Arene-ruthenium( ii ) complexes with hydrophilic P-donor ligands:...

DaltonTransactions

PERSPECTIVE

Cite this: Dalton Trans., 2014, 43,12447

Received 21st May 2014,Accepted 24th June 2014

DOI: 10.1039/c4dt01494d

www.rsc.org/dalton

Arene-ruthenium(II) complexes with hydrophilicP-donor ligands: versatile catalysts inaqueous media

Pascale Crochet and Victorio Cadierno*

In the last few years there has been increasing interest in the use of water as a reaction medium for cataly-

sis, and therefore in designing water-soluble transition-metal catalysts. Half-sandwich (η6-arene)-ruthenium(II) complexes are a versatile and well-known family of ruthenium compounds that exhibit a rich

catalytic and coordination chemistry. This Perspective article focuses on the catalytic applications in

aqueous media of (η6-arene)-ruthenium(II) complexes containing water-soluble phosphines, and related

hydrophilic P-donor ligands.

Introduction

Research on homogeneous catalysis for fine chemicals syn-thesis, preparative chemistry and drug discovery is currentlymore active than ever before.1 Ruthenium holds a prominentposition between the most employed metals.2 The rich and

well-studied coordination and organometallic chemistries ofruthenium make available a wide variety of compounds, fea-turing several oxidation states (from −II up to +VIII), coordi-nation numbers and geometries, for potential use in catalysis.This fact together with its price, comparatively lower than thatof the other platinum-group metals (Pd, Pt, Rh and Ir), hasmade ruthenium compounds the preferred choice for manycatalytic processes directed to organic synthesis. Relevantexamples where ruthenium-based catalysts have shown an out-standing behaviour include, among others, olefin metathesisreactions,3 oxidation processes,4 C–H bond activations,5 hydro-genation and transfer hydrogenation reactions,6 as well asa plethora of alkyne activation processes.7 Another interesting

Pascale Crochet

Pascale Crochet studied chem-istry at the University of Rennes I(France) and obtained her PhDin 1996 under the supervision ofProf. P. H. Dixneuf andB. Demerseman. After a two-yearpost-doctoral stay in the researchgroup of Prof. M. A. Esteruelas(University of Zaragoza, Spain)and one year as assistant pro-fessor at the “National HighSchool of Physics and Chem-istry” of Bordeaux (France), shemoved in 1999 to the University

of Oviedo where she is currently associate professor of InorganicChemistry. Her research interests deal with the design and syn-thetic applications of organometallic complexes, with a particularfocus on hydrosoluble ruthenium catalysts.

Victorio Cadierno

Victorio Cadierno studied chem-istry at the University of Oviedoand obtained his PhD degree in1996 working under the supervi-sion of Prof. J. Gimeno. He thenjoined the group of Prof. J. P.Majoral at the LCC-CNRS (Tou-louse, France) for a two-yearpostdoctoral stay. Thereafter, hereturned to the University ofOviedo where he is currentlyassociate professor of InorganicChemistry. In 2002 he wasawarded with the Spanish Royal

Society of Chemistry (RSEQ) Young Investigator Award. Hisresearch interests include the chemistry of ruthenium complexesand their catalytic applications; he is a co-author of more than140 publications in the field of organometallic chemistry.

Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC),

Centro de Innovación en Química Avanzada (ORFEO-CINQA), Departamento de

Química Orgánica e Inorgánica, Instituto Universitario de Química Organometálica

“Enrique Moles”, Facultad de Química, Universidad de Oviedo, Julián Clavería 8,

33006 Oviedo, Spain. E-mail: [email protected]; Fax: +(34) 985103446;

Tel: +(34) 985103453

This journal is © The Royal Society of Chemistry 2014 Dalton Trans., 2014, 43, 12447–12462 | 12447

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aspect of ruthenium compounds is their relatively low toxicity,which makes them ideal for the catalytic synthesis of drugs.

On the other hand, the combination of metal-catalysts withthe use of water as the solvent has led in recent years to thedevelopment of a huge number of new and more sustainablesynthetic methodologies.8 Solvents account for 80–90% ofmass utilization in a chemical process and represent a largeproportion of the volatile organic compounds (VOCs) releasedinto the atmosphere.9 Replacement, wherever possible, of pet-roleum-based organic solvents by water can help to mitigatethis environmental problem since, among the various alterna-tives considered to date, water is the green solvent parexcellence.10

Another important incentive in developing aqueous-phasecatalysis is to facilitate catalyst/product separation. The highpolarity of water makes many organic compounds insoluble oronly slightly soluble in it. This allows an easy separation of thereaction products by simple phase separation or extraction.8

Obviously, the preferential solubility of the metal catalyst inwater is key to make this catalyst/product separation reallyeffective. Introduction of hydrophilic ligands, i.e. ligands con-taining ionic substituents or functional groups capable ofestablishing H-bonds with water, into the coordination sphereof a transition-metal enables the preparation of catalysts witha high solubility profile in aqueous media.8 In this context,hydrophilic phosphines have been at the forefront in thedevelopment of aqueous catalysis.8,11 In addition to catalyst/product separation issues, it should also be highlighted thatwater can have promoting effects on catalytic transformationsinvolving hydrophobic substrates, leading in some cases toremarkable rate accelerations and selectivity improvements.12

Since the pioneering work of Winkhaus and Singer in1967,13 the chemistry of half-sandwich ruthenium(II) com-plexes containing η6-coordinated arene rings has exponentiallyexpanded, representing nowadays one of the most versatileand widely studied families of organometallic ruthenium com-pounds.14 This can be explained by the ease of access to thedimeric precursors [{RuCl(μ-Cl)(η6-arene)}2] by dehydrogena-tion of the appropriate cyclohexa-1,3-diene or cyclohexa-1,4-diene with RuCl3·nH2O (Scheme 1). Starting from thesedimers, a wide variety of mononuclear arene-ruthenium(II)complexes can be generated by cleavage of the chloridebridges with two-electron donor ligands L, and further substi-tution of one or two chloride ligands in the resulting mono-nuclear complexes [RuCl2(η6-arene)(L)].14 The relatively easyexchange and functionalization of the coordinated arene

ligand are other aspects of interest in the chemistry of thesecompounds.14

The high structural diversity that can be achieved withinthis family of complexes makes them ideal candidates forapplications in various areas, including medicinal chemistryand homogeneous catalysis.14 As a matter of fact, a variety ofcatalytic applications in aqueous media has emerged in recentyears with the aid of water-soluble phosphines and relatedhydrophilic P-donor ligands, such as alkyl-phosphites or phos-phinous acids. The aim of the present Perspective article is toprovide a comprehensive overview of the developmentsachieved in this particular research area.15 The literaturepublished up to April 2014 is covered.

Arene-ruthenium(II) complexes with anionic hydrophilicP-donor ligands

Sulfonated monodentate ligands. Ligands containing sulfo-nated substituents are certainly the most widely used toinduce the solubility in water of organometallic complexes.8,11

The great success of this type of ligand is mainly based on (i)the easy access, for most of them, by simple sulfonation withfuming H2SO4, (ii) their ionic nature throughout a wide pHrange which ensures a high water-solubility under variousexperimental conditions, and (iii) the poor coordinating abilityof the sulfonate group which avoids any interference with themetal center. Among all the sulfonated ligands designed todate, the sodium salts of (3-sulfonatophenyl)diphenylphos-phine (TPPMS in Fig. 1)16 and tris(3-sulfonatophenyl)phos-phine (TPPTS in Fig. 1)16 are undoubtedly the most commonlyemployed for the preparation of water-soluble transition-metalcatalysts.8,11

In the last few decades, arene-ruthenium(II) complexes withone or two P-donor ligands have found widespread appli-cations in a huge number of catalytic processes.14 However,and quite surprisingly, the use of arene-ruthenium(II) com-pounds containing sulfonated phosphines for promoting reac-tions in aqueous media still remains very scarce.

Pioneering studies in this area were essentially focused onhydrogenation processes. Thus, Dyson and co-workersreported the hydrogenation of arenes using the TPPTS-deriva-tive [RuCl2(η6-p-cymene)(TPPTS)] (1) in water.17 Selective for-mation of the fully hydrogenated products, i.e. cyclohexanederivatives, was observed at 90 °C using a ruthenium loadingof 0.3–0.5 mol% and a hydrogen pressure of 60 atm(Scheme 2). Since the catalytic activity of [RuCl2(η6-p-cymene)-(TPPTS)] (1) dropped drastically in the presence of elementalmercury (TOF = 2–32 h−1 vs. 98–488 h−1), the authorssuggested that ruthenium nanoparticles might be the real

Scheme 1 General synthetic route to dimers [{RuCl(μ-Cl)(η6-arene)}2].Fig. 1 Structure of the sulfonated phosphine ligands TPPMS andTPPTS.

