C-C Bond Formation - Harvard Universitysites.fas.harvard.edu/~chem153/lectures/week3.pdfhalides. Reactivity of aryl halide: P Ni (II) PCl Cl X n-BuMgBr (2 eq) 0.7 mol% Ph 2 Ph 2 X%

M.C. White, Chem 153 Cross Coupling -84- Week of October1, 2002

C-C Bond Formation

A paradigm shift:nucleophilic substitutionat an sp2 hybridizedcarbon is made routineby using transition metalmediated catalysis.

R

R

ArR R

R

Alkyl

R

Alkyl Ar

Csp2-Csp2 Bonds Csp3-Csp2 Bonds

R

R

R

Csp-Csp2

Alkyl Alkyl

Csp3-Csp3 Bonds

Kumada Coupling

Ni(0) or Pd(0)M = MgX, Li

Stille Reaction

Pd(0)M = SnR3

Negishi Coupling

Ni(0) or Pd(0)M = Al(i-Bu)2 Zr(Cl)Cp2 ZnX

Suzuki Reaction

Pd(0)M = BX2

Classifications based on the main group metal

used to transfer R2 in the transmetalation event.

Hiyama Coupling

Pd(0)M = SiR3

Sonogashira

Pd(0)M = Cu (in situ)

R = aryl, vinyl

X = I, Br, OTf, Cl

Pd(II)

LnPd(0) R1-X

LnPd(II)

R1

X

R2-M

LnPd(II)

R1

R2

oxidative addition

transmetalation

X-M

R1 R2

General Mechanism

reductiveelimination

R2= aryl, vinyl, alkyl

R2-M

R2 R2

Cl

Cl(or Ni(II)

Cl

Cl

)

M.C. White, Chem 153 Cross-Coupling -85- Week of October 1, 2002

Kumada pushes the frontier

PPh2

Ni(II)

Ph2P Cl

ClCl

Cl n-BuMgBr (2 eq)

PPh2

Ni(II)

Ph2P Cl

Cl

Cl MgBr

Kumada JACS 1972 (94) 4374.

0.7 mol%

94%

0.7 mol%

80%

Reductive elimination/Oxidative addition: Yamamoto JOMC1970 (24) C63. "Preparation of a phenyl-nickel complex, phenyl (dipyridyl)nickel chloride, an olefin dimerization catalyst.

N

N

Ni(II)

Cl

N

N

Ni(II)

Cl

+ butane

N

N

Ni(II)

Cl

N

N

Ni(0)

Cl

Transmetallation: Chatt and Shaw J. Chem. Soc. 1960 1718. Report the synthesis of alkyl and aryl nickel(II) complexes from the corresponding nickel(II) halides.

Ph3P

Ni(II)Br PPh3

Br

2 RMgBr

Ph3P

Ni(II)R PPh3

R

R = R'

All the pieces of the catalytic cycle were in the literature...

LnNi(II)

LnNi(II)

R1

XLnNi

(II) R1

R2

MgX2

R1 R2

R2 R2

Cl

Cl

R1 = aryl, vinyl

X = Cl > Br> ILnNi(0)

R1-X

R2-MgX

oxidative addition

transmetalation


R2= aryl, vinyl, alkylR2-MgX


Kumada Coupling

P P

( )n

dppm, n=0, bis(diphenylphosphino)methanedppe, n=1, bis(diphenylphosphino)ethanedppp, n=2, bis(diphenylphosphino)propanedppb, n=3, bis(diphenylphosphino)butane

P P

dmpe, bis(dimethylphosphino)ethane

P

P

Fe

dmpf, bis(dimethylphosphino)ferrocene

Common Bidentate Phosphines

Kumada Bull. Chem. Soc. Jpn. 1976 (49) 1958.

P

Ni(II)P Cl

ClCl

n-BuMgBr (2 eq)

0.7 mol%

R2

R2

Ligand

dppp

dmpf

Ph3P (2eq)

dppe

dmpe

dppb

% yield

100

94

84

79

47

28

Effect of the ligand:

· Bidentate phosphine ligandsexhibit higher catalytic activity than monodentate phosphineswith dppp being optimal for awide range of aryl and vinylhalides.

