Metal-Catalyzed Reactions in Water (Dixneuf/Metal-Catalyzed Reactions in Water) || Hydrogenation and...

173

6Hydrogenation and Transfer Hydrogenation in WaterXiaofeng Wu and Jianliang Xiao

6.1Introduction

Reduction reactions are one of the most frequently encountered transformationsin chemical synthesis. They can be effected with metals, hydrides, enzymes,and catalytic hydrogenation and transfer hydrogenation. However, it is the lastcategory of reduction that has gained far more prominence in various areasof synthetic chemistry over the past few decades. Hydrogenation and transferhydrogenation are catalyzed by both homogeneous and heterogeneous catalysts[1]. While the latter catalysts are easy to use, recyclable, and durable, the formeroffer excellent activity and selectivity under mild conditions. In this context, itis not surprising that heterogeneous hydrogenation has been widely used in theproduction of commodity chemicals such as ammonia, methanol, cyclohexane, andfatty acids, while homogeneous hydrogenation has found dominant applicationsin the synthesis of functionalized compounds [1]. It is this latter area that formsthe focal point of this chapter. Emphasis is placed on reactions catalyzed bysoluble molecular catalysts, that is, transition-metal complexes; however, examplesof heterogeneous catalysis are drawn where appropriate.

Hydrogenation, that is, reduction using H2 under catalysis, is probably themost widely studied reaction in aqueous media [2]. In the 1960s and 1970s,simple water-soluble metal salts such as [Co(CN)5]3− and RhCl3 were studied forhydrogenation of olefins in water. However, aqueous-phase hydrogenation did notgain much attention until the introduction of water-soluble phosphines as ligandsfor rhodium-catalyzed hydrogenation and hydroformylation in the mid-1970s andthe wider awareness of the product/catalyst separation issue facing homogeneouscatalysis from the 1990s onward [2c]. Today, almost all the common functionalgroups in synthetic organic chemistry have been hydrogenated in water [2, 3].

Transfer hydrogenation uses hydrogen sources other than H2. The initial stud-ies with water-soluble catalysts appeared in the late 1980s, and in spite of thewell-documented studies of aqueous-phase hydrogenation, this area had been lessdeveloped until recently [4]. As a tool in synthesis, transfer hydrogenation is com-plementary to hydrogenation; it requires neither the hazardous hydrogen gas nor

Metal-Catalyzed Reactions in Water, First Edition. Edited by Pierre H. Dixneuf and Victorio Cadierno. 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

174 6 Hydrogenation and Transfer Hydrogenation in Water

pressure vessels, and it is easy to operate. Furthermore, there are a number ofchemicals that are easily available and can be used as hydrogen donors, the mostpopular being isopropanol and formic acid though. Still further, it may enablereduction that cannot be effected under the conditions of hydrogenation.

One of the major incentives in developing the aqueous-phase hydrogenationand transfer hydrogenation chemistry is to facilitate catalyst/product separation.As water is a highly polar and protic solvent (ε = 78, EN

T = 1), most commonorganic compounds are insoluble or only sparsely soluble in water [5]. This meansthat a product can be easily separated from the solvent by simple phase separationor extraction, provided that the catalyst is preferentially water soluble. A numberof water-soluble metal catalysts are now readily accessible; these include thosecontaining hydrophilic ligands and those bonding with water. There is anothersignificant advantage on offer when water is used as a solvent. Being inexpensive,readily available, nontoxic, nonflammable, and eco-benign, water is the naturalchoice for ‘‘greening’’ chemistry.

However, the use of water also presents challenges. The insolubility of manyorganic compounds in water implies possible diffusion control if the reductionoccurs in the aqueous phase. The same is true with hydrogen, which has a lowersolubility in water (0.81 mM at 20 ◦C) than in common organic solvents. Theimmiscibility of a compound with water could be exploited, however, to benefit areaction; the hydrophobic interaction could drive a reaction to occur ‘‘on water,’’where stronger hydrogen-bonding interactions via the surface -OH groups may leadto faster reaction rates [6]. Furthermore, although it appears that hydrogenation andtransfer hydrogenation in water operate in mechanisms similar to those in organicsolvents, various studies have now shown that water is not an innocent spectator. Itmay interact with intermediates and transition states, particularly when these bearhydrogen-bond donor or acceptor functionalities, and it may react with a hydrideor dihydrogen species and participate in an acid-base equilibrium with the catalyst[2c]. The role of water is briefly addressed toward the end of this chapter.

The unique property of water has attracted a great deal of interest in its potentialapplications in catalysis, including in particular hydrogenation. Over the past onedecade or so, a number of review articles have been published on hydrogenationincluding transfer hydrogenation in water [2–4, 7]. This chapter is developed fromone of the works of the authors written in 2008 [8], focusing on the progress mademainly in the past one decade or so.

6.2Water-Soluble Ligands

A metal complex catalyst can be made water soluble by modification of itsligands such that they become sufficiently hydrophilic [3a]. This is usually doneby attaching ionic or hydrogen-bonding groups to a ligand. Typical hydrophilicstructural elements include ammonium, guanidium, phosphonium, carboxylate,phosphonate, sulfonate, carbohydrate, hydroxy, and polyether, with the sulfonate

6.2 Water-Soluble Ligands 175

and ammonium groups being the most popular tags. However, an ionic metalcomplex can be soluble in water without calling for a special ligand. Still further,there are complexes that are soluble in water by bonding to water. Examples ofwater-soluble ligands are briefly presented in the following sections; Section 6.4shows examples of water-soluble metal complexes.

6.2.1Water-Soluble Achiral Ligands

Phosphines have been the most widely used ligands for reduction in water. Repre-sentative water-soluble achiral ligands are listed in Scheme 6.1. The most intensivelyinvestigated water-soluble phosphine ligands for hydrogenation and transfer hydro-genation in aqueous media are (3-sulfonatophenyl)diphenylphosphine (TPPMS, 1)and tris(3-sulfonatophenyl)phosphine (TPPTS, 2) [2d,e, 9]. Following on from thesuccessful demonstration of these phosphines in aqueous-phase reduction, a widerange of water-soluble ligands have been investigated and applied to various re-duction reactions. Nitrogen-containing ligands have also been explored, achievingwater solubility by a similar strategy; typical examples include diamines, imines,and pyridines (5 and 6). Water-soluble catalysts are often synthesized by in situreacting a water-soluble ligand with a metal precursor complex.

PP

NaO3SNaO3S

SO3Na

SO3NaN

NN

P

1 (TPPMS)

P

NaO3S

SO3Na

P

SO3Na

SO3Na

n N NN N

2 (TPPTS)

4

3 (PTA)

6

HO OHO O

HOH2C CH2OH

N

5

Scheme 6.1

6.2.2Water-Soluble Chiral Ligands

Water-soluble chiral ligands are prepared from similar chemistry, that is, bythe introduction of a polar functional group onto a normal chiral ligand.


Scheme 6.2 features selected examples. Again, phosphorus-containing ligandshave been the most widely investigated. However, nitrogen ligands havefound wide applications in transfer hydrogenation in aqueous media becauseof a seminal paper on asymmetric transfer hydrogenation using TsDPEN(N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine) published by Noyoriet al. [10] in 1995. Water-soluble analogs have since been prepared (19–22)(Ts = p-CH3C6H4SO2

−).

6.3Hydrogenation in Water

As introduced at the beginning, hydrogenation is probably the most widely studiedreaction in aqueous media. This is a totally atom-economic reaction, and whena water-soluble catalyst is chosen, there is, in principle, no waste to generatefollowing product separation. A wide variety of substrates have been hydrogenated,with the stage dominated by achiral reactions.

6.3.1Achiral Hydrogenation

6.3.1.1 Hydrogenation of OlefinsAchiral hydrogenation of simple olefins provides the earliest examples ofaqueous-phase hydrogenation. The catalysts used were almost exclusively rhodiumand ruthenium complexes containing water-soluble phosphines [2, 4a, 7]. Arecent example is seen in the water-soluble RuCl2(TPPTS)3, which catalyzedthe hydrogenation of unsaturated hydrocarbons, such as 1-alkenes, styrene,cyclooctenes, and even benzene, in water under 10 bar H2 at 150 ◦C, affordingmoderate to high conversions [11]. As expected, aliphatic unsaturated hydrocar-bons were more easily hydrogenated than aromatic ones. Ruthenium carbonylcomplexes bearing TPPMS (1, Scheme 6.1), for example, Ru(CO)3(TPPMS)2 andRuH2(CO)(TPPMS)3, have also been shown to be efficient, recyclable catalysts forthe hydrogenation of these olefins in a water/n-heptane (1 : 1) mixture [12].

Hydrogenation of functionalized olefins was demonstrated in an early study. Asshown in Scheme 6.3, various olefins were chemoselectively hydrogenated at theC=C double bonds by using RhCl3 in the presence of TPPTS (2, Scheme 6.1) atroom temperature and 1 bar H2. In the case of dienes, the less hindered C=C bondwas first hydrogenated and the reaction could be terminated at the monoene stage[13].

Functionalized olefins that are water soluble present a problem for prod-uct separation, particularly when the catalyst is also water soluble. This hasbeen addressed by using supercritical CO2/water biphasic catalysis, in whicha CO2-philic, rather than hydrophilic, catalyst resides in the supercritical fluid,while the substrate and product dissolve in and are removed by water [14]. Ita-conic acid, α-acetamidocinnamic acid, fumaric acid, and methyl acetamidoacrylate

6.3 Hydrogenation in Water 177

PPNaO3S

NaO3SSO3Na

SO3Na

87

P

P

SO3Na

9 10

P

P

SO3Na

SO3Na

SO3Na

11 12

O

O

KO3S

KO3S

PPh2

PPh2

13

MeOP

PMeO

SO3Na

SO3Na

SO3Na

14

P

P

(CH2)3

(CH2)3

(CH2)3

(CH2)3

SO3Na

SO3Na

SO3Na

SO3Na

PPh2

PPh2

NH

HN

H2N

H2N

NH2+Cl−

NH2+Cl−

P

P

SO3NaSO3Na

SO3Na

HO

HO

OHOH

SO3Na

SO3Na

Scheme 6.2


15 16 17 18

P

P

C2H5

C2H5

C2H5

C2H5

OH

OH

OH

OH

PPh2

PPh2

P(O)(OH)2

P(O)(OH)2

OO

OHO OH

HO

OPPh2

HO

Ph2PO

OH

OH

O

OP (OCH2CH2)16OMe

H2N HN SO

O

R

19 a: R = p-SO3H(Na)b: R = o-SO3H(Na)

H2N NHTsR R

a: R = SO3H(Na)b: R = NH2

20

H2N HN SO

OSO3Na

21

NH

O

R

a: R = H, b: R = Fc: R = CF3, d: R = OMe

22

NH

Scheme 6.2 (Continued)


R1

R2 R3

R1

R2 R3+ H2RhCl3/2

Water90–95% yield

olefins =

NH2

CO2Me

CO2H OO

O

OHOMe

Scheme 6.3

were hydrogenated this way with [Rh(COD)2][BF4] and a CO2-philic PPh3 analog,P(3-C6H4CH2CH2C6F13)3, furnishing >99% conversions at 30 bar H2 and 56 ◦C.The catalyst-containing CO2 phase was reusable, with rhodium leaching at theparts per million level in each recycle run when excess ligand was used.

A rare example of indole hydrogenation in water appeared recently [15]. In thepresence of a readily available Brønsted acid such as p-toluenesulfonic acid (p-TSA),a range of unprotected indoles were selectively hydrogenated to their correspondingindulines in high yields over a heterogeneous Pt/C catalyst at room temperature(Scheme 6.4). The acid additive plays a crucial role in the reaction, facilitating thereduction by disrupting the aromaticity of the heterocyclic ring of the indole toform an easier-to-reduce iminium ion.

Pt/C (10–50 mg), H2O

H2, 30–50 bar; p-TSA, 1.2 equiv; r.t; 2–3 h

NH

R1R2

NH

R1R2

NH

NH

MeO

NH

Me

NH

F

NH

Cl

NH

EtNH

Me

NH

MeOOC

NMe

NH

NH2

NH

NH

NH

MeOMe

OMe

NH

Me

Me

Indoles = 68–96% yield

Scheme 6.4

Selective hydrogenation of α,β-unsaturated aldehydes has been extensively stud-ied in water, and a good control of the selectivity has been established. Rh andRu complexes are generally the catalyst of choice in this transformation and of-ten, but not always, the former favor hydrogenation at C=C double bonds whilethe latter prefer C=O bond saturation. For example, as shown in Scheme 6.5


OR2 R2 OHOR2

Ru-2H2O/Tol (1/1)

H2, 20–50 barS/C 20035 °C, 1–15 h

Rh-2H2O/Tol (1/1)

H2, 20–40 barS/C 20030–80 °C, 0.3–1.5 h

R1 R1 R1

R1 = H, Me; R2 = Me, Ph, Me2C=CH(CH2)2

89–93% conv.95–97% selectivity

95–100% conv.97–99% selectivity

R1 = H, Me; R2 = Me, Ph

Scheme 6.5

(S/C = substrate/catalyst molar ratio), α, β-unsaturated aldehydes were hydro-genated in a water/toluene (1 : 1) mixture, at the C=C bond by Rh-TPPTS with upto 93% conversion and 97% selectivity, and at the C=O moiety by Ru-TPPTS withup to 100% conversion and 99% selectivity. The catalyst could be recycled to yieldeven a slightly higher activity and selectivity [16].

The water-soluble tetranuclear complex Rh4(O2CPr)4Cl4(MeCN)4 (Pr = n-propyl)was reported to selectively catalyze the hydrogenation of α,β-unsaturated alcohol,ketone, nitrile, carboxylic acid, and amide substrates at the C=C bond under 1 barH2 at room temperature [17]. Similarly, the water-soluble Ru(II), Rh(I), and Rh(III)complexes of N-methyl-PTA (PTA-Me, PTA, 1,3,5-triaza-7-phosphaadamantane,3, Scheme 6.1), such as RuI4(PTA-Me)2, [RuI2(PTA-Me)3(H2O)][I3], and[RhI4(PTA-Me)2][I], were shown to be active catalysts for the hydrogenation ofcinnamaldehyde at the C=C bond with Rh but at the C=O moiety with Ru ina biphasic mixture of H2O/toluene or H2O/chlorobenzene [18]. For instance,cinnamaldehyde was converted to PhCH2CH2CHO in 95% conversion with 84%selectivity and a turnover frequency (TOF) of 190 h−1 by using RuI4(PTA-Me)2 inH2O/toluene. However, several PTA-containing half-sandwich Ru(II) complexes,such as CpRuH(PTA)2 and [CpRu(MeCN)(PTA)2][PF6], were shown to beselective toward C=C saturation, albeit with low activities [19]. Unlike the TPPTSand other PTA complexes mentioned, hydrogenation with the half-sandwichcatalysts may proceed via an ionic mechanism, involving transfer of H2 asH+ and H− and no coordination of the substrate (Scheme 6.6) [19c]. This isreminiscent of Noyori’s metal–ligand bifunctional catalysis put forward forthe Ru(II)(diphosphine)(diamine)-catalyzed hydrogenation of ketones [20]. The1,4-addition that involves activation of the double bond via N-H-O hydrogenbonding explains why the C=C bond is selectively reduced.

Half-sandwich complexes with an ionic tag have also been explored for aqueoushydrogenation. The imidazolium-functionalized complexes 23 and 24 (Scheme 6.7)are active for the hydrogenation of styrene in water/cyclohexane (1 : 2) [21]. Thereaction proceeded readily under the conditions of S/C = 1000 and 40 bar H2 at80 ◦C, with the catalyst reusable, although slightly decreased activity was notedin recycle runs. Catalysts of this type have also found use in catalysis in ionicliquids.

Phosphine-free complexes catalyze the hydrogenation of α, β-unsaturated alde-hydes in water as well. An example is seen in Scheme 6.8 [22]. The rhodium and


RuATPP

NNN

+

RuATPP

NNN

+

H

H

RuATPP

NNN

+

H

H

RuATPP

NNN

+

H

H

Ph

O

O

Ph

Ph

O

H2 Slow

Scheme 6.6

RuClCl L

N NR2

R1

Cl−

23: R1 = R2 = Me, L = PPh3

24: R1 = H, R2 = Bu, L = PPh3 Scheme 6.7

NH

N

N

HN

ROOC(H2C)3O

ROOC(H2C)3O O(CH2)3COOR

O(CH2)3COOR

R = H, K

O Rh-/ Ru-25

25

H2 (30–100 bar), 60 °C24 h, 53–100% conversion

O

Scheme 6.8


ruthenium porphyrin catalysts are air stable and could be recycled without anysignificant difference in activity and selectivity. However, the chemoselectivity islow with all the possible reduction products observed and the best selectivity to thealdehyde product being 88%.

Recent studies have revealed that the selectivity pattern of the M-TPPTS catalystsin the hydrogenation of unsaturated carbonyls is affected by a variety of parameters,for example, the H2 pressure, temperature, catalyst concentration, ligand/metalratio, substrate concentration, and solution pH [23]. Significantly, these parameterscould be maneuvered to alter the selectivity pattern. For instance, in the case of theRh-TPPTS-catalyzed process, a higher H2 pressure shifts the hydrogenation towardthe C=O bond, while a large excess of ligand 2 favors the saturation of C=C bond[23b], and although the Ru-TPPTS catalyst is selective toward C=O saturation athigh catalyst concentration, it favors hydrogenating the C=C bond when the catalystconcentration is low [24]. Solution pH has been found to be important as well. Thus,selective hydrogenation of trans-cinnamaldehyde at the C=C bond is achievable ata low pH (<5) with 1 bar of H2, but selectivity favors the C=O bond when the pHis increased to >7 [23c]. On the other hand, selective saturation of the C=O bondcould also be achieved at a low pH, but at a higher H2 pressure of 8 bar. Theseseemingly conflicting observations result from different active catalytic speciesbeing involved in the reaction, for example, RuClH(TPPMS)3 and RuH2(TPPMS)4,the proportion of which varies with the solution pH and H2 pressure. The formeris selective toward the C=C bond while the latter toward the carbonyl [25].

More recently, a DFT investigation of the Ru-catalyzed selective hydrogenationof α, β-unsaturated aldehydes in aqueous/organic biphasic media showed that thefavored C=O hydrogenation under basic conditions is due to the presence of water,which forms hydrogen bond with the aldehyde, thus facilitating C=O reduction[26]. However, a similar mechanistic study [27] revealed that the selective reductionof the C=C bond by RuClH(PR3)3 is due to a lower barrier of C=C versus C=Oinsertion into the Ru-H bond, whereas the reduction of the C=O bond, instead ofC=C, with RuH2(TPPMS)4 stems from the energy difference in the subsequentstep of protonation [28]. It is worth noting that these studies show that, beinginvolved in various steps of the catalytic cycle, water as solvent is not an innocentspectator in the hydrogenation (Section 6.5).

Hydrogenation of unsaturated polymers in water is also possible. Such reactionshave been successfully carried out in conventional organic solvents [29] and othermedia, such as ionic liquids [30]. Rh-TPPTS complexes were demonstrated tocatalyze efficient hydrogenation of polybutadiene-1,4-block-poly(ethylene oxide) inwater, as shown in Scheme 6.9 [31]. The reaction was homogeneous and proceededin PB-b-PEO/DTAC nanomicelles (DTAC, dodecyltrimethylammonium chloride; acationic surfactant), affording high conversions with high catalytic activities (TOF> 840 h−1). The catalyst could be recycled, maintaining high catalytic activity in aconsecutive run even at a rhodium concentration of only 1 ppm in water.

Higher olefins, such as 1-octene, can be difficult to hydrogenate due to reducedsolubility in water. An amphiphilic Ru nanoparticle catalyst stabilized by thewater-soluble poly(N-vinyl-2-pyrollidone) (PVP) demonstrated a high activity in the


HH

H H

H

H

Om n p (PB-b-PEO)

1,4-PB (89%) 1,2-PB (11%) PEO

Rh/2 (1/3)H2 (20 bar)H2O, DTAC100 °C, 20 min

H

H H

Om n p (HPB-b-PEO)

H

HH

H

H

HH

94% conv., 846 h−1 TOF

Scheme 6.9

hydrogenation of CH2=CH(CnH2n+1) (n = 4–9) and cyclohexene in a water/decanemixture, with TOF as high as 23 000 h−1 being reached at 40 bar H2 and 80 ◦C[32]. The amphiphilic nature of the catalyst leads to enhanced concentration of sub-strate around the polymer-trapped ruthenium and thus high hydrogenation rates.Other nanoparticle catalysts have also been shown to be active for heterogeneoushydrogenation in aqueous phase [33].

6.3.1.2 Hydrogenation of Carbonyl CompoundsApart from the unsaturated carbonyl compounds presented above, simple ketonesand aldehydes have also been reduced in aqueous solutions. The water-soluble,half-sandwich iridium complex [Cp*Ir(H2O)3]2+ (Scheme 6.27) was shown to beactive for the hydrogenation of carbonyl compounds and alkenes in water undermild reaction conditions (1–7 bar H2, 25 ◦C) [34]. An isoelectronic ruthenium com-plex, RuCl2L(p-cymene) (L = 1-butyl-3-methylimidazol-2-ylidene), displayed goodactivity in the hydrogenation of acetone, acetophenone, and propanal in waterat 10 bar H2 and 80 ◦C [35]. Remarkably, replacing the carbene ligand with aphosphine resulted in no hydrogenation. Similar to the PTA catalysts mentioned inSection 6.3.1.1, the Ru–carbene complex catalyzes the preferential hydrogenationof C=C bonds in α, β-unsaturated compounds.

Recently, a diamine-ligated half-sandwich iridium complex 26 was demonstratedto catalyze the hydrogenation of a wide range of aldehydes in neat water(Scheme 6.10) [36]. Aromatic, aliphatic, heterocyclic, and α, β-unsaturated aldehy-des were all viable substrates, and in the case where C=C and C=O bonds coexist,only the formyl group was saturated. Interestingly, this catalyst is also highly activein transfer hydrogenation of aldehydes with formate in water (see 6.4.1.1).

As with the catalysts bearing water-soluble phosphines, the phosphine-freehalf-sandwich complexes display pH dependence in hydrogenation. For instance,[Cp*Ir(H2O)3]2+ was active in pH −1 to 4 [34–35]. This dependence can again


S/C 200–1000, 20 barwater, 80 °C

Aldehydes H2 Alcohols87–98% yields

Aldehydes:

R

O

H

R = p-NO2, F, Cl, Ac, H, Me, OMem-Cl, Me, OMeo-Cl, OMe

OH

O

H

O

H

O

R

R = p-NO2, H, OMeo-NO2, OMe

H

O

H

O

H

O

H

OH

O

H

O

H

O

H2N SO

OCF3

IrCl

26+

N

Scheme 6.10

be traced to the variation of catalytic species with pH (Section 6.5.2). Similarreports have appeared recently, suggesting that the active catalyst species [37] orthe stereoselectivity of the catalyst [38] could be controlled by the pH of the aqueousphase.