Perspective Dalton Transactions

12448 | Dalton Trans., 2014, 43, 12447–12462 This journal is © The Royal Society of Chemistry 2014

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active species in this hydrogenation process, with the trisulfo-nated ligand TPPTS most probably acting as a surfactant tostabilize the colloidal system. We must note, however, that theinhibition of the catalytic activity of [RuCl2(η6-p-cymene)-(TPPTS)] (1) in the presence of mercury not necessarily impliesthe formation of nanoparticles. As discussed by the authors ina subsequent article, it could alternatively arise from the de-activation of the homogeneous catalyst 1 by Hg.18 In this case,the sulfonate groups might be responsible since they areknown to absorb on mercury.19,20

The TPPTS ligand, associated with the ruthenium dimer[{RuCl(μ-Cl)(η6-C6H6)}2] (TPPTS/Ru ratio = 2), was also involvedin the hydrogenation of sodium bicarbonate to sodiumformate.21 Under the experimental conditions employed, i.e. inwater at 60 °C and under 100 atm of H2, the catalytically activehydride arene-ruthenium(II) species [RuH(η6-C6H6)(TPPTS)2]Clis generated. Although able to promote the hydrogenationprocess (TOF = 25 h−1), we must note that this compoundshowed to be less effective than its PTA-analogues [RuH(η6-arene)(PTA)2]Cl (arene = benzene, p-cymene; PTA = 7-phospha-1,3,5-triazaadamantane; TOF up 91 h−1; see below). Relatedhydride derivatives [RuH(η6-arene)(TPPTS)2]Cl (arene =toluene, p-xylene, ethylbenzene, cumene, tetraline, cinnamicalcohol, dihydrocinnamic alcohol) were synthesized by Kalckand co-workers, as potential hydrogenation catalysts, throughthe reaction of [{RuCl(μ-Cl)(TPPTS)2}2] with an excess of theappropriate arene under hydrogen pressure.22 Unfortunately,attempts to use these complexes to promote the catalytichydrogenation of α,β-unsaturated carbonyl compounds inaqueous media failed.23

In 1998, Wakatsuki and co-workers reported the first anti-Markovnikov hydration of terminal alkynes using arene-ruthe-nium(II) catalysts.24 In particular, they explored the catalytic be-havior of different complexes of the type [RuCl2(η6-C6H6)(PR3)]as well as that of different [RuCl2(η6-C6H6)(PR3)]/3PR3 and[{RuCl(μ-Cl)(η6-C6H6)}2]/8PR3 combinations. While the formerled to the conventional addition of water onto the more substi-tuted carbon of the CuC triple bond of the alkyne with for-mation of the corresponding ketones (Markovnikov hydration),the latter favored the hitherto unknown anti-Markovnikovprocess and generated predominantly aldehydes (Scheme 3).Among the 20 different phosphines screened in this trans-

formation, the trisulfonated ligand TPPTS, along withPPh2(C6F5), showed the best performance in terms of activityand selectivity (aldehyde selectivity up to 96%). Similar resultswere further observed in the reactions promoted by thederivative [RuCl(η6-C6H6)(TPPTS)2]Cl combined with a two-foldexcess of TPPTS.25 In all the cases, arene-free species of thetype [RuCl2(PR3)x] were proposed as the truly active catalysts.

Hydrations were performed, not only with alkynes, but alsowith nitriles in the presence of water-soluble arene-ruthenium(II)catalysts. In this context, the monosulfonated compounds[RuCl2(η6-arene)(TPPMS)] (arene = C6H6 (2a), p-cymene (2b),1,3,5-C6H3Me3 (2c), and C6Me6 (2d)) proved to be able toconvert selectively nitriles into primary amides in pure water,albeit with low activity (TOF < 1 h−1).26 Reaction rates could behowever considerably enhanced when the TPPMS ligand wasreplaced by nitrogen-containing hydrophilic P-donor ligands(see below).

On the other hand, the catalytic performances of complexes[RuCl2(η6-arene)(TPPMS)] (arene = C6H6 (2a), p-cymene (2b))and their bis-phosphine counterparts [RuCl(η6-arene)-(TPPMS)2]Cl (arene = C6H6 (3a), p-cymene (3b)) were exploredin the transfer hydrogenation of several aromatic and aliphaticketones, using 2-propanol as the solvent and the hydrogensource (Scheme 4).27 In all the cases, the resulting alcohol wasgenerated in good yield in the presence of KOH. Turnover fre-quencies of up to 2982 h−1 were achieved with the best cata-lysts, namely [RuCl2(η6-arene)(TPPMS)] (2a–b). Unfortunately,despite the high efficiency observed in 2-propanol, all attemptsto perform the catalytic process in aqueous media with thesecomplexes failed.

More satisfactory results were achieved with the complex[RuCl2(η6-C6H6)(TPPMS)] (2a) in the catalytic addition of car-boxylic acids to alkynols in water.28 Thus, the treatment of a1 : 1 molar mixture of a terminal propargylic alcohol and a car-boxylic acid at 100 °C in the presence of 2 mol% of 2a gave

Scheme 2 Hydrogenation of arenes in water promoted by complex 1.

Scheme 3 First catalytic hydration of terminal alkynes with anti-Markovnikov regioselectivity.

Scheme 4 Transfer hydrogenation of ketones catalyzed by arene-ruthenium(II)-TPPMS derivatives.

Dalton Transactions Perspective


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rise to the selective formation of the corresponding β-oxo ester4 (Scheme 5).

The process proceeds through the initial Markovnikovaddition of the carboxylate anion to the alkynol CuC triplebond, activated by coordination onto the ruthenium center(Scheme 6). Further intramolecular transesterification of theresulting enol ester intermediate, followed by protonolysis,delivers the β-oxo ester products in moderate to good yields.Prop-2-yn-1-ol (R1 = R2 = H) as well as a variety of secondarypropargylic alcohols (R1 = alkyl or aryl group; R2 = H) could beefficiently transformed. In contrast, tertiary propargylic alco-hols (R1 and R2 ≠ H) resulted to be more challenging sub-strates and only those with low sterically demandingsubstituents led to high conversions. On the other hand, thesynthetic methodology was operative with a large variety ofaromatic carboxylic acids, bearing functional groups such ashalides, alkoxy, ketones or sulfonamides. Heteroaromaticacids, with tetrahydrofuran, pyrrole, thiophene, indole or2-oxo-2H-chromene fragment, or aliphatic ones were also satis-factorily transformed into the corresponding β-oxo esters.

The related TPPMS derivatives [RuCl2(η6-arene)(TPPMS)](arene = p-cymene (2b), 1,3,5-C6H3Me3 (2c), C6Me6 (2d)) led tosimilar results, giving rise selectively to the adducts 4 albeitwith slightly lower yields. In contrast, the analogues [RuCl2-(η6-arene)(PTA)], [RuCl2(η6-arene)(PTA-Bn)] and [RuCl2(η6-arene)-(DAPTA)] (arene = C6H6, p-cymene, 1,3,5-C6H3Me3, C6Me6),

featuring a more electron rich ruthenium center, showed pooractivities and selectivities due to the competing generation ofalkene side products resulting from the CuC bond cleavage ofthe alkynol.28

Sulfonated and phosphonated bidentate ligands. Inaddition to the monodentate ligands TPPTS and TPPMS,different sulfonated diphosphines have been involved in thepreparation of arene-ruthenium(II) complexes for aqueous cata-lysis. In this context, Davis and co-workers synthesized thechiral ligand (R)-BINAP-4SO3Na (Scheme 7) by selective mono-sulfonation of the four phenyl rings of (R)-BINAP at the meta-position.29 Treatment of the benzene-ruthenium(II) dimer[{RuCl(μ-Cl)(η6-C6H6)}2] with two equivalents of (R)-BINAP-4-SO3Na in a benzene–methanol mixture led to the selective for-mation of the water-soluble compound [RuCl(η6-C6H6){(R)-BINAP-4SO3Na}]Cl (5).

30 This compound was used to promotethe asymmetric hydrogenation of 2-(6′-methoxy-2′-naphthyl)acrylic acid into naproxen, a high-value pharmaceuticalproduct. Full conversions and high enantiomeric excesses (upto 91.6% ee) were achieved under homogeneous conditionsusing methanol alone, or a mixture of methanol and water, asthe solvent. However, in general, higher activities and eevalues were observed in non-aqueous media. Interestingly,two-phase reactions were also developed employing water andethyl acetate. This protocol enabled the recycling of theaqueous phase containing the catalyst without any loss inenantioselectivity, but, unfortunately, these heterogeneousconditions led to a drastic decrease of the rates, the reactionsbeing at least 350 times slower than those in homogeneousmedia. The drop in activity was ascribed to the low water-solu-bility of the substrate, which enforces the reaction to takeplace only at the interface. This problem could be solved bysupporting [RuCl(η6-C6H6){(R)-BINAP-4SO3Na}]Cl (5) onto acontrolled pore glass (CPG-204) with high surface area. Theresulting heterogeneous system, recyclable over at least 7 runs,allowed the quantitative formation of the desired naproxen ina short time, although with slightly lower ee (up to 77%).

Another optically active sulfonated diphosphine ligand,namely BIFAPS (2,2′-bis(diphenylphosphino)-1,1′-bidibenzo-furanyl-8,8′-disulfonic acid di-potassium salt), was designed toserve as the chiral auxiliary in enantioselective hydrogenation

Scheme 5 Catalytic β-oxo ester formation by addition of carboxylicacids to terminal propargylic alcohols in water.

Scheme 6 Proposed mechanism for Ru-catalyzed β-oxo esterformation.

Scheme 7 Hydrogenation of 2-(6’-methoxy-2’-naphthyl)acrylic acidinto naproxen.



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reactions.31 In particular, the corresponding arene-ruthenium(II)compound [RuCl(η6-C6H6)(BIFAPS)]Cl (6) was employed forthe hydrogenation of the CvC bond of (Z)-acetamidocinnamicacid (Scheme 8). Once again, more satisfactory results wereachieved in an organic solvent (i.e. methanol) than in anaqueous biphasic medium (H2O–EtOAc). The extremely lowrate observed in the latter case (18% yield after 48 h) was againattributed to the poor mixing of the substrate, the catalyst andthe hydrogen gas. The complex 6 resulted to be more effectivein the reduction of CvO double bonds. Thus, methyl acetoace-tate was quantitatively hydrogenated, both in water and metha-nol, within only 2 hours using a ruthenium loading of 0.1 mol% (Scheme 8). Addition of a small amount of an acid, such asH2SO4, to the reaction mixture was in this case mandatory toreach high conversions and enantioselectivities.