Reactivity of aryl halide:

P

Ni(II)P Cl

ClX

n-BuMgBr (2 eq)

0.7 mol%

Ph2

Ph2

X % yield

FClBrI

31 (2h)95 (3h)54 (4.5h)80 (3h)

· Unlike other cross-couplingmethods, aryl and vinyl chlorides exhibit higher reactivities thantheir Br or I analogs. It isnoteworthy that even arylfluorides undergo the nickelcatalyzed cross-coupling.

M.C. White, Chem 153 Cross-Coupling -87- Week of October1 , 2002

Kumada Coupling: Applications

P

Ni(II)P Cl

ClMgCl

Ph2

Ph2

t-BuO

Cl

t-BuO

P

Ni(II)P Cl

Cl

Ph2

Ph2

N Br

P

Ni(II)P Cl

Cl

Ph2

Ph2

S MgBr

Me3SiCH2MgCl

BuMgBr

N

S

NNSiMe3

0.1 mol%

· Industrial production of p-substituted styrene derivatives (Hokka Chemical Industry, Japan)

Strem 2001-2003 catalog$7.6/g (very cheap)

Banno JOMC 2002 (653) 288.

· Functionalization of heterocyclic halides

0.5-1 mol%

71%72%78%

· Formation of sterically hindered biaryls

Kumada Tetrahedron 1982 (38) 3347.

Cl

R

R = CF3, H, CH3, OCH3

O

NiIIO O

O3 mol%

+

3 mol%

NN

BF4-

NN

BF4-

imidazolium salt

RMgX

Nucleophilic N-heterocyclic carbenes are used as a phosphine mimics that (unlikemonodentate phosphines) do notdissociate from the metal

BrMg

steric hinderance toleratedonly on the Grignard

+

R

NN

BF4-

R= CF3, 91% H, >99% CH3, 95% OCH3, 98%

Herrmann ACIEE 2000 (39) 1602.

M.C. White, Chem 153 Cross-coupling -88- Week of October 1, 2002

Pd Kumada Coupling: stereospecific transmetallation

The nickel catalyzed Kumada coupling is stereospecific for vinyl mono-halides (complete retention of geometric configuration)but non-stereospecific for alkenyl Grignards:

Ph Br

MeMgBr

P

Ni(II)P Cl

Cl

R2

R2Ph Me

96% (Z)-stilbene

Ph

MeMgBr

Ph

>99% (E)-stilbene

Br Me

96% (Z)-β-bromostyrene

>99% (E)-β-bromostyrene

P

Ni(II)P Cl

Cl

R2

R2

BrMg Me

96% Z

P

Ni(II)P Cl

Cl

R2

R2

Br

Ph Me

27% Z: 73% E

Kumada TL 1975 1719.Kumada Pure & Appl. Chem. 1980 (52) 669.

Oxidative addition to Pd(0) had been reported: Fitton Chem. Comm. 1968, 6.

PPh3

PPh3

Pd

Ph3P

Ph3P

I

Ph3P

Pd(II)Ph3P

I

Palladium (0) shown to be an effective, stereospecific catalyst for cross-coupling of alkenyl halides with Grignard reagents.Murahashi JOMC 1975 (91) C39.

Ph Br

MeMgI

Ph Me

99% cis-stilbene>99% yield

99% cis-β-bromostyrene

PPh3

PPh3Pd

Ph3P

Ph3P

Palladium (0) shown to be stereospecific for alkenyl Grignards reagents. Linstrumelle TL 1978, 191.

I

n-C6H13

BrMg Me

3 mol%

PPh3

PPh3Pd

Ph3P

Ph3P5 mol%

(E)-1-iodo-1-octene

(Z)-1-propenyl-1magnesium bromide

n-C6H13

>97%, (2Z,4E)-2,4-undecadiene 87% yield

Note: Pd catalysts can also transmetallate with organolithiumreagents: Murahashi JOMC 2002 (653) 27.

Pd(0): I>Br>>Cl

Note: Nickel catalysis may involve radical pathways


Negishi Coupling: towards FG tolerance

Negishi Acc. Chem. Res. 1982 (15) 340.

n-C5H11

Al(i-Bu)2

n-C4H9

I5 mol%

n-C5H11

n-C4H9or

(PPh3)2Pd(0)*

(PPh3)2Ni(0)

Pd: 74%, >99% (E,E)Ni: 70%, 95% (E,E), 5% (E,Z)

+

* PdCl2(PPh3)2 + 2 eq. DIBAL Ni(acac)2 + 2 eq. DIBAL

Negishi JACS 1976 (98) 6729.

