heck reaction - harvard universitysites.fas.harvard.edu/~chem253/notes/2004wk5.pdf · 2004. 10....

M.C. White, Chem 253 Cross-Coupling -132- Week of October 18 , 2004

Heck ReactionThe Heck Reaction:

H

R

+ R'XL2PdIIX2 cat.

Base

R'

R

R' = aryl, heterocyclic, vinyl, benzylX = Br, I, OTf, ClBase:

2o or 3o amine, NaOAc,

K2CO3, KHCO3, KOAc

+ Base H+ X-

The base may serve a dualpurpose: reducing the Pd(II)precatalyst to Pd(0) and promoting reductive elimination of thePdH(X) intermediate by shiftingthe equilibrium towards Pd(0).

Catalyst:Pd(II) sources often used: Pd(OAc)2 , PdCl2PR3, PdCl2(CH3CN)Pd (0) sources: Pd(PPh3)4, Pd(dba)2+ PR3

Increasing the db substitution dramatically decreases therate of intermolecular Heck reactions:

> >

Olefin:

Heck is stereoselective for E olefin formation

Heck Org. React. 1982 (27) 345.

L2PdIIX2

NEt3

Et2N+

L2Pd0

PdIIR'

LX

R

cis migratoryinsertion

oxidativeaddition

PdII

XL

R

H

R'

LPd(II)H

X

PdII

R'

L

L

X

R'X

ββββ-hydrideelimination (cis)

X- +HNEt3

reductiveelimination

PdII

LX

Neutral mechanism: coordination of olefin viadissociation of a neutral ligand. Thought to operatewhen X = strong σ-donor (i.e.Cl, Br or I). When arylor vinyl halides are used, bidentate ligands can result in a partial or complete suppression of the reaction.

L

R'

R

HH

H

internalrotation

PdIIH

XL

R

R'

R

R

The reaction is stereoselective for the Eolefin because the corresponding TSleading to the cis olefin involvesenergetically unfavorable R'/R eclipsing interactions.

PdII

XL

H

H

H

reversible β-hydride elimination can lead to olefin isomerizationwhen R= alkyl

R'

R

also known as: olefin insertion, carbopalladation

M.C. White, Chem 253 Cross-Coupling -133- Week of October 18, 2004

L2PdII(X)2

NEt3

Et2N+

L2Pd0

PdIIR'

LL

R

cis migratoryinsertion

oxidativeaddition

PdII

LL

R

H

R'

LPd(II)H

PdIIR'

L

L

Br

R'Br

ββββ-hydrideelimination (cis)

HNO3

PdII

LL

Cationic mechanism: coordination of olefin via dissociation of a weakly associated anionic ligand. Thought to operate when X = OTf, OAc or when Ag or Tl salts (AgY or TlY; Y= CO3, OTf, OAc) are used that are capable of halide abstraction (metathesis- see Structure & Bonding -12-)

R'

R

HH

H

internalrotation

PdIIH

LL

R

R'

R

R

+

NO3-+

NO3-

+

NO3-

+

NO3-

PdII

XL

H

H

H

R'

R

Faster dissociation of the olefin leads to less β-hydride elimination.

AgNO3

AgBr

Heck Reaction

N

PhO

I

Halide abstraction additives minimize db isomerization

N

O

Ph N

O

PhN

O

PhPd(OAc)2 (10 mol%)

PPh3 (20 mol%)

CH3CN, 80oC

none TlOAc (1.2 eq)AgOAc (1.2 eq)

1: 2: 51: 0: 01: 0: 0

1st product formed Pd-H insertion product I Pd-H insertion product II

First example:Overman JOC 1987 (52) 4133.Grigg TL 1991 (32) 687.

Cabri Acc. Chem. Res. 1995 (28) 2.Beletskaya Chem. Rev. 2000 (100) 3009


Heck: Regioselectivity of migratory insertionwith neutral Pd complexes

Heck Org. React. 1982 (27) 345.Heck JACS 1974 (96) 1133.Hallberg Tetrahedron 1994 (50) 285.

H

R

Br (I)

CO2Me CN Ph C4H9

R

CO2Me Ph N

O

OCH3

+

PdII(OAc)2 1 mol%PPh3 2 mol%

NEt3 or

For intermolecular Heck reactions with neutral Pd complexes and unactivated or electron-poor alkenes, the regioselectivity for R' insertion is under steric control, resulting in substitution at the less sterically hindered position. In contrast, with neutral Pd complexes and electron-rich alkenes (e.g. heteroatomsubstituted olefins), the regioselectivity of R' insertion is under electronic control, resulting in substitution α to the electron-donating group.

TMED (tetramethylethylene diamine)ββββ

100% 100% 100% 100%99%

1%

80%

20%

60% 40%

αααα

100%

or

R

M.C. White, Chem 253 Cross-Coupling -135- Week October 18, 2004

Heck: Regioselectivity of migratory insertionwith cationic Pd complexes

Cabri Acc. Chem. Res. 1995 28, 2-7.Cabri JOC 1992, 57, 1481-1486.Cabri Tet. Lett. 1991 32:14, 1753-1756.

