chapter 1 - wiley...more so from hantzsch esters, which form aromatic products. in all equations,...

CHAPTER 1

CATALYTIC ASYMMETRIC HYDROGENATION OF C=NFUNCTIONS

HANS-ULRICH BLASER and FELIX SPINDLER

Solvias AG, P.O. Box, CH-4002 Basel, Switzerland

CONTENTSPAGE

INTRODUCTION . . . . . . . . . . . . . . 2SCOPE AND LIMITATIONS . . . . . . . . . . . . 4

Ligands and Catalysts . . . . . . . . . . . . 4Chiral Ligands . . . . . . . . . . . . . 4Metal Complexes . . . . . . . . . . . . 5

Rhodium Catalysts . . . . . . . . . . . . 5Iridium Catalysts . . . . . . . . . . . . 5Ruthenium Catalysts . . . . . . . . . . . 6Palladium Catalysts . . . . . . . . . . . 6Miscellaneous Catalysts . . . . . . . . . . . 6

Substrates . . . . . . . . . . . . . . 7N -Aryl Imines . . . . . . . . . . . . . 8N -Alkyl Imines . . . . . . . . . . . . . 10Endocyclic Imines . . . . . . . . . . . . 12Heteroaromatic Substrates . . . . . . . . . . . 15C=N–Y Functions (Y = OR, NHCOAr, Ts, POAr2) . . . . . . 18α- and β-Carboxy Imines . . . . . . . . . . . 21Reductive Amination . . . . . . . . . . . . 23

MECHANISM AND STEREOCHEMISTRY . . . . . . . . . . 26Rhodium Catalysts . . . . . . . . . . . . 27Iridium Catalysts . . . . . . . . . . . . . 28Titanium Catalysts . . . . . . . . . . . . . 29Ruthenium Catalysts . . . . . . . . . . . . 31Miscellaneous Catalysts . . . . . . . . . . . . 31

APPLICATIONS TO SYNTHESIS . . . . . . . . . . . 32Production Process for (S)-Metolachlor (DUAL Magnum) . . . . . 32Production Process for Sitagliptin . . . . . . . . . . 33Pilot Process for Dextromethorphane . . . . . . . . . 34Industrial Feasibility Studies . . . . . . . . . . . 34Synthesis of Tetrahydroisoquinoline Alkaloids . . . . . . . 36

ALTERNATIVE REDUCTION SYSTEMS . . . . . . . . . . 39

[email protected] Reactions, Vol. 74, Edited by Scott E. Denmark et al.© 2009 Organic Reactions, Inc. Published by John Wiley & Sons, Inc.

1

COPYRIG

HTED M

ATERIAL

2 ORGANIC REACTIONS

Chiral Hydrides . . . . . . . . . . . . . 39Hydrosilylation . . . . . . . . . . . . . 39Biocatalysis . . . . . . . . . . . . . . 39

EXPERIMENTAL CONDITIONS . . . . . . . . . . . 39Choice of Metal, Anion, Ligands, and Solvents . . . . . . . 39

EXPERIMENTAL PROCEDURES . . . . . . . . . . . 41N -(1-Phenylethyl)diphenylphosphinamide [Enantioselective Hydrogenation of

N -Alkylidenediphenylphosphinamides Using Rh-Diphosphine Catalysts] . . 41(S)-(–)-1-Phenyl-1-(2-benzoylhydrazino)ethane [Asymmetric Hydrogenation of

N -Acyl Hydrazones Using [Rh(Et-Duphos)(cod)]OTf Complexes] . . . 42(R)-N -Phenyl-1-Phenylethylamine [Asymmetric Hydrogenation of N -Aryl Imines

Using Ir-Phosphino Oxazoline Catalysts] . . . . . . . . 423-Phenoxymethyl-1,2-thiazolidine-1,1-dioxide [Asymmetric Hydrogenation of

N -Sulfonyl Imines Using a Pd(diphosphine)(CF3CO2) Catalyst] . . . 43(R)-6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline [Transfer Hydrogenation

Using a Ruthenium Catalyst] . . . . . . . . . . 44(R)-(+)-2-Phenylpyrrolidine [Hydrogenation of Endocyclic Imines with

(Ebthi)Ti(binol)] . . . . . . . . . . . . 44TABULAR SURVEY . . . . . . . . . . . . . 45

Chart 1. Designations for Ligands and Catalysts . . . . . . . 47Table 1. N -Aryl Imines . . . . . . . . . . . . 52Table 2. N -Alkyl Imines . . . . . . . . . . . 59Table 3. Endocyclic Imines . . . . . . . . . . . 63Table 4. Heteroaromatic Substrates . . . . . . . . . 74Table 5. C=N−Y Functions . . . . . . . . . . . 82Table 6. α- and β-Carboxy Imines . . . . . . . . . . 88Table 7. Reductive Amination . . . . . . . . . . 93

REFERENCES . . . . . . . . . . . . . . 98

INTRODUCTION

Chiral amines are important targets for synthetic chemists and attempts toprepare such compounds via enantioselective hydrogenation of an appropriateC=N function date back to 1941.1 Originally, only heterogeneous hydrogenationcatalysts such as Pt black, Pd/C, or Raney nickel were employed. These classicalhydrogenation catalysts were modified with chiral additives in the hope that someasymmetric induction in the delivery of dihydrogen to the reactant might occur.Only very few substrates were studied and not surprisingly, enantioselectivitieswere low and results could not always be reproduced.2 The first reports on theuse of homogeneous ruthenium3 and rhodium4,5 diphosphine complexes appearedin 1975, but useful enantioselectivities were not reported until 1984.6 Remark-able progress has been made since the 1990’s and a variety of very selectivecatalysts are now available for the enantioselective reduction of different typesof C=N functions.7 – 15 Moreover, the first industrial application was announcedin 1996.16 Despite this progress, the enantioselective hydrogenation of prochiralC=N groups such as imines, oximes, or hydrazones to the corresponding chiralamines still represents a major challenge.

CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 3

Whereas many highly enantioselective catalysts have been developed for theasymmetric hydrogenation of alkenes and ketones bearing various functionalgroups, fewer catalysts are effective for the hydrogenation of substrates with aC=N function. Several reasons can be cited for this situation. The enantioselectivehydrogenation of enamides and other C=C groups, and later of C=O compounds,has been so successful that most attention has been directed to these substrates.In addition, C=N compounds have some chemical peculiarities that make theirstereoselective reduction more complex than that of C=O and C=C compounds.Even though the preparation of imines starting from the corresponding aminederivative and carbonyl compound is relatively simple, complete conversion isnot always possible and formation of trimers or oligomers can occur. In addition,the resulting C=N compounds are often sensitive to hydrolysis, and, becausemany of the homogeneous catalysts can complex with both the starting materialand the amine product, catalytic activity is often low. Further problems arisefrom the fact that imines can be in equilibrium with their corresponding enam-ines, which can also be reduced but with different stereoselectivities. Anotherproblem is the potential coexistence of syn/anti imine isomers. These differentforms may be reduced with different selectivities, as has been shown for thereduction of an oxime.17

Generally, the C=N substrates are prepared from the corresponding ketone andamino derivative and are hydrogenated as isolated (and purified) compounds.However, reductive amination where the C=N function is prepared in situ isattractive from an industrial point of view and indeed a number of successfulexamples have been reported.18 – 20

This chapter provides a comprehensive overview of the enantioselective hydro-genation (Eq. 1) and transfer hydrogenation (Eq. 2) of various C=N functionsusing chiral catalysts. Because the net transformation is the same for both typesof reduction, the results for the various substrate types are summarized together.However, it should be noted that in many cases different catalyst types arerequired. For example, if dihydrogen is used, the metal must be able to activatethe very strong H–H bond. In contrast, the activation seems to be more facilefor the transfer of hydrogen from donor molecules such as formic acid and evenmore so from Hantzsch esters, which form aromatic products. In all equations,the specific hydrogen donor is shown in the equations, whereas only the pres-sure is given when dihydrogen is used. This review covers the literature up toSeptember 2007. Several reviews on the asymmetric reduction of C=N functionshave been published,7,9 – 11,15,21,22 and the topic has been covered as part of var-ious overviews on asymmetric hydrogenation.8,12 – 14,23,24 Alternative reductionmethods for C=N functions such as hydride reductions,25,26 hydrosilylation,26 – 28

and biocatalysis29 are addressed briefly.

R1 R2

NY

R1 R2

HN YH+ H2

chiral catalyst

solvent

Y = R3, OH, NHR3, SO2R3, POPh2

R1-3 = alkyl, (het)aryl

(Eq. 1)

4 ORGANIC REACTIONS

+ DH2

chiral catalyst

solvent

DH2:

D:

HCO2H

CO2

NH

EtO2C CO2Et

N

EtO2C CO2Et

Hantzsch ester

R1 R2

NY

R1 R2

HN YH + D

(Eq. 2)

SCOPE AND LIMITATIONS

Ligands and CatalystsMost catalysts effective for the enantioselective (transfer) hydrogenation of

C=N bonds are homogeneous complexes consisting of a central metal ion, oneor more (chiral) ligands, and anions. There is always an interdependence betweenthe nature of the C=N function and the most suitable catalyst. To identify aneffective catalyst for any specific substrate, not only the optimum metal, but alsothe optimum ligand and, with somewhat lower priority, the optimum anion haveto be chosen. Other reaction parameters are solvent, temperature, hydrogen pres-sure, and sometimes additives. Experience has shown that low-valent ruthenium,rhodium, and iridium complexes stabilized by tertiary (chiral) phosphorus-basedligands are the most active and the most versatile hydrogenation catalysts. As aresult, the majority of research has focused on these types of complexes. Com-plexes that are able to directly activate dihydrogen have somewhat different ligandrequirements than transfer hydrogenation catalysts, which formally transfer ahydrogen molecule from a suitable donor. For particular applications, cyclopen-tadienyl titanium and zirconium complexes and recently some Pd-diphosphinecomplexes show very good enantioselectivities in conjunction with dihydrogen;organocatalysts based on phosphoric acid are also promising.

Chiral Ligands. A plethora of chiral ligands have been developed for enan-tioselective hydrogenation. However, relatively few have proven effective as wellas practical, and have actually been applied to the catalytic hydrogenation.30,31

For the reduction of C=N functions, the most effective and most frequently usedligands are depicted in Fig. 1. For hydrogenations with dihydrogen, diphosphinessuch as binap (sometimes in combination with a diamine), biphep (and analogs),duphos, josiphos, and phosphine oxazoline ligands are most effective. For trans-fer hydrogenations, tosylated diphenylethylendiamine ligands (dpenTs) are mostuseful.

Recently, substituted binol esters of phosphoric acid (binol-P(O)OH) havebeen shown to be effective catalysts for transfer hydrogenation with Hantzsch

For a glossary of ligand structures, refer to Chart 1 immediately preceding the Tabular Survey.


josiphos

biphep type

NHRH2NYY

Aryl2P N

O

R

PAr2

PAr2RR

duphos

PR

R

P

R

R

binap type

PAr2

PAr2

Y

Y

phosphine oxazolines(phox)

diphenyl ethylenediamines(dpen)

FeR2PPR'2

H

Figure 1. Structures and names of privileged ligands.

esters as donors. The naming of new ligands does not follow any rules. In thisreview we will use the name given by the creator of the ligand but will usesmall letters only, except when a chemical group is specified, as in MeO-biphep.For other ligands that have not been named, a bold number will be used with ashort descriptor, for example: amino alcohol 14. The reader is referred to Chart1 preceding the Tabular Survey for structures of all ligands and catalysts referredto in this text. Those catalysts referred to by bold numbers only are reproducedin the text for convenience.

Metal Complexes. Rhodium Catalysts. Rh-diphosphine catalysts can beeasily prepared from a rhodium precursor and a chiral ligand. The catalystsare either prepared in situ or applied as preformed and isolated complexes. Inmost cases, the in situ method is preferred because it offers greater flexibility,but there are cases where preformed complexes are required, either because theligand is not stable, the complex formation is too slow, or the performance issuperior. The most common and commercially available rhodium precursors are[Rh(cod)Cl]2 and [Rh(nbd)Cl]2 complexes for catalysts with a covalently boundanion, and [Rh(nbd)2]BF4 for cationic catalysts. Preformed complexes are of thetype [Rh(nbd)(diphosphine)]Y (Y = BF4, OTf, SbF6, ClO4). The catalyticallyactive species are obtained by hydrogenation of the diene (cod or nbd), a pro-cess which can take some time.32 Pentamethylcyclopentadienyl rhodium (cp*Rh)complexes having a tosylated diamine or an amino alcohol ligand are activetransfer hydrogenation catalysts.

Iridium Catalysts. Among the various catalyst types investigated in recentyears for the hydrogenation of imines, Ir-diphosphine and Ir-phosphine oxazo-line complexes have proven to be most versatile. Ir-diphosphine catalysts are


6 ORGANIC REACTIONS

usually generated in situ from commercially available [Ir(cod)Cl]2 and a chiraldiphosphine and used in the presence of an iodide source. Also common are pre-formed complexes of the type [Ir(diphosphine)Cl]2 or [Ir(diphosphine)(cod)]BF4

and some Ir(III) complexes like HBrIr(diphosphine)OAc. The Ir-phox catalysts,[Ir(phox)(cod)]Y, are prepared starting from [Ir(cod)Cl]2 and the PN ligand. Thechloride is then exchanged for a non-coordinating anion Y, preferably BARF orPF6. As in the case for rhodium, the diene must be hydrogenated to obtain theactive iridium catalyst. Cp*Ir complexes with a tosylated diamine or an aminoalcohol ligand are active transfer hydrogenation catalysts.

Ruthenium Catalysts. In contrast to the wide scope of Ru-diphosphine com-plexes for the hydrogenation of ketones, their use for C=N reduction is stillsomewhat limited due to the tendency of these catalysts to deactivate in thepresence of bases. For hydrogenation with dihydrogen, ruthenium catalysts areusually applied as preformed complexes of the type Ru(diphosphine)Y2 (Y = Cl,OAc) or Ru(diphosphine)(diamine)Cl2.

For transfer hydrogenations with formic acid–triethylamine, (arene)Ru(dpenTs)Cl (arene = benzene or p-cymene) complexes (Noyori transfer hydro-genation catalysts described later in the text) are the catalysts of choice. It is alsopossible to prepare these catalysts in situ from Ru(cod)Cl2 or [Ru(cymene)2Cl]2

and the required sulfonylated diamine.

Palladium Catalysts. A very recent development is the use of Pd-diphosphinecatalysts, especially for C=N–Y functions and imines of α-keto esters. Eithercomplexes formed in situ from Pd(CF3CO2)2 and a diphosphine or preformedPd(diphosphine)(CF3CO2)2 complexes can be used.

(AuCl)2duphos

P P

Au AuCl Cl

ZrCl2

1

Ti

(ebthi)Ti(binol)

OOO

OP

O

OH

R

R

binol-P(O)OH

Ti

(ebthi)Ti

Figure 2. Structures of miscellaneous catalysts.



Miscellaneous Catalysts (Fig. 2). Very recently, sterically hindered binol-derived phosphoric acids (binol-P(O)OH) have shown potential for metal free,“organocatalytic” transfer hydrogenations with Hantzsch esters as hydrogendonors. Bis(cyclopentadienyl) complexes (ebthi)Ti catalysts and Zr complex 1can achieve remarkable enantioselectivities for the hydrogenation of cyclic imineswith molecular hydrogen. However, their synthetic potential may be rather low,because the ligands and complexes are difficult to prepare, the activation of thecatalyst precursor is tricky, and high catalyst loadings are needed. An unusual(AuCl)2(Me-duphos) complex has been described for the hydrogenation of anN -benzyl imine where duphos is postulated to be coordinated to two goldatoms.

Substrates

The electronic and steric nature of the substituent directly attached to the nitro-gen atom affects the properties of the C=N function (basicity, reduction potential,size, etc.) more than the substituents on the carbon atom. As a consequence, cat-alyst specificity can be highly substrate dependent. For example, Ir-diphosphinecatalysts that are very active for N -aryl imines were found to deactivate rapidlywhen used with imines possessing aliphatic N-substituents;33 titanocene-basedcatalysts are active for N -alkyl imines but not for N -aryl imines.34,35 Oximesand other C=N–Y compounds show even more pronounced differences in reac-tivity. Because quite different catalysts and/or reaction conditions are optimal fora particular type of substrate, and to facilitate the search for the optimal catalystfor the reduction of a particular type of C=N compound, the following classes ofsubstrates are distinguished: N -aryl imines, N -alkyl imines, endocyclic imines(including iminium derivatives), N -heteroarenes (including pyridinium ylides),and C=N–Y functions (including nitrones) (Fig. 3). Furthermore, the hydrogena-tion of α- and β-carboxy imine derivatives is discussed and compiled separately.The reductive amination of ketones where the imine is formed in situ is alsoconsidered separately.

When assessing the results compiled in this review, one has to keep in mindthat most new ligands have only been tested under standard conditions withselected model substrates. The results are usually optimized for enantioselectivity,whereas catalyst productivity [substrate to catalyst ratio (s/c) or turnover number(TON, measured as mol product per mol catalyst)] and catalyst activity [turnoverfrequency (TOF, measured as TON per reaction time) at high conversions] areonly a preliminary indication of the performance of a ligand. The decisive test,namely the application of a new ligand to “real world problems” are often yet tocome and will eventually tell about the scope and limitations of a given ligand,or family of ligands, vs. changes in the substrate structure and/or the presence offunctional groups. Indeed, relatively few catalyst systems have been optimizedto date for complex synthetic or industrial applications.


8 ORGANIC REACTIONS

N-aryl imines N-alkyl imines

R

N

endocyclic imines

C=N–Y compounds

Y = OR, NHR, SO2R, P(O)R2

heteroaromatic substrates

NR2

R1

+ R3NH2

reductive amination

α- and β-carboxy imines (n = 1, 2)

R1 R2

NAr

R1 R2

NAlkyl

R1 R2

NY

R1 (CH2)nCO2R2

NR

R1 R2

O

R1 R2

NHR3

Figure 3. Substrate classes.

N -Aryl Imines. The switch from the racemic form of metolachlor (seebelow), one of the major herbicides, to its S-enantiomer was undoubtedly thedriving force for the development of suitable ligands and catalysts for the enan-tioselective hydrogenation of N -aryl imines.16,36 Accordingly, much effort hasbeen devoted to finding catalysts able to hydrogenate hindered N -aryl imines(Eq. 3). Interestingly, many iridium catalysts give very high enantioselectivitiesfor 2,6-disubstituted N -aryl groups33,37,38 and in some cases ee values of >99%are achieved with an f-binaphane ligand.39

R1

NAr

R1

NHAr

+ H2

CatalystIr-bdppIr-josiphosIr-f-binaphaneIr-f-binaphane

96% conv., 90% ee100% conv., 96% ee77% conv., >99% ee80% conv., 99% ee

R1

MeOCH2

PhPh4-CF3C6H4

Ar2,6-Me2C6H3

2,6-Me2C6H3

2,6-Me2C6H3

2,6-Me2C6H3

Ref.38373939

(Eq. 3)

A number of Ir-diphosphine and Ir-phosphine oxazoline catalysts can achievemedium to very high enantioselectivities for model substrates derived from (sub-stituted) acetophenones and (substituted) anilines (Eq. 4). Enantioselectivities of96 to >99% and moderate catalytic activities are observed for iridium com-plexes of f-binaphane,39 P ,N -ferrocene 2,40 phosphino oxazoline 3,41 phosphinosulfoxime 4,42 t-Bu-bisP*,43 and josiphos.37 Enantioselectivities of 90–94% canbe obtained with iridium complexes of phosphino oxazolines 544 and 645, withddppm,46 as well as with a Ru-duphos-dach catalyst47 and the binol-P(O)OHtransfer hydrogenation catalyst 7c.48 Enantiomeric excesses of 73–87% have


been described for iridium complexes with phox2,49,50 phosphine olefin 8,51

phosphino oxazolines 952 and 10,53 phosphoramidite 11,54 and binol-P(O)OH7b.55 In addition, a number of less selective iridium catalysts with P,N ligands(ee <52%) have been described.56 – 58 Several systematic studies have shown thatthe effect of the substituents R1 and R2 on enantioselectivity is often significant,but no clear correlation between enantioselectivity and type and position of theR groups has been established.

NR2

R1

HNR2

chiral catalyst

H2

72–100% conv., 81 to >99% ee

>99.5% conv., 84–99% ee

>99.5% conv., 90–97% ee

>99% conv., 90–96% ee

(91–100%) 69–99% ee

100% conv., 96% ee

99–100% conv., 81–94% ee

53–99% conv., 83–90% ee 84–98% conv., 80–93% ee

100% conv., 90% ee

92% conv., 92% ee

Ref.39

40

41

42

43

37

46

444845

47

Chiral catalyst, reaction conditionsf-binaphane, [Ir(cod)Cl]2, s/c 100, DCM, 70 bar, 24–44 h[Ir(2)(cod)]BARF, s/c 100, toluene/MeOH, 10 bar, rt, 2–6 h[Ir(3)(cod)]BARF, s/c 100, TBME, 4 Å MS, 1 bar, 10°, 20 h4, [Ir(cod)Cl]2, s/c 100, toluene, I2, 20 bar, rt, 4–6 h[Ir(t-Bu-bisP*)(cod)]BARF, s/c 200, DCM, 1 bar, rt, 2–12 hjosiphos (Ph/4-CF3C6H4), [Ir(cod)Cl]2, s/c 200, toluene, AcOH, TBAI, 30 bar, rt[Ir(ddppm)(cod)]PF6, s/c 100, DCM, 1 bar, rt, 24 h[Ir(5)(cod)]BARF, s/c 200, DCM, 20 bar, rt, 2 hHantzsch ester,7c, s/c 100, toluene, 35°, 42–72 h[Ir(6)(cod)]BARF, s/c 50, DCM, 20 bar, rt, 12 hRu((R,R)-Et-duphos)((R,R)-dach)Cl2, s/c 100, t-BuOH, t-BuOK, 15 bar, 65°, 20 h

R1, R2 = H, Me, MeO, CF3, halogen

R1

(Eq. 4)

(R)-4

PPh2

N SO

Ph

3

PXyl2

N

O

Bn

2

Fe PPh2

HO

NN

5

PPh2

O

N

Naphthyl methyl ketone imines (Eq. 5) can be hydrogenated with similarenantioselectivities using iridium complexes with phosphino oxazoline 544 orphosphino sulfoxime 4.42 Interestingly, the 1-naphthyl and 2-naphthyl derivatives

10 ORGANIC REACTIONS

O

OP

O

OH

R

R

6

N

N

O

Ph2P

(R)-7

7a7b7c7d7e

RSi(Ph)3

3,5-(CF3)2C6H3

2,4,6-(i-Pr)3C6H2

9-phenanthryl9-anthryl

CF3SO3–

8

Oi-Pr

Ir+(cod)

PPh2

S

N

O

i-PrPPh2

9

O

OP O

t-Bu

t-Bu

PPh

MeO

10

O

OP N

OTBDMS

11

lead to opposite enantioselectivities with the catalyst system featuring ligand 4.The iridium/phosphino sulfoxime 4 complex has also been shown to hydrogenatethe imine from 4-methoxyaniline and tetralone in 91% ee.42

Ar

N

Ar

HNchiral catalyst

H2

% ee98 (+)69 (–)89 (+)

Ref.424244

Chiral catalyst, reaction conditions4, [Ir(cod)Cl]2, s/c 100, toluene, I2, 20 bar, rt, 4–6 h

[Ir(5)(cod)]BARF, s/c 200, DCM, 20 bar, rt, 1.5 h

OMe OMe

Ar1-Np2-NpPh

(—) (Eq. 5)

N -Alkyl Imines. To date, few reductions of acyclic N -alkyl imines to thecorresponding amines are of synthetic or industrial importance. Most studiesreported in this area were carried out with simple model substrates, especiallywith the N -benzyl imine of acetophenone, related substituted derivatives, andsome analogs thereof. One reason for this substrate choice could be the easypreparation of a pure crystalline starting material. Another is that syntheticallyuseful chiral phenethylamines can be obtained by hydrogenolysis of the benzylgroup. In comparison with the reduction of N -aryl imines, ee values obtainedwith N -alkyl imines are generally modest. Enantioselectivities of >90% canbe achieved with rhodium complexes of bddp, either sulfated59,60 or in reversedmicelles,61 with a Rh(cycphos) complex,62 with a Ru(dppach)(dach)HClcomplex,63 and with Ru-dpenTs in water64 (Eq. 6). Enantioselectivities of70–83% have been described for (substituted) N -benzyl imines of acetophenone,2-furyl, and 2-naphthyl methyl ketones with iridium complexes of phosphino oxa-zoline 6,45 phox2,50,65 binol-POH 12,66 tol-binap,67 and phosphine oxide 13;68

with a Rh-bdpch complex,69 with (ebthi)Ti(binol),34,70 and, somewhat surpris-ingly, with an Au/Me-duphos complex.71 Several papers have described resultswith <70% ee for a number of Ir-P,N57,72 – 75 and Ru76 catalysts.