The coordination of the achiral water-soluble diphosphineDPPBTS (1,2-bis(di-4-sulfonatophenylphosphino)benzene tetra-sodium salt) on arene-ruthenium(II) fragments has beendescribed, and the resulting complexes Na3[RuCl(η6-arene)-(DPPBTS)] (arene = C6H6 (7a), p-cymene (7b), [2.2]paracyclo-phane (7c)) were successfully employed to catalyze the selectivehydrogenation of styrene into ethylbenzene in water(Scheme 9).18 On the basis of high gas pressure NMR and elec-trospray ionization mass spectroscopy (ESI-MS) studies the η2-dihydrogen derivatives Na2[Ru(H2)(η6-arene)(DPPBTS)] wereproposed as active species for these reactions. In addition, thehydride compound Na3[RuH(η6-ethylbenzene)(DPPTS)] was

detected by ESI-MS in all the catalytic mixtures, pointing outthat arene ligand exchange takes place during the hydrogen-ation reactions.

Phosphonate substituents have also been used to preparehydrophilic phosphines;11 however, these ligands are muchless common than the sulfonated ones. In fact, as far as weknow, the only example of a phosphorylated phosphine com-bined with an arene-ruthenium(II) precursor was described byKöckritz et al. in 2001.32 They reported the activity of the cata-lytic system generated in situ from [{RuCl(μ-Cl)(η6-p-cymene)}2]and one equivalent of the diphosphine 8 (Fig. 2), i.e. thediphosphonated version of the well-known BINAP ligand, inthe asymmetric hydrogenation of dimethyl itaconate. Goodconversion (99.4%) and selectivity (79.4% ee) were achievedunder aqueous biphasic conditions (mixture of H2O–EtOH–

hexane, 0.3 mol% Ru, 60 °C, 20 atm, 2 h). Nevertheless, theenantiomeric excess remained significantly inferior to thatobserved with the non-functionalized BINAP ligand in organicmedia (up to 91.5% ee).32

Arene-ruthenium(II) complexes with cationic hydrophilicP-donor ligands

The introduction of a cationic substituent into the phosphinebackbone represents another strategy to prepare hydrophilicligands and induce water-solubility of the resulting com-plexes.11 In this context, ammonium groups, particularly thequaternary ones which maintain their ionic nature regardlessof the pH of the medium, are the most commonly used cat-ionic functions. Although the coordination of such ligands hasbeen studied with a large variety of transition metal frag-ments,11 the number of arene-ruthenium(II) derivativesremains extremely limited. The first report, in 2006, describedthe synthesis of the phosphinite, phosphonite and phosphitecomplexes [RuCl2(η6-p-cymene){Ph3−nP(OCH2CH2NMe3)n}]-[SbF6]n (n = 1 (9a), 2 (9b), 3 (9c)) through the reaction of [{RuCl-(μ-Cl)(η6-p-cymene)}2] with the neutral ligands Ph3−nP-(OCH2CH2NMe2)n, subsequent quaternization of the aminogroups by treatment with MeI, and a final counteranionexchange step (Scheme 10).33

The highly water-soluble compounds 9a–c proved to beactive in the redox isomerization of allylic alcohols intoketones in pure water (Scheme 11),33 showing performancescomparable to those of related arene-ruthenium(II)-basedsystems developed in organic media.34 Remarkably, while theuse of a base is usually required to achieve high activities inthis reaction,35 in the case of complexes 9a–c this requisite isnot mandatory. Another interesting aspect of 9a–c lies in their

Scheme 8 Asymmetric hydrogenation of (Z)-acetamidocinnamic acidand methyl acetoacetate.

Scheme 9 Catalytic hydrogenation of styrene promoted by complexes7a–c.

Fig. 2 Structure of the bi-phosphorylated BINAP ligand 8.



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high recyclability. As a representative example, the tri-ammonium derivative 9c could be reused over 10 runs in theisomerization of 1-octen-3-ol into octan-3-one (R = n-C5H11)without a significant loss in activity.

More recently, the coordination of highly hydrophilic thiazolyl-phosphine hydrochloride salts onto an arene-ruthenium(II)fragment has been performed, leading to the selective for-mation of compounds 10a–c (Scheme 12), which contain one,two and three cationic substituents, respectively.36 These com-plexes turned out to be excellent catalysts for the hydration ofnitriles into the corresponding primary amides in water. Adirect relationship between the number of thiazolium groupspresent in the ligand’s structure and the catalytic activity was

observed, the best performance being achieved with the tri-thiazolium species 10c. This behavior was ascribed to theincreasing number of heteroatoms in the catalyst, which favorsthe establishment of hydrogen bonds with water facilitating itsnucleophilic attack onto the metal-coordinated nitrile.37 Thecatalytic protocol developed with 10c was found to be appli-cable to a wide variety of functionalized benzonitriles, goodconversions being obtained using a ruthenium loading of3 mol% regardless of the substitution pattern and the elec-tronic nature of the aromatic ring of the substrate. Aliphatic orα,β-unsaturated nitriles were also satisfactorily hydrated. Highconversions in the desired amide were still observed at a lowruthenium loading (i.e. 0.01 mol% of Ru, TON = 9800) or at arelatively low temperature (i.e. at 40 °C instead of 100 °C),although longer reaction times were in these cases required(168 h and 48 h, respectively). Remarkably, the amide productscould be easily separated, as crystallized solids, by simplecooling of the reaction mixture at 0 °C, and the aqueous solu-tion containing the catalyst reused (up to 5 runs). The complex10c turned out to be also suitable for synthesizing primaryamides by catalytic rearrangement of aldoximes, as isolatedstarting materials or generated in situ from aldehydes,hydroxylammonium chloride and sodium bicarbonate(Scheme 12). Notably, the results achieved with 10c in thethree different amide-bond forming processes compare favor-ably with those reported previously with other ruthenium(II)-or ruthenium(IV)-based catalysts.37

In addition to the complexes described above, a series ofarene-ruthenium(II) derivatives with cationic N-alkylated PTAligands have been prepared and applied as catalysts inaqueous media. They will be presented in the followingsection.

Arene-ruthenium(II) complexes with neutral hydrophilicP-donor ligands

PTA, its derivatives, and related cage-like phosphines. Thecage-like phosphine 7-phospha-1,3,5-triazaadamantane (PTA)38

and its derivatives, such as DAPTA (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) or the N-alkylated salts PTA-R(Fig. 3), have received great attention in recent years for thepreparation of water-soluble metal complexes with appli-cations in diverse fields.39 In particular, arene-ruthenium(II)complexes containing PTA, known as RAPTA compounds, arebeing intensely studied in medicinal chemistry because they

Scheme 10 Synthesis of the ammonium-functionalized arene-ruthe-nium(II) complexes 9a–c.

Scheme 11 Redox isomerization of allylic alcohols into ketones pro-moted by catalysts 9a–c.

Scheme 12 Synthesis of primary amides from nitriles, aldoximes oraldehydes using complexes 10a–c as catalysts.

Fig. 3 Structure of PTA and related water-soluble phosphine ligands.



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exhibit promising antitumor properties, and represent idealtemplates for the design and development of tailored thera-peutic drugs.40 Transition-metal complexes containing thistype of ligand also present a rich and versatile behavior as cata-lysts in a variety of synthetic transformations in water.39 In thissection, the catalytic applications of arene-ruthenium(II) com-plexes with PTA, its derivatives, and related cage-like phos-phines (e.g. THPA and THDP in Fig. 3) are discussed.

RAPTA-type complexes have shown to be active catalysts indifferent hydrogenation processes. In this context, Dyson andco-workers demonstrated the utility of [RuCl2(η6-p-cymene)(PTA)] (11) and [RuCl(η6-p-cymene)(PTA)2][BF4] (12) to promotethe hydrogenation of arenes (benzene, toluene and ethyl-benzene) into the corresponding cyclohexanes, under aqueous–organic biphasic conditions.17 Turnover frequencies (TOF) of72–170 h−1 were achieved while performing the catalytic reac-tions at 90 °C under 60 atm of H2. These values are inferior tothose achieved with the sulfonated derivative [RuCl2(η6-p-cymene)(TPPTS)] (1) under identical experimental conditions(TOF up to 488 h−1; see Scheme 2 above).17 However, we mustnote that while 1 decomposes in the reaction medium to gene-rate metal nanoparticles which might be responsible for thecatalytic activity observed, complexes 11 and 12 act as homo-geneous catalysts and do not generate colloids. On the otherhand, we should also comment that the activity of [RuCl2(η6-p-cymene)(PTA)] (11) could be slightly improved employing theionic liquid [bmim][BF4] as the reaction medium (TOF =136–206 h−1).41

Kathó and co-workers studied the hydrogenation of sodiumbicarbonate into sodium formate in aqueous solution using amixture of the corresponding dimeric precursor [{RuCl(μ-Cl)-(η6-arene)}2] (arene = benzene, p-cymene) and the PTA ligand(0.2 mol% of Ru; PTA/Ru ratio = 2; T = 60 °C; p(H2) = 100atm).21 Under these conditions, quantitative conversions wereattained after 24 hours. The hydride bis-PTA derivatives [RuH-(η6-arene)(PTA)2]Cl (arene = benzene, p-cymene) were proposedby the authors as the catalytically active species, as they arereadily generated when dimers [{RuCl(μ-Cl)(η6-arene)}2] aretreated with PTA in water under hydrogen pressure (100 atm).

