substrate-directed hydrogenations with cationic...

M.C. White/M.S. Taylor Chem 253 Hydrogenation -161- Week of October 25, 2004

Substrate-directed hydrogenations with cationic complexes

It was observed experimentally (and may have been predicted) thathydrogenation of the enantiomerically enriched homoallylic alcohol with the neutral catalyst complex (Ph3P)3RhCl produced a 1:1mixture of diastereomeric products. Use of the cationic complexRh(cod)(dppb)BF4 led to a preference, albeit small, for theformation of the anti hydrogenation product.

In contrast, hydrogenation with the cationic iridiumcomplex Ir[(cod)(pyr)(PCy3)]PF6 favored the formation of the syn isomer.

CO2Et

OTBDPS

CH3 OH

CO2Et

OTBDPS

OH

HN N

ONH O

CO2HCH3

Br

P

P

Rh

Et

Et

EtEt

+OTf +OTf

HN N

ONH O

CO2HCH3

Br

CO2Et

OTBDPS

CH3 OH

>95:5 anti:syn 75:25 syn:anti

Manzacidin AManzacidin C

(5 mol%)(5 mol%)

General conditions: H2 (1000psi), CH2Cl2, rt

The use of chiral bidentate phosphine ligands makes it possible to reinforce or partiallyoverride substrate bias.

Rh PP

Du Bois JACS 2002, ASAP, Oct., 2002.

CO2Et

OTBDPS

CH3 OH

(PF6-)Ir(I)

PCy3

N

CO2Et

OTBDPS

OH(BF4

-)Rh(I)

Ph2P

PPh2

CO2Et

OTBDPS

CH3 OH

Ph3PRh(I)

Ph3P PPh3

Cl

CO2Et

OTBDPS

CH3 OH

50:50 anti:syn

+

65:35 syn:anti

()n= 3

+

60:40 anti:syn

M.W. Kanan/M.C. White Chem 253 Hydrogenation -162- Week of October 25, 2004

Asymmetric hydrogenation in the synthesis of unnatural amino acids

OH

F

NO2

F

NO2

1 atm. H2, THF, rt

S

O

(COD)RhPh2P

CMe3

+

AcHN

O

OMeNHAc

O

MeO

RhL

L*

+

RhL

L

H

*

HNR

H

RhL

LH

+

R+

94% ee, 96% yield

reductive elimination

insertion

*

OO

OH

NH

O

HN

NH

HN

O

HO

OH

O

HO

O

HO

OHN

O

NH

OOH

HO

O

NH2

Cl

Cl

Teicoplanin aglycon

Asymmetric hydrogenation is a very general andreliable route to amino acids, which are keybuilding blocks for the synthesis of many natural products. In this example, the hydrogenation iscarried out in the presence of a nitro group.

O COOMe

NHO

HCOOMe

RhL

L S

S

*

+

RhL

L*O

NHMeOOC

R

oxidative addition

+

SbF6-

H2

H2

Evans JACS 2001 (123) 12411

M.C. White, Chem 253 Hydrogenation -163- Week of October 25, 2004

Asymmetric hydrogenations of trisubstituted“unfunctionalized” olefins

(PF6-)Ir(I)

PCy3

N

+

Crabtree's catalyst

Ar2P N

O

RIr

(PF6-)

+

Recall that Crabtree's catalyst is able to effect the efficienthydrogenation of both tri-and tetrasubstituted olefins.Replacement of the monophosphane and pyridine ligandswith the bidentate phosphanodihydrooxazole ligandproduces a catalyst that is highly effective in promoting the asymmetric hydrogenation of trisubstituted,unfunctionalized olefins.

Pfaltz hydrogenation catalyst

o-Tol2P N

O

Ir

X -+

Counterion effects on conversion (and selectivity) can be dramatic

counterion catalyst loading conversion

PF6- 4 mol% 57 %

CF3

CF3

B

_

tetrakis[3,5-bis(trifluoromethyl)-phenyl]borate (BARF)

.05 mol% >99%

F

F

B

_

.1 mol% 84%

F

F

F

tetrakis(pentafluorophenyl)-borate

hexafluorophosphate

4

4

MeMe

*

97 % e.e, >99 % conv.