H

R

OTf

CO2Me CN Ph C4H9 N

O

OH

R

OAc

R'

O-n-Bu

+

PdII(OAc)2

P(dppp)

For intermolecular Heck reactions with cationic Pd complexes, the regioselectivity for R' insertion is predominantly under electronic control for all substrate classes. Coordination of the olefinπ-system to a cationic Pd complex results in an increase in polarization of the C=C bond, and selectivemigration of the aryl moiety onto the carbon with lower charge density is observed.

ββββ

100% 100% 60% 20%

80%

100%

αααα

40% 100% 95% 100%5%

or Ar-X + TlOAc

NEt3 or iPr2NEt

R'

R

R'or


PdL X

Pd(L)n(X)

exo-trig

PdL X

endo-trig

Pd(L)n(X)

For the formation of small rings (5,6, or 7 membered rings) conformational effects dominate and the exo-trig mode ofcyclization is generally preferred.

In contrast, for the formation of macrocyclic structures(>9-membered rings), steric effects dominate and the endo-trig mode of cyclization is generally preferred.

NO

I

O

O

N

O

O

O

Pd(OAc)2 N

OO

O

N

O

O

O

n

nTri-o-tolphosphineEt3N, CH3N

n=3, 29%n=5, 24%n=7, 38%

Stocks Tet. Lett. 1995 36:36 6555-6558.

I

CO2CH3Pd(OAc)2

Ph3P, Et3N

CO2CH3

H86%

H

N

I

CO2CH3Pd(OAc)2

Ph3P, Et3N

H

NCO2CH3

H

74%

Overman JOC 1987 52 4130-4133.

Intramolecular Heck: “exo-trig” vs “endo-trig” cyclization

M.C. White/ M.W. KananChem 253 Cross-Coupling -137- Week of October 18, 2004

Tandem Heck: construction of adjacent quaternary C centers

N

O O

N

OO

Bn BnI IBnN

O

NBnO

OO

Pd(PPh3)2Cl2 (10 mol%)

Et3N, DMA, 100°C

90%

BnN

O

OO

N

IBn

O

PdI

PPh3

BnN

O

OO

PdIL O

N

BnI

H

BnN

O

OO

N

I

O

Bn

BnN

O

NBnO

OOPdLI

BnN

O

NBnO

OO

PdI

L

The stereochemistry of the acetonide controls the Heck cyclizations such that only a singlestereoisomer is observed. Despite the stericcongestion of the olefins in the twocylcizations (tetra- and tri-substituted), theoverall transformation proceeds efficiently.

Pd(PPh3)2

oxidative addition

olefin insertion

β-hydrideelimination

oxidativeaddition

olefin insertion

β-hydrideelimination

Overman JACS 1999 (121) 7702.

M.C. White/M.W. Kanan Chem 253 Cross-Coupling -138- Week of October 18, 2004

Pd0P

P

TfO OMOM

HO

OH

OBOM

Pd OMOM

HO

OH

OBOMP

P

OMOMOBOM

OH

HO

PdPP

OMOM

OBOM

OH

HO

PdP

P

TfO-

Et3N

PdP

P

Et3N

OMOM

OBOM

OH

HO

OMOM

OBOM

OH

HO

Et2N

PdP

P

H

PdP

P

H

OMOM

OBOM

OH

HO

OMOM

OBOM

OH

HO

Pd2(dba)3 (15 mol%)

dppb (40 mol%)Et3N, DMAc, 120°C

+

+

+ +

+

oxidative addition

olefin insertion

b-hydride elimination

reductive elimination

In the initial insertion intermediate, there is no β-hydrogen to enable elimination of

PdII and regeneration of olefin. Et3N serves as a hydride donor, generating an

alkyl-hydrido species that reductively eliminates to release the desired product.

Hirama Org. Lett. 2002 (4) 1627.

84%

Et2N+

Intramolecular Mizoroki-Heck to construct a quaternary carbon center

M.C. White/Q.Chen Chem 253 Cross-Coupling -139- Week of October 18, 2004

Tandem Heck-Hiyama Coupling

O

O

OEt

I

SiR

iPriPr

OSi

OH

iPr iPr

O

EtO

R

O

O

OEt

SiR

iPriPr

(dppp)PdI

O

OSi

R

iPr iPr

Pd(dppp)

OEt

IOH

O

OSi

R

iPr iPr

Pd(dppp)

OEt

IOH

O

OSi

I

iPr iPr

Pd(dppp)

OEt

OHR

10% Pd(OAc)2, 20% dpppIsoprostanes &Neuroprostanes

73%Pd(dppp)

Pd(dppp), I

Following olefin insertion, there is no syn hydrogen available for β-hydride elimination. Instead, this intermediate is proposed toundergo a hydroxide-promoted, intramolecular Hiyama-typetransmetalation followed by reductive elimination to yield thedesired product.

Et3N (5 eq), H2O (2 eq), DMF, 80 °C

oxidative addition

olefininsertion

intramoleculartransmetalation

reductiveelimination

R = n-Hex

Quan, L. G.; Cha, J.K. JACS 2002, ASAP.