Csabai and Joó reported that the treatment of an aqueoussolution of the N-heterocyclic carbene complex [RuCl2(η6-p-cymene)(NHC)] (13) (NHC = 1-butyl-3-methylimidazol-2-ylidene) with a stoichiometric amount of PTA leads to amixture of the mono- and dicationic compounds [RuCl(η6-p-cymene)(NHC)(PTA)]Cl (14) and [Ru(η6-p-cymene)(NHC)(PTA)-(H2O)]Cl2 (15). This mixture, generated in situ, proved to beactive in the hydrogenation of the CvO bond of acetone,acetophenone and propanal (TOF up to 139 h−1) at pH 6.9 in aphosphate buffered aqueous solution (Scheme 13).42 Underthe same reaction conditions, cinnamaldehyde and benzylidene-acetone were preferentially hydrogenated at the CvC bond.Remarkably, hydrogenation of acetone and acetophenoneemploying the parent complex [RuCl2(η6-p-cymene)(NHC)] (13)was much less effective (TOF up to 47 h−1), and no reactionoccurred with [RuCl2(η6-p-cymene)(PTA)] (11), suggesting asynergistic effect of the NHC/PTA ligand combination.

Complexes 16–18, containing water-soluble PTA ligandsmodified at the C-6 position (Fig. 4), were also applied in thecatalytic hydrogenation of acetophenone.43 Disappointingly,although good results were obtained employing 2-propanol asthe solvent in the presence of a base, the experiments per-formed in water failed. A maximum of only 38% conversion ofacetophenone into 1-phenylethanol could be attained with thecomplex 17 in water (substrate/Ru/KOH ratio = 250 : 1 : 5; T =60 °C; p(H2) = 60 atm; time = 4 h).

On another vein, complexes of the type [RuCl2(η6-arene)-(PTA)], [RuCl2(η6-arene)(DAPTA)] and [RuCl2(η6-arene)(PTA-Bn)](arene = C6H6, p-cymene, 1,3,5-C6H3Me3, C6Me6) have shownto be active catalysts for the selective hydration of nitriles toamides.26 All of them were able to operate in pure water at100–150 °C (classical or MW heating), without the assistanceof any acidic or basic additive. In addition, they were compara-tively much more efficient than their sulfonated counterparts[RuCl2(η6-arene)(TPPMS)], due probably to the activating effectthat the nitrogen atoms of the PTA-derived ligands exert on thewater molecules by H-bonding. The best results in terms ofactivity (TOF and TON up to 127 h−1 and 100, respectively)were found with the hexamethylbenzene derivative [RuCl2(η6-C6Me6)(PTA-Bn)] (PTA-Bn = 1-benzyl-3,5-diaza-1-azonia-7-phos-

Scheme 13 Hydrogenation of carbonyl compounds with PTA/NHCcomplexes.

Fig. 4 Structure of the arene-ruthenium(II) complexes 16–18.



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phaadamantane chloride; 19 in Fig. 5). Almost quantitativeconversions of a wide variety of aromatic, heteroaromatic,α,β-unsaturated and aliphatic nitriles were achieved at 100 °Cemploying 5 mol% of 19 within 1–15 h, and the reactions tole-rated the most common functional groups. In addition, afterselective crystallization of the final amide, recycling of theaqueous phase containing 19 was possible.44 The relatedtoluene-ruthenium(II) complex 20, containing a β-aminophos-phine ligand derived from PTA (Fig. 5), featured also a goodcatalytic activity in the hydration of nitriles.45 Using 5 mol% ofthis complex, various aromatic and aliphatic nitriles could beselectively transformed into the corresponding amides inmoderate to good yields after 24 h of heating at 100 °C in purewater, and under aerobic conditions (TOF up to 3 h−1).However, we must note that attempts to hydrate α,β-unsatu-rated nitriles, such as acrylonitrile, failed. The lifetime andactivity of 20 was explored in detail for the hydration of benzo-nitrile to benzamide at various catalyst loadings (from 5 mol%to 0.001 mol%). Interestingly, the TOF increased significantlyas the catalyst loading was reduced. In particular, using only0.001 mol% of 20, TON and TOF values of 97 000 and 285 h−1

could be obtained after 14 days (97% conversion), pointing outthe remarkable longevity and activity of this catalyst.46

The catalytic hydration of nitriles has also been describedemploying a RAPTA-type complex supported on silica-coatedferrite nanoparticles (Scheme 14).47 The resulting magneticheterogeneous system 21 showed an excellent activity (TOF upto 126 h−1) and selectivity for a broad range of organonitriles,leading to the corresponding primary amides in high isolatedyields (65–94%) after 0.5–24 h of microwave irradiation at150 °C in pure water. As in the preceding cases, the use ofacidic or basic co-catalysts was not needed, several functionalgroups were tolerated, and no overhydrolysis of the amides tocarboxylic acids was observed. As shown in Scheme 14, theutility of 21 is not restricted to the catalytic hydration ofnitriles. This nanocatalyst was also able to promote the redoxisomerization of allylic alcohols under base-free conditions(TOF up to 253 h−1) and the heteroannulation of (Z)-enynolsinto furans (TOF up to 251 h−1).47 In all the processes, oncethe reactions were complete, the nanoparticles could be easilyseparated with the help of an external magnet and recycled upto 6 (nitrile hydrations), 5 (redox isomerizations) or 10 times(heteroannulations). It is also noteworthy that the use of therelated homogeneous system [RuCl2(η6-p-cymene)(PTA)] (11)under identical experimental conditions led to comparableresults in terms of activity, but its reuse, after extraction of the

reaction products from the aqueous phase with an organicsolvent, was less effective (up to 4 consecutive runs).47

In addition to the magnetic nanoferrites just discussed,RAPTA-type complexes have also been supported on thelaminar clay Montmorillonite K-10,48 as well as on the surfaceof phosphorus-based dendrimers (compounds 22-Gn inFig. 6),49 but only the latter were applied in aqueous catalysis.

Fig. 5 Structure of the nitrile hydration catalysts 19 and 20.

Scheme 14 Catalytic applications in water of the nano-RAPTAcomplex 21.

Fig. 6 Structure of complex 22 and the dendrimers 22-Gn.



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In particular, associated with Cs2CO3 (2 mol%), the water-soluble dendrimers 22-Gn (1 mol% of Ru) were able to catalyzethe redox isomerization of 1-octen-3-ol into 3-octanone in abiphasic water–n-heptane (1 : 1 v/v) mixture at 75 °C. Althoughthe turnover frequencies obtained with these systems wereonly modest (TOF up to 12 h−1), it should be stressed that aclear positive dendritic effect was observed, the conversionsgoing from 38% with the model complex 22, to 63% with 22-G1, 94% with 22-G2 and 98% with 22-G3 after 8 h. At the endof the reaction, phase separation allowed the recycling of thesedendritic catalysts (up to 4 runs with 22-G1), which alsoshowed to be active in the Markovnikov hydration of phenyl-acetylene into acetophenone in water–iPrOH mixtures at 90 °C(TOF up to 4 h−1 in combination with H2SO4).

49b

Structurally related to PTA is the trihydrazinophosphaada-mantane ligand THPA (see Fig. 3). Although the chemistry ofthis compound remains almost unexplored,50 Crochet,Zablocka, Majoral and co-workers demonstrated in 2006 itsutility for the design of new water-soluble catalysts.51 Amongthe different systems developed, the arene-ruthenium(II) com-plexes [RuCl2(η6-arene)(THPA)] (23a–d) and [RuCl2(η6-arene)(THPA-Me)][OTf] (24a–b) proved to be efficient and recyclablecatalysts (up to 5 cycles) for the base-free redox isomerizationof allylic alcohols in water (TOF up to 200 h−1). In addition,they were also able to promote the catalytic cycloisomerizationof (Z)-3-methylpent-2-en-4-yn-1-ol into 2,3-dimethylfuran(Scheme 15).51

Similar to THPA, little attention has also been paid to theclosely related cage-type ligand tris(1,2-dimethylhydrazino)-diphosphine (THDP in Fig. 3).52 In fact, its application in cata-lysis is limited to the atom-transfer radical addition of bromo-trichloromethane to olefins (Kharasch reaction) in aqueousmedia, employing a series of dinuclear complexes, including[{RuCl2(η6-p-cymene)}2(µ-THDP)] (25), as catalysts.53 As shownin Scheme 16, the diruthenium complex 25 was able topromote efficiently the addition of BrCCl3 to the aliphaticlinear olefins 1-octene and 1-dodecene, but resulted com-pletely inoperative with aromatic (e.g. styrene), cyclic (e.g.cyclooctene) or functionalized olefins (e.g. 4-penten-2-ol). Forthis type of substrates, only the use of complexes [{MCl-

(COD)}2(µ-THDP)] (M = Rh, Ir; COD = 1,5-cyclooctadiene) ledto positive results.