NR1

HNR1

R2R2

R1 = Bn, n-Bu; R2 = H, MeO

chiral catalyst

H2

93–96% conv., 86–96% ee

99–100% conv., 88–92% ee

91% conv., 92% ee

(95%) 92% ee

(>99%) 91% ee

100% conv., 91% ee

Ref.59, 60

66

63

61

62

64

Chiral catalyst, reaction conditionsbdppsulf, [Rh(cod)Cl]2, s/c 100, H2O/AcOEt, 70 bar, rt, 16 h12, [Ir(cod)Cl]2, PPh3, s/c 100, DCM, 50 bar, rt, 48 hRu(dppach)(dach)HCl, s/c 1500, i-PrOK, 3 bar, 20°, 60 h[Rh(bdpp)(nbd)]ClO4, s/c 100, C6H6/reverse micelles, 70 bar, 4–8°, 21–73 hcycphos, [Rh(cod)Cl]2, s/c 100, C6H6/MeOH, KI, 70 bar, rt, 90–144 hHCO2Na, [(C6Me6)Ru(dachTs)H2O]BF4, s/c 100, H2O, pH 9, 60°, 2–5 h

(Eq. 6)

PPh

t-Bu O

H

(R)-13

OO

12

P OH

Only (ebthi)Ti(binol) catalysts have been described to hydrogenate N -alkylimines of aliphatic ketones (Eq. 7), and very high pressures are required forgood results.34,70

(ebthi)Ti(binol), s/c 10–50

THF, 65°, 140 bar H2, 8–48 h

(64–93%) 53–92% ee

R1

HNR2

R1

NR2

R1 = n-, i- and cycloalkylR2 = Me, n-Pr, Bn

(Eq. 7)

The ruthenium-catalyzed transfer hydrogenation of α-substituted exocyclicimines occurs with excellent cis-diastereoselectivity by a dynamic kinetic asym-metric transformation, with up to 97% ee for 5-membered rings but only 50%for 6-membered rings (Eq. 8).77


R2

NBnR1

R2

NHBnR1s/c 200, DCM, rt, 144 h

R1

HMeMeH

R2

MeMeCH2=CHCH2

Me

(70%) 96% ee (82%) 97% ee (67%) 92% ee (45%) 50% ee

n1112

( )n ( )nHCO2H/NEt3,

(cymene)Ru(dpenTs)Cl(Eq. 8)

Endocyclic Imines. Because cyclic imines do not have the problem ofsyn/anti isomerism, in principle higher enantioselectivities might be expectedin their reduction. While this expectation is not generally met, in conjunctionwith several cyclic model substrates the (ebthi)Ti catalyst achieves up to 99% ee(Eq. 9). With this catalyst, enantioselectivities for acyclic imines are ≤92%, asdescribed above.34,78

(ebthi)Ti(binol), s/c 20–50

THF, 5–140 bar H2, 45–65°, 8–48 h

(71–84%) 98–99% ee

N

R

NH

R

R = Ph, (subst)alkyl; n = 1, 2, 3

( )n ( )n

(Eq. 9)

One enantiomer of racemic disubstituted pyrrolines can be reduced with veryhigh selectivities (Eq. 10a, kinetic resolution).79 Unfortunately, these highly selec-tive catalysts operate at rather low s/c ratios, exhibit TOFs of <3 h−1 and, inaddition, functional groups like esters, carboxylic acids, or nitriles are not tol-erated. Zirconium complex 1 exhibits similar properties as the (ebthi)Ti catalyst(ee 96% for R = Ph, n = 1 in Eq. 9) but is more effective (TON up to 1000).80

Simple 5- and 6-membered endocyclic imines are hydrogenated using Ir-binapcatalysts67,81 with enantioselectivities of 89–91% ee. Moderate enantioselectiv-ities of 50–78% ee, but quite good catalytic activities (TOF 100–1000 h−1)are obtained for the hydrogen transfer hydrogenation of various azirines using acatalyst prepared from [RuCl2(cymene)]2 and amino alcohol 14 (Eq. 10b).82

95–99% ee(37–42%)

(ebthi)Ti(thiobinol), s/c 20

THF, 5 bar H2, 65°, 8–48 hN NH

R R

N

R

+

95–99% ee(34–44%)

R = Ph, n-C11H23

(Eq. 10a)


NH

OO

OH

14

[RuCl2(p-cymene)]2, s/c 100

14, i-PrOH, i-PrOK, rt, 2–10 h

N

ArN

Ar

ArPh4-BrC6H4

2-Np

(80%) 70% ee(92%) 50% ee(92%) 50% ee

H

(Eq. 10b)

A number of bi- and tricyclic imines have been investigated extensively. 2,3,3-Trimethyl-3H -indole (TMI) can be reduced in up to 94% ee using a varietyof iridium complexes with diphosphine ligands such as bdpp,83 bicp,84 ferro-cenyl based ligands,37,85,86 bcpm,87 the diop analog 15,88 as well as monophos89

(Eq. 11, absolute configuration not reported). Only moderate TONs (s/c 100–250)and rather low activities (TOF 1–10 h−1) are achieved, most likely because ofsteric hindrance. Interestingly, the best enantioselectivities are observed in thepresence of a variety of additives such as phthalimides, iodine, or iodide/acid.The role of these additives is not clear. The reaction with an Ir-josiphos catalystcan also be carried out in ionic liquids with slightly lower enantioselectivitiesbut similar catalyst activities.85 Whereas no successful transfer hydrogenation isreported for TMI, the N -benzylated iminium derivative is reduced with formicacid–triethylamine in the presence of cp*Rh(dpenTs)Cl with 76% ee.90

BnO

BnO

PPh2

PPh2

15

N NH

chiral catalyst

H2

100% conv., 95% ee

100% conv., 95% ee

92% conv., 91% ee

Ref.84

37

87

Chiral catalyst, reaction conditionsbicp, [Ir(cod)Cl]2, s/c 100, DCM, phthalimide, 70 bar, 0°, 100 hjosiphos (Xyl/Xyl), [Ir(cod)Cl]2, s/c 250, toluene, TFA/TBAI, 40 bar, 30°, 47 hbcpm, [Ir(cod)Cl]2, s/c 100, C6H6/MeOH, BiI3, 100 bar, –30°, 90 h

TMI

(Eq. 11)

Several bi- and tricyclic imines have been investigated as intermediates ormodel substrates for biologically active compounds (Eqs. 12 and 13; see alsoApplications to Synthesis). These compounds are reduced with good to verygood enantioselectivities using a number of different catalytic systems. Inter-estingly, most reactions were not reported by catalyst specialists, but rather bysynthetic organic chemists. This might explain why transfer hydrogenation was


the preferred experimental method in these studies. Enantioselectivities up to99% are described for variants of the Noyori type catalysis, i.e., transfer hydro-genation using formic acid–triethylamine as the reducing agent in the presenceof an arene ruthenium complex with dpenTs as the chiral ligand.91 – 98 Withwater-soluble ligands, the reaction can be carried out with comparable enantio-selectivities in water with sodium formate as the reducing agent.64,99,100 Similarresults are also obtained with cp*Rh(dpenTs) complexes.101 The s/c ratios varywidely between 20 for some hindered substrates101 and a respectable 1000 formore active catalysts.91 (Ebthi)Ti34, Ir-bcpm, or Ir-binap catalysts in the presenceof additives102,103 can achieve 86–98% ee with s/c ratios of 20–100. An Ir-P,Ncatalyst was less stereoselective (34% ee).58

N

R

MeO

MeO

chiral catalystNH

R

MeO

MeO

(82%) 98% ee

(93–96%) 83–99% ee

(90–>99%) 84–95% ee

(85–98%) 90–98% ee

(95%) 93% ee

(84–99%) 86–89% ee

100% conv., 88% ee

Ref.34

101

91

99

100

102, 103

64

Chiral catalyst, reaction conditions(ebthi)Ti(binol), s/c 20, THF, 135 bar H2, 65°, 8–48 hHCO2H/NEt3, cp*Rh(dpenTs)Cl, s/c 200, DCM, 20°, 0.15 hHCO2H/NEt3, (cymene)Ru(dpenTs)Cl, s/c 100–1000, MeCN, 28°, 12 hHCO2Na, dpenTssulf, [(cymene)RuCl2]2, s/c 100, H2O, CTAB, 28°, 10–25 hHCO2Na, dpenTsamin, [Cp*RhCl2]2, s/c 100, H2O, 28°, 8 hBcpm, [Ir(cod)Cl]2, s/c 100, toluene/MeOH, var. additives, 100 bar H2, rt, 24–72 hHCO2Na, [(cymene)Ru(dachTs)H2O]BF4, s/c 100, H2O, pH 9, 60°, 2–5 h

R = alkyl, cycloalkyl

(Eq. 12)

NH

N

R

chiral catalyst

NH

NH

R

(83–99%) 98–99% ee

(70–85%) >98% ee

(83–86%) 96–97% ee

(94%) 93% ee

(89–96%) 93–96% ee

Ref.99

92

91

100

97

Chiral catalyst, reaction conditionsHCO2Na, dpenTssulf, [(cymene)RuCl2]2, s/c 100, s/c 500, H2O, CTAB, 28°, 4–30 hHCO2H/NEt3, (cymene)Ru(dpenTs)Cl, s/c 230, MeCN, rt, 12 hHCO2H/NEt3, (cymene)Ru(dpenTs)Cl, s/c 200, DMF, 28°, 5 hHCO2Na, dpenTsamin, [cp*RhCl2]2, s/c 100, H2O, 20°, 10 hHCO2H/NEt3, (cymene)Ru((S,S)-dpenTs)Cl, s/c 25, DMF, 20°, 12 h

X X

X = H, Br; R = alkyl, (het)aryl

(Eq. 13)


Various bicyclic imines can be reduced with high enantioselectivities butmoderate to low catalytic activity via an organocatalytic hydrogen transfer reac-tion with sterically hindered binol phosphoric acid catalysts 7a and 7d using aHantzsch ester as the reducing agent (Eq. 14).104,105 In some cases, s/c ratios ashigh as 1000 are reported, albeit with very long reaction times.

(55–95%) 93 to >99% ee

7a/d, s/c 10–1000

C6H6, 5 Å MS, 40–50°, 24–96 h+

NH

CO2EtEtO2C

Y N

RZ

Y NH

RZY = O, S; Z = O, H2

R = (subst)Ph, Np, (het)aryl

(Eq. 14)

Tri- and tetracyclic iminium compounds (intermediates in the synthesis ofalkaloids) are amenable to the Ru-dpenTs-catalyzed transfer-hydrogenation with79–92% ee but modest s/c ratios (Eq. 15).106,107 Similar cyclic amines can beobtained in 70% yield and 50–70% ee via tricyclic iminium compounds that areformed in situ.108

NH

N+Cl–

N

H

N+

MeO

MeO

Cl–

(C6H6)RuCl(dpenTs), s/c 300

HCO2H/NEt3, MeCN, 0°, 10 h

(81–97%) 79–92% ee

n

n

n

n = 1, 2

or (Eq. 15)

Heteroaromatic Substrates. Until very recently, the hydrogenation of het-eroaromatic substrates with homogeneous catalysts was considered to be verydifficult. In the last few years, a number of catalytic systems with reasonableactivities have been developed for the partial hydrogenation of substituted quino-lines, giving access to a variety of cyclic amines in fair to very good enantioselec-tivities. However, up to now, results for pyridines or pyrazines are disappointing(ee <30%), probably due to their more aromatic character.109 Exceptions arethe Ir-josiphos-catalyzed hydrogenation of a pyrazine ester (Eq. 16) with up to78% ee but very low catalyst activity110 and the recently reported organocatalytictransfer hydrogenation of pyridines with electron-withdrawing substituents in the3-position catalyzed by binol-P(O)OH 7e (Eqs. 17a and 17b).111 Furthermore, N -iminium pyridine ylides can be hydrogenated with up to 90% ee using Ir-phox


complexes (Eq. 18).112 Dimethyl derivatives give preferentially cis-substitutedpiperidines (>95% for the 2,3- and 57% for the 2,5-isomer, respectively).

N

N

CO2t-Bu

(R,SFc)-josiphos (Ph/Cy), [Rh(nbd)Cl]2

s/c 50, MeOH, 50 bar H2, 70°, 20 h

(80%) 78% ee

NH

HN

CO2t-Bu(Eq. 16)

N

O

R

Hantzsch ester, (R)-7e, s/c 20

C6H6, 50°NH

O

R

(64–84%)87–92% ee

(Eq. 17a)

N

NC

R NH

NC

R

(47–73%)84–90% ee

R = alkyl

Hantzsch ester, (R)-7e, s/c 20

C6H6, 50° (Eq. 17b)

[Ir(phox1)(cod)]BARF, s/c 50

toluene, I2, 27 bar H2, rt, 6 h

R = alkyl, Bn, BnOCH2, BnO(CH2)2

R1 = H, Me85–98% conv., 54–90% ee

N+

NBz

R2

R1NNHBz

R2

R1– (Eq. 18)

Many reports describe the partial hydrogenation of a variety of substitutedquinoline derivatives to the corresponding tetrahydro derivatives (Eq. 19). Withthe exception of the transfer hydrogenation in the presence of binol-P(O)OH7d,113 all effective catalysts are iridium phosphine complexes. Enantioselectiv-ities range from modest to >99%, depending mainly on the catalysts used andthe nature of the substituent R1 on the heteroaromatic ring. Yields are good toquantitative at s/c ratios that are usually around 100 but can go up to 1000.Enantioselectivities of 87–96% have been reported for atropisomeric diphos-phines such as MeO-biphep,114 P -phos,115 dendrimeric binap 16,116 or segphos(transfer hydrogenation with Hantzsch ester).117 Similar results are achievedusing diphosphinites H8-binapo118 or 17119 and ligand combination 18 featur-ing an achiral ligand together with a diphosphonite.120 The best catalyst activ-ities are obtained with the ferrocene-based phosphino oxazoline 19121 (TOF>80 h−1) and with the dendrimeric binap 16116 (up to 43,100 turnovers in48 hours).


N R1

R2

NH

R1

R2

R1 = (subst)alkyl, PhR2 = H, F, Me, MeO

chiral catalyst

H2

(83–94%) 75–96% ee

(97–99%) 90–92% ee77–95% conv., 76–92% ee

(90–99%) 87–97% ee

60–100% conv., 65–93% ee

>96% conv., 80–96% ee(82 to >95%) 79–92% ee(54–95%) 87 to >99% ee

(43–98%) 68–88% ee

Ref.114

115116118

119

120121113117

Chiral catalyst, reaction conditionsMeO-biphep, [Ir(cod)Cl]2, s/c 100, toluene, I2, 50 bar, rt, 18 hP-phos, [Ir(cod)Cl]2, s/c 100, THF, I2, 50 bar, rt, 20 h16, [Ir(cod)Cl]2, s/c 400, THF, I2, 45 bar, rt, 1.5 hH8-binapo; [Ir(cod)Cl]2, s/c 100, DMPEG500/hexane, I2, 50 bar, rt, 20 h17, [Ir(cod)Cl]2, s/c 100, THF or DMPEG500/hexane, I2, 50 bar, rt, 18 h18, [Ir(cod)Cl]2, s/c 200, toluene, I2, 60 bar, rt, 20 h19, [Ir(cod)Cl]2, s/c 1000, toluene, I2, 40 bar, rt, 12 hHantzsch ester, 7d, s/c 50, C6H6, 69°, 12–60 hHantzsch ester, (S)-segphos, [Ir(cod)Cl]2, s/c 100, toluene/dioxane, I2, 40 bar, rt, 42–79 h

(Eq. 19)

NHCOR

NHCOR

PPh2

PPh2

(S)-16

CH2C6H3(OBn)2-3,5

CH2C6H3(OBn)2-3,5

R =OPPh2OPPh2

17

(S,SFc)-19

FePh2PN

O

t-Bu

O

POO

P

18

OOP

Ph

2,4-Xyl 2,4-Xyl

+

The reduction of quinolines can also be carried out in the presence of chlo-roformates with an Ir-segphos catalyst122 leading to the corresponding protectedtetrahydroquinolines with moderate to good enantioselectivities and yields(Eq. 20). The hydrogenation of isoquinolines has been investigated less. Inter-estingly, the Ir-segphos catalyst122 under the same conditions in the presence ofchloroformates does not lead to the expected tetrahydroisoquinolines but rather


to the corresponding N-protected dihydroisoquinolines, in moderate enantiose-lectivities and yields (Eq. 21).

segphos, [Ir(cod)Cl]2, s/c 100+ ClCO2Bn

(41–92%) 80–90% ee

N R1

R2

N R1

R2

R1 = (subst)alkyl, PhR2 = H, F, Me, MeO

THF, Li2CO3, LiBF4,42 bar H2, rt, 12–15 h CO2Bn

(Eq. 20)

N

R2

R2

R1

N

R2

R2

R1CO2R3+ ClCO2R3

R1 = alkyl, PhR2 = H, MeOR3 = Me, Bn

(49–87%) 62–83% ee

segphos, [Ir(cod)Cl]2, s/c 100

THF, Li2CO3, LiBF4,42 bar H2, rt, 12–15 h

(Eq. 21)

Quinoxalines can be considered to be model substrates for the reduction offolic acid (see Applications to Synthesis). Only two successful catalysts havebeen described. The first success (actually one of the first hydrogenations ofan aromatic substrate) was achieved with the uncommon tetradentate iridiumcomplex 20 in good ee but low yield.123 Ru(hexaphemp)(dach)Cl2 gives betteryields of product but only 69% ee (Eq. 22).47

N

N

20, s/c 100, MeOH, 5 bar, 100°, 24 hRu((S)-hexaphemp)((R,R)-dach)Cl2, s/c 1000, t-BuOH, t-BuOK, 30 bar, 50°, 20 h

54% conv., 90% ee100% conv., 69% ee

NH

HNchiral catalyst

H2

NIr

HPPh2

H

PPh2

H

20

(Eq. 22)


C=N–Y Functions (Y = OR, NHCOAr, Ts, POAr2). Oxime derivativeswere among the first C=N functions to be tried as substrates for enantioselectivereduction. However, with ee values of <30% both with modified heterogeneouscatalysts2 as well as homogeneous catalysts,3 the results were disappointing, espe-cially for α-keto acid derivatives that provide access to α-amino acids. A fewexamples of oxime hydrogenation with Rh-binap (30–66% ee)17 and Ir-dpampp(93% ee)124 are known, but high pressures and/or temperatures are requiredto give reasonable catalyst activities. An interesting variant is the hydrogena-tion of nitrones (Eq. 23), which can be carried out with an Ir-binap catalystwith moderate enantioselectivity and often low chemical yields to provide thehydroxylamines.125

Ar

N+O–R

Ar

NOHR

binap, [Ir(cod)Cl]2, s/c 100

THF, NBu4BH4, 80 bar H2, 0°, 18 h

Ar = (subst)Ph, 2-NpR = Me, Bn

(17–82%) 69–86% ee

(Eq. 23)

High enantioselectivities are obtained for the hydrogenation of a variety ofN -tosyl imines (Eq. 24) and cyclic analogs (Eq. 25). Ru-binap complexes,126,127

Pd catalysts with tangphos,128 segphos,129,130 and synphos129,130 are effectivehydrogenation catalysts, and several Ru-dpenTs-catalyzed transfer hydrogena-tions131 – 133 have been described. In general, ee values are high and good chemicalyields are obtained both for linear and cyclic sulfonylated imines, albeit with lows/c ratios for all catalytic systems.

NTs

R1 R2

HNTs

R1 R2

chiral catalyst

H2

R1 = alkyl, arylR2 = Me, Et

>99% conv., 75 to >99% ee

(84–98%) 88–97% ee

Ref.128

129

Chiral catalyst, reaction conditionsPd(tangphos)(CF3CO2)2, s/c 100, DCM, 75 bar, 40°, 24 hPd(synphos)(CF3CO2)2, s/c 50, CF3CH2OH, 4 Å MS, 40 bar, rt, 12 h

(Eq. 24)


N

O2S

R

NH

O2S

R

chiral catalyst

R = alkyl, aryl, Bn, ROCH2

(84%) 99% ee

>99% conv., 94% ee

(93–99%) 79–93% ee

(99%) 93% ee

(—) 91–93% ee

(90%) 96% ee

(95%) 94% ee

Ref.126

128

129

131

132

133

99

Chiral catalyst, reaction conditionsbinap, Ru(cod)Cl2, s/c 100, toluene, NEt3, 4 bar H2, 22°, 12 hPd(tangphos)(CF3CO2)2, s/c 100, DCM, 75 bar H2, 40°, 24 hPd(segphos)(CF3CO2)2, s/c 50, CF3CH2OH, 4 Å MS, 40 bar H2, rt, 12 hHCO2H/NEt3, dpenTsimmob, [Ru(cymene)Cl2]2, s/c 100, neat, 40°, 1.5 hHCO2H/NEt3, (C6H6)Ru((S,S)-dpenTs)Cl, s/c 200, DCM, rt, 17 hHCO2H/NEt3, (R,R)-dpenTsdend, [(cymene)RuCl2]2, s/c 100, DCM, 28°, 10 hHCO2Na, (R,R)-dpenTssulf, [(cymene)RuCl2]2, s/c 100, H2O, CTAB, 28°, 10 h

(Eq. 25)

N -Tosylimines of cyclic ketones can be hydrogenated in moderate to highenantioselectivities using a Ru-binap127 or a Pd-tangphos128 catalyst (Eq. 26).

Pd(tangphos)(CF3CO2)2, s/c 100

DCM, 75 bar H2, 40°, 24 hNTs NHTs

n n

n12

>99% conv., 98% ee>99% conv., 94% ee

Ref.128128

(Eq. 26)

The enantioselectivities that can be achieved for Rh-duphos-catalyzed hydro-genation of N -acyl hydrazones, which were quite impressive at the time of theoriginal report,134,135 confirm the hypothesis that the presence of a second coor-dinating group in the substrate enhances enantioselectivity (Eq. 27). Whereasee values are modest for alkyl methyl acyl hydrazones, good to very goodenantioselectivities are obtained for the Rh-duphos-catalyzed hydrogenation ofacyl hydrazones derived from aryl methyl ketones and α-keto esters. Other Rh-diphosphine complexes give ee values of ≤67%.136,137 The resulting N -acylhydrazines can be reduced to the primary amines using SmI2, but a practicaleconomic method for the cleavage of the N–N bond to obtain the primary aminewithout racemization is still lacking.


[Rh(Et-duphos)(cod)]OTf, s/c 500

i-PrOH, –10° to 20°, 4 bar H2, 2–36 hR1 R2

NNHCOAr

R1 R2

HNNHCOAr

R1

alkylarylalkyl, arylPh

R2

MealkylCO2EtP(O)(OEt)2

45–73% ee88–97% ee83–91% ee

90% ee

(70–90%)

(Eq. 27)

Phosphinyl imines (Eq. 28) can be hydrogenated in moderate to excellentenantioselectivities with Rh-josiphos,138 Pd-synphos,130 as well with cp*Rh(dpenTs)Cl.90 Whereas s/c ratios for the transfer hydrogenation and the Pd-synphos catalyst are rather low, up to 500 turnovers can be obtained with Rh-josiphos.

R1 R2

NPPh2

O

R1 R2

HNPPh2

Ochiral catalyst

R1 = (subst)Ph, 2-Np, n-C6H13

R2 = Me, Et

100% conv., 86 to >99% ee

(29–93%) 87–93% ee

93–100% conv., 62–99% ee

Ref.90

130

138

Chiral catalyst, reaction conditionsHCO2H/NEt3, cp*Rh(dpenTs)Cl, s/c 50, MeCN, rt, 2–3 h Pd(segphos)(CF3CO2)2, s/c 50, CF3CH2OH, 4 Å MS, 70 bar H2, rt, 8 hjosiphos, [Rh(nbd)2]BF4, s/c 100–500, MeOH, 70 bar H2, 60°, 1–21 h

(Eq. 28)

α- and β-Carboxy Imines. α- and β-Functionalized imine derivatives areobvious precursors to α- and β-amino acids. However, effective catalytic sys-tems for this transformation have only recently been developed, with selectedexamples presented in Eq. 29. α-Amino acid derivatives are accessible via theIr-dpampp-catalyzed reduction of an oxime124 (93% ee, very low yields) or theRh-duphos-catalyzed hydrogenation of acyl hydrazones134,135 in moderate to goodenantioselectivity. In both cases, the primary amino acid can be obtained byreductive cleavage of the N–O or N–N bond, respectively. The hydrogenationof 4-MeO-phenyl imines using either Rh-tangphos,139 Pd-binap,140 or a binol-P(O)OH catalyst (7e, 21) in the presence of Hantzsch ester141,142 also providesthe corresponding amino ester in good yields and moderate to high enantios-electivities. The resulting products can be deprotected under mild conditionswith cerium ammonium nitrate.143 Reductive amination using a Rh-deguphoscatalyst144 can be achieved in medium to very high enantioselectivities (Eq. 30).Both yield and ee strongly depend on the nature of R.


(85–99%) 94–99% ee

(46–95%) 84–98% ee

85–99% conv., 83–95% ee

(70–90%) 83–91% ee

19–22% conv., 93% ee

Ref.141

142

139

134, 135

124

Chiral catalyst, reaction conditionsHantzsch ester, 21, s/c 20, toluene, rt–50°, 19–22 hHantzsch ester, 7e, s/c 10, toluene, 60°, 48 h[Rh(tangphos)(cod)]BF4, s/c 100, DCM, 50 bar H2, 50°, 24 h[Rh(Et-duphos)(cod)]OTf, s/c 500, i-PrOH, 0°, 4 bar H2, 36 h[Ir(dpampp)Cl]2, s/c 100, C6H6/MeOH, BI3, 48 bar H2, rt, 46 h

R3

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

NHCOPh

OH

R2

alkyl, aryl

alkyl, (het)aryl

alkyl, aryl

Ph, alkyl

Ph(CH2)2

PhPh

OO

PO

OH

(S)-21

R2 CO2R1

NR3

R2 CO2R1

HNR3

chiral catalyst

R1 = Et, i-Pr

(Eq. 29)

R CO2H

O[Rh(deguphos)(nbd)]BF4,

s/c 100–200+ BnNH2

R CO2H

NHBn

R = alkyl, BnR = Me, HO2C(CH)n

(80–99%) 81–98% ee(19–43%) 60–78% ee

MeOH, 60 bar H2, rt, 2–24 h (Eq. 30)

By analogy, β-amino acid derivatives have been prepared in high yieldsand good to very high enantioselectivities via the Rh-tangphos-catalyzed hydro-genation of β-imino esters (Eq. 31).145 An interesting new development is thehydrogenation of primary enamines/imines leading to β-amino acid derivatives(Eq. 32), a reaction with considerable synthetic and industrial potential.146

Whereas the hydrogenation of the analogous N -acylated derivatives is a well-known transformation, it was quite unexpected that the unprotected substrateswould be amenable to enantioselective hydrogenation. Very good enantioselectiv-ities are achieved for several different primary β-imino esters with Rh-josiphos146

and Ru-binap (and analogs)147 in trifluoroethanol, but for both catalyst activityis an issue. While the Rh-josiphos complexes give high conversion at an s/c of330 after 6–20 hours, the Ru-binap catalysts at an s/c of 100 (in some cases


1000) do not give full conversion even after 15–88 hours. Interestingly, deuter-ation experiments indicate that it is not the enamine C=C bond that is reducedbut the tautomeric primary imine. For the Rh-josiphos-catalyzed hydrogenationof β-imino N -aryl amides, the best enantioselectivities are obtained in methanol(Eq. 33).146 In the presence of (Boc)2O, the hydrogenation with Rh-josiphos leadsdirectly to the N-protected β-amino acid derivatives with improved chemicalyields and up to 99% ee (Eq. 34).148,149

R1 CO2R2N

R3

R1 CO2R2NH

R3[Rh(tangphos)(nbd)]SbF6, s/c 100

CF3CH2OH, 6 bar H2, 50–80°, 18–24 h

48–100% conv., 79–96% eeR1 = alkyl, arylR2 = Me, Et

(Eq. 31)

R

NHCO2Me

R

NH2

CO2Me

R

NH2

CO2Me

chiral catalyst

H2

R = Me, aryl, Bn

Chiral catalyst, reaction conditions(R,SFc)-josiphos (4-CF3Ph/t-Bu), [Rh(cod)Cl]2, s/c 300, CF3CH2OH, 6 bar, 50°, 16–20 h[Ru((S)-segphos)(OAc)2], s/c 100, CF3CH2OH, 30 bar, 80°, 15–88 h

(88–96%) 93–96% ee

(54–85%) 96–97% ee

Ref.146

147

(Eq. 32)

R

NHCONHPh

R

NH2

CONHPh

R

NH2

CONHPh

R = aryl, Bn

(R,SFc)-josiphos (Ph/t-Bu), [Rh(cod)Cl]2

s/c 300, MeOH, 6 bar H2, 50°, 8 h

(74–94%) 96–97% ee

(Eq. 33)

R

NH2

COY

(R,SFc)-josiphos (Ph/t-Bu), [Rh(cod)Cl]2, s/c 30–250

R

NHBocCOY

R = Me, aryl, BnY = OMe, NHPh

(57–99%)91–99% ee

MeOH, Boc2O, 3–6 bar H2, rt, 18 h (Eq. 34)

Reductive Amination. The reductive amination of ketones,20 that is, in situformation of the imine followed by hydrogenation, is an especially attractive


variant for industrial applications, because isolation and purification of the C=Ncompound is not required. However, suitable catalysts and reaction conditionsfor this process have only recently been developed. In general, the same metalprecursor–ligand combination identified for the isolated imine can be used, butoften either the solvent has to be adjusted or additives such as molecular sievesare necessary for good results. In general, the reaction works best with arylketones but aliphatic ketones have also been used.

