Raluca Malacea

Rinaldo Poli

Eric Manoury

Asymmetric hydrosilylation, transfer hydrogenation and hydrogenation of ketones catalyzed by iridium complexes

Keywords: Iridium, chiral alcohols, asymmetric hydrosilylation, asymmetric transfer hydrogenation, asymmetric hydrogenation, mechanisms, iridium hydrides

Iridium-based asymmetric reduction of ketones to chiral enantiomerically enriched alcohols has recently attracted attention by a number of research groups and interest in this area is growing. This review presents the different catalytic systems based on iridium complexes that have been used in asymmetric hydrosilylation, in asymmetric transfer hydrogenation (ATH) with alcohols or formic acid derivatives as reducing agents, and in asymmetric hydrogenation (H2 as reducing agent). A large variety of chiral ligands of various denticities and bearing various combination of coordinating atoms (N, P, S, O, C, …) have been used and will be presented. The last part critically reviews the mechanistic understanding of all the above transformations with specific reference to iridium catalysts.

pharmaceuticals and advanced materials [START_REF]Chirality in Industry: The commercial Manufacture and Applications of Optically Active Compounds[END_REF], raising great interest in finding new methods for their production. In addition, ketones are one of the most common families of unsaturated substrates, therefore the enantioselective reduction of prochiral ketones leading to optically pure secondary alcohols is a subject of considerable interest from both the academic and the industrial perspectives. Enzymes that catalyse ketone reduction (known as ketoreductase) are reliable tools leading to highly enantiomerically enriched chiral alcohols. Over the past years, a library of ketoreductases has been used to reduce ketones across several structural classes [START_REF] Moore | [END_REF].

Kinetic resolution of racemic alcohols with chiral catalysts or enzymes, has also attracted industrial interest [3]. However, the most elegant approach is enantioselective catalysis where prochiral starting materials are transformed into enantioenriched products with the help of chiral catalysts. Different perfumery ingredients, for instance alcohols responsible for woody odour, are obtained by hydrogenation of the corresponding carbonyl substrates [4]. The success of hydrogenation relies primarily on the proper combination of a metal and a ligand; therefore considerable efforts have been devoted to the development of transition metal complexes as catalysts. The majority of the work carried out in this area has employed ruthenium-based catalysts in combination with a variety of phosphine and amine ligands [5]. Of these, the most notable is a transfer hydrogenation system which incorporates the Ru(II)-TsDPEN (TsDPEN=N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine) catalyst, first reported by Noyori et al. [6]. More recently, the synthesis and application of efficient rhodium-based catalysts has been also reported in the literature [7]. However, the interest in iridium catalysts, which have often been successfully used for the asymmetric hydrogenation of olefins [8], is rapidly growing in recent years. Iridium has the advantage to be much less expensive than rhodium [9]. To the best of our knowledge, no review dedicated to the asymmetric reduction of ketones has so far been published [START_REF]A more general review on iridium-catalyzed hydrogenation and transfer hydrogenation, including asymmetric versions, has[END_REF]. The catalytic reduction of ketones to the corresponding alcohols can be carried out by hydrosilylation followed by hydrolysis (Eq. 1), by transfer hydrogenation, usually in the presence of an alcohol as a hydrogen donor and a base (Eq. 2), or by hydrogenation where the reducing agent is molecular hydrogen (Eq. 3). A problem of the transfer hydrogenation reaction in 2-propanol is the reversibility of the process. To optimize conversion in 2-propanol, the catalysis must be performed using very low substrate concentrations. On the other hand, the reaction is irreversible with formic acid as hydrogen donor because of CO2 evolution.

R 1 R 2 O DH 2 D R 1 R 2 OH R 1 R 2 O R 1 R 2 OH H 2 , [M] [M], base Equation 3 Equation 2 R 1 R 2 O R 1 R 2 OH Equation 1 1) R 3 SiH, [M]
2) H 2 O DH 2 : CH 3 CHOHCH 3 , HCOOH, HCOONa,... The first part of this review will be focussed on the asymmetric hydrosilylation of ketones while the second part will treat the asymmetric transfer hydrogenation (ATH). Then, the third part will deal with the catalytic hydrogenation, which has so far received less attention.

In a fourth and final part, we shall critically review the mechanistic understanding of all the above transformations with specific reference to iridium catalysts.

Asymmetric hydrosilylation of ketones with iridium

In recent years, asymmetric hydrosilylation of ketones has been recognised as a valuable way to obtain chiral secondary alcohols because of the often milder conditions needed to carry out the reaction in comparison with hydrogenation reactions. Various metallic complexes based on titanium, zinc, copper, … and especially on rhodium have been used to catalyze this reaction [START_REF] Jacobsen | Comprehensive Asymmetric Catalysis[END_REF], but iridium complexes have rather seldom been tested.

P,N ligands

In 1985, Nile et al. described the first attempt of asymmetric hydrosilylation of ketones catalyzed by iridium complexes in the presence of a P,N ligand with satisfactory yields but low enantiomeric excesses (see scheme 1) [12]. Kreuzfeld and coworkers used another P,N ligand, named amphos 1 (Scheme 2), in the hydrosilylation of acetophenone by diphenylsilane [13]. Good conversions could be obtained, but with low e.e., lower than with the corresponding rhodium systems with the same ligand (up to 50% and with opposite absolute configuration).

Scheme 2

However, using the oxazolylphosphine ligand DIPOF, Uemura could develop iridiumbased catalytic systems with good activities and high enantioselectivities (scheme 3) [14]. If the product absolute configuration was opposite, as usual, when iridium was used instead of rhodium, the enantioselectivities were significantly higher (for acetophenone: 96% with iridium, 91% with rhodium).

Scheme 3

High yields and enantioselectivities could also be obtained for various aryl-alkyl or heteroaryl-alkyl ketones but not with hindered ketones or dialkyl ketones (see scheme 4).

Scheme 4

Moberg et al. used cationic iridium complexes of other phosphine-oxazolines bearing a hydroxyl group in the asymmetric hydrosilylation of various ketones (scheme 5) [15]. Good yields were obtained after 16

Scheme 8

In conclusion, if some interesting asymmetric hydrosilylation systems based on iridium have been developed, they are still much rarer than systems based on other metals (in particular, rhodium, titanium, copper) and they do not seem competitive in terms of catalytic activities and enantioselectivities [4].

Asymmetric transfer hydrogenation (ATH) of ketones with iridium

Since

P and P,P ligands

One of the first reports on the iridium-based ATH of ketones was by Graziani in 1982

PROPHOS

Scheme 9.

Similar iridium complexes obtained by the in situ reaction of [Ir(COD)(acac)], one equivalent of HBF4 and two equivalents of monophosphine menthyldiphenylphosphine (MDPP) or dimenthylphenylphosphine (DMPP) (scheme 10), also proved active as catalysts for the ATH of some aryl alkyl ketones [22].

N,N ligands

2-[(N-Alky1imino)methyl pyridines and alkyl(2-pyridylmethy1)amines have often been employed among N-donor ligands as chiral modifiers in the Ir(I) catalyzed ATH of ketones [24]. For instance, a few preformed tetra-and pentacoordinated Ir(I) complexes (5, 6, 7, Scheme 12) with bidentate 2-[(N-alkylimino) methyl pyridines and alkyl(2-pyridylmethy1)amines have been prepared and tested in the ATH of ketones with propan-2-ol as H donor [25,26]. Most of these were good catalysts affording, in the presence of KOH, greater than 90% conversion in a few hours at a substrate to iridium ratio of 1000. Activity and enantioselectivity were strongly dependent on the structure of the chiral ligand and enantiomeric excesses ranging from 1.5% to 95% were recorded. In the acetophenone reduction catalyzed by complexes 5, the introduction of a phenyl group in place of an alkyl at the stereogenic carbon improves both the activity and the stereoselectivity. For the reaction catalyzed by 5, the configuration of the resulting alcohol depends of the substituents R 1 -R 3 and was reversed when complex 5b (R 1 = H; R 2 = Bz; R 3 = Ph; R = H) was used (41.5% S) instead of 5a (R 1 = H; R 2 = Me; R 3 = Ph; R = H) (15% R).

When the catalyst was prepared "in situ" from [Ir(COE)2Cl]2 and the corresponding ligand, lower e.e. were obtained.

N N Ir R R 1 R 2 R 3 N NH Ir R 1 R 2 R 3 N N Ir R R 1 R 2 R 3 I 5 6 7 R Y Y = ClO 4 -, BF 4 - - Y -

Scheme 12

A significant improvement of the stereoselectivity of the ATH was obtained upon introduction of pentacoordinated neutral iridium complexes 7 as preformed catalysts. For instance, complex 7a (R 1 = H; R 2 = Me; R 3 = Ph; R = H) promotes the ATH of tert-butyl phenyl ketone with 79.5 % e.e. instead of 50% with corresponding 5a. An even better value (84 %) could be obtained when the reduction was carried out in the presence of additional NaI. This result is one of the best ever reported for the ATH of this sterically hindered ketone, which is usually reduced with difficulty by the other previously considered catalysts.