Other hydrophilic P-donor ligands

Phosphines containing hydroxyalkyl chains constitute animportant class of water-soluble ligands. As a matter of fact,commercially available tris(hydroxymethyl)phosphine (THP) isone of the first hydrophilic ligands applied in aqueous-phasecatalysis.54 Over the last decades, THP and related hydro-xyalkyl-phosphines have enabled the development of a widerange of transition metal complexes with applications, notonly in aqueous catalysis, but also in biomedicine.55 Concern-ing the arene-ruthenium(II) series, compounds [RuCl2(η6-arene){P(CH2OH)3}] (arene = C6H6 (26a), p-cymene (26b),C6Me6 (26c)) and [RuCl(η6-arene){P(CH2OH)3}2]Cl (arene =C6H6 (27a), p-cymene (27b), C6Me6 (27c)), in combination withCs2CO3, were found to be active catalysts in the redox isomeri-zation of 1-octen-3-ol into 3-octanone at 75 °C under water–n-heptane biphasic conditions.56 Although quantitative andselective transformations were in all cases observed, theneutral complexes 26a–c were much more active than their cat-ionic counterparts 27a–c (TOF = 29–67 h−1 vs. 4–6 h−1). Inaddition, the catalytic efficiency of these complexes was foundto be strongly dependent on the nature of the arene ligand.Thus, the rate order observed in both series, i.e. C6H6 > p-cymene > C6Me6, indicated that the less sterically demandingand electron-rich the arene, the higher performances arefound. Interestingly, the catalytically active ruthenium speciescould be in all cases recycled, leading to conversions ≥86% ina second run, but only the neutral derivative [RuCl2(η6-C6H6)-{P(CH2OH)3}] (26a) showed good performances in the thirdand fourth cycles. Other allylic alcohols, such as 1-hepten-3-ol,1-hexen-3-ol, 1-penten-3-ol, 3-buten-2-ol and 2-buten-1-ol, werealso efficiently isomerized into the corresponding carbonylcompounds using the most active complexes 26a–b as cata-lysts. Remarkable results in terms of both activity and catalystrecycling (up to 8 runs) were obtained when 3-buten-2-ol wasused as the substrate, leading to TOF values up to 600 h−1 andcumulative TON values up to 782. As shown in Scheme 17, theneutral complexes 26a–c were also able to promote thehydration of terminal alkynes in a water–iPrOH mixture at90 °C, generating the corresponding ketones (Markovnikovaddition) as the major or unique reaction products.56

Scheme 15 Catalytic cycloisomerization of (Z)-3-methylpent-2-en-4-yn-1-ol with THPA-based Ru(II) complexes.

Scheme 16 Kharasch addition of bromotrichloromethane to olefins inwater.



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On the other hand, phosphino-carboxamides have emergedin recent years as highly tunable ligands for numerous practi-cal applications.57 In particular, the introduction of appropri-ate substituents on the amide moiety has allowed their use asauxiliary ligands in aqueous catalysis. A representativeexample is the polyethylene glycol-bound arene-ruthenium(II)-BINAP complex 27 described by Chan and co-workers(Fig. 7).58 This water-soluble polymer-supported complex wassuccessfully employed as the catalyst for the asymmetric hydro-genation of α,β-unsaturated carboxylic acids in a ethyl acetate–water two-phase system (Scheme 18).58 Remarkably, the activityof 27 was ca. 30 times higher than that of the previously dis-cussed sulfonated compound [RuCl(η6-C6H6){(R)-BINAP-4-SO3Na}]Cl (5)30 in the hydrogenation of 2-(6′-methoxy-2′-naphthyl)-acrylic acid (54% conversion after 84 h, with 78.4%ee, under identical reaction conditions to those of Scheme 18).In addition, the activity and enantioselectivity of 27 underthese biphasic conditions were found to be higher than those

reached employing ethyl acetate or the homogeneous metha-nol–water solvent mixture.

More recently, a series of arene-ruthenium(II) complexescontaining glycine-derived phosphinoferrocene carboxamideligands have proven to be efficient catalysts for the oxidationof secondary alcohols with tert-butyl hydroperoxide in water.59

Using the most active complex 28, different 1-phenylethanolderivatives were transformed at room temperature into thecorresponding acetophenones in high yields, even at catalystto substrate ratios as low as 1 : 100 000 (Scheme 19). The reac-tion was also operative with other secondary alcohols such as1-indanol, 1-tetralol, diphenyl-methanol, 1-cyclohexylethanol,2-butanol or cyclohexanol. However, we must note that theconversions were significantly lower with the aliphatic sub-strates. Interestingly, replacement of water by organic solventsor biphasic aqueous mixtures slowed the reactions consider-ably, making water the best reaction medium for these oxi-dation processes.

The redox isomerization of allylic alcohols in water employ-ing the closely related complex 29, containing a phosphino-ferrocene carboxamide ligand bearing a polar hydroxyalkylsubstituent on the N-atom, has also been described(Scheme 20).60 However, except for 1,3-diphenyl-2-propen-1-ol,which could be quantitatively converted into 1,3-diphenyl-1-propanone employing 2 mol% of 29 in combination withKOtBu (5 mol%), very low yields (<30%) were in generalobserved after 20 h at 80 °C. Unlike the previous case, muchbetter results were obtained with this catalyst, and also with

Scheme 17 Hydration of terminal alkynes catalyzed by complexes26a–c.

Fig. 7 Structure of the water-soluble polymer-supported catalyst 27.

Scheme 18 Ru-catalyzed asymmetric hydrogenation of α,β-unsatu-rated carboxylic acids under biphasic conditions.

Scheme 20 Redox isomerization of 1,3-diphenyl-2-propen-1-ol inwater using the arene-ruthenium(II) complex 29 as the catalyst.

Scheme 19 Ru-catalyzed oxidation of secondary alcohols in water.



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related arene-ruthenium(II) complexes bearing other phosphino-ferrocene carboxamide ligands, employing 1,2-dichloroethaneas the solvent.

Phosphites are not recognized as hydrophilic ligands foraqueous catalysis. In fact, complexes containing such P-donorligands generally require the use of surfactants to solubilise inwater.61 However, some alkyl-phosphites, such as P(OMe)3,P(OEt)3 or P(OiPr)3, have proven useful in developing arene-ruthenium(II) complexes featuring a high solubility in water.An illustrative example is found in compounds [RuCl2(η6-C6H5OCH2CH2OH)(L)] (L = P(OMe)3 (30a), P(OEt)3 (30b),P(OiPr)3 (30c)) that, unlike [RuCl2(η6-C6H5OCH2CH2OH)(L)](L = P(OPh)3 (30d), PPh3 (30e)), dissolve very well in water (seeFig. 8).62 Although this property is obviously enhanced by thepresence of the hydrophilic arene 2-phenoxyethanol, we mustnote that even the p-cymene-Ru(II) derivative [RuCl2(η6-p-cymene){P(OMe)3}] is capable of dissolving in water (7.3 g L−1)without the help of surfactants.62

Complexes 30a–c proved to be active catalysts for the redoxisomerization of allylic alcohols in water, showing a remark-able effectiveness with challenging aromatic and disubstitutedsubstrates (i.e. allylic alcohols of the type CH2vCHCH(OH)Arand R1HCvCHCH(OH)R2).62 For example, using 1 mol% ofthe trimethylphosphite complex [RuCl2(η6-C6H5OCH2CH2OH){P(OMe)3}] (30a) in combination with KOtBu (5 mol%),3-penten-2-ol was quantitatively converted into pentan-2-onein a short time at 75 °C, giving rise to a TOF value of 200 h−1

(Scheme 21). This value is the highest reported to date for theisomerization of allylic alcohols containing disubstituted CvCbonds in aqueous medium.63

The phosphite complexes 30a–c were also able to promotethe CvC bond migration of allyl-benzenes in water, leading tothe corresponding 1-propenyl-benzenes mostly as the transisomers.64 As a representative example, the results obtained inthe isomerization of eugenol into isoeugenol are shown inScheme 22. Other allyl-benzenes of industrial interest in thefragrance field, such as estragole or safrole, were similarly iso-merized in short times, and with almost complete trans-selecti-vity, using these catalysts.

Complex [RuCl2(η6-C6H5OCH2CH2OH){P(OMe)3}] (30a) wasalso checked as a potential catalyst for the hydroformylation of1-octene in a water–toluene biphasic medium.65 Thus,although a 96% conversion was reached after 21 h performingthe reaction at 125 °C with 35 mol% of 30a and 50 atm of a1 : 1 CO–H2 mixture, only a moderate selectivity towards thedesired aldehydes was observed (47%) due to the competitivehydrogenation and isomerization of the substrate. However,we must note that this selectivity was largely superior to thatshown by the analogous PTA-containing complex [RuCl2(η6-C6H5OCH2CH2OH)(PTA)] (31) (83% conversion with 6% selecti-vity under identical reaction conditions). The major isomeriza-tion of 1-octene into isooctenes was in this case observed.Both 30a and 31 could be easily recovered, just by decantingthe organic layer containing the organic products, and reusedthree times without significant drop in 1-octene conversions.

On the other hand, a series of water-soluble (η6-p-cymene)-ruthenium(II) complexes 32–34 containing 3,5,6-bicyclophos-phite-α-D-glucofuranoside-derived ligands (Fig. 9) have beentested as catalysts for the selective hydration of chloroaceto-nitriles Cl3−nCHnCuN (n = 0, 1, 2) into the corresponding chloro-acetamides Cl3−nCHnC(vO)NH2 in water.66 All of them werefound to be active, leading, with metal loadings of 0.1–0.2 mol%,to conversions of up to 58% after 24 h of heating at 75 °C.

Related to phosphites are the phosphinous acids R2P(OH),compounds that have found many applications as auxiliaryligands for metal catalysis, in both organic and aqueousmedia, in the last few years.67 In this context, in a recentarticle, Tyler and co-workers have described the catalytichydration of nitriles in water employing the arene-ruthenium(II)

Fig. 9 Structure of complexes 32–34 containing carbohydrate-basedphosphite ligands.

Fig. 8 Solubility in water of complexes [RuCl2(η6-C6H5OCH2CH2OH)(L)](30a–e).

Scheme 21 Redox isomerization of 3-penten-2-ol in water using 30aas the catalyst.

Scheme 22 Isomerization of eugenol into isoeugenol in water usingcomplexes 30a–c as catalysts.



