Wilkinson’s catalyst: not just - Harvard...

M.C. White, Chem 253 Hydrosilyation -183- Week of November 1, 2004

Wilkinson’s catalyst: not just for hydrogenationsInternal olefins are not hydrosilylated. However the catalyst isomerizes them to terminal olefins which then undergo hydrosilylation:

cis-2-pentene

RhCl(PPh3)3

PhMe2Si-H

SiMe2Ph

75%

RhCl(PPh3)3

PhMe2Si-H

SiMe2Ph

80% + trans-2-pentene

Generally, the rate of olefin isomerization for terminal olefins is much slower than the rate of isomerization. However, the yields are seldom quantitativebecause of this side reaction.

Chalk JOMC 1970 (21) 207.

Ph3P

Rh(I)

Ph3P PPh3

Cl

Rh(III)H PPh3

PPh3

SiR3

Cl

Rh(III)PPh3

PPh3

SiR3

Cl

Rh(III)

PPh3

PPh3

SiR3

Cl

R

PPh3

R3Si-HR

SiR3

Rh(III)PPh3

PPh3

SiR3

+

β-hydride elimination

olefin isomerization biproduct

Jardine Prog. Inorg. Chem. 1981 (28) 63.

ClRh(I)

Ph3P

Ph3P

H

oxidativeaddition

cis-migratory insertion

(hydrometallation)

reductiveelimination

Reductive elimination from the branchedmetal alkyl is not observed. Once formed,this intermediate can undergo β-hydrideelimination to form an internal olefin or aterminal olefin. The terminal olefin willre-enters the catalytic cycle at a faster ratethan the internal olefin (recall high sensitivity to sterics of the Wilkinson catalyst towardsalkene hydrogenations.

R

linearmetal alkyl

Cl

HR

branchedmetal alkyl

R

M.C. White, Chem 253 Hydrosilylation -184- Week of November 1, 2004

Hydrosilylation of alkynes

R3Si-HC4H9

SiR3

RhCl(PPh3)3 0.001 mol%Et3Si-H, rt 1h

SiEt3

C4H9

trans product65%

C4H9 SiEt3

cis product20%

Parish JOMC 1978 (161) 91

+

Stereospecific cis hydrometallation of the coordinated alkyne followed stereospecific reductive elimination of the alkenylsilane should result exclusively in trans product. The experimental observation that cis product formed was accounted for by envoking addition of a second round of hydrometallation on the alkene followed by β-hydride elimination. Thishypothesis is supported by the observation that pure trans product partially isomerizes to the cis upon treatment with thecatalyst and silane (note: no isomeriztion occurs in the absence of silane)

C4H9C4H9

SiR3

Rh(III)PPh3

PPh3

SiR3

SiEt3C4H9

ClRh(I)

Ph3P

Ph3P

Rh(III)

PPh3

PPh3

SiR3

Cl

H

Rh(III)

H PPh3

PPh3

SiR3

Cl

Rh(III)PPh3

PPh3

SiR3

Cl

R

cis-migratory insertion

(hydrometallation)

stereospecific reductiveelimination

Rh(III)H PPh3

PPh3

SiR3

Cl

C4H9

R3Si

Cl

H

SiR3

C4H9

H

β-hydrideelimination

R

M.C. White/Q. Chen Chem 253 Hydrosilylation -185- Week of November 1, 2004

Application of trans hydrosilylation to the synthesis of Brefeldin A

TBSO

HO

CO2Et

O

NOMe 2) CsF, EtOH

TBSO

OH

O

NOMe

CO2Et1) [Cp*Ru(CH3CN)3][PF6] 1 mol%

(EtO)3SiH, CH2Cl2 (+)-Brefeldin A

Trost JACS 2002 (124) 9328

Trost JACS 2002 (124) 9328

Cp*

Ru

L

L L

+Cp*

Ru

L

R3Si H

L

+

CO2EtRCp*

RuR3Si H

L

+

CO2EtR

Cp*

RuL SiR3

L

+

H

SiR3

RCO2Et

Cp*

Ru

L

L L

+

Note that this substrate contains a free hydroxyl and an epimerizable stereogenic center α to the Weinreb amide; both of these functionalities are well tolerated in this reaction which proceeds with very high trans selectivity.

L = CH3CN

-L -L

+LR3SiH

?+

oxidative addition

cis migratoryinsertion

CsF, EtOH

H

H

RCO2Et

R

CO2Et

H


Platinum"Speier's Catalyst" /H2PtCl6·H2O/ chloroplatinic acid is an extremely activecatalyst for olefin hydrosilylations. It demonstrates the same regioselectivityobserved with Wilkinson's catalyst in the hydrosilylation of terminal olefins. It also effects isomerization of internal olefins to terminal olefins prior tohydrosilylation. However unlike Wilkinson's catalyst, chloroplatinic acid isable to hydrosilylate cyclic internal olefins such as cyclohexene in excellentyields.

2-pentene

MeCl2Si-H

SiMe2Ph

93%

H2PtCl6·H2O 0.005 mol%

MeCl2Si-H

SiMe2Ph

89%


100oC

100oC

MeCl2Si-H


100oC

SiMe2Ph

quantitative

terminal olefins

internal olefins

cyclic internal olefins

Speier JACS 1957 (79) 974.

The widely accepted mechanism of this reaction, advanced by Chalk andHarrod, involves reduction of H2PtCl6 to a Pt(II) species that shuttles between(II) and (IV) oxidation states to effect hydrosilylation in a manner analogous tothat proposed for Wilkinson's catalyst. In support of this is the observation ofan induction period before hydrosilylations begins and that certain Pt(II)complexes can effect hydrosilylation, although the exact reactivity (substratescope, yields, etc...) has never been reproduced. It has also been suggested thatthe active catalyst is colloidal platinum metal. Colloidal metals are suspensions of fine particles (~10-1000 Å radius) of metal in a liquid. Often the solutionsappear homogeneous and are able to pass though micropore filters andsurviving centrifugation unaffected.

“On the basis of known chemistry of d8 metal complexes, a mechanism is suggested…” Chalk and Harrod JACS 1965 (87) 16.

L

Pt(II)L

L

R

R3Si-H

oxidativeaddition

Pt(IV)H L

L

SiR3

LR

L

Pt(IV)L

L

SiR3

L

R

migratory insertion

reductiveeliminationR

SiR3

R

For a lead reference on methods for testing for colloidal metal catalysis see:Crabtree OM 1983 (2) 855.

M.C. White/Q. Chen Chem 253 Hydrosilylation -187- Week of November 1, 2004

Application of an intramolecular hydrosilylation in the synthesis of Jatrophatrione

O

Me

Me

MeMe

Me

BnOMe

OSiMe2H

Me

Me

MeMe

Me

BnO

Me

Me

MeMe

Me

BnO

SiO

MeMe

O

Me

Me

MeMe

Me

BnOMe

Si PtCl Cl

H

O

Me

Me

MeMe

Me

BnOMe

SiMeMe

Pt

Cl Cl

H

O

Me

Me

MeMe

Me

BnO

(PtCl2)

1) LiAlH4Et2O

Trisubstituted olefin and benzylic ether notaffected. Directed silyl transfer from convex face of substrate. Alternative iodolactonization fromthe corresponding carbonate was ineffective.