M.C. White, Chem 253 Hydrogenation -140- Week of October 18, 2004

Wilkinson’s CatalystWilkinson's original report:

Ph3P

Rh(I)Ph3P PPh3

Cl

cat.

H2 (1 atm), benzene, rtquantitative

Investigations into the reactivity of (PPh3)RhCl uncovered its high activity as a homogeneoushydrogenation catalyst. This was the firsthomogeneous catalyst that compared in rateswith heterogeneous counterparts.

Wilkinson J. Chem. Soc. (A) 1966, 1711.

O

C N NO2O R

O

OR

O

OH

Functionality tolerated

Ph3P

Rh(I)Ph3P PPh3

Cl

Cl

Rh(III)

Ph3P H

PPh3

H

PPh3

Ph3P

Rh(I)Ph3P PPh3

Cl

Data indicates that formationof an ethylene/ Rh(Cl)(PPh3)3 complex inhibits hydrogenactivation by the complex.This implies that dihydrideformation precedes olefincomplexation in the catalyticcycle.

cat.

H2 (1 atm), benzene, rt

Ethylene is not hydrogenated under these conditions but...stoichiometric hydrogen transfer from preformed dihydride complex occurs.

+ rt +

Ph3PRh(I)

Ph3P PPh3

ClC3H7 CH3

CH3C3H7

H H

Compatibility with carbonylgroups indicates that the metalhydride intermediate is primarily covalent in character (lackshydridic properties characteristicof strongly ionic M-H). SeeStructure & Bonding pg. 28.

H2 (50 atm), benzene

20oCcis- hexene: trans-hexene

(>20:1)

+ hexaneCO2HHO2C

Ph3PRh(I)

Ph3P PPh3

Cl

D2 (1 atm), benzene

20oC

H H D D

HO2CH H

CO2H

The stereochemical outcome of this experiment indicates that the mechanism involves stereospecific cis hydrometallation of the unsaturated substrate followed by stereospecific reductive elimination from the resulting alkenyl (or alkyl) hydrido species.

meso compoundmajor product observed

Ph3P

Rh(I)Ph3P PPh3

Clcat.

H2: D2 (1:1)

H

H

50% D

D

43.9% H

D

6.1%

Minimal H/D scrambling in the product isindicative of formation of a dihydrometalintermediate that transfers both of its hydrido ligands to the unsaturated substrate.


Ph3P

Rh(I)Ph3P PPh3

Cl1 mol%

H2 (1 atms.), benzene, rt

+unsaturated

substrate

+saturatedsubstrate

competition figure =

rate of hydrogenation ofunsaturated substrate

rate of hydrogenation of1-octene

Wilkinson: substrate selectivity

Candlin Faraday Discuss. Chem. Soc. 1968 (46) 60.

HO

HO

EtO

C3H7 ,

C4H9

C2H5C2H5

C2H5

also 1-heptyne, 1-octyne

also, 1-decene, 1-dodecene

C3H7C3H7

C3H7

C3H7

NC

unsaturated substrate competition figure

14.7

9.1

3.4

1.8

1.7

2.6

0.92

0.75

0.71

0.69

0.54

0.17

1.0

cyclohexene

1,3-cyclooctadiene

Terminal alkenes between C6-C12 are hydrogenated at the same rate. The same is observed for terminal alkynes. Anincrease in carbon chain length does not appear to affectolefin/catalyst interaction.

Internal and branched alkenes (alkynes) are hydrogenatedslower than terminal alkenes (alkynes). These differences are rationalized in terms of steric effects on olefin interactionwith the catalyst and have been used to effect selectivealkene hydrogenations in polyene compounds.

Unsaturated substrates containing functionality arehydrogenated more rapidly than their unfunctionalizedcounterparts. The effect is suggested to result from polar functional group assisted olefin coordination to thecatalyst.

Terminal alkynes are hydrogenated more rapidly thanterminal alkenes. This selectivity may be enhanced by use of acidic alcohol co-solvents (e.g. in benzene/2,2,2-trifluoroethanol, 1-hexyne: 1-octene (12:1).

Conjugated dienes are reduced slower than isolated alkenes.


Wilkinson hydrogenation: classic dihydride mechanism

Ph3P

Rh(I)

Ph3P PPh3

Cl

H2

Ph3P

Rh(III)H PPh3

Cl

H

PPh3

oxidative addition

-PPh3

Ph3P

Rh(I)S PPh3

Cl

solution structuredetermined by NMR.