H2, CH2Cl2, rt

Pfaltz ACIEE 1998 37 2897.


Titanocene hydrogenation of “unfunctionalized” olefins

Ti(IV)

Cl

Cl

25 mol%

LiAlH(OR)3 (7.5 eq), H2 (16 psi),

heptane/THF, 40oCquantitative conversion

Original report of catalytic hydrogenation activity:

Stern TL 1968 (60) 6313.

First asymmetric example:

i-Pr

Me

Ti(IV)

i-Pr

Me

Cl Cl

"Red-Al" (Li(H2Al(OCH2CH2OCH3)2)]

H2 (1 atm), 20 oC

1 mol%

6 mol%Ph

Ph

(S)

15 % ee

Kagan ACIEE 1979 (18) 779.

Ti(IV)

Cl

Cl

1. 10 mol%. n-BuLi, 0oC.

H2 (1 atm)

2. 13 mol% PhSiH3

3. olefin, H2 (136 atm)

65oC

5 mol%

Me

Ph

Asymmetric hydrogenation of "unfunctionalized" trisubstituted olefins

Me

all substrates reported are alkenes α to an aromaticring.

Ph

Me

*

79% yield95% ee

Buchwald JACS 1993 (115) 12569.

First asymmetric example resulting in high ee

Ph

Ph

(S)

Ph

PhTi(IV)

Ph

Ph

1 mol%

n-BuLi (1 mol%), H2 (1 atm), -75oC

Cl Cl

95% optical purity

Vollhardt JACS 1987 (109) 8105.

E olefins are reduced more rapidly and with higher ee's than Z olefins


Titanocene hydrogenation of “unfunctionalized” olefins

Ti( IV)

Cl

Cl1. 10 mol%. n-BuLi, 0oC.

H2 (1 atm)

2. 13 mol% PhSiH3

Ti( III) H

postulated intermediate based on Martin andJellinek papers

Buchwald argues that the silane does not serve as a H source based on the following experiment: whenD2 was used in the hydrogenation of(E)-1,2-diphenylpropene, 1,2-diphenyl propaneresulted which was 98% D2 by GCMS. Buchwaldgoes on to note that the only purpose of thephenylsilane is to stabilize the catalyst duringmanipulations prior to starting the rxn.

5 mol%Me

Ph

Me

Ti(III)

Ph

note: regioselectivity of insertion notdetermined

H H

σ-bond metathesis

*

Ph

Me

*

olefin insertion

Buchwald JACS 1993 (115) 12569

Synthesis of allyldicyclopentadienyltitanium (III) complexes from dicyclopentadienyltitanium (IV) dichloride:

Ti(IV)

Cl

Cl

2 equ. MgCl

Ti(III)

2 MgCl2

H

Ti(III) H Ti(III)

Martin and Jellinek JOMC 1966 (6) 293; JOMC 1968 (12) 149.


TiH

Me

TiHMe

H

Me

HTiH (R)

(S)

Me

Me

vs.

‡

‡

major product, >99% e.e.

transition state A

transition state B

Hydride transfer via a four-centered transition state. leads to the formation of a new stereogenic center at thedisubstituted carbon of the olefin. In this model, the olefinapproaches from the "front" of the complex withhydrometallation resulting in formation of the less stericallyhindered Ti alkyl bond.

The olefin arrangement shown in transition state Aminimizes the steric interactions between the largesubstituents on the olefin and the cyclohexyl portion of thetetrahydroindenyl ligand.The rate of reduction for Z olefins is slower than the rate of reduction for E olefins. Can thisresult be rationalized based on this model for the transitionstate?

Stereochemical model


N

MeO

MeO

Me

Ti H

H2 NH

MeO

MeO

Me

82 % yield, 98 % e.e.