ZrCp2Cl

O

O

Br

O

MeO

+(PPh3)2Pd(0)*

50oC, 4h

O

O

O

MeO

70%

Negishi TL 1978 (12) 1027.

I

EtEt

i-Bu2Al(or ZrCp2Cl)

PPh3

PPh3

Pd

Ph3P

Ph3P

5 mol%

ZnCl2, 1h, 25oC, 88%

EtEt

No rxn after 1 wk w/out ZnCl2

Negishi demonstrates for the first time that metals less electropositive than Mg or Li can act as effective transmetalation reagents in the Kumada Ni and Pd catalyzedcross-coupling reaction. The stereospecificity observed in the Pd catalyzed reaction confirms that it is the preferred metal for alkenyl-alkenyl couplings to form 1,3-dienes.

The lack of functional group compatibility in both the alkyne hydroalumination and of the resulting alkenylalane prompted a shift to alkenylzirconium transmetalating reagents (generated via hydrozirconation of terminal alkynes) which can tolerate such functionalities as ethers, ketones and esters, etc... Problems still exist with highly electrophilic (e.g. aldehydes) and protic functionality (e.g. alcohols). In addition, these intermediates are moisture sensitive.

The addition of ZnCl2 increased the reactivity of the transmetalating reagent making the cross coupling of sterically hindered substrates possible. It is thought that thealkenylzirconium, alkenylalane undergo in situ transmetalations with ZnCl2 to form alkenylzinc, a more reactive transmetalating reagent.

M.C. White, Chem 153 Cross Coupling -90- Week of October 1, 2002

n-C4H9

IPdII

PPh3

PPh3

n-C4H9

β-hydride elimination


n-C4H9

n-C4H9

H

n-BuZnCl

or n-BuMgCl

n-BuMgCl

51%

25%

n-BuZnCl

2%

76%

Pd(PPh3)4

Formation of Csp2-Csp3 bonds using alkylzinc reagents.

O

BuI

O

NiII

O

Bu

O

F3C

Pent2Zn

possible intermediateF3C 50 mol%

O

NiIIO O

O

10 mol%

O

Bu

Pent

70% yield, 1h

w/out π-acid: 20%, 15h

Recall: formation of Csp3-Csp3 bonds using alkylzinc reagents.

Negishi JACS 1980 (102) 3298.

Knochel ACIEE 1998 (37) 2387.

Negishi Coupling: Csp3-Csp2 and Csp3-Csp3

Q: β-hydride elimination and reductive elimination presumably go through a similar Pd organometallic intermediate formed after the transmetalation event. Develop a hypothesis for why less β-hydride elimination product is observed when a zinc versus magnesium transmetalating reagent is used.

M.C. White/Q. Chen, Chem 153 Cross-Coupling -91- Week of October 1, 2002

Negishi Coupling: Csp3-Csp2

O O

PMP

I

OTBS O O

PMP

Zn

OTBS

O O

PMP

OTBS

OPMB

OTBS

OPMB

OTBS

I

O

NH2

OH OH

O

O

HO

O

Ph3P

O O

PMP

OTBS

PdIIPPh3

OPMB

OTBSZnCl2, t-BuLi (3 eq)

Et2O, -78 °C to rt

5% Pd(PPh3)4

Et2O, rt

66%

(+)-Discodermolide

Note: β-hydride present in alkyl zinc.

13 steps

transmetalation I

Ph3PPdII

PPh3

OPMB

OTBS

I

oxidativeaddition

+ transmetalation II-PPh3

O O

PMP

OTBS

PdII

OPMB

OTBS

PPh3

reductive elimination

Ligand dissociation to the trigonal planar intermediateis thought to favor reductiveelimination from squareplanar complexes.Yamamoto OM 1989 (8) 180.

Smith JACS 2000 (8654).