Ph3P

Rh(III)H PPh3

Cl

H

R

+PPh3

Ph3P

Rh(III)PPh3

Cl

H

S

R migratory insertion

RDS

Ph3P

Rh(III)H PPh3

Cl

H

S

-PPh3+PPh3

H2

reductive elimination

oxidative addition

catalytic cycle

coordinatively unsaturatedcomplex reacts w/ H2 104 x faster than Rh(Cl)PPh3

Ph3P

Rh(I)

PPh3

Cl

strong π-acids (e.g. ethylene) bind tightly to the electron rich Rhcenter and inhibit hydrogenation

Ph3P

Rh(I)Ph3P Cl

Cl

Rh(I)PPh3

PPh3

Ph3P

Rh(I)

Ph3P Cl

Cl

Rh(III)

H

H

PPh3

PPh3

H2

Intermediates observed by NMR or as isolatedsolids in the reaction system. Formation ofthese "side-products" results in a reduction inthe rate of hydrogenation.

Halpern Chem. Comm. 1973 629.Halpern J. Mol. Catal. 1976 (2) 65.Halpern Inorg. Chim. Acta. 1981 (50) 11.


Wilkinson: site selectivity

Ph3P

Rh(I)Ph3P PPh3

Cl

Ph3P

Rh(I)Ph3P PPh3

Cl

Strem catalog 2001-20031g = $42

Chlorotris(triphenylphosphine)rhodium IO

O

O

O

O

O

H

O

O

O1 mol%H2 (1 atm), benzene/EtOH, rt

95%

Pd/Cacetone, H2 (1 atm), rt

75%

ketone activatedcis-disubstituted

tetrasubstituted

O

CH(CH3)C2H5

OO

H

OMe

O

O

OH

H3CO

O

OH

MeO

HO

OH

H

conjugateddiene

trisubstituted

trisubstituted

cis-disubstituted

O

CH(CH3)C2H5

OO

H

OMe

O

O

OH

H3CO

O

OH

MeO

HO

OH

H

Ph3P

Rh(I)Ph3P PPh3

Cl~30 mol%

H2 (1 atm), tol, rt92%

only site of hydrogenation

O

HO

CO2Me

OAc

cis-disubstituted

trans-disubstituted

Ph3P

Rh(I)Ph3P PPh3

Cl

H2 (1 atm), benzene/acetone, rt80%

cat.

O

HOOAc

CO2Me

cis vs. trans-disubstituted olefins:

Schneider JOC 1973 (38) 951.PGE2 PGE1

Site selective hydrogenation: sterics

highly active heterogeneouscatalysts often cannot achievehigh levels of selectivity.

Site selective hydrogenation: sterics and electronics

Pedro JOC 1996 (61) 3815.

Fisher J. Med. Chem. 1980 (23) 1134. Ivermectin


Wilkinson: diastereoselectivity

Ph3P

Rh(I)Ph3P PPh3

Cl1 mol%

H2 (1 atm.), benzene/EtOH, rt

Me

H

endo exo

Me

R R R

R = H : 73% endoR = Me : 92% endo

Rationale for observed diastereoselectivity:Olefin binds the catalyst from the leaststerically hindered exo face. Subsequent cis hydrometallation of the exo face followedby stereospecific reductive elimination ofthe alkyl metal hydrido intermediate resultsin overall cis addition of H2 to the leaststerically hindered exo face of the olefin.

ClRh(III)

Ph3P H

PPh3

H

R

vs.

ClRh(III)

Ph3P H

PPh3

H

R

Rousseau J. Mol. Cat. 1979 (5) 163.Jardine Prog. Inorg. Chem. 1981 (28) 63.

BnO

OMOM

OBnBnO

olefin complexation andhydrogenation from sterically less hindered face

Ph3P

Rh(I)Ph3P PPh3

Cl30 mol%

H2 (1 atm.), tol, rt83%

BnO

OMOM

OBnBnO Lowary OL 2000 (2) 167.


Wilkinson: directing group effects

MeO

OH

trisubstituted

Ph3P

Rh(I)Ph3P PPh3

Cl0.04 mol%

H2 (6.8 atm, 100psi), benzene, 50oC

no reaction

Ph3P

Rh(I)Ph3P PPh3

Cl0.04 mol%

H2 (6.8 atm, 100psi), benzene, 50oC

68%

K+ B-

MeO

OH

H

MeO

O-K+

trisubstituted

H

ORh

H

PPh3

H

PPh3

cis isomer (exclusive)

note: when Pd/C was used a mixture of cis and transisomers resulted

Thompson JACS 1974 (96) 6232.Jardine Prog. Inorg. Chem. 1981 (28) 63.

The slow reaction without the alkoxide isattibuted to the steric hinderance of thetri-substituted double bond, which renders it lessable to coordinate to the Rh. The protonatedalcohol is not a strong enough nucleophile toassociatively displace the anionic chloride ligand. Base-assisted formation of the alkoxide results ineffective displacement of the chloride ligand andthus directs olefin complexation from the sameface.


Schrock- Osborn /Crabtree: Cationic catalystsDiene ligated cationic catalysts mode of activation:

Ir(I)PCy3

N

(PF6-) Ir(III)

PCy3

H

(PF6-)

H

N

Ir(III)PCy3

H

(PF6-)

N

+ +

+

SIr(I)

PCy3

N

(PF6-)

+

repeat

SIr(I)

S PCy3

N

(PF6-)

+

diene ligatedcatalyst precursor

solvated active catalyst

H2

cis-oxidativeaddition

cis-migratory insertion

cis-reductiveelimination

Crabtree Acc Chem Res 1979 (12) 331.