The use of complexes 5 has also been reported in a patent [27]. When the ATH of n-propyl phenyl ketone was carried out in i-PrOH/NaOH at 60°C and at a [substrate]/[Ir] ratio = 1000, optical yields in the range 12.5-64.8 % were obtained. Activities and enantioselectivities were found to be highly dependent of the substituents R, R 1 -R 3 . A significant improvement of the optical yield, from 19% to 54.2% and a 10-fold increase of the reaction rate were obtained when a methyl group was introduced into the 6-position of the pyridine ring. Further increments could be observed by changing the substituents at the stereogenic carbon (65% e.e. for R 1 = H; R 2 = 1-naphtyl; R 3 = Me; R = M). In particular, good enantioselectivities were obtained with ligand DHPPEI (R1 = H, R2 = Me, R3 = Ph, R = H) with e.e. up to 90% in the ATH of PhCO(CH2)3Ph.

Two styryl derivatives 8 and 9 have also been synthesized and used either as homogeneous catalysts or, after immobilization through copolymerization with 2-ethylhexyl methacrylate in presence of divinylbenzene as cross-linking agent, as heterogenized catalysts 10 and 11 (Scheme 13) [24]. Stereoselectivities could be greatly improved going from the homogeneous to the heterogenized systems: the enantiomeric excesses increased from 47 to 85% and from 52 to 84% with the methyl and with the benzyl substituted ligands, respectively.

In both cases the optical purity of the product did not change as the reaction proceeded. By modification of the polymeric support, the enantioselectivities could be further improved: an enantiomeric excess of 95% could be obtained at 20% conversion with a polymeric complex synthesized from tert-butyl methacrylate.

= 12c R O O O O H Ph Ph H R 1 H R 1 H 12a, R = H, R 1 = Ph 12b, R = Me, R 1 = Ph 13a, R = H, R 1 = Ph 13b, R = Me, R 1 = Ph 13c, R = H, R 1 = 4-styryl (S)

Scheme 14

Pfaltz and co-workers [28] showed that Ir I catalysts prepared "in situ" from [Ir(COD)Cl]2 and enantiomerically pure C2-symmetric bisoxazolines 14a (scheme 15) display good activity in the ATH of ketones in refluxing iPrOH in the presence of KOH. Alkyl aryl ketones were readily reduced, affording the corresponding alcohols in 47-91% e.e., whereas dialkyl ketones were less reactive and gave low yields of racemic products. The best result was obtained with the isopropyl substituted ligand and isopropyl phenyl ketone as the substrate (91% e.e. at 70% conversion). The size of the bisoxazoline ligands chelate ring appears to be critical since Ir I complexes with six-membered rings derived from ligands 14b did not show any significant catalytic activity.

O N N O R R 14a O N N O R R 14b R' R'

Scheme 15

The chiral bis(oxazoline)-Ir(I) complex 15 was prepared and used for the ATH of acetophenone in iPrOH in presence of tBuOK as base, but with only modest results (Scheme

Scheme 20

The Schiff bases derived from diaminocyclohexane (21, 22, scheme 21) were used in the presence of [Ir(COD)Cl]2 for the ATH of different aryl alky ketones in iPrOH/KOH [34]. Only moderate enantioselectivities were obtained (maximum: 61% with 21 and 50% with 22, in both cases for the hydrogenation of 2-fluorenyl methyl ketone). for acetophenone and between 65-94% for other alkyl aryl ketones, the highest one being obtained with ligand 24 in the hydrogenation of phenyl isopropyl ketone [35].

Scheme 22

The preformed or in situ prepared iridium complexes of the new chiral diamine 29 have been tested in the ATH of ketones in isopropanol in presence of KOtBu [36]. At 55°C, excellent conversions (up to 100%) but moderate enantioselectivities could be achieved (see scheme 23). ) and tested them in the ATH of acetophenone [37]. In comparison with Ru or Rh-based systems, iridium catalysts were less active but more enantioselective. Both activities and enantioselectivities were highly dependent on the oxazoline ring R substituent but also on the relative configuration of the two asymmetric carbon atoms as illustrated for the two diastereoisomeric ligands 30a and 30b. In addition, it was found that the e.e. increased with conversion. The use of monotosylated diamines and 1,2-aminoalcohols as ligands was first reported by Noyori and co-workers for the ruthenium catalyzed ATH of aromatic ketones [38]. The Cp* iridium complex of (1S,2S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine 31 (scheme 25) has been shown to be active for the ATH of acetophenone, 2-acetonaphthone, 1-tetralone, and 1-indanone to give (S)-1-phenylethanol (90% e.e.), (S)-1-(2-naphthyl)ethanol (81% e.e.), (S)-1-tetralol (96% e.e.), and (S)-indanol (91% e.e.) [39]. The reaction was carried out in iPrOH/KOH at room temperature. The KOH/31 molar ratio plays an important role, the best yield being obtained for a 1:1 ratio. The similar complex 32 (scheme 25) was used by Ikariya and Noyori [40] for the ATH of acetophenone in iPrOH/tBuOK, a 96 % enantioselectivity being obtained but with a poor conversion (36% after 12 h). For mCF3C6H4COCH3 under the same conditions, the reaction was complete after 24 h and the corresponding alcohol was obtained with a 94 % e.e.

Scheme 25

Williams reported the synthesis and application of efficient water-soluble analogues of complexes 31 and 32 for ATH in aqueous media [41].

Scheme 26

In 2005 Xiao reported that the Ir III complex 32 displays good activity (99% conversion after 1 h) and excellent enantioselectivities (93% e.e.) for the reduction of acetophenone in water by sodium formate, with no need for organic solvents or inert gas protection throughout the entire operation [42]. More recently, the same group studied in detail the reaction parameters for the ATH of ketones with complex (R,R)-31 [43]. They showed that the pH should be kept between 6.5 and 8.5 in order to maintain good activities and enantioselectivities. Under these conditions a large range of ketones, including heteroaryl ketones, have been successfully reduced with high yields and enantioselectivities (e.e. up to 97%). However, in most cases the iridium complex (R,R)-31 is less active and enantioselective than its rhodium analogue.

The iridium complex 35 of a camphor-based ligand was then tested for the ATH of a wide range of aryl alkyl and heteroaryl alkyl ketones under the same conditions with a substrate/catalyst ratio of 1000 (scheme 27). High conversions could be achieved for all ketones with a substrate/catalyst ratio of 1000 and in all cases the enantioselectivities are higher then 88% with a maximum of 98% for the ATH of acetophenone or 3-methoxy-acetophenone [44].

, R 1 = Me, R 2 = H, R 3 = Ph 50, R 1 = Me, R 2 = H, R 3 = iPr 51, R 1 = Me, R 2 = H, R 3 = Bn 52, R 1 = Ph, R 2 = H, R 3 = Ph 53, R 1 = Ph, R 2 = H, R 3 = Bn 54, R 1 = Me, R 2 = Me, R 3 = Bn

Scheme 33

Different Ir I precursors were tested: the enantioselectivity was only slightly affected but the best activities were obtained with [Ir(Cl)(COD)]2 and [Ir(COD)2]BF4. Decreasing the reaction temperature from 60 to 20 °C resulted in an enantioselectivity increase in all cases, with a maximum of 80 % e.e. for ligand 48b at 20°C. Many other ketones were tested and the enantioselectivity was found to be significantly influenced by the electronic and steric properties of the substrate, increasing for substrates with bulkier substituents. The electronic properties were also shown to be important, higher e.e. being observed with more electronwithdrawing substituents. The maximum e.e. (97%) was obtained with 1-naphtyl methyl ketone as a substrate using 2-propanol as hydrogen donor with ligand 53.

In 2001 the same group reported a comparison between the iridium(I)-amino sulfide complexes 51 and 53 and a biocatalytic system, using whole cells of the white-rot fungus Merulius tremellosus ono991, for the ATH of prochiral ketones. The two approaches were

shown to be complementary. The biocatalytic approach is most suitable for the enantioselective reduction of chloro-substituted aryl ketones (with e.e. up to 88%), whereas better results were obtained using the catalytic hydrogenation protocol in the reduction of α,β-unsaturated compounds (e.e. up to 90%) [51].

Camphor-based N,S ligands 56-59 (see scheme 34) in association with [Ir(COD)Cl]2 can catalyze the ATH of acetophenone but with moderate activities and enantioselectivities, the best e.e. (80%) being obtained using ligand 56a [52].

Scheme 35

The amino-olefin complex 61 was used by Grützmacher et al in the ATH of acetophenone (see scheme 36) with good activities and enantioselectivities [54]. mixture of undefined isomers without free phosphine groups was obtained and applied to the ATH of various aromatic ketones using isopropanol as hydrogen source. The corresponding chiral alcohols could be obtained with high yields (up to 99.4%) and excellent enantioselectivities (up to 99.0% for isopropyl methyl ketone or 1,1-diphenylacetone) under mild conditions. With propiophenone as substrate, a TON of 4780 and a TOF as high as 1593

h -1 at 55°C could be achieved. The analogous chiral iridium(I) complex with ligand 63 was also prepared and tested in the ATH of acetophenone, but the reaction was very slow under the same conditions, (R)-1-phenylethanol being obtained only in 39.8% yield and 39.5% e.e. after 48 h.