Of special interest is the preparation of primary amines because, with theexception of β-dehydro acid derivatives illustrated above, primary imines cannotusually be isolated. Ruthenium complexes with tol-binap150 as well as ClMeO-biphep151 give excellent enantioselectivities and good to high yields for thereductive amination of a variety of aryl methyl ketones with ammonium acetate(Eq. 35).

Ar R

O+ NH4OAc

Ar R

NH2

Ar = (subst)Ph, 1-Np, 2-Np

chiral catalyst

RMe, Et

EtO2CCH2

(74–93%) 89–95% ee

(79–88%) 96–99% ee

Chiral catalyst, reaction conditionsNH3/HCO2H, Ru(tol-binap)Cl2, s/c 100, MeOH, 85°, 21–48 h(Cymene)Ru(ClMeO-biphep)Cl2, s/c 100, CF3CH2OH, 30 bar H2, 80°, 16 h

Ref.150

151

(Eq. 35)

A number of ketones can be reductively aminated with a variety of arylamines (Eqs. 36–38) in up to 96% ee, using the phosphoric acid-based trans-fer hydrogenation catalyst 7a104 or an iridium f-binaphane complex.152 Whereasconversions with the iridium complex are quantitative after 10 hours, the trans-fer hydrogenation takes longer and yields are around 70–90%. The reactionof α-methoxyacetone with 2-ethyl-6-methyl aniline (Eq. 39) catalyzed by an Ir-josiphos complex153 must be carried out in a non-polar solvent like cyclohexaneto attain high turnover numbers.

chiral catalyst

R1 R2

O HNAr

R1 R2+ ArNH2

Ar = Ph, 4-MeOC6H4

R1 = Me, Et

(49–82%) 81–96% ee

(>99%) 44–96% ee

Chiral catalyst, reaction conditionsHantzsch ester, 7a, s/c 10, C6H6, 5 Å MS, 50°, 24–72 hf-binaphane, [Ir(cod)Cl]2, s/c 100, DCM, I2, Ti(i-PrO)4, 70 bar H2, rt, 10 h

R2

alkyl, aryl

(het)aryl

Ref.104

152

(Eq. 36)


Hantzsch ester, 7a, s/c 10

C6H6, 5 Å MS, 72 h

O NHPMP

(75%) 85% ee

+ 4-MeOC6H4NH2 (Eq. 37)

Hantzsch ester, 7a, s/c 10

C6H6, 5 Å MS, 72 h

H2N

R

O

S

N

+ ArNH2

R

HNAr

O

H2N

H2N

N

Ts

R

Ph

Ph

Phn-C6H13

(70%) 91% ee

(92%) 91% ee

(90%) 93% ee(75%) 90% ee

ArNH2

(Eq. 38)

H2N

OMeO

(R,SFc)-josiphos (Ph/Xyl), [Ir(cod)Cl]2, s/c 10,000

Et HNEtMeO

99% conv., 78% ee

+ C6H12, CF3CO2H, TBAI,80 bar H2, 50°, 16 h

(Eq. 39)

Only a small number of enantioselective reductive aminations with aliphaticamines have been described, and with few exceptions, enantioselectivities arelower than for the reaction with ammonium acetate or with aromatic amines.Benzylated α-amino acids can be prepared via Rh-deguphos-catalyzed reduc-tive amination of α-keto acids144 (Eq. 40) with substrate-dependent yields andenantioselectivities. The Ru-dpenTs-catalyzed transfer hydrogenation of racemic2-methylcyclohexanone (Eq. 41) occurs with acceptable enantio- and diastereo-selectivity, due to a dynamic kinetic asymmetric transformation.77

R CO2H

O[Rh(deguphos)(nbd)]BF4,

s/c 100–200BnNH2

R CO2H

NHBn+

R = alkyl, Bn, HO2C(CH2)n (19–99%) 60–98% ee

MeOH, 60 bar H2, rt, 2–24 h(Eq. 40)

O

(cymene)Ru(dpenTs)Cl

s/c 200, DCM, rt, 184 h

(77%) 90% eecis/trans 92:8

NH

+ HCO2H/NEt3 + NH2

(Eq. 41)


Cyclohexylamines can be obtained from a reaction cascade involving imineformation, enamine aldol condensation, and transfer hydrogenation (Eq. 42).154

The reaction is catalyzed by binol-P(O)OH 7c in the presence of Hantzsch esterand furnishes products in 72–89% yield in very good enantioselectivities andmedium to very high diastereomeric ratios. An interesting domino reaction is cat-alyzed by a Pd complex of duphos or the Trost ligand 22 between an aryl iodide,CO, and cyclohexylamine (Eq. 43). An initial double carbonylation yields an α-keto amide, which reacts with a second equivalent of amine, leading eventuallyto the corresponding α-amino amide in good to excellent enantioselectivities andmodest yields.155

Y

O

OR1

H2N

OR2Hantzsch ester, (R)-7c, s/c 10

cyclohexane, 5 Å MS, 50°, 72 h

YR1

HN

OR2

+

Y = CH2, O, SR1 = alkyl, 2-Np; R2 = Me, Et

(35–89%) 82–96% eecis/trans 2:1 to 99:1

(Eq. 42)

RI

+ CO + c-C6H11NH2R

O

L, Pd2dba3, s/c 25NH-c-C6H11

NH-c-C6H11

R = alkyl, NH2, MeCO (31–49%) 92 to >99% ee

NHNH

O

Ph2PO

PPh2

(R,R)-22

NEt3, 4 Å MS, 7 bar H2,120°, 24–42 h

L = duphos or 22

(Eq. 43)

MECHANISM AND STEREOCHEMISTRY

Only a few detailed studies of the reaction mechanism of the homogeneoushydrogenation of imines have been published. Generalizations about this pro-cess are very difficult to make for two reasons. First, different catalyst types areeffective and probably act by different mechanisms. Second, the effect of certainadditives (especially iodide, and acid or base) is often critical for optimum enan-tioselectivities and reaction rates, but a promoter in one case can be a deactivatorin another. Most catalytic systems described in this review most likely promotethe addition of dihydrogen directly to the C=N bond and not to the tautomeric


enamine C=C bond,70,146,135 even though enamines can also be hydrogenatedenantioselectively.156,157

Rhodium CatalystsKinetic studies on the rhodium-catalyzed N -aryl imine hydrogenations have

led to the conclusion that, by analogy with C=C hydrogenation, the so-calledhydride route is preferred.7,158 As depicted in Scheme 1, it is assumed that theimine is first η1-coordinated by the nitrogen lone pair to a RhIII-dihydride species.The isomerization to the π-coordinated intermediate thought to be necessary forthe reduction might be assisted by a bound alcohol molecule. After two hydrogentransfer steps wherein the first determines the absolute configuration, a RhI-amine complex results that either directly or in a dissociative manner reacts withdihydrogen to form the RhIII-dihydride species again.

The Rh-duphos-catalyzed hydrogenation of acyl hydrazones has also beenstudied in some detail.135 These substrates were intended to provide an addi-tional stabilizing interaction between the substrate and the rhodium center.134

Such a secondary interaction is considered to be the major reason for the excel-lent enantioselectivities observed for the hydrogenation of enamides, itaconates,or β-ketoesters.159 The stronger coordination may also be the reason why manyof these hydrogenation reactions are tolerant of functional groups such as halo-gen, formyl, or cyano. Deuteration studies indicate that the insertion of the C=Nmoiety into the Rh–H bond occurs irreversibly as proposed for the imine hydro-genation in the catalytic cycle depicted in Scheme 1.

A recent kinetic study160 of the cp*Rh-dpenTs-catalyzed transfer hydrogena-tion of an endocyclic imine with formic acid–ammonia indicates that a sim-ilar sequence of steps occurs as suggested for the hydrogenation depicted inScheme 1. The data show that a cp*Rh(dpenTs)-H species is likely to be the

RhSolvP

P

N R3

R2

NR3

R2

NR1

R3

R2 H

NR1

R3R2

HNR1

R3

R2H

H2

PP

= chiral diphosphine

NR1

R3

R2 HH

O

H H

HR1

RhPP

O

H H

HR1

RhPP

O

HH

HR1

RhPP

O

H

HR1

RhPP

O

Solv

HR1

R1

+−

R1

Scheme 1


resting state of the catalytic cycle. This rhodium hydride species is formed bythe transfer of a hydride from formic acid and reacts further by coordinating theC=N bond followed by insertion into the Rh–H bond and protonation to givethe chiral amine.

Iridium CatalystsThe Ir-diphosphine-catalyzed hydrogenation of N -aryl imines has been studied

in some detail.83 IrIII complexes of the type [Ir(diphosphine)I4]−, [Ir(diphosphine)I2]2, and [Ir(diphosphine)I3]2 have been isolated and characterized. All three typesof complexes are catalytically active, suggesting the formation, by splitting theiodo bridge, of the same active monomeric iridium species as for the catalystformed in situ from [Ir(cod)Cl]2, diphosphine, and iodide. Similar results havebeen reported for the dimethylaniline imine/Ir-josiphos system161,162 and a num-ber of reaction intermediates have been isolated. On the basis of these results,the catalytic cycle shown in Scheme 2 can be postulated.

The starting species is an IrIII-H complex that coordinates the imine by thenitrogen lone pair in a η1-manner (as proposed above for the rhodium-catalyzedreaction). A η1,η2-migration leads to two diastereomeric adducts with a π-coordinated imine, which then inserts into the Ir–H bond to give the corre-sponding iridium amide complexes. The last step involves the hydrogenolysis ofthe Ir–N bond and the formation of an Ir–H bond, presumably via heterolyticsplitting of the dihydrogen bond. In contrast to the Rh-diphosphine-catalyzedhydrogenation of C=C bonds, which most likely occurs via RhI and RhIII species,the cycle in Scheme 2 consists exclusively of IrIII species, that is, the halides Xand Y remain on the iridium during the cycle. However, this basic catalytic cycleexplains neither the mode of enantioselection nor the sometimes dramatic effectsof additives, for example, the major rate enhancement in the presence of iodide

Ir HPP

H

NR1

R3

R2

HN

R1

R3R2

NR1

R3

R2 H

NR1

R3R2

HNR1

R3

R2H

H2

IrPP

IrPP

IrPP

Ir = IrIII

Y

X

X, Y = halogen

PP

= chiral diphosphine

Scheme 2


ion and acids observed for the Ir-josiphos-catalyzed hydrogenation of N -arylimines.16

Catalyst deactivation is often a serious problem, especially when hydrogenat-ing relatively basic imines. Such a deactivation is indicated when the initialreduction rate is high but then slows significantly even at low conversion. Sev-eral studies46,163,164 show that the formation of triply hydrogen-bridged dinuclearspecies is the probable cause of deactivation for many iridium systems (Eq. 44).These catalytically inactive species are formed irreversibly, and their formation isaccelerated by base and by the absence of imine substrate. It has been shown thatwith the josiphos ligand the catalysts are much less prone to deactivation thanwith many other ligands, and that the presence of iodide ions is often beneficialfor the reaction.

X,Y = Cl, I

H

Ir

Solv

X

Y

P

P

H

IrP

P

H

IrH

H

P

PH

+ H2

– HX, – HY (Eq. 44)

The imine hydrogenation reaction using iridium phosphine oxazoline com-plexes has not yet been investigated mechanistically, but a plausible stereo-chemical model was proposed for the iridium-catalyzed hydrogenation of N -arylimines with spirophosphino oxazoline 3.41 The prediction is based on the samestereochemical model developed for the (ebthi)Ti catalysts discussed in moredetail below. For 3 the hindered quadrants are occupied by the spiroindanebackbone and by one of the P -phenyl groups, leading to the preferred coor-dination of the N -aryl imine in which the large groups point towards the emptyquadrants.

Titanium CatalystsA mechanism similar to that described for the iridium-catalyzed reactions has

been proposed for the titanium-catalyzed reactions (Scheme 3).34,78 The activecatalyst produced by reacting (ebthi)TiX2 (X2 = Cl2 or binol) with n-BuLi fol-lowed by phenylsilane is assumed to be the monohydride species (ebthi)Ti-H.Kinetic and deuterium-labeling studies are in agreement with the following reac-tion sequence: (ebthi)Ti-H reacts with the imine via a 1,2-insertion reaction toform two diastereomeric titanium–amide complexes. These intermediate amidecomplexes then react irreversibly via a σ bond metathesis reaction with dihydro-gen, as proposed for the iridium-catalyzed reaction, to regenerate the titaniumhydride and form the two amine enantiomers.

For most imine hydrogenations, the resulting absolute configuration of themajor enantiomer cannot be predicted and must be determined experimentally.Although this situation is scientifically unsatisfactory, from an experimental stand-point it poses no major problems, because all relevant ligands are available in bothenantiomeric forms. An exception is the (ebthi)Ti catalyst, where the absolute


H

NR1

R3

R2

N

R1

R3

R2 H

NR1

R3R2

HN

R1

R3

R2H

H2

(ebthi)Ti(ebthi)Ti

(ebthi)Ti-H

(ebthi)TiX

X(X = Cl or binol)

activation

transition state (TS)

Scheme 3

configuration of the major enantiomer can be predicted by a simple stereochem-ical model.34,35,70 As schematically depicted in Fig. 4, two of four quadrants(bold) are occupied by the six-membered ring of the tetrahydroindenyl ligand,whereas the other two quadrants are much less crowded. It is assumed that theimine coordinates horizontally and therefore, for the anti isomer, the preferredcoordination can be easily predicted using simple steric arguments. For the synisomer, the situation is more complicated because there might be a competitionbetween R3 and Rlarge for an empty quadrant, explaining the lower enantiose-lectivities usually realized for the hydrogenation of non-cyclic imines, and thepressure dependency of those reactions.

Nlarge

smallR3

Nlarge

smallR3

+ H2HN

large

smallR3

H

Ti

(ebthi)Ti-H

+

H Nlarge

smallR3

+ H2 HN

small

largeR3

H

favored

disfavored

major product (S)

minor product (R)

Ti HN

TS

Figure 4. Quadrant model for predicting product stereochemistry based on the transitionstate with (ebthi)Ti-H as the catalyst.


Ruthenium Catalysts

Although, to date, no mechanistic studies of imine hydrogenation with a chi-ral ruthenium complex have been reported, two recent reviews discuss possiblemechanisms of the reduction of polar C=Y bonds both for reactions with dihy-drogen as well as for hydrogen transfer reactions.165,166 As in the hydrogenationof ketones, two rather different mechanisms likely operate. The first is a classicalinner-sphere mechanism as described above for rhodium, iridium, and titaniumcomplexes. This model proposes that all reactants are coordinated to the metalcenter, and bond-breaking and bond-making occur in the first coordination sphere.The second mechanism is an outer-sphere variant of the first, where the ketonedoes not coordinate to the ruthenium center but rather interacts with Ru–H anda coordinated N–H group. This mechanism has been convincingly demonstratedto occur in enantioselective ketone reductions catalyzed by Ru-diamine com-plexes. By analogy, it is quite likely that C=N reductions with Ru-diphosphinecomplexes occur via a classical inner-sphere mechanism, whereas Ru-diaminecomplexes react via an outer-sphere mechanism as schematically depicted inScheme 4.

NR3

R2R1

HNR3

R2

R1H

RuH

NN

H

L

NR3

R2R1

H2

or H-donor

R

L = arene or phosphine

RuNLR

RuH

NN

H

NR

LR

Scheme 4

Miscellaneous Catalysts

No mechanistic information is available for the recently described Pd-diphos-phine complexes or the binol-P(O)OH-catalyzed transfer hydrogenation withHantzsch esters as donors. In the latter method, the Hantzsch ester is proba-bly involved in the stereochemistry-determining step, most likely the transfer ofa hydride to the chiral iminium+/binol-P(O)O− ion pair.48,55 The very large sub-stituents needed in the ortho positions of the binol probably form a chiral pocketin which the iminium cation is bound, selectively exposing one of the faces for


H-addition and thus leading to high enantioselectivities.104 For the transfer hydro-genation of heteroarenes, a stepwise addition/isomerization/addition as illustratedin Scheme 5 has been proposed, where the configuration-determining step is thereduction of the C=N bond.111

N+

Y

RR

Y = COR, CN

Hantzsch ester1,4-addition

Hantzsch ester1,2-addition

H

binol-P(O)O–

N

Y

RRH

N+

Y

RRH

binol-P(O)O–

N

Y

RRH

isomerization

binol-P(O)OH

N

Y

RR

Scheme 5

APPLICATIONS TO SYNTHESIS

As mentioned in the Introduction, most reactions described in this reviewhave been carried out with simple model substrates. In this section, applicationsof asymmetric C=N reductions to the synthesis of more complex molecules ofindustrial or biological interest are summarized. The (S)-metolachlor process isby far the most important application of the catalytic hydrogenation of C=Nfunctions, and for this reason it is described in detail.

Production Process for (S )-Metolachlor (DUAL Magnum)

Metolachlor is the active ingredient of Dual, one of the most important grassherbicides for use in maize and a number of other crops.167 The active com-pound is an N -chloroacetylated, N -alkoxyalkylated o-disubstituted aniline. Thecommercial product was introduced in the market in 1976 as a racemic mix-ture of two diastereomers (Fig. 5), then in 1982 it was found that about 95% ofthe herbicidal activity of metolachlor resides in the two (1′S)-diastereomers. In1997, after years of intensive research, Dual Magnum was introduced into themarket. The product contains approximately 90% of the (1′S)-diastereomers andhas the same biological effect of the racemate at about 65% of its use rate. Today,with a production volume of >10,000 tons per year, Dual Magnum represents,by far, the most significant application of enantioselective catalysis in terms ofoutput.


N

MeO

N

MeO

N

MeO

N

MeO

N

MeO

(αR,1'S) (αS,1'S) (αR,1'R) (αS,1'R)

active stereoisomers inactive stereoisomers

metolachlor

O

CH2Cl

O

CH2Cl

O

CH2Cl

O

CH2Cl

O

CH2Cl

1' 1' 1' 1'

Figure 5. Structures of metolachlor and its individual stereoisomers.

A key step in the new process is the enantioselective hydrogenation of thedistilled 2-methyl-6-ethyl aniline (MEA) imine substrate (Eq. 45). The optimizedprocess operates at 80 bar hydrogen and 50◦ with a catalyst generated in situ from[Ir(cod)Cl]2 and (R,SFc)-josiphos (Ph/Xyl) at an s/c ratio of 2,000,000. Completeconversion is reached within 3–4 hours, initial TOF exceeds 1,800,000 h−1, andenantioselectivity is approximately 80% ee.16 Key success factors for the pro-cess are the novel, very active Ir-josiphos catalyst, the use of iodide and acidas additives, and the high purity of MEA imine. Alternative processes such asdirect reductive amination153 as well as the application of immobilized josiphos168

in order to avoid the distillation of the N -alkylated aniline were investigatedas well. Whereas both catalyst systems reach respectable turnover numbers of10,000–100,000, these variants are not competitive.

NOMe H

NH

OMe

+ H2

Ir-josiphos (Ph, Xyl),acid, iodide, 50°, 80 bar H2

100% conv., 80% ee

TON up to 2,000,000TOF >400,000 h–1

(Eq. 45)

Production Process for SitagliptinMerck has developed a process for the manufacture of Sitagliptin, a DPP-IV

inhibitor for type 2 diabetes (Eq. 46). The key imine reduction reaction is carriedout with a Rh-josiphos catalyst with up to 98% ee albeit with low to medium TONand TOF.146,169 Success is dependent on the choice of the ligand, the solvent, andthe presence of trace amounts of ammonium chloride. Interestingly, deuterationexperiments indicate that it is not the enamine C=C bond that is reduced but thetautomeric imine. The reaction is now carried out on a multiton scale.170


F

FF

NH2

N

O

N

NN

CF3

josiphos ((R,S)-Ph/t-Bu), [Rh(cod)Cl]2, s/c 350, NH4Cl

F

FF

NH2

N

O

N

NN

CF3sitagliptin(—) 98% ee

MeOH, 6 bar H2, 50°, 16 h

(Eq. 46)

Pilot Process for Dextromethorphane

A pilot process for the preparation of an intermediate in the synthesis ofdextromethorphane, a traditional antitussive agent, was developed using an Ir-josiphos catalyst in a two-phase system (toluene/water) (Eq. 47).171 Key successfactors are ligand fine-tuning, the use of the phosphoric acid salt of the imine,the reaction medium, and the addition of base and iodide. Chemoselectivity withrespect to C=C hydrogenation is high but the turnover number is somewhat lowfor an economical technical application.

N•H3PO4

OMe

[Ir((R,SFc)-josiphos (Ph/t-Bu))(cod)]BF4,s/c 2000

N•HX

OMe

dextromethorphane

(80 to >95%) up to 90% eeMeO

NMeH

toluene/H2O, TBABr, 30 bar H2, rt, 6 h

(Eq. 47)

Industrial Feasibility Studies

Noyori’s Ru-PP-NN catalyst system was successfully applied in a feasibilitystudy for the hydrogenation of a sulfonyl amidine, an intermediate for S 18986,an AMPA receptor modulator (Eq. 48).172 Considering that the substrate is anamidine, the catalytic activity is surprisingly high, but at 87% ee, the enantiose-lectivity of the reaction is modest. A factorial experimental design was used tooptimize reaction conditions showing the importance of the nature and amountof base.


N

N

O2S

N

NH

O2SRu((R)-binap)((R,R)-dpen)Cl2, s/c 2500

toluene/i-PrOH, i-PrOK, 4 bar H2, 60°, 6 h

S 18986(97%) 87% ee

(Eq. 48)

The commercial viability of the CATHy catalysts based on a cp*Rh com-plex has been demonstrated for the transfer hydrogenation of phosphinyl imines(Eq. 49).173 The reaction with the 2-naphthyl derivative was scaled up to themultikilo level. Bubbling nitrogen through the reaction solution increases reactionrates significantly, due to the faster removal of the CO2 byproduct.

NP(O)Ph2 NHP(O)Ph2cp*Rh(dpenTs)Cl, s/c 200

MeCN, 20°+ HCO2H/NEt3

(100%) >99% ee

(Eq. 49)

Up to 90% ee was achieved in the hydrogenation of an intermediate in theprocess to the antibiotic levofloxacin using Ir-diphosphine complexes (Eq. 50).174

The best results were obtained with bppm and mod-diop in the presence ofbismuth iodide at low temperature.

ONF

F

ONHF

Fbppm, [Ir(cod)Cl]2, s/c 100

C6H6/MeOH, BiI3, 40 bar H2, –10°, 3 h

(96%) 90% ee

NO

N

FO

CO2H

NMe

levofloxacin

(Eq. 50)

The hydrogenation of folic acid, formally a diastereoselective reaction asdepicted in Eq. 51, has been claimed to proceed with up to 90% ee with an Ir-bppm complex adsorbed on silica gel, a claim that later had to be retracted.175 Amajor problem is the insolubility of folic acid in most organic solvents. Function-alized catalysts offer the opportunity to perform this reaction in water and it wasshown that a rhodium complex of the functionalized josiphos (josiphosfunct) canachieve diastereoselectivities of up to 49%.176 An alternative is the hydrogenationof the corresponding bis(methyl) ester, which can be carried out in methanol.


However, the best catalyst, [Rh(cod)2]BF4/(R)-binap, achieved a diastereose-lectivity of <44%.177 Even though for both processes s/c ratios up to 1000were possible, selectivity and activity are not sufficient for commercial applica-tions.

HN

N N

NNHR

H2N

O

HN

O

CO2H

CO2HH

Rh-(R,SFc)-josiphosfunct

water, s/c 100, 70°, 80 bar H2

97% conv., 49% de

(R,SFc)-josiphosfunct

HN

N NH

HN

H2N

O

R =

H

FeP(Xyl)2

PPh2

HNHN

O

O

O

OCO2H

CO2H

CO2H

NHR

(Eq. 51)

Synthesis of Tetrahydroisoquinoline Alkaloids

Several tetrahydroisoquinoline alkaloids such as salsoline, laudanosine, andcryptostyline have been synthesized starting from the corresponding endocyclicdihydroisoquinolines. With very few exceptions,34,87,102,103 Noyori’s transfer hy-drogenation catalyst system was applied.91,94,96,99 – 101,106,107,178,179 A few selectedexamples are described to illustrate the scope and limitations of the technology.The first results were reported for the synthesis of the closely related cryptosty-line II, norlaudanosine, and tetrahydrohomopapaverine alkaloids (Eq. 52) usingIr-diphosphine catalysts.103 Good results (up to 88% ee) are obtained with thebcpm ligand in the presence of phthalimides for norlaudanosine and tetrahy-drohomopapaverine, whereas poor enantioselectivity and yield are reported forcryptostyline II.

N

MeO

MeOR

NH

MeO

MeOR

bcpm, [Ir(cod)Cl]2, s/c 100

toluene/MeOH, F4-phthalimide, 100 bar H2, 20 h

R:

MeO

MeO

cryptostyline II50% conv., 31% ee

norlaudanosine84% conv., 88% ee

tetrahydrohomopapaverine89% conv., 86% ee

MeO

MeO

MeO

MeO

(Eq. 52)


Noyori’s transfer hydrogenation technology is also effective in the synthesisof tetrahydroisoquinoline alkaloids.22,96,106,107,180 The synthesis of a homopro-toberine alkaloid was achieved in good yield and 99% ee (Eq. 53).96 The keystep for the synthesis of cryspine A106 (Eq. 54), harmicine,107 and desbromoarbo-rescidine107 (Eq. 55) is the transfer hydrogenation of tri- and tetracyclic endo-cyclic iminium species, which occurs in all three syntheses in satisfactory yieldsand modest to good enantioselectivities, albeit at high catalyst loadings.