10 mol% HMDS +2 mol% H2PtCl6·6H2O

-(Me3Si)2NH2+Cl-

-(Me3Si)4N2

PtSi

MeMeCl

Cl

Nature of active catalyst unclear as platinum colloids have also beenimplicated as viable catalysts.

2) Me2SiHClEt3N

Paquette JACS 2002 (124) 6542.


Palladium

Pd(PPh3)4 cat.Cl3Si-H

SiCl3

major product

Pd(PPh3)4 0.1 mol%

Cl3Si-H, 110oCSiCl3

Pd(PPh3)4 0.1 mol%

Cl3Si-H, 110oC

SiCl3

90%

95%

Terminal olefins hydrosilylated with anti-Markovnikoff selectivities

No terminally hydrosilylated products from internal olefins were observed.

Aryl-substituted olefins underwent Pd catalyzed hydrosilylation with high regioselectivity for the Markovnikoff products.

First report on palladium catalyzed hydrosilylations:

Tsuji Tetrahedron 1974 (30) 2143.

Pd(PPh3)4 0.1 mol%

Cl3Si-H, 110oC

Cl3Si

Internal olefins hydrosilylated at slower rates and lower yields than terminal olefins.

30%

Unlike platinum catalyzed hydrosilylations, simple palladium salts areinactive. It was found that a variety of Pd(II) sources can be activatedtowards effecting hydrosilylation in the presence of phosphine ligands.Phosphines are thought to reduce Pd(II) to catalytically active Pd(0)(avoids high energy Pd(IV) intermediates) and to act as ligands to thePd(0) preventing its plating out of solution. In support of this, Pd(PPh3)4can be used directly to effect hydrosilylation. The rate of hydrosilylationis affected by the nature of the phosphine used indicating thatPd-phosphine species are present in the catalytic cycle. This observationsuggests that the selectivity of the reaction may be tuned via the phosphine ligand. Triphenylphosphine was found to afford a palladium catalyst withthe highest activity.

PPh3 > PEt3 > PBu3 > PCy3 > P(OCH3)3

Cl3Si

PdIIH

PPh3

R

Proposed intermediate in Pd catalyzed hydrosilylation:

Pd(PPh3)4 0.1 mol%

Cl3Si-H, 110oC

SiCl3

80%

1,3-dienes afford 2-silylated-3-ene products (π-allyl intermedaite?)


Preparation of optically active 2oalcohols from terminal olefins via

asymmetric hydrosilylation/Tamao oxidation sequence

R

OMe

PPh2

PdCl

PdCl

HSiCl3 (1.2 eq)

PdCl

PdCl

HSiCl3 (1.2 eq)

PdCl

PdCl

OH

RSiCl3

R

O

OP N

Me

Me

HSiCl3 (1.2 eq)Me

SiCl3

R Me

SiCl3

EtOHEt3N R Me

Si(OEt)3

HSiCl3 (1.2 eq)

PdCl

PdCl

PPh2PPh2

H2O2

BINAP

OH

R Me

OH

Hayashi JACS 1991 113 9887-9888.

+

*

Palladium complexes coordinated with a chelating bis(phosphine) (e.g. dppb, chiraphos, or

BINAP) did not catalyse the hydrosilation, even at 80 oC. Alternatively, the reaction

proceeded in good to excellent yields at 40 oC with monodentate phosphine ligands. Why?

* *minor product major product

The regioselectivities range from ~15:1 (major:minor), and the isolated yields of secondaryalcohols ranged from 45-75%. The ee's for this process are generally excellent and range from 94-97%."MOP" 0.002 mol%

regioselectivity (87:13) 70% yield 94% ee

regioselectivity (66:34)45% yield, 96% ee

Note: Only unfunctionalized, aliphatic terminal olefins were reported.

StereospecificTamao Oxidation

0.1 mol%

+ MOP1.

2. EtOH, Et3N3. H2O2

+ MOP1.

2. EtOH, Et3N3. H2O2

0.5 mol%

2 mol%

This reaction proceeds in good to excellentyields (74-94%) and with very high ee(95-99%) for a variety of styrene derivatives: R = 3-NO2, 2 or 3-Cl, 2 or 3-CF3, 2-CH3.Stereospecific Tamao oxidation yields nearlyoptically pure benzylic alcohols.

Johannsen JACS 2002 124 4558-4559.

R


PdCl

PdCl

HSiCl3 (2.2 eq)

1 mol%

Fe

PPh

Me

OMe

2.2 mol%

R

H

MeCl3Si

R

MeMgBr

Me3Si

RH

MeMe

MeO

Fe

PdCl3Si H

L*

RR

PdCl3Si H

L*

PdL*Cl3Si

Me

RR

H

MePd

L*

Cl3Si

*L PdHSiCl3

Cl3Si

RH

Me

R = t-Bu 59% yield, 85% eeR = 2,4,6-Me3C6H2 90% yield, 77% eeR = SiMe2t-Bu 40% yield, 68% ee

oxidative addition

migratoryinsertion

reductiveelimination

proposed π-propargyl(silyl)-palladium intermediate

A bulky R group required to get selectivity in the formation of allenylsilane. The authorsspeculate that this sterically bulky group isimportant in retarding the competinghydropalladtion of the alkyne moiety.

Hayashi JACS 2001 123 12915 -12916.

Preparation of optically active axially chiral allenylsilanes via hydrosilylation of 4-substituted 1-buten-3-ynes

M.C. White, Chem 253 Nu attack on Olefins -191- Week of November 1, 2004

Olefin functionalization via metal promoted Nu attack

C

CM

Dewar-Chatt-Duncanson Model

Recall that the balance of electron flow in olefin-metal bonding can be shifted predominantly in one directiondepending on the electronic properties of the metal. Ifthe metal is electron withdrawing, M-L σ-bondingpredominates and withdraws electron density from theπ-bond of the olefin (see Structure and Bonding, pg.39). This results in the induction of a δ+ charge on theolefin that activates it towards nucleophilic attack.

L

PdIIX

X

R

Nu

σ donation>>π-backbonding

Nu

RL

PdIIX

X

δδδδ+

olefin σ-donation to the electrophilic metal activates it towards Nu attackC-H σ-donation to the electrophilic metal activates the metal alkyl towards β-hydride elimination.

Nu

HLPdII

X

R

Nu

R

LPdII

X

H

recall that the equilibrium for latemetals lies towards the olefin formwhich is stabilized via π-backbonding.

LPdII

L

H

X

LPd0

LRE

HX

O2/ 2 HX

2 CuIIX2

OO

2 HX

stoichiometricoxidants

L

PdIIL O

O L

PdIIL O

O

H

H

H2O2

LPdII

L

X

X

O

O

Pd0Ln

O

OH

PdIILn

O

OHPdIILn

2 CuIX

Catalyst regeneration

H+

H+

OHHO


2 mechanistic possibilities for hydroxypalladation:

ClPdIIH2O OH

R

syn hydroxypalladation

ClPdII

H2OOH

R

ClPdIIH2O Cl

R

anti hydroxypalladation

OH2

ClPdIIH2O Cl

OH

R

Deuterium labeling study indicates that hydroxypalladation proceeds via palladium-nucleophile anti-addition.