Asymmetric hydrogenation of cyclic imines

NH

Ti H

H2NH

81 % yield, 98 % e.e.

L*TiH

HN

R

R''

R'

R' R''

RHN

H2

H

RN R'

R''

H

L*TiNR

H R'

R''

RN R''

R'

L*Ti

L*Ti

*

*

*

‡‡

*

Kinetic studies suggest that thehydrogenolysis of the Ti-N bondmay be the rate-determining step in this catalytic cycle

TiHN

R

‡e.g.

the ethylene bridge is omitted for clarity

Buchwald JACS 1994 (116) 8952


Me

N Ph

Ti H

H2

Me

N Ph

anti/syn : 11/1 93 % yield, 76 % e.e.

Asymmetric hydrogenation of acyclic imines

Acyclic imines exist as mixtures of anti and syn isomers. This property proves relevantin the asymmetric hydrogenation of thesesubstrates.

TiHN

c-hex

Ph

Me

TiHN

MePh

c-hex

Me

N Ph

Me

N Ph

Me

N Ph

favored

disfavored

anti

Me

N

Ph

TiHN

Me

Ph

Me

TiHN

c-hexPh

c-hex

Me

N Ph

Me

N Ph

favored

disfavored

syn

Buchwald JACS 1994 (116) 8952the ethylene bridge is omitted for clarity

(R)

(S)


Substrate-Directed Ketone Hydrogenations

PPh2

Ru(II)

Ph2P O

O

O

O

OEt

O O

OEt

OH O

PPh2

Ru(II)

Ph2P O

O

O

O

2 equ. HX (X= Cl, Br, I)

RuX2[(R)-binap]

molecular weight unknown

black box chemistry

N

O

N

OH

(S)

Ru(II)-BINAP dicarboxylate catalysts were found to be ineffective for ketone hydrogenationsmediated via α or β-oxygenated functionality. These hydrogenations could be effected in highyields and ee's with poorly defined halogen-containing Ru complexes. The dicarboxylate catalysts were effective for ketone hydrogenations mediated via highly basic α (or β) amino functionality.

(0.1 mol%)

MeOH, H2 (100 atm), 23oC, 48h

(R)-1

41% yield4% ee

binap

72% yield96% ee

(R)EtOH, H2 (50 atm), 23oC, 12h

(0.1 mol%)(R)-1

Ru hydride must havesome hydridic character.

Hydrogenation of ketones performedunder forcing conditions (recall thatolefin hydrogenations were performed at 4 atm with this catalyst).

R

O

X

Lewis basicfunctionality

RuX2[(R)-binap] 0.1 mol%

EtOH, H2 (50-100 atm), rt

May pre-coordinate tothe Ru center via a5-membered ring chelate

R

OH

X(R)

OH

OH

OEt

OH O

N(Me)2

OH O

OH Br OH

Br(R)

quantitative yield92% ee

quantitative yield>99% ee (best substrates)

quantitative yield>96% ee

97% yield 92% ee

<1% yield 30% ee

R

O



May pre-coordinate tothe Ru center via a6-membered ring chelate

R

OH

(R)

X X

OH

OH

quantitative yield98% ee

OH

<1% yield 74% ee

RuX2[(S)-binap] gives the (S) enantiomer

Noyori JACS 1987 (109) 5856Noyori JACS 1988 (110) 629.

Note: opposite sense of stereoinduction

PPh2

Ru(II)

Ph2P O

O

O

O

2 eq HX (X= Cl, Br, I)

RuX2[(R)-binap]

molecular weight unknown

R

O



May pre-coordinate tothe Ru center via a6-membered ring chelateR

OH

(R)

X X

HCl

H2

RuHX[(R)-binap]

Ru(II) monohydride

OO

R

O

RuP

P

H

X*

OO

R

O

RuP

P

H

X*

OO

R

O

RuP

PX

*

H

H2

R

OH X

(R)