Ph3PRh(I)

Ph3P PPh3

Cl

Ir(I)

N

PCy3(PF6

-)

Rh(I)

PPh3

PPh3(PF6

-)

+

+

Turnover Frequency (TOF)

TOF = mol reduced substrate/mol catalyst/h

CH2Cl2, 25oC

CH2Cl2, 25oC

benzene/EtOH, 25oC

Schrock-Osborn catalyst

Crabtree's catalyst

Wilkinson's catalyst

650

4000

6400

700

10

4500

13

----

3800

----

----

4000

"Coordinatively" unsaturatedcationic hydrogenation catalystsare the most active homogeneous hydrogenation catalystsdeveloped thus far. Use ofweakly coordinating solventsprovides the olefin substratewith relatively free access to themetal's reactive site. Thesecationic catalysts are alsoremarkably selective....


Cationic catalysts: substrate-directed hydrogenations

CH2Cl2, H2 (1 atm), rtMe

OHIr(I)

PCy3

N

(PF6-)

+

2.5 mol%

Me

OH

H

i-Pr

OH

Me

H

Ir(III)Cy3P Py

(PF6-)

H +

Me

OH

H

98% 64:1

Pd/C (EtOH), 1:5 (sterics)

Crabtree JOC 1986 (51) 2655.

The availability of a second "open" coordinationsite on the catalyst now makes it possible to bind aligating group on the substrate in addition to theolefin. This "two-point" binding has importantimplications on the selectivity of product formation. The ability of a late metal complex to effectivelybind hard functionality (hydroxyls, ketones, etc...)is attributed to the lewis acidic properties impartedon the complex by the overall positive charge.

Other functionalities with lewis basic sites also direct:

CO2Me

HMe

CO2Me

Me Me

MeO MeO

Me H

O

Me

MeO

Me

Me H

Esters:

56:1Pd/C 1.35:1

above

124:1Pd/C 1.26:1

above

Ketones:

97% >99%

999:1Pd/C 1:4

above

>99%

Ethers

NH

N

O

ONH

N

O

O

Me

above

>99:1Pd/C 1:9 (steric approach control)

HAmides:

5 mol%

(±) (±) (±)

For a comprehensive review of cyclic and acyclic substrate-directed hydrogenations see: Hoveyda, Evans, and Fu Chem. Rev. 1993 (93) 1307 and D.A. Evans; Chem 206 notes.

M.C. White/Q. Chen Chem 253 Hydrogenation -148- Week of October 18, 2004

High catalyst loadings: diminished yields and selectivities

Dimished yields are observed with higher catalyst loadings. This can berationalized on the basis that higher catalyst loadings promote the irreversibletrimerization of the coordinatively unsaturated catalysts to yield inactive triiridium hydride bridged complexes. Such complexes have been isolated by Crabtree fromreaction mixtures of more sterically hindered olefins that did not proceed tocompletion.

Crabtree Acc. Chem. Res. 1979 (12) 331.

CH2Cl2, H2 (1 atm), rtMe

OHIr(I)

PCy3

N

(PF6-)

+

2.5 mol%

Me

OH

H

Me

OH

H

99% 139:1

yieldselectivity (ratio A:B)

20 mol% 48%

A B

74:1

Stork JACS 1983 (105) 1072.Crabtree JOC 1986 (51) 2655.

A decrease in selectivity is observed at higher catalyst loadings. It is possible that higher catalyst loadingspromote the formation of dimeric (Crabtree suggestedM-H-M) species that no longer have the "open"coordination site necessary for providing effectivedirecting effects in olefin hydrogenation. Noexperimental data exists thus far to support thishypothesis.


Synthetic applications of directed hydrogenations

O

O

O

OH

HHOSEM

MOMO

Me

O

O

O

OH

HOSEM

MOMO

MeMOMO MOMO

[Rh(NBD)(DIPHOS-4)]+BF4-

NaH, THFH2 (800 psi), rt

Paquette OL 2002 (4) 937.

HO

H

OHO

Me H2, CH2Cl2HO

H

OHO

Me

Me

Barriault OL 2001 (3) 1925.

HO

HO

O

Me

H

HO

HO

O

Me

HMe

H

Rh(I)

Ph2P

PPh2

(BF4-)

+

()n= 3

68%

[Ir(COD)(py)(PCy3)]+PF6-

99% Yield, d.r. 11:1 at C10

10

Ir(I)PCy3

N

(PF6-)

+


Mechanism of hydrogenation:bidentate cationic complexes

Rh(I)PPh3

PPh3

(PF6-)

+


Rh(I)

Ph2P

PPh2

(PF6-)

+

()n= 3

nbd (norbornadiene) ring strain results in more facilehydrogenation

diphos

Schrock-Osborn type catalystmost commonly used:

[Rh(nbd)(diphos-4)]BF4

Halpern's mechanism for cationic Rh(I) catalysts with bidentatephosphine ligands:

Halpern Science 1982 (217) 401.