LnPdII

H D

D H D H

OHLnPdII

H D

OH2

H+

CO

HD DH

OHO PdIILn

O

HD D

H

OPd0Ln

Stille JOMC 1979 (169) 239.

Wacker Oxidation

H2O

HCl2 CuCl2H2O

ClPdIIH2O Cl

OH2

ClPdIIH2O Cl

R

ClPdIIH2O Cl

OH2+

R

ClPdIIH2O

OH

RH

ClPdIIH2O H

OH

R

H2OPdIIH2O

Cl

H

R

R

HO

O

R

R

O

R

HCl

Commericial production of acetaldehyde

ββββ-hydride elimination

LnPd(0)

2 CuCl

1/2 O2+ 2 HCl

· Binding specificity: terminal olefins· Regioselectivity: 2o carbon· Remote functionality tolerated

PdCl2 (cat)CuCl2 (cat)

O2, H2O, HCl

The Wacker oxidation is usedindustrially to produce ~ 4 million tons of acetaldehyde/year.

hydroxypalladation


Oxidation of terminal olefinsSelective oxidation of terminal olefins

O

PdCl2 (cat.)CuCl2 (cat.)/O2

DMF/H2OO

O

70%Chadha J. Chem. Soc. Perkin I 1979 2346.

Cuprous chloride (CuCl)/O2 as the oxidant system leads to faster reactions with no chlorinated biproducts.

H

H OTHP

O

H

H OTHP

O

O

PdCl2 (30 mol%)CuCl (1.6 eq)/O2

DMF/H2O (10:1.2)

77%

Ikegami Tetrahedron 1981 (37) 4411.

H

PdCl2 (20 mol%)CuCl (10 mol%)/O2

DMF/H2O (9:1)

91%OTBS

OO

H

OTBS

OO

O

Money Tetrahedron 1996 (52) 6307.

Benzoquinone can be used as a stoichiometric oxidant:

H

H

H

O

O

HPd(OAc)2 (10 mol%)

HClO4 (0.3M), CH3CN

OO

85%

H

H

H

O

O

H

O

Santelli TL 1994 (35) 6481.

Cu(OAc)2/O2 oxidant system:

O O

PdCl2 (10 mol%)Cu(OAc)2 (20 mol%)/O2

DMF: H2O (7:1) O O

O

Smith JACS 1999 (121) 10468.

Standard Wacker conditions:

M.C. White,M.S. Taylor Chem 253 Olefin Nu attack -194- Week of November 1, 2004

Cl2PdO

O

CH3

R

BnOH2C

BnOOBn

OAc

OAc

Cl2PdO

O

R

BnOH2C

CH3

BnOOBn

OAc

OAc

Cl2Pd O

O

CH3

R

BnOH2C

PdCl2(MeCN)2 (10 mol%)

THF, 23°C82%

BnOOBn

OAc

OAc


THF, 23°C

Palladium (II)-mediated [3,3]-sigmatropic rearrangements

Saito TL 1988 (29) 1157.

OEtOEt

Me

OEt

Me

The vinyl ether 1 is unreactive to Pd(II) catalysis. However, the similar substrate 2 shows good reactivity:


THF, 23°C

Recovered starting material

1


THF, 23°C

71%

The authors speculate that when reacting with 1, Pd(II) binds preferentially to the electron-rich vinyl ether olefin over the terminal olefin.Such binding does not lead to a productive reaction. When the steric bulk of the vinyl ether is increased, as in 2, binding to the vinyl ether is less favourable. Pd(II) coordination to the terminal allylic olefin occurs resulting in catalysis of the Claisen rearrrangement. Note that thesestructural requirements limit the scope of this reaction.

2

Bickelhaupt TL 1986 (27) 6267.


N

O

R

O

N

R

PdIIOCOCF3

OCOCF3

Asymmetric version:

OH

Pd(OCOCF3)2 (10 mol%)(S,S)-boxax (10 mol%)

MeOH

OO (4 eq)

O

OH

Pd(OCOCF3)2 (10 mol%)

(S,S)-boxax (10 mol%)MeOH

OO (4 eq)

5 membered ring formation

6 membered ring formation

O*

71 % yield 93 % ee

61 % yield 97 % eeHayashi JACS 1997 (119) 5063.

OH

Pd(OAc)2 (20 mol%)Cu(OAc)2 (50 mol%)/O2

MeOH/H2O O

54%

OH

PdII

OAcO

O

O PdII

H

O OHOAc

LnPdII

H

OAc

Pd(OAc)2

LnPd0

Pd(OAc)2

HOAc

2 Cu(OAc)2

2 Cu(OAc) 1/2 O2

+ 2 HOAc

H2O

Cycle A Cycle B

Hosokawa Bull. Chem. Soc. Jpn. 1975 (48) 1533.

Cyclic ether formation

5-exo-trig

5-exo-trig

6-exo-trig

Stereochemistry of Oxypalladation

Hayashi JACS 2004 ASAP

OH

D

H

D

H

O

Pd

O

H

O

H

D

O

D

O

D

Pd-D

Pd(MeCN)4(BF4)25 mol%

(S,S)-ip-boxax 10 mol%

BQ (4 eq), MeOH40oC, 4h

syn-oxypalladation

1 (A: 16%; B: 6%)

2 (A: 46%; B: 5%) 3 (A: 29%; B: 7%)

4 (A: 9%, B: 0%)

syn-β hydride elimination

OH

D

HPdCl2(MeCN)2

(10 mol%)Na2CO3 (2 eq),

LiCl (2 eq)BQ (1 eq), THF,

reflux, 24h

conditions A(no base)

conditions B(base)

D

H

O

D

H

O

Pd

anti-oxypalladationH

5 (A: 0%; B: 82%)

syn-β hydride elimination

OR

D

H

O

Pd syn-oxypalladationHanti-β hydride

eliminationB:

Anti-ββββ-Hydride Elimination

AcO

CH(CO2Me)2 CHE2

Pd

H

H

H

CH(CO2Me)2

CH(CO2Me)2

H

anti-elimination

anti- or syn-elimination

Pd(dba)2 2 mol%dppe

4 mol%N(i-Bu)3

Pd(0)SN2

CHE2

Pd

H

H

H

(CO2Me)2HC

CH(CO2Me)2

To test for isomerized π-allyl,1h into the reaction treated withsodium malonate

94% trans

95% trans AcO

To see if a syn acetate migration had occuredmonitored sm and saw no sm isomerization

47%

26%

Andersson OM 1995 (14) 1

EtO2CO

Me

H

H

TBSO

Tsuji/Trost conditions for

diene formation

Me

Hanti

Hsyn

TBSO

Pd

Pd(OAc)2 (10 mol%)PBu3 (10 mol%)

syn-elimination

Me

HTBSO

anti-elimination

H

TBSO Me

only product observedby 1H NMR analysis ofcrudeTakacs JACS 1997 (119) 5956.

CO3Et


M.C. White, M.S. Taylor Chem 253 Nu attack on Olefins -197- Week of November 1, 2004

Application of an intramolecular Wacker oxidation in the synthesis of Garsubellin A

OOO

O

HO

Garsubellin A

Shibasaki OL 2002 (4) 859.