M.C White, Chem 153 Cross-Coupling-92- Week of October 1, 2002

P O

O

O

Catalyst

PPh3

PPh3

Pd

Ph3P

Ph3P

Palladium(0)

Palladium(II)

Pd2(dba)3

O

dibenzylideneacetone (dba)Strem 2001-2003

$53/g Strem 2001-2003$28/g

Cl

PdIIH3CCN Cl

NCCH3

Strem 2001-2003$39/g

O

PdIIO O

O

Strem 2001-2003$52/g

Monodentate phosphines are added to palladium sources with poorlycoordinating ligands to prevent catalyst decomposition ("plating out")to metallic Pd(0). Bidentate phosphines result in low reaction rates and poor yields.

PPh3

As

tri-2-furylphosphine triphenylarsine

Ligands

Stille Coupling

Stille JACS 1979 (101) 4992.

LnPd(II)

LnPd(II) R

1

XLnPd

(II)R1

R2

XSn(R3)3

R1 R2

R2 R2

Cl

Cl

R1 = aryl, vinyl, alkynyl

X = I>Br>OTf>>ClLnPd(0)

R1-X

R2-Sn(R3)3

oxidative addition

transmetalation


R2= alkynyl, aryl, vinyl, alkylR2-Sn(R3)3

Transfer from tin:

alkynyl>alkenyl>aryl>benzyl>allyl>alkyl.

Allows for simple alkyl groups (Me, Bu) to

serve as"dummy" R3 substituents thereby

avoiding using four identical expensive and/or

difficult to synthesize R2 groups. Alkyl

transfers are only practical for methyl or butyl.

Br Me4Sn

Ph3PPdII

Ph3P Cl

Ph

HMPA, 62oC

Me

Me3SnCl

The original report:

+1 mol%

+

The rate-determining step in

Stille-couplings with reactive

electrophiles ( i.e. R1-X=

unsaturated iodides, triflates)

M.C. White/M.W. Kanan Chem 153 Cross-Coupling -93- Week of October 1, 2002

Unmatched stability and low cross-reactivity of organotins Organotin reagents are:· Highly functional group tolerant· Readily synthesized via a variety of methods*· Air and moisture stable (often distillable)· Stable to the vast majority of organic reagents.

OH OHBu3Sn

CHOBu3Sn Bu3Sn

CO2Et

OTf

CO2Et

PO(EtO)2

CO2Et

i) n-BuLi, DMPU, THF, 0°Cii) aldehyde, -78°C-> -20°C

2.5 mol% Pd2(dba)320 mol% AsPh3, NMP

Dominguez Tetrahedron 1999 (55) 15071

3 eq. SO3 Py, 3eq. Et3N,

CH2Cl2/DMSO

96%

73%

62%

oxidation

HWE condensation

retinoic acid precursor

Stille Coupling

(n-Bu3Sn)(Bu)CuLi.LiCN

* For comprehensive review of synthesis of aryl and vinyl stannanes see A.GMyers/A. Haidle Chem 115: "The Stille Reaction".


Stille: Ligand EffectsPd2dba3 + Ligand

Bu3Sn

Ligand Pd:LRelative

rate

PPh3

(2-furyl)3P

AsPh3

It has been observed experimentally that increasing the concentration of monodentate phosphine ligands decreases the rate of the Stille reaction.No correlation exists between cone angles (θ) and observed rates indicating that the ligand effect is not of steric origin. The ligand effect is thought tobe electronic in nature where phosphines that are poor σ-donors promote the cross-coupling more effectively than those that are strong σ-donors.

θ

145o

ND

142o

1:2

1:2

1:2

1

20

78

I

THF, 50oC

Farina JACS 1991 (113) 9585.

Pd

L

L

I Pd

[S]

L

IBu3Snk1

+ L + Bu3SnI

1 2

I Pd2(dba)3,L (1:4)

50oC, THF k-1 k2

The existence of this pre-equilibrium in the transmetalation mechanism is a subject of much debate in the literature. An alternative proposal involves a tin-mediated associative substitution where transmetalation occurs via a pentacoordinate Pd intermediate. Espinet JACS 2000(122) 11771 and Espinet JACS 1998 (120) 8978.

Ligand k1/k-1

PPh3

(2-furyl)3P

AsPh3

Relativekobs

1

105

1100


Stille: Mechanism of Pd/Sn Transmetalation

The mechanism for Pd/Sn transmetalation is highly dependent on reaction conditions, and the subject of ongoing debate in the literature.

