cells. Intercalation of the free aromatic pendant arm of the phosphines seems to be fundamental for such interactions.

pendant arm, it is possible to obtain the tethered [RuCl₂(κ-P*-

η⁶-arene)] compounds. If the aryl pendant arm contains

suitable substituents, it is possible to introduce diﬀerent new

elements of chirality in the tethered complex.

In electronically saturated metal complexes it is expected that

the ﬁrst step of almost any metal-mediated process must be the

total or partial dissociation of ligands to form free coordination

positions.⁶In arene complexes [RuCl₂(η⁶-p-cymene)(P*)] the

use of basic trialkylphosphines disfavors their dissociation in

comparison with triarylphosphines. Chiral phosphino−arene

tethered ruthenium complexes present a more rigid and less

INTRODUCTION

■

The chemistry of η⁶-arene ruthenium complexes has received

considerable attention in recent years, since a large number of

applications in catalysis,^1,2supramolecular chemistry,³and

medicinal chemistry⁴have been developed with excellent or

promising results. The usual pseudotetrahedral three-legged

piano-stool structure of the Ru(II) complexes opens the

possibility of modifying the nature of each of the four ligands,

giving neutral or ionic complexes. Furthermore, chirality can be

introduced through the ligands or even at the ruthenium center,

which becomes stereogenic when all ligands are diﬀerent.⁵One

way to introduce an initial stereogenic center is using a P-

stereogenic phosphine in [RuCl₂(η⁶-p-cymene)(P*)] arene

complexes. When the phosphine contains an appropriate aryl

Received: December 19, 2012

A

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labile environment around the metal center in comparison with

the nontethered counterparts, a feature that could be

particularly useful in order to use these compounds for the

discrimination of prochiral substrates in catalytic organic

synthesis.⁷

epoxides (Scheme 5) were used as electrophiles. To ensure

high enantioselectivities, the reactions must be performed at

−78 °C, and only after the addition of a slight excess of

electrophile the temperature can be allowed to reach room

temperature very slowly. A possible excess of lithium species as

the temperature increases could produce side deprotonation

reactions of the second methyl group or in the methylene links,

decreasing the overall yield, as observed by O’Brien.¹⁸

Conversions that could reach 90% were achieved with t-Bu

phosphines, but those containing the ferrocenyl or cyclohexyl

groups only reached around 60% conversion according to ³¹P

NMR spectra of the crude products. Since the reactivity of

organolithium reagents is increased by coordination to

(−)-sparteine, O’Brien envisaged the possibility of using

substoichiometric amounts of the chiral auxiliary and developed

ligand-accelerated asymmetric deprotonations,¹⁷but in order to

obtain the best enantioselectivities, the ratio RLi/(−)-sparteine

was kept stoichiometric or with a slight excess of (−)-sparteine.

Direct dilithiation of (BH₃)PPhMe₂was recently reported by

Strohmann, who used the diamine (R,R)-TMCDA and t-BuLi

for the deprotonation reaction, but this reaction was not

observed under our conditions.¹⁹

The use of meta-substituted benzyl halides is convenient in

order to introduce a second element of chirality in the metal-

tethered complexes. Another important modulation of the

pendant arm of the phosphines is the selection of the length of

the chain between the phosphorus atom and the aromatic

moiety. Direct substitutions on benzyl bromides gave yields in a

satisfactory range (35−90% estimated by ³¹P NMR of the

reaction solution), but this was not the case when the number

of carbon atoms increased between the aryl and bromide

groups (1h). To improve the reproducibility and yields in the

preparation of phosphines containing longer arms, nucleophilic

substitution was performed on appropriately substituted

chlorosilanes (Scheme 2). With these electrophiles, a group

of phosphines with spacers of three (i) and two atoms (j) for a

comparison of their coordination behaviors was obtained in

excellent yields (Scheme 3).

Moreover, the polydentate nature of the κ-P*-η⁶-arene ligand

could also increase the usual low isomerization barriers of

racemization in the chiral ruthenium−arene intermediates.⁸

In a previous communication⁹we explored this synthetic

approach using P-stereogenic phosphines obtained by the

methodology developed by Muci and Evans.¹⁰In the present

work we have extended the study in two aspects: the design of

appropriate potentially bidentate phosphino−arene and

phosphino--pyridine ligands and the use of some of these

chiral phosphino−arene ligands in the preparation of arene−

ruthenium complexes in order to evaluate diﬀerences between

tethered and nontethered complexes in catalysis and in their

interactions with DNA.

RESULTS AND DISCUSSION

■

Preparation of the Phosphine−Borane Adducts by

Desymmetrization of Dimethylphosphines. Several meth-

ods to prepare optically pure P-stereogenic phosphines have

been developed using diﬀerent approaches.¹¹In particular the

synthetic potential of lithium salts of carbanions stabilized by

coordination to chiral ligands such as (−)-sparteine has been

known for some time¹²and even the crystal structures of some

of these salts have been determined.¹³The application of this

type of asymmetric deprotonation to the synthesis of P-

stereogenic phosphines, originally proposed by Muci and

Evans,¹⁰is one of the most successful achievements of that

methodology. Since the ﬁrst report, the procedure has been

successfully applied to the synthesis of many families of P-

stereogenic mono- and diphosphines.¹⁴

To improve the Evans methodology of desymmetrization of

prochiral substrates, a number of sparteine surrogates have

been developed to overcome the limitation of the availability of

only one enantiomer of sparteine and its limited supply.^14b,15

Here we expand our initial communication on the application

of this methodology to the synthesis of P-stereogenic

phosphines containing an aromatic pendant arm able to form

tethered arene ruthenium complexes or potentially act as

bidentate or tridentate ligands.

To explore the scope of the Evans methodology, dimethyl-

(tert-butyl)phosphine−borane (1) was initially used as the

prochiral dimethylphosphine model for all reactions with

diﬀerent electrophiles, but subsequently another two protected

dimethylphosphines (2, 3) were also tested to evaluate the role

of the third substituent (Chart 1). Previously reported

phosphine−borane adducts of this kind by us^9,16or others^17a,b

are depicted in Chart 2.

When chlorodimethyl(phenyl)silane was used as electrophile

(j), the methylenic group that is initially formed after the

electrophilic attack on the carbanion is suﬃciently acidic to

compete with the methyl group of another molecule of the

starting material and suﬀers a second deprotonation. To

minimize this side reaction, a very slow increase of the

temperature upon addition of the electrophile is crucial. The

phosphine−borane 1j has been described previously but has

not been further developed.^17a,b

The reaction of the lithium carbanion with carbonyl

compounds is very eﬃcient, giving quantitative yields and

good enantioselectivities on the obtained phosphines. Living-

house, Kann, and O’Brien used benzophenone for quenching

the lithium complex of prochiral phosphine−boranes with

diﬀerent chiral dinitrogen auxiliaries as a method to evaluate the

enantioselectivities achieved.^{14b,15a−c,17a,b,20}Indeed, 1l was

obtained but its deprotection was not described. We explored

the reaction with other three diﬀerent carbonyl reagents, which

included one or two pyridine rings: benzopyridyl ketone,

dipyridyl ketone and pyridylaldehyde (Scheme 4).

The deprotonation reaction was carried out using sec-BuLi/

(−)-sparteine in a 1/1 ratio at low temperature. Three hours

later the electrophile was added. Benzyl bromides or silyl

halides (Schemes 1−3), ketones or aldehydes (Scheme 4), and

Chart 1

Livinghouse²¹developed an eﬀective route to optically pure

secondary phosphine−boranes (R)-(BH₃)PPhHMe from

(BH₃)PPhMe₂. We have reproduced the preparation of

compound 1l′, precursor of the secondary phosphine, with

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Chart 2

Scheme 1

conversion (80%) and with complete regioselectivity of the

nucleophilic attack at the secondary carbon of the oxirane ring

(Scheme 5). When racemic styrene oxide was used, the two

diastereomers (S_P,S_Cand S_P,R_C) were obtained, but using

optically pure styrene oxide allowed the isolation of a single

diastereomer. In this example (R)-styrene oxide has been used

to characterize 1p (S_P,R_C).

Scheme 2

The new phosphine−boranes obtained were characterized by

means of elemental analysis, infrared spectroscopy, NMR

spectroscopy, HPLC analysis, and polarimetry (see the

Supporting Information). In some cases, their absolute

conﬁguration was conﬁrmed by a crystal structure determi-

nation.

HPLC analyses have allowed the evaluation of the optical

purity of the phosphine−boranes. In general, the ee has been

found to be higher than 95% after workup and puriﬁcation

(Table 1). Phosphine−boranes obtained from silyl chlorides

and those containing the ferrocenyl substituent showed

reduced ee’s, as observed by Kann.^14cJamison reported that

monodentate chiral ferrocenylphosphines prepared from the

ephedrine-based oxazaphospholidine−borane complex were

obtained with better than 95% ee values in most cases.²²

³¹P NMR spectroscopy of phosphine−borane adducts

showed a single broad quartet due to the coupling to the ¹¹B

atom (Table 1). The two diastereomers of 1k could be

separated by ﬂash chromatography and were observed at 22.45

and 25.27 ppm. The diastereomeric mixture of 1m appeared as

a broad signal at 20.20 ppm. The chemical shifts of the

phosphine−boranes spanned a narrow range of values for each

group of compounds 1, 2, or 3, with those of the

ferrocenylphosphine adducts (3) appearing at lower ﬁelds.

¹H spectra at room temperature did not show any remarkable

particularities, except for the duplicity of the signals of the

Scheme 3

the same excellent yields. The preparation of phosphine−

borane 1l″ conﬁrms the previous formation of the alcohol.

In the preparation of adducts 1k,m a new stereogenic carbon

atom was created but no diastereoselection was observed, since

the two possible diastereomers, S_P,S_Cand S_P,R_C, were formed in

the same amounts and they could be separated and isolated by

ﬂash chromatography.

Other functionalities susceptible to nucleophilic attack are

epoxides, which upon opening lead to phosphino−alcohols.

The reaction with styrene oxide takes place with good

C

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Scheme 4

nucleus, although with frequently overlapped signals. Accord-

ingly, doublets of doublets or pseudotriplets could appear for

each proton of the methylene group bound to the phosphorus

atom, a doublet for each proton of the methylene group bound

to the aryl moiety in the adducts i and two singlets for the

SiMe₂linker in adducts i and j.

Scheme 5

¹H and ¹³C NMR spectra of the phosphine−borane 3

showed a similar pattern for the signals of the cyclopentadienyl

rings of the ferrocenyl substituent: one single peak for the

unsubstituted Cp ring and a group of more or less overlapped

signals for the Cp-P ring, in which all atoms are diﬀerent,

reﬂecting the lack of symmetry in the phosphine−borane

adduct.

The molecular structures of some of the borane-protected

phosphines were determined by single-crystal X-ray analysis to

conﬁrm the absolute conﬁguration of the obtained enantiomer.

Bond distances and angles are similar to those previously

hydrogen atoms belonging to the methylene or dimethylsilyl

linkers of the pendant arm due to their diastereotopic character.

The pattern is complicated when the chain between the

phosphorus atom and the aryl moiety is an ethylene group,

since the spin system is a ﬁve-nucleus AA′BB′X. The signals of

the CH₂Ar methylene appeared at lower ﬁelds than those of

CH₂P methylene. In the rest of the adducts, assignments were

possible using 2D HSQC experiments and taking into account

the diﬀerent contributions of the coupling constants to the ³¹P

Table 1. Relevant Data of Selected Phosphines and Diﬀerent Adducts Obtained by Stereoselective Deprotonation of BH₃PMe₂R

a

(R = t-Bu (1), Cy (2), Fc (3))

P−BH₃ee (S), %

δ(³¹P) P−BH₃q (J_PB

)

δ(³¹P) free P

δ(³¹P) P−Se d (J_PSe

)

δ(³¹P) P−H⁺d (J_PH

)

1a⁹

1b⁹

3b

1c⁹

1d⁹

2d

3d¹⁶

1e⁹

3e

99

90

98

99

98

99

82

99

82

75

70

99

84

82

99

86

25.0 (60)

−15.5

−15.7

−46.2

−14.4

−15.3

24.9 (57)

48.8 (697)

21.6 (709)

48.3 (693)

49.0 (692)

6.20 (58)

24.9 (57)

25.2 (55)

15.40 (75)

2.01 (62.2)

25.2 (57.4)

6.8 (73)

−46.1

−15.5

21.8 (710)

1f

27.4 (54)

−15.4

−23.4

−36.6

−51.5

−23.2

−36.8

−52.1

−19.2

1g

27.1 (52.0)

24.1 (59.7)

14.0 (61.7)

4.26 (60.6)

24.0 (68.8)

14.7 (60.4)

4.59 (57.7)

20.2 (62.4)

26.0 (69.0)

1i

41.2 (683)

29.3 (678)

14.4 (697)

39.5 (705)

27.8 (702)

12.8 (722)

4.64 (470)

4.70 (475)

0.80 (502)

2i

3i

1j^16,17a

2j

3j¹⁶

1l

1p (S_P,R_C)

a

ee values were obtained by HPLC with a Chiracel OD-H column. ³¹P NMR spectra (inset of acetone-d₆, 298 K, 101 MHz, δ in ppm, J in Hz).