OOO

OO

Na2PdCl4 (40 mol%)t-BuOOH

OOO

OHHO

OOO

OHHO

Cl2PdII

OOO

O

HO

PdIICl2

t-BuOOH

PdIICl2

OOO

O

HO

OOO

O

HO

PdIICl

AcOH / H2O

69%

AcOH / H2OPd0

– HCl

– HCl

OOO

O

HO

HClPdII

H

HCl


reductive elimination

of HCl


HO OBz

PdII OCOCF3

N

N

OCOCF3

OOBz

PdIIN

N

H OCOCF3

OOBz

PdIIN

N

HOCOCF3

H

O OBz

PdIIN

N

H

OCOCF3

OOBz

PdIIN

N

HOCOCF3

OOBz

PdIIN

N H

O OBz

OCOCF3

PdIIN

N

H

OCOCF3

O

H

OBz

PdN

N

H OCOCF3

O

H

OBz

Pd0N

N

O

O

OH

OHPdII

N

N

OCOCF3

OCOCF3

*

6-endo-trig

2 HOCOCF3 +

Proposed mechanism:

Tandem oxopalladation/Heck-type cyclization

Sasai JACS 2001 (123) 2907.

HO OBz

O N N O

H H

i-Pr

i-Pr

i-Pr

i-Pr

PdII

F3COCO OCOCF3

OO CH2Cl2, 0oC

O

H

OBz

O OBz

O OBz

20 mol%

(4 eq)

68%, 95% ee(single diastereomer)

+5%, 45% ee

27%, 60% ee


OH

Pd(OAc)2 (10 mol%)CuCl (1 eq)/O2, DMF

CO2Me O

PdIIAcO

CO2Me

(or Ph)

O

CO2Me

89%

Semmelhack TL 1993 (34) 7205.

β-hydride elimination is not an option for this intermediate

Oxo-palladation/intermolecular Heck

R

OH

Pd(Cl)2 (10 mol%)CuCl2 (3 eq), MeOH

CO OR

PdII

CO

ClL

OR

O

Pd(Cl)Ln

HOMe OR

O

OMe

note: O2 is not necessary to re-oxidize Pd if supra-stoichiometric amounts of Cu(II) salts are used

70%

+ 30% of the furan product

Semmelhack JACS 1984 (106) 1496.

Oxo-palladation/carbonylation

OMe O

O

Pr

OH

CO

OMe O

O

O

Pr

PdII

L Cl

CO

OMe O

O

O

Pr

CO2Me

Pd(Cl)2 (10 mol%)CuCl2 (3 eq), MeOH

OH O

O

O

Pr

CO2Me

70% (trans:cis ,3:1)Semmelhack JACS 1982 (104) 5850.

Tandem sequences


Nitrogen nucleophiles

NH

PdCl2(CH3CN)2 (10 mol%)THF

O O (1 eq)NR

NR

Both benzoquinone and Cu(II) saltsare effective stoichiometric oxidants for Pd(0) in the presence of readilyoxidized o-allylanilines and indoles.

Conversion of o-allylanilines to indoles:

R

R= H, 86%R = Me, 89%R= C(O)CH3, 71% NH2

O O

NHN

The excess quinone and the Cl arethought to alter the regioselectivityof aminopalladation by coordinating to the Pd.

Disubstituted olefins

PdCl2(CH3CN)2 (10 mol%)

LiCl (10 eq)

(2 eq)

standard cat.conditions

79%mj. productHegedus JACS 1978 (100) 5800.

NH2

PdCl2(CH3CN) (1 eq)NEt3, THF

no reaction occurs in the absence of NEt3

NH PdClLn

H2 NH

Hydrogenation of "trapped" Pd-alkyl intermediate leads to formal hydroamination product

+

NH2

O

NHTs

X OAc

5 mol% pre-cat*/AgOCOCF3CH2Cl2:MeNO2 (1:1)

rt (10-20 h)X NTs

O

H

X = O, 96% (91% ee) NH, 96% (90% ee) CH2, 95% (90% ee)

Asymmetric synthesis of 5-membered nitrogen heterocycles

pre-catalyst:

Fe

SiMe3

N

Ot-Bu

PdII

I

Proposed mechanism:

XO

NHTs

O

OR

PdII

CN

OCOCF3

XOCOR

PdII

O

N

TsN

C

or

TsN

X

O

O

OR

Pd

N C

*

TsN

X

O*

PdIIC

N

O

O

Overman JACS 2001 (124) 12.

HOCOCF3

Pd-Catalyzed Aryl C-H Functionalization

Mechanistic Possibilities:

N

CH3

PdII

H

Ln

N

CH3

N

CH3

N

CH3

Pd(OAc)

N

CH3

Pd(OAc)2

N

CH3

Pd(OAc)2N

CH3

HPd(OAc)2

+ PdH(OAc)

Olefin activation

Palladation

Palladation via:

or

N

CH3 N

CO2Et N

CH3

Stoltz JACS 2003 (125) 9578.

Pd(OAc)2 (10 mol%)

(40 mol%)

t-amyl alcohol/AcOH (4:1)

1 atm O2, 80oC, 24h

Evidence for Palladation:

NH

N

NH

ND

NH

NLnPd

Ibogamine. Trost JACS 1978 (100) 3930.

1.PdCl2(CH3CN)2/AgBF42. NaBD4-MeOD

NH

NH

Ph

Sames JACS 2003 (125) 5274.

Pd(OAc)2 (5 mol%)PPh3 (20 mol%)

PhI (1.2 eq)MgO (1.2 eq)

"Pd (0)"

PdI(Ph)N

MgOH

N

MgOH

Pd

PhH

For more stoichiometric examples in synthesis:(+)-Paraherquamide. Williams JACS 1993 (115) 9323.(+) Austamide. Corey JACS 2002 (124) 7904.Okaramine N. Corey JACS 2003 (125) 5628.


Pt(II)-catalyzed indole alkylation

Widenhoefer JACS 2004 (126) 3700.

R2N

R1

R1 = H, OMeR2 = Bn, MeR3 = H, MeR4 = H, Et

olefin substitutiontolerated at both theterminal and internal positions

PtCl2 (2 mol%)

HCl (5 mol%)

dioxane 60oC

R2N

R1R3

R4

R3

R4

80-98 %

R1, R3, R4 = H, R2 = Me, 92%R1, R4 = H, R2, R3 = Me, 91%

PtIICl2

MeN

EED

D

MeN

EED

D

Cl2Pt

MeN

EEDH

ClPtD

HCl

MeN

EEDH

HD

MeN

EEDH

Cl2LnPtIV

DHCl

MeN

EED

D

ClPtHCl

MeN

EEDH

DClPt

MeN

EEDH

DH

HCl

H

Nu "outer-sphere" pathwayAr-H activation/

carbometallation "inner-sphere pathway"

anti-d2syn-d2

only product observed

"protonolysis"

HCl

RE

H+ Ni

Pd

Pt

1.9

2.2

2.3

C

2.5

increasing electronegativity/ increasingly strong covalentbonds to C

Potential for an asymmetric process:

MeN

EE

O

O P

PPt

Ar2

Ar2

Cl

Cl

(R)-cat, Ar = C6H24-OMe-3,5-t-Bu

(R)-cat (10 mol%)AgOTf (10 mol%)

84%, 69% ee

E = CO2Me

MeN

Me

EE*



Nitrogen nucleophiles/O2 as a stoichiometric oxidant

NHR

Pd(OAc)2 (10 mol%)

pyridine (10 mol%)

O2, toluene, 80oC

TsN

R = Ts, 87% Ns, 87% Cbz, 76%

TsN

60%

TsN

91%

NPdII

N OAc

OAc NHR

NPdII

N OAc

NHR

OAc

N

PdIIN OAc

NTs

NPdII

N

NTs

H

statistically andsterically preferedsite of elimination

OAcNPdII

N OAc

H

NPd0

N

NPdII

N O

O

AcOH

TsN

AcOH

O2

2 AcOH H2O2

Proposed mechanism:

Stahl ACIEE 2002 (41) 164. Stahl JACS 2001 (129) 7188.