H2MeOH

Ph CO2Me

NHAc

H2 oxidative addition (OA)RDS

(rate determining step)

stereospecificcis-migratory

insertion

stereospecificreductive

elimination

observed by NMR

observed by NMRobserved by NMR

SRh(I)

SPh2P

PPh2

+

Rh(I)

Ph2P

PPh2

+

NH

PhH

O

Rh(I)

Ph2P

PPh2

+

R

NH

PhH

HRh(III)

Ph2P

PPh2

+

R

H

O

(R)

NHO

Rh(III)

Ph2P

PPh2

+

HPh

H

R

H

S

Ph CO2Me

NHAc


Mechanism of monodentate cationic complexesHalpern notes that the hydrogenation mechanism for bidentate ligated cationic complexes where olefin substrate coordination precedes oxidative addition of H2 maynot be operating for cationic catalysts with monodentate ligands. Schrock-Osborn invoke involvement of the dihydride complex (below) in the principle hydrogenation pathway for their catalyst. Halpern notes some significant differences in the reactivities towards H2 of the catalysts w/ bidentate and monodentate phosphine ligands.

Rh(I)PPh3

PPh3Ph3P

Rh(III)S PPh3

H

H

S

++

Rh(I)

Ph2P

PPh2

H2

SRh(I)

SPh2P

PPh2

+ +

In the absence of olefin substrate, no further uptake of H2 can bedetected. The only species observedby NMR is the cationic,4-coordinate solvated species.

Treatment of the monodentatecatalyst with H2 resulted in detection of the Rh(III)-dihydride complex.

Halpern JACS 1977 (99) 8055. Schrock & Osborn JACS 1976 (98) 2135.

Ph3PRh(I)

S PPh3

S

+

only speciesobserved by NMR

k1

k-1

HRh(I)S

Ph2P

PPh2

+

k1

k-1

H2

only species observed by NMR

H

S

To explain the difference in reactivities towards H2 of the catalysts, Halpern invokes the trans effect. The trans effect is defined as thelabilization of ligands trans to certain other ligands. The trans effect often arises when a ligand shares an orbital with another ligand of strongσ-bonding character. Because phosphine forms a strong σ bond with Rh, trans Rh-H bonds formed will be weak because the orbital is not asavailable for bonding to H. In the case of the bidentate complex, cis addition of H2 requires that one hydride share an orbital with a phosphine. Since both hydride and phosphine are strong σ-bonding ligands, the dihydride adduct, once formed, is highly unstable and thus rapidly revertsback via reductive elimination to the solvated 4-coordinate species. In the case of the monodentate phosphine complex, a H2 adduct can formwhere neither H ligand is trans to a phosphine.

Classic example of the trans effect: synthesis of "cis-platinum" a chemotherapeutic agent

ClPt(II)

Cl Cl

Cl

2-NH3

ClPt(II)

Cl Cl

NH3

-

Cl has a stronger "trans influence" than NH3

NH3

ClPt(II)

Cl NH3

NH3

only the cis isomer is formed

H3NPt(II)

H3N NH3

NH3

2+

Cl

H3NPt(II)

H3N Cl

NH3

+

Cl has a stronger "trans influence" than NH3

ClPt(II)

H3N Cl

NH3

only the trans isomer is formed

Cl

The Trans Effect:


Asymmetric Hydrogenation

A variety of bidentate chiral phosphines have since been synthesized and used to effect the hydrogenation of aromatic enamides (important substrates for the efficientgeneration of amino acids):

PPh2

PPh2

Chiraphos (99% ee)

PPh2

PPh2

SKEWPHOS (92% ee)

PPh2

PPh2

BINAP (100% ee)

P

P

R

RR

RDuPHOS (99% ee)

PPh2

PPh2

NORPHOS (95% ee)

HH

PPh2

PPh2

BICP (97% ee)

O

O

PPh2

PPh2

H

H

DIOP (85% ee)

Fe PPh2

NMe2

PPh2

BPPFA (93% ee)

Fe PPh2

PCy2

PPh2

JOSIPHOS (96% ee) E. N. Jacobsen. Chem 153 notes. Spring 2001.For review on DuPhos: Burk Acc. Chem. Res. 2000 (33) 363.

We'll see these ligands again effecting asymmetry ina wide assortment of mechanistically unrelated metal catalyzed reactions with prochiral substrates."Privileged ligand class": ligands that communicateasymmetry effectively with a transition statelocalized at the metal center, irrespective of thenature of the transition state.

E.N. Jacobsen;personal communication

Rh(I)PPh3

PPh3

(PF6-)

+


A bidentate, C2 symmetric version of the cationic Schrock-Osborn catalyst affords extraordinarily high levels of enantioselectivity in the hydrogenation of achiral enamides. This was the first demonstration that a chiraltransition metal complex could effectively transfer chirality to a non-chiral substrate with selectivities that rivalthose observed in enzymes. Recall that this led to the 1st commericalized asymmetric process using a chiraltransition metal complex: Monsanto Process for the industrial production of L-DOPA (see Structure andBonding, pg. 4)

CO2H

NHAc

Rh(I)P

P

(PF6-)

+MeO

OMe

i-PrOH, H2 (1 atm), rt>99% yield

CO2H

NHAc

93% eeKnowles JACS 1975 (97) 2567.