A half-sandwich Ru(II)–phenanthroline complex, immobilized onamino-functionalized MCM-41, is shown to be highly chemoselective andefficient for the hydrogenation of unsaturated ketones in aqueous media [39].Thus, hydrogenation of 3-methylpent-3-en-2-one afforded full conversion in 6 hat 100 ◦C, with up to >99% chemoselectivity for 3-methylpent-3-en-2-ol, and thecatalysts can be reused four times [39b].

Nanoparticles have also shown promise in water. The aforementionedPVP-stabilized Ru nanoparticles allow for rapid hydrogenation of ketones [32].Similarly, Ru nanoparticles immobilized on the water-soluble polymer poly-organophosphazenes (-[N=PR2]n-) were found to be active for the hydrogenationof unsaturated ketones or aromatic compounds such as pyruvic acid andp-aminomethylbenzoic acid in water [40]. For example, as shown in Scheme 6.11,pyruvic acid was completely reduced to lactic acid by Ru on PDMP (PDMP,polydimethylphosphazene) in 100% selectivity and SA of 14.3 (specific activity:moles of converted substrate per gram atom ruthenium per hour) under mildconditions; no catalyst deactivation was observed in the recycle runs. Similarly,methyl pyruvate was hydrogenated with good TONs (turnover numbers) underthe catalysis of Pt nanoparticles supported on poly(diallydimethyl ammoniumchloride) (PDDA) (Scheme 6.11). The catalyst also allows for the hydrogenation


O

OOH

OH

OOHRu/PDMP 5%

1 bar H2, 25 °CH2O, 7 h

100% conv. with 100% selectivity, SA = 14.3

(in both 1st and 2nd run)

O

OOMe

OH

OOMePt/PDDA

50 bar H2, 27 °CH2O, 12 h

100% conv., 1202 TON

Scheme 6.11

of aliphatic and aromatic aldehydes under the same conditions in water[33e, 41].

6.3.1.3 Hydrogenation of Aromatic RingsAromatic rings are difficult to saturate, and the hydrogenation is generally effectedwith heterogeneous catalysts. A number of soluble metal complexes were previouslyreported to catalyze arene hydrogenation in water [33f, 42]. In most cases, however,decomposition into heterogeneous metal particles took place, which catalyzedthe hydrogenation. In the case of half-sandwich Ru(II)–cymene complexes, thedecomposition was shown to be a function of solution pH; the decompositionaccelerated at higher pH, correlating with an increasing hydrogenation activity[42e, 43].

Water is a viable alternative to the frequently used polar organic solvents. TheRu-PVP catalysts mentioned in Section 6.3.1.1 enable rapid, complete hydro-genation of simple benzenes, styrene, anisol, and benzoate, with TOF as high as45 000 h−1 reported at 40 bar H2 and 80 ◦C in a water/cyclohexane mixture [44]. Sim-ilarly, colloidal Rh suspension stabilized by highly water-soluble N,N′-dimethyl-N-cetyl-N-(2-hydroxyethyl)ammonium bromide or chloride (HEA16X, X = Br or Cl)catalyzes the hydrogenation of N- and O-heteroaromatic compounds in water undermild conditions (Scheme 6.12) [45]. The catalyst could be reused without losingactivity. However, no catalytic activities were detected for sulfur compounds suchas thiophene.

Yet, a simpler example is seen in the commercial Rh/C catalyst, which catalyzesthe hydrogenation of a range of aromatic rings under mild conditions in water [46].Selected examples are provided in Scheme 6.13. The rhodium catalysts in bothScheme 6.12 and 6.13 allow for efficient reduction of pyridine derivatives, whichare known to poison platinum metal catalysts.

A more efficient catalyst is the TiO2-supported Rh(0) nanoparticles, whichare very active and recyclable in the hydrogenation of mono- or disubstitutedand functionalized arene derivatives with TOF up to 470 h−1 in neat water underambient conditions (Scheme 6.14) [47]. The catalytic activity increased dramatically,


NH HN

N

N

N

HN

N

N

O

O

NN

N

NHHN

HN

Substrate Product

Substrates =

Products =

Rh-HEA16X (X = Br or Cl)

1 bar H2, S/C 100–100020–50 °C, 1–30 hwater

100% selectivity6–200 h−1 TOF

Scheme 6.12

Substrate Product

Substrates =

Products =

10% Rh/C

5 bar H2, 80 °C, 0.5–2 hwater

73–97% yield

CO2H

O N N

OH CONH2

C5H11

CO2H

O NH

NH

OH CONH2

C5H11

Scheme 6.13

Substrate Product

Substrates =

Products =

1 mol% Rh@TiO2

1 or 30 bar H2, r.t., 0.01–20 hwater

100% conversion

O

O

O

O

O

O

N

NH

Scheme 6.14

leading to TOF up to 33 000 h−1 at a higher H2 pressure of 30 bar, with thereduction completed from less than a minute to several minutes in most cases.The SiO2-supported rhodium was less active, however.

Phenols can be hydrogenated to cyclohexanone or cyclohexanol in water overheterogeneous Pd, Ru, or Ni catalysts [48]. An example is seen in the hydro-genation with a bifunctional Pd nanoparticle catalyst supported on a highlyacidic metal-organic framework (MOF) [48b]. The reduction was carried out atatmospheric pressure and room temperature, showing >99.9% selectivity to cyclo-hexanone at phenol conversion >99.9% (Scheme 6.15). The catalyst is reusable,affording identical activities and selectivities after five runs [48b].


Substrate Product5 mol% Pd/MIL-101

1 bar H2, 35 °C, 7–14 hwater

90 - >99.9% conversion

OH

O

Substrates =

Products =

OH

O OH

OH OH

HO

OH

91% 9%>99.9%

O OH

97% 3%

O

HO

OH

HO94% 6%

OH OH

9% 91%

Scheme 6.15

6.3.1.4 Hydrogenation of Other Organic GroupsIn addition to those discussed, compounds such as imines, nitros, and nitrileshave also been hydrogenated in water. The examples are far fewer, however,and most are concerned with heterogeneous catalysts. Benzonitrile was cleanlyhydrogenated to benzylamine over Pd/C in the presence of NaH2PO4 in a mixtureof H2O/CH2Cl2, affording 90% isolated yield under mild reaction conditions (30 ◦C,6 bar H2) [33f]. The PDDA-supported Pt nanoparticles mentioned in Section 6.3.1.2enable efficient hydrogenation of chloronitrobenzenes at 50 bar H2 and 27 ◦C,affording a higher TON in neat water than in a water/toluene mixture [41].Somehow similarly, addition of water accelerates significantly the hydrogenationof p-chloronitrobenzene catalyzed by various supported metal catalysts, M/SiO2

(M = Ru, Ni, Co, and Fe), in ethanol [49]. In a recent example, nitroarenes wereselectively reduced to the corresponding arylamines in water by using colloidal Ptnanoparticles supported on gum acacia (Scheme 6.16) [50]. The reaction was carriedout at ambient conditions, affording good yields for a range of nitroarenes, and thecatalyst was recycled five times with consistent activity [50]. Nitrobenzene, along

NO20.24 mol% GA-Pt colloidal nanoparticle

1 bar H2, r.t., 6–8 h, water

NH2R R

72–95% yield

NO2 NO2 NO2 NO2 NO2

MeO OMe

NO2 NO2 NO2 NO2 NO2

Cl Cl II

HO

NO2 NO2 NO2 NO2 NO2

F Br H

O OO2N

Scheme 6.16


with benzaldehyde and cyclohexanone, has been reduced in pressurized water athigh temperature, using H2 in situ generated from formate and thus providing a‘‘gasless’’ approach to hydrogenation [51]. The reduction of nitrates in water hasalso been demonstrated, using heterogeneous catalysts or photocatalysts [52].

Imines have been reduced with β-cyclodextrin (β-CD) modified Pd nanoparticlesin water [53]. β-CD is capable of transferring hydrophobic molecules into waterby hosting the molecules inside its cavity, thereby facilitating the hydrogenationof water-insoluble substrates in water. A range of aldimines were hydrogenated;examples are seen in Scheme 6.17. The catalyst is also effective in reducing variousα,β-unsaturated ketones and aldehydes under similar conditions. In the case ofisophorone hydrogenation, the presence of β-CD leads to a 250-fold increase inTOF.

1 mmol imine,20 bar,water, 25 °C

+ H2

R1 = p-F, H, Me; o-F, OMeR2 = p-F, H, OMe; m-F; o-F, Me

70–100% yields

R1 NR2

R1 NH

R2Pd/b-CD, 10 mg

Scheme 6.17

6.3.1.5 Hydrogenation of CO2

CO2 can be hydrogenated to formic acid or its derivatives (Scheme 6.18). A numberof ruthenium and rhodium complexes have been shown to catalyze the reactionin water, and the area has been summarized in recent literature [54]. Waterappears to be an ideal solvent for hydrogenation. In the gas phase, hydrogenation isendergonic, with �Go

298 = 33 kJ mol−1, while in the aqueous solution, the standardfree energy becomes −4 kJ mol−1. In the latter case, however, hydrogenation ismore complicated, as CO2 is in equilibrium with hydrogen carbonate (pK1 = 6.35)and carbonate (pK2 = 10.33), both of which can be hydrogenated to formate. Inaddition, the product formic acid ionizes in water (pKa = 3.6). Thus, as maybeexpected, CO2 hydrogenation in water is pH dependent. Most hydrogenationreactions have been run under basic conditions, enhancing the possibility ofhydrogenating hydrogen carbonate instead of CO2.

Rhodium and ruthenium complexes dominated the scene, most containingphosphine ligands. Typical examples are RhCl(TPPTS)3 and [RuCl2(TPPMS)2]2. Inthe hydrogenation reaction in water using RhCl(TPPTS)3, a TOF of 7260 h−1 wasobserved at a total pressure of 40 bar (H2/CO2 = 1/1) and 81 ◦C in the presence

CO2 + H2 HCOOH

CO2 + H2O H2CO3 HCO3− + H+ CO3

2− +

HCOOH HCO2− + H+

pKa

pK1 pK22H+

Scheme 6.18


of NHMe2 [55], while the Ru(II) catalyst afforded a TOF of 9600 h−1 at a totalpressure of 95 bar (H2/CO2 ∼ 2/1) and 80 ◦C in the presence of NaHCO3 [56]. Freeformic acid can be produced by the hydrogenation of CO2 in aqueous solutions ofHCOONa with Rh-1 [57]. A high pressure, appropriate concentration of HCOONaand a 1 : 1 ratio of H2/CO2 were crucial for the production of free formic acid withhigh yield and concentration in the final reaction mixture. For instance, in a 0.5 MHCOONa solution, free formic acid was produced in a concentration of 0.13 M.

Recent studies have revealed a variety of other metal complexes capable ofreducing CO2 in aqueous media (Scheme 6.19 and Table 6.1) [54, 57–59]. Agood example is seen in an Ir(III) complex 27 bearing the dihydroxy-bipy ligand6 (Scheme 6.1), which afforded a TON of 190 000 in 57 h with an initial TOFof 42 000 h−1 at a total pressure of 60 bar (H2/CO2 = 1/1) and 120 ◦C in anaqueous KOH (1 M) solution (entry 1, Table 6.1) [59c]. The analogous rhodiumand ruthenium catalysts were less active, however. A kinetic study of the closelyrelated Ru(II) and Ir(III) complexes suggests that the hydrogenation is rate limitedby hydride formation in the case of the former but by hydride transfer to CO2 inthe case of the latter [59b].

IrN

N

Cl

27

++

+

HO

HO

NPiPr2 PiPr2Ir

HH

H

28

Si NH S

Me

RuCl

PPh3

Cl

Cl

29

NO

RuOH2

30 31

N

N N

N

Me MeRu

+

N

N N

NRu

+

32 33

OHHO NN N N N

N

Me MeRu

+

34

N

N N

NIr

+

36

OHHO

RuN

N

Cl

35

+

IrN

N

Cl

+

38

Ir Cl

39

NN ClN

N N

N

Me MeRu

+

37

P

Ph2PPh2P

PPh2

Fe

H

Cl Cl Cl

Cl Cl

Scheme 6.19

The high catalytic activity of 27 stems from the electron-rich nature of ligand 6,which is deprotonated during the reaction; the resulting oxyanion is a much strongerelectron donor than the hydroxyl group (σ+

p : −2.3 vs − 0.91). There indeed existsa correlation between the initial TOF and σ+

p , and this is consistent with previoustheoretical and experimental studies, which suggest that electron-rich ligandsfacilitate the hydrogenation [60]. The equilibrium shown in Scheme 6.18 also


Table 6.1 Catalytic hydrogenation of CO2 to formic acid and formates in water.

Entry Catalyst Additive p(H2)/p(CO2) (bar) T (◦C) t (h) TON TOF (h−1) References

1 27 KOH 30/30 120 57 190 000 42 000 [59c]2 28 KOH, THF 29/29 120 48 3 500 000 73 000 [58a,d]3 29 ILa 89/89 80 2 1 840 920 [58c]4 30 NEt3 49/49 100 10 400 40 [58b]5 31 PP3

b 60/30 100 20 585 49 [58n]6 32 KOH 20/20 200 75 23 000 306 [58g]7 33 KOH 20/20 80 20 132 7 [58g]8 34 KOH 20/20 80 20 311 16 [58g]9 35 KOH 20/20 80 20 214 11 [58g]10 36 KOH 20/20 80 20 122 6 [58g]11 36 KOH 20/20 200 20 9 500 475 [58g]12 37 KOH 30/30 80 18 1 600 88 [58h]13 38 KOH 30/30 80 18 180 10 [58h]14 39 KOH 30/30 80 18 67 4 [58h]

aIL, 1,3-di(N,N-dimethylaminoethyl)-2-methylimidazolium trifluoromethanesulfonate; methylformate is the product.bPP3, P(CH2CH2PPh2)3.

confers tunable solubility onto the catalyst: on completion of the hydrogenation,the solution turns acidic, rendering the ligand neutral and thus triggering theprecipitation of the catalyst. Indeed, the catalyst was shown to be recyclableby filtration, with iridium leaching <1 ppm in each run. The product HCO2Kwas separated from the catalyst-free aqueous solution by evaporation of H2O.Electron-rich N-heterocyclic carbenes (NHCs) are also effective in the ruthenium-and iridium-catalyzed hydrogenation (entries 6–8, 10–12, 14, Table 6.1) [58g].

A more active catalyst is the trihydride iridium pincer complex 28 (Scheme 6.19)containing an electron-rich PNP ligand [58a]. Under conditions similar to thoseemployed for 27, this complex afforded HCOOK in aqueous KOH with a remarkableTOF of 73 000 h−1 and TON of 3 500 000 (entry 2, Table 6.1); these represent thehighest values reported thus far for CO2 hydrogenation, pointing to the potentialof commercial production of formats via aqueous hydrogenation. The PNP ligandappears to undergo deprotonation during the catalysis, which is believed to facilitatethe dissociation of formate from the iridium.

From both an eco-benign and economic point of view, iron as catalyst is appealing.Combining Fe(BF4)2 with the tetradentate ligand P(CH2CH2PPh2)3 (PP3) under H2

results in an active catalyst capable of promoting hydrogenation of CO2, affordingmethyl formate in the presence of MeOH (entry 5, Table 6.1) [58n]. The catalyst ismost likely 31, which has been isolated by subjecting Fe(BF4)2 and PP3 under 10bar H2. The catalyst also enables the hydrogenation of bicarbonate into formate,furnishing 680 TON in 20 h at 60 bar H2 and 80 ◦C [58d,n]. Much earlier, it wasshown that 31 can be readily formed by reacting Fe(BF4)2 with PP3 in the presenceof HCOOH. Interestingly, 31 also catalyzes the decomposition of HCOOH into H2


and CO2, with the intermediate η2-formato complex isolable, and it reacts with H2

to give a stable FeH(H2)PP+3 complex [58o]. Ruthenium catalysts have also been

explored for the hydrogenation of bicarbonates in aqueous media without additionof CO2 [58e].

6.3.2Asymmetric Hydrogenation

Water is attractive for enantioselective hydrogenation, as it can ‘‘green’’ the pro-cesses of fine chemicals and pharmaceutical synthesis and enable easy separationand recycle of expensive chiral catalysts including the metals and ligands. Inmany cases, however, chiral catalysts in water afford reduced enantioselectivitiesand/or activities than in organic solvents, especially in the early days [2b, 7a,b].This is partly due to factors such as change in catalyst, altered solvation, diffusioncontrol, and reduced substrate and catalyst solubility. As with achiral hydrogena-tion, aqueous-phase asymmetric hydrogenation usually necessitates the use ofwater-soluble ligands. However, these are generally more difficult to access thanachiral ligands, explaining in part why asymmetric hydrogenation reactions inwater are much limited in scope.

6.3.2.1 Asymmetric Hydrogenation of OlefinsMost reports in this area are concerned with some standard substrates.Methyl 2-acetamidoacrylate was hydrogenated with the water-soluble, hydroxy-functionalized complex [RhL(NBD)][SbF6] (40) (NBD, norbornadiene andL = 14; Scheme 6.2), giving rise to 100% conversion and >99% ee in waterat about 3 bar H2 at room temperature in 5–7 h (Scheme 6.20) [61]. Thecatalyst was stable, being recyclable up to four times without losing anyactivity and enantioselectivity. The hydroxyl ligand 14 is derived from thewell-established DuPhos ligands [62]. A similar catalyst 41 bearing theligand 15 (Scheme 6.2) was explored for the hydrogenation of itaconic acidin water in the presence of a small amount of MeOH, affording excellentee’s (Scheme 6.21) [63]. With no erosion in enantioselectivity, these results

CO2Me

NHAc+ H2

40 (1 mol%)

Water, 5–7 h

CO2Me

NHAc100% conv.>99% ee

P

P

Rh

+

SbF6−

HO OH

OHHO40

Scheme 6.20


+ H2

10 bar100% conv. >99% ee

P

P

EtEt

EtEt

Rh

+OHHO

HO OH

HO2CCO2H

HO2CCO2H

H2O/MeOH12 h

41

PF6−

41

Scheme 6.21

demonstrate the potential of this type of ligand in aqueous-phase asymmetrichydrogenation.

2-Acetamidoacrylic acid can be directly hydrogenated in water with the catalyst40 [64]. In a more recent study, monodentate phosphorus ligands were shown to beeffective as well. The phosphoramidite 42 derived from (S)-BINOL and the relatedpolyethylene glycol-functionalized 43 allow for the Rh-catalyzed enantioselectivehydrogenation, affording ee’s up to 95% (Scheme 6.22) [65]. While 42 led to fastercatalysis in CH2Cl2 (400 h−1 vs 133 h−1 TOF), the water-soluble 43 was far moreeffective in a polar mixture of MeOH-H2O (1200 h−1 vs 20 h−1 TOF). In neat water,however, the catalysts derived from both ligands showed decreased activity andenantioselectivity, although 43 was still considerably more effective than 42 (82%vs 16% ee; 55 h−1 vs 20 h−1 TOF), highlighting a typical problem for aqueous-phaseasymmetric hydrogenation.

Asymmetric hydrogenation coupled with enzymatic hydrolysis has been exploredfor the direct synthesis of amino acids in water. In one such example, thecatalyst Rh-42, immobilized on oxide surface via ionic interactions, was used tocatalyze the hydrogenation of methyl 2-acetamidoacrylate in water, affording methylN-acetylalanate in 95% ee at 5 bar H2 [66]. Following filtration of the catalyst, anaminoacylase, for example, Aspergillus melleus (AM), was introduced to catalyze the

O

OP NMe2

N

O

OO

4

N

O

OO

O

OP NMe2

42

43

4

Scheme 6.22


CO2Me

HN+ H2

Rh-42 (0.5 mol%)

Water, 1 h

CO2Me

HNCOMe COMe

CO2H

NH2

AMpH 7.524 h

100% conv.95% ee

98% conv.98% ee

Scheme 6.23

hydrolysis in a phosphate-buffered solution, leading to the formation of l-alaninewith an increased ee of >98% (Scheme 6.23). It is noted that the hydrolysis tookplace first at the ester group. The two-step reaction could also be performed in aone-pot manner, circumventing the need for filtration.

In some instances, the low rates and enantioselectivities encountered in hy-drogenation in water can be improved by addition of amphiphiles [2d, 67].An early example is the asymmetric hydrogenation of phosphonates to giveα-aminophosphonic acids by a water-insoluble Rh-44 catalyst (Scheme 6.24) [68].Various phosphonates were readily reduced with ee’s in the range of 96–99% in thepresence of a surfactant, sodium dodecyl sulfate (SDS). The introduction of SDSresulted in both a higher enantioselectivity and a much improved reaction rate.This is at least partly due to the increased catalyst and substrate solubility in water.

SDS has also been shown to influence asymmetric hydrogenation of dehy-droamino acids with water-soluble catalysts. This is seen in the hydrogena-tion of methyl (Z)-α-acetamidocinnamate by a rhodium catalyst containing atrehalose-derived phosphinite ligand, which furnished a faster reaction and ahigher ee value of >99% in the presence of SDS (10–200%) at 5 bar of H2 androom temperature. A number of other enamides were also fully hydrogenatedwithin 1 h with excellent ee’s under such conditions [69]. While the precise role ofthe amphiphiles remains speculative, it appears that the formation of micelles isimportant [70].

Asymmetric hydrogenation has recently been shown to be feasible in mixturesof water and imidazolium ionic liquids. One benefit of using such mixed solventsis that common chiral ligands can be directly used without modification, becausetheir metal complexes are generally soluble in ionic liquids. Surprisingly, somehow,the mixed solvents can also confer better catalyst performance [71]. Thus, methyl

NHCOPh

P(OMe)2

O

R

NHCOPh

P(OMe)2

O

R

+ H2

[Rh(COD)2][BF4]44

1 equiv SDSwater25 °C

1 bar

96–99% eeR = p-Cl, p-F, o-F, m-F, p-CH3,p-CF3, p-i-Pr, p-NO2

N

PPh2

PPh2

CO

Ot-Bu

44

Scheme 6.24


2-acetamidoacrylate was hydrogenated under the catalysis of Rh-EtDuPhos in amixture of [bmim][PF6]/H2O (1 : 1, v/v) at 20 ◦C and 5 bar of H2, furnishing a68% conversion and 96% ee in 20 min. The catalyst-containing ionic liquid phasecould be reused after extracting the product. In contrast, in [bmim][PF6] withoutwater, there was no reaction at all. The role of water was ascribed to helping createa well-mixed ‘‘emulsionlike’’ system [71a].