These results indicate that the NH functions are responsible for the high activity, possibly stabilizing a catalytic intermediate [55].

NH HN

Ph 2 P PPh 2 N N Ph 2 P PPh 2 62 63 R 1 R 2 O [IrCl(62)] (0.5% mol) iPrOH, RT, 2-4h KOH (1% mol) R 1 R 2 OH R 1 = Ph, R 2 = Me R 1 = Ph, R 2 = Et R 1 = Ph, R 2 = iPr R 1 = Ph, R 2 = tBu R 1 = 2-MeC 6 H 4 , R 2 = Me R 1 = 3-MeC 6 H 4 , R 2 = Me R 1 = 3-MeOC 6 H 4 , R 2 = Me R 1 = Ph, R 2 = Cy R 1 = Ph 2 CH, R 2 =
N O N O R 2 R 1 R 2 R 1 68a, R 1 = H, R 2 = iPr 68a, R 1 = Ph, R 2 = H

Scheme 41

Zhang and coworkers used ferrocenyl diphosphine-diimine 69 in association with [Ir(COD)Cl]2 and KOH in the ATH of acetophenone [START_REF] Zhang | Synthesis and Reactivity in Inorganic, Metal-Organic[END_REF]. The catalytic systems exhibited moderate activities and enantioselectivities (up to 49% e.e. for 69a, scheme 42). Good activities but low enantioselectivities (e.e. < 50%) were obtained with TANIAPHOS 70.

MANDYPHOS 71b was even worse with low activities and enantioselectivities (e.e. up to 37%). However, good yields and e.e. could be achieved with MANDYPHOS 71a for a large range of ketones, especially for the very hindered PhC(O)tBu (see scheme 43) [65].

Asymmetric hydrogenation (AH) of ketones with iridium

Although the asymmetric transfer hydrogenation of ketones with iridium complexes has been well studied and developed, the use of molecular H2 as hydrogen donor has been much less explored.

P,P ligands

One of the first examples of AH of ketones in the presence of iridium under H2 was described by Monsanto [66] [74]. The same authors studied also the AH of acetophenone with iridium complexes containing the same C2symmetric diamine ligands 77 (Scheme 47). E.e. values of up to 63% were observed when the reaction was performed in THF. The introduction of different hydrophilic groups on the ligand allowed the asymmetric hydrogenation of acetophenone in aqueous media but lower activities and enantioselectivities were observed relative to the reaction in THF. The use of such ligands allowed catalyst recovery without loss of activity and enantioselectivity in at least four hydrogenation cycles [74].

HN NH R' R' R R 77a, R = H, R' = Me 77b, R = OMe, R' = Me 77c, R = OH, R' = Me 77d, R = O-(C 2 H 4 O) 3 CH 3 , R' =

Other ligands

In 2004, Götz and Dahlenburg [82] reported the synthesis and use of chiral P,N-chelated Ir I complexes of the general type [(COD)Ir(P-NR 1 R 2 )]BF4 (84)(85)(86) in the AH of ketones (scheme 54). In the presence of an alkaline or amine base, all complexes catalyzed the direct hydrogenation of alkyl aryl ketones to the corresponding 1-phenylalkanols in methanol under H2 (10-50 bar) between 25 and 50 °C. The AH of acetophenone occurred with modest to moderate enantioselectivity (30-55% e.e.) in the presence of iridium complex 86(R,R) and different bases. In all cases the enantioselectivities obtained in the presence of KOH were higher then with (-)sparteine (19-55% and 4-47% respectively). Other alkyl aryl ketones were tested with 86(R,R) as catalyst and a maximum of 68% e.e. was obtained for the AH of phenyl 3chloropropyl ketone.

Scheme 54

The same group also tested several Ir III complexes bearing chiral diamines, diphosphines, or a combination of both (87-90, scheme 55) [83]. All complexes are catalytically active in the AH of acetophenone. The dihydride 87 and 88 are less active and poorly enantioselective (e.e. < 30%), whereas good activities and enantioselectivities were obtained with complexes 89-90 in particular with 90a, used as a preformed complex or obtained in situ from 89 and (R,R)-DPEN (e.e. up to 84%).

N N H 2 R 1 R 4 R 2 R 3 90a : R 1 = R 3 = H; R 2 = R 4 = Ph 90b : R 1 = R 3 = H; R 2 ,R 4 = (CH 2 ) 4 90c : R 1 = R 2 = R 3 = R 4 = CH 3

Scheme 55

In 2007, we [84] showed that the iridium complexes 91 and 92 (Scheme 56) bearing planar-chiral ferrocenyl phosphine-thioether ligands are active in the AH of simple ketones.

Different additives were tested for the hydrogenation of acetophenone in isopropanol at 30 bars H2, and total conversion was obtained with strong bases like NaOMe, KOtBu or KOH. The catalytic activities are especially high (TON up to 915 and TOF up to ca. 250 h -1 at 25°C). The AH of acetophenone gave 43-77% e.e. at RT, the best value being obtained with the complex 91c having benzyl as substituent on the sulphur atom. Various other ortho, meta and para substituted acetophenones were studied and again complex 91c showed the best enantioselectivities (for instance, 76% e.e. for the AH of 4-chloroacetophenone). When the reaction was carried out at 10°C, much higher enantioselectivities (up to >99% for 4fluoroacetophenone) were obtained while the catalytic activities remained acceptably high. The reaction also takes place in toluene, whereas no activities were recorded in alcohol solvents in the absence of molecular H 2 .

Mechanistic considerations

In many respects, one can imagine that the reductive transformation of ketones examined in this review follow the same mechanistic pathways as with other metals such as rhodium, ruthenium, iron, etc. The purpose of this section is not to review the mechanistic understanding of ketone hydrogenation in general. We wish, however, to highlight the mechanistic studies that have appeared in the literature with specific reference to the use of iridium.

Hydrosilylation

No mechanistic considerations making specific reference to the use of Ir in hydrosilylation appear to be available, paralleling the less frequent use of this metal for the catalytic tests. An early study on the use of [Ir(COE) 2 Cl] 2 /PPh 3 as a precatalyst for the hydrosilylation of cyclohexanone by Et3SiH has shown that the best activity is obtained with a P/Ir ratio of 1:1, whereas the catalyst becomes inactive when using a 2:1 ratio. This result has been attributed to the inertness of the [IrHCl(SiEt3)(PPh3)2] adduct [12].

One interesting aspect is the reversal of enantioselectivity on going from Rh to Ir, observed experimentally in several cases [13,16,14,15]. Moberg has observed an increase of enantioselectivity, the extent of which depends on the nature of the anion, upon the addition of silver salts to the [MCl(COD)]2/L* precatalyst (M = Rh, Ir) (Scheme 7). The cause of this phenomenon has been attributed to a secondary interaction, established by an OH function in the ligand. The Ir complex 93 (Scheme 57) was prepared and evidence for the presence of the secondary interaction was obtained by NMR. In further support of this hypothesis, a similar e.e. enhancement was not observed when using related ligands devoid of the OH function, e.g. 94.

However, whether this interaction may also be associated to the reversal of absolute configuration is not clear.

Survey of the proposed mechanisms

All mechanistic possibilities are summarized in Scheme 58 in their simplest possible representation and consist of the "Noyori-Morris" or "outer sphere" mechanism (A) [85], two "inner-sphere" hydride mechanisms involving ketone coordination, insertion into the metalhydride bond, and product elimination (distinguished as a "monohydride" (B) and a "dihydride" (C) version [86]), and an "inner-sphere" direct transfer from the reducing agent to the coordinated substrate (D, a metal-templated, Meerwein-Ponndorf-Verley-type concerted mechanism which only applies to the TH process) [9]. The D cycle is generally considered less likely than the hydride mechanisms for transition metal-catalyzed TH processes [86], but certain experimental evidence, as will be shown below, seems most consistent with this mechanism for specific systems.

R 1 R 2 O H R 2 OH R 1 O H OH [M] H E H [M] E d- d+ [M] H E H R 1 R 2 O [M] H E H O [M] H R 1 R 2 O [M] H R 1 R 2 O [M] H R 1 R 2 O [M] H O H R 2 OH R 1 H OH A B H 2 H 2 O H OH R 1 R 2 O H R 2 OH R 1 [M] H H [M] [M] H O R 1 H R 2 [M] H O H C H 2 O [M] O O R 2 H R 1 [M] O O R 2 H R 1 [M] O O R 2 H R 1 [M] O H R 1 R 2 O [M] O R 2 H R 1 H R 2 OH R 1 H OH O D

Scheme 58. Mechanistic pathways for hydrogenation and transfer hydrogenation of ketones

Cycle A can be subdivided into two versions, depending on whether the H + and H - components are transferred to the C=O substrate concertedly or stepwise (only the concerted version is shown in Scheme 58). Several other variants are possible for each mechanism, depending on whether the Ir center has the oxidation state I or III, on the state of protonation (many systems need a strong base to be activated), on the H2 activation mode (homolytic or heterolytic) for the hydrogenation process, and so forth. Note that the key hydride intermediate for cycles A-C (shown at the top of each cycle) can always be regenerated either by H2 or by a dihydrogen source (exemplified by isopropanol in Scheme 58). Therefore, these mechanistic possibilities apply to both hydrogenation and transfer hydrogenation. The metal center formally changes its oxidation state in cycle C while it does not need to in cycles A and B. However, it may do so, limited to the hydrogenation cycles, if H2 is activated homolytically.