N

MeO

MeO HCO2H/NEt3, (C6H6)RuCl((R,R)-dpenTs)

s/c 100, MeCN, rt, 12 h

(92%) 99% ee

MeOOMe

NH

MeO

MeO

(CH2)2

MeOOMe

OMe OMe

(CH2)2

N

MeO

MeO OMe

OMe

OMehomoprotoberine

(Eq. 53)

(C6H6)RuCl((S,S)-dpenTs)

s/c 20, MeCN, 0°, 10 hN+

MeO

MeOCl–

N

MeO

MeOH

cryspine A(96%) 92% ee

+ HCO2H/NEt3

(Eq. 54)

Cl– + HCO2H/NEt3NH

N+NH

N

H

n = 1 harmicinen = 2 desbromoarborescidine

( )n( )n

(81%) 79% ee(84%) 90% ee

(C6H6)RuCl((S,S)-dpenTs)

s/c 20, MeCN, 0°, 10 h

(Eq. 55)

The (S)-cryptostyline moiety of the short-acting neuromuscular blocker GW0430 has been prepared via transfer hydrogenation of an appropriate dihydroiso-quinoline derivative (Eq. 56).95 Classical Noyori conditions using a Ru-dpen(1-Nps) catalyst affords the tetrahydro derivative in 83% ee, which was enriched bycrystallization to 99% ee.


N

MeO

MeONH

MeO

MeO(C6H6)RuCl((R,R)-dpen(1-Nps))

s/c 150, MeCN, rt, 16 h

OMeOMe

OMeOMe

MeO MeO

+ HCO2H/NEt3

(—) 83% ee

N+

OMe

OMe

MeOOMe

OMe

(S)-cryptostyline

N+

MeO

MeO(CH2)2

MeO

MeO

OMe

MeO

O

Cl

O

O

Me

GW 0430(R)-methoxylaudanosine

(Eq. 56)

All possible stereoisomers of emetine, an Ipecacuanha alkaloid, have beenprepared via two consecutive asymmetric transfer hydrogenations under standardconditions (see Eq. 57, where the synthesis of the natural stereoisomer, (–)-emetine, is depicted).98 The predominant absolute configuration of the stereogeniccenters is controlled by the choice of the appropriate dpenTs ligands. For thefirst reduction, 2.5% of the catalyst was needed to give the desired tetrahydro-quinolines in 93% yield and >95% ee. The second, diastereoselective reductionrequired 10% catalyst and, depending on the relative absolute configuration ofthe catalyst and the substrate, yields of 71–82% and diastereoselectivities of 81to >96% de were obtained.

N

MeO

OTIPS

NH

MeO

MeO

OTIPS

s/c 40, DMF, rt, 1 h

(93%) >95% ee

N

MeO

MeO

N

MeOOMe

N

MeO

MeO

HN

MeOOMe

H

H

H

H

H

(cymene)RuCl((S,S)-dpenTs)

s/c 10, DMF, rt, 1 h

(–)-emetine(71–82%) >96% de

HCO2H/NEt3,(cymene)RuCl((R,R)-dpenTs)

(Eq. 57)


ALTERNATIVE REDUCTION SYSTEMS

Chiral HydridesHydride reductions of C=N groups are well known in organic chemistry and

several chiral reducing agents derived from BH3, LiAlH4, or NaBH4 and rela-tively cheap amino alcohols or diols have been developed for the reduction ofimines and oxime derivatives.25,26,181 – 183 Enantioselectivities are medium to high.Most of the effective chiral auxiliaries can be prepared in one or two steps fromrather inexpensive starting materials such as binol, amino acids, tartaric acid,or sugars, and can potentially be recycled. A major drawback of most hydridereduction methods is the fact that stoichiometric or higher amounts of chiralreagents are needed, and that disposal of the hydrolyzed borate and aluminatebyproducts leads to increased costs for the reduction step. Chiral hydrides arecurrently useful on a laboratory scale but their potential for commercial applica-tions is medium to low. Hydroboration of the C=N function catalyzed by chiraloxazaborolidines has also been reported.184,185

HydrosilylationBecause the silane has to be used in stoichiometric amounts, reactions involv-

ing hydrosilylation of C=N functions have cost and disposal issues similar tothose noted for hydride reductions, except that fewer effective reduction systemshave been developed.27,28,186 Despite some recent progress with highly selec-tive Ti-187 and Cu-based188 catalysts using cheap polymethylhydrosiloxane asthe reducing agent, and of organocatalysts able to activate trichlorosilane,189,190

hydrosilylation will probably have major application only in small-scale labora-tory syntheses.

BiocatalysisChiral amines can also be produced using aminotransferases either by kinetic

resolution of the racemic amine or by asymmetric synthesis from the corre-sponding prochiral ketone.191 A variety of chiral amines can be obtained withgood to excellent enantioselectivities. Several transformations have been devel-oped and can be carried out on a 100-kg scale.29 At the moment, application tosynthetic problems, especially to more elaborate targets, is challenging becauseoptimization of the enzyme and reaction conditions is time-consuming.

EXPERIMENTAL CONDITIONS

Note: Hydrogen forms explosive mixtures with air (explosion limit in air: 4.75vol % ). The apparatus must be tested at elevated pressure for leaks before thereaction (H2-tightness). For large-scale applications or with higher pressures, adetection system for H2 leaks during the run is recommended.

Choice of Metal, Anion, Ligands, and SolventsUnfortunately, there are no general guidelines for any of the substrate classes

described in this review. The specific combination of these process variables


must be optimized for each transformation. Nevertheless, existing results allowthe identification of catalytic systems with the best chance of success and theseare listed in Table A.

As a rule, relatively high pressures are needed to achieve acceptable reactiontimes, but, in general, pressure does not significantly affect enantioselectivities.For transfer hydrogenations, the azeotropic mixture formic acid–ammonia (5:2)is generally used in organic solvents and sodium formate in water, whereasHantzsch esters are required for organocatalytic reactions.

Substrate Class

N-aryl

N-alkyl

Endocyclic

Heteroarene

C=N–Ts

C=N–NHAc

C=N–P(O)Ph2

α-CO2R

β-CO2R

Metal (anion)

Ir (H+/ iodide)Ir (BARF)Ir (Cl / I2)Rh (BF4)

TiRu (Cl)Rh

TiRu (Cl)cp*Rh (Cl)Ir (halide)—

Ir (iodide)binol-P(O)OH

Ru (Cl)Pd (CF3CO2)

Rh (OTf)

Rh (BF4)Pd (CF3CO2)cp*Rh (Cl)

Rh (BF4)—

Ru (OAc)Rh (Cl)Rh (SbF6)

Chiral Ligand

josiphosphox (PN ligands)PN=SOtangphos

ebthidpenTsbdpp

ebthidpenTsdpenTsdiphosphinebinol-P(O)OH

diphosphinebinol-P(O)OH

binapsegphos, tangphos

duphos

josiphossynphosdpenTs

deguphosbinol-P(O)OH

segphosjosiphostangphos

Solvent

tolueneDCMtolueneDCM

THFDCMMeOH or biphasic

THFH2O, DCMMeOH or biphasicvariablebenzene, CHCl3

THF, toluenebenzene

tolueneCF3CH2OH

i-PrOH

MeOHCF3CH2OHMeCN

MeOHtoluene

CF3CH2OHCF3CH2OH, MeOHCF3CH2OH

Pressure

10–50 bar10–50 bar20 bar50 bar

140 barH-donor50–70 bar

5–30 barH-donorH-donor30–100 barH-donor

30–50 barH-donor

4 bar40–70 bar

4 bar

70 bar40–70 barH-donor

60 bar a

H-donor

30 bar a

6 bar6 bar

a reductive amination

Table A. Successful catalyst systems for selected substrate classes.


Temperatures are usually between room temperature and 50◦ with a varyingeffect on enantioselectivity. Catalyst loadings vary greatly, depending on all com-ponents of the reaction system. Of special importance is the purity of the startingmaterial. Impurities such as traces of amines (from the preparation of the C=Nfunction), acid, or anions can have a strong negative effect on catalytic activity,and sometimes also on enantioselectivity.

Many of the most active ligands are commercially available (indicated by thepound (#) symbol in Chart 1 of the Tabular Survey) in small quantities fromAldrich and Strem, and in larger quantities from ChiralQuest, Dow, JohnsonMatthey, Solvias, or Takasago. Most diphosphines should be handled with care,especially ligands with alkylphosphino groups, which are very air-sensitive. If ahydrogenation reaction is carried out using an in situ approach, either Schlenktechniques or a glove box are recommended. An alternative is to use the pre-formed complexes, which are also available with selected ligands and are usuallyless air-sensitive.

Preparative reactions at normal pressure can be carried out using two-neckedround-bottom flasks with a magnetic stirrer. The dihydrogen can be providedeither from a dihydrogen-filled balloon or a gas burette that allows measuring thedihydrogen consumption. Pressures up to 4 bar and measurement of dihydrogenuptake can be handled with the well-known and reliable Parr Shaker, supplied byLabeq.192 However, temperature control with this apparatus is poor, and pricesare on the order of $3,000.

For higher pressures, the construction of special hydrogenation stations withthe necessary safety installations (rupture disc, expansion vessel, reinforced cubi-cle, etc.) is recommended. Depending on the size and construction material ofthe autoclave, the safety installations and the accuracy of the measurement ofdihydrogen consumption, the price for such a system is between $20,000 and$100,000. Suppliers are Autoclave Engineers,193 Buchi,194 and others. We wouldalso strongly recommend consulting colleagues who have practical experiencewith the setup and the operations of a hydrogenation laboratory.

EXPERIMENTAL PROCEDURES

NPPh2

O

HNPPh2

O

(R,SFc)-josiphos, [Rh(nbd)2]BF4, s/c 100

MeOH, 70 bar H2, 60°, 21 h

(>99% conv.) 99% ee

N -(1-Phenylethyl)diphenylphosphinamide [Enantioselective Hydrogena-tion of N -Alkylidendiphenylphosphinamides Using Rh-Diphosphine Cata-lysts].138 N -(1-phenylethyliden)diphenylphosphinamide (0.5 g, 1.55 mmol) wasdissolved in 7 mL of MeOH under argon. A catalyst solution was preparedby dissolving [Rh(nbd)2]BF4 (5.8 mg, 0.0155 mmol) and (R)-(1)-{[((S)-2-di-cyclohexylphosphino)ferrocenyl]ethyl}dicyclohexylphosphine ((R, SFc)-josiphos


(Cy/Cy)) (10.6 mg, 0.0173 mmol) in 8 mL of MeOH under argon. This solutionwas stirred for 15 minutes at room temperature. The substrate and the catalystsolutions were transferred via steel tubing into a 50-mL stainless steel auto-clave. The inert gas was then replaced by H2 (three cycles of vacuum/H2) to apressure of 70 bar, and the reaction temperature set to 60◦. After 21 hours, theheating was discontinued, the pressure was released and, once the reaction hadreached room temperature, the autoclave was opened. The conversion was deter-mined by GLC [DB-17, 30 m; temperature program: 60◦/1 minute to 220◦/15minutes, �T = 10◦/minute] as compared to a standard. The enantiomeric purityof the N -(1-phenylethyl)diphenylphosphinamide was determined by GLC afterderivatization with perfluorobutyric acid anhydride [Lipodex-D, 50 m; tempera-ture = 160◦, isotherm; carrier He (170 kPa)]. The conversion was determined tobe ≥99% with 99% ee (R).

[Rh((R)-Et-duphos)(cod)]OTf, s/c 588

i-PrOH, 0°, 4 bar H2, 12 hPh

NNHCOPh

Ph

HNNHCOPh

(91%) 92% ee

(S )-(–)-1-Phenyl-1(2-benzoylhydrazino)ethane [Asymmetric Hydrogena-tion of N -Acyl Hydrazones Using [Rh(Et-Duphos)(cod)]OTf Complexes].135

In a N2-filled dry box, a 100-mL Fisher Porter glass pressure vessel [avail-able from Andrews Glass Co., 3740 NW Boulevard, Vineland, NJ 08360; www.andrewsglass.com] was charged with a stirring bar, and acetophenone N -benzoyl-hydrazone (200 mg, 0.80 mmol) was added, followed by degassed 2-propanol(10 mL), and [Rh((R)-Et-duphos)(cod)]CF3SO3 (1 mg, 0.0014 mmol). The lineswere purged of air (six cycles of vacuum/H2), then the reaction mixture waspurged twice more using the same technique. The vessel was pressurized to 4bar of H2. The reaction was stirred at 0◦ until no further H2 uptake was observed(12 hours). The reaction was evaporated to dryness and the residue subjectedto chromatography on a short silica column (6 × 0.5 cm) using 50% EtOAcin hexane as eluent. The appropriate fractions were evaporated to yield the titlecompound as a colorless solid (182 mg, 91% yield). Chiral analysis (HPLC, Dai-cel column Chiralcel OJ, 10% i-PrOH in hexane, 40◦, 0.5 mL/minute) indicateda product of 92% ee: mp 75–76.5◦; [α]20

D = −163.6 (c 2.72, CHCl3); 1H NMR(300 MHz, CDCl3) δ 7.7 (m, 2H), 7.6–7.2 (m, 8H), 4.37 (q, J = 6.7 Hz, 1H),1.50 (d, J = 6.7 Hz, 3H). Anal. Calcd for C15H16N2O: C, 74.97; H, 6.71; N,11.66. Found: C, 74.81; H, 6.83; N, 11.61.

Ph

N [Ir(3)(cod)BARF], 4 Å MS, s/c 100

MTBE, 1 bar H2, −10°, 20 h

Ph

Ph

HNPh

(>99%) 93% ee

(R)-N -Phenyl-1-Phenylethylamine [Asymmetric Hydrogenation of N -Aryl Imines Using Ir-Phosphino Oxazoline Catalysts].41 A Schlenk tube was


charged with N -Phenyl(4-methylphenyl)ethylidene)amine (39 mg, 0.20 mmol),4 A molecular sieves (80 mg), and catalyst [Ir(3)(cod)]BARF (3.8 mg, 2.0 μmol).Then tert-butyl methyl ether (1 mL) was added, and the solution was stirred atroom temperature for 10 minutes. The mixture was cooled to −10◦, degassedusing three freeze/thaw cycles, then placed under a balloon of H2 (atmosphericpressure), stirring at −10◦ for 20 hours, after which time the conversion was com-plete (GC, see below). The solution was evaporated and the residue applied to asilica gel column, eluting with EtOAc/petroleum ether (1:12 v/v). The title com-pound was obtained in >99% yield as a colorless oil: [α]18

D − 37 (c 0.91, CH2Cl2);1H NMR (300 MHz, CDCl3) δ 7.39–7.06 (m, 7H), 6.64 (t, J = 7.2 Hz, 1H), 6.50(d, J = 7.5 Hz, 2H), 4.48 (dd, J = 13.5 and 6.6 Hz, 1H), 4.03 (bs, 1H), 1.51 (d,J = 6.9 Hz, 1H). Conversion was determined by GC using an HP-5 column (T= 100–220◦ at 5◦/minute); retention times = 14.77 minutes (product) and 15.22minutes (starting material). The ee was determined as 93% by HPLC [Chiral-cel OD-H column, hexane/i-PrOH (98:2), 1.0 mL/minute, λ 254 nm]; retentiontimes = 14.91 minutes (S), and 19.10 minutes (R).

Pd[(S)-SegPhos](CF3CO2)2, s/c 45

CF3CH2OH, 41 bar H2, rt, 20 hN S

PhO

OO HN S

PhO

OO

H

(99%) 93% ee

3-Phenoxymethyl-1,2-thiazolidine-1,1-dioxide [Asymmetric Hydrogenationof N -Sulfonyl Imines Using a Pd(diphosphine)(CF3CO2) Catalyst].129 (S)-Segphos (60.4 mg, 0.099 mmol) and Pd(CF3CO2)2 (29.9 mg, 0.09 mmol) wereplaced in a dried Schlenk tube under a N2 atmosphere, and degassed anhy-drous acetone (8 mL) was added. The mixture was stirred at room temperaturefor 2 hours. The solvent was removed under vacuum to give the catalyst. Thiscatalyst was transferred into a glove box filled with N2 and dissolved in drytrifluoroethanol (16 mL). The catalyst solution was added to 3-phenoxymethyl-1,2-thiazoline-1,1-dioxide (1.014 g, 4.50 mmol) and then the mixture was trans-ferred to an autoclave. The autoclave was pressurized to 41 bar with H2, andthe reaction was stirred at room temperature for 20 hours. After the releaseof H2, the autoclave was opened and the reaction mixture evaporated. Thecrude product was purified by chromatography on silica gel using petroleumether/EtOAc (1:1) as eluent, to yield the title compound (1.013 g, 99% yield,93% ee), [α]30

D = +14.1 (c 1.12, CHCl3). In order to improve the optical purity,this product was recrystallized from EtOH/water (3:2) to yield a white solid(738 mg, 72%, >99% ee). Enantiomeric excess was determined by HPLC [Chi-ralcel OD-H column, i-PrOH:hexane (20:80), 0.8 mL/minute, λ 254 nm]. 1HNMR (400 MHz, CDCl3) δ 7.28–7.33 (m, 2H), 7.00 (t, J = 7.4 Hz, 1H), 6.79(d, J = 7.9 Hz, 2H), 4.74 (br s, 1H), 3.99–4.07 (m, 3H), 3.15–3.26 (m, 2H),2.35–2.38 (m, 1H).


N

MeO

MeONH

MeO

MeO

HCO2H/NEt3, (cymene)Ru((S,S)-dpenTs)Cl, s/c 1000

MeCN, 28°, 12 h

(97%) 94% ee

(R)-6,7-Dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline [Transfer Hy-drogenation Using a Ruthenium Catalyst].91 Preparation of the Catalyst. Amixture of [(p-cymene)2RuCl2] (1.53 g, 2.5 mmol), (1S,2S)-N -p-toluenesulfo-nyl-1,2-diphenylethylenediamine (1.83 g, 5.0 mmol) and triethylamine (1.4 mL,10 mmol) in 2-propanol was heated at 80◦ for 1 hour. The orange solution wasconcentrated and the solid Ru complex collected by filtration. The crude materialwas washed with a small amount of water and dried under reduced pressure toafford [(cymene)Ru(dpenTs)Cl] (2.99 g, 94%).

Transfer hydrogenation. To a solution of 6,7-dimethoxy-1-methyl-3,4-dihy-droisoquinoline (4.10 g, 20 mmol) and the preformed ruthenium catalyst(12.7 mg, 0.02 mmol) in MeCN (40 mL), a formic acid/triethylamine (5:2)azeotropic mixture (10 mL) was added. The mixture was stirred at 28◦ for12 hours, made basic by addition of aqueous Na2CO3, and then extracted withEtOAc. The organic layer was washed with brine, dried over MgSO4, and concen-trated under reduced pressure. The crude product was purified by flash chromatog-raphy on silica gel using EtOAc/MeOH/NEt3 (92:5:3) as eluent to afford (R)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (4.02 g, 97%) in 94% eeas determined by HPLC [Daicel Chiralcel OD column (4.6 mm x 25 cm), hex-ane/isopropanol/diethylamine (90:10:0.1), 0.5 mL/minute]; retention times = 30.2minutes (R), 39.6 minutes (S). The identification was confirmed by optical rota-tion, the title compound having a rotation equal but opposite in sign comparedto that reported for the S-enantiomer.195

(ebthi)Ti(binol), s/c 10

THF, 140 bar,n-BuLi, PhSiH H2, 65°, 48 3, hN

Ph

NH

R

(74%) >98% ee

(R)-(+)-2-Phenylpyrrolidine [Hydrogenation of Endocyclic Imines with(Ebthi)Ti(binol)].34 To a dry Schlenk flask under argon was added (R,R, R)-(ebthi)Ti(binol) (50 mg, 0.084 mmol) and dry THF (10 mL). A solution of n-BuLi (130 μL, 0.168 mmol, 1.29 M in hexane) was added and after 2–3 minutesthe solution became green-brown. Phenylsilane (26 μL, 0.21 mmol) was addedand the solution turned dark brown. The mixture was moved to a glove boxand transferred to a Parr model 4565 autoclave containing a magnetic stirringbar. 2-Phenylpyrroline (122 mg, 0.84 mmol) was added, and the solution waspressurized to 140 bar with H2, and stirred for 48 hours at 65◦. The solventwas evaporated and the product was dissolved in Et2O, then extracted with1 M HCl solution. The aqueous phase was made basic and re-extracted with


Et2O. The Et2O layer was dried and evaporated, leaving the title compound asa pure liquid (92 mg, 74% yield): [α]22

D + 35 (c = 3.42, MeOH); 1H NMR(300 MHz, CDCl3) δ 7.38–7.31 (m, 4H), 7.29–7.20 (m, 1H), 4.11 (t, J =7.5 Hz), 3.25–3.17 (m, 1H), 3.05–2.97 (m, 1H), 2.21–2.13 (m, 1H), 2.01–1.70(m, 2H), 2.01 (br s, 1H), 1.73–1.61 (m, 1H). GC analysis (Cyclodex B col-umn from J&W Scientific) of the α-methoxy-α-(trifluoromethyl)phenylacetamidederivative indicated >98% ee.

TABULAR SURVEY

Chart 1 presents the structures of ligands and catalysts and the bold numbersthat are used to refer to them, or their associated acronyms or abbreviations.

Tables 1–7 list hydrogenation and transfer-hydrogenation reactions that haveappeared in the literature up to September 2007. When articles describe thedetailed optimization of a specific hydrogenation reaction under a variety ofconditions, only the optimal conditions are tabulated in this review. In entrieswhere a variety of effective (>90% ee) ligands are available, single contributionswhere the ee is <70% are not tabulated.

Entries within each table are arranged according to increasing carbon count ofthe substrate. The carbon count in Table 7, which covers reductive aminations,is that of the amine and the ketone combined.

The reaction conditions are given as follows:• Reducing agent (if not dihydrogen).• Ligand, metal precursor for in situ preparation; for preformed metal com-

plexes the following conventions have been used: π-bound ligands are infront of the metal, the chiral ligand and ligands that are removed (if any) fol-low in this order, and the coordinated anion is at the end. Non-coordinatinganions follow the complex set in [brackets].

• Substrate to catalyst ratio (s/c 100 corresponds to 1 mol% catalyst).• Solvent, additives (if any), hydrogen pressure (1 bar = 14.5 psig), temper-

ature, and reaction time.

In many publications product yields have not been determined, but rather it isstated that “full conversion” was obtained. In these cases, the conversion is givenas (100). Unreported percent conversions or yields are indicated by an em-dashin parentheses (—). If available, the absolute configuration of the products isgiven for the major enantiomer.