6.3.2.2 Asymmetric Hydrogenation of Carbonyl and Related CompoundsAsymmetric hydrogenation of ketones provides synthetically important chiralalcohols, but it has been even less studied in water. In recent examples, β-ketoesterswere reduced in excellent ee’s (>97%) in water with Ru(II) complexes containingthe 4,4′ and 5,5′-diammonium methyl-BINAP ligands 45 and 46 (Scheme 6.25)[72]. The catalyst could be recycled up to eight times without loss of activity orenantioselectivity. Further studies showed that the same ligands could also beused in the Ru-catalyzed hydrogenation of ethyl trifluoroacetoacetate in an acidicaqueous medium (1.0 ml water, 0.13 ml acetic acid, and 0.13 ml trifluoroacetic acid)to give about 70% ee, one of the best enantioselectivities obtained for the reductionof this substrate with Ru-BINAP or its derivatives [73]. The improved selectivitymaybe due to acid-facilitated equilibration of keto-enol-hydrate involved in thecatalytic cycle.

Water may improve catalyst performance in common solvents. Thus, in theRu-(R)-BINAP-catalyzed asymmetric hydrogenation of methyl acetoacetate inmethanol, the catalytic activity and selectivity were both enhanced by the addi-tion of 3 wt% of water (TOF from 98 to 594 h−1 and selectivity from 77 to 99.9%)[74]. Water was considered to restrict acetal formation in the initial stage of thehydrogenation. However, addition of more than 5 wt% of water caused a drop inboth the TOF and ee.

R

O OOEt

H2 (40 bar)45 or 46

S/C 1000Water, 50 °C, 15 h

R

OOEt

OH

100% conv., >98% ee

NH3+

NH3+

Br−

NH3+

Br−

Br−NH3

+

Br−

Ph2P

PPh2

RuBr

Br

Ph2P

PPh2

RuBr

Bror

R = Me, Ph8th reuse, 100% conv., 97% ee

45 46

Scheme 6.25


Fe PPh2

PR′2

NH

O R

R = HNC[CH2OCH2CH2CO2H]3R′ = 3,5-xylyl

HN

N N

NNH

NH

O

O

OH

O

OH

H2N

O

HN

N NH

HN

NH

NH

O

O

OH

O

OH

H2N

O

[Rh(NBD)2][BF4]/L

70 °CWater

H2

80 bar

L =

47

Scheme 6.26

When dealing with highly polar substrates, water can be an ideal solvent. Anexample is the diastereoselective hydrogenation of folic acid disodium salt. Thisis a difficult reaction, involving the enantioselective saturation of a pyrazine ring.Among a series of water-soluble diphosphine ligands, the modified Josiphos 47was found to be suitable for the rhodium-catalyzed hydrogenation in water atpH 7, giving up to 49% de for l-tetrahydrofolic acid, a pharmaceutically relevantintermediate, with 97% conversion at 30 ◦C after 12 h reaction (Scheme 6.26) [75].At a higher temperature, TOF of up to 334 h−1 and TON of up to 2800 could beobtained, although the diastereomeric excess was lowered. The TOF and TON wereconsidered to be technically viable, but the diastereoselectivity was still too low.

Heterogeneous catalysts have also been explored in aqueous-phase asymmetrichydrogenation. For instance, Ru/C could be used to reduce the amino acidl-alanine to l-alaninol in >90% yield and 99% ee under 70 bar H2 at 100 ◦C inan acidic aqueous phase [76]. A kinetic study predicted that the acidified solutionwas necessary to give high conversions. Under such conditions, the amino acidwould be protonated and so readily hydrogenated [77]. Surfactant-stabilized Pt(0)nanoparticles, modified with (−)-cinchonidine, were shown to efficiently catalyzethe asymmetric hydrogenation of ethyl pyruvate in water at 25 ◦C under 40 bar


of H2, giving rise to a complete reaction with ee’s up to 55% in 1 h. Both theconversion and ee were higher than those without using the surfactant [67b].

6.3.2.3 Asymmetric Hydrogenation of IminesSignificant development has been witnessed in transition-metal-catalyzed asym-metric hydrogenation of imines in the last decade or so [78]. An outstandingexample is seen in the iridium-catalyzed asymmetric imine hydrogenation forthe synthesis of (S)-metolachlor, which has been commercialized [79]. The vastmajority of the hydrogenation reactions have been carried out under anhydrouscondition, however. To avoid imine decomposition by water, hydrogenation inaqueous media requires a catalyst capable of much faster reduction of imines thantheir reaction with water.

There are only a few examples of asymmetric hydrogenation of imines inaqueous media. An early example is the rhodium-catalyzed reduction of N-benzylimines in biphasic media (Table 6.2) [78a,b]. With water-soluble chiral phos-phine as ligand, the imines were hydrogenated to the corresponding chiralamines with enantioselectivity up to 96% ee in a H2O–AcOEt mixture. Whilea mixture of sulfonated 48 (35% disulfonated and 65% monosulfonated) iseffective, the monosulfonated 49 appears to give similar results. However, oversulfonation led to much lower enantioselectivities. For instance, reduction of

Table 6.2 Asymmetric hydrogenation of N-benzyl imines in a biphasic medium.a

N

R

CatalystH2, solvents

HN

R

PhmAr2-mP PPhnAr2-n

48 m = 1, n = 1 (35%)m = 1, n = 2 (65%)

Ar = m-NaO3S-C6H4

P P SO3Na

49

R Catalyst Time (h) Conversion (%) ee (%) References

H Rh-48 6 96 96 [78a]H Rh-49 —b 98 94 [78b]4-OMe Rh-48 6 96 95 [78a]4-OMe Rh-49 —b 98 92 [78b]4-Cl Rh-49 —b 98 92 [78b]3-OMe Rh-48 6 93 89 [78a]2-OMe Rh-48 6 94 91 [78a]

aConditions: H2O-EtOAc (1/1), 20 ◦C, H2 (70 bar), S/C = 100.b—, not reported.

6.4 Transfer Hydrogenation in Water 197

Table 6.3 Asymmetric hydrogenation of 3,4-dihydroisoquinolines with a cationic rhodiumcatalyst.

N

N

Ph

Ph

Rh

N

R1

R2

R3

50 (1 mol%), AgSbF6 (4 mol%)

H2 (20 bar), CH2Cl2/H2O (67/1)NH

R1

R2

R3

50

HH

Ts SbF6

R1 R2 R3 Time (h) Yield (%) ee (%) References

H H Me 1 94 99 [81]H H Et 8 95 97 [81]H H Cy 24 90 91 [81]OMe OMe Me 4 95 96 [81]OMe OMe Et 4 90 93 [81]OMe OMe NPr 4 95 93 [81]OMe OMe Cy 4 94 95 [81]OMe OMe 3,4-(MeO)2C6H3(CH2)2 5 95 99 [81]

acetophenone N-benzylimine using the disulfonated ligand yielded the amine withonly 2% ee.

Chiral amines generated from asymmetric hydrogenation of 3,4-dihydroisoqui-nolines and 3,4-dihydro-β-carbolines are important building blocks for the synthesisof bioactive compounds. Several catalysts have been successfully demonstratedfor this reduction in organic solvents, affording up to 98% ee [80]. A rhodiumcatalyst (50) containing a bulky counteranion, derived in situ from 64b (seebelow) and AgSbF6, is highly effective for the hydrogenation in CH2Cl2, affordingtetrahydroisoquinolines and tetrahydro-β-carbolines in up to 99% ee. Table 6.3shows examples obtained from the hydrogenation of 3,4-dihydroisoquinolines.This is not an aqueous-phase reaction; however, the presence of a small quantityof water is shown to give much faster reduction [81].

6.4Transfer Hydrogenation in Water

Transfer hydrogenation is often performed in isopropanol and the azeotropicformic acid and triethylamine mixture [7c, 9c, 82], which act as both the solvent andhydrogen source. While formic acid and its salts are viable hydrogen sources and


soluble in water, and aqueous formate has been used by enzymes for reductionreactions for millions of years, only in recent years has asymmetric transferhydrogenation in water received significant attention. To some degree, this reflectsthe relatively limited research into transfer hydrogenation undertaken in the pastdecades. In the case of aldehydes, this is also partly due to concern over possibledecarbonylation of the substrates and poisoning of the catalyst by the resultingCO [83].

Scheme 6.27 shows examples of chiral and achiral half-sandwich metal com-plexes, which have recently found successful applications in aqueous-phase transferhydrogenation. In contrast to many other metal catalysts, these complexes catalyzethe transfer hydrogenation with no need for ligand modifications. They exhibitvarying solubilities in water, and their water solubility derives from their capabilityto coordinate with water and/or the hydrogen-bonding interactions of their anionswith water. For example, 54, with SO4

2− being the counteranion, has a solubilityof 136 mg ml−1 (pH 3, 25 ◦C), and the related Cp*–Ir(III) complexes, such as 55a,display solubilities up to 760 mg ml−1 [34, 59b]. It is noted, however, that most ofthese complexes show only a limited solubility in water; this can be considerablyenhanced when the ligands are made water soluble, for example, 19–21.

6.4.1Achiral Transfer Hydrogenation

6.4.1.1 Achiral Transfer Hydrogenation of Carbonyl CompoundsOrganometallic catalysis in aqueous media has attracted interest since the 1970s[9b,d, 84]. In spite of the well-documented studies of aqueous-phase hydrogenation,transfer hydrogenation in water had been less developed until recently. In the 1980s,aqueous-organic biphasic transfer hydrogenation of C=C and C=O double bondswith formate was reported [84b,c,g]. Up to 76% conversion was obtained foraldehyde reduction with RuCl2(PPh3)3 in 30 min at 90 ◦C; the reduction was lesseffective for ketones, however [84g].

Transition-metal-catalyzed transfer hydrogenation of aldehydes in neat waterwas first carried out by Joo and coworkers [9b, 84f]. Unsaturated aldehydes werereduced to unsaturated alcohol by HCOONa with a ruthenium catalyst bearingthe water-soluble TPPMS (1) (Scheme 6.28). The reduction was efficient, withmost reactions complete in a few hours, including those involving multisubstitutedaromatic aldehydes. For example, 2,6-dichlorobenzaldehyde was converted intothe corresponding alcohol in 1.5 h without hydrodechlorination occurring, andthe reduction of α,β-unsaturated aldehydes was chemoselective, only furnishingunsaturated alcohol as the products. However, there was no reaction for substratescontaining an OH group, for example, 2-hydroxybenzaldehyde. Among the variouscatalysts tested, Ru(II)-1 was found to be the most efficient [9b,d, 84f]. Subsequentwork demonstrated the transfer hydrogenation as well as asymmetric transferhydrogenation of unsaturated carboxylic acids to saturated carboxylic acids byformate in water, using a rhodium catalyst containing a water-soluble phosphine[84d].


TsN

NH2

Ph

PhM

Cl

a: M = Rh, b: M = Ir

RN

NH2

RuCl

a: R = Ts, b: R = TsCF3

M

Cl

a: M = Rh, b: M = Iri: R = Ts, ii: R = TsCF3

RN

NH2

TsN

NH2

Ph

PhRu

Cl

CsN

NH2

Ph

PhRu

Cl

CsN

NH2

Ph

PhM

Cl


O

NH2

RuCl

O

NH2

M

Cl


60 61 62 63

64

H2NNH2

RuH2O

2+

TsNNH2

RuH2O

+

69 70

NTsN

RhCl

H

68

NNRuH2O

+

R

71

SN

NH2RuCl

72

O

OS

RhCl

N

NH2

S OO

S

73

NRuCl

74

CF3 NRuCl

75

HO

65 66 67

NN

Ru

2+

NN

M

2+

OH2OH2

OH2Ir

2+

OH2

OH2OH2

M

2+

OH2

N

54 555351

NNRuH2O

NNRu

H2O

NO2

2+2+

NNRuH2O

NH2

2+

59

a: M = Irb: M = Rh

NNRhH2O

2+

56 57

M = a: Cob: Rhc: Ir

MoOTf

52

58

H

ON N

O

R = 2,4,6-triisopropyl-benzenesulfonyl

Scheme 6.27


R

O

R

OHRu-1

HCOONa, H2O, 80 °CS/C 100

Substrate =

1.5–7 h,93–100% conv., 66–99% yield

H

O

RR = Me, MeO,

Br, NMe2

H

O

Cl

Cl

H

O

OMeMeO

MeOH

O

NO2

O OO

O

H

NH O

H

H H

Scheme 6.28

More recent research has revealed that ketones and aldehydes can be reduced byHCOONa or HCOOH in water with water-soluble half-sandwich Ru(II) and Ir(III)complexes 51, 53–55 (Scheme 6.27) [34, 85]. The reduction was shown to be solutionpH dependent, an important finding reminiscent of that in aqueous hydrogenationreactions [9d]. Both water-soluble and water-insoluble substrates were reduced,and in the favored pH window, TOFs up to 525 h−1 were obtained with theIr(III) catalyst 55a and 153 h−1 with the Ru(II) catalyst 54 (Table 6.4) [85b,c,e].A water-soluble molybdocene monohydride (52) was also found to catalyze thetransfer hydrogenation of ketones and aldehydes in water, again with pH-dependentcharacteristics. Acetone could be converted into isopropanol in about 8 h at 40 ◦Cin water, and the reduction of benzaldehyde under the same conditions wasinstantaneous [86].

A series of water-soluble ruthenium-arene and rhodium complexes contain-ing chelating 1,10-phenanthroline ligands have also been introduced (56–59,Scheme 6.27) [87]. These complexes were found to catalyze transfer hydrogenationof ketones in aqueous solution using formic acid as hydrogen source, with 57displaying a higher activity. For instance, TONs up to 164 were obtained in thereduction of acetophenone [87a]. However, when the water-soluble ligand 1 wasused instead of phenanthroline, similar half-sandwich Ru(II) complexes displayedmuch reduced activities on going from isopropanol to water [87g].

The half-sandwich catalysts above are unlikely to enable metal–ligand bifunc-tional catalysis [88]. This explains, to some degree, why the reduction rates aregenerally low. Accordingly, diamine ligands, having a −NH2 functionality andso capable of activating a carbonyl substrate, were shown to be more effective.This is seen in the Ir(III)-catalyzed reduction of a wide range of aldehydes byHCOONa [89]. In particular, the catalyst 26 (Scheme 6.10) formed in situ from[Cp*IrCl2]2 and the corresponding ligand afforded TOFs of up to 1.3 × 105 h−1

in the transfer hydrogenation of aldehydes in neat water. In contrast, when car-ried out in isopropanol or the azeotropic HCOOH-NEt3 mixture, a much slowerreduction resulted. The catalyst works for aromatic, α,β-unsaturated, and aliphatic


Table 6.4 Transfer hydrogenation of carbonyl compounds by HCOONa with 54a and 55ab inwater.

Substrate Catalyst Time (h) Yield (%) TOFc

Cyclohexanone 54 pH 4.0 4 99 982-Butanone 6 97 58Pyruvic acid 4 99 964′-Acebenzsulf assd 3 98 103acp 4 98 752-Trifluro-acp 4 99 153α-Tetralone 13 97 21Cyclohexanone 55a pH 2.0 1 99 376Acp 1 97 3432-CF3-acpe 1 99 525Butanone 4 99 150Pyruvic acid 1 98 4814′-SO3Na-acp 1 99 4191-Tetralone 3 98 203

a0.32 mmol ketones, 0.16 mol% 54, 3 ml H2O, 1.92 mol HCOONa, 70 ◦C, pH 4.0 [85c].b0.32 mmol substrates, 0.5 mol% 55a, 3 ml H2O, 0.32 mol HCOOH, 70 ◦C, pH 2.0 [85e].cTurnover frequency: h−1.d4′-acebenzsulf ass, 4′-acetylbenzenesulfonic acid sodium salt.eacp, acetophenone.

aldehydes and for those bearing functional groups, such as halo, acetyl, alkenyl,and nitro groups, and is highly chemoselective toward the formyl group. Forexample, 4-acetylbenzaldehyde was reduced only to 4-acetylphenylethanol, and thereduction of 4-acetylcinnamaldehyde took place without affecting the ketone andolefin double bonds. Selected examples are presented in Scheme 6.29.

An interesting observation arising from the aldehyde reduction was that noreaction was detected with water-soluble substrates under the conditions employed.For example, the water-soluble 4-carboxybenzaldehyde or its sodium salt could notbe reduced; but its ester analog, methyl 4-formyl benzoate, was reduced in a shortperiod of 40 min with 26 at 80 ◦C at an S/C ratio of 5000. This suggests that thecatalysis takes place on water rather than in water in these biphasic reactions. Asdiscussed in Section 6.3.1.2, 26 and its analogs also catalyze the hydrogenation ofaldehydes in water [36].

More recently, Ru(II) complexes containing multidentate pyridine-type ligandshave been explored [90–92]. For instance, [Ru(η6-p-cymene)(DHBP)Cl][Cl] (DHBP,6,6′-dihydroxy-2,2′-bipyridyl) is shown to be efficient for transfer hydrogenationof ketones with formate in aqueous media [90]. In a mixture of MeOH/H2O(10/90, v/v) at 85 ◦C with an S/C ratio of 100, it afforded high conversion ofaromatic ketones to the corresponding alcohols in 6 h in most cases. The OHgroup may engage in metal–ligand bifunctional activation of the substrate; but


H

O

R′

H

O

O

H

H

O

O

H

O

H

O

O

H

O

H

O

H

O

R H

O

R

O

R

OH26

HCOONa, H2O80 °C, S/C 5000–1000

Substrate =

S

H

O O

H

O

O

H

OH

R′

H

OH

O

H

H

OH

O

H

OH

H

OH

OH

H

OH

H

OH

H

OH

R H

OH

Product =

S

H

OH O

H

OH

O

O2N

O2N

R′ = F, Cl, Br,Me, MeO, NO2

R′ = F, Cl, Br,Me, MeO, NO2

H H

Scheme 6.29

under the catalytic conditions, it is likely to be deprotonated, having an estimatedpKa ∼ 5.

Gold nanoclusters supported on mesoporous ceria have recently been reportedto be active and chemoselective for transfer hydrogenation of aldehydes in water.A wide range of aldehydes, including those that are aromatic, aliphatic, andα,β-unsaturated, are reduced to the corresponding alcohols with high yields [93].α,β-Unsaturated ketones can also be reduced to the allylic alcohols in excellent yieldand good selectivity [93c]. These compounds can be reduced at the C=C bonds inaqueous solution as well. Using PdCl2/SiO2 in a mixture of MeOH–HCOOH–H2O(1 : 2 : 3) with microwave heating, saturated carbonyls were obtained in moderateto excellent yields with high chemoselectivity [94].

CO2 has been reduced as well under transfer hydrogenation conditions catalyzedby the NHC catalysts (32–34, 36, 37, and 39, Scheme 6.19). Using a water-solubleIr(III)–NHC ([IrI2(AcO)(bis-NHC)]) complex, CO2 was reduced to formate in


a mixture of H2O/iPrOH (9 : 1, v/v), with up to 2700 TONs obtained. Thereaction was performed at 110 ◦C and 50 bar CO2 in the presence of 0.5 M KOH[58i].

6.4.1.2 Achiral Transfer Hydrogenation of Imino CompoundsTransition-metal-catalyzed achiral transfer hydrogenation of imines is less docu-mented [95], and even lesser so in aqueous media [95j]. The Ir–diamine complex26 has recently been shown to be highly efficient for the transfer hydrogenationof quinoxalines with HCOONa in water [95j]. Displaying a narrow pH window(around pH 5.5), the reduction was performed in a HOAc/NaOAc buffer solution,affording good to excellent yields for the corresponding tetrahydroquinoxalines(Table 6.5).

As is seen from Table 6.5, 2-alkylated quinoxalines are easily reduced, althoughthe reaction time varies with the size of the side chain (entries 1–8, 10, Table 6.5),with a longer time needed for the substrate bearing a sterically demanding

Table 6.5 Achiral transfer hydrogenation of quinoxalines in water.

N

NR1

R1

R3

R2HCOONa, 80 °CHOAc/NaOAc buffer

26

NH

HNR1

R1

R3

R2

Entry R1 R2 R3 pH Time (h) Yield (%) References

1 H Me H 5.5 0.25 96 [95j]2 H Et H 5.5 1 97 [95j]3 H nBu H 5.5 1 93 [95j]4 H iBu H 5.5 2 96 [95j]5 H Hexyl H 5.5 2 97 [95j]6 H Cyclohexyl H 5.5 6 92 [95j]7 Me Me H 5.5 1 97 [95j]8 Me Et H 5.5 1 96 [95j]9 H H H 5.5 0.25 97 [95j]10 H Me Me 5.5 4 94 [95j]11 H Ph H 4.3 10 97 [95j]12 H 4-F-Ph H 4.3 10 97 [95j]13 H 4-Cl-Ph H 4.3 10 95 [95j]14 H 4-Br-Ph H 4.3 10 95 [95j]15 H 4-MeO-Ph H 4.3 10 97 [95j]16 H 2-MeO-Ph H 4.3 10 94 [95j]17 H p-Tolyl H 4.3 10 93 [95j]18 H 4-Biphenyl H 4.3 10 91 [95j]19 H Styryl H 4.5 12 95 [95j]20 H 2-Cl-styryl H 4.5 12 96 [95j]21 H 3-NO2-styryl H 4.5 12 95 [95j]


alkyl group (entry 6, Table 6.5). Interestingly, the 2,3-disubstituted substrate isreduced only to the cis-isomer and in high yield (94%). However, under thesame conditions, the reduction of 2-aryl substituted quinoxalines is problematic,necessitating lowering the pH from 5.5 to 4.3 and longer reaction times (entries11–21, Table 6.5). Asymmetric transfer hydrogenation of quinoxalines in thepresence of a chiral ligand was also explored; however, the enantioselectivity waspoor, up to 20% ee.

6.4.2Asymmetric Transfer Hydrogenation

6.4.2.1 Asymmetric Transfer Hydrogenation of C=C Double BondsAsymmetric transfer reduction of C=C double bonds in water has been muchless investigated than that of C=O and C=N bonds (see below) [96, 97]. The lesspolar nature of these bonds does not encourage hydride transfer, rendering theirreduction by the catalysts discussed earlier difficult (Section 6.4.1). However, highlypolar C=C bonds can be reduced by transfer hydrogenation in aqueous media [96].A recent example is seen in the chemoselective and enantioselective reductionof β,β-disubstituted nitroalkenes in water [98]. With Rh-76 as catalyst generatedin the usual way, the reduction using formate afforded high yields and good ee’sat 28 ◦C at an S/C ratio of 100 (Table 6.6). A wide range of β,β-disubstitutednitroalkenes, including those bearing electron-donating (entries 1–5, Table 6.6)and electron-withdrawing groups (entries 6–9, Table 6.6), were successfully re-duced with the catalyst. However, the reduction was pH sensitive, with pH5.10–5.58 being found as the optimum pH window, thus necessitating a mixtureof HCOONa/HCOOH as reductant. A stepwise, conjugation addition mechanismappears in operation, which is supported by deuterium-labeling experiments.