Noyori substrate-directed ketone hydrogenation: mechanism

M.W. Kanan/M.C. White, Chem 253 Hydrogenation -171- Week of October 25, 2004

Dynamic Kinetic Resolution of 2-substituted-ß-keto esters

O

OMe

O

NHAc

O

OMe

OH

NHAc

99:1 syn:anti, 98% ee, 100% conversion

Noyori JACS1989 (111), 9134

RuBr2[(R)-BINAP]

H2 (100 atm)CH2Cl2 15°C, 50h

O

OMe

O

NHAc

O

OMe

O

NHAc

O

OMe

OH

NHAc

O

OMe

OH

NHAc

O

OMe

OH

NHAc

O

OMe

OH

NHAc

+

+

k1

k2

k1>k2

major product

RuBr2[(R)-BINAP], H2

Scenario 1: There are at least two possibilities for the mechanism of stereoselectivity. One is that the β-keto-ester enantiomers can interconvert under the reaction conditions and thecatalyst reacts with one isomer much more rapidly than the other and with highstereoselectivity to produce a single product.

O

OMe

O

NHAc

O

OMe

OH

NHAc

O

OMe

OH

NHAc

major product

RuBr2[(R)-BINAP], H2

Scenario 2: Both starting enantiomers are converted to a singleintermediate species (a prochiral enol formed via deprotonation of the α-proton) and the catalyst reacts stereoselectively withthis species to produce a single stereoisomer.

O

OMe

O

The following observations support the interconversion mechanism:

reacts to give β-hydroxy ester in88-96% ee depending on the solvent

O

OMe

O OH

OMe

O1:99 syn: anti, 93% ee[RuCl(C6H6)((R)-BINAP)]Cl

H2 (100 atm)CH2Cl2 50°C, 70h

Question: why does the result with the cyclicsubstrate support the interconversion mechanism?

Excellent enantioselectivity and syn diastereoselectivity is seen in the dynamic kinetic resolution ofracemic α-acetamido-ß-keto-esters when the reaction is carried out in CH2Cl2. The observed synselectivity with these substrates can be rationalized by considering the Felkin-Anh model for thetransition state of hydride addition in which the small substituent (H) is adjacent to the Burgi-Dunitz trajectory of the incoming hydride and the best acceptor (acetamido group) ispreferentially oriented anti to the incoming hydride.

Recall that in this system hydrogenation is thought toproceed through a Ru-monohydride species, capable ofcoordinating the adjacent ester moiety. The transition statewith the acetamido group anti to the incoming hydride mayadditionally be stabilized via hydrogen bonding between theNH of the acetamido group and the OR of the ester.Interruption of this hydrogen bonding interaction viacompetetive binding to solvent may account for thediminished syn selectivity seen in MeOH.

Me OMe

NHAc

OORuBr2[(R)-BINAP] (R)

Me OMe

NHAc

OOH

(S)

(R)

Me OMe

NHAc

OOH

(R)

+ syn:anti 99:1 in CH2Cl2 syn:anti 71:29 in MeOHH2, CH2Cl2

H

OO

NHAc

R

ORuP

P

H

X

N

HOO

H

R

O

Me

ORuP

P

H

X

(R)(S)

vs.

favored

syn anti

* *

Diastereoselectivity in the Noyori dynamic kinetic resolution

M.C. White/M.W. Kanan Chem 253 Hydrogenation -172- Week of October 25, 2004

CO2MeH

NHAc

CO2MeAcHN

H

H

AcHN

(H-)

(H-)

NHAc

H

CO2Me

CO2Me H

AcHN

NHAc

H

CO2Me

CO2Me

Me OMe

NHAc

OOH

Me OMe

NHAc

OOH

interconversion under reaction

conditions

‡

‡

=

=

OMe OMe

H

Me OH

OMe OMe

H

Me OH

(S)

(R)