DIPAMP (common name for this bidentate chiral phosphineligand)


Origin of Asymmetric Induction

It was concluded from kinetic measurements thatthe minor diastereomer was 580 fold more reactivetowards H2 oxidative addition (recall the RDS at rt). This factor offsets its lower concentration insolution and results in a 60:1 product ratio in favorof the R enantiomer.


CO2H

NHAc

H2 (1 atm), 25oC, MeOH

CO2Et

NHAc

N-acetyl-(R)-phenylalanine>95% ee

(R)

Rh(I)P

P

(ClO4-)

+

H3C

H3C

(S,S-CHIRAPHOS)

Rh(I)P

P O

NH

(ClO4-)

+

H3C

H3C

MeO2C

Ph

olefin bound to Rh via its

si-face

stereospecific H migratory insertion /stereospecific H/C reductive elimination

both to the olefin face bound to Rh

minor diastereomer formednone detected by NMR (must be less than 5% present in solution)

Rh(I)P

PO

HN

(ClO4-)

+

CH3

CH3

CO2Me

Ph

olefin boundto Rh via its

re-face

major diastereomer formedin solution (identified by NMR

and x-ray crystallography)


Rh(I)P

PO

HN

(ClO4-)

+

CH3

CH3

CO2Me

Ph

olefin boundto Rh via its

re-face

major diastereomer formedin solution (identified by NMR

and x-ray crystallography)


Crystal structure of major diastereomer

CO2Et

NHAc

N-acetyl-(R)-phenylalanine>95% ee

(R)

Major enantiomer observed upon exposing crystal to H2:

CO2Et

NHAc

Minor enantiomer observed uponexposing crystal to H2.

(S)


Monohydride catalysts: RuClH(PPh3)3

O

O

cat.

H2 (126 atm), base (1 eq)

benzene, 40oC, 6h

RuCl2(PPh3)2

O

O

Base % Conversion

NEt3Et2NHBuNH2anilineCa2CO3Na2CO3none

95.495.486.588.195.273.076.0

Effect of base on conversion

fully satuturatedproducts

+

Tsuneda Bull. Chem. Soc. Jpn. 1973 (46) 279.

RuCl(H)(PPh3)3, highly distortedtrigonal bipyramidal. Skapski Chem.

Comm. 1968 1230.

Wilkinson's original report:

cat.

H2 (1 atm), benzene:ethanol, rtquantitative

The active species was identified as the monohydride, thought to form via heterolytic cleavage of H2, with ethanol acting as a base. The monohydride can also be prepared in 100% benzene if anequivalent of NEt3 is added. One mole of H2 is absorbed with respect to Ru and aminehydrochloride is quantitatively formed. Wilkinson J. Chem. Soc. (A) 1968 3143.

Ph3P Ru(II)

PPh3

PPh3

H

Cl

RuCl2(PPh3)2

"In contrast to the rhodium system, ethanol plays an intimate part in the hydrogenation mechanism; in theabsence of such a co-solvent, hydrogenation is exceedingly slow." Wilkinson Nature 1965 (208) 1203.

RuCl2(PPh3)3H2 (1 eq)

NEt3 (1 eq), benzene+ -Cl +HNEt3


Mechanism of H2 Activation

σ-bond metathesis: the base is effectively one of the ligands on the metal

RuCl2(PPh3)3H2

RuCl(PPh3)3

Cl

H

H

δ−

δ+ RuHCl(PPh3)3

HCl

σ-bond metathesis

external amine base may still drive the rxn forward by forming insoluble amine hydrochloride salts

Crabtree The Organometallic Chemistry of the Transition Metals: 3rd Edition; Wiley: New York; 2001.

Base promoted heterolytic cleavage:

H

H

Mn

σ-donation>>π-backbonding

heterolytic cleavage

σ-complex

Mn H BH++

note: there is no oxidation statechange at themetal

generally observed for electrophilicmetals that are in their highest stableoxidation state within the context of their ligand framework.

Example:

N NH2

Ir(III)

L

H

L H

H

+

(BF4)-

N NH3+

Ir(III)

L

H

H

L

+(BF4)

-

Complexation of dihydrogen to the electrophilic, cationicIr(III) center is predominantly σ-donating in nature.Donation of electron density from the H-H σ-bond to anempty Ir orbital leaves the H-H with a partial positivecharge. The pendent NH2 group is thought to act as aninternal base effecting heterolytic cleavage of the acidifieddihydrogen σ-complex via deprotonation.When L = PPh3,the equilibrium lies far to the right and only the dihydride 2 is observed. When more basic alkyl phosphines are used(L= PBu3) the equilibrium lies to the left with the H2complex 1 being observed exclusively by NMR. It washypothesized that moving to a more basic phosphineincreases the electron density at the metal center. Thismakes the metal a less effective σ-acceptor and attenuatesits ability to effectively acidify the dihydrogen complex.