6.4.2.2 Asymmetric Transfer Hydrogenation of Simple KetonesAs with most other catalytic reactions, research into asymmetric transfer hydro-genation of ketones in water started with searching for water-soluble catalysts.And as would be expected, this was achieved by synthesizing ligands that dissolvein water (19–22, Scheme 6.2). However, recent studies have demonstrated thatunmodified, water-insoluble ligands can deliver high activity and enantioselectivityfor ketone reduction in water [2g, 4a, 87b–d, 99]. Scheme 6.27 shows examplesof catalysts containing water-insoluble ligands that are effective in aqueous-phaseasymmetric transfer hydrogenation.

Williams and coworkers were the first to explore the asymmetric transferhydrogenation of ketones with water-soluble Noyori-Ikariya-type catalysts in 2001[99ax,ay]. The reduction was performed using catalyst containing a sulfonatedTsDPEN or TsCYDN ligand (19 or 21, Scheme 6.2) in isopropanol with water(up to 51%, v/v) added. The catalyst was in situ generated by reacting the ligandwith [RuCl2(p-cymene)]2 or [Cp*MCl2]2 (M = Rh, Ir). While good to excellentee’s (up to 96%) were achieved, the reaction was generally sluggish under thechosen conditions. It was shown that the reaction went faster with increasing


Table 6.6 Asymmetric transfer hydrogenation of nitroalkenes with Rh-76 in water.

R

NO2

HCOONa/HCOOH28 °C

Rh-76 (1 mol%)

O2N NO2

H2N HN SO

O

CF3

CF376

R

NO2

Entry R HCOONa/HCOOH/SM Time (h) Yield (%) ee (%) References

1 Ph 29/1/1 1 99 86 [98]2 3-MeO-Ph 29/1/1 5 90 90 [98]3 4-MeO-Ph 29/1/1 3 96 81 [98]4 3,4-DiMeO-Ph 29/1/1 5 94 86 [98]5 4-Me-Ph 28/2/1 2 92 79 [98]6 4-F-Ph 28/2/1 2 99 82 [98]7 3-Cl-Ph 28/2/1 2 95 86 [98]8 4-Cl-Ph 28/2/1 2 96 83 [98]9 4-Br-Ph 28/2/1 3 94 82 [98]10 2-Naphthyl 28/2/1 10 90 78 [98]

volume of water in the case of the Ir(III) catalysts. For example, the reductionof 3-fluoroacetophenone with the Ir-21 catalyst gave 82% conversion in 2.5 hwhen the water content was 34%, but 94% conversion when the water level wasincreased to 51%. The enantioselectivities remained virtually unchanged, however,at 93–94% ee.

Asymmetric transfer hydrogenation of aromatic ketones by formate in neatwater was demonstrated at about the same time, where a water-soluble catalyst wasformed by combining [RuCl2(p-cymene)]2 with an (S)-proline amide ligand (22b,Scheme 6.2) [99aw,az]. The reduction was carried out with or without a surfactant,with better results obtained in its presence. As is seen from Scheme 6.30, thereaction afforded good conversions with moderate to good ee’s at 40 ◦C. Theseresults represent the first example of asymmetric transfer hydrogenation in waterwith no organic cosolvents. Water-soluble Rh(III)–Schiff base complexes werelater reported to catalyze similar reductions in aqueous formate solution, affordingmoderate to good reaction rates and ee’s [99av].

A highly water-soluble ligand 20a (Scheme 6.2) was developed around the sametime [99au]. Asymmetric transfer hydrogenation of ketones catalyzed by Ru-20ashowed good activities and moderate to excellent enantioselectivities in the presenceof a surfactant, namely, SDS. Moreover, the catalyst, as it was designated for, can


R

O

R

OHRu-22b

HCOONa, H2O, 40 °CS/C 400, 15–20 h 44–99% conv.

41–94% ee

Substrate = O O

RR = Me, Br, Cl

OMeO

O

MeO

O O O

MeO

MeO

OMeO

OMe

*

Scheme 6.30

be recycled twice without loss of enantioselectivity. Guanidinium has recentlybeen used to modify the TsDPEN ligand, leading to a water-soluble cationicTsDPEN, which, when combined with [Cp*RhCl2]2, permits the asymmetrictransfer hydrogenation of ketones as well as imines and keto esters in water, withee’s up to >99% [100].

A common feature of these investigations, like those in other areas ofaqueous-phase catalysis, is to make the catalysts soluble in water, and surfactantsare usually used to circumvent the problem of low solubility of most organicsubstrates in water. However, an investigation into the behavior of thewater-soluble 77 (Scheme 6.31) and water-insoluble TsDPEN in ketone reductionby HCOONa in neat water revealed surprises [99q, 101]. While Ru-77 was shownto be highly effective in neat water (see below), the TsDPEN-containing 60 wasequally good. Thus, using the precatalyst generated by reacting TsDPEN with[RuCl2(p-cymene)]2, acetophenone was fully reduced into (R)-1-phenylethanol in95% ee by HCOONa in water at 40 ◦C in 1 h at an S/C of 100. In comparison, thereaction run in the HCOOH-NEt3 azeotropic mixture afforded a conversion ofless than 2% in 1 h [99q]. This initial finding has since been proved to be quitegeneral; that is, water enables fast and enantioselective asymmetric reductionof unfunctionalized ketones by HCOONa with a range of metal–diaminecatalysts. These catalysts can generally been prepared in situ by reacting anunmodified ligand with one of the metal dimers aforementioned without addinga base. They show varying solubilities in water, with those containing rhodium

H2N NHTs

O

77

OMeO OMen n

Scheme 6.31


and iridium being more soluble than the ruthenium analogs. However, theydisplay much higher solubility in ketones and alcohols. Hence, the reduction isoften biphasic, with the catalysis probably taking place on water, as mentionedbefore.

The performance of these catalysts in the reduction of the benchmark substrateacetophenone is shown in Table 6.7 [4a, 7d]. The monotosylated diamines, whichhave been shown to be successful ligands for asymmetric transfer hydrogenation ofketones in isopropanol or the HCOOH-NEt3 azeotropic mixture, can all be appliedto the hydrogenation of acetophenone by HCOONa in water, with full conversionsand up to 99% ee’s reached in short reaction times. In general, the reaction in water isfaster than in organic solvents, but with similar enantioselectivities. Under the givenconditions, the Rh(III) catalysts appear to outperform both Ru(II) and Ir(III) in waterin terms of catalytic activity and enantioselectivity, and the camphor-substituted 61and 65 lead to the best enantioselectivity (Table 6.7). It is noted that the reactionwith the Rh–diamine catalysts can be carried out effectively in the open air withoutdegassing and/or inert gas protection throughout, thus making the reduction easierto operate than reactions catalyzed by most organometallic complexes (entries 21,23, 29, and 32, Table 6.7).

Amino alcohol ligands were believed to be incompatible with formic acid asreductant in the past [83g, 99bc]. Table 6.7 shows that 63 and 67 do catalyze thehydrogenation of acetophenone by HCOONa in water; however, the reduction ratesand enantioselectivities were much lower than those obtained with the diamines.The metal complexes containing (−)-ephedrine yielded better results than othersin terms of rates and/or ee’s, and in general, the iridium catalysts exhibited a higheractivity [99n,s,ao]. Terpene-based amino alcohol–Cr(II) complexes have also beenexplored in asymmetric transfer hydrogenation in water, but only with limitedsuccess [103].

The diamine-based protocol has been applied to a range of ketones. Selectedexamples of simple ketones are shown in Scheme 6.32 [4a, 7d]. These substratescan be reduced efficiently with the catalysts 60–75 by HCOONa in water. Unfunc-tionalized aromatic ketones and heterocyclic ketones are all viable substrates withthis reduction system. The reduction is generally easy to perform, affording thechiral alcohols with high ee’s in a short reaction time for most of the substrates. S/Cratios of 100−10 000 have been demonstrated to be feasible [99p]. Of particularnote is the Rh–diamine catalyst 66a, which delivered high conversions for most ofthe ketones in a short reaction time and in most cases, the enantioselectivities weregood to excellent, with ee’s up to 99% and TOFs close to 4000 h−1 in water in theopen air [99o]. The protocol works particularly well for some heteroaryl ketones.Thus, for instance, the reduction of 2-acetylfuran with 66ai was complete within5 min, yielding (R)-1-(2-furyl)ethanol in 99% ee.

Amino acid-derived amides and hydroxamic acids have recently been evaluatedas ligands for asymmetric transfer hydrogenation of ketones in aqueous media[104]. The catalysts were formed by reacting a ligand with a Rh(III) or Ir(III)metal precursor, and the reduction was performed in water using HCOOLi ashydrogen source at 28 ◦C in the presence of 10 mol% SDS as surfactant, leading


Table 6.7 Asymmetric transfer hydrogenation of acetophenone with various catalysts inaqueous media.

Entry Catalyst [H]a S/Cb Temperature Time Conversion ee References(◦C) (h) (%) (%)

1 Ru-20a HCOONa 100 40 24 >99 95 [99au]2 Rh-20a HCOONa 100 40 24 92 84 [99au]3 Ir-20a HCOONa 100 40 24 10 58 [99au]4 Ru-20b HCOONa 100 28 0.5 33 95 [99ab]5 Rh-20b HCOONa 100 28 0.5 97 97 [99ab]6 Ir-20b HCOONa 100 28 0.5 29 94 [99ab]7 Ru-22b HCOONa 400 40 18 98 69 [99aw]8 60 HCOONa 100 40 1 99 95 [99q]9 60 F/Tc 100 40 1.5 >99 97 [99p]10 60 F/Tc 1000 40 9 >99 96 [99p]11 60 F/Tc 5000 40 57 98 96 [99p]12 60 F/Tc 10 000 40 110 98 94 [99p]13 60d HCOONa 100 40 3 >99 96 [99z]14 61 HCOONa 100 40 2 99 97 [99ai]15 61 HCOONa 1000 40 20 95 96 [99ai]16 62a HCOONa 100 40 2 99 85 [99o]17 62b HCOONa 100 40 2.5 >99 81 [102]18 63 HCOONa 100 40 12 84 71 [99n]19 63 HCOONa 40 50 — 13 81 [99s]20 64a HCOONa 100 40 0.5 99 97 [99ba]21 64ae HCOONa 100 40 0.5 99 97 [99ba]22 64b HCOONa 100 40 3.5 99 93 [99ba]23 64be HCOONa 100 40 12 95 92 [99ba]24 65a HCOONa 100 40 0.7 99 99 [99ai]25 65a HCOONa 1000 40 20 89 99 [99ai]26 65b HCOONa 100 40 0.7 99 97 [99ai]27 65b HCOONa 1000 40 2.5 97 98 [99ai]28 66ai HCOONa 100 40 0.25 >99 95 [99o]29 66aie HCOONa 100 40 0.25 99 96 [99o]30 66bi HCOONa 100 40 3 99 93 [99o]31 66aii HCOONa 100 40 0.25 >99 94 [102]32 66aiie HCOONa 100 40 0.25 >99 94 [102]33 66bii HCOONa 100 40 1.5 >99 92 [102]34 67a HCOONa 100 40 20 92 55 [99n]35 67b HCOONa 100 40 5 >99 27 [99n]36 68 HCOONa 200 28 3 100 96 [99ah]37 69 HCOONa 100 60 2–5 >99 93 [87]c]38 71 HCOONa 100 60 2–5 >99 44 [87]c]39 73 HCOONa 100 40 0.5 100 93 [99ac]40 73f HCOONa 100 40 0.5 100 94 [99ac]


Table 6.7 (Continued)

Entry Catalyst [H]a S/Cb Temperature Time Conversion ee References(◦C) (h) (%) (%)

41 73g HCOONa 100 40 0.5 100 94 [99ac]42 74 HCOONa 20 30 12 100 67 [99r]43 75 HCOONa 20 30 40 100 84 [99r]

a[H] refers to hydrogen source.bS/C is substrate to catalyst molar ratio.cF/T, formic acid/triethylamine (mixtures at various molar ratios).dThe reaction was carried out in PEG/H2O.eThe reaction was carried out in open air without inert gas protection.f In the presence of the surfactant, CTAB (cetyltrimethylammonium bromide).g In the presence of the surfactant, SDS.

to high conversions (up to 99%) and enantioselectivities (up to 90% ee) for arylketones [104a]. In related studies, the water-soluble Ru(II) complexes 71, 74, and75 (Scheme 6.27) were applied to the aqueous reduction of ketones, affordinggood yields and ee’s up to 93% [87b–d], and a Ru(II)–prolinamide catalyst wasexplored for the reduction of more challenging aliphatic ketones in water; but onlymoderate enantioselectivities were obtained [105]. The study reveals the importanceof tosylation of the diamine and substitution on the arene ring to both catalyticactivity and enantioselectivity in water.

The tethered complex 68 (Scheme 6.27) was shown to be effective in both organicand aqueous-phase reduction of ketones (Scheme 6.32) [99ah]. Thus, acetophenonewas reduced by HCOONa in water with 68 to give 100% conversion and 96% ee at28 ◦C in 3 h, and in the case of 2-acetylfuran, the catalyst loading could be reducedto 0.01 mol% with an ee of 98% obtained. Remarkably, the catalyst even allows forthe reduction of aliphatic ketones in water, albeit with slightly lower ee’s.

The PNNP ligand 78, which is highly effective in ruthenium-catalyzed asymmetrictransfer hydrogenation of ketones in isopropanol [106], could also be used for theaqueous-phase reduction when combined with [IrHCl2(COD)]2 [99af,aj]. As shownin Scheme 6.33, the reduction of propiophenone was completed in 9 h with 88%ee at 60 ◦C and an S/C ratio of 100 in the presence of a phase-transfer catalyst. Thesame reaction could be run without inert gas protection at a higher S/C ratio of8000 : 1. In the latter case, the reaction afforded 80% isolated yield with 85% ee in101 h. The reduction with the analogous Schiff base ligand led to a much reducedenantioselectivity (34% ee for propiophenone), indicating again the importance ofthe N–H moiety to the reduction.

6.4.2.3 Asymmetric Transfer Hydrogenation of Functionalized KetonesApart from the relatively simple ketones covered so far, functionalized ketones havealso been subjected to asymmetric transfer hydrogenation. For instance, using thecatalysts 64 or 65 under the conditions given in Table 6.7, ketones shown inScheme 6.34 have been reduced with good enantioselectivities.


Cl

O

Me

O

MeO

O

O2N

O

NC

O

OO O

O

OO S

NO O

O

O

O

O

Cl

OMe

O

60 91% ee64a 94% ee66ai 94% ee65b 96% ee

64a 88% ee66ai 87% ee65b 93% eeRu-20a 88% ee

64a 91% ee66ai 90% ee65b 94% ee

60 90% eeRu-22a 90% ee

60 90% ee64a 93% ee66ai 92% eeRu-20a 94% ee

60 97% ee64a 97% ee64b 91% ee66ai 93% ee

Ru-19a 91% eeRh-19a 94% eeRh-21 95% ee65b 97% ee73 95% ee

Ru-19a 95% eeRu-22a 94% ee

Ru-20b 97% ee65b 92% ee73 95% ee68 94% ee

60 94% ee64a 99% ee64b 97% ee66ai 97% eeRh-20a 98% eeRh-20b 98% eeRu-22a 94% ee59 94% ee73 100% ee

60 95% ee64a 97% ee64b 95% ee66ai 95% eeIr-19a 91% eeIr-21 97% eeRu-20b 97% ee

60 95% ee64a 96% ee66ai 95% eeRu-19a 95% eeRu-21 90% eeRh-21 96% eeIr-21 96% ee

Ru-20a 94% eeRu-20b 98% ee65b 97% ee68 91% ee73 100% ee

68 84% ee60 96% ee64a 99% ee64b 96% ee66ai 99% ee68 98% ee

64a 99% ee64b 93% ee66ai 94% eeRh-20a 95% eeRh-20b 98% ee68 97% ee

60 96% ee64a 98% ee

64a 95% ee64b 90% ee66ai 96% ee65b 94% ee

60 90% ee66ai 92% eeRu-20b 95% ee65b 97% ee68 96% eeIr-78 92% ee75 92% ee

Scheme 6.32

Chiral α-hydroxy esters are useful building blocks in asymmetric synthesis [83a,107]. Asymmetric transfer hydrogenation of α-keto esters in water to produce theseesters has recently been demonstrated with Ru(II) catalyst in the presence of a sur-factant (Table 6.8) [107c]. Ru-79, generated from [RuCl2(p-cymene)]2 and 79, whichfeatures a bulky tosyl variant, afforded good conversion and enantioselectivity. Theless bulky ligands were less effective. There are, however, significant effects from thearyl group of the substrates. Thus, high ee’s were obtained with electron-donatinggroup on the aryl ring, while with electron-withdrawing substitutes, much lower eeresulted. In addition, ortho substitution erodes the enantiomeric excess. Surfactant


R

O

R

OHIr-78

HCOONa, H2O, 60 °CS/C 100, 9–50 h 48-99% yield,

55-99% eeSubstrate =

O O O O

O

O

OCl

O

Cl

O O

L =NH HN

Ph2P

78

PPh2

*

Scheme 6.33

O

O

O

F3COEt

O OOO

64a >99% ee64b 97% ee

64a 93% ee65b 92% ee

64a 92% ee64b 85% ee

64a 80% ee 64a 98% ee64b 95% ee

Scheme 6.34

was necessary, and dodecyl trimethyl ammonium bromide (DTAB) proved to bethe best for conversion.

As with asymmetric transfer hydrogenation of α-keto esters, catalytic reductionof α-substituted aryl ketones with high enantioselectivity is still challenging. Anaqueous-phase asymmetric transfer hydrogenation protocol has recently been de-veloped, using an Ir(III) catalyst 80, which bears a perfluorinated, electron-deficientsulfonamide ligand (Table 6.9) [108]. A range of α-cyno aryl ketones were reducedby HCOOH in water at a low catalyst loading. Electron-rich and electron-deficientgroups at the meta and para positions of aryl ring did not adversely affect theselectivity or the conversion, and heteroaromatic ketones, such as furan- andthiophene-substituted ones, are viable substrates as well.

α-Nitro aryl ketones were also reduced efficiently, although a modest increasein catalyst loading was necessary to achieve full conversion. Still interestingly,an α-chloro aryl ketone was shown to be feasible, affording excellent yield andee (Table 6.9) [108]. The resulting chiral chloroalcohol is precursor to terminalepoxides. In contrast to the asymmetric transfer hydrogenation of acetophenones,which perform well at neutral pH, these α-cyano and nitro ketones necessitate a


Table 6.8 Asymmetric transfer hydrogenation of keto esters with a Ru(II) catalyst by formatein water.

R1

OR2O

O Ru-79H2O, HCOONa, 28 °C50 mol% DTAB, S/C 100

R1

OR2O

OH

HNH2N SO2

79

R1 R2 Time (h) Conversion (%) ee (%) References

Ph CH3 1.5 100 90.9 [107c]2-ClPh CH3 1.5 100 75.5 [107c]4-ClPh Et 1.5 100 69.9 [107c]4-OMePh Et 2 100 90.1 [107c]2,4,6-Me3Ph Et 20 50 34.5 [107c]Ph(CH2)2 Et 1.5a 100 63.2 [107c]4-MePh CH3 1.5 100 99.2 [107c]2-OMePh Et 2 100 33.0 [107c]Ph Et 1.5 100 88.5 [107c]Ph iPr 1.5 100 90.0 [107c]1-Naphthyl Et 1.5 100 83.7 [107c]4-MePh Et 1.5 100 91.1 [107c]2-ClPh Et 1.5 100 78.6 [107c]2-ClPh iPr 1.5 100 77.0 [107c]

aS/C = 40.

more acidic condition, with the former preferentially reduced at pH 3.5 while thelatter at 2.0.

A simpler catalytic system has been reported, which enables efficient asymmetrictransfer hydrogenation of α-cyano aryl ketones as well as ketone esters and simplearyl ketones. Using 60 (Scheme 6.27) as catalyst, the reduction was performedin an emulsion formed by CH2Cl2 in aqueous HCOONa in the presence of asurfactant, TBAI (tetra-butylammonium iodide) [109, 110]. Table 6.10 shows theresults obtained with α-cyano aryl ketones, β-keto esters, and an amide. The systemtolerates both solid and liquid substrates, affording excellent enantioselectivities inmost cases. For example, asymmetric transfer hydrogenation of β-keto amide (lastentry, Table 6.10) afforded the corresponding chiral alcohol with 90% yield and98% ee in 1 h, while the same reaction in the azeotropic HCOOH-NEt3 mixture ledto 93% yield and 86% ee in a longer time of 22 h [111].


Table 6.9 Asymmetric transfer hydrogenation of α-substituted aryl ketones with HCOOH inwater.

R1

OR2

80H2O, HCOOH, r.t, 24 h

R1

OHR2

N

NH2

Ph

PhIr

H2O

SO

O

F

F F

F

F

SO42−

80

R1 R2 Catalyst (mol%) S/C pH Yield (%) ee (%) References

Ph CN 0.25 400 3.5 96 94 [108]Ph CN 0.1 1000 3.5 83a 94 [108]3-ClPh CN 0.25 400 3.5 90 90 [108]3-OMePh CN 0.25 400 3.5 96 95 [108]4-FPh CN 0.25 400 3.5 95 91 [108]4-MePh CN 0.25 400 3.5 96 93 [108]4-CNPh CN 0.25 400 3.5 97 86 [108]2-Naphthylb CN 0.25 400 3.5 95 96 [108]2-Furyl CN 0.25 400 3.5 83 96 [108]2-Thiophenyl CN 0.25 400 3.5 94 92 [108]Ph NO2 0.5 200 2.0 94 93 [108]4-tBuPh NO2 0.5 200 2.0 92 99 [108]3-BrPh NO2 0.5 200 2.0 54 91 [108]3-ClPh NO2 0.5 200 2.0 95 95 [108]2-OMePh NO2 0.5 200 2.0 93 83 [108]2-Naphthylb NO2 0.5 200 2.0 53 93 [108]Ph Cl 0.25 400 3.5 93 91 [108]

aThe reaction time was 72 h.b10 mol% hexafluoroisopropanol was added.