Note that ester position is fixed b/cof chelate formation w/the catalyst

M.W. Kanan/M.C.White Chem 253 Hydrogenation -173- Week of October 25, 2004

As part of an effort to develop a stereocontrolled synthesis of dolaproine, Genet and coworkers carried out the Noyori DKR shownbelow. Based on the literature precedents for DKR with α-methyl-substituted ß-keto esters. the authors were expecting a synrelationship between C2 and C3. Instead that observed very good diastereoselectivity in the formation of the undesired antiisomer. This example highlights a lilmitation of the Noyori methodology. In DKR of α-substituted-β-keto esters, the ligand onRu controls the stereochemistry of the ketone being reduced, but the diastereoselectivity is controlled by the substrate. This meansthat only one of the syn or anti relationships between the two stereocenters can be accessed reliably and, in this case, preventsaccess to the desired product. This particular substrate has a γ-stereocenter which may be exerting an influence on the selectivity.

NH

O

OH

Me

OMe

2R3R

4S

Dolaproine

N

O

OEt

Me

OH

PPh2PPh2

MeOMeO

4S3R

N

O

OEt

Me

OHH

2S 4S3R

N

O

OH

Me

OMeBoc

2S

HCl; HCl;

10 bar H2, EtOH, 50°C

1 mol% Ru[(S)-MeO-BIPHEP]Br2

(S)-MeO-BIPHEP

Boc-(2S)-iso-dolaproine

quant. yield (2S,3R):(2R,3S) 92.5:7.5

N

O

OEt

Me

OH

N

O

OEt

Me

OH

4S

4S

3S

3R

N

O

OEt

Me

OHH

N

O

OEt

Me

OHH

2S

2R

HCl;

HCl;

Ru[(S)-MeO-BIPHEP]Br2, H2

kfast

Ru[(S)-MeO-BIPHEP]Br2, H2

kslow

HCl;

HCl;

Stereoselective synthesis of iso-dolaproine: the power and limitations of DKR with α-substituted-β-keto esters

Genet Org. Lett. 2001, (3) 1909.


Non-directed carbonyl hydrogenations:a reversal in chemoselectivity

0.5 mol%

H2 (10 atm), benzene, 70oC

83% yield

O OH

The Original Report:

under these conditions, ketones arenot hydrogenated.

Suzuki Chem. Lett. 1977 1085.

0.5 mol%

H2 (29 atm), ethanol/benzene, rt93% yield

O O

strong preference forhydrogenation ofsterically unhindered olefins. Suzuki Chem. Lett. 1977 1083.

RuCl2(PPh3)3

RuCl2(PPh3)3

Selective hydrogenation of carbonyl vs. olefinic functionality using hydrogenation conditions B:

OH

n-C8H17 OH

OH

OHOH

OH

95% isolated yield98.6:1.4 (unsat. alcohol: sat. alcohol)

88% isolated yield100:0 (unsat. alcohol: sat. alcohol)

97% isolated yield98.2:1.8 (unsat. alcohol: sat. alcohol)

quantitative isolated yield70:30 (unsat. alcohol: sat.

alcohol)98% isolated yield100:0 (unsat. alcohol: sat. alcohol)

90% isolated yield99.6:0.4 (unsat.

alcohol: sat. alcohol)

Noyori JACS 1995 (117) 10417.

O

+

Hydrogenation conditions A:RuCl2(PPh3)2 ,0.2 mol%

H2 (4 atm), 2-propanol/toluene, rt250 xfaster

O+

Hydrogenation conditions B:RuCl2(PPh3)2 ,0.2 mol%

NH2(CH2)2NH2 (0.5 mol%), KOH (1.0 mol%)

H2 (4 atm), 2-propanol/toluene, rt

1500 xfaster

Bases have been used in conjunction with Ru(II) catalysts to effect olefin hydrogenations. Recall that base is thought to promoteheterolytic cleavage of H2 to form the catalytically active Rumonohydride species. Therefore, the observed reversal inchemoselectivity must be primarily due to the added 1,2 diamine.