The following abbreviations (excluding those appearing in Chart 1) are usedin the tables:

BARF tetrakis[3,5-bis(trifluoromethyl)phenyl] boratecod 1,5-cyclooctadienecp* pentamethylcyclopentadienylC10mim 1-decyl-3-methylimidazoliumCTAB cetyltrimethylammonium bromide


cymene p-cymeneDCM dichloromethaneDMA 2,6-dimethylanilineDMPEG poly(ethylene glycol) dimethyletheremim ethyl methylimidazoliumMEA 2-methyl-6-ethylanilineMS molecular sievesnbd norbornadieneNp naphthylNps naphthylsulfonylPMP p-methoxyphenylPy pyridinyls/c substrate to catalyst ratioscCO2 supercritical CO2

TBABr tetrabutylammonium bromideTBAI tetrabutylammonium iodideTBDMS tert-butyldimethylsilylTBME tert-butyl methyl etherTf trifluoromethanesulfonylTFA trifluoroacetic acidTHF tetrahydrofuranTIPS tri-iso-propylsilylTMP 2,4,6-trimethylphenylTol p-tolyl, 4-methylphenylTs p-toluenesulfonylXyl 3,5-dimethylphenyl

CH

AR

T 1

. DE

SIG

NA

TIO

NS

FOR

LIG

AN

DS

AN

D C

AT

AL

YST

S

ZrC

l 2

N H

O

OO

H

14

1

O OP

O OH

R R

7a 7b 7c 7d 7e

R (Ph)

3Si

3,5-

(CF 3

) 2C

6H3

2,4,

6-(i

-Pr)

3C6H

2

9-ph

enan

thry

l

9-an

thry

l

N

5PPh 2 ON

O OP

O

t-B

u

t-B

u

P

Ph

MeO

10

6

N

N

O

Ph2P

(R)-

4

PPh 2

NS

O Ph CF 3

SO3–

8

PPh

t-B

uO H

(R)-

13

S

N

O

i-Pr

PPh 2

9

3PXyl

2

NO

Bn

(R)-

7

2

O O

12

PO

HO O

PN

OT

BD

MS

11

FePP

h 2

MeO N

O

i-Pr

Ir+(c

od)

PPh 2

47

(#)

com

mer

cial

ly a

vaila

ble

BnO

BnO

PPh 2

PPh 2

15

NH

CO

R

NH

CO

R

PPh 2

PPh 2

(S)-

16

CH

2C6H

3(B

nO) 2

-3,5

CH

2C6H

3(B

nO) 2

-3,5

R =

20(S

,SFc

)-19

(#)

O

PO

O P

18

OPP

h 2O

PPh 2

17

PPh

2PC

rO

CC

OC

O

23

N HN

H

O

Ph2P

O

PPh 2

(R,R

)-22

(#)

Ph Ph

O OP

O OH

(S)-

21

O

O NH

PAr 2

PAr 2 24

Ar

= 3

,5-(

t-B

u)2C

6H3

FePh

2PNO

t-B

u

N Ir HP Ph

2

H

P Ph2

H

OO

PPh

2,4-

Xyl

Xyl

-2,4

+

CH

AR

T 1

. DE

SIG

NA

TIO

NS

FOR

LIG

AN

DS

AN

D C

AT

AL

YST

S (C

onti

nued

)

48

NH

2

H2N

ande

n (#

)bd

pchO

PPh 2

OPP

h 2

bcpmN

(c-C

6H11

) 2P

CO

2t-B

u

PPh 2

(R)-

bina

p (#

)

(R)-

bino

l (#)

Y Y

Y PPh 2

OH

bdpp

bdpp

sulfPA

r 2PA

r 2

Ar

Ph 3-N

aO3S

C6H

4

ddpp

m

OOPP

h 2PP

h 2

HH

(R,R

)-da

ch (

#)

(R,R

)-da

chT

s

(R,R

)-dp

pach

NH

R1

NH

R2

PPh 2

PPh 2

MeO

MeO

(R)-

ClM

eO-b

iphe

p (#

)

Cl

Cl

Ph2P

PPh 2

cycp

hos

Ph2P

PPh 2

bicp

R1

H H PPh 2

bppm

N

PPh 2

PPh 2

Bn

(R,R

)-de

guph

os

N

Ph2P

CO

2t-B

u

PPh 2

R2

H SO2(

4-T

ol)

PPh 2

49

NH

RH

2N

YY

dpen

(#)

dpen

(1-N

ps)

dpen

SO2T

MP

dpen

Ts

(#)

dpen

Ts a

min

dpen

Ts s

ulf

dpen

Ts d

end

dpen

Ts i

mm

ob

dpen

Ts S

MF

R H SO2(

1-N

p)

SO2T

MP

SO2(

4-T

ol)

SO2(

4-T

ol)

SO2(

4-T

ol)

SO2

(CH

2)2S

i(O

) 3 /

SiO

2

SO2

NH

C(O

)

O O

OB

n

OB

n

O O

Bn

Bn

2

(S,S

)-dp

en

SO2

(CH

2)2S

i(O

) 3 /

SMF

SM

F =

sili

ceou

s m

esoc

ellu

lar

foam

Y H H H H NH

2

SO3N

a

H H H

(#)

com

mer

cial

ly a

vaila

ble

(R)-

hexa

phem

p (#

)(R

)-f-

bina

phan

e (#

)

PPh 2

PPh 2

Y =

PT

i

(ebt

hi)T

i

NPhPh PP

h 2PP

h 2

Me

dpam

pp(R

,R)-

duph

os (

#)

R =

Me,

Et

PR

R

P

R

R

Fe

Y Y

CH

AR

T 1

. DE

SIG

NA

TIO

NS

FOR

LIG

AN

DS

AN

D C

AT

AL

YST

S (C

onti

nued

)

50

mod

-dio

p(R

,SFc

)-jo

siph

os (

R/R

') (#

)(R

)-M

eO-b

iphe

p (#

)

OPP

h 2

(R)-

H8-

bina

po

(R)-

P-ph

os (

#)

Ar 2

PN

O

R2

phox

1

phox

2 (#

)

phox

3

PP

HH

t-B

u tang

phos

(#)

t-B

u

Ar

4-FC

6H4

Ph Ph

R2

t-B

u

i-Pr

i-Pr

t-B

u-bi

sP*

PP

t-B

ut-

Bu

OOH H

PAr 2

PAr 2

PPh 2

PPh 2

MeO

MeO

Ar

= 3

,5-M

e 2-4

-MeO

C6H

2

N N

PPh 2

PPh 2

OM

e

OM

e

MeO

MeO

(R)-

segp

hos

(#)

PPh 2

PPh 2

PPh 2

PPh 2

O O O O

(R)-

synp

hos

(#)

O O

(R)-

thio

bino

l

(R)-

Tol

-bin

ap (

#)

YY

Y SH P(4-

Tol

) 2

(R)-

mon

opho

s

OOP

NM

e 2

O O

OPP

h 2Fe

R2P

H

PR' 2

(#)

com

mer

cial

ly a

vaila

ble

R1

H H Me

R1

R1

51

37

C10

N

S

HN

S

MeO

MeO

(R,S

Fc)-

Josi

phos

(Ph

/Ph)

, [Ir

(cod

)Cl]

2,

s/c

200

, tol

uene

, AcO

H, T

BA

I, 3

0 ba

r, r

t

(100

)a , 78

NH

N

MeO

MeO

Ir((

S,S)

-bdp

p)(C

F 3C

O2)

3, s

/c 5

00,

TH

F/D

CM

, 40

bar,

0°,

145

h

(96)

a , 90

38

C12

C12

-19

R

N

OM

e

R

HN

OM

e

Han

tzsc

h es

ter,

(S)

-7c,

s/c

100

,

tol

uene

, 35°

48

R i-Pr

2-N

p

Tim

e

60 h

42 h

% C

onv.

, % e

e

(80)

, 90

(85)

, 84

16 37

C13

(R,S

Fc)

-Jos

ipho

s (R

1 /R2 ),

[Ir

(cod

)Cl]

2,

nea

t, 50

bar

, 50°

, 3-4

hN

HN

MeO

MeO

Et

Et

R1 /R

2

Ph/X

yl

Ph/4

-(n-

Pr) 2

NX

yl

s/c

2,00

0,00

0

100,

000

Add

itive

s

HI

AcO

H, T

BA

I

% e

e

80 87

23, [

Ir(c

od)C

l]2,

s/c

100

,

tol

uene

, 80

bar,

rt,

16 h

196

(S)-

I

(96)

a , 82

(S)-

I

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 1

. N-A

RY

L I

MIN

ES

(100

)a

52

NH

N

C14

[Ir(

6)(c

od)]

BA

RF,

s/c

50,

DC

M, 2

0 ba

r, r

t, 12

h

[Ir(

(S)-

phox

3)(c

od)]

BA

RF,

s/c

100

0,

DC

M, 1

00 b

ar, 4

5°, 5

h

[Ir(

(S)-

phox

2)(c

od)]

BA

RF,

s/c

700

,

scC

O2,

30

bar,

40°

, 20

h

8, s

/c 1

00, D

CM

, 50

bar,

50°

, 2 h

Ru(

(R,R

)-E

t-du

phos

)((R

,R)-

dach

)Cl 2

,

s/c

100

, t-B

uOH

, t-B

uOK

,

15

bar,

65°

, 20

h

[Ir(

9)(c

od)]

BA

RF,

s/c

100

0,

DC

M, 5

0 ba

r, r

t, 4

h

(100

)a , 90

45

(S)-

I

(R)-

I (

99)a , 8

950

(R)-

I (

100)

a , 81

49

(R)-

I (

100)

a , 86

51

(S)-

I (

92)a , 9

247

(R)-

I (

>99

)a , 86

52

11, [

Ir(c

od) 2

]BF 4

, s/c

100

,

DC

M, 8

0 ba

r, r

t, 17

h

(S)-

I (

—),

73

54C

14-1

5

N

R2

R1

HN

R2

R1

[Ir(

ddpp

m)(

cod)

]PF 6

, s/c

100

,

DC

M, 1

bar

, rt,

24 h

46

R1

H 4-F

4-M

eO

H

R2

H H H 4-M

eO

% C

onv.

, % e

e

(99)

, 84

(99)

, 80

(100

), 8

1

(100

), 9

4

[Ir(

(S)-

phox

2)(c

od)]

BA

RF,

s/c

500

,

[em

im]B

AR

F/sC

O2,

30

bar,

40°

, 22

h

(R)-

I (

>99

)a , 78

65

53

C14

-15

N

R2

R1

HN

R2

R1

10, [

Ir(c

od)C

l]2,

s/c

100

,

DC

M, 3

0 ba

r, r

t, 24

h

53

R2

H H H H H 4-M

eO

R1

H 4-M

e

4-M

eO

4-F

4-C

l

H

% e

e

84 72 85 79 82 81

[Ir(

(S,S

)-t-

Bu-

bisP

*)(c

od)]

BA

RF,

s/c

200

, DC

M, 1

bar

, rt

43C

14-1

6R

1

H 4-F

H H 4-M

eO

H H H 4-M

eO

R2

H H 4-F

4-C

l

H 4-M

eO

4-C

F 3

3,5-

(CF 3

) 2

4-M

eO

(91)

, 86

(92)

, 84

(99)

, 84

(99)

, 83

(98)

, 69

(93)

, 86

(95)

, 99

(97)

, 90

(98)

, 83

(R)-

I

Tim

e

1.5

h

1.5

h

12 h

12 h

2 h

2 h

12 h

12 h

2 h

[Ir(

5)(c

od)]

BA

RF,

s/c

200

,

DC

M, 2

0 ba

r, r

t

44(R

)-I

R1

H 4-F

2-M

e

4-M

eO

H H 4-C

l

4-M

eO

R2

H H H H 2-M

e

4-M

eO

4-M

eO

4-M

eO

% C

onv.

, %ee

(98)

, 90

(99)

, 89

(53)

, 83

(99)

, 86

(99)

, 80

(99)

, 89

(99)

, 89

(99)

, 86

Tim

e

2 h

2 h

12 h

3 h

3 h

1.5

h

1.5

h

2 h

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 1

. N-A

RY

L I

MIN

ES

(Con

tinu

ed)

(100

)a

(R)-

I

54

HN

R2

R1

R1

H 3-C

l

4-C

l

3-B

r

4-B

r

4-M

e

4-M

eO

3,4-

Me 2

H H H H H

R2

H H H H H H H H 4-C

l

3-B

r

4-B

r

3-M

e

4-M

e

% e

e

93 93 90 92 91 94 94 94 97 94 96 91 93

[Ir(

3)(c

od)]

BA

RF,

s/c

100

,

TB

ME

, 4 Å

MS,

1 b

ar, 1

0°, 2

0 h

41

f-B

inap

hane

, [Ir

(cod

)Cl]

2, s

/c 1

00,

DC

M, 7

0 ba

r, 1

4–44

h

39

R1

NR

2

R1

HN

R2

C14

-20

R1

Ph Ph Ph Ph 4-M

eOC

6H4

4-C

F 3C

6H4

Ph 1-N

p

R2

Ph 4-M

eOC

6H4

2-M

eOC

6H4

2,6-

Me 2

C6H

3

2,6-

Me 2

C6H

3

2,6-

Me 2

C6H

3

2-M

eO-6

-MeC

6H3

2-M

eO-6

-MeC

6H3A

dditi

ve

I 2 I 2 — — — — — —

Tem

p

–5°

–5°

rt rt rt rt rt rt

% C

onv.

, % e

e

(100

), 9

4

(100

), 9

5

(100

),81

(77)

, >99

(77)

, 98

(80)

, 99

(72)

, 98

(75)

, 96

(>99

.5)a

55

N

R1

48

C15

-16

R1

H 4-C

l

2-M

e

3-M

e

4-M

e

2-M

eO

3-M

eO

4-M

eO

Tim

e

4 h

4 h

4 h

4 h

4 h

6 h

4 h

4 h

% C

onv.

, % e

e

(99)

, 96

(99)

, 95

(99)

, 94

(99)

, 93

(99)

, 96

(99)

, 90

(99)

, 96

(99)

, 94

(S)-

I

42

OM

e

HN

R1

OM

e

4, [

Ir(c

od)C

l]2,

s/c

100

,

tol

uene

, I2,

20

bar,

rt

Han

tzsc

h es

ter,

(S)

-7c,

s/c

100

,

tol

uene

, 35°

R1

H 2-F

4-N

O2

2-M

e

4-M

e

2-M

eO

4-C

N

2,4-

Me 2

3,4-

(MeO

) 2

Tim

e

45 h

45 h

42 h

71 h

42 h

45 h

42 h

71 h

45 h

% C

onv.

, % e

e

(96)

, 88

(95)

, 85

(96)

, 80

(91)

, 93

(98)

, 88

(92)

, 80

(87)

, 80

(88)

, 92

(84)

, 89

R1

R2

N

R1

R2

HN

[Ir(

5)(c

od)]

BA

RF,

s/c

200

,

DC

M, 2

0 ba

r, r

t

197

R1

Ph 2-N

p

Tim

e

6 h

1 h

% C

onv.

, % e

e

(99)

, 78

(99)

, 91

C15

-17

C15

-18

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 1

. N-A

RY

L I

MIN

ES

(Con

tinu

ed)

R2

Et

Me

(S)-

I

56

C15

-19

R1

Ph Ph 1-N

p

2-N

p

Tim

e

12 h

4 h

6 h

4 h

% e

e

79 92 98 61

R3

2-M

eO

4-M

eO

4-M

eO

4-M

eO

42(S

)-4,

[Ir

(cod

)Cl]

2, s

/c 1

00,

tol

uene

, I2,

20

bar,

rt

NH

N

37

C15

-21

R1

4-C

F 3

H 2-F

3-B

r

2-M

e

2-M

eO

2-C

F 3

4-C

F 3

3,5-

Me 2

4-Ph

R2

H 4-M

eO

4-M

eO

4-M

eO

4-M

eO

4-M

eO

4-M

eO

4-M

eO

4-M

eO

4-M

eO

(58)

, 70

(76)

, 74

(82)

, 84

(62)

, 72

(74)

, 78

(76)

, 72

(46)

, 82

(71)

, 72

(91)

, 78

(71)

, 74

55H

antz

sch

este

r, 7

b, s

/c 5

,

C6H

6, 6

0°, 7

2 h

N

C16

HN

(R,S

Fc)-

Josi

phos

(Ph

/4-C

F 3C

6H4)

,

[Ir

(cod

)Cl]

2, s

/c 2

00, t

olue

ne,

AcO

H, T

BA

I, 3

0 ba

r, r

t

(100

)a , 96

R2

R2

R1

R1

R1

R2

N

R1

R2

HN

R3

R3

N

OM

e

HN

OM

e

424,

[Ir

(cod

)Cl]

2, s

/c 1

00,

tol

uene

, I2,

20

bar,

rt,

4 h

(99)

a , 91

C17

(99)

a

R2

Me

Et

Me

Me

57

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 1

. N-A

RY

L I

MIN

ES

(Con

tinu

ed)

NR

HN

R

C19

Ar

R1

N

R2

R2

R3

Ar

R1

HN

R2

R2

R3

[Ir(

2)(c

od)]

BA

RF,

s/c

100

,

tol

uene

/MeO

H, 1

0 ba

r, r

t, 2–

6 h

40

Ar

Ph Ph Ph Ph 3-FC

6H4

4-C

lC6H

4

2-M

eC6H

4

3-M

eC6H

4

4-C

F 3C

6H4

Ph Ph 4-M

eO2C

C6H

4

4-Ph

C6H

4

2-N

p

Ph

R1

Me

Me

Me

Me

Me

Me

Me

Me

Me

Et

n-C

5H11

Me

Me

Me

Bz(

CH

2)3

% e

e

84 85 94 94 93 92 94 93 89 94 95 94 92 93 99

C17

-24

(>99

.5)a

R3

H MeO

H MeO

MeO

MeO

MeO

MeO

MeO

MeO

MeO

MeO

MeO

MeO

MeO

R2

H H Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

a Thi

s va

lue

is th

e pe

rcen

t con

vers

ion.

b T

he s

tere

oche

mis

try

of th

e pr

oduc

t was

not

rep

orte

d in

the

orig

inal

ref

eren

ce.

[Ir(

5)(c

od)]

BA

RF,

s/c

200

,

DC

M, 2

0 ba

r, r

t, 2

h

44R

= H

(

99)a , 9

1b

55H

antz

sch

este

r, (

R)-

7b, s

/c 5

,

C6H

6, 6

0°, 7

2 h

I (

82),

70;

R

= P

MP

I

58

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 2

. N-A

LK

YL

IM

INE

S

R

NR

1

(Ebt

hi)T

i(bi

nol)

, TH

F, 6

5°, 8

–48

h34

R c-C

6H11

c-C

6H11

i-Pr

c-C

3H5

n-B

u

2-fu

ryl

Me 2

C=

CH

(CH

2)2

c-C

6H11

Ph c-C

6H11

4-M

eOC

6H4

2-N

p

R1

Me

n-Pr

Bn

Bn

Bn

Bn

Bn

Bn

Bn

4-M

eOB

n

Bn

Bn

s/c

20 20 10 20 10 20 10 20 50 20 20 20

Pres

sure

35 b

ar

140

bar

140

bar

140

bar

140

bar

140

bar

140

bar

140

bar

140

bar

140

bar

140

bar

140

bar

(85)

, 92

(70)

, 79

(66)

, 76

(91)

, 61

(68)

, 58

(70)

, 53

(64)

, 62

(93)

, 76

(93)

, 85

(92)

, 78

(86)

, 86

(82)

, 70

R

HN

R1

C9-

19

C11

91

YS

N

YS

HN

HC

O2H

/NE

t 3,

(cy

men

e)R

u((S

,S)-

dpen

SO2(

1-N

ps))

Cl,

s/c

100

, MeC

N, 2

8°

Y S SO2

Tim

e

2 h

5 h

(82)

, 85

(84)

, 88

Ph

Nn-

Bu

C12

Ru(

(R,R

)-dp

pach

)((R

,R)-

dach

)HC

l,

s/c

150

0, n

eat,

i-Pr

OK

, 3 b

ar, 2

0°, 6

0 h

(91)

a , 92b

63

Ph

HN

n-B

u

59

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 2

. N-A

LK

YL

IM

INE

S (C

onti

nued

)

NB

n

(AuC

l)2(

(R,R

)-M

e-du

phos

), s

/c 1

000,

EtO

H, 4

bar

, 20°

, ~1

h

(S)-

I (

100)

a , 75

71

[Ir(

6)(c

od)]

BA

RF,

s/c

50,

DC

M, 2

0 ba

r, r

t, 12

h

(S)-

I (

100)

a , 82

45

(R)-

I

C15

HN

Bn

50

NR

R1

HN

R

R1

[Ir(

(S)-

phox

3)(c

od)]

BA

RF,

s/c

25,

DC

M, 1

00 b

ar, r

t, 16

h

C12

-16

R n-B

u

Bn

Bn

R1

H H Me

% e

e

75 76 79

HC

O2H

/NE

t 3,

(cy

men

e)R

u((S

,S)-

dpen

SO2T

MP)

Cl,

s/c

200

, DC

M, 2

8°, 3

6 h

91(S

)-I

(72

), 7

7

(S)-

I (

>99

)a , 70–

7269

[Rh(

(R,R

)-bd

pch)

(cod

)]B

F 4, s

/c 5

00,

MeO

H, 5

0 ba

r, r

t

HC

O2N

a,

[(C

6Me 6

)Ru(

(R,R

)-da

chT

s)H

2O]B

F 4,

s/c

100

, H2O

, pH

9, 6

0°, 2

h

(100

)a , 91

64

1, s

/c 1

000,

tol

uene

, 150

bar

, 80°

, 12

h

(S)-

I (

95),

76

80

(S)-

Tol

-bin

ap, [

Ir(c

od)C

l]2,

s/c

100

,

C6H

6, B

nNH

2, 6

0 ba

r, 2

0°, 1

8 h

(R)-

I (

100)

a , 70

67

[Ir(

phox

2)(c

od)]

BA

RF,

s/c

500

,

[em

im]B

AR

F/sc

CO

2, 3

0 ba

r, 4

0°, 2

2 h

(R)-

1 (

>99

)a , 78

65

(100

)a

60

Ar

NB

n

12, [

Ir(c

od)C

l]2,

PPh

3, s

/c 1

00,

DC

M, 5

0 ba

r, r

t, 48

h

66

ArH

NB

n

C15

-17

Ar

Ph 4-C

lC6H

4

4-M

eOC

6H4

2-N

p

% C

onv.

, % e

e

(100

), 8

8

(99)

, 90

(99)

, 92

(100

), 9

2

C15

-16

NB

n

(R)-

I

HN

Bn

[Rh(

bdpp

)(nb

d)]C

lO4,

s/c

100

,

C6H

6/re

vers

e m

icel

les,

70

bar,

4–8

°, 21

–73

h

61

R H 4-M

eO

(96)

, 89

(95)

, 92

Cyc

phos

, [R

h(co

d)C

l]2,

s/c

100

,

C6H

6/M

eOH

, KI,

70

bar

62

R H 2-M

eO

4-M

eO

RR

Tim

e

90 h

120

h

144

h

(90)

, 79

(>99

), 7

1

(>99

), 9

1

(S)-

I

Bdp

p sul

f, [R

h(co

d)C

l]2,

s/c

100

,

H2O

/AcO

Et,

70 b

ar, r

t, 16

h

60

R H 2-M

eO

3-M

eO

4-M

eO

(94)

, 88–

96

(94)

, 91–

92

(93)

, 86–

89

(96)

, 86–

95

(R)-

I

N

R1

R

HN

R1

R

13, [

Ir(c

od)C

l]2,

s/c

100

,

tol

uene

, 25

bar

68

R H H MeO

H

R1

H Cl

H MeO

Tem

p

0° rt 0° rt

Tim

e

120

h

24 h

120

h

24 h

% C

onv.

, % e

e

(75)

, 82

(75)

, 77

(80)

, 83

(85)

, 76

Tem

p

20°

20°

–20°

61

R1

NB

nR

R1

NH

Bn

R

HC

O2H

/NE

t 3,

(cy

men

e)R

u((R

,R)-

dpen

Ts)

Cl,

s/c

200

, DC

M, r

t, 14

4 h

77

R H Me

Me

R1

Me

Me

ally

l

(70)

, 96

(82)

, 97

(67)

, 92

R

NB

n

C17

-20

C17

-18

R

NH

Bn

77

HC

O2H

/NE

t 3,

cp*

Ir((

S,S)

-dpe

nTs)

Cl,

s/c

500

, DC

M, r

t

77

NB

n

R

NH

Bn

RR al

lyl

(CH

2)2C

N

Ph

Tim

e

24 h

144

h

24 h

% c

is

93 96 >99

(75)

, 63

(60)

, 72

(55)

, 50

C16

-19

HC

O2H

/NE

t 3,

(cy

men

e)R

u((S

,S)-

dpen

(1-N

ps)C

l,

s/c

100

, DC

M, 2

8°, 6

h

91R

= H

(90

), 8

9

(R,R

)-I

HC

O2H

/NE

t 3,

(cy

men

e)R

u((R

,R)-

dpen

Ts)

Cl,

s/c

200

, DC

M, r

t, 12

0 h

(S,S

)-I

R =

Me

(45

), 5

0

C19

NB

nH

NB

n

HC

O2H

/NE

t 3,

(cy

men

e)R

u((S

,S)-

dpen

Ts)

Cl,

s/c

200

, DC

M, 2

0°, 6

h

90(8

0)a , 8

8b

a Thi

s va

lue

is th

e pe

rcen

t con

vers

ion.

b The

ste

reoc

hem

istr

y of

the

prod

uct w

as n

ot r

epor

ted

in th

e or

igin

al r

efer

ence

.

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 2

. N-A

LK

YL

IM

INE

S (C

onti

nued

)

62

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 3

. EN

DO

CY

CL

IC I

MIN

ES

Ir((

S)-b

inap

)HB

r(O

Bz)

, s/c

100

,

tol

uene

, 60

bar,

20°

, 18

h

(S)-

I (

38),

89

1, s

/c 1

000,

tol

uene

, 150

bar

, 80°

, 12

h

(S)-

I (

96),

98

80 81

(56)

, 78

(75)

, 65

(83)

, 72

C8-

9

14, [

(cym

ene)

RuC

l]2,

s/c

100

,

i-P

rOH

, i-P

rOK

, 0.1

–1 h

R Ph 3-T

ol

4-T

ol

82

ON

F

FOH N

F

F

(2S,

4S)-

bppm

, [Ir

(cod

)Cl]

2, s

/c 1

00,

C6H

6/M

eOH

, BiI

3, 4

0 ba

r, –

10°,

3 h

(96)

, 90

Han

tzsc

h es

ter,

(R

)-7a

, s/c

10,

C6H

6, 5

Å M

S, 4

0°

C9

174

104

(82)

, 97

(27)

, 79

R Me

Et

C9-

10

OH N

ORT

ime

7 h

50 h

ON

OR

N

R

N H

RT

emp

0° rt rt

C10

34N

PhN H

Ph(8

4), 9

9(E

bthi

)Ti(

bino

l), s

/c 1

00,

TH

F, 5

bar

, 65°

, 8–4

8 h

(S)-

I

63

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 3

. EN

DO

CY

CL

IC I

MIN

ES

(Con

tinu

ed)

(Ebt

hi)T

i(bi

nol)

, s/c

20,

TH

F, 5

bar

, 65°

, 8–4

8 h

N

(82)

, 99

O

O

N H

O

O34

C10

N

Ru(

(R,R

)-E

t-du

phos

)((R

,R)-

dach

)Cl 2

,

s/c

100

, i-P

rOH

, t-B

uOK

,

15

bar,

50–

65°,

20 h

NH

(80)

, 79

47

NR

N HR

(Ebt

hi)T

i(bi

nol)

, s/c

20,

TH

F, 8

–48

h

C10

-14

C10

R CH

2=C

H(C

H2)

4

(Z)-

EtC

H=

CH

(CH

2)5

(E)-

TM

SCH

=C

H(C

H2)

4

Me 2

C=

CH

(CH

2)2

n-C

6H13

HO

(CH

2)7

TB

DM

SO(C

H2)

4

34

I

(0),

—

(31–

42),

99

(65–

68),

99

(79)

, 99

(81)

, 98

(84)

, 99

(82)

, 99

II

(72)

, 99

(~15

), 9

9

(5–8

), 9

9

— — — —

(E)-

EtC

H=

CH

(CH

2)5

(~16

), 9

9

+N H

Rsa

t

Rsa

t = s

atur

ated

R g

roup

III

Tem

p

45°

45°

50°

50°

65°

65°

65°

Pres

sure

5 ba

r

5 ba

r

5 ba

r

5 ba

r

138

bar

5 ba

r

5 ba

r

64

C11

PhPh

(Ebt

hi)T

i(bi

nol)

, s/c

20,

TH

F, 3

5 ba

r, 6

5°, 8

–48

h

(78)

, 98

NN H

(S)-

Tol

-bin

ap, [

Ir(c

od)C

l]2,

s/c

100

,

C6H

6, B

nNH

2, 6

0 ba

r, 2

0°, 1

8 h

(R)-

I (

100)

a , 90

[Ir(

(S)-

bina

p)H

I 2] 2

, s/c

100

0,

tol

uene

, 60

bar,

20°

, 3 h

(S)-

I (

99),

91

34 67 81

(S)-

I

(Ebt

hi)T

i(th

iobi

nol)

, s/c

20,

TH

F, 5

bar

, 65°

, 8–4

8 h

I

(34)

, 99

(41)

, 98

(41)

, >95

79

II

(37)

, 99

(43)

, 98

(41)

, >95

C11

-16

R Ph TIP

SOC

H2

n-C

11H

23

III

NR

N HR

NR

+

65

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 3

. EN

DO

CY

CL

IC I

MIN

ES

(Con

tinu

ed)

C11

NN H

Bic

p, [

Ir(c

od)C

l]2,

s/c

100

,

DC

M, p

htha

limid

e,

70 b

ar, 0

°, 10

0 h

(100

)a , 95

(R,S

Fc)

-Jos

ipho

s (X

yl/X

yl),

[Ir

(cod

)Cl]