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complexes [RuCl2(η6-p-cymene){PMe2(OH)}] (35) and[RuCl2(η6-p-cymene){P(OEt)2(OH)}].68,69 Good results wereobtained with the former (TOF up to 32 h−1 at 100 °C) due tothe higher hydrogen bond accepting properties of the OHgroup of PMe2(OH) vs. that of P(OEt)2(OH). This point is a keyfactor in this catalytic transformation, since the nucleophilicaddition of water on the metal-coordinated nitrile is favouredwhen the water molecule is activated by H-bonding by theligands present in the catalyst (bifunctional catalysis).37

Remarkably, the complex [RuCl2(η6-p-cymene){PMe2(OH)}] (35)is active in the challenging hydration of cyanohydrins (α-hydro-xynitriles), substrates usually difficult to hydrate because theydegrade in solution to produce cyanide which poisons thecatalysts. As shown in Scheme 23, using 5 mol% of 35 and per-forming the catalytic reactions at room temperature, con-ditions where decomposition of the cyanohydrins into thecorresponding aldehydes and HCN is minimized, glyconitrile(R = H) and lactonitrile (R = Me) could be completely trans-formed into the corresponding α-hydroxyamides at the fastestrate ever described in the literature.68 However, we must notethat, despite this relevant result, the complex [RuCl2(η6-p-cymene){PMe2(OH)}] (35) is also susceptible to cyanide poison-ing since it failed in the hydration of acetone cyanohydrin, asubstrate particularly prone to decompose into acetone andhydrogen cyanide.

Compounds of the type [RuCl2(η6-arene){P(NMe2)3}] havealso shown to be active catalysts, although somewhat slower,for the hydration of glyconitrile and lactonitrile in water.70

Similar to [RuCl2(η6-p-cymene){PMe2(OH)}] (35), H-bondingbetween one of the NMe2 units of the tris(dimethylamino)phosphine ligand and the incoming water molecule in thecoordination sphere of the catalyst was evidenced by DFT cal-culations. The utility of complexes [RuCl2(η6-arene){P(NMe2)3}](arene = C6H6, C6H5Me, p-cymene, 1,3,5-C6H3Me3, C6Me6) topromote the hydration of CuN bonds in water was fullydemonstrated by Crochet, Cadierno and co-workers.71 In par-ticular, the hexamethylbenzene derivative [RuCl2(η6-C6Me6)-{P(NMe2)3}] (36) showed an outstanding activity, providing thedesired amides from a wide range of organonitriles in excel-lent yields and short times. TOF values up to 11 400 h−1, thehighest reported to date for this catalytic transformation inwater, were reached with complex 36 performing the catalyticreactions at 150 °C under MW irradiation. Notably, the highactivity of 36 was exploited to develop unprecedented syntheticroutes for the preparation of the non-steroidal anti-inflamma-tory drugs (NSAIDs) ibuprofenamide (37) and ketoprofenamide

(38) (see Fig. 10) by hydration of 2-(4-isobutylphenyl)propio-nitrile and 2(3-benzoylphenyl)propionitrile, respectively.71

Complex [RuCl2(η6-C6Me6){P(NMe2)3}] (36) proved alsoeffective for the conversion of δ-ketonitriles to ene-lactams (arepresentative example is given in Scheme 24).71 The processinvolves a tandem hydration/cyclocondensation sequence andhas no precedent in water.72

The utility of 36 for the synthesis of amides is not restrictedto the hydration reaction of nitriles since, using 5 mol% ofthis complex, the catalytic rearrangement of a wide range ofaromatic, heteroaromatic, aliphatic and α,β-unsaturated aldo-ximes could be successfully performed in water at 100 °C.73

Representative examples of the synthetic utility of this processare the high yield preparation of the optically active amides(S)-(−)-citronellamide, (S)-(−)-perillamide and (1R)-(−)-myrte-namide, compounds of interest in the fragrance field(Scheme 25).

Complex 36 also showed a remarkable activity, scope andfunctional group tolerance in the one-pot synthesis of primaryamides from aldehydes in water, via rearrangement of in situformed aldoximes.74 Both commercially available aqueoushydroxylamine solution and the NH2OH·HCl–NaHCO3 combi-nation were employed to generate the aldoxime intermediate,with the former improving notably the green character of theprocess since it avoids the formation of salts as reaction by-products. Notably, this methodology could be successfullyapplied to the synthesis of ferrocenecarboxamide, a valuable

Fig. 10 Structure of the NSAIDs ibuprofenamide (37) and ketoprofena-mide (38).

Scheme 24 Ene-lactam formation from a δ-ketonitrile.

Scheme 23 Cyanohydrin hydration using [RuCl2(η6-p-cymene){PMe2(OH)}] (35) as the catalyst.



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starting material in the chemistry of ferrocene, starting fromferrocenecarboxaldehyde (Scheme 26). Unlike other aldehydes,addition of a small amount of methanol was in this caseneeded to ensure the total solubilisation of the startingmaterial during the process.

Conclusions

Extraordinary attention is currently devoted to syntheticorganic chemistry in water and research, particularly in thefield of aqueous catalysis, is increasing exponentially.Throughout this Perspective article we have tried to highlightthe enormous potential and versatility of arene-ruthenium(II)complexes containing hydrophilic P-donor ligands for thedevelopment of catalytic transformations in aqueous media.Among others, a variety of hydrogenation, oxidation, isomeri-zation and hydration reactions have been successfully develo-ped employing these readily accessible and robust catalysts.Although there is already a body of work in the area, it is clearthat further advances can be expected in the near future asnew water-soluble phosphines are designed and different cata-lytic reactions explored. We hope that the reading of thisarticle serves as a catalyst to advance this promising researchfield.

Acknowledgements

Financial support by the Spanish MINECO (project CTQ2010-14796/BQU) is gratefully acknowledged.

Notes and references

1 See, for example: (a) Green Chemistry and Catalysis, ed.R. A. Sheldon, I. Arends and U. Hanefeld, Wiley-VCH,Weinheim, 2007; (b) Applications of Transition Metal Cataly-sis in Drug Discovery and Development, ed. M. L. Crawley andB. M. Trost, John Wiley & Sons, Hoboken, 2012;(c) Sustainable Catalysis: Challenges and Practices for thePharmaceutical and Fine Chemical Industries, ed. P. J. Dunn,K. K. Hii, M. J. Krische and M. T. Williams, John Wiley &Sons, Hoboken, 2013.

2 (a) Ruthenium Catalysts and Fine Chemistry, ed. C. Bruneauand P. H. Dixneuf, Springer-Verlag, Berlin, 2004;(b) Ruthenium in Organic Synthesis, ed. S.-I. Murahashi,Wiley-VCH, Weinheim, 2004.

3 See, for example: Handbook of Metathesis, ed. R. H. Grubbs,Wiley-VCH, Weinheim, 2003.

4 See, for example: W. P. Griffith, in Ruthenium OxidationComplexes: Their Uses as Homogeneous Organic Catalysts,Springer, Dordrecht, 2011.

5 See, for example: (a) F. Kakiuchi and S. Murai, Acc. Chem.Res., 2002, 35, 826; (b) F. Kakiuchi and T. Kochi, Synthesis,2008, 3013; (c) L. Ackermann, Chem. Commun., 2010, 46,4866; (d) L. Ackermann and R. Vicente, Top. Curr. Chem.,2010, 292, 211; (e) B. Li and P. H. Dixneuf, Chem. Soc. Rev.,2013, 42, 5744; (f ) P. B. Arockiam, C. Bruneau andP. H. Dixneuf, Chem. Rev., 2012, 112, 5879;(g) L. Ackermann, Acc. Chem. Res., 2014, 47, 281.

6 See, for example: (a) Handbook of Homogeneous Hydrogen-ation, ed. J. G. de Vries and C. J. Elsevier, Wiley-VCH, Wein-heim, 2007; (b) Modern Reduction Methods, ed.P. G. Andersson and I. J. Munslow, Wiley-VCH, Weinheim,2008; (c) Hydrogenation, ed. Y. Karame, InTech, Rejika,2012.

7 See, for example: (a) C. Bruneau and P. H. Dixneuf, Chem.Commun., 1997, 507; (b) B. M. Trost, F. D. Toste andA. B. Pinkerton, Chem. Rev., 2001, 101, 2067; (c) B. M. Trost,M. U. Frederiksen and M. T. Rudd, Angew. Chem., Int. Ed.,2005, 44, 6630; (d) C. Bruneau and P. H. Dixneuf, Angew.Chem., Int. Ed., 2006, 45, 2176; (e) R.-S. Liu, Synlett, 2008,801; (f ) B. M. Trost and A. McClory, Chem. – Asian J., 2008,3, 164; (g) L. Hintermann, Top. Organomet. Chem., 2010, 31,123.

8 (a) Aqueous-Phase Organometallic Catalysis: Concepts andApplications, ed. B. Cornils and W. A. Herrmann, Wiley-VCH, Weinheim, 1998; (b) Aqueous Organometallic Catalysis,ed. I. T. Horváth and F. Joó, Kluwer, Dordrecht, 2001;(c) Recoverable and Recyclable Catalysts, ed. M. Benaglia,John Wiley & Sons, Chichester, 2009; (d) Metal-CatalyzedReactions in Water, ed. P. H. Dixneuf and V. Cadierno,Wiley-VCH, Weinheim, 2013.

9 D. J. C. Constable, C. Jimenez-Gonzalez andR. K. Henderson, Org. Process Res. Dev., 2007, 11, 133.

10 See, for example: (a) W. M. Nelson, in Green Solvents forChemistry: Perspectives and Practice, Oxford UniversityPress, New York, 2003; (b) J. H. Clark and S. J. Taverner,

Scheme 25 Catalytic synthesis of some chiral amides in water throughrearrangement processes.