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reported for related P-chiral phosphines (Figure 1S and Table

1S in the Supporting Information).²³In all structures the

stereogenic phosphorus atom had an S conﬁguration, as

expected.

of two phenyl groups; the proton of the ﬁnal −CHPh₂

fragment could be abstracted from the borane decomposition

products. The other phosphine−borane coming from the

addition over CO double bonds, potentially bidentate PN

ligands, were not deprotected.

Free phosphines were very easily oxidized and therefore were

immediately coordinated with ruthenium or converted to the

selenides to avoid decomposition.

Deprotection of the Phosphorus−Borane Adducts.

Borane protection can be removed by diﬀerent protocols. For

arylphosphine−borane adducts amines such as morpholine and

diethylamine are commonly used, and when secondary amines

are not compatible with some functional groups present in the

starting adduct, a tertiary amine such as DABCO is a good

option.²⁴Even the use of polymer-supported amines has been

reported.²⁵For trialkylphosphine−boranes the use of strong

acids with a weakly coordinating, nonoxidizing conjugate base

such as HBF₄·Et₂O is more convenient.²⁶The use of alcohols

with or without molecular sieves to perform the deprotection

has been proposed, but only for phosphine adducts containing

at least one phenyl group attached to the phosphorus atom. We

have veriﬁed this extreme.²⁷

To conﬁrm that the deprotection of the phosphine−boranes

retained the original optical purity, the diastereomeric ratio of

the product of the reaction between the free phosphine and a

chiral dinuclear cyclopalladated complex was evaluated. This

1

known fast methodology uses H or ³¹P NMR spectroscopy to

roughly assess the enantiomeric purity of the phosphine.²⁸

Palladium cyclometalated complexes derived from (R)-1-(1-

naphthyl)ethylamine have been prepared as chiral derivatizing

agents to perform this kind of control (Scheme 8).²⁹

Given the electron-rich character of all the phosphine−

boranes synthesized in this work, the strong acid deprotection

method was used to attain the free phosphine (Scheme 6).

Scheme 8

a

Scheme 6. Removal of the Borane Unit by HBF₄·Et₂O

If ³¹P NMR signals corresponding to the two diastereomers

have diﬀerent enough chemical shifts, it is possible to evaluate

the diastereomeric ratio of the mixture from the relative areas of

the signals. Alternatively, the same measurement could be

performed using the methyl signal of the cyclometalated ligand

in the H NMR. This ratio reﬂects the enantiomeric excess of

the original mixture of the starting phosphine.

To check this methodology, the phosphine−borane 1i in

racemic form was prepared using the same standard procedure

without addition of (−)-sparteine (Scheme 9).

a

The deprotection is complete after 1 h for all of the substrates.

Initially the addition of HBF₄·Et₂O to a solution of the

phosphine−borane in CH₂Cl₂led to the formation of the

protonated phosphine [HP*]⁺, which in a second step was

converted into the corresponding free phosphine by addition of

a degassed aqueous solution of NaHCO₃. The deprotection

process was monitored by ³¹P NMR. One advantage of this

methodology is that the protonated phosphine is indeﬁnitely

stable, even in contact with air. This operation was performed

with the phosphine adducts that were used to explore their

coordination to ruthenium.

1

Scheme 9. Synthesis of Phosphine−Borane 1i in Racemic

Form

Deprotection by HBF₄·Et₂O showed a limitation with some

phosphine adducts, since for the products 1j, 2j, and 3j variable

amounts of the starting dimethylphosphine were recovered

(Scheme 7).

The ³¹P spectra of the corresponding cyclometalated

palladium complexes with deprotected phosphine−borane

rac-1i and S-1i obtained with the (−)-sparteine methodology

are depicted in Figure 1, showing that it is possible to evaluate

the enantiomeric purity of the free phosphine obtained after the

deboronation (ratio close to 9/1). The same veriﬁcation was

performed with 2d (∼99% ee), 3d (∼99% ee), and 3i (∼65%

ee), giving results roughly similar to those obtained by HPLC

of the protected phosphines.

Comparison of the σ-Donating Power between

Phosphines. The inﬂuence of the substituents on the

phosphorus lone pair in a phosphine is a combination of

electronic and steric factors. Electron-withdrawing groups

increase the s character of the lone pair of the phosphine,

while bulky substituents widen the intervalence angles and

reduce the s character of the phosphorus lone pair.^30,31

Therefore, an experimental comparison of the σ-donating

ability of phosphines surrounded by diﬀerent substituents must

be referred to the selected acceptor. Tolman³²used a carbonyl

Scheme 7. Deprotection of Phosphines 1j, 2j, and 3j

The combination of the stabilizing eﬀect of the phenyl ring

directly connected to the silyl fragment and the high aﬃnity

between silicon and ﬂuoride led to the elimination of the silyl

unit with consequent formation of dimethylphosphine after

neutralization. This kind of behavior is not new; O’Brien took

advantage of it by using the dimethylphenylsilyl moiety as a

protecting group for the methyl group in tert-butyldimethyl-

phosphines.¹⁸To overcome this limitation, adducts 1j, 2j, and

3j were deprotected using DABCO in hot toluene. Another

side reaction was the elimination of the −OH group of 1l when

it was deprotected in acidic media, a fact conﬁrmed after

preparation of the ruthenium complex. The abstraction of OH

could be favored by the charge stabilization due to the presence

E

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Figure 1. ³¹P NMR spectra of the cyclopalladated complex with phosphine 1i prepared with the standard (−)-sparteine methodology or in racemic

form. A solution of the deprotected phosphine in CH₂Cl₂was added to a solution of the cyclopalladated dimer in CH₂Cl₂.

Scheme 10. Synthesis of Ruthenium Complexes

nickel complex to perform this kind of evaluation, but another

way to perform this comparison is to use the magnitude of ¹J_PX,

where X should ideally be a nucleus with S = ¹/₂. Selenium is an

phosphines SePMe₂(t-Bu) and SePMe₂Fc (δ(³¹P) 39.2 (J_PSe

690 Hz) and 11.5 (J_PSe= 702 Hz), respectively).

=

The change of the group R′ in the pendant arm of the

1

excellent candidate, since it contains a 7.58% of the isotope ⁷⁷Se

phosphine is also reﬂected in J_PSe. The most signiﬁcant

1

diﬀerence, probably for steric reasons, was observed when

comparing the remote −SiMe₂Ph group (3j for instance) with

the more basic −SiMe₂CH₂Ph (3i).

with S =

/ and the phosphine−selenides can be easily

2

obtained by direct reaction between selenium or SeCN⁻and

the free phosphine.^31,33The results collected in Table 1 were

obtained from phosphine−selenides prepared by overnight

stirring of the corresponding deprotected phosphines with

elemental selenium in toluene at room temperature or with

gentle heating. The ¹J_PSevalues were obtained from satellites of

the ⁷⁷Se isotopologue present in the spectra of the

corresponding phosphine−selenides; no further character-

ization was attempted. The values obtained are in the range

reported for these kinds of phosphines (PPh₃, 728.9 Hz;³¹

PPh₂Fc, 731.1 Hz;³¹PnBu₃, 689 Hz;³⁴PCy₃, 672,9 Hz;³¹

Since it is necessary to monitor the formation of the

phosphonium salts [P*H]⁺by ³¹P{¹H} NMR spectroscopy in

the ﬁrst step of the deprotection of the phosphine−borane

adducts in acidic media, it is possible to record the same spectra

1

without proton decoupling. The values of J_PHobtained with

the adducts 1i−3i (Table 1) showed a trend similar to that

obtained from the ¹J_PSecoupling constants, suggesting that ¹J_PH

values could be used for the same comparative purposes with

the minimum possible steric distortion.

Preparation of Ruthenium Complexes. A group of

[RuCl₂(η⁶-p-cymene)(P*)] (P* = deprotected phosphine)

complexes was synthesized by reaction of the dimeric p-

cymene ruthenium precursor and the appropriate pure

deprotected phosphines containing a pendant arm potentially

capable of stabilizing a polydentate κ-P*-η⁶arene ligand.

Ruthenium-tethered complexes were obtained through an

intramolecular arene substitution reaction by heating the

35

PtBu₃, 693 Hz;³⁵PiPr₃, 696 Hz ). The J_PSevalues increase

with the s character of the lone pair, reﬂecting a decrease in the

basicity of the phosphine.

1

The data in Table 1 show some interesting features; in

phosphines with the same primary substituent R (PMeR-

(CH₂R′), 1−3), the order of σ basicity is t-Bu ≈ Cy > Fc (see

series i and j), a trend also observed for the prochiral

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Chart 3. New Open Complexes Obtained

complexes [RuCl₂(p-cymene)(P*)] (P* = tert-butyl- and

cyclohexylphosphines) in chlorobenzene at 120 °C (Scheme

10).³⁶The ferrocenyl-containing phosphines were thermally

unstable under these conditions, and even the use of

[RuCl₂(benzene)(P-ferrocenyl)] complexes as starting materi-

als was unsuccessful. Attempts to prepare the ferrocenyl-

tethered complexes using [RuCl₂(DMSO)₄] or [RuCl(μ-

Cl)(CO)₃]₂as starting materials were also unsuccessful (see

the Supporting Information for more details). Recent examples

of tethered chiral ruthenium complexes of this type have been

described, in which the phosphine−arene chelates have a

stereogenic center located in the bridge³⁷or possess either

planar chirality³⁸or a stereogenic center in the phosphine

substituents.³⁹Other κ¹-X-η⁶-arene complexes containing

nitrogen, oxygen, sulfur, or carbene coordination arms are

also known.⁴⁰

product ∼23% de, isolated product 11% de) but only one

diastereomer was detected for 7d (tethered complex from

PMe(t-Bu)CH₂CH₂(2-Napth)).⁹Careful examination of 1D

and 2D NMR data conﬁrmed that in all compounds the major

diastereomer has the substituent of the coordinated aryl moiety

located in an opposite position relative to the tert-butyl

substituent of the phosphine.

(2) When the incoming phosphine contains a pendant arm

with two equivalent arene groups, an additional stereogenic

center is formed in the tether upon ring closure, as in the case

of 7l. Once again, it is possible to evaluate the discrimination

ability of the stereogenic phosphorus atom in this reaction. tert-

Butyl and methyl substituents of phosphine l showed very

limited discrimination capacity between the two phenyl groups

of the pendant arm (isolated product, 5% de).

(3) The length of the linker between the phosphorus atom

and the arene group is another important parameter, since the

spatial disposition of the remaining phosphine substituents and

the position of the substituents of the arene ligand could

change as a function of the number of atoms in the linker (7i,j

and 8i,j).⁴¹Crystal structures of tethered complexes with two-

or three-membered linkers are useful in evaluating the

importance of these eﬀects.

1

Elemental analyses and ³¹P, H, and ¹³C NMR spectral data

of all new complexes are given in the Experimental Section

(Charts 3 and 4).

Chart 4. New Tethered Complexes Obtained

Monocrystals of suﬃcient quality to perform X-ray

diﬀraction studies were obtained with the tethered complexes

7c,g described in the previous communication⁹and 7l and 8i.

Only in one case has it been possible to crystallize the open

compounds (5i). The crystals were obtained by slow diﬀusion

of hexane over a chloroform or dichloromethane solution of the

complex. All complexes adopt a distorted three-legged “piano

stool” geometry, showing the underlying octahedral arrange-

ment of the diﬀerent ligands. The ruthenium atom is η⁶-

coordinated to the p-cymene or to the arene fragment of the

pendant arm of the phosphine, blocking three coordination

positions in the complex. The other three positions are

occupied by two chlorine atoms and one phosphorus atom with

angles not far from 90° between them. In complex 7c the unit

cell contains two molecules that diﬀer in the relative position of

The nature of the diﬀerent pendant arms hanging from the

phosphine allowed the study of several aspects of the

substitution reaction of the coordinated p-cymene group.

(1) When the incoming pendant arm of the phosphine

contains a nonsymmetric arene moiety, namely for 2-naphthyl

(d), 3-methoxyphenyl (e), and 3-biphenylyl (g), a new element

of planar chirality is created. NMR spectra showed the

formation of diastereomeric mixtures for tert-butyl complexes

7e (tethered complex from PMe(t-Bu)(3-MeOPh))⁹(crude

product ∼16% de, isolated product 45% de) and 7g (crude

G

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the planes deﬁned by the pentamethylphenyl arene and the

three opposite ligands (Figure 2).

P distances decrease to around 2.8 Å without changes in the

arene−Cl distances (Supporting Information). Therefore, in

the solid state the claw eﬀect of the formally tetradentate κ¹-η⁶

ligand with the arene−phosphorus bridge containing two atoms

in the linker introduces a certain tension that is also reﬂected in

the Cl−Ru−P and Ru−P−CH₂− angles and in the slight

diﬀerences in the Ru−C distances of the arene moiety, as could

be observed on comparing the non trained 5i and 8i with

complexes 7 (Figure 5 and Table 2).^7a,cThis pincer eﬀect does

not allow us to observe diﬀerences in the distance Ru−C₆plane

when the number of methyl substituents on the arene moiety is

increased: 7l < 7b < 7c. The change of the spherical tert-butyl

to the ﬂat Cy substituents is reﬂected in the large diﬀerences of

the Cl₁−Ru−P and Ru−P−C_Rangles, where Cl₁is directed

toward R. The introduction of a silicon atom in the chain of the

tethered complexes is reﬂected mainly in the angles C−Si−C,

which are smaller than the equivalent C−C−C counterparts in

analogous compounds.