NN

Ph Ph

PdII

O O


Hydroamination

NH2

P

P

PhPh

PhPh

Fe PdIIOTf

OTf NHPh

H

NH2

NHPh

2 mol%

toluene, 100oC97%

10 mol%

toluene, 45oC, 36 h

>99% yield, 64% ee

Original mechanism proposed:

PdII

P OTf

P OTf

P

Ph2P

PdII

Ph2

OTf

OTf

PdII

P OTf

P

Ar

NH2Ar

PdIIP OTf

P

Ar

ArH2N

OTf

Ar

NH2Ar

NHAr

H

Revised mechanism based on "isolation of a catalytic intermediate"

P

P

PdII

Ph2

Ph2

OTf

OTf Hartwig claims the η3-arylethyl complex is chemically and kinetically competent to be a reactiveintermediate. When heated in the presence of excessaniline at 75oC for 2h, hydroaminated products wereformed in 61-83% yields (note, no direct comparisonwith the catalytic system under identical conditions ismade).

Me

HPdP P

OTf

H2NAr

NHAr

MeH

(S)NHAr

HMe

(S)

Hartwig claims that minor diastereomer (not isolated) reacts faster (3.5 x) based on a comparison of rates of the mj. vs. the mixture of η3-aryl complexes. Note that he never makes a reaction rate comparison with the catalytic reaction.

inversion(R)

major diastereomer isolated

observed

retention

observed in catalytic reaction

based on crystal

PdII

P OTf

P OTf

PdII

P H

P OTf

Ar

NH2NAr

PdII

P H

P

Ar

OTf

Ar

PdII

P

P

OTf

Ar

PdII

P

P

NH2Ar

Pd0

P

P

Ar

NHPh

H

Hartwig JACS 2000 (122) 9546.

Hartwig JACS 2002 (124) 1166.

ArNH2-H+

M.P. Lalonde/ M.C. White, Chem 253 Nu attack on Olefins -205- Week of November 1, 2004

HydroaminationRh

N

H

RR

RhAr

HNR

R

Ar

RhN

ArH

R RAr

Rh

ArN

R

RH

Ar

Rh

ArN

R

R

CH3

Ar

HN

OH3C

PhN

O

NO

H3CPh

NO

HN

O Ph

Ar

PhN

O

PhN

O

ArN

O

ArN

O

ReductiveElimination

Favored

Reductive Eliminationor

β-Hydride Elimination

β−Hydride Elimination Only

Observations:•The enamine is formed with equimolar amounts of ethylarene•Increasing the styrene concentration increases the reaction rate and decreases the amine:enamine ratio•Reactions with the monodentate Ph3P ligand give enamine as major product•Primary aliphatic and aromatic amines are unreactive•Electron rich vinyl arenes give higher selectivity for amine products and electron poor vinyl arenes are more reactive•The amine and enamine products are formed in a constant ration over the course of the reaction

0.2 mmol

+0.8 mmol

0.2 mmol5 mol%

[Rh(COD)DPEphos]BF4

0.2 mL toluene70 °C, 48 h

54% yieldA/E = 2.39 0.06% yield

+

5 mol%[Rh(COD)DPEphos]BF4

0.2 mL toluene70 °C, 48 h0.2 mmol

Ar = m-CF3C6H4

Entry 3 (mmol) 4 (mmol) 5 : 6 7 : 8

3

4

5

7

6

8

1

23

0.4

0.80.0

0.4

0.00.8

50 : 50 47 : 53

72 : 28 –– 38 : 62

Hartwig concludes that the complex that determines amine : enamine selectivity has two vinylarenes in its coordination sphere

Hartwig JACS 2003 (125) 5608.

M.P. Lalonde/ M.C. White, Chem 253 Nu attack on Olefins -206- Week of November 1, 2004

Hydroamination

RhP

P BF4

NH

O

BF4HN

O

RhP

P

N

O

RhP

P

BF4

Rh

P P

NO HL

BF4

NH

O

NH2

O

BF4

NH2

O

BF4NH

O

NH

O

NO

Rh

H

L

HP

P

BF4

N

O

N

O

BF4

Rh

P PN

O

L

Rh

P PN

O

L

H

Rh

H

L

HP

P

BF4HN

O

RhP

P

Ru

P

P

P CH2

P CH2

OH

CH3

Ru

H

P PP P

O

CH3

+

β-HydrideElimination

Insertion

Dissociative Substitution

+

–30 °C+

Bergman et al. Acc. Chem. Res. 2002, 35, 44-56


C nucleophiles

CO2EtO

SiMe3

CO2EtO

SiMe3Ln(OAc)Pd O

CO2Et

PdIILn

HO

CO2Et

A catalytic process for the addition of Cnucleophiles to Pd(II) activated olefins isprecluded in this case (as in most) by thecompetative oxidation of the carbonnucleophile by the stoichiometric oxidant.

Pd(OAc)2 (1 eq)

CH3CN

58%O O

O

Quadrone

Kende JACS 1982 (104) 5808.

Enol ether nucleophilic attack/β-hydride elimination

(OAc)HPdII

Hydroalkylation

R

OO

PdCl2(CH3CN)2 5-10 mol%

dioxane, rt

R

OHO

PdII

Cl

Cl NCCH3

OOH

R

O O

R

PdCl2(CH3CN)2

protonolysis

Widenhoefer JACS 2001 (123) 11290.

It's unclear why protonolysis rather thanβ-hydride elimination occurs in this system.

PdIIClCl

NCCH3

H

Pd-Catalyzed Aryl C-H Functionalization

NR

O

Cl NR

O

Ph

P(t-Bu)2

1

NR

O

PdCl

NR

PdIIH

O

Cl HCl

NR

PdII

O

NR

O

NR

O

HPdCl

HPdCl

NR

PdH

Cl

O

RN

O

PdCl

HCl

NR

PdII

O

Mechanistic Possibilities:Buchwald JACS 2003 (125) 12084.

NR

O

Cl

NR

O

Cl

d6

NR

D

H

O

PdII Cl

Pd(OAc)2 (1-3 mol%)ligand 1 (2-6 mol%)

NEt3 (1.5 eq)

toluene, 80oCyields: most in mid-90's

"Pd (0)"

R' R'

vs.

kH/kD = 1

· Overall RDS for the reaction does not involve Ar C-H bond cleavage.