Scheme 26 Ruthenium-catalyzed synthesis of ferrocenecarboxamidefrom ferrocenecarboxaldehyde in water.



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Org. Process Res. Dev., 2007, 11, 149; (c) F. M. Kerton, inAlternative Solvents for Green Chemistry, RSC Publishing,Cambridge, 2009; (d) R. K. Henderson, C. Jiménez-Gonzá-lez, D. J. C. Constable, S. R. Alston, G. G. A. Inglis,G. Fisher, J. Sherwood, S. P. Binks and A. D. Curzons, GreenChem., 2011, 13, 854; (e) D. Prat, O. Pardigon,H.-W. Flemming, S. Letestu, V. Ducandas, P. Isnard,E. Guntrum, T. Senac, S. Ruisseau, P. Cruciani andP. Hosek, Org. Process Res. Dev., 2013, 17, 1517.

11 For specific reviews on water-soluble ligands, see:(a) W. A. Herrmann and C. W. Kohlpaintner, Angew. Chem.,Int. Ed., 1993, 32, 1524; (b) N. Pinault and D. W. Bruce,Coord. Chem. Rev., 2003, 241, 1; (c) K. H. Shaughnessy,Chem. Rev., 2009, 109, 643.

12 Examples can be found in the following review articles:(a) A. Chandra and V. V. Fokin, Chem. Rev., 2009, 109, 725;(b) R. N. Butler and A. G. Coyne, Chem. Rev., 2010, 110,6302.

13 G. Winkhaus and H. Singer, J. Organomet. Chem., 1967, 7,487.

14 (a) H. Le Bozec, D. Touchard and P. H. Dixneuf, Adv. Organo-met. Chem., 1989, 29, 163; (b) M. A. Bennett, in Compre-hensive Organometallic Chemistry II, ed. E. W. Abel, F. G. A.Stone and G. Wilkinson, Pergamon Press, Oxford, 1995,vol. 7, pp. 549–602; (c) M. A. Bennett, Coord. Chem. Rev.,1997, 166, 225; (d) F. C. Pigge and J. J. Coniglio, Curr. Org.Chem., 2001, 5, 757; (e) J. H. Rigby and M. A. Kondratenko,Top. Organomet. Chem., 2004, 7, 181; (f ) J. Gimeno,V. Cadierno and P. Crochet, in Comprehensive Organometal-lic Chemistry III, ed. R. H. Crabtree and D. M. P. Mingos,Elsevier, Oxford, 2007, vol. 6, pp. 465–550; (g) J. Gimenoand V. Cadierno, in Comprehensive Organometallic Chem-istry III, ed. R. H. Crabtree and D. M. P. Mingos, Elsevier,Oxford, 2007, vol. 6, pp. 551–628; (h) V. Cadierno andP. Crochet, in Advances in Organometallic ChemistryResearch, ed. K. Yamamoto, Nova Science Publishers,New York, 2007, pp. 37–65; (i) L. Delaude andA. Demonceau, Dalton Trans., 2012, 41, 9257; ( j) P. Kumar,R. K. Gupta and D. S. Pandey, Chem. Soc. Rev., 2014, 43,707.

15 Some aspects of the aqueous chemistry of arene-rutheniumcomplexes have been recently reviewed: G. Süss-Fink,J. Organomet. Chem., 2014, 751, 2.

16 In this manuscript, the abbreviations TPPTS and TPPMSrefer to the sodium salts, unless otherwise indicated.

17 P. J. Dyson, D. J. Ellis and G. Laurenczy, Adv. Synth. Catal.,2003, 345, 211.

18 C. Daguenet, R. Scopelliti and P. J. Dyson, Organometallics,2004, 23, 4849.

19 H. M. Hubbard and C. A. Reynolds, J. Am. Chem. Soc., 1954,76, 4300.

20 Despite this, we must say that ruthenium nanoparticleshave been systematically proposed as the real active speciesin the hydrogenation reactions of arenes promoted byother water-soluble arene-ruthenium(II) complexes. See, forexample: (a) C. M. Hagen, L. Vieille-Petit, G. Laurenczy,

G. Süss-Fink and R. G. Finke, Organometallics, 2005, 24,1819; (b) L. Vieille-Petit, G. Süss-Fink, B. Therrien,T. R. Ward, H. Stoeckli-Evans, G. Labat, L. Karmazin-Brelot,A. Neels, T. Bürgi, R. G. Finke and C. M. Hagen, Organo-metallics, 2005, 24, 6104.

21 H. Horváth, G. Laurenczy and A. Kathó, J. Organomet.Chem., 2004, 689, 1036.

22 M. Hernandez and P. Kalck, J. Mol. Catal. A: Chem., 1997,116, 117.

23 M. Hernandez and P. Kalck, J. Mol. Catal. A: Chem., 1997,116, 131.

24 M. Tokunaga and Y. Wakatsuki, Angew. Chem., Int. Ed.,1998, 37, 2867.

25 M. Tokunaga, T. Suzuki, N. Koga, T. Fukushima,A. Horiuchi and Y. Wakatsuki, J. Am. Chem. Soc., 2001, 123,11917.

26 V. Cadierno, J. Francos and J. Gimeno, Chem. – Eur. J.,2008, 14, 6601.

27 J. Díez, M. P. Gamasa, E. Lastra, A. García-Fernández andM. P. Tarazona, Eur. J. Inorg. Chem., 2006, 2855.

28 V. Cadierno, J. Francos and J. Gimeno, Green Chem., 2010,12, 135.

29 K.-T. Wan and M. E. Davis, J. Chem. Soc., Chem. Commun.,1993, 1262.

30 K. T. Wan and M. E. Davis, J. Catal., 1994, 148, 1.31 A. E. S. Gelpke, H. Kooijman, A. L. Spek and H. Hiemstra,

Chem. – Eur. J., 1999, 5, 2472.32 A. Köckritz, S. Bischoff, M. Kant and R. Siefken, J. Mol.

Catal. A: Chem., 2001, 174, 119.33 P. Crochet, J. Díez, M. A. Fernández-Zúmel and J. Gimeno,

Adv. Synth. Catal., 2006, 348, 93.34 See, for example: (a) P. Crochet, M. A. Fernández-Zúmel,

J. Gimeno and M. Scheele, Organometallics, 2006, 25, 4846;(b) R. García-Álvarez, F. J. Suárez, J. Díez, P. Crochet,V. Cadierno, A. Antiñolo, R. Fernández-Galán andF. Carrillo-Hermosilla, Organometallics, 2012, 31, 8301.

35 For selected reviews on the redox isomerization of allylicalcohols, see: (a) R. Uma, C. Crévisy and R. Grée, Chem.Rev., 2003, 103, 27; (b) R. C. van der Drift, E. Bouwman andE. Drent, J. Organomet. Chem., 2002, 650, 1; (c) V. Cadierno,P. Crochet and J. Gimeno, Synlett, 2008, 1105;(d) P. Lorenzo-Luis, A. Romerosa and M. Serrano-Ruiz, ACSCatal., 2012, 2, 1079; (e) J. García-Álvarez, S. E. García-Garrido, P. Crochet and V. Cadierno, Curr. Top. Catal.,2012, 10, 35.

36 R. García-Álvarez, M. Zablocka, P. Crochet, C. Duhayon,J.-P. Majoral and V. Cadierno, Green Chem., 2013, 15, 2447.

37 For recent reviews on the catalytic hydration of nitrilescovering mechanistic aspects, see: (a) V. Y. Kukushkin andA. J. L. Pombeiro, Chem. Rev., 2002, 102, 1771;(b) V. Y. Kukushkin and A. J. L. Pombeiro, Inorg. Chim.Acta, 2005, 358, 1; (c) T. J. Ahmed, S. M. M. Knapp andD. R. Tyler, Coord. Chem. Rev., 2011, 255, 949; (d) R. García-Álvarez, P. Crochet and V. Cadierno, Green Chem., 2013, 15,46; (e) R. García-Álvarez, J. Francos, E. Tomás-Mendivil,P. Crochet and V. Cadierno, J. Organomet. Chem., 2014,



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DOI: 10.1016/j.jorganchem.2013.11.042; (f ) P. Crochet andV. Cadierno, Top. Organomet. Chem., 2014, DOI: 10.1007/3418_2014_78.

38 D. J. Daigle, A. B. Pepperman Jr. and S. L. Vail, J. Heterocycl.Chem., 1974, 11, 407.

39 For reviews covering the chemistry of PTA and its deriva-tives, see: (a) A. D. Phillips, L. Gonsalvi, A. Romerosa,F. Vizza and M. Peruzzini, Coord. Chem. Rev., 2004, 248,955; (b) J. Bravo, S. Bolaño, L. Gonsalvi and M. Peruzzini,Coord. Chem. Rev., 2010, 254, 555; (c) M. Zablocka,A. Hameau, A.-M. Caminade and J.-P. Majoral, Adv. Synth.Catal., 2010, 352, 2341; (d) L. Gonsalvi and M. Peruzzini,Catalysis by Metal Complexes, 2011, vol. 37, pp. 183;(e) L. Gonsalvi, A. Guerriero, F. Hapiot, D. A. Krogstad,E. Monflier, G. Reginato and M. Peruzzini, Pure Appl.Chem., 2013, 85, 385.