Figure 2. ORTEP drawings of the molecular structure of the two

conformers of compound 7c. Hydrogen atoms have been omitted for

clarity.

All new compounds were characterized in solution by means

of multinuclear NMR spectroscopy. ¹H−¹³C-HSQC and

¹H−¹H-NOESY experiments were performed to unambigu-

ously assign ¹H NMR spectra. The position of the ³¹P, ¹H, and

¹³C NMR signals are, in general, quite similar for the phosphine

ligands in complexes [RuCl₂(p-cymene)(P*)] containing the

same substituent t-Bu (4), Cy (5), or Fc (6). The small

variation is consistent with the similarity of the groups attached

to the phosphorus atom (see the Experimental Section).

³¹P{¹H} NMR spectra of t-Bu complexes (4) showed a

singlet around 29 ppm. The spectrum of compound 4l, which is

unique in having two phenyl groups at the β-carbon of the

tether, and those containing the silicon atom in a β-position

(4i,j) showed a slight displacement to lower ﬁeld (31 and 36

ppm, respectively). The signals of the Cy complexes (5)

appeared around 25.5 ppm, and those of the Fc series (6)

appeared in the narrow range 9−10 ppm; in this group no

eﬀect from the silyl fragment is observed (Table 3).

To assign the proton spectra of the CH₂groups of the

pendant arm of the coordinated phosphine, it is convenient to

obtain the ¹³C spectra and the corresponding HSQC. The ¹³C

NMR signals of the PCH₂and PCH₃groups appear as doublets

as a consequence of the P−C coupling, of about 20 5 Hz for

the PCH₂link, 6−10 Hz lower than that observed for the PCH₃

group. The signal of the second CH₂Ar appeared in some cases

as a singlet or a doublet (J_CP< 4 Hz).

Both isomers of complexes 7g (11% de) and 7l (5% de) were

observed in solution, but the crystal used in the determination

of 7g contains only the isomer with the 3-phenyl substituent of

the arene directed opposite to the tert-butyl group of the

phosphine and 7l is a 1/1 mixture of both isomers R_P,S_Cand

R_P,R_C(Figure 3). Bond distances and angles are quite similar to

those reported for analogous ruthenium complexes; a selection

of distances and angles is given in Table 2.⁴²

With the phosphine 2i (S, 75% ee) it was possible to obtain

the molecular structures of the open (5i) and tethered (8i)

ruthenium complexes. In 5i only the isomer arising from the

coordination of the S isomer of the phosphine is present, but in

the crystal there are two independent identical molecules

disordered in the ratio 93/7. In 8i the unit cell of the crystals

studied contain a 1/1 mixture of the tethered complex of both

isomers of the phosphine. Although is not possible to discard

completely some racemization in the thermal formation of the

tethered complex, the preferred crystallization of the pairs of

enantiomers seems more probable (Figures 4 and 5).

It is interesting to note that in the open p-cymene complexes

such as 5i and examples reported in the literature the distances

arene plane−Cl and arene plane−P are similar, with a value of

around 3.1 Å. In the tethered complexes, those with a chain

with three-membered linkers the distances arene−P are similar,

but when the chain contains two atoms in the linker the arene−

Figure 3. ORTEP drawings of the molecular structures of the ruthenium complexes 7b (left),⁹7g (middle), and the R_P,S_Cisomer of 7l (right) shown

at the 50% probability level. Hydrogen atoms have been omitted for clarity.

H

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Table 2. Selected Angles (deg) and Distances (Å) of the Tethered Complexes 7b,⁹7c,g,l, and 8i (with Esd’s in Parentheses)

[RuCl₂(η¹:η⁶-S-PMe(R)(CH₂R′)]

b

c

d

R = t-Bu (7b)

R = t-Bu (7c)

R = t-Bu (7g)

R = t-Bu (7l)

R = Cy (8i)

links

2

3

Ru−P

2.3299(10)

2.4267(13)

2.3925(13)

1.694

2.3319(14)

2.4199(17)

2.4049(16)

1.698

2.3203(19)

2.4197(17)

2.4306(18)

1.707

2.3433(13)

2.4044(14)

2.4027(10)

1.693

2.3403(12)

2.4171(12)

2.4037(12)

1.702

Ru−Cl₁(R)

Ru−Cl₂(Me)

Ru−C₆plane

a

Ru−C_arenechain

Ru−C_arenet-chain

P−CH₂−

P−C_R

P−CH₃

Cl₁−Ru-Cl₂

Cl₁−Ru−P

Cl₂−Ru−P

P−Ru−C_{arene‑chain}

Ru−P−CH₂−

Ru−P−C_R

2.165(4)

2.244(3)

1.823(4)

1.839(4)

1.832(5)

85.61(4)

96.95(3)

88.93(4)

79.29(11)

104.07(14)

124.46(13)

2.141(5)

2.271(6)

1.847(6)

1.869(7)

1.831(7)

86.85(7)

97.39(2)

87.84(5)

81.17(17)

104.2(2)

124.3(2)

113.6(2)

2.163(7)

2.262(7)

1.924(8)

1.869(9)

1.777(6)

86.82(6)

95.99(6)

88.73(6)

80.5(2)

2.12(2)

2.251(4)

2.239(5)

1.817(5)

1.853(5)

1.818(5)

86.71(4)

83.99(4)

90.25(4)

95.56(13)

115.78(15)

113.72(17)

114.01(14)

2.297(14)

1.809(5)

1.850(5)

1.809(4)

87.47(5)

96.19(5)

87.94(5)

81.36(5)

102.9(3)

123.20(15)

113.85(17)

105.5(3)

126.0(3)

116.0(2)

Ru−P−CH₃

112.32(16)

a

b

c

Plane deﬁned by the six ring carbon atoms. Data from conformer 1. The dihedral angle between the atoms C1−C2−C14−C15 of the two phenyl

planes (Ph−Ph) is 47.3°. R_P,S_Cisomer.

d

Table 3. ³¹P Chemical Shifts (CDCl₃, 298 K, 400 MHz, δ in

ppm)

open

complex

δ(³¹P) NMR

(ppm)

tethered

complex

δ(³¹P) NMR

(ppm)

4g

4i

29.6

35.8

36.4

32.5

25.6

25.8

9.4

7g

7i

7j

7l

8i

8j

63.6

32.5

32.9

47.2

30.2

32.8

4j

4l

5i

5j

6b

6d

6e

6i

10.5

10.6

8.8

Figure 4. Molecular structure and atom-labeling scheme for the S

isomer of compound 8i. Hydrogen atoms have been omitted for

clarity.

6j

9.2

isopropyl substituent of the p-cymene. The signals of four of

the CH aromatic carbon atoms appeared between 83 and 89

ppm coupled with the phosphorus atom (J_PC≈ 3−6 Hz) and

the other two at 92−94 and 107−108 ppm with few exceptions.

The ferrocenyl group showed one intense signal of the carbon

atoms of the free Cp in the range 68−70 ppm, but in the Cp

bonded to the phosphorus atom it is possible observe up to

four signals in the range 68−72 ppm coupled with the

phosphorus atom (J_PC≈ 6−10 Hz), although they are

overlapped in some complexes.

In the ¹H NMR spectra the signals of the phosphine protons

of the PMe and the P(t-Bu) moieties are observed between

1.00 and 1.60 ppm as two doublets. The cyclohexyl protons are

dispersed between in the 1−2 ppm range and those of the

ferrocenyl fragment appeared divided for the two Cp rings, near

4.15 ppm for the unsubstituted Cp and four more or less

overlapped signals for the four protons of the CpP ring in the

range 4.1−4.5 ppm. The pendant arm of the phosphine showed

the diastereotopic nature of the protons of the PCH₂, CH₂Ar,

and SiMe₂groups. In some complexes the pattern of the signals

are complex, as expected for a AA′BB′X system; the pairs of

Figure 5. Molecular structure and atom-labeling scheme for

compound 5i. Hydrogen atoms have been omitted for clarity. Selected

bond distances (Å) and bond angles (deg): Ru1−P11, 2.350(2); Ru1−

Cl1, 2.410(2); Ru1−Cl2, 2.415(2); Cl1−Ru1−Cl2, 87.34(7); Cl1−

Ru1−P11, 86.59(7); Cl2−Ru1−P11, 85.49(7); Ru1−P11−C19,

115.8(3); P11−C19−Si2, 124.4(5); C19−Si2−C23, 106.2(4).

The consequence of the presence of the stereogenic

phosphorus atom in the coordination sphere is the lack of

any symmetry in the complex, reﬂected in the nonequivalence

of the four CH aromatic carbons and two methyl groups of the

I

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diastereotopic protons could reach a diﬀerence of 0.3 ppm. The

CH₂Ar signal usually appears at lower ﬁeld than the PCH₂

methylene signals. Finally, the signal of the protons

corresponding to the noncoordinated aromatic ring of the

phosphine appears in the normal range.

dissolved in 2-propanol and heated to reﬂux for 30 min, before

the addition of acetophenone. This activation period was the

same for all reactions.

Initially the transfer hydrogenation reactions were tested with

several complexes under reﬂux in isopropyl alcohol (Scheme

11, Table 4). Several precursors reach almost complete

The signals of the p-cymene moiety showed the same lack of

symmetry in the complex; the two methyl groups of the

isopropyl substituent appeared as two doublets or a partially

overlapped pseudotriplet in the range 1.2 0.2 ppm, and the

methyl substituent appears in the range 1.8 0.2 ppm. The

four CH aromatic protons appeared around 5.50 ppm; in

complexes 4l and 6i,j four clean independent doublets are

observed, but in general the signals appeared more overlapped.

In the tethered complexes 7a−f the ³¹P chemical shift

increases ∼30 ppm with respect to that in the open p-cymene

compounds 4a−f. Complex 7g showed the same ring

contribution, but for those complexes with a silicon atom in

the tether the chemical shift changed slightly up and down from

the former open complexes (Table 3).

Scheme 11

Table 4. Comparison of the Diﬀerent Catalytic Precursors

on the Transfer Hydrogenation of Acetophenone in

a

Isopropyl Alcohol

conversion at 9 h

(24 h) and

conversion at

24 h and

40 °C

entry precursor

82 °C, %

ee (S), %

The most signiﬁcant changes were observed in the ¹H NMR

spectra, since the substitution of the p-cymene simpliﬁes the

aliphatic part and now all the arene hydrogen atoms appeared

separated, showing a multiplicity of the signals according to the

substituents present in the phenyl ring. The signals of the

diastereotopic CH₂Ar invert the position with respect to the

open complexes and appear usually at higher ﬁelds than the

PCH₂signals; the diﬀerentiation between diasterotopic protons

could increase up to ∼0.5 ppm, and the multiplicity remains

complex except for the SiCH₂Ar methylene protons, where just

a doublet appears for each proton by geminal coupling. The

rigidity of the κ-P*-η⁶-arene ligand allowed observing the

vicinity of the diﬀerent protons of the tether and their contacts

with those of the phosphine substituents and arene hydrogen

atoms by NOESY experiments, some of which are depicted in

the Supporting Information.

Transfer Hydrogenation. The asymmetric version of the

hydrogen transfer reaction applied to the reduction of ketones

has been studied in detail in recent years. The most commonly

used metal catalysts are ruthenium-based complexes, usually

with +II as the formal oxidation state of the Ru atom. The

stabilizing ligands are a wide range of combinations between

chiral polydentate nitrogen and phosphorus ligands. Arene

ruthenium precursors play an interesting role, since three

coordination positions located in a fac manner are blocked by

the arene ligand, a fact that limits the numbers of possible

stereoisomers. Typically, with arene ruthenium complexes,

bidentate or monodentate chiral ligands have been used as

fundamental partners; this has allowed the development of

excellent systems for enantioselective reductions.^1,2,43

1

7a⁹

7b⁹

7c⁹

7i

74 (97)

30 (66)

23 (58)

4

2

rac

3

4

55

44

43

22

32

rac

8

5

7j

6

7d⁹

8i

28 (73)

23 (20)

50

rac

7

8

8j

95

69 (95)

36 (93)

rac

9

4c⁹

4d⁹

4i

8 (5)

8 (6)

10

11

12

13

14

15

16

17

18

19

42

9

58

20

4j

29

42

21

6

rac

59

4l

5i

5 (R)-

rac

20

5j

93

rac

6d

6i

15

24

20

21

rac

56

6j

4lH2

[RuCl₂(p-cymene)(P(t-Bu)MeCH₂CH₂R′)]:⁹R′ = −C₆Me₅(4c),

a

−2-Napth (4d). [RuCl₂(κ-P(t-Bu)Me-η⁶-arene)]:⁹arene = C₆H₅(7a),

2,3-Me₂C₆H₃(7b), C₆Me₅(7c), 2-Napth (7d). Conditions: substrate/

catalyst/base 250/1/5, [Ru] 0.5 mM, isopropyl alcohol, after 30 min

of activation.

conversion in 24 h, but the enantioselectivity was negligible,

with the exception of complex 7d, which includes a new planar

element of chirality. The open [RuCl₂(p-cymene)(P(t-Bu)-

MeCH₂CH₂R′)]⁹precursors 4c (R′ = −C₆Me₅) and 4d (R′ =

−2-Napth) presented higher activity than the tethered

counterparts.