1 2

Crabtree Chem. Commun. 1999 297.

δ+


BINAP-Ru complexes: Noyori increases the substrate scopefor asymmetric hydrogenations

The first report: asymmetric hydrogenation of (Z)-enamides

NCOCH3

H3CO

AcO

OAc

OCH3

PPh2

Ru(II)

Ph2P O

O

O

O

(0.5-1 mol%)

EtOH:CH2Cl2 (5:1), H2 (4 atm), 23oC

NCOCH3

H3CO

AcO

OAc

OCH3

NCH3

HO

HO

O

H

morphine92% yield95% ee

Interestingly, E-enamides are completely unreactive towards these hydrogenation conditions. Norationale for this has been presented.

Noyori JACS 1986 (108) 7117.Noyori ACIEE 2002 (41) 2008.

(R)-1

air-sensitive

Asymmetric hydrogenation of allylic and homoallylic alcohols:

PTol2

Ru(II)

Tol2P O

O

O

O

0.01 mol%

MeOH, H2, 18-20oC

(S)-1OH

OH

geraniol

nerol

0.2 mol%

MeOH, H2, 18-20oC

(S)-1

OH

OH

(R)-citronellol

97 to >99% yields

(S)-citronellol

96% ee

98% ee

allylic olefin geometry may dictate the stereochemical outcome of thehydrogenation. Practical consequence:to obtain high ee's must start withstereochemically pure olefins.

E-olefin

Z-olefin

regioselectivity: allylic and homoallylic alcohols are hydrogenated whereas bis homoallylic and higheranalogues are left untouched.

Noyori JACS 1987 (109) 1596.


BINAP-Ru complexes: Noyori increases the substrate scopefor asymmetric hydrogenations

The first demonstration of high asymmetric induction in the hydrogenation of substrates lacking an acylamino group: asymmetric hydrogenation of α,β-unsaturated carboxylic acids

The degree of asymmetric induction is significantlyaffected by the H2 pressure in a substrate specificmanner. The implication of this is that a range of H2pressures must be screened to achieve optimalasymmetric induction on a substrate by substrate basis. No trend was observed and no rationale for theemperical observation was given.

H3C CH3

CO2H

PPh2

Ru(II)

Ph2P O

O

O

O

(0.5-1 mol%)

MeOH, H2, 15-30oC

(S)-1

H3C CH3

CO2H

(S)

H2 (4 atm): 91% eeH2 (101 atm): 50% ee

CO2H

Ph

CO2H

(S)

H2 (4 atm): 48% eeH2 (112 atm): 92% ee

Asymmetric Synthesis of (S)-Naproxen:

H3CO

CO2H (0.5 mol%)

MeOH, H2 (135 atm), 15-30oC

(S)-1

H3CO

CO2H

(S)-Naproxen92% yield97% ee Noyori JOC 1987 (52) 3174.


Mechanism of BINAP-Ru hydrogenation of α,β-unsaturated acids

Reactions in MeOD

H3C CH3

CO2H

H CO2HCH3H3C

D H

(S)-1H2, MeOD

Experiment indicates that the hydrogen α to the acid comes from H2 whereas the β-hydrogencomes from MeOH. Regio- and stereospecific deuterium incorporation indicates that cis-migratoryinsertion of the Ru-H is stereospecific as is cleavage of the Ru-C bond via protonolysis. The lack of D incorporation into the α position indicates that the rate of H/D exchange between the Ru-H andsolvent is slow.

Halpern JACS 1991 (113) 589.

PPh2

Ru(II)

Ph2P O

O

O

O

CO2H

PPh2

Ru(II)

Ph2P O

O

O

O

AcOH

PPh2

Ru(II)

Ph2P O

O

O

H

O

H2

H+

PPh2

Ru(II)

Ph2P O

O

O

O

H

PPh2

Ru(II)

Ph2P O

O

O

O

H+

CO2H

CO2H

Heterolytic cleavage of H2RDS

note: no oxidationstate change to themetal

note: mechanism is valid for both enantiomers of BINAP. No rationalization for the enantiofacialselectivity is given.

protonolysis

1

cis-migratory insertion


Question of the Week

PPh2

Ru(II)

Ph2P O

O

O

ONH

O

CH3

O

MeO

Ph

Ru(CH3CO2)2-[(S)-BINAP] catalyzes the hydrogenation of α-(acylamino)acrylic esters to give the (S) saturated product in >90% ee's.Propose a mechanism that accounts for the observed mixture of hydrogenation products when the reaction is run in MeOD. Note: your mechanism need not rationalize the absolute stereochemistry obtained.

H

NH

O

CH3

O

OMe

Ph

H HH

NH

O

CH3

O

OMe

Ph

H DH

NH

O

CH3

O

OMe

Ph

H HD

(S)-1

H2 (1 atm), MeOD

79:14:2

heck reaction - harvard universitysites.fas.harvard.edu/~chem253/notes/2004wk5.pdf · 2004. 10....

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