Intermolecular kinetic isotope study Intramolecular kinetic isotope study

kH/kD = 4

ElectrophilicSubstitution RE

Carbo-palladation

σ-bond metathesis

π,η1 interactionortho-CH activation

C-H Activation RE

O2N

NR

O

Cl NR

O

ClF3C

D6

CH3O+SbF6-

O

H/D

SbF6-

O

H5/D5

Arguements against electrophilic aromatic substitition: · electron deficient aromatics are good substrates, no reported difference in reaction rates

· large intramolecular primary kinetic isotope effect: kH/kD = 4

σσσσmeta = 0.46

σpara = 0.53

91% yield 96% yieldσσσσpara = 0.81

Olah JACS 1964 (86) 2203.

Arguement against ππππ,,,,ηηηη1 induced ortho-CH activation: no evidence that this

interaction induces C-H activation.

Pd

Me3P

TfO PMe3

PhTfOH

Pd

Me3P

TfO

CD3ODNR

Note: no H-Dexchange wasobserved at the ortho positions

3d

Campora ACIEE 1999 (38) 147.

X

PdXPh

Pd(PPh3)4

KOtBu

110oC

Carbopalladation?

kH/kD = 2.2

rt

Meijere ACIEE 1994 (33) 2379.


M.C. White, Chem 253 ππππ-Allyl chemistry -209- Week of November 1, 2004

X

X = OAc (most common) OCO2Me halide, epoxide, sulfone

MnLm cat

M = Pd0 (most common)

Mo0, W0, Fe0, Ni0,

IrI, RhI

Nu

Nu = soft carbanions (malonate) heteroatom nucleophiles O, N organometallics (main group)

Nu

Highly regio- and stereoselective allylic substitutions are possible with metal mediated reactions

Allylic substitutions via metal π-allyl intermediates

General mechanism:

MnLmX

Mn+2Lm

X

MnLm

One representation of a metal π-allyl hasthe metal in its reduced form and the allylligand with a full positive charge.Consideration of the LUMO of an allylcation indicates that nucleophilic attack ismost likely at the terminal positions of the allyl group.

HOMO of allyl cation

LUMO of allyl cation

Nu

or

Mn+2Lm

X

Nu

MnLm

Nu

Nu

Mn+2(X)Lm

OA

Lneutral ligand

Nu


Substitution with net retention.Mechanism

OAcMeO2C

Pd(PPh3)4 cat.

CO2Me

CO2MeNa

MeO2C

CO2Me

CO2MePPh3

THF, reflux92%

net retentionTrost JOC 1976 (19) 3215.

OAc

inert towards Pd0- catalyzed allylicsubstitution

Mo(CO)6 15 mol%

toluene, 100oC

CO2Me

CO2MeNa MoII(OAc)Ln

OA

CO2Me

CO2MeNa

NaOAc

ligand exchange

MoII(CH(CO2Me)2)Ln

CO2Me

CO2Me

96%

RE

Kocovsky JACS 1995 (117) 6130.

Evidence for double retention has been established in one case of Mo mediated allylic substitution.

OAcMeO2C

OAc

MeO2C

SN2MeO2C

LnPdII (OAc)

OAc

MeO2CLnPd0

Pd(PPh3)4 cat.

CO2Me

CO2MeNa

MeO2C

CO2Me

CO2Me

PPh3

MeO2C

LnPdII(-OAc)

CO2Me

CO2Me

PPh3

PPh3

Double inversion mechanism is thought to operate for Pd allylic substitutions that proceed with net retention. This mechanism operates with stabilized "soft" C nucleophiles such as malonates, sulfonylacetates and may operate in part for amines.

=

Thought to proceedvia SN2 vs. SN2' b/c of Pd's sensitivitytowards sterics.

THF, reflux92%

net retention

ionization

Pd0Ln

Pd π-allyl intermediates have been isolated and shown to undergonucleophilic substitution withinversion.


CO2Me

Cl

Pd(dba)2

CO2Bnn-Bu3Sn

THF, 50oC

CO2Me

CO2Bn

Pd0Ln

LnPdII (Cl)MeO2CCO2Bnn-Bu3Sn

n-Bu3SnCl

LnPdIIMeO2C CO2Bn

RE

87%OAviaSN2

MechanismSubstitution with inversion:

Stille JACS 1984 (106) 4833.

CO2Me

OAc H2N

OMe

OMe

Pd(PPh3)4 3-8 mol%THF, rt

CO2Me

NHR

CO2Me

NHR

+

81% (2:3 identity of major isomer is not specified)

(OAc)

MeO2C

LnPdII

Pd0Ln

(-OAc)MeO2C

LnPdII

+

NH2R

(-OAc)MeO2C

LnPdII (+NH2R)

Amine nucleophiles:

Trost JOC 1979 (44) 3451.


Olefin geometry

OAcCO2Me

SO2Ph

CO2Me

SO2PhNa

OAc CO2Me

SO2Ph

geranyl acetate (E) 92%, only E isomer observed by NMR

Pd(PPh3)4 cat.

78%, only the Zisomer wasobserved by NMR

neryl acetate (Z)

THF

For sterically unhindered olefins, the rate of isomerization may be rapid and favors the syn π-allyl intermediate. This feature can used to synthesize stereodefined, functionalized E olefins from terminal olefins.

OAc

CO2Me

SO2PhNa

Pd(PPh3)4 cat.

Nu

32%

Nu

30%

+ +regioisomer

(38%)(cis:trans, 9:1)

THF

R

OAc

CO2Me

SO2PhNa

Pd(PPh3)4 cat.

THF

R Nu

77%, the Eisomer was formed exclusively

Trost JACS 1980 (102) 4730.

For sterically hindered olefins, the rate anti/syn isomerization is often slow relative to Nu attack, thus the initial olefin geometry is preserved in the product:

R

R

RH

OAcOAc

PdLn

HR

H

H

PdLn

RHPdLn

H

R

R

Nu R Nu

EZ

syn: favoredanti: disfavored

η3/η1 η1/η3

Nu Nu

anti/syn nomenclature of η3

π-allyl is relative to the internal H of the allyl group

Z E

PdLn

anti/syn isomerization


RegioselectivityFactors influencing regioselectivity in metal-mediated allylic substitutions:

RS

MIILn

RL Me

Nua

steric demands of thenucleophile: path a is favored forbulky nucleophiles. Pd catalystsgenerally lead to reaction at theleast hindered terminus of the allyl fragment.

RS

M0Ln

RL

Nub

Me

electronic demands based on thecharge distribution of the ππππ-allylintermediate: allylmetal complexesmay be thought of as allyl cationsbonded to zerovalent metals. Thepositive charge should bepreferentially stabilized at the moresubstituted position, therefore path b is the favored site of nucleophilic attackbased on electronic considerations.

Nu

Rs

RL

Me

M0Ln

steric demands of the metal: Path b is favored because it results in the leaststerically hindered zerovalent M-olefincomplex.

LnM0

RsNu

RLMe

Trost JACS 1984 (106) 6837.

Pd mediated catalysis: sterics of the nucleophile dominate the regioselectivity:

CO2Me

RNaOAc

CO2Me

R

Pd(PPh3)4 cat.

neryl acetate (Z)

THF

R = CO2Me 37:63 (linear: branched) SO2Ph 90:10

CO2Me

R

+

Trost JOC 1976 (41) 3215.