To check whether lowering the temperature could improve

the enantioselectivity of the process, two known complexes

containing (S)-isopropyl(aryl)phenylphosphines^45aand 4d that

showed a limited degree of enantioselection were tested at 40

°C (see the Supporting Information). An expected decrease of

conversion and a clear increase of enantioselectivity was

observed in comparison with the experiments at 82 °C. A

slight evolution of ee with time could be a consequence of the

ketone−alcohol equilibrium of the hydrogen transfer reaction.

Therefore, in order to evaluate the discrimination ability of the

ruthenium complexes, the hydrogen transfer reactions were

carried out at 40 °C.

Ruthenium complexes of the type [RuCl₂(η⁶-arene)(P)] with

P as a monodentate phosphorus ligand have been seldom used

in the hydrogen transfer reaction, despite being stable and easy

to prepare.⁴⁴These complexes can be prepared through

straightforward syntheses and give good activities in the

standard hydrogen transfer reaction; they have also been tested

in the asymmetric version of the reaction using chiral

phosphines with some success.⁴⁵To obtain more information

about the conditions needed to improve the stability of the

active species and the asymmetric induction generated by the

ligand, we have tested some of the tethered and nontethered

complexes in the model acetophenone reduction reaction.

In order to generate the catalytically active species, the

ruthenium complexes and potassium tert-butoxide were

J

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Regarding the activity, some trends were observed. The

activities of the tethered precursors are lower than those of the

open analogues in isopropyl alcohol at reﬂux; however, at 40 °C

the reverse order is observed. In the group of tethered

complexes in which the arene moiety presents a gradual

increase in the number of methyl substituents (7a−c) the

activity decreases with an increase in the number of methyl

substituents on the arene, in parallel with the increase of arene

basicity and steric hindrance. The presence of tert-butyl (4i,j),

cyclohexyl (5i,j), and ferrocenyl (6i,j) substituents on the

phosphine in p-cymene complexes or a change of the tether

length from two (7j, 8j) to three atoms (7i, 8i) does not

signiﬁcantly aﬀect the activity. The diﬀerent basicities of tert-

butyl- and cyclohexylphosphines with respect to ferrocenyl-

phosphines or the increased basicity of −SiMe₂CH₂Ph-

containing phosphines (i) in comparison to those containing

−SiMe₂Ph (j) is not reﬂeted in any change on the rate of the

transfer hydrogenation.

With regard to the enantioselectivity, the eﬀect of the

pendant arm of the phosphines is determinant; those

containing the terminal groups 2-naphthyl and −CHPh₂in p-

cymene or tethered complexes have signiﬁcant enantiomeric

excess.

The solutions containing catalytic half-sandwich precursors

sometimes darken after 24 h of reaction time, which indicates

decomposition of the ruthenium complex. This color change

was not observed in the solutions containing tethered catalytic

precursors. Similar complexes stabilized by triaryl- or diary-

lalkylphosphines showed reaction rates higher than those

reported here with trialkylphosphines but conversely lower

stability of the catalytic species.^44c,45

pointing out that the discrimination ability of the active species

does not depend on the starting complex.

To investigate the species obtained after the activation of the

ruthenium complexes, 20 mL of a 0.01 M solution of [RuCl₂(p-

cymene)(P*)] (5i) and [RuCl₂(κ-P*-η⁶-arene)] (8i) with 5

equiv of t-BuOK were reﬂuxed for 30 min in isopropyl alcohol

1

(Scheme 13). The H and ³¹P spectra of the solution reaction

of 5i showed the formation of several species with hydride and

phosphorus signals in the range observed for mono- and

dihydride complexes (Figure 6). In contrast, the solution of the

reaction of 8i showed the formation of mainly a monohydride

single product (Figures 7 and 8).

The results of the reduction of acetophenone can be

discussed considering that the successive reaction steps must

be initiated by ligand dissociation to open a free coordination

position. Arene slippage or phosphine exchange are accessible

initiation steps available for dihydride intermediates; exchange

of the chloride ligand is also available for monohydride

intermediates, although it seems less accessible as reported.^45b

Regarding the activity, the arene and phosphine ligands in the

tethered complexes must be less labile than the p-cymene

parent complexes, but in the reactions at 40 °C the higher

activity of the tethered complexes probably can be associated to

the major stability of a single active species. The enantiose-

lectivity observed is very limited, with the exceptions of the

complexes bearing PCH₂CHPh₂or PCH₂CH₂(2-naphthyl)

substituents in the pendant arm of the phosphines, both

tethered and in the parent p-cymene complexes. Furthermore,

the dihydride and dichloride precursors of the same phosphine

tested as catalytic precursors give similar selectivities, showing

that the standard activation process leads to the same

catalytically active species. These facts point toward an

activation process by arene slippage or complete decoordina-

tion, as suggested for ruthenium carbene analogues.⁴⁷

Exploration of the Anticancer Activity. Since several

ruthenium arene complexes showed important interactions

with DNA and therefore are of pharmacological interest, two p-

cymene complexes (5j, 6j) and one tethered complex (8j) have

been used to evaluate the diﬀerence between tethered and open

complexes in their interaction with DNA and possible

cytotoxicity.^4,48The results obtained in the study of the

interactions with DNA: circular dichroism and tapping mode

atomic force microscopy (TMAFM) are described in the

Supporting Information.

It is generally accepted that the active species in transfer

hydrogenation with precursors of the type [RuCl₂(η⁶-arene)-

(P*)] could be either a monohydride or a dihydride species.⁴⁶

To explore the origin of the diﬀerences observed, some tests

have been performed in order to know the kind of

intermediates present in solution after activation of the

precursors. The position of the NMR signals of monohydride

and dihydride complexes have been determined starting from

the method developed by Demerseman^46cto directly obtain the

dihydride complexes (Scheme 12). Therefore, 4lH2 and 5iH2

Scheme 12

Cytotoxicity of the Ruthenium Complex against HL-60

Cells. The eﬀect of the ruthenium complexes was examined on

human leukemia cancer cells (HL-60) using the MTT assay, a

colorimetric determination of cell viability during in vitro

treatment with a drug. The assay, developed as an initial stage

of drug screening, measures the amount of MTT reduction by

mitochondrial dehydrogenase and assumes that cell viability

(corresponding to the reductive activity) is proportional to the

production of purple formazan that is measured spectrophoto-

metrically. A low IC₅₀value is desired and implies cytotoxicity

or antiproliferation at low drug concentrations.

The drugs tested in this experiment were cisplatin and

ruthenium complexes. Cells were exposed to each compound

continuously for a 24 or 72 h period and then assayed for

growth using the MTT end point assay. The IC₅₀values of

ruthenium complexes and cisplatin for the growth inhibition of

HL-60 cells are summarized in Table 5.

were obtained, a single doublet is observed in the hydride

region of the crude solution (4lH2, δ −12.05 ppm, J_PH= 42.5

Hz; 5iH2, δ −10.38 ppm, J_PH= 47.5 Hz). ³¹P{¹H} and coupled

¹³P NMR spectra showed that the amount of other species is

low, conﬁrming the nature of the main products of these

reactions (see spectra of mono- and dihydride species in the

Supporting Information). The CDCl₃solutions of the

dihydride complexes slowly evolve to the starting dichloride

compound, and the solids obtained after concentration to

dryness were used without further puriﬁcation.

The dihydride complex 4lH2 was used as a precatalyst

without an induction period (Table 4), showing less activity

than its precursor 4l but retaining the same enantioselectivity,

The values of IC₅₀for ruthenium complexes 5j and 6j are

similar to those of cisplatin for HL-60 tumor cell lines for 72 h

K

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Scheme 13

Figure 6. Hydride region of the ¹H NMR spectrum of solution of the reaction of 5i in Scheme 13: spectrum obtained of the crude solution using an

insert with d₆-acetone at room temperature.

1

Figure 7. Hydride region of the H NMR spectrum of 8iH: spectrum obtained as in Figure 6.

L

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Figure 8. ³¹P{¹H} and ³¹P coupled NMR spectra of 8iH: spectra obtained as in Figure 6.

Table 5. IC₅₀Values of Ruthenium Compounds and

Cisplatin against HL-60 Cells

allowed us to compare their σ-donating abilities, which were

similar for 1 and 2 and more basic in comparison to 3. Those

phosphines with a pendant arm bearing a secondary aryl

functionality have been selected to prepare two series of Ru(II)

arene complexes. From the ﬁrst series, [RuCl₂(η⁶-p-cymene)-

(P*)] (4−6), a second group of tethered [RuCl₂(κ-P*-η⁶-

arene)] complexes (7, 8) have been prepared by thermal arene

substitution. All phosphines and ruthenium compounds have

been fully characterized both in solution and in the solid state.

When the terminal aryl fragment of the pendant arm was

substituted in a nonsymmetrical way (meta substitution or

fused aromatic rings) a new planar element of chirality was

introduced when complexes 7 were prepared. The diaster-

eoselectivity of the synthesis depends on the nature of the

phosphine substituents R and R′. Within the group of

complexes explored, complete diastereoselectivity was observed

for R = t-Bu and R′ = CH₂(2-naphthyl). Thus, this

methodology to prepare diastereomerically pure ruthenium

tethered complexes seems promising, since it depends on the

appropriate selection of substituents on the P-stereogenic

phosphines.

The eﬀect of diﬀerent structural parameters of the ruthenium

complexes has been evaluated in the model hydrogen transfer

reduction of acetophenone. In reactions carried out at 40 °C,

the tethered ruthenium complexes showed better activity

probably by a combination of more robustness and the

presence of mainly a unique monohydride species after

activation of the precursor. The enantioselectivity observed is

signiﬁcant when the pendant arm of the phosphine contains a

bulky aryl terminus (d, l) in the open or tethered catalytic

precursors. The results obtained point to an arene slippage as

the way to open the coordination position needed to operate

the hydrogenation transfer reaction.

IC₅₀(μM)

complex

72 h

24 h

5j

3.36 0.42

25.91 4.24

3.72 0.34

2.15 0.1

5.15 0.29

52.06 10.47

5.38 0.45

8j

6j

CDDP

15.61 1.15

and lower than that of the platinum drug for 24 h. However,

compound 8j exhibits a lower activity for both 24 and 72 h of

treatment.

Quantiﬁcation of Apoptosis by Annexin V Binding and

Flow Cytometry. We have also analyzed by Annexin V-PI ﬂow

cytometry whether ruthenium complexes are able to induce

apoptosis in HL-60 cells after 24 h of incubation at equitoxic

concentrations (IC₅₀values). Annexin V binds phosphatidyl

serine residues, which are asymmetrically distributed toward the

inner plasma membrane but migrate to the outer plasma

membrane during apoptosis.⁴⁹

As can be seen in Table 6, ruthenium complexes induce cell

death by apoptosis at IC₅₀treatment (29.72% for 5j, 23.67% for

Table 6. Quantiﬁcation of Apoptosis after 24 h Exposure to

Concentration Equal to IC₅₀Values of Cisplatin and

Ruthenium Complexes against HL-60 Cells

treatment (IC₅₀

24 h, μM)

% vital

cells (R1)

% apoptotic

cells (R2)

% dead

cells (R3)

% damaged

cells (R4)

control

92.03

40.18

50.75

78.45

53.67

2.37

42.77

29.72

7.71

5.21

13.88

17.81

13.03

15.02

0.40

3.16

1.73

0.81

1.38

CDDP (15.6)

5j (5.15)

8j (52.06)

6j (5.38)

23.67

Some complexes were tested for potential antitumor activity

against the human promyelocytic leukemia cell line HL-60

using a MTT assay. Compounds 5j and 6j exhibit excellent

antitumor activity, with IC₅₀values similar to that of cisplatin.

Compound 8j presents a higher value for IC₅₀, being less active.

The apoptotic behavior studies gave results in the same

direction.

The study of the interaction of DNA with these three

ruthenium compounds were carried out by CD and AFM.

Results indicated modiﬁcations in tertiary ct-DNA and pBR322

plasmid DNA structures after incubation with the three

6j, and 7.71% for 8j). The percentages for complexes 5j and 6j

are lower than that for cisplatin but much higher than that

obtained for complex 8j.

CONCLUSIONS

■

A small library of P-stereogenic phosphines S-PMeR(CH₂R′)

were obtained by the Evans methodology, where R = t-Bu (1),

Cy (2), Fc (3) and R′ contains an aryl, pyridyl, or alcohol

functionality. The preparation of the corresponding selenides

M

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Dichloro(η⁶-p-cymene)[(R)-tert-butyl(2-(3-phenylphenyl)ethyl)-

methylphosphine]ruthenium(II) (4g). The phosphine was depro-

tected with method A. The preparation of this compound was carried

out following the general protocol, but starting from 0.350 g (1.19

mmol) of 1g and 0.309 g (0.50 mmol) of [RuCl₂(p-cymene)]₂. Yield:

0.445 g, 75%. Anal. Calcd for C₂₉H₃₉Cl₂PRu: C, 58.98; H, 6.66.

Found: C, 59.1; H, 7.0%. ¹H NMR (400.0 MHz, 298 K): δ (ppm) 1.25

compounds, showing that DNA could be one of the targets of

their antitumor mechanisms of action. The results obtained

strongly suggest that the biologically active organic group is the

pendant aromatic substituent available in 5j and 6j, but it is

unavailable in the tethered complex 8j.