One important feature distinguishes cycles A, B and D on one side and C on the other, limited to transfer hydrogenation. For A, B (both "monohydride" mechanisms) and D, the "hydridic" H atom in the reductant (e.g. the -H atom of isopropanol) selectively becomes the "hydridic" (-H) atom in the product, whereas in cycle C this atom is distributed with equal probability to the CH and OH positions. Thus, useful information can be obtained by use of selectively deuterated reductants such as d1-cyclohexanol or racemization studies of an optically active -deuterated alcohol such as d1-phenylethanol (see scheme 59), allowing to exclude at least one mechanistic possibility. However, cycles A, B and D cannot be told apart by this experiment.

D Ph OH [M] Ph O + [M]HD [M]D + H + -[M] + 1 : 1 Cycles A,B,D Cycle C OH D [M] O + [M]HD [M]D + H + R 1 R 2 O D R 2 OH R 1 D R 2 OH R 1 H R 2 OD R 1 + Cycles A,B,D Cycle C -[M] 1 : 1 D Ph OH D Ph OH H Ph

OD

Scheme 59

Isotope labelling experiments of these types have been carried out in transfer hydrogenation mechanistic studies, including some involving Ir compounds. Bäckvall et al. [87] reported that catalysts 95-99 (Scheme 60) give rise to a high deuterium incorporation into the product -C position, the slight D loss being attributed to ortho-metallation processes that are more pronounced for the phosphine-containing catalysts (98 and 99). Crabtree et al. found analogous results for the transfer hydrogenation of acetophenone by d1-cyclohexanol catalyzed by the bis(NHC) Ir III complex 100 [88]. [50], where a pronounced donor-dependence (isopropanol vs. formic acid) of the enantioselectivity was observed. For instance, reduction of acetophenone gave the alcohol product with an e.e. of 23% (S) when using formic acid/NEt3 and 24% (R) when using isopropanol in the presence of ligand 49, or 58% (S) and 80% (R), respectively, in the presence of ligand 52. Thus, the authors conclude that a metal-templated direct transfer might be possible for this system. It is also possible that a different mechanism is operating with each of the two different H transfer agents. However, one must be cautious because an important effect on the enantioselectivity may also be caused by the different solvent nature (neat HCOOH/NEt3 azeotrope and iPrOH, respectively).

The highest activity in ketone reduction processes, especially the transfer hydrogenation (TH) type, is arguably shown by catalysts featuring the Ru-NH linkage [90] with TOF up to 10 6 h -1 at 50% conversion [91]. The utility of complexes having the Ir-NH functionality, or other Ir-EH functionalities with mobile protons (e.g. Ir-OH with aminoalcohol ligands), has also been demonstrated and these systems are therefore proposed to operate through cycle A [29,32,40,54,92]. In a recent study of the ATH by formate catalyzed by Rh III and Ir III complexes in water, the activity was found to be highest at intermediate pH (ca. 7 for both metals) [43].

This catalyst was proposed to operate by the outer-sphere cycle A with the highest activity resulting from the neutral form A (Scheme 61, M = Rh or Ir; cycle I), obtained in situ from the chloride precursor and formate. At low pH a less active cationic complex B would operate though an alternative cycle II (possibly through decoordination of the NHTs function in order to explain the lower enantioselectivities), whereas an inactive hydroxide complex C would form at high pH (the enantioselectivity is not affected at high pH). The related catalyst 36a (Scheme 28) was also shown to provide the highest activity in the presence of mild bases, whereas stronger ones deactivate it [45]. This system gives the same activity as the mononuclear chloride analogue, suggesting that the active form is a mononuclear solvated species D (Scheme 62), which seems consistent with the observed negative influence of excess chloride ions. This species would then be converted into the active hydride complex E in the presence of base. Both cycles A and B have been considered as possibilities, although it was argued that the lower activity of the Me-substituted prolinate complex (36b) militates in favour of cycle A. The intermediate of cycle B would also require partial decoordination of the prolinate ligand or Cp* slippage in order to avoid a 20-electron configuration. The hydrogenation and transfer hydrogenation processes are also catalyzed, however, by complexes with "non N-H" ligands, such as those of Scheme 60. The highest activity for Ir catalysts has in fact been obtained with ligands that do not contain mobile protons on the donor functions. 65

Scheme 65

On the basis of the above observations, Dahlenburg and Götz proposed a mechanism for the hydrogenation catalytic cycle which involves ketone coordination and insertion (type B, Scheme 58) into an Ir III -H bond of a neutral Ir III amido species in which the positions formerly occupied by the COD ligands are saturated by solvent molecules. However, the reactivation by H2 would not occur by H2 addition to the neutral alkoxide intermediate but rather to a cationic species obtained after protonolysis of the Ir-alkoxide function, liberating the product, as shown in Scheme 66 [82]. Complex G in this scheme would be common to the catalytic ketone hydrogenation and H/D exchange cycles. This mechanism, of course, cannot be valid when using compound 102 (Scheme 64), which was also shown within the same contribution to be an active catalyst [82].

Open questions

As is evident from the above survey, the variety of catalytic systems and conditions and the paucity of mechanistic investigations do not provide a clear view of the structure/activity and structure/mechanism relationship. Several points deserve consideration, only few of them being explicitly addressed in previously published studies.

(a) Ir(I) or Ir(III)?

For hydrogenation reactions, it is usually assumed that the cycle operates through Ir III species because of the well known propensity of iridium to undergo H2 oxidative addition reactions. Studies by Crabtree et al. have shown that [Ir(COD)L2] + complexes react with hydrogen to yield [IrH2L2S2] + derivatives (S = solvent), which were proven intermediate of the olefin hydrogenation catalytic cycle. 93 The involvement of the same type of intermediates in the hydrogenation or transfer hydrogenation of polar substrates such as ketones, however, is not clear, especially for processes taking place through the "outer-sphere" pathway. The precatalysts used in TH are often Ir I complexes which, in the presence of bases and hydrogen donors, should give rise to Ir I hydride species as exemplified in Scheme 67 for the specific examples of a neutral chloro complex and for a cationic (COD)IrL2 + complex. The [IrCl(LL')]2 system can convert to an isopropoxide complex M to yield the hydride N through elimination of acetone (or through an equivalent formate intermediate and elimination of CO2 if HCOOH is used as transfer agent). The [Ir(COD)(LL')] + system, on the other hand, can analogously lead to the 16-electron or 18-electron hydride P via the isopropoxide O. The question is then whether this system can catalyse itself transfer hydrogenation, or whether it does so only after elimination of the COD ligand as cyclooctene or cyclooctane by transfer hydrogenation (this point will be discussed again later). At any rate, the system would remain in the oxidation state I. In order to generate Ir III , oxidative addition of alcohol to yield a hydrido alkoxo derivative is necessary, but this process has not so far been documented to the best of our knowledge for an Ir I system. On the other hand, use of Ir III pre-catalysts does not guarantee that this oxidation state is retained in the active form, because basic conditions may facilitate reduction (Scheme 68). These considerations also apply to hydrogenation catalysts, when these operate under strongly basic conditions, especially in alcohol solvents. Ir III -H + + B Ir I + BH +

Scheme 68

The direct comparison between Ir I and Ir III precursors with the same ligand system is rare. Studies of a series of different catalytic precursors containing the PYBOX ligand show that higher activities and enantioselectivities are obtained when using the Ir III hydrogenation catalyst 100 (Scheme 60, R = iPr) and found that the catalyst is stable in the absence of base or in the presence of base and substrate, but decomposes in the presence of the base alone. This indicates that gradual decomposition of the active catalyst occurs under strongly basic conditions unless protected by the substrate [88]. The precise nature of the decomposition products, however, could not be elucidated.

(b) Denticity/activity relationship

Most catalysts use bidentate LL' (L' = or ≠ L) ligands. Others, however, use tridentate ligands such as PYBOX and even tetradentate ones such as the P,N,N,P ligands 62 and 63 or N4 ligands 64 and 65 (Schemes 37 and 38), several of them being devoid of donor function with mobile protons. Thus, the question is whether the ligand must decoordinate to generate a free coordination site (such as in N in Scheme 67, or whether the Ir I system is capable to operate through 5-coordinate intermediates, or finally whether the active form is an Ir III complex with an octahedral coordination environment. The systems based on PYBOX appear rather slow, since high conversions within 1-2 h with 0.2% catalyst required the use of high temperatures (82°C) [63], while other systems with bidentate ligands give similar rates at room temperature.

The P,N,N,P ligand 62, on the other hand, gives nearly quantitative conversion in 2 h at room temperature for acetophenone (0.5% catalyst). The nature of the precatalyst was shown to be [IrCl (41)] by isolation and spectroscopic characterization [55].