Stille JACS 1983 105 669-670, 6129-6137.Epsinet JACS 1998 120 8978-8985, 2000 122 11771-11782.

Pd C

H H

R'

SnR3R

ClR'Sn

X Pd R

L L

δδδδ++++δδδδ++++

δδδδ−−−−

L

SE2 (open) SE2 (cyclic, pentacoordinate)

R'Sn

X Pd R

SE2 (cyclic)

L

favored in highly polar and/or nucleophilic solvents

favored in non-polar solvents

Farina Pure & Appl. Chem. 1996 68:1 pp 73-78.


Stille: Copper Effects

I

Bu3Sn

Pd2dba3, PPh3, +/- CuI

dioxane, 50 oC

Pd:L:CuImolar ratio

Relativerate

HPLCYield (%)

1:4:0

1:4:1

1:4:2

1:4:4

1:2:0

1

5

114

197

64

85

85

>95

45

91

LigandPd:L:CuI

molar ratioRelative

rate

HPLCYield (%)

PPh3 1:4:0 1 85AsPh3 1:4:0 2710 >95AsPh3 1:4:1 3459 >95AsPh3 1:4:2 3624 >95 CuI

-ISnBu3

Bu3SnLnCu

OTf

O

Bu3Sn

t-Bu

PdCl2(PhCN)2

t-Bu

O O

Bu

Group transfer selectivity

A B

A : B

- CuI 90 : 10

+ CuI >98 : 2

NMP, 80 oCAsPh3 +/- CuI

+

When weakly coordinating ligands such as ArPh3 are used, an enhancement in the rate cross-coupling is still observed upon addition of CuI, although to a lesserextent. To account for this the authors propose an initial transmetalation from anorganostannane to an organocuprate, followed by more facile transmetalation ofthe alkenylcuprate with the palladium catalyst. This proposal is supported by thechange in selectivity of the group transfered from the organostannane in thepresence of CuI.

To explain the observed rate enhancements in the presence of the cocatalyst CuI, the authors propose that CuI acts as a ligandscavenger, binding to free PPh3 and thereby promoting ligand dissociation. This proposal is supported by

31P NMR studies where Cu complexed phosphine is detected.

Farina& Liebeskind JOC 1994 (59) 5905.

M.C. White, Chem 153 Cross-Coupling -97- Week October 1, 2002

ONfPd(PPh3)4

Nf = n-C4F9SO2

Bu3Sn

n-C5H11

OH

+n-C5H11

OHCuX, LiCl

~ 40 hsolvent

Conditions optimized yield

X = I, solvent = DMA 38 %

X = Cl solvent = DMSO 88 %

DMA = dimethylacetamide

LnPd(II)

Ar

XLnPd

(II)Ar

R

R Ar LnPd(0)

oxidative addition

transmetalation II


Ar-X

RSnBu3 + CuCl + LiCl

-Bu3SnCl

RCuLiCl

transmetalation I

Proposed catalytic cycle

The authors propose that the greater electrophilicity of CuClrelative to CuI (expected from the greater electronegativity of Cl relative to I) leads to faster and more efficient transmetalation ofthe hindered vinylstannane to the corresponding vinyl Cu(I)species.

Corey, E.J. JACS 1999 121 7600-7605.

Stille reaction: "the copper effect"a general coupling system for sterically congested substrates


Stille: nucleophilically-accelerated transmetalation

Vedejs JACS 1992 114 6556-6558.

The authors propose that using the reagent 1-aza-5-stannabicyclo[3.3.3]undecane accelerates the Pd/Sn transmetallation event, possibly via one of the following transition states:

Sn

N

CH3

Pd[S]

BrAr

L

δ+

δ-

Sn

N

H3C

Pd

δ+

Br

L[S] or LAr

SE2 (open) SE2 (cyclic)

Farina Pure & Appl. Chem. 1996 68:1 pp 73-78.

Br

MeO

+ Me4Sn

Me

MeO

Pd(PPh3)4

PhMe, 75 oC, 7h

Br

MeO

Pd(PPh3)4

Me

MeOPhMe, 75 oC, 7h


Stille: Extraordinary FG Tolerance

Williams, JACS, 2001, (123), 765.