(d, J = 6.6, CH₃CH, 3H); 1.27 (d, J = 6.6, CH₃CH, 3H); 1.33 (d, J_HP

=

EXPERIMENTAL SECTION

■

13.2, (CH₃)₃C, 9H); 1.53 (d, J_HP= 10.4, CH₃P, 3H); 2.09 (s, CH₃p-

cymene, 3H); 2.14−2.25 (m, CH₂P, 1H); 2.49−2.60 (m, CH₂P, 1H);

2.75 (tt, J_HP≈ J_HH,gem= 13.6, J_HH= 4.6, 1H); 2.85 (septet, J = 7.0,

CH₃CH, 1H); 3.11 (tt, J_HP≈ J_HH,gem= 13.5, J_HH= 4.7, 1H); 5.52 (d, J

= 6.3, p-cymene, 1H); 5.58 (d, J = 5.9, p-cymene, 1H); 5.63 (d, J = 6.1,

p-cymene, 1H); 5.65 (d, p-cymene, 1H); 7.19 (d, Ph, 1H); 7.31−7.38

(m, 2H); 7.39−7.47 (m, 4H); 7.54−7.61 (m, 1H). ¹³C{¹H} NMR

(100.6 MHz, 298 K): δ (ppm) 5.8 (d, J_PC= 29.4, CH₃P); 18.1 (s, CH₃

p-cymene); 22.0 (s, CH₃CH); 22.6 (s, CH₃CH); 27.6 (d, J_PC= 2.7,

C(CH₃)₃); 28.4 (d, J_PC= 21.6, CH₂P); 30.7 (s, CH₃CH); 31.8 (d, J_PC

= 4.6, CH₂Ph); 34.7 (d, J_PC= 22.9, (CH₃)₃C); 83.0 (d, J_PC= 4.9, CH

p-cymene); 83.6 (d, J_PC= 6.5, CH p-cymene); 88.2 (d, J_PC= 4.1, CH p-

cymene); 89.9 (d, J_PC= 4.0, CH p-cymene); 93.2 (s, p-cymene); 107.8

(s, p-cymene); 125.1 (s, CH Ph,); 126.90 (s, CH Ph,); 126.95 (s, 2CH

Ph,); 127.2 (s, 2CH Ph,); 127.3 (s, CH Ph,); 129.0 (s, CH Ph,); 141.1

(s, C Ph,); 141.5 (s, C Ph,); 142.7 (d, J_PC= 11.7, C Ph). ³¹P{¹H} NMR

(101.2 MHz, CH₂Cl₂, 298 K): δ (ppm) 29.6 (s).

General Data. All compounds were prepared under a puriﬁed

nitrogen atmosphere using standard Schlenk techniques. All solvents

were puriﬁed by standard procedures⁵⁰and distilled under nitrogen.

¹H, ¹³C{¹H}, ³¹P{¹H}, and HSQC ¹H−¹³C NMR spectra were

recorded on Bruker DRX 250, Varian Unity 300, and Varian Mercury

400 spectrometers. NOESY spectra (¹H−¹H) were obtained on a

Varian Inova 500 spectrometer. The spectra were recorded in CDCl₃

unless otherwise speciﬁed. Chemical shifts are reported downﬁeld

from standards. HPLC analyses were carried out in a Waters 717 Plus

autosampler chromatograph with a Waters 996 multidiode array

detector, ﬁtted with a Chiracel OD-H chiral column. The eluent, in all

determinations, was a mixture of n-hexane and iPrOH (95/5) unless

otherwise noted. Optical rotations were determined with a Perkin-

Elmer 241MC polarimeter at 23 °C using a sodium lamp at the

sodium D-line wavelength (589.592 nm). The solvent and

concentration (g/mL) for each compound are indicated in

parentheses. Elemental analyses (C, H) were performed at the Serveis

Dichloro(η⁶-p-cymene)[(R)-tert-butyl-(2,2-dimethyl-3-phenyl-2-

sila-1-propyl)methylphosphine]ruthenium(II) (4i). The phosphine−-

borane was deprotected with method A. The preparation of this

compound was carried out following the general protocol. The crude

orange resin was crystallized from dichloromethane/hexane to obtain

the title compound as an orange powder in 90% yield. Anal. Calcd for

̀

Cientiﬁcotecnics of the University of Barcelona. The ruthenium

dimers [RuCl(μ-Cl)(C₆H₆)]₂and [RuCl(μ-Cl)(C₁₀H₁₄)]₂and tert-

butyldimethylphosphine−borane were prepared as previously descri-

bed.^14a,44aOther reagents were used as received from commercial

suppliers. The analytical results of some of the silicon-containing

complexes are outside the range viewed as establishing analytical

purity; they are provided to illustrate the best values obtained to date.

All NMR spectra of these complexes are included in the Supporting

Information.

1

C₂₅H₄₁Cl₂PRuSi: C, 52.44; H, 7.22. Found: C, 51.29; H, 7.34. H

NMR (400 MHz): δ (ppm) 0.08 (s, CH₃Si, 3H); 0.15 (s, CH₃Si, 3H);

1.01 (dd, J = 14.80, J = 13.20, CH₂P, 1H); 1.20−1.24 (m, (CH₃)₃C,

CH₃CH, 15 H); 1.51 (d, J = 10.4, CH₃P, 3H); 1.62 (pt, J = 14.80,

CH₂P, 1H); 1.97 (s, CH₃p-cymene, 3H); 2.12 (d, J = 14.00, CH₂Si,

1H); 2.17 (d, J = 14.00, CH₂Si, 1H); 2.78 (septet, CH₃CH, 1H); 5.48

(d, J = 5, p-cymene, 1H); 5.54 (s, p-cymene, 2H); 5.58 (d, J = 5, p-

cymene, 1H); 6.90 (d, J = 4, o-Ph, 2H); 7.02 (t, J = 4, p-Ph, 1H); 7.18

(t, J = 4, Ph, 1H). ¹³C{¹H} NMR (100.6 MHz): δ (ppm) −0.44 (s,

CH₃Si); −0.15 (s, CH₃Si); 10.06 (d, J = 28.17, CH₃P); 11.01 (d, J =

22.14, CH₂P); 17.82 (s, CH₃p-cymene); 21.91 (s, CH₃CH p-cymene);

22.22 (s, CH₃CH, p-cymene); 27.32 (s, (CH₃)₃C); 27.79 (s,

PhCH₂Si); 30.47 (s, CH₃CH, p-cymene); 34.66 (d, J = 23.14,

(CH₃)₃CP); 82.40 (d, J = 6.04, CH p-cymene); 83.18 (d, J = 6.04, CH

p-cymene); 88.79 (s, CH, p-cymene); 89.53 (d, J = 3.02, CH p-

cymene); 91.94 (p-cymene); 107.76 (p-cymene); 123.98 (s, Ph);

128.02 (s, Ph); 128.11 (s, Ph);139.54 (s, Ph). ³¹P{¹H} NMR (101.2

MHz): δ (ppm) 35.8 (s). FT-IR: ν (cm⁻¹) 476; 700; 765; 828; 888;

1056; 1135; 1205; 1249; 1281; 1366; 1470; 1492; 1599; 2870; 2898;

2958; 3021; 3056.

General Procedure for Phosphine−Borane Deprotection.

Method A. A 1 mmol portion of phosphine−borane was placed in a

Schlenk ﬂask under a nitrogen atmosphere and dissolved in 10 mL of

dichloromethane. The mixture was cooled to 0 °C, and HBF₄·OEt₂

(0.70 mL, ∼5 mmol) was added dropwise. The solution was stirred for

30 min. The disappearance of the initial phosphine−borane signal and

the presence of a new singlet corresponding to the protonated

phosphine in the ³¹P NMR spectra was observed. A degassed saturated

solution of NaHCO₃(10 mL) was added, and the mixture was stirred

for 1 h. ³¹P NMR conﬁrmed the quantitative formation of the free

phosphine. The organic phase was separated, dried on sodium sulfate,

and ﬁltered to obtain a solution containing the free phosphine.

Method B. A 1 mmol portion of phosphine−borane was placed in a

Schlenk ﬂask under a nitrogen atmosphere and dissolved in 10 mL of

toluene. A 10 mmol portion of DABCO (1.12 g) was added, and the

solution was stirred for 6 h at 90 °C. ³¹P NMR conﬁrmed the

quantitative formation of free phosphine. The solution was puriﬁed by

column chromatography (alumina, toluene) to yield a solution of the

free phosphine.

Dichloro(η⁶-p-cymene)[(R)-tert-butyl((dimethylphenylsilyl)-

methyl)methylphosphine]ruthenium(II) (4j). The phosphine−borane

was deprotected with method B. The preparation of this compound

was carried out following the general protocol. The crude orange resin

was crystallized from dichloromethane/hexane in order to obtain the

title compound as an orange powder in 80% yield. Anal. Calcd for

Half-Sandwich [RuCl₂(η⁶-arene)(P*)] Complexes. Phosphine

Deprotected with Method A. Solid [RuCl₂(p-cymene)]₂(0.31 g, 5 ×

10⁻⁴mol) was added to a solution containing the free phosphine, and

the mixture was stirred for 30 min at room temperature. ³¹P NMR

conﬁrmed the coordination of the phosphine. The solvent was

removed under vacuum, and the crude product was puriﬁed by

crystallization or by ﬂash chromatography.

Phosphine Deprotected with Method B. A solution of [RuCl₂(p-

cymene)]₂(0.31 g, 5 × 10⁻⁴mol) in 20 mL of CH₂Cl₂was added to

the toluene solution containing the free phosphine, and the mixture

was stirred for 15 min. ³¹P NMR conﬁrmed the coordination of the

phosphine. The solvent was removed under vacuum, and the crude

solid was dissolved in dichloromethane. The resulting solution was

washed several times with a 1 M aqueous solution of HCl to eliminate

DABCO, DABCO−borane, and other derivatives. The organic phase

was dried with sodium sulfate and ﬁltered, and the crude product was

puriﬁed by crystallization or by ﬂash chromatography.

1

C₂₄H₃₉Cl₂PRuSi: C, 51.60; H, 7.04. Found: C, 51.52; H, 7.34. H

NMR (400 MHz): δ (ppm) 0.42 (s, CH₃Si, 3H); 0.49 (s, CH₃Si, 3H);

1.16 (d, J = 12.00, (CH₃)₃C, 9H); 1.20−1.24 (m, CH₂P, CH₃CH, 8H);

1.47 (d, J = 10.40, CH₃P, 3H); 2.01 (s, CH₃p-cymene, 3H); 2.82

(septet, Me₂CH, 1H); 5.49 (d, J = 6.00, p-cymene, 1H); 5.54 (s, p-

cymene, 2H); 5.59 (d, J = 5.60, p-cymene, 1H); 7.31−7.34 (m, Ph,

3H); 7.50−7.53 (m, 3,5-Ph, 2H). ¹³C{¹H} NMR (100.6 MHz): δ

(ppm) −0.26 (s, CH₃Si); 0.41 (d, J = 1, CH₃Si); 9.71 (d, J = 29.18,

CH₃P); 12.95 (d, J = 20.52, CH₂P); 17.84 (s, CH₃p-cymene); 21.98

(s, CH₃CH); 22.27 (s, CH₃CH); 27.39 (d, J = 4.02, CH₃CP); 30.51 (s,

Me₂CH); 34.6 (d, J = 6.04, CP); 82.72 (d, J = 5.03, CH, p-cymene);

83.09 (d, J = 7.04, CH, p-cymene); 88.93 (d, J = 4.03, CH, p-cymene);

89.52 (d, J = 3.02, CH, p-cymene); 92.08 (s, p-cymene); 107.50 (s, p-

N

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cymene); 127.80 (s, Ph); 129.08 (s, 4-Ph); 133.54 (s, Ph); 139.40 (d, J

= 3.4, 1-Ph). ³¹P{¹H} NMR (101.2 MHz): δ (ppm) 36.4 (s). FT-IR: ν

(cm⁻¹) 469; 632; 702; 783; 822; 888; 1111; 1246; 1365; 1425; 1463;

1741; 2896; 2931; 2959; 3053.

22.25 (s, CH₃CH); 26.17 (s, Cy); 26.52 (d, J_CP= 11.07, Cy); 26.89 (d,

J_CP= 11.07, Cy); 28.05 (s, Cy); 28.27 (s, Cy); 30.51 (s, Me₂CH);

42.23 (d, J_CP= 26.16, CHP); 82.52 (d, J = 5.03, CH p-cymene); 83.78

(d, J = 6.03, CH p-cymene); 88.62 (d, J = 4.02, CH p-cymene); 89.53

(d, J = 4.02, CH p-cymene); 92.17 (s, p-cymene); 107.73 (s, p-

cymene); 128.01 (s, 2,6-Ph); 129.32 (s, 4-Ph); 133.61 (s, 3,5-Ph)

138.83 (s, 1-Ph). ³¹P{¹H} NMR (101.2 MHz): δ (ppm) 25.8 (s, P-

BH₃). FT-IR: ν (cm⁻¹) 472; 628; 663; 704; 743; 792; 826; 907; 1115;

1247; 1428; 1448; 1468; 2846; 2921; 3036; 3069.