(c) Solvent effects on activity and on enantioselectivity

For TH, it seems that isopropanol is the reagent/solvent of choice and the need of a large excess in order to displace equilibrium for the nearly thermoneutral reaction limits the investigation of solvent effects. For hydrogenation reactions, the solvent nature appears to have a dramatic effect. The Ir-catalyzed hydrogenation of the ,-unsaturated ketone trans-PhCH=CHCOMe [94] gives predominantly the saturated ketone (C=C hydrogenation product) with low activities in CH3COOH and 1,2-C2H4Cl2, whereas the unsaturated alcohol (C=O hydrogenation product) is obtained in alcohols, THF, dioxane, DMF and toluene. Thus, the solvent seems to play a determining role in the chemoselectivity toward the reduction of C=C vs. C=O bonds. Low activities in C=O hydrogenation are typically found in chlorinated solvents and attributed to the release of Cl -under the reaction conditions, blocking the catalytic activity by irreversibly coordinating to the metal center [73]. High activities in the reduction of polar unsaturations are generally observed in polar coordinating solvents. The relative performance of THF and water for the catalysts with the chiral diamines 77 (Scheme 47) was shown to depend on the nature of the chiral ligand and substrate [74]. Alcohols always appear as suitable solvents for hydrogenation activity, though not always leading to the highest enantioselectivities. The relative activity in the alcohol solvents is often in favour of iPrOH (for instance for catalysts 91 [84] and IrH3(P[CH2CH(Me)Et]Ph2)3 [94]) hinting at the possibility of a transfer hydrogenation mechanism, but exceptions have also been recorded (for instance MeOH > EtOH, iPrOH for catalyst 90b) [95] and the systems are also often active in solvents incapable of acting as hydrogen donors [84,94], demonstrating that H2 is the reducing agent, at least in the latter solvents. In alcohol solvents, the coexistence of hydrogenation and transfer hydrogenation is possible, since the active catalyst can be regenerated by both the alcohol and H2 (see Scheme 58). An intriguing observation has been obtained in our group for the hydrogenation with catalysts 91: while good activity is observed in MeOH, EtOH and iPrOH, the catalyst does not work in tBuOH. Since this alcohol is devoid of -H atoms, the occurrence of a TH mechanism would seem indicated. However, this catalyst also works well in toluene and MeCN, demonstrating the viability of a hydrogenation mechanism [84]. How the presence of tBuOH blocks the hydrogenation pathway, contrary to the lower alcohols and the other non protic solvents, is not yet understood.

(d) Is diene removal in "Ir(diene)"-type pre-catalysts necessary?

An interesting and much debated question is whether the diene ligand in dienecontaining pre-catalysts remains in the coordination sphere of the active catalyst or whether it Calculations on catalytic cycles that involve Ir III catalysts or intermediates have

apparently not yet been reported. No calculations seem to be reported also for Ir-based hydrogenation mechanisms, which as stated above differ from TH only in the regeneration of the hydride complex (Scheme 58). As already mentioned, complexes containing COD or other olefins are likely to be transformed into solvent-stabilized species of type [Ir(LL')(S)2] + under these conditions, although whether these are stable as Ir I derivatives or are transformed into Ir III species is not yet clear. One intriguing possibility (valid also for the TH process with [IrCl(LL')]2 catalysts such as 96, 97 or 99) that has apparently not yet been considered is that an outer sphere mechanism is operational, even when L and L' do not contain mobile protons, with intervention of a coordinated alcohol molecule, as shown in Scheme 70. After all, if this mechanism is proposed for alcohol functions that are part of a chelating ligand (e.g. aminoalcohols), why not for simple alcohol molecules? An ongoing computational study in our laboratory seems to confirm that this is a viable pathway [102].

  Scheme 1

  the pioneering work of Mestroni et al. on the use of iridium complexes in the transfer hydrogenation of ketones [19], numerous iridium-based catalytic systems have been studied. Most of these systems are asymmetric ones. Various types of chiral ligands have been studied. The different catalytic systems will be presented according to the coordination pattern of the ligands involved.

[ 20 ]

 20 . Dichlorobis(1,4-cyclooctadiene)diiridium ([Ir(COD)Cl]2) was used as a precatalyst in the presence of chiral phosphines (Scheme 9) for the asymmetric reduction of various ketones with isopropanol as a hydrogen source. The work was extended in 1986, in particular by studying the precatalyst activation conditions[21]. A first activation time (T1) of [Ir(COD)L] + in refluxing isopropanol, followed by a second activation time (T2) under the same conditions but in presence of 8 equivalents of KOH, were necessary for optimum catalytic performance. The precise structures of the different species produced during the activation process were not determined by the authors, but the presence of different iridium hydrides at the end of the first activation time (T1) was revealed by 1 H NMR. Although the influence of T1 and T2 on the catalytic activities was low, the enantioselectivities dramatically changed. Thus, using the same precatalyst [Ir(COD)CHIRAPHOS] + , the reduction of acetophenone yields the corresponding alcohol with an e.e. of 28% in favour of the S enantiomer if T1 = 15 min and T2 = 15 min but an e.e. of 11% in favour of the R enantiomer if T1 = 7 h and T2 = 15 h. High levels of enantioselectivities were observed with the PROPHOS ligand (up to 66% in the hydrogenation of PhCOEt).

  Scheme 19

21 A

 21 Scheme 21

23 Andersson

 23 Scheme 23

  Scheme 24.

5 .

 5 Scheme 34

  Scheme 36

  Scheme 40

42 Stradiotto

 42 Scheme 42

  Scheme 43

Takaya 5 - 76 ( 45

 57645 Scheme44

  , 100% yield, 30% e.e., NEt 3 R = Me, 62% yield, 55% e.e., KOH R = (CH 2 ) 3 Cl, 46% yield, 68% e.e., (-)sparteine

  Scheme 56

2

 2 Scheme 57

Scheme 60 .

 60 Scheme 60. Use of iridium catalysts for mechanistic studies with -deuterated reductant

  Scheme 61

  Scheme 62

  Scheme 66

  Scheme 67

  Scheme 69

  Scheme 70

  Lower e.e. were also reported by Uemura et al. with the diferrocenyl dichalcogenide ligands 3 (e.g. for ligand 3b: e.e. up to 23% for Ir, 85% for Rh, see scheme 7)[17].Iridium and rhodium complexes of carbene-naphtoxy ligands have been used by Crabtree et al. in the asymmetric hydrosilylation of acetophenone by diphenylsilane (Scheme 8)[18].

		O					OH
			Ph 2 SiH 2		H +
			5% ([Ir(COD)Cl] 2 , 2.2 2)			PPh 2	S
			0°C-> RT, 18h				NMe 2	2
						92% yield, 33% e.e.
					Scheme 6
		O				OH	Me	NMe 2
			Ph 2 SiH 2	H +			H	E	E
			2.5% ([Ir(COD)Cl] 2 , 2 3)				Fe	H	Fe
			15-25°C, 15-120h				Me 2 N	Me
				82% yield, 15% e.e., 3a
								3a : E=S
				100% yield, 23% e.e., 3b
								3b : E=Se
				81% yield, 22% e.e., 3c	3c : E=Te
			Ph 2 SiH 2	R Scheme 7 H +	OH	L* =	O	N	PPh 2
			RT, 16h				Ph	OH
	O Rhodium complexes gave high activities but low enantioselectivities (e.e. up to 23%), whereas O O O
	the corresponding iridium complexes gave slightly lower activities, lower chemoselectivities
	Br (ca. 15 % of silyl enol ether produced, see scheme 8), but better enantioselectivities (e.e. up to MeO
	60%).	Conv = 98%	Conv = 97%		Conv = 98%	Conv = 100%
		e.e. = 69%	e.e. = 62%		e.e. = 13%	e.e. = 9%
		(81% with Rh)	(85% with Rh)	(67% with Rh)	(55% with Rh)
		O	Ph 2 SiH 2	Scheme 5	OSiHPh 2	OSiHPh 2
	2.2. Other ligands	0.25% ([Ir(COD)Cl] 2 , 2 eq 4) 15-25°C, 15-120 h
						97%		3% with4a
						97%		3% with 4b
	85% The use of tridentate P,N,S chiral ligands with [Ir(COD)Cl]2 as precatalyst by Faller et al. 15% with 4c 83% 17% with 4d
			OH
	gave up to 33% e.e. in the hydrosilylation of acetophenone by diphenylsilane (see scheme 6) MeOH 12% e.e. with 4a 4a : R = iPr, M=Rh
		NaOH		13% e.e. with 4b 50% e.e. with 4c		N	N	R	4b : R =Bn, M=Rh 4d : R =Bn, M=Ir 4c : R = iPr, M=Ir
				60% e.e. with 4d		O M(COD)

h (quasi-quantitative conversions but with 2-10% of silyl enol ether) with good enantioselectivities for aromatic ketones. With this ligand, iridium-based systems were again less selective than their rhodium counterparts. R O 0.5% [Ir(COD)Cl] 2 , 2% L*

[16]

. However, the reactions were slower, less enantioselective (e.e. up to 64% with the best ligand 2) and, once again, with opposite absolute configuration than with the corresponding rhodium systems.