6.4.2.4 Asymmetric Transfer Hydrogenation of IminesAsymmetric transfer hydrogenation of imines and related compounds in waterhas only recently been demonstrated. Using the water-soluble ligand 20a, iminesand iminium salts could be smoothly reduced by HCOONa with Ru(II) cataly-sis in water in the presence of cetyltrimethylammonium bromide (CTAB) as aphase-transfer catalyst (Scheme 6.35) [99ag]. The reduction afforded moderate toexcellent yields and ee’s for both imines and iminiums. However, the catalystfailed to reduce acylic imines, which decomposed under the aqueous conditions.The water-soluble, aminated ligand 20b is also effective for the aqueous-phase


Table 6.10 Asymmetric transfer hydrogenation of α-functionalized ketones with catalyst 60 inemulsions.a

Substrates Products Time (h) Yield (%) ee (%) References

3.5 >99 99 [109]OCN

OHCN

6.5 >99 94 [109]OCN

Me

OHCN

Me

4 >99 95 [109]OCN

Cl

OHCN

Cl

0.9 >99 97 [109]

OEt

OO

OEt

OOH

1.5 98 97 [109]

OEt

OOBnO

OBn

OEt

OOHBnO

OBn

1.5 98 48 [109]OMe

O O

OMe

OH O

1.5 93 53 [109]OMe

O OBnO

OMe

OH OBnO

0.9 95 72 [109]OMe

O OF

F

FOMe

OH OF

F

F

1 90 98 [109]

NHMe

OO

NHMe

OOH

aConditions: 1 mmol of substrate, 5 M HCOONa (20 ml), DCM (1 ml), TBAI (2.0 mmol), 40 ◦C, andS/C = 100.

reduction [99ab]. In comparison with the analogous Ru(II) and Ir(III) cata-

lysts, Rh(III)-20b afforded the best performance in the transfer hydrogenation

in terms of reaction rates and enantioselectivities. For instance, the reduction of

6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline gave a 95% yield with a 93% ee in

8 h at 28 ◦C and an S/C ratio of 100. The catalyst also worked well for cyclic imines,

affording up to 93% ee.


NH

MeO

MeOR

*

R = Me, 10 h, 97% yield, 95% eeR = Et, 25 h, 68% yield, 92% eeR = iPr, 25 h, 90% yield, 90% ee

NR1

R2 5 equiv HCOONa0.5 equiv CTAB H2O, S/C 100, 28 °C

HNR1

R2R3R3 *

NH

NH

R*

R = Me, 8 h, 97% yield, 99% eeR = Et, 20 h, 94% yield, 99% eeR = cyclohexyl, 25 h, 96% yield, 98% ee

SNH

O O

R

*

R = Me, 6 h, 97% yield, 65% eeR = tBu, 10 h, 95% yield, 94% ee

NH

MeO

MeOR

*Bn

Br−+

R = Me, 18 h, 86% yield ,90% eeR = Ph, 12 h, 94% yield, 95% ee

Ru-20a

Scheme 6.35

The water-soluble Ru(II)–arene complexes 58 and 69–71 (Scheme 6.27) havebeen shown to catalyze both ketone and imine reduction by HCOONa in water[87c]. In the case of imines, cyclic as well as acyclic substrates could be reducedby the catalysts, with ee’s up to 91% obtained for acyclic and 88% for cyclicimines.

Although the water-soluble catalysts M-20 are effective for the asymmetrictransfer hydrogenation of dihydroisoquinoline type substrates, the Noyori catalyst60 again offers a simpler option in the presence of a surfactant or AgSbF6

[112]. As shown in Table 6.11, a range of 3,4-dihydroisoquinolines and relatedcyclic imines were reduced with sodium formate in water, affording excellentenantioselectivities in most cases. However, a large quantity of CTAB (100 mol%)is generally necessary. Polycyclic iminium salts are also viable under similarreduction conditions but necessitate the addition of AgSbF6, which presumablyhelps generate a cationic Ru(II) catalyst. The protocol allows for the easy accessto indoloquinolizidine alkaloid (−)-(S)-harmicine and its homolog. In addition,imine substrates with aryl substituents conjugated to the imino bond can alsobe reduced. A Lewis acid is added in this case, activating the imine towardhydride attack. In general, these imines have been found more challenging inreduction.

Asymmetric transfer hydrogenation of quinolines has recently been shown tobe highly efficient in water, providing easy access to optically active and bioactivetetrahydroquinolines [78c, 113]. Using the Rh(III) complex 81, an analog of 64,quinolines of diverse electronic and steric properties have been reduced withsodium formate, affording excellent enantioselectivities (Table 6.12) [113a]. Thechain length of the alkyl substituent at the 2-position has little effect on the


Tabl

e6.

11A

sym

met

ric

tran

sfer

hydr

ogen

atio

nof

dihy

droi

soqu

inol

ines

and

dihy

dro-

β-c

arbo

lines

with

60in

wat

er.

Imin

esPr

oduc

tsC

ondi

tions

Tim

e(h

)Yi

eld

(%)

ee(%

)R

efer

ence

s

0.6

mol

%ca

taly

st,

0.25

mm

olim

ine,

CT

AB

,H

2O

,HC

OO

Na,

rt

1690

99[1

12]

N

MeO

MeO

Me

NH

MeO

MeO

Me

0.6

mol

%ca

taly

st,

0.25

mm

olim

ine,

CT

AB

,H

2O

,HC

OO

Na,

40◦ C

1687

99.5

[112

]

N

MeO

MeO

iPr

NH

MeO

MeO

iPr

0.6

mol

%ca

taly

st,

0.25

mm

olim

ine,

CT

AB

,H

2O

,HC

OO

Na,

rt

1690

>99

[112

]

NN H

Me

NH

N HM

e

0.6

mol

%ca

taly

st,

0.25

mm

olim

ine,

CT

AB

,H

2O

,HC

OO

Na,

40◦ C

1692

>99

[112

]

NN H

iPr

NH

N HiP

r

1.2

mol

%ca

taly

st,

0.12

5m

mol

imin

ium

salt

,7

mol

%A

gSbF

6,C

TA

B,

H2O

,HC

OO

Na,

40◦ C

16a

4594

[112

]

N

MeO

MeO

Cl

N

MeO

MeO

H


1.2

mol

%ca

taly

st,

0.12

5m

mol

imin

ium

salt

,7

mol

%A

gSbF

6,C

TA

B,

H2O

,HC

OO

Na,

40◦ C

16a

6596

[112

]

N

MeO

MeO

Cl

N

MeO

MeO

H

1.2

mol

%ca

taly

st,

0.12

5m

mol

imin

ium

salt

,7

mol

%A

gSbF

6,C

TA

B,

H2O

,HC

OO

Na,

40◦ C

1694

98[1

12]

NN H

Cl

NN H

H

1.2

mol

%ca

taly

st,

0.12

5m

mol

imin

ium

salt

,7

mol

%A

gSbF

6,C

TA

B,

H2O

,HC

OO

Na,

40◦ C

1685

98[1

12]

NN H

Cl

NN H

H

1.3

mol

%ca

taly

st,

0.12

5m

mol

imin

e,2.

4m

ol%

AgS

bF6,3

3m

ol%

Bi(

OT

f)3,C

TA

B,H

2O

,H

CO

ON

a,40

◦ C

1687

b94

[112

]

N

MeO

MeO

Ph

NH

MeO

MeO

Ph

1.3

mol

%ca

taly

st,

0.12

5m

mol

imin

e,2.

4m

ol%

AgS

bF6,C

TA

B,

H2O

,HC

OO

Na,

40◦ C

1690

99[1

12]

N

MeO

MeO

Bn

NH

MeO

MeO

Bn

(con

tinu

edov

erle

af)


Tabl

e6.

11(C

ontin

ued)

Imin

esPr

oduc

tsC

ondi

tions

Tim

e(h

)Yi

eld

(%)

ee(%

)R

efer

ence

s

1.3

mol

%ca

taly

st,

0.12

5m

mol

imin

e,2.

4m

ol%

AgS

bF6,3

3m

ol%

La(O

Tf)

3,H

2O

/MeO

H(2

/1),

HC

OO

Na,

40◦ C

4078

98[1

12]

NN H

Ph

NH

N HP

h

1.3

mol

%ca

taly

st,

0.12

5m

mol

imin

e,2.

4m

ol%

AgS

bF6,3

3m

ol%

La(O

Tf)

3,H

2O

/MeO

H(2

/1),

HC

OO

Na,

40◦ C

1699

b70

[112

]

N

MeO

MeO

O

NH

MeO

MeO

O

1.3

mol

%ca

taly

st,

0.12

5m

mol

imin

e,2.

4m

ol%

AgS

bF6,3

3m

ol%

La(O

Tf)

3,H

2O

/MeO

H(2

/1),

HC

OO

Na,

40◦ C

1650

94[1

12]

N

MeO

MeO

S

NH

MeO

MeO

S

a[R

uC

l 2(b

enze

ne)

] 2w

asu

sed

aspr

ecu

rsor

to60

.bC

onve

rsio

n.


N NH

2 mol% 81B, HCOONapH 5 buffer, 40 °C

Me Me

Me Me

NH

N

89% yield,92% ee (dr : 4 : 1)

95% yield,86% ee (dr : 99 : 1)

Scheme 6.36

enantioselectivity (96–97% ee, from methyl to hexyl); the same is true for varioussubstituents at the 6- or 7-position. Of particular note are the high ee values observedwith some sterically demanding substituents at the 2-position, and the observationthat isolated C=C bonds are tolerated under these conditions. 2,3-Disubstitutedquinolines are also reduced, with good enantioselectivities (Scheme 6.36) [113a].

A notable feature of this hydrogenation protocol is the effect of solution pH,which impacts dramatically on the reduction rate, with the best value being 5 [113a].This is in contrast to the optimal pH window (pH ∼ 7) for simple ketones andsuggests that it is the protonated quinoline (pKa ∼ 5) that is reduced. As a result,the reactions shown in Table 6.12 and Scheme 6.36 were performed in a solutionbuffered to pH 5. In the case of the less basic 2-aryl-substituted substrates, a moreacidic condition (pH 4) was necessary and the complex 81B was more effective than81A [113a].

6.4.3Asymmetric Transfer Hydrogenation with Biomimetic Catalysts

Unlike organometallic catalysis, asymmetric transfer hydrogenation of ketonesin aqueous media with enzymes and microorganisms is well documented [114].Various aromatic as well as aliphatic ketones can be reduced stereoselectively usingalcohol dehydrogenases, microorganisms, and whole microbial cells [114a, 115].However, baker’s yeast is by far the most widely used microorganism [114a].

Aiming to broaden the substrate specificity of natural enzymes and discovernew enzymes for novel transformations, artificial metalloenzymes, which inte-grate metal complexes with biocatalysts, have been explored in enantioselectivecatalysis since the 1970s [116]. The recent study by Ward et al. [117] of combinedchemogenetic optimization of artificial metalloenzymes, that is, chemically tuningthe active metal centers while genetically modifying the host proteins, offers anew strategy to discover more efficient, enzymelike catalysts. Biotin displays astrong affinity for strept(avidin), allowing biotinylated molecular metal catalysts tobe incorporated into proteins and potentially forming artificial metalloenzymes.Indeed, the incorporation of a biotinylated achiral Ru(II)/1,2-diamine catalyst intoa host protein, avidin or streptavidin, has been shown to afford a versatile artificial


Table 6.12 Asymmetric transfer hydrogenation of quinolines with rhodium catalysts inwater.

NR1

NH

R1

NH2

NPh

Ph

Rh

SO O

Ar

Cl

A: Ar = 4-tBu-C6H4

B: Ar = 3,5-(CF3)2C6H3

81

R2 R2

81 (1 mol%), HCOONapH 5 buffer, 40 °C

R1 R2 Catalyst Time (h) Yield (%) ee (%) References

H Me 81A 6 96 97 [113a]H Et 81A 6 95 96 [113a]H nPr 81A 6 93 97 [113a]H nBu 81A 6 94 97 [113a]H Pentyl 81A 6 95 97 [113a]H Hexyl 81A 6 92 97 [113a]H iPr 81A 12 86 91 [113a]H Cy 81A 12 88 98 [113a]H iBu 81A 6 97 97 [113a]H Cy 81A 24 87 96 [113a]H 4-MeOC6H4(CH2)2 81A 12 84 97 [113a]H 4-MeOC6H4CH2 81A 24 80 96 [113a]H i-Pentyl 81A 9 90 97 [113a]H Ph 81B 24 96 90 [113a]H 4-MeOC6H4 81B 24 95 90 [113a]H 4-FC6H4 81B 24 93 89 [113a]6-F Me 81A 6 96 96 [113a]6-Cl Me 81A 6 95 96 [113a]6-Br Me 81A 6 96 95 [113a]6-Me Me 81A 12 91 96 [113a]6-OMe Me 81A 12 90 98 [113a]7-F Me 81A 6 97 96 [113a]

metalloenzyme capable of reducing ketones with formate in buffered aqueoussolution (Scheme 6.37) [99aq, 117, 118]. The reduction of aromatic ketones wentsmoothly under optimized conditions, furnishing enantioselectivities of up to 97%ee. Selected chiral products are shown in Scheme 6.37 [99aq]. To identify the bestmetalloenzyme with matched active metal site and chiral protein pocket, the metalcomplex was modified by varying the arene ligand and the spacer group, whilethe host protein was genetically optimized by point mutations. The study suggests


O

R2 R2

H OHArtificial metalloenzyme

HCOOH, buffer, 55 °C40–64 h, Initial pH = 6.3

OH OH OH

Br Me95% conv., 90% ee 88% conv., 92% ee 98% conv., 91% ee

NOH

O

OH

OH

OH

79% conv., 97% ee95% conv., 76% ee 71% conv., 30% ee 98% conv., 48% ee

97% conv. 69% ee

OH

Product =

R1 R1

M = Ru(II), n = 6M = Rh(III), Ir(III), n = 5

Artificial metalloenzyme

HN

HN

S

O

SN

O

O

N

MHH

H O

++Spacer

(Strept)avidin

(Biotin)

hn-CnHn

Scheme 6.37

that the catalytic activity of these artificial metalloenzymes is dependent on thelocalization of the biotinylated metal catalyst, with the properties of the η6-boundarenes playing a critical role in the enantioselection.

In a twist to the approach above, β-cyclodextrin has been used to modify metalcatalysts, enhancing the solubility of hydrophobic substrates in water [119]. A Ru(II)complex so generated (82) served as efficient catalysts in transfer hydrogenationin water using HCOONa as hydrogen source [99b,c]. Unconjugated ketones werereduced with high ee’s and yields, although the S/C ratios were low (Scheme 6.38).The β-cyclodextrin also appears to play an important role in the enantiocontrolthrough preorganization of the substrates in its hydrophobic cavity. More recently,an achiral ruthenium unit has been attached to the secondary face of β-cyclodextrin(83). The catalyst allows for the reduction of challenging aliphatic ketones, affordingee’s up to 98% remarkably [119c]. The enantioselection presumably arises fromchiral relay from β-cyclodextrin to ruthenium, which changes the later into a‘‘chiral-at-metal’’ species.

Enzymatic reduction of ketones with alcohol dehydrogenases often uses expen-sive NADH cofactors. Metal catalysts can be used to recycle the oxidized cofactors.For instance, the achiral rhodium complexes 55b and 59 (Scheme 6.27), whichare compatible with alcohol dehydrogenases, are able to catalyze the reduction


OH OH OH OH OH

77% ee 80% eeMe

94% ee

Cl tBu82: 87% ee83:

97% ee

OH OH OH OH

OH

OH

O

OH OH O

82: 51% ee83: 85% ee

82: 42% ee83: 82% ee

86% ee 95% ee 88% ee

82: 95% ee83: 98% ee

82: 74% ee83: 92% ee 57% ee

R1 R2

O

R1 R2

H OH82

HCOONa, H2O/DMF, 50 °C

Product =

Catal =

NRu

O

ClbCD bCD

Ru

82 83

N

O

OHOH

H

Cl

89% ee

Scheme 6.38

of NAD+ with formate in water, thereby closing the catalytic cycle of transferhydrogenation. As shown in Table 6.13, aliphatic ketones were reduced with highenantioselectivity and good conversion (Table 6.13) [87d, 120]. The reduction canbe scaled up to produce gram quantities of the chiral alcohols.

6.4.4Asymmetric Transfer Hydrogenation with Immobilized Catalysts

Catalyst separation is an important issue in homogeneous catalysis, and this canbe addressed by using catalysts that bear water-soluble ligands or are immobilizedon solids. The unmodified chiral diamine ligands discussed above are soluble incommon organic solvents but generally insoluble in water and thus present aproblem to catalyst separation and reuse. This has been dealt with to various degreeof success in recent studies, which are briefly summarized in this section.


Table 6.13 Chemoenzymatic asymmetric transfer hydrogenation of ketones with HCOONa.

Catalyst/enzyme

R1

O

R1

H OH

NADH NAD+

HCO2−CO2

R1 Enzymea Catalyst Time (h) Conversion (%) ee (%) References

Ph(CH2)2 S-ADH 55b 43 89 >99 [120]Ph(CH2)2 HLADH 55b 23 90 96 [120]Ph(CH2)2 HLADH 59 24 80 96 [87d]Ph S-ADH 59 24 20 98 [87d]

aS-ADH, alcohol dehydrogenase from Rhocodoccus sp.; HLADH, horse liver alcohol dehydrogenase.

The half-sandwich catalysts of Sections 6.4.1–4.2 are often (partially) soluble inwater but insoluble in nonpolar solvents. In this case, the product can be extractedwith a nonpolar solvent such as diethyl ether without recourse to purposely builtwater-soluble catalysts, and this has been demonstrated [4a, 7d, 99l]. A good exampleis the reduction catalyzed by Ru-22b mentioned earlier, which could be reusedup to six times without compromising ee’s [99az]. Recently, a similar catalyst wasalso shown to be effective in the asymmetric transfer hydrogenation of aromaticketones and recyclable in water [99ae].

For more practical and easier catalyst/product separation, highly water-solubleligands or those that are supported on solid surfaces are desirable. As describedpreviously, Ru-20 has been shown to be an efficient catalyst for asymmetric transferhydrogenation of ketones and imines in water. Given the hydrophilic nature of20 (Scheme 6.2), the catalyst can be readily separated from the product by simpledecantation [99au]. The PEG-supported 77 (Scheme 6.31) represents an exampleof water-soluble polymeric ligand. As with its nonsupported counterpart, Ru-77 isalso highly effective for the asymmetric transfer hydrogenation in water towarda wide range of aromatic ketones, with results comparable to those obtainedwith 60 (Scheme 6.27). The advantage in using Ru-77 is that the product can beeasily separated from the catalyst-containing aqueous phase. To demonstrate itsrecyclability, the reduction of acetophenone by HCOONa with Ru-77 in water wascarried out, with the product extracted with diethyl ether [99as]. An ICP analysisshowed that 0.4 mol% of ruthenium leached into the organic phase. Remarkably,the PEG-immobilized catalyst could be reused 14 times with no loss in enantios-electivity, demonstrating its excellent recyclability and durability under aqueousconditions. In contrast, when carried out in HCOOH-NEt3 without water, therecycle was possible only for two runs without the rates and ee’s being eroded [101a].


NH2

NHSO O S OO

O−

X+ O−

X+

a: X = Na+

b: X = PhCH2(n-Bu)3N+

NH2

NHSO O S OO

a: X = Na+

b: X = PhCH2(n-Bu)3N+

84 85

SO

OX

86 = Silica gel87 = MCM-4188 = SBA-15

90 = PEG

SO

O

HN C

O

95 = Dendrimer

91 = C12H25

89 = SBA-100 nanocage

92 = Flourinated dendrimer

NN

Rh

PhPh

Cl

HS

O

OHN

OR

OR = 98 OMe

99 NH-PG100 NH-PP memberane101 NH-PE sinter chip

93 = SiO2-coated F3O4 nanoparticle

96 = Resin

TsHN HN OO

Rn94

a: R = H, n = PEG-200b: R = Me, n = PEG-750c: R = H, n = PEG-2000

SO

OX 97 = SiO2-coated F3O4 nanoparticle

0.1 0.1 0.1 0.80.9

H2N HN

H2N HN

H2N HN

Scheme 6.39


A variety of diamine ligands have been immobilized at the nitrogen side.Examples are found in Scheme 6.39, with their use in the reduction of thebenchmark acetophenone given in Table 6.14. The PEG-supported 90 is effectiveand recyclable in Ru(II)-catalyzed asymmetric transfer hydrogenation in water[99t, 107c, 121]. Similar results were obtained with the ligands 94, in which thePEG chain is attached to the amino moiety (entries 13–15, Table 6.14) [121c].Unlike 90, the ligand 91 bears a lipophilic, long aliphatic chain. In asymmetrictransfer hydrogenation in micelles created by SDS, the aliphatic chain increasesthe solubility of the catalyst in water. Indeed, the catalyst works very well for arylketones at room temperature, furnishing good to excellent conversion and ee; it is,however, less efficient with aliphatic ketones [99y].

The polystyrene-supported diamine 84 has been combined with [RuCl2(p-cymene)]2 and [Cp*RhCl2]2 for asymmetric transfer hydrogenation [99am,127]. As shown in Table 6.14, the reduction of acetophenone with Ru-84 byHCOONa in water affords excellent enantioselectivity (entry 2, Table 6.14) [99am].The cross-linked polymer 85 has also proved to be efficient in the reduction ofketones in water, and the catalyst can be recycled five times, giving about thesame ee values in each run (entry 3, Table 6.14). These polymeric catalysts arealso effective for asymmetric transfer hydrogenation of imines in MeCN withthe azeotropic HCOOH/NEt3 as hydrogen source [127d]. For these catalysts,the microenvironment within the polymer network appears to be important tostereoselection.

Dendrimer-supported ligands provide yet another example of recyclable catalysis.A Ru(II) catalyst, Ru-92, derived from the fluorinated dendritic ligand 92, isshown to be viable for asymmetric reduction of ketones, exhibiting remarkablerecyclability (entry 10, Table 6.14) [110]. In the asymmetric transfer hydrogenationof acetophenone, excellent conversion and ee’s were obtained in the first nineruns with no extension of reaction time, and the reaction still afforded 93%conversion and 91% ee in 18 h in the 24th run. In addition, the first-generationdendritic ligand 95 ligated to Rh(III) could be reused up to six times withoutenantioselectivity eroded (entry 16, Table 6.14) [99ak]. The S/C ratio could beincreased to 10 000 : 1.

Tethered Rh(III)–diamine catalysts have been immobilized on amine-functionalized hyperbranched polyglycerol (PG), polypropylene (PP), andpolyethylene (PE) (98–101, Scheme 6.39) [126, 128]. The catalysts give excellentenantioselectivties in asymmetric transfer hydrogenation of ketones in water.Using a HCOONa/HCOOH (1 : 1) mixture as hydrogen source, catalyst 101can be used seven times without loss of enantioselectivity in the reductionof acetophenone at 40 ◦C and an S/C ratio of 430. The reduction is faster inthe presence of HCOOH, a phenomenon somewhat in contrast to the neutralconditions aforementioned. Other catalysts that are soluble in ionic liquids orare immobilized on polymers and other materials have also been investigated forasymmetric transfer hydrogenation [4a].