Dichloro(η⁶-p-cymene)[(R)-tert-butyl(2,2-diphenylethyl)-

methylphosphine]ruthenium(II) (4l). The phosphine was deprotected

with method A. The preparation of this compound was carried out

following the general protocol, but starting from 0.160 g (0.51 mmol)

of 1l and 0.128 g (0.21 mmol) of [RuCl₂(p-cymene)]₂. Yield: 0.152 g,

Dichloro(η⁶-p-cymene)[(R)-ferrocenyl(2-(3,5-dimethylphenyl)-

ethyl)methylphosphine]ruthenium(II) (6b). The phosphine−borane

was deprotected with method A. The preparation of this compound

was carried out following the general protocol. The crude product was

puriﬁed by ﬂash chromatography (hexane/ethyl acetate, 9/1; R_f=

0.27) to obtain the title product as an orange solid in 90% yield. Anal.

Calcd for C₃₁H₃₉RuCl₂PFe: C, 55.54; H, 5.86. Found: C, 55.76; H,

5.85. ¹H NMR (400 MHz): δ (ppm) 1.00 (d, J = 6.80, CH₃CH, 3H);

1.08 (d, J = 8.00, CH₃CH, 3H); 1.78 (s, CH₃p-cymene, 3H); 1.84 (d,

J = 11.60, CH₃P, 3H); 2.34 (s, CH₃Ph, 6H); 2.58 (m, CH p-cymene,

1H); 2.60−2.73 (m, CH₂P, 2H); 3.10 (m, CH₂Ph, 2H); 4.30 (s, Cp,

5H); 4.45 (s, Cp, 1H); 4.49 (s, Cp, 2H); 4.60 (s, Cp, 1H); 5.02 (d, J =

6.00, p-cymene, 1H); 5.12 (d, J = 6.00, p-cymene, 1H); 5.16 (d, J =

6.00, p-cymene, 1H); 5.19 (d, J = 6.00, p-cymene, 1H); 6.90 (s, 4-Ph,

1H); 6.92 (s, 2,6-Ph, 2H). ¹³C{¹H} NMR (100.6 MHz): δ (ppm) 9.18

(d, J = 34, CH₃P); 17.71 (s, CH₃p-cymene); 21.32 (s, CH₃Ph); 21.82

(s, CH₃CH); 22.03 (s, CH₃CH); 30.21 (s, CH p-cymene); 30.41 (s,

CH₂Ph); 32.39 (d, J = 27, CH₂P); 68.60 (d, J = 8, Cp); 69.37 (s, Cp);

69.87 (d, J = 7, Cp); 70.49 (d, J = 11, Cp); 70.71 (d, J = 8.8, Cp);

83.89 (d, J = 5, CH p-cymene); 84.60 (d, J = 6, CH p-cymene); 89.90

(d, J = 4, CH p-cymene); 90.57 (d, J = 5.5, CH p-cymene); 92.76 (s, p-

cymene); 107.15 (s, p-cymene); 125.86 (s, 2,6-Ph); 127.98 (s, 4-Ph);

138.28 (s, Ph); 141.88 (d, J = 11.00, 1-Ph); 159.81 (s, Ph). ³¹P{¹H}

NMR (101.2 MHz): δ (ppm) 9.4 (s). FT-IR: ν (cm⁻¹) 460; 848;

1080; 1104.06; 1280; 1383; 1466; 2867; 2914; 2960; 3083.

61%. Anal. Calcd for C₂₉H₃₉Cl₂PRu: C, 58.98; H, 6.66. Found: C,

1

58.5; H, 6.6. H NMR (400.0 MHz, 298 K): δ (ppm) 0.93 (d, J_HP

=

11.1, CH₃P, 3H); 1.15 (d, J_HH= 7.0, CH₃CH, 3H); 1.22 (d, J_HH= 6.9,

CH₃CH, 3H); 1,29 (d, J_HP= 13.0, (CH₃)₃C, 9H); 1.95 (s, CH₃p-

cymene, 3H); 2.73 (septet, J_HH= 7.0, CH₃CH, 1H); 2.90−3.07 (m,

CH₂P, 2H); 4.89 (m, CHPh₂, 1H); 5.47 (d, J = 5.9, p-cy,1H); 5.54 (d,

J = 6.0, p-cy, 1H); 5.59 (d, J = 5.9, p-cy, 1H); 5.63 (d, J = 5.9, p-cy,

1H); 7.08−7.14 (m, Ph, 2H); 7.20−7.27 (m, Ph, 4H); 7.36−7.40 (m,

Ph, 4H). ¹³C{¹H} NMR (100.6 MHz, 298 K): δ (ppm) 5.1 (d, J_PC

=

27.8, PCH₃); 18.0 (s, CH₃p-cymene); 21.6 (s, CHCH₃); 22.9 (s,

CHCH₃); 27.8 (d, J_PC= 2.8, C(CH₃)₃); 30.5 (s, CH(CH₃)₂); 33.4 (d,

J_PC= 18.5, CH₂P); 34.7 (d, J_PC= 23.3, C(CH₃)₃); 46.2 (d, J_PC= 4.2,

CHPh₂); 82.6 (d, J_PC= 4.3, CH p-cymene); 84.4 (d, J_PC= 6.8, CH p-

cymene); 87.7 (d, J_PC= 4.3, CH p-cymene); 90.3 (d, J_PC= 3.7, CH p-

cymene); 107.5 (s, C p-cymene); 126.2 (s, CHPh); 126.3 (s, CHPh);

127.3 (s, 2CHPh); 127.6 (s, 2CHPh); 128.6 (s, 2CHPh); 128.7 (s,

2CHPh); 145.5 (s, J_PC= 4, CPh); 145.6 (d, J_PC= 8, CPh). ³¹P{¹H}

NMR (101.2 MHz, 298 K): δ (ppm) 32.55 (s). IR: ν (cm⁻¹) 3052,

3030, 2960, 2900, 2870; 1596, 1492, 1468, 1450,1365, 922, 893, 749,

709, 535.

Dichloro(η⁶-p-cymene)[(R)-cyclohexyl(2,2-dimethyl-3-phenyl-2-

sila-1-propyl)methylphosphine]ruthenium(II) (5i). The phosphine

was deprotected with method A. The preparation of this compound

was carried out following the general protocol. Monocrystals of the

title product were obtained after slow evaporation from a solution of

hexane/dichloromethane in 90% yield. Anal. Calcd for

Dichloro(η⁶-p-cymene)[(R)-ferrocenyl(2-(2-naphthyl)methyl)-

methylphosphine]ruthenium(II) (6d). The phosphine was depro-

tected with method A. The preparation of this compound was carried

out following the general protocol. The crude product was puriﬁed by

ﬂash chromatography (hexane/ethyl acetate, 9/1; R_f= 0.25) to obtain

the title product as an orange solid in 90% yield. Anal. Calcd for

C₃₃H₃₇RuCl₂PFe: C, 57.24; H, 5.38. Found: C, 57.9; H, 5.3. ¹H NMR

(400 MHz): δ (ppm) 1.01 (d, J = 8, CH₃CH, 3H); 1.08 (d, J = 8,

CH₃CH, 3H); 1.81 (s, CH₃p-cymene, 3H); 1.89 (d, J = 12, CH₃P,

3H); 2.62 (septet, J = 8, Me₂CH, 1H); 2.71 (m, CH₂P, 1H); 2.84 (m,

CH₂P, 1H); 3.30 (m, CH₂Ar, 1H); 3.39 (m, CH₂Ar, 1H); 4.31 (s, Cp,

5H); 4.47 (s, Cp, 1H); 4.51 (s, Cp, 2H); 4.60 (s, Cp, 1H); 5.05 (d, J =

8, p-cymene 1H); 5.15 (s, p-cymene 2H); 5.20 (d, J = 8, p-cymene

1H); 7.41−4.50 (m, Ar, 3H); 7.75 (s, Ar, 1H); 7.80−7.86 (m, Ar, 3H).

¹³C{¹H} NMR (100.6 MHz): δ (ppm) 9.50 (d, J = 34.3, CH₃P); 17.74

(s, CH₃p-cymene); 21.80 (s, CH₃CH); 21.99 (s, CH₃CH); 30.21 (s,

CH p-cymene); 30.68 (s, CH₂Ar); 30.20 (d, J = 28.30, CH₂P); 68.65

(d, J = 9.1, Cp); 69.35 (s, Cp); 69.97 (d, J = 7.07, Cp); 70.32 (d, J =

11.00, Cp); 70.67 (d, J = 8.08, Cp); 84.03 (d, J = 6.05, CH p-cymene);

84.65 (d, J = 6.05, CH p-cymene); 90.16 (d, J = 6.05, CH p-cymene);

90.56 (d, J = 6.05, CH p-cymene); 92.73 (s, p-cymene); 107.15 (s, p-

cymene); 125.44 (s); 126.12 (d, J = 5.00, Ar); 126.74 (s); 127.47 (s,

Ar); 127.64 (s, Ar); 128.42 (s); 132.13 (s); 133.64 (s); 139.50 (d, J =

13.10, Ar); ³¹P{¹H} NMR (101.2 MHz): δ (ppm) 10.5 (s). FT-IR: ν

(cm⁻¹) 455; 487; 743; 821; 896; 1003; 1034; 1105; 1167; 1279;1385;

1470; 1599; 1632; 2862; 2917; 2951, 3056.

1

C₂₇H₄₃Cl₂PRuSi: C, 54.17; H, 7.24. Found: C, 53.41; H, 7.25. H

NMR (400 MHz): δ (ppm) 0.11 (s, CH₃Si, 3H); 0.13 (s, CH₃Si, 3H);

1.14 (dd, J_HP= 15, J_HH= 10, CH₂P, 1H); 1.22 (d, J = 6.5, CH₃CH,

3H); 1.23 (d, J = 6.5, CH₃CH, 3H); 1.24−1.30 and 1.76−1.94 (m, Cy,

11H); 1.48 (d, J = 11, CH₃P); 1.57 (pt, J = 15, CH₂P, 1H); 1.99 (s,

CH₃p-cymene, 3H); 2.14 (s, CH₂Si, 2H); 2.78 (m, J = 6.5, Me₂CH,

1H); 5.40 (s, 2H, p-cymene); 5.46 (s, 2H, p-cymene); 6.96 (d, J = 8,

2H, o-Ph); 7.05 (t, J = 8, 1H, p-Ph); 7.18 (t, J = 8, 2H, m-Ph). ¹³C{¹H}

NMR (100.6 MHz): δ (ppm) −0.56 (s, CH₃Si); −0.53 (s, CH₃Si);

10.80, (d, J = 23.14, CH₃P); 11.08 (d, J = 15, CH₂P); 17.98 (s, CH₃p-

cymene); 21.71 (s, CH₃CH p-cymene); 22.44 (s, CH₃CH p-cymene);

26.16 (s, Cy); 26.8 (d, J = 10, Cy); 26.9 (d, J = 10, Cy); 27.62 (d, J =

3, Cy); 28.11 (s, Cy); 28.17 (s, SiCH₂Ph); 30.46 (s, CH₃CH p-

cymene); 42.79 (d, J = 25.6, C_CyP); 82.28 (d, J = 5, CH p-cymene);

84.48(d, J = 6, CH p-cymene); 88.12 (d, J = 3, CH p-cymene);

89.67(d, J = 4, CH p-cymene); 92.50 (s, p-cymene); 107.64 (s, p-

cymene); 124.16 (s, Ph); 128.15 (s, Ph); 139.33 (s, Ph). ³¹P{¹H}

NMR (101.2 MHz): δ (ppm) 25.6 (s). FT-IR: ν (cm⁻¹) 484; 700;

763; 820; 872; 892; 918; 1116; 1203; 1250; 1448; 1492; 1598; 1637;

2850; 2924; 2957; 3022; 3050.

Dichloro(η⁶-p-cymene)[(R)-cyclohexyl(2-methyl-2-phenyl-2-sila-

1-propyl)methylphosphine]ruthenium(II) (5j). The phosphine was

deprotected with method B. The preparation of this compound was

carried out following the general protocol. The crude orange resin was

crystallized from dichloromethane/hexane to obtain the title product

as an orange powder in 90% yield. Anal. Calcd for C₂₆H₄₁Cl₂PRuSi: C,

Dichloro(η⁶-p-cymene)[(R)-ferrocenyl(2-(3-methoxyphenyl)ethyl)-

methylphosphine]ruthenium(II) (6e). The phosphine−borane was

deprotected with method A. The preparation of this compound was

carried out following the general protocol. The crude product was

puriﬁed by ﬂash chromatography (hexane/ethyl acetate, 9/1; R_f=

0.15) to obtain the title product as an orange foam in 90% yield. Anal.