2,

s/c

250,

tolu

ene,

TFA

/TB

AI,

40 b

ar, 1

5°, 4

7 h

I (

100)

a , 95

Bcp

m, [

Ir(c

od)C

l]2,

s/c

100

,

C6H

6/M

eOH

, BiI

3, 1

00 b

ar, –

30°,

90 h

I (

92)a , 9

1

Ru(

(S)-

MeO

-bip

hep)

((S,

S)-a

nden

)Cl 2,

s/c

100,

i-Pr

OH

, t-B

uOK

, 15

bar,

50–6

5°, 1

8 h

I (

—),

88

(R,S

Fc)

-Jos

ipho

s (P

h/X

yl),

[Ir

(cod

)Cl]

2,

s/c

250,

(C

10m

im)B

F 4, T

FA/T

BA

I,

40 b

ar, 5

0°, 1

5 h

I (

100)

a , 86

[Ir(

bdpp

)HI 2

] 2, s

/c 5

00,

TH

F/D

CM

, 40

bar,

30°

, 43

h

I (1

00)a ,

80

I (

97)a , 8

515

, [Ir

(cod

)Cl]

2, s

/c 1

00,

DC

M,

I 2, 7

5 b

ar, 0

°, 24

h

84 37 87 47 85 88 83

I

Ph

34(E

bthi

)Ti(

bino

l), s

/c 2

0,

TH

F, 3

5 ba

r, 4

5°, 8

–48

h

(S)-

I (

71),

98

N

C12

PhN H

Ir((

S)-b

inap

)HB

r(O

Bz)

, s/c

100

,

tolu

ene,

60

bar,

20°

, 18

h(R

)-I

(99

),69

81

66

C12

-30

N H

N R

HC

O2N

a, (

R,R

)-dp

enT

s sul

f,

[(c

ymen

e)R

uCl 2

] 2, H

2O, C

TA

B, 2

8°(9

9), 9

9

(94)

, 99

(92)

, 99

(96)

, 98

(83)

, 99

99

HC

O2H

/NE

t 3,

(cy

men

e)R

u((S

,S)-

dpen

Ts)

Cl,

s/c

230

, MeC

N, r

t, 12

h

92

HC

O2H

/NE

t 3,

(cy

men

e)R

u((S

,S)-

dpen

Ts)

Cl,

s/c

200

, DM

F, 2

8°, 5

h

(86)

, 97

(83)

, 96

91

(S)-

I

HC

O2N

a, (

S,S)

-dpe

nTs a

min

,

[cp

*RhC

l 2] 2

, s/c

100

, H2O

, 28°

, 10

h

100

(R)-

I

R =

Me

(94

), 9

3

R Me

Et

i-Pr

n-C

6H13

Ph

(R)-

I

s/c

500

100

100

100

100

Tim

e

38 h

20 h

30 h

25 h

4 h

R Me

Ph

(84)

, >98

(79)

, >98

(85)

, >98

(79)

, >98

(84)

, >98

(70)

, >98

R Me

n-Pr

n-C

8H17

Me(

CH

2)16

(Z)-

Me(

CH

2)7C

H=

CH

C8H

16

(Z)-

Me(

CH

2)3(

CH

2CH

=C

H) 4

(CH

2)3

N H

NH

R

HC

O2H

/NE

t 3,

(cy

men

e)R

u((S

,S)-

dpen

Ts)

Cl,

s/c

25,

DM

F, r

t, 12

h

(89)

, 96

(96)

, 93

97

R (CH

2)3C

O2H

(CH

2)3C

H=

CH

2N H

NB

r

(R)-

I

N H

NH

R

Br

R

67

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 3

. EN

DO

CY

CL

IC I

MIN

ES

(Con

tinu

ed)

(Ebt

hi)T

i(bi

nol)

, s/c

20,

TH

F, 1

35 b

ar, 6

5°, 8

–48

h

(S)-

I (

82),

98

34

HC

O2H

/NE

t 3,

(cy

men

e)R

u((S

,S)-

dpen

Ts)

Cl,

s/c

100

0, M

eCN

, 28°

, 12

h

91

HC

O2N

a, (

S,S)

-dpe

nTs a

min

,

[C

p*R

hCl 2

] 2, s

/c 1

00, H

2O, 2

8°, 8

h

100

I (

95),

93b

HC

O2H

/NE

t 3,

(cy

men

e)R

u((S

,S)-

dpen

Ts S

MF)

Cl,

s/c

100

, DC

M, r

t, 12

h

199

(R)-

I (

95–1

00),

90–

91

HC

O2N

a,

[(c

ymen

e)R

u((R

,R)d

achT

s)H

2O]B

F 4,

s/c

100

, H2O

, pH

9, 6

0°, 2

–5 h

64(R

)-I

(10

0)a , 8

8

C12

N

MeO

MeO

(97)

, 94

NH

MeO

MeO

NH

MeO

MeO

R

R Me

Et

i-Pr

n-C

5H11

(95)

, 99

(93)

, 83

(96)

, 99

(94)

, 97

HC

O2H

/NE

t 3, c

p*R

h((S

,S)-

dpen

Ts)

Cl,

s/c

200

, DC

M, 2

0°, 0

.15

h

101

(R)-

I

C12

-16

HC

O2N

a, (

R,R

)-dp

enT

s sul

f,

[(c

ymen

e)R

uCl 2

] 2,

s/c

100

, H2O

, CT

AB

, 28°

99

R Me

Et

i-Pr

(97)

, 95

(68)

, 92

(90)

, 95

(S)-

I

C12

-14

Tim

e

10 h

25 h

15 h

N

R

MeO

MeO R

= M

e, E

t, i-

Pr, n

-C5H

11

(R)-

I

68

N H

N+

Cl–

HC

O2H

/NE

t 3,

(C

6H6)

Ru(

(S,S

)-dp

enT

s)C

l,

s/c

300

, MeC

N, 0

°, 10

hN H

N

H

(81)

, 79

107

N+

MeO

MeO

Cl–

N

MeO

MeO

H

(96)

, 92

106

HC

O2H

/NE

t 3,

(C

6H6)

Ru(

(S,S

)-dp

enT

s)C

l,

s/c

300

, MeC

N, 0

°, 10

h

C14

-16

Han

tzsc

h es

ter,

(R

)-7d

, s/c

100

,

CH

Cl 3

, rt

R1

H 4-C

l

H H H H

R2

Ph Ph 4-B

rC6H

4

4-M

eOC

6H4

3,4-

Me 2

C6H

3

2-th

ieny

l

(85)

, 98

(55)

, 96

(92)

, >99

(91)

, >99

(90)

, >99

(81)

, 90

105

ONR

2

O

R1

OH NR

2

O

R1

C14

Han

tzsc

h es

ter,

(R

)-7d

, s/c

100

,

CH

Cl 3

, rt

N S

Ar

C14

-20

H N S

Ar

Ar

3-B

rC6H

4

4-FC

6H4

4-B

rC6H

4

4-T

ol

4-Ph

C6H

4

2-N

p

(51)

, 94

(70)

, >99

(87)

, >99

(50)

, 96

(78)

, 94

(54)

, 93

105

69

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 3

. EN

DO

CY

CL

IC I

MIN

ES

(Con

tinu

ed)

(Ebt

hi)T

i(bi

nol)

, s/c

20,

TH

F, 3

5 ba

r, 6

5°, 8

–48

h

(83)

, 99

34

N O

H N O

R2

R1

H H H Cl

H H H

(90)

, 93

(95)

, 98

(93)

, 98

(93)

, >99

(95)

, >99

(92)

, 98

(94)

, 98

105

C14

-20

Han

tzsc

h es

ter,

(R

)-7d

, CH

Cl 3

R2

s/c

10,0

00

1000

1000

1000

1000

1000

1000

Tem

p

60°

rt rt rt rt rt rt

N H

N+C

l–

N+

MeO

MeO

Cl–

C15

(84)

, 90

(97)

, 87

N H

N

H

N

MeO

MeO

H10

7

107

HC

O2H

/NE

t 3,

(C

6H6)

Ru(

(S,S

)-dp

enT

s)C

l,

s/c

300

, MeC

N, 0

°, 10

h

HC

O2H

/NE

t 3,

(C

6H6)

Ru(

(S,S

)-dp

enT

s)C

l,

s/c

300

, MeC

N, 0

°, 10

h

NN B

nH

NN B

n

HC

O2H

/NE

t 3,

(C

6H6)

Ru(

(S,S

)-dp

enT

s)C

l, D

CM

, rt

93

NN

H

R2

R2

R2

R2

C17

-30

R1

R1

R2

H H 3-B

r

4-B

r

4-M

e

4-O

Me

4-Ph

R1

R1

70

R1

H Br

Br

NH

2

NO

2

N(C

H2O

Me)

Ms

NH

Ts

N(C

H2O

Me)

Ts

N(C

H2O

Me)

(1-N

ps)

N(B

n)T

s

Tim

e

8 h

13 h

13 h

16 h

13 h

84 h

72 h

84 h

84 h

72 h

% C

onv.

, % e

e

(99)

, 84

(41)

, 94

(67)

, 99

(66)

, 85

(20)

, 97

(53)

, 93

(11)

, 96

(58)

, >99

(53)

, 97

(76)

, >98

R2

MeO

H MeO

H MeO

MeO

MeO

MeO

MeO

MeO

s/c

200

100

150

50 100

14 14 14 14 14

(Ebt

hi)T

i(th

iobi

nol)

, s/c

20,

TH

F, 5

bar

, 65°

, 8–4

8 h

79

C16

(Ebt

hi)T

i(th

iobi

nol)

, s/c

20,

TH

F, 5

bar

, 65°

, 8–4

8 h

(44)

, 99

cis/

tran

s 3:

1

79(3

3), 4

9

(44)

, 98

(42)

, 96

NN B

nH

NN B

nN

N Bn

+

NPh

Ph

N HPh

Ph

NPh

Ph

+

N•H

3PO

4

PMP

[Ir(

cod)

((R

,SFc

)-jo

siph

os

(4-

MeO

Xyl

/t-B

u))]

BF 4

,

s/c

110

0, to

luen

e/H

2O, N

aOH

, TB

AB

r,

70

bar,

rt,

6 h

171

24, [

Ir(c

od)C

l]2,

s/c

100

,

TH

F/H

2O, 1

00 b

ar, r

t, 44

h

198

N•H

3PO

4

PMP

C17

(92)

, 81

N•H

2SO

4

PMP

N•H

2SO

4

PMP

(46)

, 86

71

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 3

. EN

DO

CY

CL

IC I

MIN

ES

(Con

tinu

ed)

N

R

NH

R

MeO

MeO

MeO

MeO

(R)-

Bin

ap, [

Ir(c

od)C

l]2,

s/c

200

,

tol

uene

/MeO

H, 1

00 b

ar, 2

–5°,

72 h

102

C17

-22

HC

O2H

/NE

t 3,

(ar

ene)

Ru(

(*,*

)-dp

enSO

2Ar)

Cl,

s/c

200

, DC

M o

r D

MF,

28°

, 8 h

R

Ph 3,4-

(MeO

) 2C

6H3

(3,4

-(M

eO) 2

C6H

3)C

H2

(3,4

-(M

eO) 2

C6H

3)(C

H2)

2

91

(99)

, 84

(R)

(>99

), 8

4 (S

)

(90)

, 95

(S)

(99)

, 92

(S)

Tim

e

8 h

12 h

7 h

12 h

aren

e

C6H

6

C6H

6

cym

ene

cym

ene

R

BnO

CH

2

BnO

(CH

2)3

(85)

, 86

(99)

, 89

Add

itive

F 4-p

htha

limid

e

para

bani

c ac

id

(S,S

)-B

cpm

, [Ir

(cod

)Cl]

2, s

/c 1

00,

tol

uene

/MeO

H, 1

00 b

ar, 2

–5°,

20–4

0 h

103

R

3,4-

(MeO

) 2C

6H3C

H2

3,4-

(MeO

) 2C

6H3(

CH

2)2

(E)-

3,4-

(MeO

) 2C

6H3C

H=

CH

% C

onv.

, % e

e

(84)

, 88

(89)

, 86

(79)

, 86

Add

itive

F 4-p

htha

limid

e

F 4-p

htha

limid

e

phth

alim

ide

Tim

e

20 h

72 h

HC

O2H

/NE

t 3,

(C

6H6)

Ru(

(S,S

)-dp

en(1

-Nps

))C

l,

s/c

150

, MeC

N, r

t, 16

h

(R)-

I

R =

3,4

,5-(

MeO

) 3C

6H2

(

—),

83

95

HC

O2H

/NE

t 3, (

C6H

6)R

u((S

,S)-

dpen

Ts)

Cl,

s/c

100

, MeC

N, r

t, 12

h

96(R

)-I

R

= (

3,4,

5-(M

eO) 3

C6H

2)(C

H2)

2

(92

), 9

9

N N

O(5

2), 6

218

0

HC

O2H

/NE

t 3,

(C

6H6)

Ru(

(R,R

)-dp

enT

s)C

l,

s/c

150

, MeC

N, r

t, 5

h

NH

N

O

O

C19

O

I

*,*

S,S

R,R

R,R

R,R

Ar

1-N

p

1-N

p

TM

P

TM

P

(S)-

I

(S)-

I

72

N

R2

NH

R2

MeO

MeO

HC

O2H

/NE

t 3,

(cy

men

e)R

u((S

,S)-

dpen

Ts)

Cl,

s/c

20–

40, D

MF,

20–

30°,

1.5–

2 h

94

C18

-32

R1

R1

N+

MeO

MeO

R

N

R

HC

O2N

a, (

R,R

)-L

, [R

uCl 2

(cym

ene)

] 2,

s/c

100

, H2O

, CT

AB

, 28°

(86)

, 90

(85)

, 90

(98)

, 98

(94)

, 95

99B

nB

n

Br–

C19

-24

L dpen

Ts s

ulf

dpen

Ts

dpen

Ts

dpen

Ts s

ulf

R Me

Me

Ph Ph

Tim

e

18 h

18 h

18 h

12 h

MeO

MeO

HC

O2N

a,

[(c

ymen

e)R

u(da

chT

s)H

2O]B

F 4,

s/c

100

, H2O

, pH

9, 6

0°, 2

–5 h

64

a Thi

s va

lue

is th

e pe

rcen

t con

vers

ion.

b The

ste

reoc

hem

istr

y of

the

prod

uct w

as n

ot r

epor

ted

in th

e or

igin

al r

efer

ence

.

(R)-

I R

1 = H

, R2 =

3,5

-(B

nO) 2

-4-M

eOC

6H3;

86%

ee

(100

)a

(R)-

I R

1 = M

eO, R

2 = 2

-NO

2-5-

ClC

6H3;

68%

ee

(R)-

I

73

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eH

eter

oam

ine

TA

BL

E 4

. HE

TE

RO

AR

OM

AT

IC S

UB

STR

AT

ES

NN

CO

2t-B

u

C9

NN

(R,S

Fc)-

Josi

phos

(Ph

/c-C

6H11

),

[R

h(nb

d)C

l]2,

s/c

50,

MeO

H, 5

0 ba

r, 7

0°, 2

0 h

(80)

a , 78

N HH N

CO

2t-B

u

110

20, s

/c 1

00,

MeO

H, 5

bar

, 100

°, 24

h

(54)

a , 90

Ru(

(S)-

hexa

phem

p)((

R,R

)-da

ch)C

l 2,

s/c

100

0, t-

BuO

H, t

-BuO

K,

30

bar,

50°

, 20

h

(R)-

I

(100

)a , 69

123

47

N HH N

(R)-

I

N

R2

R2

R1

N

R2

R2

R1

CO

2R3

ClC

O2R

3 , (S)

-seg

phos

,

[Ir

(cod

)Cl]

2, s

/c 1

00, T

HF,

Li 2

CO

3,

LiB

F 4, 4

2 ba

r, r

t, 12

–15

h

R1

Me

Et

n-B

u

Ph Me

R2

H H H H MeO

R3

Bn

Me

Me

Bn

Bn

(87)

, 83

(85)

, 62

(87)

, 60

(49)

, 83

(46)

, 65

122

NR

1

R2

N HR

1

R2

18, [

Ir(c

od)C

l]2,

s/c

200

,

tol

uene

, I2,

60

bar,

rt,

20 h

R1

Me

Me

Et

Me

n-B

u

HO

Me 2

CC

H2

R2

H F H Me

H H

% C

onv.

, % e

e

(>96

), 9

6

(>96

), 9

0

(>96

), 9

1

(>96

), 8

0

(>96

), 9

1

(>96

), 9

2

120

C10

-15

C10

-16

74

N HR

1

R2

C10

-19

R1

Me

Me

Et

Me

Me

n-Pr

n-B

u

HO

Me 2

CC

H2

Ph 1-H

O(C

6H10

)CH

2

R2

H F H Me

MeO

H H H H H

(98)

, 97

(96)

, 94

(97)

, 94

(98)

, 95

(90)

, 94

(99)

, 95

(99)

, 94

(98)

, 97

(98)

, 87

(98)

, 96

118

NR

Han

tzsc

h es

ter,

(R

)-7d

, s/c

50,

C6H

6, 6

0°

R ClC

H2

n-B

u

2-fu

ryl

n-C

5H11

Ph 2-FC

6H4

3-B

rC6H

4

2-T

ol

4-M

eOC

6H4

4-C

F 3C

6H4

PhC

H2C

H2

2,4-

Me 2

C6H

3

2-N

p

3,4-

(MeO

) 2C

6H3(

CH

2)2

Tim

e

12 h

12 h

12 h

12 h

12 h

30 h

18 h

48 h

12 h

30 h

12 h

60 h

12 h

12 h

(91)

, 88

(91)

, 87

(93)

, 91

(88)

, 90

(92)

, 97

(93)

, 98

(92)

, 98

(54)

, 91

(90)

, 98

(91)

, >99

(90)

, 90

(65)

, 97

(93)

, >99

(95)

, 90

113

N HR

(S)-

H8-

Bin

apo,

[Ir

(cod

)Cl]

2, s

/c 1

00,

sol

vent

, I2,

50

bar,

rt,

20 h

Solv

ent

DM

PEG

500/

hexa

ne

DM

PEG

500/

hexa

ne

DM

PEG

500/

hexa

ne

DM

PEG

500/

hexa

ne

TH

F

DM

PEG

500/

hexa

ne

DM

PEG

500/

hexa

ne

DM

PEG

500/

hexa

ne

DM

PEG

500/

hexa

ne

TH

F

75

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eH

eter

oam

ine

TA

BL

E 4

. HE

TE

RO

AR

OM

AT

IC S

UB

STR

AT

ES

(Con

tinu

ed)

C10

-23

NR

1

R2

N HR

1

R2

(S)-

I

121

R1

Me

Me

Me

Et

Me

n-C

5H11

1-H

OC

6H10

CH

2

Ph(C

H2)

2

3,4-

(MeO

) 2C

6H3(

CH

2)2

HO

Ph2C

CH

2

R2

H H F H Me

H H H H H

(>95

), 8

6

(95)

, 90

(86)

, 89

(95)

, 91

(93)

, 92

(94)

, 92

(82)

, 79

(92)

, 72

(82)

, 87

(89)

, 80

s/c

1000

100

100

100

100

100

100

100

100

100

(R)-

I

117

Han

tzsc

h es

ter,

(S)

-seg

phos

,

[Ir

(cod

)Cl]

2, s

/c 1

00, t

olue

ne/d

ioxa

ne,

I2,

40

bar,

rt,

42–7

9 h

R1

Me

Me

Et

Me

Me

n-B

u

n-C

5H11

Ph(C

H2)

2

3,4-

(OC

H2O

) 2C

6H3(

CH

2)2

3,4-

(MeO

) 2C

6H3(

CH

2)2

Ph2C

(OH

)CH

2

R2

H F H Me

MeO

H H H H H H

(86)

, 87

(90)

, 86

(92)

, 87

(82)

, 86

(43)

, 81

(98)

, 81

(94)

, 68

(88)

, 87

(87)

, 87

(92)

, 88

(76)

, 78

19, [

Ir(c

od)C

l]2,

tol

uene

, I2,

40

bar,

rt,

12–1

6 h

76

119

17, [

Ir(c

od)C

l]2,

s/c

100

,

TH

F or

DM

PEG

500/

hexa

ne,

I2,

50

bar,

rt,

18 h

R1

Me

Et

n-Pr

n-B

u

n-C

5H11

Me

Me

Me

Ph Ph(C

H2)

2

HO

Me 2

CC

H2

1-H

O-(

c-C

6H10

)CH

2

R2

H H H H H Me

MeO

F H H H H

% C

onv.

, % e

e

(100

), 9

2

(100

), 8

7

(100

), 9

1

(100

), 8

7

(100

), 9

0

(100

), 9

2

(66)

, 92

(100

), 8

9

(100

), 6

5

(100

), 8

3

(100

), 9

1

(100

), 9

3

116

R1

Me

Me

Et

Me

Me

n-Pr

HO

Me 2

CC

H2

1-H

OC

6H10

CH

2

Ph(C

H2)

2

3,4-

(MeO

) 2C

6H3(

CH

2)2

HO

Ph2C

CH

2

R2

H F H MeO

Me

H H H H H H

% C

onv.

, % e

e

(>95

), 9

0

(>95

), 8

7

(>95

), 8

9

(87)

, 89

(77)

, 87

(>95

), 8

9

(>95

), 9

2

(>95

), 9

3

(>95

), 8

4

(83)

, 82

(77)

, 76

16, [

Ir(c

od)C

l]2,

s/c

400

,

TH

F, I

2, 4

5 ba

r, r

t, 1.

5 h

N HR

1

R2

(R)-

I

77

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eH

eter

oam

ine

TA

BL

E 4

. HE

TE

RO

AR

OM

AT

IC S

UB

STR

AT

ES

(Con

tinu

ed)

C10

-23

115

NR

1

R2

(R)-

P-ph

os, [

Ir(c

od)C

l]2,

s/c

100

,

TH

F, I

2, 5

0 ba

r, r

t, 20

h

R1

Me

Me

Et

n-C

5H11

HO

Me 2

CC

H2

Ph(C

H2)

2

HO

Ph2C

CH

2

R2

H F H H H H H

(97)

, 91

(90)

, 90

(99)

, 92

(97)

, 91

(99)

, 91

(99)

, 90

(98)

, 90

N HR

1

R2

114

(R)-

MeO

-bip

hep,

[Ir

(cod

)Cl]

2, s

/c 1

00,

tol

uene

, I2,

50

bar,

rt,

18 h

R1

Me

HO

CH

2

Me

Et

Me

Me

n-Pr

i-Pr

AcO

CH

2

n-B

u

n-C

5H11

HO

Me 2

CC

H2

1-H

O-(

c-C

6H10

)CH

2

Ph(C

H2)

2

3,4-

(MeO

) 2C

6H3(

CH

2)2

HO

Ph2C

CH

2

R2

H H F H Me

MeO

H H H H H H H H H H

(94)

, 94

(83)

, 75

(88)

, 96

(88)

, 96

(91)

, 91

(89)

, 84

(92)

, 93

(92)

, 94

(90)

, 87

(86)

, 92

(92)

, 94

(87)

, 94

(89)

, 92

(94)

, 93

(86)

, 96

(94)

, 91

I

I

78

N

R2

R1

CO

2Bn

ClC

O2B

n, (

S)-s

egph

os,

[Ir

(cod

)Cl]

2, s

/c 1

00, T

HF,

Li 2

CO

3,

42

bar,

rt,

12–1

5 h

R1

Me

Et

n-Pr

n-B

u

n-C

5H11

Me

Me

Me

Ph Ph(C

H2)

2

3,4-

(MeO

) 2C

6H3(

CH

2)2

3-B

n-4-

MeO

C6H

3(C

H2)

2

R2

H H H H H Me

F MeO

H H H H

(90)

, 90

(85)

, 90

(80)

, 90

(88)

, 89

(91)

, 89

(90)

, 89

(83)

, 89

(92)

, 90

(41)

, 80

(86)

, 90

(80)

, 90

(88)

, 88

121

C10

-25

Han

tzsc

h es

ter,

(R

)-7e

, s/c

20,

C6H

6, 5

0°

R n-B

u

n-C

5H11

Ph(C

H2)

2

n-C

10H

21

(55)

, 84

(73)

, 90

(47)

, 86

(68)

, 89

111

N

NC

RN H

NC

R

C11

-17

79

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eH

eter

oam

ine

TA

BL

E 4

. HE

TE

RO

AR

OM

AT

IC S

UB

STR

AT

ES

(Con

tinu

ed)

C13

-22

N+

N−

BzR

1

N NH

Bz

R Me

Et

n-Pr

Me

Me

Bn

BnO

CH

2

BnO

(CH

2)2

(98)

a , 90

(96)

a , 83

(98)

, 84

(91)

a , 54

(92)

a , 84–

86

(97)

a , 58

(85)

a , 76

(88)

a , 88

>95

% c

is

57%

cis

[Ir(

(S)-

phox

1)(c

od)]

BA

RF,

s/c

50,

tol

uene

, I2,

27

bar,

rt,

6 h

112

C12

-18

Ir((

S)-s

ynph

os)H

I(O

Ac)

, s/c

200

,

TH

F, 5

0 ba

r, 3

0°, 4

5 h

(42)

, 64

81N

PhN H

Ph

C15

N

O

R

Han

tzsc

h es

ter,

(R

)-7e

, s/c

20,

C6H

6, 5

0°N H

O

R

R n-Pr

n-B

u

n-C

5H11

Ph(C

H2)

2

n-C

10H

21

(E,Z

)-C

H3(

CH

2)4C

H=

CH

(CH

2)2

(69)

, 89

(72)

, 91

(84)

, 91

(66)

, 92

(73)

, 92

(83)

, 87

111

R1

RR

R1

H H H 3-M

e

5-M

e

H H H

80

NR

N HR

(*)-

MeO

-bip

hep,

[Ir

(cod

)Cl]

2, s

/c 1

00,

tol

uene

, I2,

rt

(R)-

I

C18

-25

* R S

Pres

sure

50 b

ar

35 b

ar

Tim

e

18 h

12–1

5 h

R

OO(C

H2)

2

(CH

2)2

OB

nOM

e

(88)

, 93

(94)

, 96

114

200

Ena

nt.

(R)-

I

(S)-

I

a Thi

s va

lue

is th

e pe

rcen

t con

vers

ion.

81

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eSu

bstr

ate

TA

BL

E 5

. C=

N–Y

FU

NC

TIO

NS

NS O

2

R

HN

S O2

R

Pd((

S)-s

egph

os)(

CF 3

CO

2)2,

s/c

50,

CF 3

CH

2OH

, 4 Å

MS,

40

bar,

rt,

12 h

R Me

Ph n-C

6H13

PhO

CH

2

BnO

CH

2

4-C

F 3C

6H4O

CH

2

2-T

olO

CH

2

4-T

olO

CH

2

2-N

pOC

H2

%C

onv.