Scheme 17 Uemura tested ligands 3 also in the ATH of acetophenone in the presence of

  -diamine derivatives 17 (scheme 19). The ATH of alkyl aryl ketones was carried out in 2-propanol at room temperature in the presence of potassium hydroxide. For acetophenone, the reduction product was obtained after 12 h in good yields (68-96%) and good enantioselectivities. Many other aryl alkyl ketones were also tested but only with the [Ir(COD)Cl]2/17c system, yielding, in most cases, the corresponding alcohols in good yields and with good e.e. (see scheme 19).

	Another catalytic system with chiral amine ligands for ATH was reported by Inoue and
	Noyori [32]. The iridium(I) complexes were prepared from [Ir(COD)Cl]2 and 1,1-di(p-
	16) [29]. anisyl)ethylene
							Ph
	O					OH	HOH 2 C	O
	[Ir*] (1% mol)				N
	tBuOK (15% mol) iPrOH, 24 h			Ir* :	Ir	Cl
							N
					yield = 22% e.e. = 20%	HOH 2 C	O
							15	Ph
					Scheme 16
	Lemaire et al. used ureas 16 (see scheme 17) as chiral ligands in the ATH of propiophenone
	in the presence of [Ir(COD)Cl]2 and tBuOK in isopropanol at 60°C [30]. After 9 days, the
	conversion was almost complete but the enantioselectivity was moderate (e.e. = 57%). For this
	ligand, the iridium-based catalytic system was less active and enantioselective than its rhodium-
	based counterpart.
					Ph	Ph
			HNPh	C	N	N	C NHPh
				O Me Me	O
					16
							[Ir(COD)Cl]2
	and NaOH in refluxing isopropanol to give the (R)-phenylethanol with moderate yields and
	enantioselectivities (Scheme 18) [31].
	O		[Ir(COD)Cl] 2 , (0.5 mol %)	OH
			L* (1 mol %)
	Ph	Me	1 h NaOH, iPrOH, 80°C	Ph	*	Me
						L* = 3a, 0 % yield
						L* = 3b, 32 % e.e., 47 % yield
						L* = 3c, 35 % e.e., 40 % yield
					Scheme 18

  Xiao et al. used complexes similar to 31 (see scheme25), synthesized in situ from 1,2aminoalcohols and [Cp*IrCl2]2[48]. Good conversions could be achieved but enantioselectivities were low (e.e.= 3-55%). Sinou et al. used -aminoalcohols 39 with [Ir(COD)Cl]2 in the ATH of acetophenone, with low activities and enantioselectivities (e.e. up to 30% for 39a, R=H), see scheme 30[49].

								O			O
				R	R	S	H Ph	N OH NH 2 R 1	R	S	OH R NH 2	H MeS Ph	N Me NH 2 OH
				N 49	H NH 2 40a, R= Me 40b, R= Bn R 3 S NHR 2 40c, R= Tr	41a, R= Bn 41b, R= Tr	Ph O N	S	O 55a	NH 2 42 NH 2 H
									OBn		NH Ph	NO 2 Me
				37a: R= OMe 37b: R= H S NH 2 Bn		Bn	S	Ph 38a: R= OMe Ph 38b: R= H NH 2 S	NH 2
	Ar	O	R	0.1 % 35 43 5 eq. HCOONa, H 2 O, 40°C Ph Ph OH Ar	OH Scheme 29 R	Ph H 2 N Cl OH	44 35 Ir	N O Cp* 55b	S O O O	OH
	3.3. N,O ligands					Ph	S	NH 2		Bn	S	NH 2	Bn	S	NHR
								45	Scheme 27 46	47a, R= Ts
											47b, R= Boc
											Cp*
											Ir
	Ph	O	CH 3			iPrOH, RT, 3-120h KOH 5% [Ir(COD)Cl] 2 /39	NR	Ph	O O 3 CH 3 (BF 4 ) 3 OH	HO RNH	OCH 2 Ph OCH 2 Ph
											e.e. =16-30%	39
											OH
		O				Scheme 30 [Ir(COD)Cl] 2 , (0.5 mol %) 48 (2.5 mol %)	OH *	Ph	S	O	NH 2
	Ph		Me			HCOOH/NEt 3 (5/2), 60°C	Ph	Me	48a	OH
	3.4. N,S ligands
	48a, 56% conversion after 1h, 27% e.e. (R) 48b, 99% conversion after 30 min, 65% e.e. (S)	Ph	S	O	NH 2
	Van Leeuwen has developed a new class of efficient catalytic systems [50]. Several chiral 48b
										Scheme 32
	N,S-chelating ligands (40-55, Schemes 31-33) were synthesized and used as ligands in the
	iridium(I)-catalyzed reduction of ketones in formic acid or iPrOH, both proving to be suitable
	Moreover, the Ir complex of 38 could be recovered in high yields with dilute hydrochloric acid hydrogen donors. Tested in the ATH of acetophenone with formic acid in the presence of For ligands 49-55, which contain an additional stereogenic carbon in the  position in
	and reused. In the asymmetric transfer hydrogenation of acetophenone, the enantioselectivity [Ir(Cl)COD]2/NEt3, the amino-sulfide ligands 40-47 gave in some cases good conversion (98 addition to the  position, the stereoselectivities in the ATH of acetophenone were moderate
	was maintained after six cycles [46]. % after 1 h at 60°C with 41a) but the enantioselectivities were poor (5-18%). (23-65% with the maximum e.e. for ligand 51). Catalytic activities were also moderate:

Iridium trimers 36 (see scheme 29) synthesized from natural L-prolinol have been used in the ATH of acetophenone with sodium formate

[45]

. Unlike 36b, 36a showed good catalytic activities and enantioselectivities (e.e. up to 64%). 36a: R = H; 36b: R = Me

Scheme 28

In 2006 the group of Zhang described the synthesis of compounds 37 and 38 (Scheme 29), starting from the natural products quinine, quinidine, cinchonine and cinchonidine, and their use in the ATH of aromatic ketones in iridium catalytic systems using isopropanol as the hydrogen source

[46,47]

. Good to excellent yields (50-90%) and enantioselectivities (72-97%) were observed with a variety of aromatic ketones using [Ir(COD)Cl]2 as a metal precursor.

Scheme 31

The two diastereoisomeric ligands 48 which differ only by the configuration on sulphur have been tested in the ATH of acetophenone (scheme 32). The chirality on sulphur played a major role and with the matched diastereoisomer 48b a more active and more enantioselective catalytic system could be obtained (65% e.e. in favour of S vs 27% e.e. in favour of R with 48a, see scheme 32).

quantitative conversions could only be obtained after 3 h with ligands 50 and 51. The introduction of the sulfoxide group (ligands 55a and 55b obtained by oxidation of compound 51) decreased considerably the conversion and the stereoselectivity of the reaction even for the matched diasteroisomer 55a (32% e.e. (S) instead of 65% e.e. (S) with 51, see scheme 33).

  Gao et al. have also shown that complexes obtained in situ from [IrHCl2(COD)]2 and the same ligand 62 have a remarkable ATH catalytic activity under ambient conditions and afford improved enantioselectivities in certain cases (for instance, the ATH of t-butyl phenyl ketone yields 93% e.e. instead of 82% with IrCl(62)). The amount of catalyst could be decreased to the level of 0.01-0.05%. For instance, the alcohol derived from 1,1-diphenylacetone could be obtained with up to 99% e.e. in 89% yield after 63 h with a substrate-to-catalyst molar ratio of and excellent e.e. (up to 99%)[57]. In the presence of a different metal precursor, [IrH(CO)(PPh3)3], ligand 62 afforded a 90% e.e. and a 97% yield after 0.5 h in isopropanol at 75°C for the ATH of propiophenone, without any base. Different other ketones were tested and the results were very similar, with excellent yields and e.e. (up to 99% and 97%, respectively)[58]. The reaction could be also carried out in a isopropanol/water mixture using [IrCl(COD)(Ph3P)] and a water-soluble analogue of 62 prepared by sulfonation of 62 with oleum, but with with reduced catalytic activities and sometimes slightly lower enantioselectivities[59].Using again 1,2-cyclohexanediamine as a source of chirality, Gao et al. tested tetraaza ligands 64 and 65 in the ATH of propiophenone (scheme 38). Catalytic systems based on 64 proved to be more active and more enantioselective than the systems with 65 (e.e. up to 67% for 64, 56% for 65)[60]. High level of enantioselectivities could be obtained in the ATH of various aromatic ketones using 64 and [IrHCl2(COD)]2 as a source of iridium (see scheme 32). ,O,O macrocycle 67 in presence of [IrCl(COD)]2 could also been successfully used in the ATH of phenyl ethyl ketone (see scheme 40)[62].