Calcd for C₃₀H₃₇RuPCl₂FeO: C, 53.59; H, 5.55. Found: C, 53.90; H,

1

53.41; H, 7.07. Found: C, 53.62; H, 7.30. H NMR (400 MHz): δ

(ppm) 0.38 (s, CH₃Si, 3H); 0.45 (s, CH₃Si, 3H); 0.97−1.2 (m, Cy,

5H); 1.21 (d, J = 5.5, CH₃CH, 3H); 1.22 (d, J = 5.5, CH₃CH, 3H);

1.44 (d, J = 12, CH₃P, 3H); 1.46 (pt, J = 12.5, CH₂P, 1H); 1.83 (pt, J

= 15.3, CH₂P, 1H); 1.65−1.95 (m, Cy, 6H); 2.01 (s, CH₃p-cymene,

3H); 2.81 (septet, CH, 1H); 5.40−5.50 (m, p-cymene, 4H); 7.37 (m,

Ph, 3H); 7.55 (m, 3,5-Ph, 2H). ¹³C{¹H} NMR (100.6 MHz): δ (ppm)

−0.58 (s, CH₃Si); 0.15 (s, CH₃Si); 11.36 (d, J_CP= 36.22, CH₃P); 11.98

(d, J_CP= 23.14, CH₂P); 17.97 (s, CH₃p-cymene); 21.93 (s, CH₃CH);

1

5.50. H NMR (400 MHz): δ (ppm) 0.98 (d, J = 8, CH₃CH, 3H);

1.06 (d, J = 8, CH₃CH, 3H); 1.77 (s, CH₃p-cymene, 3H); 1.83 (d, J =

12, CH₃P, 3H); 2.56−2.66 (m, CH p-cymene, 1H); 2.69−2.80 (m,

O

dx.doi.org/10.1021/om3012294 | Organometallics XXXX, XXX, XXX−XXX

Organometallics

Article

CH₂P, 2H); 3.05−3.22 (m, CH₂Ph, 2H); 3.82 (s, CH₃O, 3H); 4.28 (s,

Cp, 5H); 4.43 (s, Cp, 1H); 4.48 (s, Cp, 2H); 4.57 (s, Cp, 1H); 5.01

(d, J = 4, p-cymene 1H); 5.13 (s, p-cymene 2H); 5.19 (d, J = 4, p-

cymene 1H); 6.78 (d, J = 8, Ph, 1H); 6.86 (s, Ph, 1H); 6.89 (d, J = 8,

Ph, 1H); 7.24−7.26 (m, Ph, 1H). ¹³C{¹H} NMR (100.6 MHz): δ

(ppm) 9.29 (d, J = 34.4; CH₃P); 17.66 (s, CH₃p-cymene); 21.74 (s,

CH₃CH); 21.95 (s, CH₃CH); 30.17 (s, CH p-cymene); 30.46 (s,

CH₂Ph); 32.14 (d, J = 27.3; CH₂P); 55.19 (s, CH₃O); 68.56 (d, J =

9.1; Cp); 69.29 (s, Cp); 69.90 (d, J = 7.7; Cp); 70.31 (d, J = 11; Cp);

70.65 (d, J = 8.8; Cp); 83.94 (d, J = 6.6; CH p-cymene); 84.55 (d, J =

6.60; CH p-cymene); 90.05 (d, J = 4.42; CH p-cymene); 90.57 (d, J =

5.50; CH p-cymene); 92.62 (s, p-cymene); 107.07 (s, p-cymene);

111.54 (s, Ph); 113.82 (s, 2-Ph); 120.26 (s, Ph); 129.68 (s, 5-Ph);

143.60 (d, J = 13, 1-Ph); 159.81 (s; 3-Ph). ³¹P{¹H} NMR (101.2

MHz): δ (ppm) 10.6 (s). FT-IR: ν (cm⁻¹) 452; 483; 690; 772; 823;

878; 1035; 1166; 1258; 1384; 1436; 1465; 1490; 1583; 1599; 2832;

2868; 2920; 2957; 3076.

cymene)(P*)] was dissolved in 20 mL of chlorobenzene and the

mixture stirred at 130 °C for 4 h. ³¹P NMR conﬁrmed the quantitative

formation of the tethered complex with total consumption of the

starting product. The solution was cooled down slowly to 25 °C. The

addition of 10 mL of hexane caused, after 10 min, the precipitation of

the desired complex. The product was ﬁltered and puriﬁed by

crystallization from CH₂Cl₂/hexane.

Dichloro[κ-P-η⁶-(R)-tert-butyl(2-(3-phenylphenyl)ethyl)-

methylphosphine]ruthenium(II) (7g). This compound was obtained

as described in the general procedure, but starting from 0.117 g (0.193

mmol) of 4g. Yield: 41 mg, 45%. Anal. Calcd for C₁₉H₂₅Cl₂PRu: C,

50.01; H, 5.52. Found: C, 49.8; H, 5.3.

¹H NMR (500.0 MHz, 298 K): major isomer, δ (ppm) 1.27 (d, J_HP

= 14.7, (CH₃)₃C, 9H); 1.63 (d, J_HP= 10.5, CH₃P, 3H); 2.20−2.32 (m,

CH₂Ph, 1H); 2.64−2.72 (m, CH₂P, 1H); 3.01−3.19 (m, CH₂P,

CH₂Ph, 2H); 4.94 (s, Ar, 1H); 5.28 (d J_HH= 5.8, Ar, 1H), 5.80 (t, J_HH

= 5.9, Ar, 1H); 6.26 (d, J_HH= 5.9, Ar, 1H); 7.41−7.51 (m, Ph, 3H);

7.68−7.74 (m, Ph, 2H); minor isomer, δ (ppm) 1.24 (d, J_HP= 14.8,

(CH₃)₃C, 9H), 1.60 (d, J_HP= 10.6, CH₃P, 3H); 2.52−2.64 (m,

CH₂Ph, 1H); 2.72−2.92 (m, CH₂P, CH₂Ph, 2H), 3.08−3.16 (m,

CH₂P, 1H); 4.97 (d, J_HH= 5.4, Ar, 1H); 5.24 (s, Ar, 1H); 6.11 (t, J_HH

= 5.9, Ar, 1H); 6.37 (d, J_HH= 6.3, Ar, 1H); 7.41−7.51 (m, Ph, 3H);

7.62−7.66 (m, Ph, 2H). ¹³C{¹H} NMR (100.6 MHz, 298 K, CDCl₃):

major isomer, δ (ppm) 10.7 (d, J_PC= 25.6, PCH₃); 25.9 (d, J_PC= 2.5,

C(CH₃)₃); 28.9 (d, J_PC= 3.35, CH₂Ph); 32.6 (d, J_PC= 22.1, C(CH₃)₃);

37.7 (d, J_PC= 27.9, CH₂P); 73.8 (s, CHAr); 75.3 (s, CHAr); 89.1 (d,

J_PC= 13.1, CHAr); 95.2 (s, CHAr); 110.0 (d, J_PC= 4.04 Hz, CAr);

116.5 (d, J = 5.87 Hz, CAr); 129.5 (s, CPh); 130.1 (s, CPh); 133.6 (s,

CPh); minor isomer: δ (ppm) 10.6 (d, J_PC= 25.6, PCH₃), 26.1 (d, J_PC

= 2.40, C(CH₃)₃); 29.7 (d, J_PC= 3.9, CH₂Ph); 32.7 (d, J_PC= 21.4,

C(CH₃)₃); 38.5 (d, J_PC= 27.6, CH₂P); 73.4 (s, CHAr), 76.4, (s,

Dichloro(η⁶-p-cymene)[(R)-ferrocenyl(2,2-dimethyl-3-phenyl-2-

sila-1-propyl)methylphosphine]ruthenium(II) (6i). The phosphine

was deprotected with method A. The preparation of this compound

was carried out following the general protocol. The crude orange oil

was crystallized from dichloromethane/hexane to obtain the title

product as an orange powder in 90% yield. Anal. Calcd for

1

C₃₁H₄₁Cl₂RuFePSi: C, 53.15; H, 5.90. Found: C, 52.49; H, 6.08. H

NMR (400 MHz): δ (ppm) 0.28 (s, CH₃Si, 3H); 0.32 (s, CH₃Si, 3H);

1.01 (d, J = 7.2, CH₃CH, 3H); 1.03 (d, J = 7.2, CH₃CH, 3H); 1.76 (s,

CH₃p-cymene, 3H); 1.76−1.79 (m, CH₃P, CH₂P, 5H); 2.24−2.37

(m, CH₃CH, 1H); 2.25 (d, J = 12.00, CH₂Si, 1H); 2.35 (d, J = 12.00,

CH₂Si, 1H); 4.19 (s, Cp, 5H); 4.35 (s, Cp, 1H); 4.44 (s, Cp, 2H); 4.55

(s, Cp, 1H); 4.89 (d, J = 5.6, p-cymene, 1H); 5.03 (d, J = 5.6, p-

cymene, 1H); 5.14 (d, J = 5.2, p-cymene, 1H); 5.24 (d, J = 5.6, p-

cymene, 1H); 7.09−7.11 (m, Ph, 3H); 7.24−7.28 (m, Ph, 2H).

¹³C{¹H} NMR (100.6 MHz): δ (ppm) −0.08 (s, CH₃Si); 0.00 (s,

CHAr); 87.8 (d, J_PC= 14.0, CHAr); 98.5 (s, CHAr); 111.0 (d, J_PC

=

4.09, CAr); 111.3 (d, J = 1.45, CAr); 129.6 (s, CHPh); 130.0 (s,

CHPh). ³¹P{¹H} NMR (101.2 MHz, C₆H₅Cl, 298 K): δ (ppm) major

isomer 63.6 (s), minor isomer 61.4 (s). X-ray: red crystals suitable for

X-ray diﬀraction were obtained by slow diﬀusion of hexane over a

solution of the complex in dichloromethane, at room temperature.

Dichloro[κ-P-η⁶-(R)-tert-butyl-(2,2-dimethyl-3-phenyl-2-sila-1-

propyl)methylphosphine]ruthenium(II) (7i). The preparation of this

compound was carried out following the general protocol. The

product was isolated as an orange solid in 90% yield. Anal. Calcd for

CH₃Si); 13.74 (d, J = 36.22, CH₃P); 15.86 (d, J = 19.12, CH₂P); 17.87

(s, CH₃p-cymene); 21.73 (s, CH₃CH); 22.60 (s, CH₃CH); 28.26 (d, J

= 4.02, CH₂Si); 29.85 (d, J = 37, CH₃CH); 69.12 (Cp); 69.75 (d, J =

7, Cp); 70.24−70.44 (m, Cp); 84.53 (d, J = 5.03, CH p-cymene);

85.70 (d, J = 5.03, CH p-cymene); 87.95 (d, J = 4.02, CH p-cymene);

88.49 (d, J = 6.04, CH p-cymene); 95.69 (s, p-cymene); 106.32 (s, p-

cymene); 124.26 (s, Ph); 128.26 (s, Ph); 128.32 (s, Ph);139.93 (s,

Ph). ³¹P{¹H} NMR (101.2 MHz): δ (ppm) 8.8 (s). FT-IR: ν (cm⁻¹)

482; 501; 700; 763; 826; 880; 1030; 1052; 1124; 1204; 1242; 1276;

1491; 1598; 2959; 3029; 3083.

1

C₁₄H₂₆Cl₂RuPSi: C, 39.53; H, 6.21. Found: C, 39.5; H, 6.1. H NMR

(400 MHz): δ (ppm) 0.29 (s, CH₃Si, 3H); 0.40 (s, CH₃Si, 3H); 1.02

(pt, J = 15, CH₂P, 1H); 1.12 (pt, J = 15.00, CH₂P, 1H); 1.27 (d, J =

14.10, C(CH₃)₃, 9H); 1.43 (d, J = 12, CH₃P, 3H); 1.63 (d, J = 15,

CH₂Si, 1H); 1.86 (d, J = 15, CH₂Si, 1H); 5.07 (t, J = 5.4, Ph, 1H);

5.13 (d, J = 6, Ph, 1H); 5.35 (t, J = 4.8, Ph, 1H); 6.12 (t, J = 6, Ph,

1H); 6.23 (t, J = 5.7, Ph, 1H). ¹³C{¹H} NMR (100.6 MHz): δ (ppm)

−1.04 (s, CH₃Si); −0.11 (d, J = 5, CH₃Si); 7.53 (d, J = 9.06, CH₂P);

10.1 (d, J = 30.2, CH₃P); 18.28 (s, CH₂Si); 27.92 (s, C(CH₃)₃); 35.18

(d, J = 25.15, C(CH₃)₃,); 79.54 (s, Ph); 79.91 (s, Ph); 86.42 (s, Ph);

95.46 (d, J = 10.62, Ph); 96.58 (s, Ph); 101.48 (d, J = 11.1, Ph).