Non-directed carbonyl hydrogenations

Noyori JOC 1996 (61) 4874.D.A. Evans. Chem 206 Notes. October 2000

Ru-H formed acts as a "bulky hydride"

Reactive Ru-H species generated acts as a bulky source of hydridedisplaying similar diastereoselectivities observed with other stoichoimetric large hydride reagents such as KBH(s-Bu)3.

O

H

t-Bu

H

H

M-H

M-H

a. sterically favored equatorial trajectory generally observedfor bulky hydride reagents(recall: avoids unfavorablesteric interactions with diaxialH's during approach).

b. torsionally favored axial trajectorygenerally observed for non-bulky hydride sources (recall: avoids formation ofeclipsing interactions in TS)

a b

H

t-Bu

H

t-Bu

H

OH

OH

H

cis trans

a

b

Hydride source

Li in NH3 (non-bulky)KBH(s-Bu)3 (bulky)RuCl2(PPh3)3/NH2(CH2)2NH2/KOH

ratio (cis: trans)

1:9997:3

98.4:1.6

O OH

Ph Ph

H2N NH2

Ph Ph

H2N NH2

H2N NH2

PPh2

PPh2

Ph Ph

H2N NH2

RuCl2[(S)-binap](dmf)n ,0.2 mol%

Diamine 0.5 mol%, KOH 1.0 mol%

H2 (4 atm), 28 oC, 6h

Diamine % ee

(S,S)-Diamine

97%

14%

57%

75%

(R,R)-Diamine

Phosphine

(S)-Binap

PPh3 (in RuCl2(PPh3)3)

(S,S)-Diamine

Noyori JACS 1995 (117) 2675.

1,2-Diamine is a ligand for the Ru

Both the chiralityof the diphosphine(binap) and the 1,2-diamineaffect the stereochemicaloutcome of the carbonyl hydrogenation. Therefore, the diamine ligand is attached to the Ru center during the catalytic cycle.

M.C. White Chem 253 Hydrogenation -176- Week of October 25, 2004

NH2

NH2

MeO

MeORuCl2[(S)-binap](dmf)n ,0.5 mol%

(S)-Diamine, 0.5 mol%, KOH 1.0 mol%

H2 (8 atm), 28 oC, 3h

>99 % yield>99 % chemoselectivity

70 % ee

(S)-Diamine

Noyori JACS 1995 (117) 10417.

In situ method using binap

O OH

DAIPEN = 1,1-dianisyl-2 -isopropyl- 1,2-ethylenediamine

Noyori JACS 1998 (120) 13529.

PAr2

Ru(II)

Ar2P

H2N

NH2

Cl

Cl

OMe

OMe

Ar =

(S,S)-1

n-C5H11

O

(S,S)-1 (0.2 mol%)

K2CO3 (0.04 mol%)2-propanol, H2 (8 atm),

rt, 43 h

n-C5H11

OH

(R)

98% yield>99% chemoselectivity

97% ee

O

R

for: R = p-OMe

(S,S)-1 (0.002 mol%)KOt-Bu (0.08 mol%)

2-propanol, H2 (8 atm), rt, 16 h

R = F, Cl, Br, I, CF3, C(O)OR, NO2, NH2 in m, p, o positions

OH

R

99.9% yield99% ee

base-sensitive

Preformed catalyst using xylbinap

Ph

O

(S,S)-1 (0.001 mol%)K2CO3 (0.04 mol%)

2-propanol, H2 (80 atm), rt, 43 h

Ph

OH

(R)

>99% yield>99% chemoselectivity

97% ee

N

O

(S,S)-1 (0.2 mol%)

KOt-Bu (0.08 mol%)2-propanol, H2 (50 atm),

rt, 24 h

N

OH

99.9% yield96% ee

αααα,ββββ-unsaturated ketones:

aryl ketones: heteroaromatic ketones

also effective for furyl andthiazolyl ketones

Noyori OL 2000 (2) 1749.