O

O

H

HOHOTIPS

H

Bu3Sn

H

H

OH

O

CH3

I

H3CH

O

O

H

HOHOR

HH

H

OH

O

H3CH

OH

O

CH3

Pd

H3CH

I AsPh3

AsPh3

O

O

H

HOHOTIPS

H

Bu3Sn

H

H

O

O

H

HOHOTIPS

H

H

HLnCu

O

O

H

HOHOTIPS

HH

H

OH

O

CH3

PdLnH3CH

The successful cross-coupling in the presence of an epoxide, alcohol,carboxylic acid and several olefins illustrates the compatability of the Stille cross-coupling with nearly all functional groups.

(Ph3As)2Pd0

Pd2(dba)3 (0.2 eq.)Ph3As (0.8 eq.)CuTC (1.5 eq.)NMP, 35°C 50%

LnCuTC+ ISnBu3

II

oxidative addition

transmetalation II


transmetalation ICuTC

Cu(I) thiophene-2-carboxylate

Cu

O

S

key intermediate in total synthesis of(+)-Amphidinolide

M.C. White/ M.W. Kanan Chem 153 Cross-Coupling -100- Week of October 1, 2002

Stille: Double Couplings

Overman JACS 2002 (124)9008.

HN N

I

NH

N

I

H

H

OTf

N

ONMeTs

SnBu3Bn

Pd2(dba)3 CHCl3, P(2-furyl)3, CuI, NMP, rt

HN N

NH

N

H

HOTf

N

ONMeTs

Bn

OTf

N

ONMeTs

Bn

HN N

HPdI PR3

PR3II

(PR3)2Pd0

HN N

HPdLn

OTf

N

O

TsMeN

Bn

OTf

N

ONMeTs

SnBu3BnOTf

N

ONMeTs

Cu(L)nBn

CuI(L)n

oxidative addition

+ CuI(L)n

transmetalation I

transmetalation II


71%

II

The cross-coupling is effected at the aryl iodide positions in the presence of aryl triflates. This generates a product that is a substrate for a intramolecular Heck reaction, which is the next step in the sequence. Also of note is the steric hindrance of the stannane due to theadjacent protected amide.

Key intermediate in Quadrigemine C

M.C. White/M.W. Kanan Chem 153 Cross-Coupling-101- Week of October 1, 2002

Stille: MacrocyclizationSnBu3

TfO

O OO

O

OO

H

H

Pd(CH3CN)2Cl2, 5 mol%

LiCl, DMF, 20°C

SnBu3

PdLn

O O

Cl

PdLn

O OO O

48%

[4+2]

oxidative addition

transmetalation reductive elimination

The Stille coupling has proven to be an effectivestrategy for macrocyclization through diene or eneyneformation. In this case, the product is a substrate for a transannular 4+2 cycloaddition, which proceedsspontaneously to afford the polycyclic product.

SnBu3

LnPd

O O

+

OTf-

Cl- substitution for OTf oftenreferred to as the "LiCl effect" isthought to promote the rate-limitingtransmetalation event

O2

Suffert Org. Lett. 2002 (4) 3391.

highly unsaturatedpolycyclic ring systems

Stille JACS 1986 (108) 3033.

M.C. White, Chem 153 Cross Coupling -102- Week of October1, 2002

Hiyama Coupling

SiMe3

In-C6H13

THF, 50oC

PdCl

PdCl

n-C6H13

Reaction is stereospecific. It proceeds w/complete retention of db geometry.

2.5 mol%

TASF* (1.1 eq)

P(OEt)3 5 mol%78%

I

HMPA, 50oC

+2.5 mol%

SiMe3

PdCl

PdCl

TASF* (1.3 eq)

TASF = tris(diethylamino)sulfonium difluorotrimethylsilicate good source of F-

No reaction in absence of TASF

"ligandless system"

1.3 eq89%

The F- reagent believed to first attack the organosilicon compound to generate apentacoordinate silicate. This has the effect of enhancing the anionic character of the typically non-polar organosilicon bond , thereby promoting transmetalation.

Si

Me

MeMe

TASF Si

Me

MeMe

F

_

[(CH3)2N]3S+

Hayama JOC 1988 (53) 918.