, % e

e

(91)

, 88

(93)

, 79

(99)

, 90

(99)

, 92

(93)

, 86

(99)

, 93

(95)

, 92

(93)

, 91

(97)

, 90

129

N

O2

S R

NH

O2

S R

C4-

14

C7

(R)-

Bin

ap, R

u(co

d)C

l 2, s

/c 1

00,

tol

uene

, NE

t 3, 4

bar

, 22°

, 12

h

R =

Me

(84

), 9

912

6

(R)-

I

Pd(t

angp

hos)

(CF 3

CO

2)2,

s/c

100

,

DC

M, 7

5 ba

r, 4

0°, 2

4 h

(R)-

I

R =

Me

(>

99)a , 9

412

8

Pd((

S)-s

egph

os)(

CF 3

CO

2)2,

s/c

50,

CF 3

CH

2OH

, 4 Å

MS,

40

bar,

rt,

12 h

129

R Me

n-B

u

Bn

(98)

, 92

(98)

, 90

(93)

, 88

(90)

, 96b

HC

O2H

/NE

t 3, (

R,R

)-dp

enT

s den

d,

[(c

ymen

e)R

uCl 2

] 2, s

/c 1

00, D

CM

, 28°

, 10

h

133

C8-

14

I

R =

n-B

u (

>99

), 9

3bH

CO

2H/N

Et 3

, dpe

nTs i

mm

ob,

[(c

ymen

e)R

uCl 2

] 2, s

/c 1

00, n

eat,

40°,

1.5

h

131

NS O

2

t-B

u

HN

S O2

t-B

u(S)-

I

(S)-

I

82

HC

O2H

/NE

t 3, c

p*R

h((*

,*)-

dpen

Ts)

Cl,

s/c

200,

DC

M, 2

0°, 0

.5 h

101

(R)-

I

(R)-

I

(S)-

I

(S)-

I

R Me

n-B

u

4-C

lC6H

4

Bn

(98)

, 68

(98)

, 67

(96)

, 81

(93)

, 68

HC

O2N

a, (

R,R

)-dp

enT

s sul

f,

[(c

ymen

e)R

uCl 2

] 2, s

/c 1

00, H

2O, C

TA

B, 2

8°99 13

2

(97)

, 65

(95)

, 94

R Me

n-B

u

Tim

e

6 h

10 h

HC

O2H

/NE

t 3, (

C6H

6)R

u((S

,S)-

dpen

Ts)

Cl,

s/c

200

, DC

M, r

t, 17

h

(—),

91

(—),

93

R t-B

u

Bn

I

C10

C9-

13

R1

Ph Ph 2-C

lC6H

4

3-C

lC6H

4

4-C

lC6H

4

4-B

rC6H

4

2-N

p

(78)

, 75

(45)

, 69

(17)

, 78

(68)

, 81

(82)

, 83

(76)

, 86

(64)

, 80

(S)-

Bin

ap, [

Ir(c

od)C

l]2,

s/c

100

,

TH

F, N

Bu 4

BH

4, 8

0 ba

r, 0

°, 18

h

125

N

N

O2

S

N

NH

O2

S

Ru(

(R)-

bina

p)((

R,R

)-dp

en)C

l 2, s

/c 2

500,

tol

uene

/i-Pr

OH

, i-P

rOK

, 4 b

ar, 6

0°, 6

h

(97)

, 87

172

R2

Bn

Me

Me

Me

Me

Me

Me

C11

-19

R

NN

HB

z

[Rh(

(R)-

Et-

duph

os)(

cod)

]OT

f, s

/c 5

00,

i-P

rOH

, 4 b

ar

134,

135

R

HN

NH

Bz

R Et

i-Pr

t-B

u

c-C

6H11

2-N

p

T

emp

–10°

–10°

20°

–15° 0°

Tim

e

36 h

36 h

48 h

36 h

12 h

% e

e

43 73 45 72 95

(*,*

)

R,R

R,R

R,R

S,S

R2

N+

Me R

1

O–

R2

NM

e R1

OH

(70–

90)

(R)-

I

(S)-

I

83

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eSu

bstr

ate

TA

BL

E 5

. C=

N–Y

FU

NC

TIO

NS

(Con

tinu

ed)

C12

-19

NT

s

R1

R2

HN

Ts

R1

R2

Pd((

S,S)

-tan

gpho

s)(C

F 3C

O2)

2, s

/c 1

00,

DC

M, 7

5 ba

r, 4

0°, 2

4 h

128

HN

OH

NO

HC

12

[Rh(

(S)-

bina

p)(n

bd)]

BF 4

, s/c

250

,

C6H

6/M

eOH

, 70

bar,

100

°, 5

dE

or

Z

E

(—

), 3

0

Z

(—

), 6

6

17

CO

2Et

NO

H

CO

2Et

NH

OH

[Ir(

dpam

pp)C

l]2,

s/c

100

,

C6H

6/M

eOH

, BI 3

or

n-B

u 4I,

48

bar,

rt,

46 h

124

(19–

22)a , 9

3

R1

c-C

3H5

t-B

u

Ph 4-FC

6H4

3-C

lC6H

4

4-C

lC6H

4

4-T

ol

3-M

eOC

6H4

4-M

eOC

6H4

1-N

p

2-N

p

Ph

R2

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Et

% e

e

75 98 99 99 >99 99 96 >99 99 99 >99 93

(>99

)a

84

C15

-18

Pd((

S)-s

ynph

os)(

CF 3

CO

2)2,

s/c

50,

CF 3

CH

2OH

, 4 Å

MS,

40

bar,

rt,

12 h

129

R1

t-B

u

Ph Ph 4-FC

6H4

4-M

eOC

6H4

3-M

eOC

6H4

2-M

eOC

6H4

C6H

4

C6H

4

2-N

p

R2

Me

Me

Et

Me

Me

Me

Me

Me

(94)

, 91

(84)

, 96

(90)

, 88

(98)

, 96

(98)

, 97

(86)

, 93

(84)

, 94

(95)

, 95

NN

HB

z

R

HN

NH

Bz

R[R

h((R

)-E

t-du

phos

)(co

d)]O

Tf,

s/c

500

–100

0,

i-P

rOH

, 4 b

ar

134,

135

R H 4-N

O2

4-B

r

4-M

eO

4-E

tOC

2

Tem

p

–10° 0° 0° 0° 0°

% e

e

95 97 96 88 96

Tim

e

24 h

12 h

12 h

12 h

12 h

C13

-19

Ru(

(R)-

bina

p)(O

Ac)

2, s

/c 2

0,

TH

F, 7

5 ba

r, 4

0°, 9

6 h

(48)

, 48

(82)

, 62

(80)

, 84

(86)

, 44

127

R1

R2

HN

Ts

R1

i-B

u

Ph Ph 2-N

p

R2

Me

Me

Et

Me

C16

-18

[Rh(

(R)-

Et-

duph

os)(

cod)

]OT

f, s

/c 5

00–1

000

i-P

rOH

, 4 b

ar

134,

135

Ar

Ph 4-M

eO

4-M

e 2N

Ph Ph Ph

Tem

p

–10°

20°

20°

0° –10°

20°

% e

e

85 91 92 96 84 51

R Et

Me

Me

Me

Bn

CF 3

Tim

e

24 h

2 h

2 h

12 h

24 h

2 h

R

NN

HC

OA

r

R

HN

NH

CO

Ar (70–

90)

(70–

90)

(R)-

I

(S)-

I

85

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eSu

bstr

ate

TA

BL

E 5

. C=

N–Y

FU

NC

TIO

NS

(Con

tinu

ed)

(R)-

I n

= 2

(

77),

82

Ru(

(R)-

bina

p)(O

Ac)

2, s

/c 2

0,

TH

F, 7

5 ba

r, 4

0°, 9

6 h

127

C16

-17

HN

Ts

Pd(t

angp

hos)

(CF 3

CO

2)2,

s/c

100

,

DC

M, 7

5 ba

r, 4

0°, 2

4 h

128

% e

e

98 94(

)n

( )

n

n 1 2

C16

-24

R1

NP(

R)22

P(R

)22

O

R1H

N

O

HC

O2H

/NE

t 3, c

p*M

(dpe

nTs)

Cl,

s/c

50,

MeC

N, r

t, 2–

3 h

90

R1

2-N

p

Ph n-C

6H13

2-N

p

R2

Et

Ph Ph Ph

% e

e

>90 86 95 >99

M Rh

Rh

Ir Rh

C18

PhP(

O)(

OE

t)2

NN

HC

OPh

[Rh(

Et-

duph

os)(

cod)

]OT

f, s

/c 5

00,

i-P

rOH

, 4 b

ar, –

10°,

48 h

132,

135

(70–

90),

90

Pd((

S)-s

egph

os)(

CF 3

CO

2)2,

s/c

50,

CF 3

CH

2OH

, 4 Å

MS,

70

bar,

rt,

8 h

130

(29)

, 87

(93)

, 87

(70)

, 93

PhP(

O)(

OE

t)2

HN

NH

CO

Ph

Ar

R

NPP

h 2

O

Ar

R

HN

PPh 2

OA

r

2-fu

ryl

Ph 2-N

p

C18

-25

R Me

Et

Me

NT

s

C20

-21

NPP

h 2

O

R1

HN

PPh 2

O

R1

(R,S

Fc)-

Josi

phos

(R

2 /R3 ),

[R

h(nb

d)2]

BF 4

,

MeO

H, 7

0 ba

r, 6

0°13

8

(R)-

I

(100

)a

(>99

)a

(R)-

I

86

R1

H 4-C

l

4-M

e

4-C

F 3

4-M

eO

R2 /R

3

c-C

6H11

/c-C

6H11

c-C

6H11

/t-B

u

c-C

6H11

/c-C

6H11

c-C

6H11

/c-C

6H11

c-C

6H11

/c-C

6H11

s/c

500

100

100

100

100

Tim

e

1 h

18–2

1 h

18–2

1 h

18–2

1 h

18–2

1 h

% C

onv.

, % e

e

(100

), 9

9

(93)

, 67

(100

), 9

7

(98)

, 93

(100

), 6

2

Pd((

S)-s

egph

os)(

CF 3

CO

2)2,

s/c

50,

CF 3

CH

2OH

, 4 Å

MS,

70

bar,

rt,

8 h

(R)-

IR H 4-

F

4-C

l

4-M

e

4-M

eO

3-M

eO

2-M

eO

(98)

, 96

(87)

, 94

(90)

, 94

(93)

, 97

(96)

, 96

(97)

, 96

(80)

, 99

130

a Thi

s va

lue

is th

e pe

rcen

t con

vers

ion.

b The

ste

reoc

hem

istr

y of

the

prod

uct w

as n

ot r

epor

ted

in th

e or

igin

al r

efer

ence

.

87

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 6

. α-

AN

D β

-CA

RB

OX

Y I

MIN

ES

C5

NH

2

CO

2Me

R

NH

2

CO

2Me

Ru(

(S)-

segp

hos)

(AcO

) 2, s

/c 1

00,

CF 3

CH

2OH

, 30

bar,

80°

, 15

h

(85)

, 96

NH

2

CO

2Me

147

C9-

11

(R,S

Fc)-

Josi

phos

(4-

CF 3

Ph/t-

Bu)

,

[R

h(co

d)C

l]2,

s/c

300

,

CF 3

CH

2OH

, 6 b

ar, 5

0°

R 3-Py

Ph 4-FC

6H4

4-M

eOC

6H4

Bn

Tim

e

24 h

6 h

11 h

11 h

11 h

(91)

, 96

(96)

, 96

(85)

, 96

(88)

, 95

(94)

, 93

R

NH

2

CO

2Me

146

R

O

CO

2Et

(Cym

ene)

Ru(

(R)-

ClM

eO-b

iphe

p)C

l 2,

s/c

100

, CF 3

CH

2OH

, 30

bar,

80°

, 16

h

R Me

Ph 3-C

lC6H

4

4-C

lC6H

4

4-FC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

C8-

14

R

NH

2

CO

2Et

(80)

, 96

(88)

, 98

(81)

, 98

(79)

, 99

(80)

, 96

(88)

, 96

(83)

, 98

151

+ N

H4O

Ac

(Boc

) 2O

, (R

,SFc

)-jo

siph

os (

Ph/t-

Bu)

,

[R

h(co

d)C

l]2,

s/c

30–

250,

MeO

H,

3–6

bar

, rt,

18–2

4 h

(85)

, 96

(75)

, 95

(62)

, 91

(57)

, 97

(93)

, 99

(84)

, 97

(98)

, 98

(99)

, 97

(88)

, 97

R

NH

2

CO

YR

NH

Boc

CO

Y

R Me

i-Pr

t-B

u

Ph Bn

Me

Ph Bn

2,4,

5-F 3

C6H

2

Y OM

e

OM

e

OM

e

OM

e

OM

e

NH

Ph

NH

Ph

NH

Ph

OM

e

149

C5-

16

88

R1

CO

2R2

NA

r

C11

-17

R1

CO

2R2

NH

Ar

[Rh(

tang

phos

)(nb

d)]S

bF6,

s/c

100

,

CF 3

CH

2OH

, 6 b

ar

145

R1

Me

Me

CF 3

Me

Me

Et

Me

Me

i-C

5H11

4-FC

6H4

Ph 4-T

ol

2-M

eOC

6H4

2-T

ol

R2

Me

Et

Et

Et

Et

Et

Et

Et

Et

Me

Et

Me

Me

Me

Ar

Ph Ph Ph 4-FC

6H4

3-B

rC6H

4

H 4-T

ol

3-T

ol

Ph Ph Ph Ph Ph Ph

Tem

p

50°

50°

50°

50°

50°

50°

50°

50°

50°

80°

80°

80°

80°

80°

Tim

e

18 h

18 h

18 h

18 h

18 h

18 h

18 h

18 h

18 h

24 h

24 h

24 h

24 h

24 h

% C

onv.

, % e

e

(100

), 9

1

(100

), 9

5

(48)

, 79

(100

), 9

6

(83)

, 96

(100

), 9

5

(78)

, 94

(88)

, 96

(100

), 9

0

(100

), 9

5

(100

), 9

2

(100

), 9

1

(100

), 9

0

(67)

, 79

RC

O2H

O[R

h((R

)-de

guph

os)(

cod)

]BF 4

,

MeO

H, 6

0 ba

r, r

t

BnN

H2

RC

O2H

NH

Bn

R Me

HO

2CC

H2

HO

2C(C

H2)

2

Me 2

CH

CH

2

Me 3

CC

H2

Bn

Ph(C

H2)

2

s/c

100

100

100

200

200

200

100

Tim

e

24 h

24 h

24 h

2 h

24 h

3 h

24 h

(43)

, 78

(38)

, 73

(19)

, 60

(94)

, 90

(99)

, 86

(99)

, 98

(80)

, 81

C10

-17

144

+

NH

2

CO

2Me

Ru(

(S)-

Tol

-bin

ap)(

AcO

) 2, s

/c 1

00,

CF 3

CH

2OH

, 30

bar,

50°

, 15

h

(54)

, 97

C10

NH

2

CO

2Me

147

89

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 6

. α-

AN

D β

-CA

RB

OX

Y I

MIN

ES

(Con

tinu

ed)

CO

2Et

NO

H

CO

2Et

NH

OH

[Ir(

dpam

pp)C

l]2,

s/c

100

,

C6H

6/M

eOH

, BI 3

or

TB

AI,

48

bar,

rt,

46 h

124

(19–

22)a , 9

3

C12

C12

-17

RC

O2E

t

NN

HC

OPh

RC

O2E

t

HN

NH

CO

Ph

[Rh(

(R)-

Et-

duph

os)(

cod)

]OT

f, s

/c 5

00,

i-P

rOH

, 4 b

ar, 0

°, 36

h

134,

135

R Me

Et

n-Pr

n-C

6H13

Ph

% e

e

89

91 90 83 91

C12

-19

R1

N

R2

R1H

N

R2

Han

tzsc

h es

ter,

(S)

-21,

s/c

20,

tol

uene

, 19–

22 h

141

R1

Me

n-C

6H13

Ph Ph Ph 4-C

lC6H

4

4-B

rC6H

4

3,5-

F 2C

6H3

4-C

F 3C

6H4

4-T

ol

4-M

eOC

6H4

Ph(C

H2)

2

R2

OM

e

OM

e

H OM

e

OM

e

OM

e

OM

e

OM

e

OM

e

OM

e

OM

e

OM

e

Tem

p

rt rt 50°

50°

50°

50°

50°

50°

50°

50°

50°

rt

(88)

, 99

(S)

(90)

, 96b

(94)

, 95b

(99)

, 98

(R)

(93)

, 96b

(95)

, 98b

(93)

, 98b

(95)

, 98b

(98)

, 96b

(98)

, 96b

(96)

, 94b

(85)

, 98b

R3

Et

Et

Et

Me

Et

Et

Et

Et

Et

Et

Et

Et

CO

2R3

CO

2R3

(70–

90)

90

R

NH

2

CO

NH

PhR

NH

2

CO

NH

Ph14

6

C14

-15

(R,S

Fc)-

Josi

phos

(Ph

/t-B

u), [

Rh(

cod)

Cl]

2,

s/c

300

, MeO

H, 6

bar

, 50°

, 8 h

R Ph 4-FC

6H4

4-M

eO6H

4

Bn

(75)

, 96

(74)

, 96

(82)

, 96

(94)

, 97

Ar

NH

2

N

O

N

NN CF 3

169

C16

(R,S

Fc)-

Josi

phos

(Ph

/t-B

u), [

Rh(

cod)

Cl]

2,

s/c

350

, CF 3

CH

2OH

, 6 b

ar, 5

0°, 7

hA

r

NH

2

N

O

N

NN CF 3

(95)

a , 94

R1

c-C

6H11

Ph 2-FC

6H4

3-FC

6H4

4-FC

6H4

4-C

lC6H

4

4-B

rC6H

4

2-M

eOC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

Ph 4-T

ol

3-O

2N

C6H

4

2-N

p

1-N

p

R2

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Et

Me

Me

Me

Me

% C

onv.

, % e

e

(85)

, 94

(99)

, 95

(99)

, 91

(95)

, 94

(95)

, 93

(99)

, 92

(95)

, 92

(95)

, 95

(99)

, 93

(95)

, 93

(>95

), 8

4

(99)

, 93

(99)

, 93

(99)

, 90

(95)

, 91

R1

CO

2R2

N

OM

e

R1

CO

2R2

HN

OM

eC

16-2

0

[Rh(

tang

phos

)(co

d)]B

F 4, s

/c 1

00,

DC

M, 5

0 ba

r, 5

0°, 2

4 h

139

R1

CF 3

CF 3

CC

lF2

CF 3

n-C

7F15

R2

Et

t-B

u

t-B

u

Bn

Bn

(>99

), 8

8

(92)

, 85

(69)

, 81

(95)

, 84

(98)

, 61

(R)-

Bin

ap, P

d(C

F 3C

O2)

2, s

/c 2

5,

CF 3

CH

2OH

, 100

bar

, rt,

24 h

140

C12

-23

R1

CO

2R2

N

OM

e

R1

CO

2R2

HN

OM

e

Ar

= 2

,4,5

-F3C

6H2

91

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eIm

ine

TA

BL

E 6

. α-

AN

D β

-CA

RB

OX

Y I

MIN

ES

(Con

tinu

ed)

R thie

nyl

Ph Ph c-C

6H11

4-B

rC6H

4

4-C

lC6H

4

4-FC

6H4

Ph Ph 3-M

eC6H

4

4-M

eC6H

4

4-M

eOC

6H4

2-N

p

Ph

Y i-Pr

O

EtO

i-Pr

O

i-Pr

O

i-Pr

O

i-Pr

O

i-Pr

O

t-B

uO

t-B

uNH

i-Pr

O

i-Pr

O

i-Pr

O

i-Pr

O

BnO

(78)

, 84

(88)

, 92

(87)

, 97

(46)

, 88

(92)

, 97

(95)

, 98

(82)

, 97

(78)

, 98

(85)

, 96

(89)

, 98

(90)

, 98

(94)

, 97

(93)

, 98

(86)

, 95

RC

OY

N

OM

e

RC

OY

HN

OM

e

C16

-22

Han

tzsc

h es

ter,

(S)

-7e,

s/c

100

,

tol

uene

, 60°

, 48

h

142

a Thi

s va

lue

is th

e pe

rcen

t con

vers

ion.

b The

ste

reoc

hem

istr

y of

the

prod

uct w

as n

ot r

epor

ted

in th

e or

igin

al r

efer

ence

.

92

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eK

eton

e

TA

BL

E 7

. RE

DU

CT

IVE

AM

INA

TIO

N

Am

ine

R1

O

NH

3R

2

1. H

CO

2NH

4, R

u((R

)-T

ol-b

inap

)Cl 2

,

s/c

100

, MeO

H, 8

5°2.

HC

l, E

tOH

, ref

lux

R1

NH

2

R2

R2

H 4-C

l

4-B

r

4-N

O2

3-M

e

4-M

e

4-M

eO

H

R1

Me

Me

Me

Me

Me

Me

Me

Et

Tim

e

20 h

24 h

48 h

48 h

24 h

21 h

25 h

21 h

(92)

, 95

(93)

, 92

(56)

, 91

(92)

, 95

(74)

, 89

(93)

, 93

(83)

, 95

(89)

, 95

C10

-11

150

O

HC

O2H

/NE

t 3,

(cy

men

e)R

u((S

,S)-

dpen

Ts)

Cl,

s/c

200

, DC

M, r

t, 18

4 h

(77)

, 90–

92%

cis

77N H

C10

NH

2

RC

O2H

O[R

h((R

)-de

guph

os)(

nbd)

]BF 4

,

MeO

H, 6

0 ba

r, r

t

BnN

H2

RC

O2H

NH

Bn

R Me

HO

2CC

H2

HO

2C(C

H2)

2

Me 2

CH

CH

2

Me 3

CC

H2

Bn

Ph(C

H2)

2

s/c

100

100

100

200

200

200

100

Tim

e

24 h

24 h

24 h

2 h

24 h

3 h

24 h

(43)

, 78

(38)

, 73

(19)

, 60

(99)

, 90

(94)

, 86

(99)

, 98

(80)

, 81

C10

-17

144

R

O

CO

2Et

(Cym

ene)

Ru(

(R)-

ClM

eO-b

iphe

p)C

l 2,

s/c

100

, CF 3

CH

2OH

, 30

bar,

80°

, 16

h

R Me

Ph 3-C

lC6H

4

4-C

lC6H

4

4-FC

6H4

3-M

eOC

6H4

4-M

eOC

6H4

C8-

14

R

NH

2

CO

2Et

(80)

, 96

(88)

, 98

(81)

, 98

(79)

, 99

(80)

, 96

(88)

, 96

(83)

, 98

151

NH

4OA

c

93

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eK

eton

e

TA

BL

E 7

. RE

DU

CT

IVE

AM

INA

TIO

N (

Con

tinu

ed)

Am

ine

H2N

R3

R1

R2

OH

antz

sch

este

r, (

R)-

7a, s

/c 1

0,

C6H

6, 5

Å M

S

R1

Et

CH

2=C

H(C

H2)

2

Ph Ph n-C

6H13

c-C

6H11

Ph Ph Ph Ph 2-FC

6H4

3-FC

6H4

4-FC

6H4

4-C

lC6H

4

4-O

2NC

6H4

4-M

eC6H

4

4-M

eOC

6H4

Ph(C

H2)

2

4-E

tCO

C6H

4

BzO

CH

2

2-N

p

R2

Me

Me

Me

CH

2F

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

R3

MeO

MeO

H MeO

MeO

MeO

CF 3

H CF 3

MeO

MeO

MeO

MeO

MeO

MeO

MeO

MeO

MeO

MeO

MeO

MeO

Tem

p

40°

40°

50°

5° 40°

50°

40°

50°

50°

50°

50°

50°

50°

50°

50°

50°

50°

40°

50°

40°

50°

Tim

e

72 h

96 h

24 h

7 h

96 h

96 h

24 h

24–7

2 h

24–7

2 h

24–7

2 h

24–7

2 h

24–7

2 h

24–7

2 h

24–7

2 h

24–7

2 h

24–7

2 h

24–7

2 h

72 h

24–7

2 h

96 h

72 h

(71)

, 83

(60)

, 90

(73)

, 93

(70)

, 88

(72)

, 91

(49)

, 86

(55)

, 95

(73)

, 93

(55)

, 95

(87)

, 94

(60)

, 83

(81)

, 95

(75)

, 94

(75)

, 95

(71)

, 95

(79)

, 91

(77)

, 90

(75)

, 94

(85)

, 96

(72)

, 81

(73)

, 96

104

HN

R3

R1

R2

C11

-19

94

R

IN

H2

R

HN

O

H N

C13

-15

R H H 4-N

H2

3-M

e

4-M

e

4-M

eCO

4-E

t

L Me-

duph

os

22 22 Me-

duph

os

Me-

duph

os

22 Me-

duph

os

(31)

, >99

b

(49)

, 98b

(45)

, 90

b

(43)

, 93b

(45)

, 92b

(44)

, >99

b

(46)

, 94b

155

L, P

d 2db

a 3, s

/c 2

5,

NE

t 3, 4

Å M

S, 7

bar

H2,

55

bar

CO

, 120

°, 24

–42

h

H2N

O

MeO

(R,S

Fc)-

Josi

phos

(Ph

/Xyl

),

[Ir

(cod

)Cl]

2, s

/c 1

0,00

0,

C6H

12, C

F 3C

O2H

, TB

AI,

80

bar,

50°

, 16

hE

t

C13

HN

Et

MeO

(99)

a , 78

153

H2N

OM

e

R1

R2

O(S

,S)-

f-B

inap

hane

, [Ir

(cod

)Cl]

2,

s/c

100

, DC

M, I

2, T

i(i-

PrO

) 4,

70

bar,

rt,

10 h

152

HN

OM

e

R2

R1

R1

2-fu

ryl

Ph Ph

R2

Me

Et

n-B

u

(>99

), 9

2

(>99

), 8

5

(>99

), 7

9

C13

-18

+

CO

HC

O2H

/NE

t 3,

(cy

men

e)R

u((R

,R)-

dpen

Ts)

Cl,

s/c

200

, DC

M, r

t, 14

4 h

77

C12

-13

OR

HN

R

R H Me

(55)

, 90

(60)

, >98

NH

2

95

Ref

s.C

ondi

tions

Prod

uct(

s) a

nd Y

ield

(s)

(%),

% e

eK

eton

e

TA

BL

E 7

. RE

DU

CT

IVE

AM

INA

TIO

N (

Con

tinu

ed)

Am

ine

Y

O

OR

1

H2N

OR

2

Han

tzsc

h es

ter,

(R

)-7c

, s/c

10,

cyc

lohe

xane

, 5 Å

MS,

50°

, 72

h

154

YR

1

HN

OR

2

R1

Me

Me

Me

i-Pr

n-B

u

i-B

u

Bn

Ph(C

H2)

2

(c-C

5H9)

CH

2

(c-C

6H11

)CH

2

(c-C

6H11

)(C

H2)

2

2-N

p

R2

Et

Et

Et

Me

Et

Et

Et

Et

Et

Me

Et

Et

Y O S CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

CH

2

(72)

, 92

(35)

, 90

(88)

, 84

(76)

, 92

(75)

, 90

(79)

, 96

(77)

, 86

(82)

, 96

(72)

, 96

(89)

, 96

(78)

, 92

(73)

, 82

cis/

tran

s

99 2 6 3 10 12 6 24 24 19 4 2

C14

-24 A

rE

t

O

Ar

Et

NH

2

(69)

, 86

(91)

, 95

Ar

1-N

p

2-N

p

150

C15

NH

3

1. H

CO

2NH

4, R

u((R

)-T

ol-b

inap

)Cl 2

,

s/c

100

, MeO

H, 8

5°2.