Asymmetric, non-directed ketone hydrogenations


Catalyst Synthesis

ClH3N

CO2Mep-MeOC6H5MgBr

H2N

OMe

OMe

OH1. CbzCl, 60%2. NaN3, 95%

BzCN

OMe

OMe

N3H2 (50 psi)10% Pd/C

85%HH2N

OMe

OMe

NH2

Takaya, JOC, 1994, 59, 3064

Burrows, TL, 1993, 34, 1905

(S)-DAIPEN

(S)-XylBINAP

1. Mg2. Ar2POCl

1.dibenzoy-L- tartaric acid2. HSiCl3, NEt3, 92%

Br

Br

P(O)Ar2

P(O)Ar2

PAr2

PAr2

XylBINAP Prep:

Ar =

~ 89%

(±)

optical resolution usingchiral organic acid

L-alanine methyl esterhydrochloride

67%

DAIPEN Prep:

[RuCl2(benzene)]2+

(S)-XylBINAP

1. DMF (degassed),

Ar, 100oC,10 min

PAr2

Ru(II)

Ar2P

H2N

NH2

Cl

Cl

OMe

OMe

Ar =

(S,S)-1

2. (S)-DAIPEN, 25oC

6h

Workup done under strictly anhydrous conditions under an Ar atomosphere· Remove DMF (pump)· Dissolve in Et2O (degassed, dried)· Filter through Si pad· Concentrate · Add hexanes (degassed, dried)· Cannula filtration · Concentrate and store under Ar

Noyori, JACS, 1998, 120, 13529

Chiral elements are not commercially available

Catalyst is O2 sensitive: does not store well


Non-Classical Bifunctional Catalyst

1

PPh2

Ru(II)

Ph2P

H2N

NH2

Cl

H

H2, KOH

KCl, H2O

PPh2

Ru(II)

Ph2P

H2N

NH2

H

H

PPh2

Ru(II)

Ph2P N

NH2

H

H

H

H

O

δ-δ+

PPh2

Ru(II)

Ph2P N

NH2H

H

hydridoamido intermediate:observed by NMR when dihydride is treatedwith ketone in the absence of H2.When the hydridoamido complex isplaced under H2, the dihydride isregenerated.

H H

O

H

O

H

The proposed mechanism for ketone hydrogenation involves aconcerted transfer of the hydridic Ru-H and protic N-H to theketone via a 6-membered pericyclic TS. The ketone substratecannot interact directly with the 18 e-, coordinatively saturatedRu-H catalyst without disrupting one of it's chelate rings ordisplacing a hydride, both energetically unfavorable processes. This may account for the observation that 1,2-diamines areeffective at shutting down the olefin hydrogenation pathway,known to proceed through olefin coordination to the metalfollowed by hydride migratory insertion.

trans effect results in weakening of the Ru-H bond and mayincrease it's hydridic behavortowards ketones.

1

note: 1 is generated from theRuH(Cl)(R-binap)(tmen) precursorrather than the dichloro precursortypically used in ketonehydrogenations

Morris JACS 2001 (123) 7473.


Transfer hydrogenations: organic hydride donorsThe catalysts:

NH

TsN

RuII

RnNH2

TsN

RuII Rn

Cl

(S,S)-2 is the active transfer hydrogenation catalyst and can be formed in situ from pre-catalyst (S,S)-1 in the presence of KOH or from [RuCl2(aryl)]2/ligand/KOH. For base sensitive substrates, (S,S)-2 can be prepared and isolated separately.

Cl

Ru

Cl

Cl

RuCl

(S,S)-2(S,S)-1[RuCl2(mesitylene)]2

NH2

NTsH

(S,S)-TsDPEN

+

O

R

R = H Cl OMe

[RuCl2(mesitylene)]2 0.5 mol%(S,S)-TsDPEN 1 mol%, KOH 2.5 mol%

i-PrOH (0.1M in ketone)

OH

R

(S)

R = H: 95% yield, 97% ee Cl: 95% yield, 93% ee OMe: 53% yield, 72% ee

Aryl ketones

Noyori JACS 1995 (117) 7562.

