CHAPTER 1 - Wiley...more so from Hantzsch esters, which form aromatic products. In all equations,...
Transcript of 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.
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 5
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
For a glossary of ligand structures, refer to Chart 1 immediately preceding the Tabular Survey.
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.
For a glossary of ligand structures, refer to Chart 1 immediately preceding the Tabular Survey.
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 7
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.
For a glossary of ligand structures, refer to Chart 1 immediately preceding the Tabular Survey.
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
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 9
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.
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 11
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
12 ORGANIC REACTIONS
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)
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 13
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
14 ORGANIC REACTIONS
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)
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 15
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
16 ORGANIC REACTIONS
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).
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 17
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
18 ORGANIC REACTIONS
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)
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 19
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)
20 ORGANIC REACTIONS
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.
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 21
[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.
22 ORGANIC REACTIONS
(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
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 23
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
24 ORGANIC REACTIONS
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)
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 25
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)
26 ORGANIC REACTIONS
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
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 27
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
28 ORGANIC REACTIONS
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
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 29
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
30 ORGANIC REACTIONS
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.
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 31
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
32 ORGANIC REACTIONS
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.
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 33
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
34 ORGANIC REACTIONS
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.
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 35
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.
36 ORGANIC REACTIONS
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)
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 37
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.
38 ORGANIC REACTIONS
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)
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 39
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
40 ORGANIC REACTIONS
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.
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 41
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
42 ORGANIC REACTIONS
(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
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 43
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).
44 ORGANIC REACTIONS
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
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 45
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
46 ORGANIC REACTIONS
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
98 ORGANIC REACTIONS
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.
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 99
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.
100 ORGANIC REACTIONS
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.
CATALYTIC ASYMMETRIC HYDROGENATION OF C=N FUNCTIONS 101
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.
102 ORGANIC REACTIONS
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.