³¹P{¹H} NMR (101.2 MHz): δ (ppm) 32.53 (s). FT-IR: ν (cm⁻¹)

Dichloro(η⁶-p-cymene)[(R)-ferrocenyl(2-methyl-2-phenyl-2-sila-1-

propyl)methylphosphine]ruthenium(II) (6j). The phosphine-borane

was deprotected with method B. The preparation of this compound

was carried out following the general protocol. The crude orange oil

was crystallized from dichloromethane/hexane to obtain the title

product as an orange powder in 80% yield. Anal. Calcd for

1

C₃₀H₃₉Cl₂PFeRuSi: C, 52.49; H, 5.73. Found: C, 52.21; H, 5.89. H

NMR (400 MHz): δ (ppm) 0.60 (s, CH₃Si, 3H); 0.64 (s, CH₃Si, 3H);

1.01 (d, J = 8, CH₃CH, 3H); 1.03 (d, J = 8, CH₃CH, 3H); 1.74 (d, J =

8, CH₃P, 3H); 1.75 (s, CH₃p-cymene, 3H); 2.04 (d, J = 16, CH₂P,

2H); 2.38 (septet, J = 8, CH₃CH, 1H); 4.15 (s, Cp, 5H); 4.38 (s, Cp,

1H); 4.41 (s, Cp, 2H); 4.50 (s, Cp, 1H); 4.94 (d, J = 8, p-cymene,

1H); 5.00 (d, J = 4,1 p-cymene, 1H); 5.14 (d, J = 4.1, p-cymene, 1H);

5.22 (d, J = 4.1, p-cymene, 1H); 7.38−7.39 (m, Ph, 3H); 7.64−7.66

(m, m-Ph, 2H). ¹³C{¹H} NMR (100.6 MHz): δ (ppm) 0.13 (s,

CH₃Si); 13.41 (d, J = 35.22, CH₃P); 17.68 (d, J = 21.13, CH₂P); 17.82

(s, CH₃p-cymene); 21.82 (s, CH₃CH); 22.38 (s, CH₃CH); 30.07 (s,

CH₃CH); 69.07 (s, Cp); 69.47 (d, J = 10, Cp); 69.74 (d, J = 8, Cp);

70.17 (d, J = 10, Cp); 70.26 (d, J = 9, Cp); 84.56 (d, J = 6, CH p-

cymene); 85.27 (d, J = 5, CH p-cymene); 88.61 (d, J = 4, CH p-

cymene); 88.96 (d, J = 6, CH p-cymene); 94.98 (s, p-cymene); 106.45

(s, p-cymene); 128.04 (s, Ph); 129.21 (s, Ph); 133.49 (s, Ph); 140.22

(s, Ph). ³¹P{¹H} NMR (101.2 MHz): δ (ppm) 9.2 (s). FT-IR: ν

(cm⁻¹) 456; 502; 698; 725; 785; 821; 891; 1031; 1114; 1246; 1280;

1426; 1469; 2923; 2950; 3043; 3076; 3096.

809; 839; 897; 1102; 1251; 1448; 1464; 2864; 2897; 2947; 3057.

Dichloro[κ-P-η⁶-(R)-tert-butyl(2-methyl-2-phenyl-2-sila-1-propyl)-

methylphosphine]ruthenium(II) (7j). The preparation of this

compound was carried out following the general protocol. The

product was isolated as an orange solid in 90% yield. Anal. Calcd for

1

C₁₄H₂₅Cl₂PRuSi: C, 39.62; H, 5.94. Found: C, 39.5; H, 5.9. H NMR

(400 MHz): δ (ppm) 0.46 (s, CH₃Si, 3H); 0.54 (s, CH₃Si, 3H); 1.23

(d, J = 15.00, C(CH₃)₃, 9H); 1.49 (d, J = 10.8, CH₃P, 3H); 1.66 (pt, J

= 14.5, CH₂, 1H); 2.09 (dd, J = 14.6, J = 10.7, CH₂, 1H); 5.19 (d, J =

5.3, Ph, 1H); 5.35 (d, J = 4.3, Ph, 1H); 5.52 (t, J = 5.7, Ph, 1H); 6.07

(t, J = 6, Ph, 1H); 6.19 (t, J = 6, Ph, 1H). ¹³C{¹H} NMR (100.6

MHz): δ (ppm) −3.92 (d, J = 7.04, CH₃Si); −2.08 (d, J = 8.05,

CH₃Si); 11.53 (d, J = 27.16, CH₃P); 21.79 (d, J = 12.07, CH₂P); 26.28

(d, J = 3.0, C(CH₃)₃); 34.30 (d, J = 21.13, C(CH₃)₃); 82.40 (s, Ph);

86.35 (s, Ph); 88.53 (s, Ph); 96.76 (d, J = 9.05, Ph); 98.67 (d, J =

10.00, Ph). ³¹P{¹H} NMR (101.2 MHz): δ (ppm) 32.88 (s). FT-IR: ν

Tethered [RuCl₂(κ-P*-η⁶-arene)] Complexes. General Proce-

dure. A 1 mmol portion of the half-sandwich complex [RuCl₂(η⁶-

P

dx.doi.org/10.1021/om3012294 | Organometallics XXXX, XXX, XXX−XXX

Organometallics

Article

(cm⁻¹) 425; 753; 794; 812; 848; 888; 1013; 1096; 1256; 1280; 1364;

1392; 1463; 1637; 2882; 2944; 3025.

816; 844; 878; 894; 920; 1090; 1117; 1252; 1279; 1447; 2849; 2924;

3056.

Dichloro[κ-P-η⁶-(R)-tert-butyl(2-(2,3,4,5,6-pentamethylphenyl)-

ethyl)phosphine]ruthenium(II) (1c). X-ray: red crystals suitable for X-

ray diﬀraction were obtained by slow diﬀusion of hexane over a

solution of the complex 1c prepared previously in chlorobenzene, at

room temperature.⁹

Dichloro[κ-P-η⁶-(R)-tert-butyl(2,2-diphenylethyl)-

methylphosphine]ruthenium(II) (7l). This compound was obtained as

described in the general procedure, but starting from 0.117 g (0.198

mmol) of 4l. Yield: 41 mg, 45%. Anal. Calcd for C₁₉H₂₅Cl₂PRu: C,

50.01; H, 5.52. Found: C, 50.2; H, 5.3.

¹H NMR (500.0 MHz, 298 K): major isomer, δ (ppm) 1.37 (d, J_HP

= 15.0, (CH₃)₃C, 9H); 1.64 (d, J_HP= 10.9, CH₃P, 3H); 3.18 (ptd, J =

11.3, J = 8.4, CH₂P, 1H); 3.47−3.55 (m, CH₂P, 1H); 4.01 (ddd, J =

13.9, J = 6.0, J = 1.5, CHPh₂, 1H); 5.00 (d, J = 5.9, Ar, 1H); 5.31 (d, J

= 5.9, Ar, 1H); 5.81 (t, J = 5.8, Ar, 1H); 6.08 (t, J = 5.9, Ar, 1H); 6.25

(td, J = 6.0, J = 2.6, Ar, 1H); 7.30−7.41 (m, Ph, 5H)’ minor isomer, δ

(ppm) 1.31 (d, J_HP= 15.2, (CH₃)₃C, 9H); 1.76 (d, J_HP= 10.5, CH₃P,

3H); 3.02 (ddd, J = 13.7, J = 11.7, J = 5.6, CH₂P, 1H); 3.41−3.48 (m,

CH₂P, 1H); 3.83 (ddd, J = 13.7, J = 5.5, J = 1.7, CHPh₂, 1H); 5.02 (d,

J = 5.4, Ar, 1H); 5.27 (d, J = 6.0, Ar, 1H); 5.72 (t, J = 5.7, Ar, 1H);

6.16 (td, J = 5.9, J = 2.0, Ar, 1H); 6.31 (t, J = 5.7, Ar, 1H); 7.30−7.41

(m, Ph, 5H). ¹³C{¹H} NMR (100.6 MHz, 298 K, CDCl₃): major

isomer, δ (ppm) 11.5 (d, J_PC= 27.8, PCH₃); 26.7 (d, J_PC= 2.85,

C(CH₃)₃); 33.1 (d, J_PC= 20.1, C(CH₃)₃); 44.3 (d, J_PC= 27.0, CH₂P);

49.6 (d, J_PC= 3.35, CHPh₂); 73.8 (s, CHAr); 77.9 (s, CHAr); 91.2 (d,

J_PC= 13.4, CHAr); 95.4 (s, CHAr); 102.5 (d, J_PC= 4.63, CHAr); 112.8

(d, J_PC= 2.12, CAr); 126.7 (s, Ph); 128.1 (s, Ph); 129.1 (s, Ph); minor

isomer, δ (ppm) 10.0 (d, J_PC= 25.1, PCH₃); 25.8 (d, J_PC= 2.28,

C(CH₃)₃); 32.6 (d, J_PC= 21.9, C(CH₃)₃); 41.9 (d, J_PC= 27.1, CH₂P);

45.3 (d, J_PC= 6.02, CHPh₂); 73.7 (s, CHAr); 77.2 (s, CHAr); 89.3 (d,

J_PC= 14.5, CHAr); 94.8 (s, C_arH); 101.8 (d, J_PC= 6.10, CHAr); 110.3

(d, J_PC= 2.37, CAr); 126.8 (s, Ph); 128.1 (s, Ph); 129.2 (s, Ph).

³¹P{¹H} NMR (101.2 MHz, 298 K), major isomer δ (ppm) 47.2 (s),

General Procedure for the Enantioselective Transfer Hydro-

genation. A typical transfer hydrogenation run was performed as

follows. A 50 mL Schlenk ﬂask was charged with the ruthenium

precursor (0.02 mmol) and potassium tert-butoxide (11.2 mg, 0.1

mmol) and was purged with three vacuum/argon cycles. Under a

gentle ﬂow of argon, 25 mL of degassed 2-propanol was added and the

ﬂask heated to reﬂux (82 °C) for 30 min. After that time acetophenone

(600 mg, 4.0 mmol) was rapidly added to start the catalytic run. The

reaction was monitored by GC analysis.

ASSOCIATED CONTENT

* Supporting Information

■

S

Text, tables, ﬁgures, and CIF ﬁles giving details of the synthesis

of the P-stereogenic phosphines and molecular structure

information, NMR spectra of selected phosphines and

complexes, HPLC of selected phosphines, structural and

electrochemical data of ruthenium complexes, time dependence

of hydrogen transfer, techniques used to evaluate the anticancer

activity, and crystallographic data. This material is available free

of charge via the Internet at http://pubs.acs.org. CCDC

916123−916131 contain supplementary crystallographic data

for this paper. These data can be obtained free of charge from

The Cambridge Crystallographic Data Centre via www.ccdc.

cam.ac.uk/data_request/cif.

minor isomer δ (ppm) 45.1. X-ray: red crystals suitable for X-ray

diﬀraction were obtained by slow diﬀusion of hexane over a solution of

the complex in chlorobenzene, at room temperature.

Dichloro[κ-P-η⁶-(R)-cyclohexyl(2-dimethylbenzylsilyl)-

methylphosphine]ruthenium(II) (8i). The preparation of this

compound was carried out following the general protocol. The

product was isolated as an orange solid in 90% yield. Monocrystals of

the title product were obtained after slow evaporation from a solution

of dichloromethane/hexane. Anal. Calcd for C₁₇H₂₉Cl₂PRuSi: C,

AUTHOR INFORMATION

Notes

The authors declare no competing ﬁnancial interest.

■

ACKNOWLEDGMENTS

We thank the Ministerio of Educacion

■

1

43.96; H, 6.29. Found: C, 42.1; H, 6.25. H NMR (400 MHz): δ

́

y Ciencia, (MEC, grant

(ppm) 0.32 (s, CH₃Si, 3H); 0.34 (s, CH₃Si, 3H); 1.15 (d, J = 14.8,

CH₂P, 2H); 1.15−1.33 (m, Cy, 6H); 1.37 (d, J = 11.2, CH₃P, 3H);

1.66 (d, J = 12, CH₂Ar, 1H); 1.80−1.95 (m, Cy, 4H); 1.96 (d, J = 12,

CH₂Si, 1H); 2.05 (m, CHP, 1H); 4.87 (d, J = 5.60, Ph, 1H); 4.94 (t, J

= 3.60, Ph, 1H); 5.07 (t, J = 5.20, Ph, 1H); 6.15 (t, J = 5.60, Ph, 1H);

6.24 (t, J = 5.60, Ph, 1H). ¹³C{¹H} NMR (100.6 MHz): δ (ppm)

−0.62 (d, J = 23.14, CH₃Si); 0.14 (d, J = 4.03, CH₃Si); 6.03 (d, J =

12.73, CH₂P); 7.86 (d, J = 32.10, CH₂P); 18.24 (s, CH₂Ph); 26.12 (s,

Cy); 26.95 (d, J = 11, Cy); 27.07 (d, J = 12, Cy); 27.53 (s, Cy); 27.84

(d, J = 3, Cy); 39.25 (d, J = 33.1, CHP); 79.38 (s, CHPh); 81.98 (s,

CHPh); 83.01 (s, CHPh); 97.58 (s, CPh); 97.75 (d, J = 10.6, CHPh);

98.57 (d, J = 10.1, CHPh). ³¹P{¹H} NMR (101.2 MHz): δ (ppm)

30.21. FT-IR: ν (cm⁻¹) 647; 737; 782; 808; 837; 897; 1098; 1173;

1200; 1251; 1405; 1446; 1508; 2850; 2923; 3056.

number CTQ2010-15292/BQU CTQ2008-02064) and

BIO2007-6846-C02-01) for ﬁnancial support of this work.

Financial support from MEC (FPI 2008-002758) and the

Consiglio Nazionale delle Ricerche and Regione Autonoma

della Sardegna (Master and Back 2.2-139, PRR-MAB-A2011-

19282) are gratefully acknowledged by A.M. R.A. thanks the

DURSI of the Autonomous Government of Catalonia for the

award of a Ph.D. grant.

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dx.doi.org/10.1021/om3012294 | Organometallics XXXX, XXX, XXX−XXX

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[RuCl2(η6-p-cymene)(P*)] and [RuCl 2(κ-P-η6-arene)] complexes containing p -stereogenic phosphines. activity in transfer hydrogenation and interactions with DNA

DOI: 10.1021/om3012294

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