						Scheme 39
	N,NO			1% [IrCl(COD)] 2 /67	OH		NH	HN
				KOH
	Ar	TMS	iPrOH/40°C	Ar	Et
				7 h
					yield = 98%; e.e. = 84%
	N			N	N	N		N	NH	HN	N
									83% e.e.
				64					65	94% e.e.
									99% e.e.
								Ar=Ph, R=Me	82% e.e. 76% e.e.
	O		[IrHCl 2 (COD)] 2 /64 KOH	OH	Ar=Ph, R=Et Ar=Ph, R=nPr Ar=Ph, R=iPr	99% e.e. 80% e.e. 88% e.e. 85% e.e. 64% e.e.
	Ar	R		isopropanol/RT	Ar	R	Ar=Ph, R=nBu	82% e.e. 91% e.e.
				60-100 min			Ar=2-tolyl, R=Me	98% e.e. 90% e.e.
						Scheme 38		Me	99% e.e.
						Scheme 37
	Gao and coworkers used also tetradentate S,N,N,S ligands 66 in the ATH of various
	aromatic ketones in isopropanol in air with good activities and very good enantioselectivities
	(see scheme 39) [61].
	O	1% [IrCl(COD)PPh 3 ]/66	OH
	Ar	R		KOH isopropanol/RT	Ar	R
				6-48h				NH	HN
				Ar=Ph, R=Me	83% e.e.
				Ar=Ph, R=Et Ar=Ph, R=nPr	87% e.e. 88% e.e.		S	66	S
				Ar=Ph, R=iPr	95% e.e.
				Ar=Ph, R=nBu	90% e.e.
				Ar=2-tolyl, R=Me	90% e.e.

10000:1. In addition, the reaction was neither affected by air nor by the addition of water

[56]

.

This catalytic system is also efficient in the asymmetric transfer hydrogenation of aromatic ketones with HCOONa in water, giving the corresponding optically active alcohols again in high yields

  For the AH of acetophenone in MeOH at 45 atm of H2, total conversion and enantioselectivities varying between 34 and 55% were obtained as a function of the metal/ligand/substrate ratio. Different other ketones were tested under the same conditions and a maximum of 72% e.e. was obtained for the AH of phenyl t-butyl ketone.Ohkuma et al. used DPEN-based complexes 79 and 31, as a catalyst for the AH of various -hydroxyketones[76]. The best results were obtained with complex 79 yielding diols in good yields and with high enantioselectivities for a large variety of substrates (scheme 49)Complexes obtained from tetradentate ligands 81 and 82 (scheme 52) and different salts of Ru(II), Rh(III) and Ir(III) were tested in the AH of acetophenone. Mixtures of the products resulting from ketone or aromatic ring reduction were obtained except in the case of Ir III compounds, which yielded only 1-phenylethanol. However, the observed enantioselectivities were moderate (e.e. up to 43% with 81)[81].

						O	0.4% 80	OH
							40bars H 2
			X		iPrOH, 50°C	X
							>99% e.e., X = H,
		O	R			H 2 (45atm)	(HO) 2 (O)P >99% e.e., X = p-Me OH >99% e.e., X = p-F R 99% e.e., X = p-OMe (run 1)	P(O)(OH) 2
					[Ir(COD) 2 ]BF 4 , 78 Ph NH HN	Ph	88% e.e., X = p-OMe (run 6) Ph NH HN Ph
	HN CH 3 HN Ts Iridium deposed on silica in presence of cinchonidine was used in the heterogenous NH CH 3 MeOH 50°C, NaOH, 21h Scheme 50 Ph NH HN Ph Ph NH Ph 93% yield, 55% e.e., R = Me Ts Ts Ts 99% yield, 72% e.e., R = tBu 78 Scheme 48 81 82
	hydrogenation of various ketones. Good enenantioselectivities could be obtained (1-phenyl-1,2
	except for electron-rich substrates like (4-methoxyphenyl)(hydroxymethyl)ketone which could
	not be reduced at all.				Ph	Ph	R 1 = Ts or alkyl
		O	R 1 Ph	O	R 1 2 = Ts or alkyl OH R 3 = H or alkyl R Ph %Ir on SiO 2 / 2% 37b or 38b 10 bars H 2 NH N 1 R R 2 R 3 0.1-0.015% 79 OH MeOH, 60°C 60 bars H 2 Ph Ph Ph 83	OH Ph	OH
	X	O Ts	H 2 (50bars) [Ir(COD) 2 ]BF 4 , 2L* THF 50°C, 15 h 71% yield, 63% e.e., 77a OH 44% yield, 46% e.e., 77b 50% yield, 61% e.e., 77c N N H 2 Ir Cp* Ph SO 2 CH 3 96% e.e., R 1 = Ph L* = 94% e.e., R 1 = p-Me-Ph Yields > 89% after 15h X MeOH, LiOH, NH HN NH HN Ts Ph NH HN Ts 30 °C for 37b 83a 83b 83c 40 °C for 38b 97% e.e., R 1 = m-CF 3 -Ph Ph Ph Ph Ph 94% e.e., R 1 = p-NC-Ph OTf Ph 79 74% e.e., R 1 = o-F-Ph 99% e.e., R 1 = 2-thienyl NH HN Ts NH HN Ts Ph 83d 83e 80% e.e., R 1 = CH 3 O O O Me Me	Ph
						43% yield, 51% e.e., 77d Scheme 49	Me
	Me The same group [75] prepared a water-soluble version of N,N-dimethyl-1,2-Scheme 51 Scheme 47 diphenylethane-1,2-diamine by introduction of phosphonic acid moieties on the para position A mesoporous silica-supported chiral iridium catalyst 80 was prepared by Li and A similar strategy was used by the same authors with other cinchona alkaloids like e.e.= 63% with 83c e.e.=61% with 83c e.e.=83% with 83c e.e.=63% with 83d e.e.=68% with 83e e.e.=84% with 83e e.e.=66% with 83e coworkers by grafting {IrCl[PPh2(CH2)2Si(OEt)3]2[(R,R)-DPEN]} on SBA-15 silica [77]. PPh3 for the stabilisation of iridium on silica surface [80]. After optimisation, an e.e. of 80% tBu Various aromatic ketones have been reduced to the corresponding alcohols with high yields and cinchonine, cinchonidine, quinine, O-methyl cinchonidine or O-acetyl cinchonidine instead of O O Me O CF 3
					e.e.=73% with 83e e.e.=68% with 83b	e.e.=83% with 83e Me	e.e.=74% with 83e Me
							Scheme 53

of the aromatic rings (78,

Scheme 48)

. Preliminary investigations under biphasic conditions showed that iridium complexes of this ligand compared well with the homogeneous counterpart for the asymmetric hydrogenation of ketones but with noticeably higher reaction rates. enantioselectivities (scheme 50). The catalyst could be recycled and reused with only a slight decrease in activity and enantioselectivity (from 99% e.e. in run 1 to 88% e.e. in run 6; see scheme 50).

propanedione: ee up to 70%; ethyl pyruvate: ee up to 75%, acetophenone: ee up to 33%)

[78]

.

Silica modified by reaction with H2IrCl6 and PPh3 was used as source of iridium together to chiral diamines 37b and 38b in the AH of various aromatic ketones by Chen and co-workers

[79]

. Activities were moderate but high enantioselectivities were observed (e.e. up to 96%, see scheme 51). X = H: 88% e.e. for 37b, 74% for for 38b X = o-F: 86% e.e. for 37b, 77% for for 38b X = o-Cl: 96% e.e. for 37b, 86% for for 38b X = o-Br: 92% e.e. for 37b, 90% for for 38b X = o-OMe: 94% e.e. for 37b, 95% for 38b X = o-CF 3 : 81% e.e. for 37b, 83% for for 38b X = p-OMe: 87% e.e. for 37b, 76% for 38b could be obtained in the AH of acetophenone in the presence of (1S,2S)-DPEN and LiOH in MeOH at 333K. The catalysts could be recycled and reused in 8 successive runs with only a slight loss in activities and enantioselectivities (e.e. = 56% in run 8 instead of 71% in run 1).

Scheme 52

The same authors tested several bidentate ligands 83 based on diphenylethylene-1,2diamine. Ligands 83a-83e were identified as the most successful in the AH of various ketones (e.e. = 17-84%, scheme 53)

[81]

.

  Thus, cycles B or D seem more appropriate for these systems if the deuterium labelling experiments suggest a "monohydride" route. Cycle B has been proposed, for instance, by Crabtree et al.[88] for system 100 (Scheme 60) and by Lemaire et al. for system [Ir(COD)Cl]2/16 (Scheme 17)[30]. Many of these mechanistic propositions, however, do not address the metal oxidation state and the precise coordination geometry of the operational catalyst. Other authors, on the other hand, have proposed the metal-templated cycle D. In the Dahlenburg and Götz have reported H/D exchange processes involving the Ir catalysts 86 and 101 (Schemes 54 and 64)[82]. Hydrogenation of acetophenone or benzophenone with H2 in CH3OD gave invariably mixtures of R 1 R 2 CHOD and R 1 R 2 CDOD in approximately 1:1 ratio, accompanied by the observed evolution of HD and the increase in the amount of nondeuterated methanol. However, no such uptake of D + as D -into the carbinol products was observed when using 102 (Scheme 64), which does not contain a mobile proton on the nitrogen donor function. The Ir complexes containing NH donor groups, but not 102 were also shown Whereas the Ir I complexes do no undergo rapid acid/base equilibration, the Ir III complexes do, this being attributed to the better availability of the N lone pair in the electronically saturated Ir III species. These Ir III products are also capable to undergo H/D exchange between the coordinated NH proton(deuteron) and H2. At longer reaction times, however, COD is lost as hydrogenation product, yielding solvated Ir III hydrides.