SiMe3

Essentially complete FG tolerance: esters, ketones, free hydroxyls, aldehydes

THF, 50oC

PdCl

PdCl

BrPh

HO

HO

Ph

2.5 mol%

TASF* (1.1 eq)


Hiyama Coupling

enhanced nucleophilicity of the γcarbon of the intermediatepentacoordinate allylic silicate isused to rationalize regoiselectivity of substition.

Hiyama JACS 1991 (113) 7075.

SiF3

F3CO2SO C(O)Me C(O)MePd(PPh3)4, 5 mol%

TBAF (2 eq), THF

2 eq(S)-1-phenyl-1-(trifluorosilyl)ethane (34% ee)

50oC

41% (S)-1-phenyl-1-(4 formylphenyl)

ethane (32-34% ee)retention

(S)

(R)

0

20

40

20

40

%ee

40 50 60 70 80 90 100

temperature (oC)

SiF3

I

Br Br

SiF3

I

OO

Pd(PPh3)4, 5 mol%

TBAF (1.0 eq), THF

100oC (sealed tube)

37 h

78%

Pd(PPh3)4, 5 mol%

TBAF (1.0 eq), THF

100oC (sealed tube)

46 h

70%

α

β

γ

Exclusive γ substitution of allyltrifluorosilanes

Hiyama JACS 1990 (112) 7794

Temperature dependent retention of stereochemistry during transmetalation event

Since reductive elimination is known togo with retention of configuration at the alkyl center, the observedstereochemical outcome of thecross-coupling reaction is thought to bereflective of the transition state fortransmetalation.

SiPh

HF

F

F

F

Pd(Ar)LnF‡

SE2 (cyclic): retention

Si

Ph

H

SE2 (open): inversion

F

F

FF

Pd(Ar)Ln

F‡


Hypervalent Organotin· monoorganotins are less reactive to Stille coupling than traditional tetraorganotins· the reactivity of monoorganotins towards transmetalation with organopalladium compounds can be increased by nucleophilic assistance that procedes via hypervalent tin intermediates

· like silicon, tin is fluorophilic

Substrate assistedtransmetalation:

C

Sn

Br

N(TMS)2N(TMS)2

Br

CO2Me

O

EtO

CO2Me

CO2Et

CO2Et

Sn

Br

N(TMS)2N(TMS)2

BrPdII

PPh3

PPh3

MeO2C

Ph

Pd2dba3, 3 mol%

PPh3, Toluene, 90oC

71%

possible transmetalation intermediates

_

+

hypervalent tin

ISn

Br

N(TMS)2N(TMS)2

Br

Sn[N(TMS)2]2 t-Bu t-Bu

Sn

Br

N(TMS)2N(TMS)2 Sn

F

N(TMS)2N(TMS)2

F

TBAF

"Lampert's stannylene"

1 step

Lampert Chem. Commun. 1974, 895.

Pd(PPh3)4, 1 mol%

TBAF (3 eq)

dioxane, 110oC

12h 76%

_

In contrast to tetraorganotins, monoorganotinscan be used transfer value added alkyl substituents.

proposed transmetalating reagent: hypervalent tin species

F- assisted transmetalation:

Fouquet JOC 1997 (62) 5242

M.C. White, Chem 153 Cross-Coupling -105- Week of October1 , 2002

General method for Stillecross- coupling with aryl chlorides

Me

ClBu3Sn

Me

Additive (1.1 eq) % GC Yield

none

NEt3CsCO3NaOH

TBAF

KF

CsF

CsF (2.2)

Bulky, electron rich phosphines are are known to sucessfully promote the oxidativeaddition of Pd(0) to aryl chlorides in the Suzuki reaction (presumably via theformation of highly nucleophilic, coordinatively unsaturated (14e-) palladium(0)complexes). The poor reactivity of this system in promoting the Stille coupling of aryl chlorides to simple vinyltributyltin prompted Fu to hypothesize that the problematicstep was transmetallation. In order to test this hypothesis, he began to screen additivesknown enhance the reactivity of organotins towards transmetalation (Lewis bases andfluoride additives).