O

CH3

C4H9

OH

CH3

C4H9

O

NHCBz

(S,S)-1 0.5 mol%KOH 0.6 mol% i-PrOH (0.1M)

Both aryl and alkylethynyl ketones serve a good substrates.

70% yield98% ee

αααα,,,,ββββ-Acetylenic ketones

Noyori JACS 1997 (119) 8738.

Overriding substrate bias:

(S)

OH

NHCBz

(S)(R)

OH

NHCBz

(S)(S)

98% ee

(R,R)-2 1 mol%i-PrOH, rt

98% ee97% yield

(S,S)-2 2 mol%i-PrOH, rt

>99% ee>97% yield


Proposed mechanism of Noyori transfer hydrogenations

RuII

TsN

N

Cl

HH

pre-catalyst

Ru

X

N

H

HH O

Ph R

base

HCl· base

RuII

NHX

true catalyst

OH

Ru

X

N

H

HH O

H3C CH3

±

hydrogen transfer

RuII

X

N

H

HH

loaded catalyst

2-propanol

O

±

Ph R

O

Ph R

OH

X = NTs, O

*

*

* *

**

**

**

The presence of NH or NH2 on thechelating ligand is critical for catalyticactivity. The dialkylamino analogues are ineffective.

Both the hydroamido ("true catalyst") and dihydride("loaded catalyst") Ru complexes have been isolatedand characterized by x-ray crystallography. Bothcompounds are capable of effecting transferhydrogenations to aryl ketones at comparable rates to the pre-catalyst without the presence of base.

Noyori Acc. Chem. Res. 1997 (30) 97.Noyori JACS 2000 (122) 1466 Noyori JOC 2001 (66) 7931.

The reversability of the hydrogenation step may lead to an erosion in ee's and incompleteconversions for substrates with low oxidationpotentials. To minimize interaction of the product with the catalyst, the reactions are often run atsubstrate concentrations of 0.1M.


Origin of asymmetric induction: C-H/π attraction

Ru

O

N

H

(S)

HPh

Ph

H

"loaded catalytic intermediate"

O

Ar R

Ru

O

N

H

HPh

Ph

H O

Ph R

Si-TS

±

Ru

O

N

H

HPh

Ph

H O

R Ph

Re-TS

±H H

Ar

OH

R

(R)

Ar

OH

R

major enantiomer observed in aryl ketone and benzaldehyde-1-dtransfer hydrogenations

(S)

The partial positive charge on the C(sp2)H of the benzene

is enhanced by binding to the metal (recall: benzene is agood π-donor) resulting in its increased ability to act as a

CH donor to the electron rich π-system of the aryl groupon the substrate.

Noyori ACIEE 2001 (40) 2818.

DFT calculations indicate that thesterically more congested Si-TS for thehydrogenation of benzaldehyde is 8.6kcal/mol more stable than its relativelyuncrowded diastereomeric Re-TS. Therationale given is that Si-TS is stabilizedby the C-H/π attractive interactionbetween a C(sp2)H substituent on thebenzene ligand of the Ru complex and the π system of the aryl group on thesubstrate.

M.C. White/M.S. Taylor Chem 253 Hydrogenation -182- Week of October 25, 2004

Synthetic application of Noyori transfer hydrogenation

Jacobsen ACIEE 2001 (113) 3779.

OO

O

TMS

PMBO

OTESMe

i-PrOH

O

R

O

TMSR

OH

TMS

OO

OH

TMS

PMBO

OTESMe

Fostriecin

93% yield>95:5 d.r.

OH

Ru(II)

d6, 16e-

Ru(II)

d6, 18e-

NH

TsN

RuII

i-Pr

NH

TsN

RuII

i-Pr

NH2

TsN

RuII

i-PrH

It was possible to control the relativestereochemistry of the 1,3 diol unit by selection of the appropriate enantiomer of Noyori'stransfer hydrogenation catalyst.

substrate-directed hydrogenations with cationic...

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