	Ir to catalyze H/D exchange with formation of HD from H2/CH3OD mixtures, as well as from Ir P P MeOH, H 2 O Ph 2 Ph 2 +
	H2/D2 mixures in CH3CN, in the absence of ketone substrates. Long-lived Ir(H2) complexes N H Me Me N H 2 Me Me KOH
	could not be detected, but this observation indicated the ability of Ir + to bind H2, to activate it 101 101H +
	heterolytically, and to exchange the H2 "proton" with the NH function, the absence of which H 2 (5 bar) H 2 (5 bar)
	does not allow any exchange. H					H	+
		Ir	Ph 2 P PPh 2 H				KOH MeOH, H 2 O	P Ph 2	Ph Ir	PPh 2 H
		HN	Ir				Ir	H 2 N
		Me	N H Me		Me Me	N Me 2	Me	Me	Me
		103	101				102 (R,R)	103H +
		O		86/(-)-sparteine	OD	OD
		R	or 101 (1 mol %) H 2 (10 bar), CH 3 OD, 50°C	R H	+	R D
		R = Me, Ph						(56±5%)	(44±5%)
								(+HD+CH 3 OH)
	proposition by Zassinovich and Mestroni [25], the key system obtained from [Ir(COD)L2] + O OD
	would be the 5-coordinate Ir I species F (see scheme 63), a proposition later reinforced by the observed increased activity in the presence of the iodide ion [26] (which would occupy the X 102 (1 mol %) R R H 2 (10 bar), CH 3 OD, 50°C H
	position).	R = Me, Ph		[Ir	+ ]	*
		H-H + CH 3 OD		5-10 bar	H-D + CH 3 OH
				[Ir	+ ]	*	L
		H-H + D-D		L		2 H-D
				Ir 10 bar, CD 3 CN	O
		X * Any NH-containing Ir	+ complex
								O Scheme 64 H
								R 1 R 2
	In the same contribution, it was also established that H2 oxidatively adds to neutral F, X = iPrOH, OH -Scheme 63 amido complexes such as 101 and also to the corresponding protonated cationic amino

complexes (e.g. 101H + in Scheme 65), to yield dihydrido Ir III derivatives (103 and 103H + , respectively).

  PYBOX catalyst also performs less efficiently. All these systems, however, require activation to generate the active form. The best results were obtained by addition of the iridium catalyst precursor to a solution of ketone in iPrOH, stirring the resulting mixture at 82 °C for 15 min, and final addition of KOH. Unfortunately, no spectroscopic studies are reported on the product of this catalyst activation step. Other attempts at identifying the nature of the iridium complex formed under catalytic conditions failed[54,88], indicating that these species are quite delicate. Crabtree et al. have investigated the deactivation of the transfer

	precursors. For
	instance, complexes [IrClH(η 2 -C2H4)(iPr-PYBOX)][PF6] and [IrCl3(iPr-PYBOX)] gave
	reduction of acetophenone by isopropanol with conversions (and e.e. for the alcohol product)
	of 96 [67(R)%] and 96% [56(R)%] in two hours, whereas complex [Ir(η 2 -C2H4)2(iPr-
	PYBOX)][PF6] gave 66% conversion with e.e. of 50(R)% under the same conditions [63]. The
	in situ [IrCl(COE)2]2/

is eliminated as a hydrogenated product. This point has already been outlined in Scheme 67 for the typical case of COD-containing systems. For hydrogenation processes with H2, there is little doubt that the catalytic species no longer contains the COD ligand. Indeed, evidence for the generation of COD hydrogenation products under ketone hydrogenation catalytic conditions has been presented [82]. For TH catalysis, an early study by Bakos et al. [23] shows that [Ir(COE)2Cl]2 in combination with the diphosphinite ligand BDPOP (Scheme 11) in isopropanol led to quantitative loss of free COE within 5 min at room temperature, whether NaOMe was present or not. The resulting catalyst was able to isomerize 1,5-COD to 1,3-COD and to hydrogenate both dienes to COE, but not further to cyclooctane. In contrast, the related [Ir(1,5-COD)Cl]2 precatalyst needed 60 min for complete loss of the organic ligand, again selectively as COE. After 5 min at room temperature in the absence of base, the distribution of the free organic ligand was 40% 1,5-COD, 40% 1,3-COD and 20% COE, but subsequent reflux for 30 min in the presence of base let to selective and quantitative hydrogenation to COE. It therefore appears that hydrogenation of COD to COE by hydrogen transfer from isopropanol is a facile process, at least when L2 is a diphosphinite ligand. Thus, the presence of an induction times, as expected if the activation follows the pathway of Scheme 67 leading from P to N, may be difficult to detect. Activation times are well established when rhodium catalysts of this type are used for the hydrogenation of olefins [96].

Graziani et al. have reported the need to activate [Ir(diene)L2] + precatalysts (diene = norbornadiene, COD; L2 = diphosphine) by reflux in isopropanol for a certain time T1, followed by treatment with KOH for an additional time T2, in order to obtain best activities in ATH [21].

The solution colour changed from red to yellow during the initial time T1 and the yellow product was isolated but could not be characterized. Based on NMR ( 1 H and 31 P) and IR evidence, this seemed to correspond to a fluxional complex containing terminal and bridging hydrides, similar to dinuclear Ir(III) complexes reported by Crabtree, [Ir2(-H)3H2L4] + , which were inactive as olefin hydrogenation catalysts [97] but which could reconverted into a catalytically active form upon treatment with KOH [21]. This evidence, therefore, seems to indicate that COD elimination is necessary to improve catalytic activity. It does not, however, prove that the active catalyst contains Ir III , because deprotonation by KOH would generate again an Ir I species. Under identical conditions, systems of type [IrCl(LL')]2 have been shown to need shorter times that those of type [Ir(COD)(LL')] + with the same bidentate ligand to yield comparable conversions, also hinting to the need to remove the COD ligand [87].

On the other hand, evidence that the diene ligand is retained in the active catalyst in transfer hydrogenation catalysis has been reported for related rhodium systems (for which no induction times could be detected) by the Lemaire group, as suggested by the different catalytic transfer agent: HCOOH/NEt3) [50] seems to exclude the need of COD reduction for activation. Indeed, if COD hydrogenation were necessary to generate the active species, the activity of [IrCl(COD)]2 would be lower, not higher, than that of [IrCl(COE)2]2.

Computational studies

Computational investigations of hydrogenation catalysis specifically using Ir systems are rare. Partly on the basis of the evidence presented in the previous section, computational studies were carried out on various possible pathways starting from intermediates of type P (Scheme 67), most of these involving only Rh systems. For the RhH(C2H4)2(NH3)2 model system, the "inner-sphere" monohydride pathway (cycle B in Scheme 58) was found to be a viable pathway, with a smooth energy profile and relatively low activation barriers [99].

However, a later study showed that the "inner-sphere" concerted mechanism (cycle A in Scheme 58) has even lower activation barriers. This mechanism is also low-energy for the model complex RhH(C2H4)2(MeHNCHRCHRNMeH) (R = H, Me, Ph) [100]. The only computational study specifically addressing an Ir catalyst that has appeared to date, to the best of our knowledge, examines the model systems IrH(COD)(NH2CH2CH2X) (X = OH, SCH3) [101]. In this study, the three cycles A, B and D of Scheme 58 are compared, the critical transition states being represented in Scheme 69. Although the barrier for cycle A leading from the hydride intermediate to the Ir(COD)(NHCH2CH2X) + iPrOH products is small and comparable to that found for the Ru model (C6H6)RuH(NH2CH2CH2O), the system was found to be much more stabilized by isopropanol coordination with formation of Ir(OiPr)(COD)( 1 :N-NH2CH2CH2X) (Q in Scheme 69), relative to the Ru model. Thus, the H-bonded hydride complexcarbonyl substrate adduct leading to TS (cycle A) is located at 27.2 and 22.8 kcal/mol above Q for the Ir systems with X = OH and SMe, respectively, vs. only 15.7 kcal/mol for the corresponding Ru model. Starting from the resting state Q, the lowest barrier leading to the TH process turns out to be that of cycle D for the Ir systems.

Several iridium-based catalytic systems for asymmetric transfer hydrogenation or asymmetric hydrogenation of prochiral ketones systems have now already reached high levels of efficiency in term of activity and enantioselectivity, although there is still large room for improvement. However, iridium complexes can now be considered by synthetic chemists as useful tools to access chiral enantiomerically enriched alcohols which can complement methodologies based on Ru or Rh complexes, with respect to which it presents specific advantages, and interest in this metal will probably continue to grow.

From the point of view of the mechanistic pathways, iridium catalysis has been much less investigated than Ru and even Rh systems. The limited information obtained so far seems to indicate than a metal-templated direct transfer pathway may be operational in transfer hydrogenation for certain [Ir(diene)(LL')] + systems which retain the diene or olefins in the coordination sphere, whereas results obtained in the presence of CH3OD indicate the active participation of iridium-bonded NH functions in H/D exchange processes with D incorporation into the -C position in hydrogenation processes. However, the multitude of available lowenergy pathways and the variety of coordination environments that have been found compatible with catalytic activity require many additional mechanistic investigations before reaching a full understanding of how the mechanistic pathway, activity and enantioselectivity are affected by the catalyst structure.


Marius Cocou

Michel Raous

Elaine Pratt