Inorganic support has been explored as well, as seen in the ligands 86–89 and93 [99ab,ak,an,ap,ar, 122, 125–127a, 128, 129]. These ligands are effective in both


Table 6.14 Asymmetric transfer hydrogenation of acetophenone (acp) with supportedcatalysts.

O OHCatalystsHCOONa, H2O

Entry Catalysts Conditions Run Time (h) Conversion (%) ee (%) References

1 Ru-77 acp (1 mmol), H2O(2 ml), 40 ◦C, S/C 100

1–14 1–8 >99−87 93−92 [99as]


1 3 100 98 [99am]


1–5 3 100 98−97 [99am]

4 Ru-86 H2O (2 ml), 40 ◦C,S/C 100, TBAB(4 mol%)

1–7 2–60 >99−60 96 [99ar]

5 Ru-87 acp (0.4 mmol), H2O(0.4 ml), 40 ◦C, SDS

1 22 >99 87 [99ap]

6 Ru-88 acp (0.4 mmol), H2O(0.4 ml), 40 ◦C, SDS

1–4 8–47 >99−43 92–94 [99ap]

7 Ru-89 acp (0.1 mmol), H2O(0.2 ml), 40 ◦C, S/C100

1 2.5 >99 92 [122]


1–8 2–4 >99−96 97−95 [99t]

9 Rh-91 H2O (2.5 ml), 28 ◦C,SDS (10 mol%), S/C100

1 17 97 97 [99y]

10 Ru-92 H2O (2 ml), 40 ◦C,TBAI (0.5 equiv),S/C 100

1–26 4–24 >99−93 97−88 [110]

11 Rh-93 H2O (2 ml), 40 ◦C,TBABr (0.4 equiv),S/C 500

1–10 8 97−92 98−93 [123]

12 Ir-93 H2O (2 ml), 40 ◦C,TBABr (0.4 equiv),S/C 500

1–10 8 99−96 89−86 [124]

13 Ru-94a H2O (1 ml), 40 ◦C,PEG-200 (1.0 g), S/C100

1–4 6 99−87 94−93 [121c]

14 Ru-94b H2O (1 ml), 40 ◦C,PEG-750 (1.0 g), S/C100

1–7 6–12 >99−80 94−93 [121c]

15 Ru-94c H2O (1 ml), 40 ◦C,PEG-2000 (1.0 g),S/C 100

1–10 6 >99−85 94 [121c]


Table 6.14 (Continued)

O OHCatalystsHCOONa, H2O

Entry Catalysts Conditions Run Time (h) Conversion (%) ee (%) References

16 Rh-95 acp (0.4 mmol), H2O(1 ml), 40 ◦C, S/C 100

1–6 0.67–1.5 >99−85 96−94 [99ak]

17 Rh-96 H2O (1 ml), 40 ◦C,S/C 100

1–3 — 98−31 84−80 [125]

18 Rh-97 H2O (2 ml), 40 ◦C,TBABr (0.4 equiv),S/C 500

1–10 8 >99−97 88−84 [124]

19 98 acp (0.43 mmol),H2O (1 ml), 40 ◦C,S/C 100

1 6 100 98 [126]

20 99 acp (0.43 mmol),H2O (1 ml), 40 ◦C,S/C 100

1 6 100 98 [126]

21 100 acp (1 mmol), H2O(40 ml), 50 ◦C, S/C450

1 8 100 98 [126]

22a 101 acp (1 mmol), H2O(10 ml), 40 ◦C, S/C430

1–7 4 82−59 98 [126]

a1 : 1 HCOONa/HCOOH.

organic and aqueous media, with 86 being most efficient. Although taking a longtime to complete in recycle runs even in the presence of a surfactant, the catalystdisplayed excellent recyclability in terms of enantioselectivity – up to 11 recycleswithout loss of ee’s [99ap,ar].

Catalyst separation could be made easy with molecularly imprinted catalysts,with the potential benefit of enzymelike shape selectivity. This is seen in arecent example where the catalyst 60 is immobilized on SiO2 surface and im-printed onto hydrophobic organic polymer matrices with a chiral alcohol product,(R)-1-(o-flurophenyl)ethanol, as template [130]. The imprinted catalyst showed fineshape selectivity and good enantioselectivity (80% ee) in the asymmetric transferhydrogenation of o-fluoroacetophenone in water.

Magnetically recoverable catalysts have also been explored for asymmetric trans-fer hydrogenation in water. The chiral ligands, such as TsDPEN and TsCYDN, weremodified and attached to SiO2-coated Fe3O4 nanoparticles (93, 97, Scheme 6.39)[123, 124]. When combined with a rhodium or iridium precursor compound, theresulting catalyst exhibits high catalytic activities and enantioselectivities in the


reduction of aromatic ketones, and it can be recovered easily via a small magnetand reused 10 times in the reduction of acp in water without obviously losing theactivity and enantioselectivity (entries 11–12, 18, Table 6.14).

6.5Role of Water

It is clear now that hydrogenation in water is not only viable but can also gain inreaction rates and selectivities. In most cases, however, the role of water is not clear.In fact, this aspect of aqueous reduction has only received significant attention inrecent years. What is clear now is that water is in general not an innocent spectatorand it could play a role in every step of a catalytic cycle.

6.5.1Coordination to Metals

Many metal complexes are known that contain coordinated water molecules. Thewater molecule may render the complex water soluble, stabilize it, and enhanceor impede its reaction with a substrate. An illustrative example is found insome half-sandwich Ru(II), Rh(III), and Ir(III) chloro complexes, which can beused in both hydrogenation and transfer hydrogenation. These complexes readilyundergo Ia type of aquation to give monoaqua dications in water (Scheme 6.40).In several instances, the aquation and anation equilibrium constants have beendetermined, which generally favor the formation of anation products [131]. In thecase of [Ru(arene)(ethylene diamine)Cl][PF6], the equilibrium constants are in theorder of K ∼ 0.01 M and do not vary significantly with the arene ligand [131c].The monoaqua complexes have been isolated and structurally characterized in anumber of cases [85e, 87b, 131c].

The aqua complexes may undergo deprotonation in water, forming hydroxospecies, which can slow down catalysis by inhibiting the coordination of reductantssuch as H2 or formate (Scheme 6.40). The pKa values of these half-sandwichcomplexes are about 7–9, and interestingly, they do not appear to vary significantlywith the central metal atom and its ligands [59b, 131b,c]. However, the closely

+ 2+

+ + Cl−H2O

2+ +

+ H+pKa

KM ClLL

M OH2LL

M OHLL

M OH2LL

Scheme 6.40

6.5 Role of Water 229

related triaqua complexes [M(arene)(H2O)3]2+ are much more acidic, showing theimportance of LL in attenuating the electrophilic properties of M.

6.5.2Acid–Base Equilibrium

Water involvement in acid–base equilibra is ubiquitous. In hydrogenation reac-tions, water can act as a proton carrier, facilitating protonation of substrates andcatalysts, or use its conjugate base to affect deprotonation. For instance, dependingon the solution pH, a dehydroamino acid may exist in either neutral or ionizedform in water. Consequently, the hydrogenation rate and/or selectivity may varywith the pH, as the mode of olefin coordination to catalysts could be affected [77,132]. The effect of pH on the reduction of CO2, ketone, and imino bonds has beentouched earlier.

Recent DFT calculations revealed that hydride generation in hydrogenationreactions is facilitated by water [27, 28]. Thus, the model dihydrogen complexRuCl(H2)(OR)(PPh3) is deprotonated by water molecules, leading to the corre-sponding hydride and H3O+ with a barrier of only about 16 kJ mol−1 [27]. Ina related complex RuH(OR)(PPh3)(H2O), external water was shown to act as anacid, protonating the coordinated alkoxide. In contrast, intramolecular reductiveelimination to give HOR is more costly in energy [28].

A significant consequence of the acid–base equilibrium is the pH effect onthe rate and selectivity of hydrogenation. As aforementioned, the Ru–TPPMScatalyst exists mainly as RuClH(TPPMS)3 at low pH but as RuH2(TPPMS)4

under basic conditions, and they show contrasting selectivities for α,β-unsaturatedcarbonyls [25]. A good example illustrating the complex interplay of solution pH,concentration of reactants and catalysts, and hydride stability is found in thehalf-sandwich complex 55a-catalyzed transfer hydrogenation of ketones in water.The reaction is highly pH dependent, showing a maximum rate at around pH 2 inthe case of cyclohexanone. This pH dependence can be traced to the equilibriain Scheme 6.41 (LL = bipy). In particular, below pH 1, the hydride is protonated,giving off H2, and at pH > 7, the aqua complex is deprotonated, resulting in aninactive hydroxo species. At the optimum pH 2, the reduction is facilitated byproton–carbonyl interactions, which lowers the LUMO of the latter. It is noted,however, that the hydride itself is stable in a wide pH window of 1–9 [85e].

Imine reduction is particularly affected by solution pH. Most of the reactionsconcerning imino compounds covered in this chapter proceeds via an ionicmechanism, in which the hydride is generated from H2 or formate and is transferredinto a protonated imine without its coordination to the metal. Scheme 6.42highlights the key aspects of the mechanism [78c]. One can easily envisionthat solution pH will affect the concentration of both the hydride and iminiumcation and hence the reaction rates. Examples are found in Sections 6.4.1.2and 6.4.2.4.

A further example, illustrating the effect of pH on catalyst stability, is seen inasymmetric transfer hydrogenation. The catalysts 64a and 64b displayed a pH


+

+ + H2H+ pH < 1lrLL

H

2+

lrLL

OH2H2O

HCOOH HCO2− + H+

pKa = 3.6

pKa = 6.6

2+

lrLL

OH2

+

lrLL

OH + H+

Scheme 6.41

M+

N

R2R1

R3

H H

M-H +N

R2R1

R3H

N

R2R1

R3H

Scheme 6.42

window of 5.5–10 and 6.5–8.5, respectively, for TOF > 50 h−1 in the asymmetrictransfer hydrogenation of acetophenone in water [99ba]. At lower pH values, notonly did the TOF decrease, the enantioselectivites eroded as well. Various lines ofevidence indicate that apart from the effect of pH on [HCOO−] (Scheme 6.41), thepH effect on both the reaction rate and the enantioselectivity can be accounted forby the equilibrium shown in Scheme 6.43. The protonation of the chiral ligandexplains why the catalyst behaves poorly at low pH values [99m].

6.5.3H–D Exchange

Hydrogenation in water often encounters H/D exchange. This has beenstudied both experimentally and theoretically. For instance, the water-solubleCpRuH(PTA)2 catalyst, discussed in Section 6.3.1.1, readily undergoes H/D

6.5 Role of Water 231

M

Ph

TsHN NH2

Ph

OH2M

Ph

TsN NH2

Ph

OHM

Ph

TsN NH2

Ph

OH2

−H+

HXX

++

Scheme 6.43

exchange in D2O, having a t1/2 of 127 min at 25 ◦C. Kinetic measurements showthat this process is associated with an activation enthalpy �H �= = 68 kJ mol−1

and activation entropy �S�= = −94 J K−1 mol−1, indicative of an associativemechanism. A possible process explaining the exchange involves protonation ofthe hydride to give a dihydrogen intermediate, deprotonation of which by theresulting hydroxide then leads to H/D exchange (Scheme 6.44) [133].

RuATPATP

H

D2O

H2ORu

ATPATP

DRuATP

ATPD

H

+OD−/OH−

Scheme 6.44

Water-soluble phosphine complexes of rhodium and ruthenium are known tocatalyze the H/D exchange between H2 and D2O. DFT calculations show thatthis is likely to occur again via a dihydrogen species formed by protonationof a metal hydride, highlighting the possibility of extensive H/D exchange inhydrogenation reactions in water [134]. In asymmetric transfer hydrogenation,RuCl(TsDPEN)(p-cymene) 60 is also known to catalyze H/D exchange betweenDCOO− and H2O [99m].

6.5.4Participation in Transition States

Well-documented examples are available, which show that water can acceler-ate chemical reactions. The acceleration may stem from hydrophobic effects orhydrogen-bonding interactions, although the exact role of water remains to bedefined in most cases. As aforementioned, there are examples of hydrogenationreactions, which run faster in water than in common organic solvents. Recent DFTcalculations have traced this to water participating in the transition states of hydridetransfer.

The example of CO2 hydrogenation catalyzed by RuH2(PMe3)4 is illustrative.Calculations show that the reduction of CO2 to formate with this complex in thepresence of water involves an unusual mechanism (Scheme 6.45) [135]. CO2 doesnot directly interact with the metal center; instead, a nucleophilic attack by thehydride takes place, with a low activation barrier of only 14 kJ mol−1. As shown,this process is facilitated by hydrogen bonding between a coordinated H2O andthe CO2 oxygen [135b]. A similar interaction is suggested for the aqueous-phasehydrogenation of α,β-unsaturated aldehydes with RuH2(PR3)4 (Section 6.3.1.1).


L Ru HL

LO

H

H H

+ L Ru RuHL

LO

H

H H OCO L O

L

LO

H

H H O

HCO2

Scheme 6.45

Furthermore, the presence of water suppresses the reverse reaction, that is,deinsertion of CO2 from the resulting formate. In contrast, in the absence of water,the formate is formed by the usual CO2 insertion into the Ru-H bond, the energybarrier of which is much higher, at 74 kJ mol−1. Still further, deinsertion is easierin the absence of water, further reducing the reduction rate in aprotic solvents[135b].

Asymmetric transfer hydrogenation of ketones provides another example, wherewater has been shown to confer faster reduction rates [99q]. For instance, instoichiometric reduction of acp by isolated Ru(II)-H, the rate in wet CD2Cl2 was sixtimes that in dry CD2Cl2. DFT calculations revealed that water participates in thetransition state of hydrogen transfer, stabilizing it by about 16 kJ mol−1 throughhydrogen bonding with the ketone oxygen (Scheme 6.46) [99m]. Of further interestis that the calculations, together with kinetic isotope measurements, suggest thatthe participation of water renders the hydrogen transfer process more stepwisethan concerted [99m, 136].

Ar

OC

O

Ar

H

RuN

NPh

Ph

HH

HTs RuN

NPh

Ph

HH

HTs RuN

NPh

Ph

H

Ts

OH

Ar

OH+H2O

Scheme 6.46

Hydride formation can also be accelerated by water. DFT calculations show thatthe reaction of CpRuCl(PTA)2 with H2 proceeds heterolytically, forming the hydridespecies shown in Scheme 6.6 (Scheme 6.44). Three water molecules participatein the transition state of this reaction, resulting in a hydrogen-bonding networkbetween a nitrogen atom of the PTA ligand and the departing proton from H2. Asa result, the energy barrier of H2 activation is lowered [19d].

6.6Concluding Remarks

Aqueous-phase hydrogenation reactions have been extensively investigated overthe past few decades. Numerous examples have been documented in the literature,as attested by this chapter, showing that the reduction in water is viable and,

References 233

importantly, can gain from using water as solvent. Apart from making easycatalyst/product separation, water can confer enhanced activities and selectivitiesonto a catalyst. These benefits come often with a price, however, that is water-solubleligands are usually necessary, and furthermore, their use may result in severemass transfer problems. This said, the half-sandwich metal complexes in thepreceding sections function remarkably well in asymmetric transfer hydrogenation,necessitating no ligand modifications. This brings up a fundamentally importantissue, the role of water in catalytic hydrogenations or in any other reactions. Inmost cases, this is not clear or has been neglected. Although progress has beenmade, much remains to be done if more advantageous use of water is to beexpected.

Water is the ‘‘greenest’’ solvent man has. It has contributed toward greeningreduction reactions both commercially and in laboratories in the past. With theever pressing environment issues facing the chemical industries, water is expectedto play an increasing role in one of the most important areas of organic synthesis,hydrogenation, and transfer hydrogenation.

References

1. (a) Augustine, R.L. (1996) Heteroge-neous Catalysis for the Synthetic Chemist,Marcel Dekker, Inc., New York; (b)Devries, J.G. and Elsevier, S.J. (eds)(2006) Handbook of Homogeneous Hy-drogenation, Wiley-VCH Verlag GmbH,Weinheim; (c) Ertl, G., Knozinger, H.,Schuth, F., and Weitkamp, J. (eds)(2008) Handbook of Heterogeneous Catal-ysis, Wiley-VCH Verlag GmbH, NewYork, Weinheim.

2. (a) Li, C.J. and Chan, T.H. (1997) Or-ganic Reactions in Aqueous Media, JohnWiley & Sons, Inc., New York; (b)Cornils, B. and Herrmann, W.A. (1998)Aqueous-phase Organometallic Catalysis:Concepts and Applications, Wiley-VCHVerlag GmbH, Weinheim; (c) Joo, F.(2001) Aqueous Organometallic Catalysis,Kluwer, Dordrecht; (d) Dwars, T. andOehme, G. (2002) Adv. Synth. Catal.,344, 239–260; (e) Sinou, D. (2002)Adv. Synth. Catal., 344, 221–237; (f)Breno, K.L., Ahmed, T.J., Pluth, M.D.,Balzarek, C., and Tyler, D.R. (2006)Coord. Chem. Rev., 250, 1141–1151; (g)Liu, S.F. and Xiao, J.L. (2007) J. Mol.Catal. A-Chem., 270, 1–43.

3. (a) Shaughnessy, K.H. (2009) Chem.Rev., 109, 643–710; (b) Butler, R.N. andCoyne, A.G. (2010) Chem. Rev., 110,

6302–6337; (c) de Cienfuegos, L.A.,Robles, R., Miguel, D., Justicia, J., andCuerva, J.M. (2011) ChemSusChem, 4,1035–1048.

4. (a) Wu, X.F. and Xiao, J.L. (2007)Chem. Commun., 2449–2466; (b)Robertson, A., Matsumoto, T., andOgo, S. (2011) Dalton Trans., 40,10304–10310.

5. Reichardt, C. (2004) Solvents andSolvent Effects in Organic Chemistry,Wiley-VCH Verlag GmbH, Weinheim.

6. (a) Narayan, S., Muldoon, J., Finn,M.G., Fokin, V.V., Kolb, H.C., andSharpless, K.B. (2005) Angew. Chem.Int. Ed., 44, 3275–3279; (b) Jung, Y.and Marcus, R.A. (2007) J. Am. Chem.Soc., 129, 5492–5502.

7. (a) Herrmann, W.A. and Kohlpaintner,C.W. (1993) Angew. Chem. Int. Ed., 32,1524–1544; (b) Benyei, A.C., Lehel,S., and Joo, F. (1997) J. Mol. Catal.A-Chem., 116, 349–354; (c) Nomura,K. (1998) J. Mol. Catal. A-Chem., 130,1–28; (d) Wang, C., Wu, X.F., andXiao, J.L. (2008) Chem. Asian J., 3,1750–1770.

8. (a) Wu, X.F. and Xiao, J.L. (2010) inScience of Synthesis: Water in OrganicSynthesis (ed. S. Kobayashi), Thieme,


Stuttgart, pp. 257–300; (b) Wu, X.F.and Xiao, J.L. (2008) in Handbookof Green Chemistry, vol. 1 (ed. C.J.Li), Wiley-VCH Verlag GmbH, pp.255–290.

9. (a) Ahrland, S., Chatt, J., Davies, N.R.,and Williams, A.A. (1958) J. Chem.Soc., 276–288; (b) Joo, F. and Benyei,A. (1989) J. Organomet. Chem., 363,C19–C21; (c) Joo, F. and Katho, A.(1997) J. Mol. Catal. A-Chem., 116,3–26; (d) Joo, F. (2002) Acc. Chem.Res., 35, 738–745.

10. (a) Hashiguchi, S., Fujii, A., Takehara,J., Ikariya, T., and Noyori, R. (1995)J. Am. Chem. Soc., 117, 7562–7563; (b)Fujii, A., Hashiguchi, S., Uematsu,N., Ikariya, T., and Noyori, R. (1996)J. Am. Chem. Soc., 118, 2521–2522; (c)Uematsu, N., Fujii, A., Hashiguchi,S., Ikariya, T., and Noyori, R. (1996)J. Am. Chem. Soc., 118, 4916–4917; (d)Noyori, R. and Hashiguchi, S. (1997)Acc. Chem. Res., 30, 97–102.

11. Parmar, D.U., Bhatt, S.D., Bajaj, H.C.,and Jasra, R.V. (2003) J. Mol. Catal.A-Chem., 202, 9–15.

12. (a) Baricelli, P.J., Rodriguez, G.,Rodriguez, A., Lujano, E., andLopez-Linares, F. (2003) Appl. Catal.A-Gen., 239, 25–34; (b) Baricelli, P.J.,Izaguirre, L., Lopez, J., Lujano, E., andLopez-Linares, F. (2004) J. Mol. Catal.A-Chem., 208, 67–72.

13. Larpent, C., Dabard, R., and Patin,H. (1987) Tetrahedron Lett., 28,2507–2510.

14. Burgemeister, K., Francio, G., Gego,V.H., Greiner, L., Hugl, H., andLeitner, W. (2007) Chem.—Eur. J.,13, 2798–2804.

15. Kulkarni, A., Zhou, W.H., and Torok,B. (2011) Org. Lett., 13, 5124–5127.

16. Grosselin, J.M., Mercier, C.,Allmang, G., and Grass, F. (1991)Organometallics, 10, 2126–2133.

17. Yang, Z.Y., Ebihara, M., andKawamura, T. (2000) J. Mol. Catal.A-Chem., 158, 509–514.

18. Smolenski, P., Pruchnik, F.P., Ciunik,Z., and Lis, T. (2003) Inorg. Chem., 42,3318–3322.

19. (a) Akbayeva, D.N., Gonsalvi, L.,Oberhauser, W., Peruzzini, M., Vizza,

F., Bruggeller, P., Romerosa, A., Sava,G., and Bergamo, A. (2003) Chem.Commun., 264–265; (b) Bolano, S.,Gonsalvi, L., Zanobini, F., Vizza,F., Bertolasi, V., Romerosa, A., andPeruzzini, M. (2004) J. Mol. Catal.A-Chem., 224, 61–70; (c) Mebi, C.A.and Frost, B.J. (2005) Organometallics,24, 2339–2346; (d) Rossin, A.,Gonsalvi, L., Phillips, A.D., Maresca,O., Lledos, A., and Peruzzini, M. (2007)Organometallics, 26, 3289–3296; (e)Bravo, J., Bolano, S., Gonsalvi, L., andPeruzzini, M. (2010) Coord. Chem. Rev.,254, 555–607.