40 For selected reviews covering this topic, see:(a) C. G. Hartinger and P. J. Dyson, Chem. Soc. Rev., 2009,38, 391; (b) A. Casini, C. G. Hartinger, A. A. Nazarov andP. J. Dyson, Top. Organomet. Chem., 2010, 32, 57;(c) G. Süss-Fink, Dalton Trans., 2010, 39, 1673;(d) W. H. Ang, A. Casini, G. Sava and P. J. Dyson, J. Organo-met. Chem., 2011, 696, 989; (e) A. L. Noffke,A. Habtemariam, A. M. Pizarro and P. J. Sadler, Chem.Commun., 2012, 48, 5219; (f ) C. G. Hartinger, N. Metzler-Nolte and P. J. Dyson, Organometallics, 2012, 31, 5677;(g) N. P. E. Barry and P. J. Sadler, Chem. Commun., 2013, 49,5106; (h) S. K. Singh and D. S. Pandey, RSC Adv., 2014, 4,1819.

41 P. J. Dyson, D. J. Ellis, W. Henderson and G. Laurenczy,Adv. Synth. Catal., 2003, 345, 216.

42 P. Csabai and F. Joó, Organometallics, 2004, 23, 5640.43 D. A. Krogstad, A. Guerriero, A. Ienco, G. Manca,

M. Peruzzini, G. Reginato and L. Gonsalvi, Organometallics,2011, 30, 6292.

44 Recycling of complex 19 by selective extraction of theamide product with ethyl acetate could also be achievedemploying a glycerol–water (1 : 1 v/v) mixture as the reac-tion medium. However, longer reaction times and a highertemperature (160 °C) were in this case needed to attaingood conversions. See: A. E. Díaz-Álvarez, R. García-Álvarez,P. Crochet and V. Cadierno, in Glycerol: Production,Structure and Applications, ed. M. D. S. Silva andP. C. Ferreira, Nova Science Publishers, New York, 2012,pp. 249–261.

45 (a) W.-C. Lee, J. M. Sears, R. A. Enow, K. Eads,D. A. Krogstad and B. J. Frost, Inorg. Chem., 2013, 52, 1737;(b) B. J. Frost and W.-C. Lee, US Pat. Appl., US 2013/0096344, 2013.

46 The utility of PTA-type ligands for ruthenium-catalyzednitrile hydration reactions in water is not restricted to thearene-ruthenium(II) series just discussed, since octahedralcomplexes have also shown a remarkable activity. See, forexample: (a) W.-C. Lee and B. J. Frost, Green Chem., 2012,14, 62; (b) E. Bolyog-Nagy, A. Udvardy, F. Joó and A. Kathó,Tetrahedron Lett., 2014, 55, 3615.

47 S. E. García-Garrido, J. Francos, V. Cadierno, J.-M. Bassetand V. Polshettiwar, ChemSusChem, 2011, 4, 104.

48 L. Menéndez-Rodríguez, P. Crochet and V. Cadierno, J. Mol.Catal. A: Chem., 2013, 366, 390.

49 (a) P. Servin, R. Laurent, L. Gonsalvi, M. Tristany,M. Peruzzini, J.-P. Majoral and A.-M. Caminade, DaltonTrans., 2009, 4432; (b) P. Servin, R. Laurent, H. Dib,L. Gonsalvi, M. Peruzzini, J.-P. Majoral andA.-M. Caminade, Tetrahedron Lett., 2012, 53, 3876.

50 (a) J. P. Majoral, R. Kraemer, J. Navech and F. Mathis, Tetra-hedron, 1975, 16, 1484; (b) J. Jaud, M. Benhammou,J. P. Majoral and J. Navech, Z. Kristallogr., 1982, 160, 69;(c) M. Benhammou, R. Kraemer, H. Germa, J. P. Majoraland J. Navech, Phosphorus, Sulfur Relat. Elem., 1982, 14,105; (d) M. Zablocka and C. Duhayon, Tetrahedron Lett.,2006, 47, 2687; (e) M. A. Lacour, M. Zablocka, C. Duhayon,J. P. Majoral and M. Taillefer, Adv. Synth. Catal., 2008, 350,2677; (f ) V. Cadierno, J. Díez, J. Francos and J. Gimeno,Chem. – Eur. J., 2010, 16, 9808.

51 A. E. Díaz-Álvarez, P. Crochet, M. Zablocka, C. Duhayon,V. Cadierno, J. Gimeno and J. P. Majoral, Adv. Synth. Catal.,2006, 348, 1671.

52 (a) D. S. Payne, H. Nöth and G. Henniger, Chem. Commun.,1965, 327; (b) S. F. Spangenberg and H. H. Sisler, Inorg.Chem., 1969, 8, 1004; (c) R. Goetze, H. Nöth andD. S. Payne, Chem. Ber., 1972, 105, 2637; (d) H. Noth andR. Ullmann, Chem. Ber., 1974, 107, 1019;(e) R. D. Kroshefsky, J. G. Verkade and J. R. Pipal, Phos-phorus, Sulfur Relat. Elem., 1979, 6, 377;(f ) R. D. Kroshefsky and J. G. Verkade, Phosphorus, SulfurRelat. Elem., 1979, 6, 397; (g) R. M. Matos andJ. G. Verkade, J. Braz. Chem. Soc., 2003, 14, 71;(h) L. I. Rodríguez, M. Zablocka, A. M. Caminade, M. Seco,O. Rosell and J. P. Majoral, Heteroatom. Chem., 2010, 21,290.

53 A. E. Díaz-Álvarez, P. Crochet, M. Zablocka, C. Duhayon,V. Cadierno and J. P. Majoral, Eur. J. Inorg. Chem., 2008,786.

54 J. Chatt, G. J. Leigh and R. M. Slade, J. Chem. Soc., DaltonTrans., 1973, 2021.

55 See, for example: (a) P. G. Pringle and M. B. Smith, Plati-num Metals Rev., 1990, 34, 74; (b) K. V. Katti, H. Gali,C. J. Smith and D. E. Berning, Acc. Chem. Res., 1999, 32, 9;(c) B. R. James and F. Lorenzini, Coord. Chem. Rev., 2010,254, 420.

56 V. Cadierno, P. Crochet, S. E. García-Garrido andJ. Gimeno, Dalton Trans., 2004, 3635.

57 For a recent review, see: P. Štěpnička, Chem. Soc. Rev., 2012,41, 4273.

58 Q.-H. Fan, C.-J. Deng, X.-M. Chen, W.-C. Xie, D.-Z. Jiang,D.-S. Liu and A. S. C. Chan, J. Mol. Catal. A: Chem., 2000,159, 37.

59 J. Tauchman, B. Therrien, G. Süss-Fink and P. Štěpnička,Organometallics, 2012, 31, 3985.

60 J. Schulz, I. Císařová and P. Štěpnička, Eur. J. Inorg. Chem.,2012, 5000.



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61 See, for example: A. Cavarzan, A. Scarso and G. Strukul,Green Chem., 2010, 12, 790.

62 B. Lastra-Barreira, J. Díez and P. Crochet, Green Chem.,2009, 11, 1681.

63 The isomerization of the model substrate 1-octen-3-ol bymeans of [RuCl2(η6-p-cymene){P(OMe)3}]/KO

tBu in waterhas also been reported. Although it was active (TOF =46 h−1), much better results were obtained using anorganic solvent (THF) as the reaction medium (TOF =588 h−1): see ref. 34a.

64 (a) B. Lastra-Barreira and P. Crochet, Green Chem., 2010, 12,1311; (b) B. Lastra-Barreira, A. E. Díaz-Álvarez,L. Menéndez-Rodríguez and P. Crochet, RSC Adv., 2013, 3,19985.

65 L. C. Matsinha, P. Malatji, A. T. Hutton, G. A. Venter,S. F. Mapolie and G. S. Smith, Eur. J. Inorg. Chem., 2013,4318.

66 S. M. Ashraf, I. Berger, A. A. Nazarov, C. G. Hartinger,M. P. Koroteev, E. E. Nifantév and B. K. Keppler, Chem. Bio-divers., 2008, 5, 1640.

67 For reviews, see: (a) L. Ackermann, Synthesis, 2006, 1557;(b) T. M. Shaikh, C.-M. Weng and F.-E. Hong, Coord. Chem.Rev., 2012, 256, 771.

68 S. M. M. Knapp, T. J. Sherbow, R. B. Yelle, J. J. Juliette andD. R. Tyler, Organometallics, 2013, 32, 3744.

69 The application of related [RuX2(η6-arene){PR2(OH)}] (X =Cl, Br, I; arene = C6H6, p-cymene, C6Me6; R = Ph, nBu, OEt,OPh, OnBu, OtBu; not all combinations) complexes as cata-lysts for nitrile hydration in aqueous media has also beenpatented: T. Oshiki and M. Muranaka, PCT Int. Appl., WO2012/017966, 2012.

70 (a) S. M. M. Knapp, T. J. Sherbow, J. J. Juliette andD. R. Tyler, Organometallics, 2012, 31, 2941; (b) S. M. M.Knapp, T. J. Sherbow, R. B. Yelle, L. N. Zakharov,J. J. Juliette and D. R. Tyler, Organometallics, 2013, 32, 824.

71 (a) R. García-Álvarez, J. Francos, P. Crochet andV. Cadierno, Tetrahedron Lett., 2011, 52, 4218; (b) R. García-Álvarez, J. Díez, P. Crochet and V. Cadierno, Organometal-lics, 2011, 30, 5442.

72 For a previous example in organic medium, see:S.-I. Murahashi, S. Sasao, E. Saito and T. Naota, Tetra-hedron, 1993, 49, 8805.

73 R. García-Álvarez, A. E. Díaz-Álvarez, J. Borge, P. Crochetand V. Cadierno, Organometallics, 2012, 31, 6482.

74 R. García-Álvarez, A. E. Díaz-Álvarez, P. Crochet andV. Cadierno, RSC Adv., 2013, 3, 5889.



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