CyclizationsCarbon and oxygen spirocycles:OAc

CO2Et

CO2Et

CO2EtCO2Et

OAc

O

CO2Me

O

CO2Me

O

CO2Me

Ln(OAc)PdII

Pd(PPh3)4 7 mol%

NaH, THF , 65oC

66%

note that attack at the least sterically hinderedposition results in abridgehead olefin:

Pd(PPh3)4 7 mol%

NaH, THF , 65oC

>99%Godleski JOC 1982 (47) 383.

O

OTESTESO

TMSO O

Ot-Bu

O

O

OMe

O

OTMS

O

O-tBu

TESOOTES

19-membered ring formation

Pd2dba3 10 mol%

THF, 40oC, 12h

80% O

O O

H

H

CH3

CH3H

H

OH

H3C

HO

CH3

H

H

H

H

(+)-FR182877

Macrocyclizations occur readily. Regioselectivity favors substitution at the least sterically hindered carbon, particularly when bulky nucleophiles are used.

Sorenson JACS 2002 (124) 4552.

cis-fused decalin systems:

AcO O

CO2R

Pd2dba3/PPh3 cat

NaH, THF, 65oC

CO2RRO2CH

H

EE

O

E

>98% ciscomplements the Robinson annulation approach which generally leads totrans-fused rings.

AcO

O

CO2R

CO2RRO2C

= E

Pd2dba3/PPh3 cat

NaH, THF, 65oCO

E

EEH

H

75%, >98% cis

Backvall TL 1989 (30) 617.review on cyclizations: Trost ACIEE 1989 (28) 1173.


O

O Br

NH2

+

I

AcO

O

O Br

HN

AcO

O

O Br

N

Pd(PPh3)4 (8 mol%)

Et3N, CH3CN, 50 oC

85 %

O

ON

H

O

O Br

NH

LnPd

O

O PdLn

N

Br

O

ON

H

LnPd

Br

PPd(OAc)

oToloTol

2

nBu4NOAcCH3CN/DMF/H2O

80 %

6 mol%

readily accessible, simplestarting materials

Efficient route to Cephalotaxine core via iterative Pd-mediated cyclizations

Tietze ACIEE 1997 35:10 1124-1125.

M.C. White/Q. Chen, Chem 253 ππππ-Allyl chemistry -216- Week of November 1, 2004

Anti attack of allenes on (π-allyl)palladium complexes

Tietze ACIEE 1997 35:10 1124-1125.

t-BuCO2·

E EPd(dba)22 mol%

CH3CN orToluene

·

PdLn PdLn

EE

EE

E = CO2Me

EEH

H

76 % yield

t-BuCO2·

E E

E = CO2Me

Pd(dba)22 mol%

CH3CN orToluene

no reaction

The authors speculate that the electron-withdrawing nature of the dba ligand increases the electrophilicity of the allyl group of the (π-allyl)palladium intermediate, and thus renders the allyl group susceptible to nucleophilic attack by the electron-rich double bond of the allene.

To support the proposed mechanism involving the intermediate (π-allyl)palladium complex shown above, the authors demonstrate that the corresponding trans-allylic pivalate does not react under identical reaction conditions

·

E E

t-BuCO2

E = CO2Me

Pd(dba)21 eq.

Pd(dba)21 eq.

LiCl 4 eq.

·

E E

·

E E

(dba)Pd

PdCl Cl

EEH

H

EEH

H(dba)Pd

trans attackof allene

EEHE

EHcis olefin insertion

HH

PdCl

Cl

88%

90%


trans

cis

The pathway via trans attack on the allene is blocked upon the addition of LiCl. The authors rationalize this result by invoking the formation of a Pd-ate complex in which the dba ligand has been replaced with chloride anions. This intermediate (π-allyl)palladium complex lacking electron-withdrawing ligands alternatively undergoes olefin insertion followed by β-hydride elimination to give the corresponding cis-fused bicycle.


Allylic carbonatesPh O

O

OMe

Pd2dba3 2.5 mol%PPh3 10-20 mol%

THF, rt

note: no external base is needed

Ph

LnPdII

O

OMe

O

CO2

Ph

LnPdII

OMe

+

O

CO2Me

PPh3 Ph

LnPdII

PPh3

OMe

H

Ph

CO2Me

O90%

O

H

CO2MeMe

O

MeO2CMe

Chemoselectivity: allylic carbonates are more reactive towards Pd mediated oxidative addition than allylic acetates.

AcOOCO2Me +

O

CO2Me

H

Pd2dba3 2.5 mol%PPh3 10-20 mol%

THF, rtAcO

O

CO2Me

77%

no product corresponding to attack at the allylic acetate was observed.

Olefin geometry: anti/syn isomerization of the π-allyl intermediate occurs at a faster rate than nucleophilic attack.

OCO2Meneryl acetate (Z)

+

O

CO2MePd2dba3 2.5 mol%PPh3 10-20 mol%

THF, rt

O

CO2Me54%, (52:48 E/Z)

Tsuji TL 1982 (23) 4809.review: Tsuji Acc. Chem. Res. 1987 (20) 140.


Mo-catalyzed allylic alkylation In Mo-catalyzed allylic alkylations, electronic factors and the steric demands of the metal effectively compete with steric requirements of the nucleophile:

t-Bu

OAc

Mo0(CO)6 5 mol%

NaH, tol, 110oC

CO2Me

CO2Me

CO2Me

CO2Me

t-Bu

CO2Me

CO2Me

89%

t-Bu

MoII(OAc)Ln

electronically favored site of Nu attack

sterically favored site of Nu attack

t-Bu

Mo0LnNu

t-Bu

Mo0Ln

Nu

t-Bu81%

CO2Me

CO2Me

The high reactivity of the malonate anion and its modest steric requirements leads to attack at the electronically favored position which leads to the sterically prefered Mo-olefin complex.

Increasing the steric bulk of the nucleophilereverses the regioselectivity towards substitution at the least sterically hindered position.

Why do electronic factors and/or steric demands of the metal play a greater role in influencing the regioselectivity ofMo-mediated allylic substitutions vs. Pd? A few possibilitiesare: 1. Mo is an early metal therefore, it's bonding to C ismore ionic in character than Pd. The carbonium ionresonance form may be more prevalent in the Mo π-allylintermediate. The strong π-acceptor properties of the COligands on Mo may also serve to promote carbonium ioncharacter, 2. Mo(CO)6 is octahedral, therefore it has greatersteric requirements than a square planar Pd complex. Trost JACS 1983 (105) 3343.

Stereoselectivity: dependent on the base used?CO2Me

OAc

Mo0(CO)6 5 mol%

base, tol, 110oC

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

:

NaH 50:50

NTMS

OTMS

>95:<5

Reaction monitoring by GC indicated that no isomerization of the startingacetate was occuring under eithercondition.

Trost JACS 1982 (104) 5543.


W-catalyzed allylic alkylation

N

WCO

CO

CO

CO

N

Ph O

O

OMe 15 mol%

note: formed in situfrom (CH3CN)2W(CO)4 and bpy

THF, reflux CO2Me

CO2MeNa

Ph

MeO2C CO2Me

91% yield, >98% regioselectivity

N

WCO

CO

CO

CO

N

15 mol%

THF, reflux CO2Me

CO2MeNa

Me

O

O

OMe

Me O

O

OMeor

Me

MeO2C CO2Me

Me+ CO2Me

CO2Me

76: 24

Regioselectivity:

Stereoselectivity:

CO2Me

OCO2Me

(CH3CN)2W(CO)4 15 mol%bpy 15 mol%, THF, reflux

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

:

Li

90:10

No isomerization of the starting materialor product was observed under thereaction conditions. However, in acontrol experiment without metal, lowlevels of direct SN2 displacement of thecarbonate were observed upon prolonged reaction times.