20. (a) Yamakawa, M., Ito, H., and Noyori,R. (2000) J. Am. Chem. Soc., 122,1466–1478; (b) Noyori, R., Yamakawa,M., and Hashiguchi, S. (2001) J. Org.Chem., 66, 7931–7944.

21. Geldbach, T.J., Laurenczy, G.,Scopelliti, R., and Dyson, P.J. (2006)Organometallics, 25, 733–742.

22. Stangel, C., Charalambidis, G., Varda,V., Coutsolelos, A.G., and Kostas, I.D.(2011) Eur. J. Inorg. Chem., 4709–4716.

23. (a) Fujita, S.I., Sano, Y., Bhanage,B.M., and Arai, M. (2004) J. Catal.,225, 95–104; (b) Niuthitikul, K. andWinterbottom, M. (2004) Chem. Eng.Sci., 59, 5439–5447; (c) Papp, G., Elek,J., Nadasdi, L., Laurenczy, G., andJoo, F. (2003) Adv. Synth. Catal., 345,172–174.

24. Nuithitikul, K. and Winterbottom, M.(2007) Catal. Today, 128, 74–79.

25. (a) Joo, F., Kovacs, J., Benyei, A.C.,and Katho, A. (1998) Catal. Today, 42,441–448; (b) Joo, F., Kovacs, J., Benyei,A.C., and Katho, A. (1998) Angew.Chem. Int. Ed., 37, 969–970.

26. Joubert, J. and Delbecq, F. (2006)Organometallics, 25, 854–861.

27. Kovacs, G., Ujaque, G., Lledos, A.,and Joo, F. (2006) Organometallics, 25,862–872.

28. Rossin, A., Kovacs, G., Ujaque,G., Lledos, A., and Joo, F. (2006)Organometallics, 25, 5010–5023.

29. Singha, N.K., Bhattacharjee, S., andSivaram, S. (1997) Rubber Chem. Tech-nol., 70, 309–367.

30. (a) Wei, L., Jiang, J., Wang, Y., andJin, Z. (2004) J. Mol. Catal. A-Chem.,

References 235

221, 47–50; (b) MacLeod, S. and Rosso,R.J. (2003) Adv. Synth. Catal., 345,568–571.

31. Kotzabasakis, V., Georgopoulou, E.,Pitsikalis, M., Hadjichristidis, N., andPapadogianakis, G. (2005) J. Mol. Catal.A-Chem., 231, 93–101.

32. Lu, F., Liu, J., and Xu, J. (2007) J. Mol.Catal. A-Chem., 271, 6–13.

33. (a) Musolino, M.G., Cutrupi, C.M.S.,Donato, A., Pietropaolo, D., andPietropaolo, R. (2003) J. Mol. Catal.A-Chem., 195, 147–157; (b) Semagina,N.V., Bykov, A.V., Sulman, E.M.,Matveeva, V.G., Sidorov, S.N.,Dubrovina, L.V., Valetsky, P.M.,Kiselyova, O.I., Khokhlov, A.R.,Stein, B., and Bronstein, L.M.(2004) J. Mol. Catal. A-Chem., 208,273–284; (c) Semagina, N., Joannet,E., Parra, S., Sulman, E., Renken, A.,and Kiwi-Minsker, L. (2005) Appl.Catal. A-Gen., 280, 141–147; (d)Drelinkiewicz, A., Laitinen, R., Kangas,R., and Pursiainen, J. (2005) Appl.Catal. A-Gen., 284, 59–67; (e) Omota,F., Dimian, A.C., and Bliek, A. (2005)Appl. Catal. A-Gen., 294, 121–130; (f)Hegedus, L. and Mathe, T. (2005) Appl.Catal. A-Gen., 296, 209–215.

34. Makihara, N., Ogo, S., and Watanabe,Y. (2001) Organometallics, 20, 497–500.

35. Csabai, P. and Joo, F. (2004)Organometallics, 23, 5640–5643.

36. Wu, X., Corcoran, C., Yang, S., andXiao, J. (2008) ChemSusChem, 1,71–74.

37. Gulyas, H., Benyei, A.C., and Bakos,J. (2004) Inorg. Chim. Acta, 357,3094–3098.

38. Horvath, H.H. and Joo, F. (2005) React.Kinet. Catal. Lett., 85, 355–360.

39. (a) Deshmukh, A., Kinage, A., Kumar,R., and Meijboom, R. (2010) J. Mol.Catal. A-Chem., 333, 114–120; (b)Deshmukh, A., Kinage, A., Kumar, R.,and Meijboom, R. (2010) Polyhedron,29, 3262–3268.

40. Spitaleri, A., Pertici, P., Scalera, N.,Vitulli, G., Hoang, M., Turney, T.W.,and Gleria, M. (2003) Inorg. Chim.Acta, 352, 61–71.

41. Maity, P., Basu, S., Bhaduri, S., andLahiri, G.K. (2007) Adv. Synth. Catal.,349, 1955–1962.

42. (a) Plasseraud, L. and SussFink,G. (1997) J. Organomet. Chem.,539, 163–170; (b) Fidalgo, E.G.,Plasseraud, L., and Suss-Fink, G.(1998) J. Mol. Catal. A-Chem., 132,5–12; (c) Suss-Fink, G., Faure, M.,and Ward, T.R. (2002) Angew. Chem.Int. Ed., 41, 99–101; (d) Faure, M.,Vallina, A.T., Stoeckli-Evans, H., andSuss-Fink, G. (2001) J. Organomet.Chem., 621, 103–108; (e) Daguenet,C. and Dyson, P.J. (2003) Catal. Com-mun., 4, 153–157; (f) Daguenet, C.,Scopelliti, R., and Dyson, P.J. (2004)Organometallics, 23, 4849–4857;(g) Meister, G., Rheinwald, G.,Stoecklievans, H., and Sussfink, G.(1994) Dalton Trans., 3215–3223.

43. Zhang, L., Zhang, Y., Zhou, X.-G., Li,R.-X., Li, X.-J., Tin, K.-C., and Wong,N.-B. (2006) J. Mol. Catal. A-Chem.,256, 171–177.

44. Lu, F., Liu, J., and Xu, J. (2006) Adv.Synth. Catal., 348, 857–861.

45. Mevellec, V. and Roucoux, A. (2004) In-org. Chim. Acta, 357, 3099–3103.

46. Maegawa, T., Akashi, A., and Sajiki, H.(2006) Synlett, 1440–1442.

47. Hubert, C., Bile, E.G.,Denicourt-Nowicki, A., and Roucoux,A. (2011) Green Chem., 13, 1766–1771.

48. (a) Diaz, E., Mohedano, A.F., Calvo,L., Gilarranz, M.A., Casas, J.A., andRodriguez, J.J. (2007) Chem. Eng. J.,131, 65–71; (b) Liu, H.L., Li, Y.W.,Luque, R., and Jiang, H.F. (2011)Adv. Synth. Catal., 353, 3107–3113;(c) Lu, F., Liu, J., and Xu, J. (2008)Mater. Chem. Phys., 108, 369–374; (d)Makowski, P., Cakan, R.D., Antonietti,M., Goettmann, F., and Titirici, M.M.(2008) Chem. Commun., 999–1001; (e)Morales, J., Hutcheson, R., Noradoun,C., and Cheng, I.F. (2002) Ind. Eng.Chem. Res., 41, 3071–3074; (f) Xiang,Y.Z., Ma, L., Lu, C.S., Zhang, Q.F.,and Li, X.N. (2008) Green Chem., 10,939–943.

49. Ning, J., Xu, J., Liu, J., Miao, H., Ma,H., Chen, C., Li, X., Zhou, L., and


Yu, W. (2007) Catal. Commun., 8,1763–1766.

50. Sreedhar, B., Devi, D.K., and Yada,D. (2011) Catal. Commun., 12,1009–1014.

51. Garcia-Verdugo, E., Liu, Z.M., Ramirez,E., Garcia-Serna, J., Fraga-Dubreuil,J., Hyde, J.R., Hamley, P.A., andPoliakoff, M. (2006) Green Chem., 8,359–364.

52. (a) Mikami, I., Kitayama, R., andOkuhara, T. (2006) Appl. Catal. A-Gen.,297, 24–30; (b) Nakamura, K., Yoshida,Y., Mikami, I., and Okuhara, T. (2006)Appl. Catal. B-Environ., 65, 31–36;(c) Sakamoto, Y., Kamiya, Y., andOkuhara, T. (2006) J. Mol. Catal.A-Chem., 250, 80–86; (d) Wehbe,N., Jaafar, M., Guillard, C., Herrmann,J.M., Miachon, S., Puzenat, E., andGuilhaume, N. (2009) Appl. Catal.A-Gen., 368, 1–8; (e) Marchesini, F.A.,Gutierrez, L.B., Querini, C.A., andMiro, E.E. (2010) Chem. Eng. J., 159,203–211; (f) Neyertz, C., Marchesini,F.A., Boix, A., Miro, E., and Querini,C.A. (2010) Appl. Catal. A-Gen., 372,40–47; (g) Palomares, A.E., Franch,C., and Corma, A. (2011) Catal. Today,172, 90–94.

53. Mhadgut, S.C., Palaniappan, K.,Thimmaiah, M., Hackney, S.A., Torok,B., and Liu, J. (2005) Chem. Commun.,3207–3209.

54. (a) Himeda, Y. (2007) Eur. J. Inorg.Chem., 3927–3941; (b) Jessop, P.G.,Joo, F., and Tai, C.C. (2004) Coord.Chem. Rev., 248, 2425–2442.

55. Gassner, F. and Leitner, W. (1993)Chem. Commun., 1465–1466.

56. Elek, J., Nadasdi, L., Papp, G.,Laurenczy, G., and Joo, F. (2003)Appl. Catal. A-Gen., 255, 59–67.

57. Zhao, G.Y. and Joo, F. (2011) Catal.Commun., 14, 74–76.

58. (a) Tanaka, R., Yamashita, M., andNozaki, K. (2009) J. Am. Chem. Soc.,131, 14168–14169; (b) Thai, T.T.,Therrien, B., and Suss-Fink, G. (2009)J. Organomet. Chem., 694, 3973–3981;(c) Zhang, Z.F., Hu, S.Q., Song, J.L.,Li, W.J., Yang, G.Y., and Han, B.X.(2009) ChemSusChem, 2, 234–238; (d)Federsel, C., Jackstell, R., and Beller,

M. (2010) Angew. Chem. Int. Ed., 49,6254–6257; (e) Federsel, C., Jackstell,R., Boddien, A., Laurenczy, G., andBeller, M. (2010) ChemSusChem,3, 1048–1050; (f) Hoffmann, F.M.,Yang, Y.X., Paul, J., White, M.G.,and Hrbek, J. (2010) J. Phys. Chem.Lett., 1, 2130–2134; (g) Sanz, S.,Azua, A., and Peris, E. (2010) Dal-ton Trans., 39, 6339–6343; (h) Sanz,S., Benitez, M., and Peris, E. (2010)Organometallics, 29, 275–277; (i) Azua,A., Sanz, S., and Peris, E. (2011)Chem.—Eur. J., 17, 3963–3967; (j)Cokoja, M., Bruckmeier, C., Rieger,B., Herrmann, W.A., and Kuhn, F.E.(2011) Angew. Chem. Int. Ed., 50,8510–8537; (k) Tanaka, R., Yamashita,M., Chung, L.W., Morokuma, K., andNozaki, K. (2011) Organometallics,30, 6742–6750; (l) Wang, W., Wang,S.P., Ma, X.B., and Gong, J.L. (2011)Chem. Soc. Rev., 40, 3703–3727; (m)Yang, X.Z. (2011) ACS Catal., 1,849–854; (n) Federsel, C., Boddien,A., Jackstell, R., Jennerjahn, R., Dyson,P.J., Scopelliti, R., Laurenczy, G., andBeller, M. (2010) Angew. Chem. Int. Ed.,49, 9777–9780; For the early reporton the Fe-PP3 complexes and relatedcatalysis, please see: (o) Bianchini, C.,Peruzzini, M., Polo, A., Vacca, A., andZanobini, F. (1991) Gazz. Chim. Ital.,121, 543–549.

59. (a) Hayashi, H., Ogo, S., andFukuzumi, S. (2004) Chem. Com-mun., 2714–2715; (b) Ogo, S.,Kabe, R., Hayashi, H., Harada, R.,and Fukuzumi, S. (2006) DaltonTrans., 4657–4663; (c) Himeda,Y., Onozawa-Komatsuzaki, N.,Sugihara, H., and Kasuga, K. (2007)Organometallics, 26, 702–712; (d)Bosquain, S.S. (2007) Appl. Organomet.Chem., 21, 947–951; (e) Erlandsson,M., Landaeta, V.R., Gonsalvi, L.,Peruzzini, M., Phillips, A.D., Dyson,P.J., and Laurenczy, G. (2008) Eur. J.Inorg. Chem., 620–627.

60. (a) Ohnishi, Y.Y., Matsunaga, T.,Nakao, Y., Sato, H., and Sakaki,S. (2005) J. Am. Chem. Soc., 127,4021–4032; (b) Tai, C.C., Pitts, J.,Linehan, J.C., Main, A.D., Munshi, P.,

References 237

and Jessop, P.G. (2002) Inorg. Chem.,41, 1606–1614.

61. RajanBabu, T.V., Yan, Y.Y., and Shin,S.H. (2001) J. Am. Chem. Soc., 123,10207–10213.

62. Burk, M.J. (2000) Acc. Chem. Res., 33,363–372.

63. Li, W.G., Zhang, Z.G., Xiao, D.M., andZhang, X.M. (2000) J. Org. Chem., 65,3489–3496.

64. Holz, J., Heller, D., Sturmer, R., andBorner, A. (1999) Tetrahedron Lett., 40,7059–7062.

65. Hoen, R., Leleu, S., Botman, P.N.M.,Appelman, V.A.M., Feringa, B.L.,Hiemstra, H., Minnaard, A.J., and vanMaarseveen, J.H. (2006) Org. Biomol.Chem., 4, 613–615.

66. Simons, C., Hanefeld, U., Arends,I.W.C.E., Maschmeyer, T., andSheldon, R.A. (2006) Adv. Synth. Catal.,348, 471–475.

67. (a) Oehme, G., Grassert, I., paetzold,E., Fuhrmann, H., Dwars, T., Schmidt,U., and Iovel, I. (2003) Kinet. Catal.,44, 766; (b) Mevellec, V., Mattioda, C.,Schulz, J., Rolland, J.P., and Roucoux,A. (2004) J. Catal., 225, 1–6.

68. Grassert, I., Schmidt, U., Ziegler, S.,Fischer, C., and Oehme, G. (1998)Tetrahedron: Asymmetry, 9, 4193–4202.

69. Yonehara, K., Ohe, K., and Uemura, S.(1999) J. Org. Chem., 64, 9381–9385.

70. Grassert, I., Kovacs, J., Fuhrmann,H., and Oehme, G. (2002) Adv. Synth.Catal., 344, 312–318.

71. (a) Wolfson, A., Vankelecom, I.F.J., andJacobs, P.A. (2005) Tetrahedron Lett.,46, 2513–2516; (b) Pugin, B., Studer,M., Kuesters, E., Sedelmeier, G., andFeng, X. (2004) Adv. Synth. Catal., 346,1481–1486.

72. Berthod, M., Saluzzo, C., Mignani, G.,and Lemaire, M. (2004) Tetrahedron:Asymmetry, 15, 639–645.

73. Berthod, M., Mignani, G., and Lemaire,M. (2005) J. Mol. Catal. A-Chem., 233,105–110.

74. Bartek, L., Drobek, M., Kuzma, M.,Kluson, P., and Cerveny, L. (2005)Catal. Commun., 6, 61–65.

75. Pugin, B., Groehn, V., Moser, R.,and Blaser, H.U. (2006) Tetrahedron:Asymmetry, 17, 544–549.

76. Jere, F.T., Miller, D.J., and Jackson, J.E.(2003) Org. Lett., 5, 527–530.

77. Jere, F.T., Jackson, J.E., and Miller,D.J. (2004) Ind. Eng. Chem. Res., 43,3297–3303.

78. (a) Bakos, J., Orosz, A., Heil, B.,Laghmari, M., Lhoste, P., and Sinou,D. (1991) Chem. Commun., 1684–1685;(b) Lensink, C. and Devries, J.G. (1992)Tetrahedron: Asymmetry, 3, 235–238;(c) Wang, C., Villa-Marcos, B., andXiao, J.L. (2011) Chem. Commun., 47,9773–9785; (d) Xie, J.H., Zhu, S.F.,and Zhou, Q.L. (2011) Chem. Rev., 111,1713–1760.

79. Blaser, H.U. (2002) Adv. Synth. Catal.,344, 17–31.

80. (a) Spindler, F. and Blaser, H.U. (2007)in Handbook of Homogeneous Hy-drogenation vol. 3 (eds J.G. deVriesand C.J. Elsevier), Wiley-VCH VerlagGmbH, Weinheim, pp. 1193–1214; (b)Claver, C. and Fernandez, E. (2008)in Modern Reduction Methods (edsP.G. Andersson and I.M. Munslow),Wiley-VCH Verlag GmbH, Weinheim.

81. Li, C.Q. and Xiao, J.L. (2008) J. Am.Chem. Soc., 130, 13208–13209.

82. Wagner, K. (1970) Angew. Chem. Int.Ed., 9, 50–54.

83. (a) Yang, J.W. and List, B. (2006) Org.Lett., 8, 5653–5655; (b) Yang, J.W.,Fonseca, M.T.H., and List, B. (2004)Angew. Chem. Int. Ed., 43, 6660–6662;(c) Peris, E. and Crabtree, R.H. (2004)Coord. Chem. Rev., 248, 2239–2246;(d) Naskar, S. and Bhattacharjee,M. (2005) J. Organomet. Chem., 690,5006–5010; (e) Miecznikowski, J.R. andCrabtree, R.H. (2004) Polyhedron, 23,2857–2872; (f) Miecznikowski, J.R. andCrabtree, R.H. (2004) Organometallics,23, 629–631; (g) Gladiali, S. andAlberico, E. (2006) Chem. Soc. Rev.,35, 226–236.

84. (a) Joo, F., Csuhai, E., Quinn, P.J.,and Vigh, L. (1988) J. Mol. Catal.,49, L1–L5; (b) Bar, R. and Sasson, Y.(1981) Tetrahedron Lett., 22, 1709–1710;(c) Bar, R., Bar, L.K., Sasson, Y., andBlum, J. (1985) J. Mol. Catal., 33,161–177; (d) Sinou, D., Safi, M.,Claver, C., and Masdeu, A. (1991) J.Mol. Catal., 68, L9–L12; (e) Zoran,


A., Sasson, Y., and Blum, J. (1984) J.Mol. Catal., 26, 321–326; (f) Benyei,A. and Joo, F. (1990) J. Mol. Catal.,58, 151–163; (g) Bar, R., Sasson, Y.,and Blum, J. (1984) J. Mol. Catal., 26,327–332.

85. (a) Ogo, S., Makihara, N., andWatanabe, Y. (1999) Organometallics,18, 5470–5474; (b) Ogo, S., Makihara,N., Kaneko, Y., and Watanabe, Y.(2001) Organometallics, 20, 4903–4910;(c) Ogo, S., Abura, T., and Watanabe,Y. (2002) Organometallics, 21,2964–2969; (d) Ogo, S., Hayashi, H.,Uehara, K., and Fukuzumi, S. (2005)Appl. Organomet. Chem., 19, 639–643;(e) Abura, T., Ogo, S., Watanabe, Y.,and Fukuzumi, S. (2003) J. Am. Chem.Soc., 125, 4149–4154.

86. (a) Kuo, L.Y., Weakley, T.J.R., Awana,K., and Hsia, C. (2001) Organometallics,20, 4969–4972; (b) Kuo, L.Y., Finigan,D.M., and Tadros, N.N. (2003)Organometallics, 22, 2422–2425.

87. (a) Canivet, J., Karmazin-Brelot, L.,and Suss-Fink, G. (2005) J. Organomet.Chem., 690, 3202–3211; (b) Canivet,J., Labat, G., Stoeckli-Evans, H.,and Suss-Fink, G. (2005) Eur. J. In-org. Chem., 4493–4500; (c) Canivet,J. and Suss-Fink, G. (2007) GreenChem., 9, 391–397; (d) Canivet, J.,Suss-Fink, G., and Stepnicka, P.(2007) Eur. J. Inorg. Chem., 4736–4742;(e) Govindaswamy, P., Canivet, J.,Therrien, B., Suss-Fink, G., Stepnicka,P., and Ludvik, J. (2007) J. Organomet.Chem., 692, 3664–3675; (f) Therrien,B., Said-Mohamed, C., and Suss-Fink,G. (2008) Inorg. Chim. Acta, 361,2601–2608; (g) Diez, J., Gamasa, M.P.,Lastra, E., Garcia-Fernandez, A., andTarazona, M.P. (2006) Eur. J. Inorg.Chem., 2855–2864.

88. Ikariya, T., Murata, K., and Noyori, R.(2006) Org. Biomol. Chem., 4, 393–406.

89. Wu, X.F., Liu, J.K., Li, X.H.,Zanotti-Gerosa, A., Hancock, F., Vinci,D., Ruan, J.W., and Xiao, J.L. (2006)Angew. Chem. Int. Ed., 45, 6718–6722.

90. Nieto, I., Livings, M.S., Sacci, J.B.,Reuther, L.E., Zeller, M., and Papish,E.T. (2011) Organometallics, 30,6339–6342.

91. Romain, C., Gaillard, S., Elmkaddem,M.K., Toupet, L., Fischmeister, C.,Thomas, C.M., and Renaud, J.L. (2010)Organometallics, 29, 1992–1995.

92. Yano, Y., Kojima, T., and Fukuzumi,S. (2011) Inorg. Chim. Acta, 374,104–111.

93. (a) He, L., Ni, J., Wang, L.C., Yu, F.J.,Cao, Y., He, H.Y., and Fan, K.N. (2009)Chem.—Eur. J., 15, 11833–11836; (b)Su, F.Z., He, L., Ni, J., Cao, Y., He,H.Y., and Fan, K.N. (2008) Chem. Com-mun., 3531–3533; (c) Wang, M.M.,He, L., Liu, Y.M., Cao, Y., He, H.Y.,and Fan, K.N. (2011) Green Chem., 13,602–607.