HC

l, E

tOH

, ref

lux

H2N

O

SNH

NSN

Han

tzsc

h es

ter,

(R

)-7a

, s/c

10,

C6H

6, 5

Å M

S, 5

0°, 7

2 h

104

(70)

, 91

96

Han

tzsc

h es

ter,

(R

)-7a

, s/c

10,

C6H

6, 5

Å M

S, 5

0°, 7

2 h

104

H2N

OM

eO

HN

OM

eC

16

(75)

, 85

H2N

R

OM

eO

R

HN

OM

e

C15

-16

(S,S

)-f-

Bin

apha

ne, [

Ir(c

od)C

l]2,

s/c

100

,

DC

M, I

2, T

i(i-

PrO

) 4, 7

0 ba

r, r

t, 10

h

152

R H 4-F

4-C

l

4-B

r

2-M

e

3-M

e

4-M

e

4-M

eO

% e

e

94 93 92 94 44 89 96 95

(>99

)

Han

tzsc

h es

ter,

(R

)-7a

, s/c

10,

C6H

6, 5

Å M

S, 5

0°, 7

2 h

104

C20

OO

H2N

HN

O

H2N

R

ONT

s

HN

R

NTs

C23

(92)

, 91

R Ph n-C

6H13

(90)

, 93

(75)

, 90

Han

tzsc

h es

ter,

(R

)-7a

, s/c

10,

C6H

6, 5

Å M

S, 5

0°, 7

2 h

104

a Thi

s va

lue

is th

e pe

rcen

t con

vers

ion.

b The

ste

reoc

hem

istr

y of

the

prod

uct w

as n

ot r

epor

ted

in th

e or

igin

al r

efer

ence

.

97


REFERENCES

1 Nakamura, Y. Bull. Chem. Soc. Jpn. 1941, 16, 367.2 For an overview on chiral heterogeneous catalysts see Blaser, H. U.; Muller. M. Stud. Surf. Sci.

Catal. 1991, 59, 73.3 Botteghi, C.; Bianchi, M.; Benedetti, E.; Matteoli, U. Chimia 1975, 29, 256.4 Kagan, H. B.; Langlois, N.; Dang, T. P. J. Organomet. Chem. 1975, 90, 353.5 Levi, A.; Modena, G.; Scorrano, G. Chem. Commun. 1975, 6.6 Vastag, S.; Bakos, J.; Toros, S.; Takach, N. E.; King, R. B.; Heil, B.; Marko, L. J. Mol. Catal.

1984, 22, 283.7 James, B. R. Catalysis Today 1997, 37, 209.8 Ohkuma, T.; Kitamura, M.; Noyori R. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.,

Wiley-VCH: Weinheim, 2000; p 1.9 Blaser, H. U.; Spindler F. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;

Yamamoto H., Eds., Springer: Berlin, 1999; p 247.10 Spindler, F.; Blaser H. U. In Transition Metals for Organic Synthesis, 2nd ed.; Bolm, C.; Beller,

M., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, p 113.11 Brunel, J. M. Recent Res. Devel. Org. Chem. 2003, 7, 155.12 Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029.13 Gladiali, S.; Alberico, E. In Transition Metals for Organic Synthesis, 2nd ed.; Bolm, C.; Beller,

M., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2, p 145.14 Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226.15 Yurovskaya, M. A.; Krachav, A. V. Tetrahedron: Asymmetry 1998, 9, 3331.16 Blaser, H. U.; Buser, H. P.; Coers, K.; Hanreich, R.; Jalett, H. P.; Jelsch, E.; Pugin, B.; Schneider,

H. D.; Spindler, F.; Wegmann, A. Chimia 1999, 53, 275.17 Chan, A. S. C.; Chen, C.-C.; Lin, C.-W.; Lin, Y-C.; Cheng, M.-C.; Peng, S.-M. Chem. Commun.

1995, 1767.18 Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.; Fischer, C.; Borner, A. Adv. Synth. Catal. 2004,

346, 561.19 Tararov, V. I.; Borner, A. Synlett 2005, 203.20 For a general review on reductive amination, see: Baxter, E.W.; Reitz, A.B. Org. React. 2002,

59, 1.21 Blaser, H.U.; Spindler, F. In Handbook of Homogeneous Hydrogenation; de Vries J.G.; Elsevier

C. J. Eds.; Wiley-VCH: Weinheim, 2007; p 1193.22 Roszkowski, P.; Czarnocki, Z. Mini-Reviews in Org. Chem. 2007, 4, 190.23 Glorius, F. Org. Biomol. Chem. 2005, 3, 4171.24 Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357.25 Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763.26 Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.27 Riant, O.; Mostefeı, N.; Courmarcel, J. Synthesis 2004, 2943.28 Nishiyama, H. In Transition Metals for Organic Synthesis, 2nd ed.; Bolm, C.; Beller, M., Eds.;

Wiley-VCH: Weinheim, 2004; Vol. 2, p 182.29 Bommarius, A.S. In Enzyme Catalysis in Organic Synthesis, 2nd ed.; Drauz, K.; Waldmann H.,

Eds.; Wiley-VCH, Weinheim, 2002; p 1047.30 Handbook of Homogeneous Hydrogenation; de Vries J. G.; Elsevier C. J. Eds.; Wiley-VCH:

Weinheim, 2007.31 Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: Weinheim, 2000.32 Drexler, H-J.; Baumann, W.; Spannenberg, A.; Fischer, C.; Heller, D. J. Organomet. Chem. 2001,

621, 89 and references cited therein.33 Spindler, F.; Pugin, B.; Blaser, H. U. Angew. Chem., Int. Ed. Engl. 1990, 29, 558.34 Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8952.35 Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1992, 114, 7562.36 Blaser, H. U. Adv. Synth. Catal., 2002, 344, 17.37 Blaser, H. U.; Buser, H. P.; Hausel, R.; Jalett, H. P.; Spindler, F. J. Organomet. Chem. 2001,

621, 34.


38 Sablong, R.; Osborn, J. A. Tetrahedron: Asymmetry 1996, 7, 3059.39 Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425.40 Cheemala, M. N.; Knochel, P. Org. Lett. 2007, 9, 3089.41 Zhu, S.-F.; Xie, J.-B.; Zhang, Y.-Z.; Li, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 12886.42 Moessner, C.; Bolm, C. Angew. Chem., Int. Ed. 2005, 44, 7564.43 Imamoto, T.; Iwadate, N.; Yoshida, K. Org. Lett. 2006, 8, 2289.44 Trifonova, A.; Diesen, J. S.; Chapman, C. J.; Andersson, P. G. Org. Lett. 2004, 6, 3825.45 Blanc, C.; Agbossou-Niedercorn, F.; Nowogrocki, G. Tetrahedron: Asymmetry 2004, 15, 2159.46 Dervisi, A.; Carcedo, C.; Ooi, L-l. Adv. Synth. Catal. 2006, 348, 175.47 Cobley, C. J.; Henschke, J. P. Adv. Synth. Catal. 2003, 345, 195.48 Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005, 44, 7424.49 Kainz, S.; Brinkmann, A.; Leitner, W.; Pfaltz, A. J. Am. Chem. Soc. 1999, 121, 6421.50 Schnider, P.; Koch, G.; Pretot, R.; Wang, G.; Bohnen, F. M.; Kruger, C.; Pfaltz, A. Chem. Eur.

J. 1997, 3, 887.51 Maire, P.; Deblon, S.; Breher, F.; Geier, J.; Boehler, C.; Ruegger, H.; Schoenberg, H.; Gruetz-

macher, H. Chem. Eur. J. 2004, 10, 4198.52 Cozzi, P. G.; Menges, F.; Kaiser, S. Synlett 2003, 833.53 Vargas, S.; Rubio, M.; Suarez, A.; del Rio, D.; Alvarez, E.; Pizzano, A. Organometallics 2006,

25, 961.54 Murai, T.; Inaji, S.; Morishita, K.; Shibahara, F.; Tokunaga, M.; Obora, Y.; Tsuji, Y. Chem. Lett.

2006, 35, 1424.55 Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett. 2005, 7, 3781.56 Cahill, J. P.; Lightfoot, A. P.: Goddard, R.; Rust, J.; Guiry, P. J. Tetrahedron: Asymmetry 1998,

9, 4307.57 Guiu, E.; Munoz, B.; Castillon, S.; Claver, C. Adv. Synth. Catal. 2003, 345, 169.58 Guiu, E.; Claver, C.; Benet-Buchholz, J.; Castillon, S. Tetrahedron: Asymmetry 2004, 15, 3365.59 Bakos, J.; Orosz, A.; Heil, B.; Laghmari, M.; Lhoste, P.; Sinou, D. Chem. Commun. 1991, 1684.60 Lensink, C.; Rijnberg, E.; de Vries, J. G. J. Mol. Catal. A: Chem. 1997, 116, 199.61 Buriak, J. M.; Osborn, J. A. Organometallics 1996, 15, 3161.62 Kang, G.-J.; Cullen, W. R.; Fryzuk, M. D.; James B. R.; Kutney, J. P. Chem. Commun. 1988, 1466.63 Abdur-Rashid, K.; Lough, A. J.; Morris R. H. Organometallics 2001, 20, 1047.64 Canivet, J.; Suss-Fink, G. Green Chemistry 2007, 9, 391.65 Solinas, M.; Pfaltz, A.; Cozzi, P. G.; Leitner, W. J. Am. Chem. Soc. 2004, 126, 16142.66 Reetz, M. T.; Bondarev, O. Angew. Chem., Int. Ed. 2007, 46, 4523.67 Tani, K.; Onouchi, J.; Yamagata, T.; Kataoka, Y. Chem. Lett. 1995, 955.68 Jiang, X.-B.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.; Duchateau, A. L. L.; Andrien, J. G.

O.; Boogers, J. A. F.; de Vries, J. G. Org. Lett. 2003, 5, 1503.69 Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.; Holz, J.; Boerner, A. Tetrahedron: Asymmetry

1999, 10, 4009.70 Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11703.71 Gonzalez-Arellano, C.; Corma, A.; Iglesias, M.; Sanchez, F. Chem. Commun. 2005, 3451.72 Ezhova, M. B.; Patrick, B. O.; James, B. R.; Waller, F. J.; Ford, M. E. J. Mol. Catal. A: Chem.

2004, 224, 71.73 Margalef-Catala, R.; Claver, C.; Salagre, P.; Fernandez, E. Tetrahedron: Asymmetry 2000, 11,

1469.74 Okuda, J.; Verch, S.; Spaniol, T. P.; Stuermer, R. Chem. Ber. 1996, 129, 1429.75 Rethore, C.; Riobe, F.; Fourmigue, M.; Avarvari, N.; Suisse, I.; Agbossou-Niedercorn, F. Tetra-

hedron: Asymmetry 2007, 18, 1877.76 Fogg, D. E.; James, B. R.; Kilner, M. Inorg. Chim. Acta 1994, 222, 85.77 Ros, A.; Magriz, A.; Dietrich, H.; Ford, M.; Fernandez, R.; Lassaletta, J. M. Adv. Synth. Catal.

2005, 347, 1917.78 Willoughby, C. A.; Buchwald, S. L. J. Org. Chem. 1993, 58, 7627.79 Viso, A.; Lee, N. E.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 9373.80 Ringwald, M.; Sturmer, R.; Brintzinger, H. H. J. Am. Chem. Soc. 1999, 121, 1524.


81 Yamagata, T.; Tadaoka, H.; Nagata, M.; Hirao, T.; Kataoka, Y.; Ratovelomana, V.; Genet, J. P.;Mashima, K. Organometallics 2006, 25, 2505.

82 Roth, P.; Andersson, P. G.; Somfai, P. Chem. Commun. 2002, 1752.83 Chan, N. G. Y.; Osborn, J. A. J. Am. Chem. Soc. 1990, 112, 9400.84 Zhu, G.; Zhang, X. Tetrahedron: Asymmetry 1998, 9, 2415.85 Giernoth, R.; Krumm, M. S. Adv. Synth. Catal. 2004, 346, 989.86 Reetz, M. T.; Beuttenmuller, E. W.; Goddard, R.; Pasto, M. Tetrahedron Lett. 1999, 40, 4977.87 Morimoto, T.; Nakajima, N.; Achiwa, K. Synlett 1995, 748.88 Liu, D.; Li, W.; Zhang, X. Tetrahedron: Asymmetry 2004, 15, 2181.89 Faller, J. W.; Milheiro, S. C.; Parr, J. J. Organomet. Chem. 2006, 691, 4945.90 Campbell, L. A. Proceedings of the ChiraSource ’99 Symposium; The Catalyst Group: Spring

House, USA, 1999.91 Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916.92 Roszowski, P.; Wojtasiewicz, K.; Leniewsky, A.; Maurin, J. K.; Lis, T.; Czarnocki, Z. J. Mol.

Catal. A: Chem. 2005, 232, 143.93 Vedeijs, E.; Trapencieris, P.; Suna, E. J. Org. Chem. 1999, 64, 6724.94 Meuzelaar, G. J.; van Vliet, M. C. A.; Leendert, M., Sheldon, R. A. Eur. J. Org. Chem.

1999, 2315.95 Samano, V.; Ray, J. A.; Thompson, J. B.; Mook, R. A.; Jung, D. K.; Koble, C. S.; Martin, M.

T.; Bigham, E. C.; Regitz, C. S.; Feldman, P. L.; Boros, E. E. Org. Lett. 1999, 1, 1993.96 Szawkalo, J.; Czarnocki, Z. Monatsh. Chem. 2005, 136, 1619.97 Santos, L. S.; Pilli, R. A.; Rawal, V. H. J. Org. Chem. 2004, 69, 1283.98 Tietze, L. F.; Zhou, Y.; Topken, E. Eur. J. Org. Chem. 2000, 2247.99 Wu, J.; Wang, F.; Ma, Y.; Cui, X.; Cun, L.; Zhu, J.; Deng, J.; Yu, B. Chem. Commun. 2006, 1766.

100 Li, L.; Wu, J.; Wang, F.; Liao, J.; Zhang, H.; Lian, C.; Zhu, J.; Deng, J. Green Chem. 2007,9, 23.

101 Mao, J.; Baker, D. C. Org. Lett. 1999, 1, 841.102 Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron: Asymmetry 1998, 9, 183.103 Morimoto, T.; Suzuki, N.; Achiwa, K. Heterocycles 1996, 43, 2557.104 Storer, R. I.; Carrera, D. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84.105 Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 6751.106 Szawkalo, J.; Zawdzka, A.; Wojtasiewicz, K.; Leniewski, A.; Drabowicz, J.; Czarnocki, Z. Tetra-

hedron: Aysmmetry 2005, 16, 3619.107 Szawkalo, J.; Czarnocki, S. J.; Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.;

Czarnocki, Z.; Drabowicz, J. Tetrahedron: Aysmmetry 2007, 18, 406.108 Williams, G. D.; Wade, C. E.; Wills, M. Chem. Commun. 2005, 4735.109 Blaser, H. U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal. 2003,

345, 103.110 Fuchs, R. European Patent 0803502 (1997). Chem. Abstr. 2004, 141, 206915.111 Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2007, 46, 4562.112 Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966.113 Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683.114 Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003,

125, 10536.115 Xu, L.; Lam, K. H.; Ji, J.; Wu, J.; Fan, Q.-H.; Lo, W.-H.; Chan, A. S. C. Chem. Commun.

2005, 1390.116 Wang, Z.-J.; Deng, G.-J.; Li, Y.; He, Y.-M.; Tang, W.-J.; Fan, Q.-H. Org. Lett. 2007, 9, 1243.117 Wang, D-W.; Zeng, W.; Zhou, Y-G. Tetrahedron: Asymmetry 2007, 18, 1103.118 Lam, K. H.; Xu, L.; Feng, L.; Fan, Q.-H.; Lam, F. L.; Lo, W.-G.; Chan, A. S. C. Adv. Synth.

Catal. 2005, 347, 1755.119 Tang, W.-J.; Zhu, S.-F.; Xu, L.-J.; Zhou, Q.-L.; Fan, Q.-H.; Fan, Q.-H.; Zhou, H.-F.; Lam, K.;

Chan, A. S. C. Chem. Commun. 2007, 613.120 Reetz, M. T.; Li, X. Chem. Commun. 2006, 2159.121 Lu, S.-M.; Han, X.-W.; Zhou, Y.-G. Adv. Synth. Catal. 2004, 346, 905.


122 Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2006, 45, 2260.123 Bianchini, C.; Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani, M. Organometallics 1998, 17,

3308.124 Xie, Y.; Mi, A.; Jiang, Y.; Liu, H. Synth. Commun. 2001, 31, 2767.125 Murahashi, S.-I.; Tsuji, T.; Ito, S. Chem. Commun. 2000, 409.126 Oppolzer, W.; Wills, M.; Starkemann, C.; Bernardinelli, G. Tetrahedron Lett. 1990, 31, 4117.127 Charette, A.; Giroux, A. Tetrahedron Lett. 1996, 37, 6669.128 Yang, Q.; Shang, G.; Gao, W.; Deng, J.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 3832.129 Wang, Y.-Q.; Lu, S.-M.; Zhou, Y.-G. J. Org. Chem. 2007, 72, 3729.130 Wang, Y.-Q.; Zhou, Y.-G. Synlett 2006, 1189.131 Liu, P.-N.; Gu, P.-M.; Deng, J.-G.; Tu, Y.-Q.; Ma, Y.-P. Eur. J. Org. Chem. 2005, 3221.132 Ahn, K. H.; Ham, C.; Kim, S.-K.; Cho, C.-W. J. Org. Chem. 1997, 62, 7047.133 Chen, Y.-C.; Wu, T.-F.; Jiang, L.; Deng, J.-G.; Liu, H.; Zhu, J.; Jiang, Y-Z. J. Org. Chem. 2005,

70, 1006.134 Burk, M. J.; Feaster, J. E. J. Am. Chem. Soc. 1992, 114, 6266.135 Burk, M. J.; Martinez, J. P.; Feaster, J. E.; Cosford, N. Tetrahedron 1994, 50, 4399.136 Ireland, T.; Tappe, K.; Grossheimer, G.; Knochel, P. Chem. Eur. J. 2002, 8, 843.137 Yamazaki, A.; Achiwa, I.; Horikawa, K.; Tsurubo, M.; Achiwa, K. Synlett. 1997, 455.138 Spindler, F.; Blaser, H. U. Adv. Synth. Catal. 2001, 343, 68.139 Shang, G.; Yang, Q.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 6360.140 Abe, H.; Amii, H.; Uneyama, K. Org. Lett. 2001, 3, 313.141 Li, G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 5830.142 Kang, Q.; Zhao, Z.-A.; You, S.-L. Adv. Synth. Catal. 2007, 349, 1656.143 Hasegawa, M.; Taniyama, D.; Tomioka, K. Tetrahedron 2000, 56, 10153.144 Kadyrov, R.; Riermeier, T. H.; Dingerdissen, U.; Tararov, V. I.; Borner, A. J. Org. Chem. 2003,

68, 4067.145 Dai, Q.; Yang, W.; Zhang, X. Org. Lett. 2005, 7, 5343.146 Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; Wang, F.; Sun, Y.; Armstrong, J.

D.; Grabowski, E. J. J.; Tillyer, R. D.; Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918.147 Matsumura, K.; Zhang, X.; Saito, T. European Patent 1386901 (2004); Chem. Abstr. 2004,

141, 206915.148 Kubryk, M.; Hansen, K. B. Tetrahedron: Asymmetry 2006, 17, 205.149 Hansen, K. B.; Rosner, T.; Kubryk, M.; Dormer, P. G.; Armstrong, J. D. Org. Lett. 2005, 7, 4935.150 Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003, 42, 5472.151 Bunlaksananusorn, T.; Rampf, F. Synlett 2005, 2682.152 Chi, Y.; Zhou, Y.-Z.; Zhang, X. J. Org. Chem. 2003, 68, 4120.153 Blaser, H. U.; Buser, H. P.; Jalett, H. P.; Pugin, B.; Spindler, F. Synlett 1999, 867.154 Zhou, J.; List, B. J. Am. Chem. Soc. 2007, 129, 7498.155 Nanayakkara, P.; Alper, H. Chem. Commun. 2003, 2384.156 Lee, N.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 5985.157 Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.; Holz, J.; Boerner, A. Tetrahedron Lett. 2000,

41, 2351.158 Becalski, A. G.; Cullen, W. R.; Fryzuk, M. D.; James, B. R.; Kang, G.-J.; Rettig, S. J. Inorg.

Chem. 1991, 30, 5002.159 Handbook of Homogeneous Hydrogenation; de Vries, J. G., Elsevier C. J., Eds.; Wiley-VCH:

Weinheim, 2007.160 Blackmond, D. G.; Ropic, M.; Stefinovic, M. Org. Process Res. Dev. 2006, 10, 457.161 Dorta, M.; Broggini, D.; Stoop, R.; Ruegger, H.; Spindler, F.; Togni, A. Chem. Eur. J. 2004,

10, 267.162 Dorta, M.; Broggini, D.; Kissner, R.; Togni, A. Chem. Eur. J. 2004, 10, 4546.163 Smidt, S. P.; Pfaltz, A.; Martinez-Viviente, E.; Pregosin, P. S.; Albinati, A. Organometallics

2003, 22, 1000.164 Blaser, H. U.; Pugin, B.; Spindler, F.; Togni, A. C. R. Chim. 2002, 5, 379.165 Clapham, S. E.; Hadzovic; A.; Morris, R. H. Coord. Chem. Rev. 2004, 248, 2201.


166 Samec, J. S. M.; Backvall, J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev. 2006, 35, 237.167 Hofer, R. Chimia 2005, 59, 10.168 Pugin, B.; Landert, H.; Spindler, F.; Blaser, H. U. Adv. Synth. Catal. 2002, 344, 974.169 Clausen, A. M.; Dziadul, B.; Cappuccio, K. L.; Kaba, M.; Starbuck, C.; Hsiao, Y.; Dowling, T.

M. Org. Process Res. Dev. 2006, 10, 723.170 Thayer, A. M. Chem. Eng. News 2007, 85 (32), 11.171 Imwinkelried, R. Chimia 1997, 51, 300.172 Cobley, C. J.; Foucher, E.; Lecouve, J.-P.; Lennon, I. C.; Ramsden, J. A.; Thominot, G. Tetra-

hedron: Asymmetry 2003, 14, 3431.173 Blacker, J.; Martin J. In Large-Scale Asymmetric Catalysis; Blaser, H. U.; Schmidt, E., Eds.;

Wiley-VCH: Weinheim, 2003; p 201.174 Satoh, K.; Inenaga, M.; Kanai, K. Tetrahedron: Asymmetry 1998, 9, 2657.175 Brunner, H.; Rosenboem, S. Monatsh. Chem. 2000, 131, 1371.176 Pugin, B.; Groehn, V.; Moser, R.; Blaser, H. U. Tetrahedron: Asymmetry 2006, 17, 544.177 Groehn, V.; Moser, R.; Pugin, B. Adv. Synth. Catal. 2005, 347, 1855.178 Tietze, L. F.; Rackelmann, N.; Sekar, G. Angew. Chem., Int. Ed. 2003, 42, 4254.179 Mujahidin, D.; Doye, S. Eur. J. Org. Chem 2005, 2689.180 Roszowski, P.; Maurin, J. K.; Czarnocki, Z. Tetrahedron: Asymmetry, 2007, 17, 1415.181 Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3, 1475.182 Yamada, T.; Nagata, T.; Sugi, K. D.; Yoruzu, K.; Ikeno, T.; Ohtsuka, Y.; Miyazaki, D.;

Mukaiyama, T. Chem. Eur. J. 1993, 9, 4485.183 Graves, C. R.; Scheidt, K. A.; Nguyen, S. T. Org. Lett. 2006, 8, 1229.184 Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2004, 73, 581.185 Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer, R. A.; Chen, C.; Volante, R. P. Org. Lett. 2005,

7, 355.186 Carpentier, J. F.; Bette, V. Curr. Org. Chem. 2002, 6, 913.187 Hansen, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 713 and references cited therein.188 Lipshutz, B. H.; Shimizu, H. Angew. Chem., Int. Ed. 2004, 43, 2228.189 Wang, Z.; Ye, X.; Wie, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett. 2006, 8, 999.190 Malkov, A. V.; Stoncius, S.; MacDougall, K. N.; Mariani, A.; McGeoch, G. D.; Kocovsky, P.

Tetrahedron 2006, 62, 264.191 Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler, M.; Stuermer, R.; Zelinski, T. Angew.

Chem., Int. Ed. 2004, 43, 788.192 Labeq Laboratory Equipment AG, CH-8006 Zurich, Switzerland.193 Autoclave Engineers Europe, F-Nogent sur Olle, Cedex, France.194 Buchi AG, CH-8610 Uster, Switzerland.195 Battersby, A. R.; Edwards, T. P. J. Chem. Soc. 1960, 1214.196 Braun, W.; Salzer, A.; Spindler, F.; Alberico, E. Appl. Catal., A 2004, 274, 191.197 Trifonova, A.; Diesen, J. S.; Andersson, P. G. Chem. Eur. J. 2006, 12, 2318.198 Broger, E. A.; Burkart, W.; Henning, M.; Scalone, M.; Schmid, R. Tetrahedron: Asymmetry,

1998, 9, 4043.199 Huang, X.; Ying, J. Y. Chem. Commun. 2007, 1825.200 Yang, P.-Y.; Zhou, Y-G. Tetrahedron: Asymmetry 2004, 15, 1145.

chapter 1 - wiley...more so from hantzsch esters, which form aromatic products. in all equations,...

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