Trost JACS 1983 (105) 7757.Trost JACS 1984 (106) 6837.

In alkyl substituted π-allyl systems, the steric demands of thenucleophile compete with the electronic bias of the W π-allylintermediate and the steric demands of the metal. In arylsubstituted systems, the larger orbital coefficient in the LUMO of the π-allyltungsten intermediate at the benzylic positionoverrides the steric demands of the nucleophile resultingexclusively in the branched product.


n-Pr OAc[Ir(cod)Cl]2 2 mol%L 8 mol%, THF, rt

CO2Et

CO2EtNa

n-Pr

EtO2C CO2Et

+n-Pr CO2Et

CO2Et

L: PPh3, 6% yield, branched:linear (24:76) P(OEt)3, 81% yield, branched: linear (59:41) P(OPh)3, 89% yield, branched:linear (96:4)

Use of a strong π-acceptor ligand, P(OPh)3, results in high selectivity for alkylation at the more sterically hindered terminus.

The rationale presented for the highlevel of branched product observedwith the P(OPh)3 ligand was that itsstrong π-acceptor properties promotecarbonium ion character in the π-allyl Ir intermediate.

Ir-catalyzed allylic alkylation

Construction of quaternary carbon centers:

OAc [Ir(cod)Cl]2 2 mol%P(OPh)3 8 mol%, THF, rt

CO2Et

CO2EtNa

EtO2C CO2Et

1: 80% yield (100% regioselectivity)2: 70% yield (95:5, branched:linear)

COCF3IrIIILn

MeMe

IrILn

Me

Nu

Me1

2

Takeuchi ACIEE 1997 (36) 263.full paper: Takeuchi JACS 1998 (120) 8647.

Results are consistent with a common Ir-π allyl intermediate.

Stereochemistry:

CO2Me

OCO2Me

[Ir(cod)Cl]2 2 mol%P(OPh)3 8 mol%, THF, rt

CO2Me

CO2MeNa

CO2Me

CO2Me

CO2Me

36 % yieldonly product observed

The mechanism of allylic substitution may proceed via double

inversion or double retention. Given the improbability of direct

SN2 displacements at a 3o center, double retention (via OA/

ligand substitution/ RE) is most likely. Double inversion via

SN2' is also a possibility.


Rh-catalyzed allylic alkylation

Ph3PRhI

Ph3P Cl

PPh35-10 mol%

P(OMe)3 15-20 mol%THF, rt

CO2Me

CO2MeNa

Wilkinson's catalyst

MeMe

OCO2Me

MeMe

MeO2C CO2Me

CO2Me

CO2Me+

89% yield, >99:1 branched:linear

High levels of regioselectivity for alkylation at themore substituted allylic terminus were observed in all cases examined.

PrMe

MeO2C CO2Me

73% yield96:4 branched: linear

EtMe

MeO2C CO2Me

78% yield96:4 branched: linear

P.A. Evans TL 1998 (39) 1725.

Regioselectivity:

Me

OCO2Me

(S)

Ph3PRhI

Ph3P Cl

PPh35 mol%

P(OMe)3 20 mol%THF, rt

CO2Me

CO2MeNa

97% ee

Me (S)

95% ee

MeO2C CO2Me

Stereoselectivity: Rh catalyzed allylic alkylation of enantioenriched allylic carbonates proceeds with complete retention of absolute configuration . Heteroatom nucleophiles:

Me

OCO2Me

(R)

Ph3PRhI

Ph3P Cl

PPh35 mol%


95% ee

Me

O

(S)

96% yield>99:1 (branched:linear)

98% ee

Ph

ONa

PhRoute to chiral allylic aryl ethers:

Route to chiral allylic amines:

Ph

OCO2MePh3P

RhIPh3P Cl

PPh35 mol%

P(OMe)3 20 mol%THF, rt99% ee

BnN(Ns)Li

Ph

N

87% yield55:1 (branched: linear)

99% ee

PhNs

P.A. Evans JACS 1999 (121) 6761.

P.A. Evans JACS 2000 (122) 5012.

Me i-Pr

OCO2Me

Mechanism: Results suggest that regioisomeric allylic carbonates 1 and 2 do not share a common intermediate.

Ph3PRhI

Ph3P Cl

PPh3

CO2Me

CO2MeNa

Me i-Pr

OCO2Me

Me i-Pr

Nu

Me i-Pr

Nu

5 mol%


1

2

1a

2a

from 1: 83% yield, 97:3 (1a:2a)from 2: 87% yield, 3:97 (1a:2a)


Mechanism of Rh-catalyzed allylic alkylation P.A. Evans proposes an intermediate with discreet σ- and π-metal C interaction (enyl organorhodium intermediate) that cannot readily isomerize to account for the stereospecific nature of the reaction and the different products obtained via the different regioisomeric allylic carbonates.

Me

OCO2Me

Me

RhIII(OCO2Me)(Cl)

Ph3PRhI

Ph3P Cl

PPh3

CO2Me

CO2MeNa

Me5 mol%


MeO2C CO2Me

Ln

RhI

Nu

enyl intermediate is necessary toaccount for enantiospecificity ofthe reaction despite destruction of the stereogenic center.

SN2' SN2'

inversion inversion

Me

RhIII(OCO2Me)(Cl)Ln

Me

RhIII(Nu)(Cl)Ln

Concerted OA

OCO2Me

Nu

Stereospecific RE

retention retention

A second possibility (not adressed by Evans) is a double retention

pathway that may proceed via:1. stereospecific insertion of RhI into

the weak C-O bond of the allylic carbonate, 2. exchange of the

weakly coordinating carbonate by the malonate anion via associative

or dissociative displacement, 3. stereospecific reductive elimination.


Pd-catalyzed diene 1,4-diacetoxylation

Pd(OAc)2 5 mol%

AcOH, LiOAc, 30oC

OO

LiCl (cat.)OAcAcO

85% yield>96% cis

OAcAcO

93% yield91% trans

OAcAcO

LiCl: 51% yield 95% cis

OAcAcO

71% yield91% trans

OAcAcO

70-85% yield>98% cis

(both w/ and w/out LiCl)

Acyclic dienes give significantlylower yields of 1,4-diacetoxylated with much lower selectivities.

The chloride effect does not operates for larger ring systems or for acyclic dienes:

OAcAcO

+

OAc

OAc

49% (3:1), E:Z (94:6)

The chloride effect

1,4-Diacetoxylation of cyclohexadiene:

PdIIAcO

OAc

OAc

PdII

O

O

O

O

AcO

OAc

PdIILnO

O

OAc

OAc

LnPd0

O

O

LnPdII

AcOH

OHHO

OAc

PdIIO

O

Cl

with LiCl:

OAc

OAcOAc

Proposed mechanism:

Backvall JOC 1984 (49) 4619.

Wilkinson’s catalyst: not just - Harvard...

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