94. Sharma, A., Kumar, V., and Sinha,A.K. (2006) Adv. Synth. Catal., 348,354–360.

95. (a) Watanabe, Y., Ohta, T., Tsuji, Y.,and Hiyoshi, T. (1984) Bull. Chem. Soc.Jpn., 57, 2440–2444; (b) Balczewski,P. and Joule, J.A. (1990) Synth. Com-mun., 20, 2815–2819; (c) Zacharie,B., Moreau, N., and Dockendorff, C.(2001) J. Org. Chem., 66, 5264–5265;(d) Derdau, V. (2004) Tetrahedron Lett.,45, 8889–8893; (e) Fujita, K., Kitatsuji,C., Furukawa, S., and Yamaguchi, R.(2004) Tetrahedron Lett., 45, 3215–3217;(f) Frediani, P., Rosi, L., Cetarini, L.,and Frediani, M. (2006) Inorg. Chim.Acta, 359, 2650–2657; (g) Wu, J.S.,Liao, J., Zhu, J., and Deng, J.E. (2006)Synlett, 2059–2062; (h) Voutchkova,A.M., Gnanamgari, D., Jakobsche, C.E.,Butler, C., Miller, S.J., Parr, J., andCrabtree, R.H. (2008) J. Organomet.Chem., 693, 1815–1821; (i) Parekh, V.,Ramsden, J.A., and Wills, M. (2010)Tetrahedron: Asymmetry, 21, 1549–1556;(j) Tan, J., Tang, W.J., Sun, Y.W.,Jiang, Z., Chen, F., Xu, L.J., Fan, Q.H.,and Xiao, J.L. (2011) Tetrahedron, 67,6206–6213.

96. (a) Muniz, K. (2005) Angew. Chem. Int.Ed., 44, 6622–6627; (b) Xue, D., Chen,Y.C., Cui, X., Wang, Q.W., Zhu, J., andDeng, J.G. (2005) J. Org. Chem., 70,3584–3591; (c) Li, X.F., Li, L.C., Tang,Y.F., Zhong, L., Cun, L.F., Zhu, J.,Liao, J., and Deng, J.G. (2010) J. Org.Chem., 75, 2981–2988.

References 239

97. (a) Brown, J.M., Brunner, H., Leitner,W., and Rose, M. (1991) Tetrahedron:Asymmetry, 2, 331–334; (b) Leitner, W.,Brown, J.M., and Brunner, H. (1993)J. Am. Chem. Soc., 115, 152–159.

98. Tang, Y.F., Xiang, J., Cun, L.F., Wang,Y.Q., Zhu, J., Liao, J.A., and Deng,J.G. (2010) Tetrahedron: Asymmetry, 21,1900–1905.

99. (a) Blaser, H.U., Malan, C., Pugin,B., Spindler, F., Steiner, H., andStuder, M. (2003) Adv. Synth. Catal.,345, 103–151; (b) Clapham, S.E.,Hadzovic, A., and Morris, R.H. (2004)Coord. Chem. Rev., 248, 2201–2237; (c)Cornils, B., Herrmann, W.A., and Eckl,R.W. (1997) J. Mol. Catal. A-Chem.,116, 27–33; (d) Everaere, K., Mortreux,A., and Carpentier, J.F. (2003), Adv.Synth. Catal., 345, 67–77; (e) Ikariya,T. and Blacker, A.J. (2007) Acc. Chem.Res., 40, 1300–1308; (f) Liu, J.K., Wu,X.F., Iggo, J.A., and Xiao, H.L. (2008)Coord. Chem. Rev., 252, 782–809; (g)Pinault, N. and Bruce, D.W. (2003)Coord. Chem. Rev., 241, 1–25; (h)Rautenstrauch, V., Hoang-Cong, X.,Churlaud, R., Abdur-Rashid, K., andMorris, R.H. (2003) Chem.—Eur. J.,9, 4954–4967; (i) Saluzzo, C. andLemaire, M. (2002) Adv. Synth. Catal.,344, 915–928; (j) Samec, J.S.M.,Backvall, J.E., Andersson, P.G., andBrandt, P. (2006) Chem. Soc. Rev.,35, 237–248; (k) Wu, X.F., Mo, J., Li,X.H., Hyder, Z., and Xiao, J.L. (2008)Prog. Nat. Sci., 18, 639–652; (l) Xiao,J., Wu, X., Zanotti-Gerosa, A., andHancock, F. (2005) Chem. Today, 23,50–55; (m) Wu, X., Liu, J., Tommaso,D.D., Iggo, J.A., Catlow, R., Bacsa, J.,and Xiao, J. (2008) Chem.—Eur. J., 14,7699–7715; (n) Wu, X.F., Li, X.H.,McConville, M., Saidi, O., and Xiao,J.L. (2006) J. Mol. Catal. A-Chem.,247, 153–158; (o) Wu, X.F., Vinci,D., Ikariya, T., and Xiao, J.L. (2005)Chem. Commun., 4447–4449; (p) Wu,X.F., Li, X.G., King, F., and Xiao,J.L. (2005) Angew. Chem. Int. Ed.,44, 3407–3411; (q) Wu, X., Li, X.,Hems, W., King, F., and Xiao, J. (2004)Org. Biomol. Chem., 2, 1818–1821;(r) Zeror, S., Collin, J., Fiaud, J.C.,

and Zouioueche, L.A. (2008) Adv.Synth. Catal., 350, 197–204; (s) Xu, Z.,Mao, J.C., Zhang, Y.W., Guo, J., andZhu, J.L. (2008) Catal. Commun., 9,618–623; (t) Liu, J.T., Zhou, Y.G., Wu,Y.N., Li, X.S., and Chan, A.S.C. (2008)Tetrahedron: Asymmetry, 19, 832–837;(u) Liu, J.T., Wu, Y.N., Li, X.S., andChan, A.S.C. (2008) J. Organomet.Chem., 693, 2177–2180; (v) Cortez,N.A., Aguirre, G., Parra-Hake, M., andSomanathan, R. (2008) Tetrahedron:Asymmetry, 19, 1304–1309; (w) Alza,E., Bastero, A., Jansat, S., and Pericas,M.A. (2008) Tetrahedron: Asymmetry,19, 374–378; (x) Akagawa, K., Akabane,H., Sakamoto, S., and Kudo, K. (2008)Org. Lett., 10, 2035–2037; (y) Ahlford,K., Lind, J., Maler, L., and Adolfsson,H. (2008) Green Chem., 10, 832–835;(z) Zhou, H.F., Fan, Q.H., Huang,Y.Y., Wu, L., He, Y.M., Tang, W.J.,Gu, L.Q., and Chan, A.S.C. (2007)J. Mol. Catal. A-Chem., 275, 47–53;(aa) Wettergren, J., Zaitsev, A.B., andAdolfsson, H. (2007) Adv. Synth. Catal.,349, 2556–2562; (ab) Li, L., Wu, J.S.,Wang, F., Liao, J., Zhang, H., Lian,C.X., Zhu, J., and Deng, J.G. (2007)Green Chem., 9, 23–25; (ac) Cortez,N.A., Aguirre, G., Parra-Hake, M.,and Somanathan, R. (2007) Tetrahe-dron Lett., 48, 4335–4338; (ad) Chen,G., Xing, Y., Zhang, H., and Gao,J.X. (2007) J. Mol. Catal. A-Chem.,273, 284–288; (ae) Zeror, S., Collin,J., Fiaud, J.C., and Zouioueche, L.A.(2006) J. Mol. Catal. A-Chem., 256,85–89; (af) Xing, Y., Chen, J.S., Dong,Z.R., Li, Y.Y., and Gao, J.X. (2006)Tetrahedron Lett., 47, 4501–4503; (ag)Wu, J.S., Wang, F., Ma, Y.P., Cui,X.C., Cun, L.F., Zhu, J., Deng, J.G.,and Yu, B.L. (2006) Chem. Commun.,1766–1768; (ah) Matharu, D.S., Morris,D.J., Clarkson, G.J., and Wills, M.(2006) Chem. Commun., 3232–3234;(ai) Li, X.H., Blacker, J., Houson, I.,Wu, X.F., and Xiao, J.L. (2006) Syn-lett, 1155–1160; (aj) Li, B.Z., Chen,J.S., Dong, Z.R., Li, Y.Y., Li, Q.B.,and Gao, J.X. (2006) J. Mol. Catal.A-Chem., 258, 113–117; (ak) Jiang,L., Wu, T.F., Chen, Y.C., Zhu, J.,


and Deng, J.G. (2006) Org. Biomol.Chem., 4, 3319–3324; (al) Cortez,N.A., Rodriguez-Apodaca, R., Aguirre,G., Parra-Hake, M., Cole, T., andSomanathan, R. (2006) TetrahedronLett., 47, 8515–8518; (am) Arakawa, Y.,Haraguchi, N., and Itsuno, S. (2006)Tetrahedron Lett., 47, 3239–3243; (an)Wang, F., Liu, H., Cun, L.F., Zhu,J., Deng, J.G., and Jiang, Y.Z. (2005)J. Org. Chem., 70, 9424–9429; (ao)Mao, J.C., Wan, B.S., Wu, F., andLu, S.W. (2005) Tetrahedron Lett., 46,7341–7344; (ap) Liu, P.N., Gu, P.M.,Deng, J.G., Tu, Y.Q., and Ma, Y.P.(2005) Eur. J. Org. Chem., 3221–3227;(aq) Letondor, C., Humbert, N., andWard, T.R. (2005) Proc. Natl. Acad. Sci.U.S.A., 102, 4683–4687; (ar) Liu, P.N.,Deng, J.G., Tu, Y.Q., and Wang, S.H.(2004) Chem. Commun., 2070–2071;(as) Li, X.G., Wu, X.F., Chen, W.P.,Hancock, F.E., King, F., and Xiao, J.L.(2004) Org. Lett., 6, 3321–3324; (at)Ajjou, A.N. and Pinet, J.L. (2004) J.Mol. Catal. A-Chem., 214, 203–206;(au) Ma, Y.P., Liu, H., Chen, L., Cui,X., Zhu, J., and Deng, J.G. (2003) Org.Lett., 5, 2103–2106; (av) Himeda, Y.,Onozawa-Komatsuzaki, N., Sugihara,H., Arakawa, H., and Kasuga, K. (2003)J. Mol. Catal. A-Chem., 195, 95–100;(aw) Rhyoo, H.Y., Park, H.J., Suh,W.H., and Chung, Y.K. (2002) Tetra-hedron Lett., 43, 269–272; (ax) Thorpe,T., Blacker, J., Brown, S.M., Bubert,C., Crosby, J., Fitzjohn, S., Muxworthy,J.P., and Williams, J.M.J. (2001) Tetra-hedron Lett., 42, 4041–4043; (ay)Bubert, C., Blacker, J., Brown, S.M.,Crosby, J., Fitzjohn, S., Muxworthy,J.P., Thorpe, T., and Williams, J.M.J.(2001) Tetrahedron Lett., 42, 4037–4039;(az) Rhyoo, H.Y., Park, H.J., andChung, Y.K. (2001) Chem. Commun.,2064–2065; (ba) Wu, X.F., Li, X.H.,Zanotti-Gerosa, A., Pettman, A., Liu,J.K., Mills, A.J., and Xiao, J.L. (2008)Chem.—Eur. J., 14, 2209–2222; (bb)Venkatakrishnan, T.S., Mandal, S.K.,Kannan, R., Krishnamurthy, S.S.,and Nethaji, M. (2007) J. Organomet.Chem., 692, 1875–1891; (bc) Palmer,

M.J. and Wills, M. (1999) Tetrahedron:Asymmetry, 10, 2045–2061.

100. Tang, Y.F., Li, X.F., Lian, C.X., Zhu,J., and Deng, J.G. (2011) Tetrahedron:Asymmetry, 22, 1530–1535.

101. (a) Li, X.G., Chen, W.P., Hems, W.,King, F., and Xiao, J.L. (2004) Tetra-hedron Lett., 45, 951–953; (b) Li, X.G.,Chen, W.P., Hems, W., King, F.,and Xiao, J.L. (2003) Org. Lett., 5,4559–4561.

102. Wu, X.F. (2007) Asymmetric TransferHydrogenation and Transfer Hydro-genation in Water. PhD thesis. TheUniversity of Liverpool, Liverpool, UK.

103. (a) Micskei, K., Hajdu, C., Wessjohann,L.A., Mercs, L., Kiss-Szikszai, A., andPatonay, T. (2004) Tetrahedron: Asym-metry, 15, 1735–1744; (b) Watts, C.C.,Thoniyot, P., Cappuccio, F., Verhagen,J., Gallagher, B., and Singaram, B.(2006) Tetrahedron: Asymmetry, 17,1301–1307.

104. (a) Ahlford, K. and Adolfsson, H.(2011) Catal. Commun., 12, 1118–1121;(b) Zani, L., Eriksson, L., andAdolfsson, H. (2008) Eur. J. Org. Chem.,4655–4664.

105. Boukachabia, M., Zeror, S., Collin,J., Fiaud, J.C., and Zouioueche,L.A. (2011) Tetrahedron Lett., 52,1485–1489.

106. Gao, J.X., Ikariya, T., and Noyori, R.(1996) Organometallics, 15, 1087–1089.

107. (a) Copolla, G.M. and Schuster, H.F.(1997) Alpha-hydroxy Acids in Enan-tioselective Synthesis, Wiley-VCH VerlagGmbH, Weinheim; (b) Sheldon, R.A.(1993) Chirotechnology, Macel Dekker,New York; (c) Yin, L., Jia, X., Li, X.S.,and Chan, A.S.C. (2009) Tetrahedron:Asymmetry, 20, 2033–2037.

108. Soltani, O., Ariger, M.A., Vazquez-Villa,H., and Carreira, E.M. (2010) Org. Lett.,12, 2893–2895.

109. Wang, W.W., Li, Z.M., Mu, W.B.,Su, L., and Wang, Q.R. (2010) Catal.Commun., 11, 480–483.

110. Wang, W.W. and Wang, Q.R. (2010)Chem. Commun., 46, 4616–4618.

111. Li, Y.Z., Li, Z.M., Li, F., Wang, Q.R.,and Tao, F.G. (2005) Org. Biomol.Chem., 3, 2513–2518.

References 241

112. Evanno, L., Ormala, J., and Pihko,P.M. (2009) Chem.—Eur. J., 15,12963–12967.

113. (a) Wang, C., Li, C.Q., Wu, X.F.,Pettman, A., and Xiao, J.L. (2009)Angew. Chem. Int. Ed., 48, 6524–6528;(b) Durrenberger, M., Heinisch, T.,Wilson, Y.M., Rossel, T., Nogueira, E.,Knorr, L., Mutschler, A., Kersten, K.,Zimbron, M.J., Pierron, J., Schirmer,T., and Ward, T.R. (2011) Angew.Chem. Int. Ed., 50, 3026–3029;(c) Ringenberg, M.R. and Ward,T.R. (2011) Chem. Commun., 47,8470–8476.

114. (a) Faber, K. (2004) Biotransformationsin Organic Chemistry, John Wiley &Sons, Inc., New York; (b) Eder, U.,Sauer, G., and Weichert, R. (1971)Angew. Chem. Int. Ed., 10, 496–497;(c) Faber, K. and Kroutil, W. (2005)Curr. Opin. Chem. Biol., 9, 181–187; (d)Hoffmann, S., Seayad, A.M., and List,B. (2005) Angew. Chem. Int. Ed., 44,7424–7427; (e) Malkov, A.V., Liddon,A., Ramirez-Lopez, P., Bendova, L.,Haigh, D., and Kocovsky, P. (2006)Angew. Chem. Int. Ed., 45, 1432–1435.

115. (a) Edegger, K., Gruber, C.C., Poessl,T.M., Wallner, S.R., Lavandera,I., Faber, K., Niehaus, F., Eck, J.,Oehrlein, R., Hafner, A., and Kroutil,W. (2006) Chem. Commun., 2402–2404;(b) Zhu, D.M., Yang, Y., and Hua, L.(2006) J. Org. Chem., 71, 4202–4205.

116. (a) Kaiser, E.T. and Lawrence, D.S.(1984) Science, 226, 505–511; (b)Kramer, R. (2006) Angew. Chem. Int.Ed., 45, 858–860; (c) Mahammed, A.and Gross, Z. (2005) J. Am. Chem. Soc.,127, 2883–2887; (d) Panella, L., Broos,J., Jin, J.F., Fraaije, M.W., Janssen,D.B., Jeronimus-Stratingh, M., Feringa,B.L., Minnaard, A.J., and de Vries, J.G.(2005) Chem. Commun., 5656–5658;(e) Roelfes, G., Boersma, A.J., andFeringa, B.L. (2006) Chem. Commun.,635–637; (f) Roelfes, G. and Feringa,B.L. (2005) Angew. Chem. Int. Ed.,44, 3230–3232; (g) Wilson, M.E. andWhitesides, G.M. (1978) J. Am. Chem.Soc., 100, 306–307.

117. Letondor, C., Pordea, A., Humbert, N.,Ivanova, A., Mazurek, S., Novic, M.,

and Ward, T.R. (2006) J. Am. Chem.Soc., 128, 8320–8328.

118. (a) Thomas, C.M. and Ward, T.R.(2005) Chem. Soc. Rev., 34, 337–346;(b) Ward, T.R. (2005) Chem.—Eur. J.,11, 3798–3804.

119. (c) Liu, K., Haeussinger, D., andWoggon, W.D. (2007) Synlett,2298–2300; (b) Schlatter, A., Kundu,M.K., and Woggon, W.D. (2004) Angew.Chem. Int. Ed., 43, 6731–6734; (c)Schlatter, A. and Woggon, W.D. (2008)Adv. Synth. Catal., 350, 995–1000; Forreviews, please see: (d) Woggon, W.D.,Schlatter, A., and Wang, H. (2008) inAdvances in Inorganic Chemistry, vol. 60(ed. R. van Eldik), Elsevier AcademicPress Inc., San Diego, CA, pp. 31–58;(e) Bricout, H., Hapiot, F., Ponchel, A.,Tilloy, S., and Monflier, E. (2010) Curr.Org. Chem., 14, 1296–1307.

120. Steckhan, E., Herrmann, S., Ruppert,R., Thommes, J., and Wandrey, C.(1990) Angew. Chem. Int. Ed., 29,388–390.

121. (a) Wu, Y.U., Lu, C.J., Shan, W.J.,and Li, X.S. (2009) Tetrahedron: Asym-metry, 20, 584–587; (b) Huang, L.,Liu, J.T., Shan, W.J., Liu, B., Shi,A.D., and Li, X.S. (2010) Chirality, 22,206–211; (c) Shan, W.J., Meng, F.C.,Wu, Y.U., Mao, F., and Li, X.S. (2011)J. Organomet. Chem., 696, 1687–1690.

122. Bai, S.Y., Yang, H.Q., Wang, P.,Gao, J.S., Li, B., Yang, Q.H., andLi, C. (2010) Chem. Commun., 46,8145–8147.

123. Sun, Y.Q., Liu, G.H., Gu, H.Y., Huang,T.Z., Zhang, Y.L., and Li, H.X. (2011)Chem. Commun., 47, 2583–2585.

124. Liu, G.H., Gu, H.Y., Sun, Y.Q., Long,J., Xu, Y.L., and Li, H.X. (2011) Adv.Synth. Catal., 353, 1317–1324.

125. Barron-Jaime, A., Narvaez-Garayzar,O.F., Ganzalez, J., Ibarra-Galvan, V.,Aguirre, G., Parra-Hake, M., Chavez,D., and Somanathan, R. (2011) Chiral-ity, 23, 178–184.

126. Dimroth, J., Keilitz, J., Schedler, U.,Schomacker, R., and Haag, R. (2010)Adv. Synth. Catal., 352, 2497–2506.

127. (a) Arakawa, Y., Chiba, A., Haraguchi,N., and Itsuno, S. (2008) Adv. Synth.Catal., 350, 2295–2304; (b) Takahashi,


M., Haraguchi, N., and Itsuno, S.(2008) Tetrahedron: Asymmetry, 19,60–66; (c) Haraguchi, N., Tsuru, K.,Arakawa, Y., and Itsuno, S. (2009)Org. Biomol. Chem., 7, 69–75; (d)Haraguchi, N., Nishiyama, A., andItsuno, S. (2010) J. Polym. Sci., Part A:Polym. Chem., 48, 3340–3349.

128. Dimroth, J., Schedler, U., Keilitz, J.,Haag, R., and Schomacker, R. (2011)Adv. Synth. Catal., 353, 1335–1344.

129. (a) Chen, Y.C., Wu, T.F., Jiang, L.,Deng, J.G., Liu, H., Zhu, J., andJiang, Y.Z. (2005) J. Org. Chem., 70,1006–1010; (b) Huang, X.H. andYing, J.Y. (2007) Chem. Commun.,1825–1827; (c) Li, C., Zhang, H.D.,Jiang, D.M., and Yang, Q.H. (2007)Chem. Commun., 547–558; (d) Yang,H.Q., Li, J., Yang, J., Liu, Z.M., Yang,Q.H., and Li, C. (2007) Chem. Com-mun., 1086–1088; (e) Liu, G.H., Yao,M., Wang, J.Y., Lu, X.Q., Liu, M.M.,Zhang, F., and Li, H.D. (2008) Adv.Synth. Catal., 350, 1464–1468; (f)Li, J., Zhang, Y.M., Han, D.F., Gao,Q., and Li, C. (2009) J. Mol. Catal.A-Chem., 298, 31–35; (g) Liu, X.A.,Wang, P.Y., Zhang, L., Yang, J., Li, C.,and Yang, Q.H. (2010) Chem.—Eur. J.,16, 12727–12735; (h) Marcos, R.,

Jimeno, C., and Pericas, M.A. (2011)Adv. Synth. Catal., 353, 1345–1352.

130. Weng, Z.H., Muratsugu, S., Ishiguro,N., Ohkoshi, S., and Tada, M. (2011)Dalton Trans., 40, 2338–2347.

131. (a) Darensbourg, D.J., Stafford, N.W.,Joo, F., and Reibenspies, J.H. (1995)J. Organomet. Chem., 488, 99–108;(b) Poth, T., Paulus, H., Elias, H.,Ducker-Benfer, C., and van Eldik, R.(2001) Eur. J. Inorg. Chem., 1361–1369;(c) Wang, F., Chen, H., Parsons, S.,Oswald, I.D.H., Davidson, J.E., andSadler, P.J. (2003) Chem.—Eur. J., 9,5810–5820.

132. Malmstrom, T., Wendt, O.F., andAndersson, C. (1999) J. Chem. Soc.,Dalton Trans., 2871–2875.

133. Frost, B.J. and Mebi, C.A. (2004)Organometallics, 23, 5317–5323.

134. Kovacs, G., Schubert, G., Joo, F., andPapai, I. (2005) Organometallics, 24,3059–3065.

135. (a) Yin, C., Xu, Z., Yang, S.Y., Ng,S.M., Wong, K.Y., Lin, Z., and Lau,C.P. (2001) Organometallics, 20,1216–1222; (b) Ohnishi, Y., Nakao,Y., Sato, H., and Sakaki, S. (2006)Organometallics, 25, 3352–3363.

136. Handgraaf, J.W. and Meijer, E.J. (2007)J. Am. Chem. Soc., 129, 3099–3103.

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