+

1.5% [Pd2(dba)3]6% Pt-Bu3

dioxane, 100 oC

12%

12

16

40

42

24

28

50

59

the air-sensitivity of P(t-Bu)3 is a drawback to this methodology: Pd(P(t-Bu)3)2, a more air-stable, crystalline complex is more easily handled and is now commercially available from Strem.

Cl Bu3Sn

BrO

Bu3SnO

Csp3-Csp2 Stille couplings

ClMeO

Bu3Sn-Bu

BuMeO

Synthesis of sterically hindered biaryls

3.0 % Pd(P(t-Bu)3)22.2 eq. CsF

dioxane, 100 oC

89%

Room temperature aryl bromide Stille couplings

0.5% [Pd2(dba)3]1.1% Pt-Bu3

toluene, rt88%

1.5% [Pd2(dba)3]6% Pt-Bu3

2.2 eq. CsF

dioxane, 100 oC

Fu ACIEE 1999 (38) 2411Fu JACS 2002 (124) 6343


Negishi-Suzuki Coupling?

M

I "(PPh3)2Pd(0)"

generated in situ fromCl2Pd(PPh3)2 and DIBAL

THF

M

Li

MgBr

ZnCl

Al(Bu-i)2

HgCl

BBu3Li

SnBu3

ZrCp2Cl

temp (oC)

25

25

25

25

25

reflux

25

25

Product yield %

24

24

1

3

1

1

6

1

time (h)

3

49

91

49

trace

92

83

0

Negishi's metal counterion screen:

Negishi JOMC 2002 (653) 34.

Negishi chose to pursue thislead, rather than the organo-borane and organotin results


Suzuki Cross Coupling

B

C4H9

O

OHB

O

O

catecholboraneHC4H9

regiospecificsyn hydroboration

Br Ph

Pd(Ph3)4 (1 mol%)

NaOEt, benzenereflux

C4H9

Ph100% stereospecific the configurations of thevinylborane and vinylhalide are retained.Excellent method forthe construction ofconjugated dienes.86%

Representative Suzuki Cross Coupling

Catalytic Cycle:

LnPd(II)

R1

XLnPd

(II)R1

R2

R1 R2R1 = aryl, vinyl, alkynyl

X = I>OTf>Br>>ClLn Pd(0)

R1-X

oxidative addition

transmetalation


R2= alkynyl, aryl, vinyl, alkyl

The rate-determining step in

Suzuki-couplings with

reactive electrophiles (i.e.

R1-X= unsaturated iodides)

LnPd(II)

R1

OR2

R2OMM = Na, K, Tl

XM

BY2

R3

BY2OR2

A variety of different organoboron reagents can beused to effect transfer of the R2 group viatransmetalation. Generally, electron rich unhindered organoboranes are most reactive towardstransmetalation. Organoboranes are non-toxic andair and moisture stable.*

R2 B(Oi-Pr)2

R2 B

O

O

pinacolborane

R2 B

O

O

B R2

9-BBN(9-Borabicyclo[3.3.1]nonane)

Organoboranes

*See: Chem 115 Suzuki Handout for comprehensive review of synthesis of organoboron compounds (A.G. Meyers/A. Haidle)

Palladium Catalysts

Pd(PPh3)4(most common)

Pd2(dba)3 + phosphinePd(0)

Pd(II)

Pd(OAc)2 + phosphine PdCl2(dppf) (for sp3-sp2)


Suzuki Coupling: Role of the Base

B R

ROO B

R

RO B

R

R

boron ate-complexR'L2Pd

Organoboron compounds can be activated to undergo transmetalation by adding a nucleophilic base. Thiseffect is thought to be due, at least in part, to theformation of a hypervalent, anionic boron "ate"complex, which undergoes transmetalation morereadily and can coordinate the Pd metal.

The boron-carbon bonds in most organoboron compounds are considered to be highly covalent/non-ionic. As a result, organoboron compounds are generally insensitive to water and related solvents, and highly compatible with most organic functionality. However, for the same reason, these intermediates do not readily undergo transmetalation.

It is also proposed that a nucleophilic base candisplace the Pd-bound halide that results fromoxidative addition, to generate a metal center that is capable of coordinating the organoborane.

XRO

O

RB R

O

R

B

R

R'L2Pd R'L2Pd

R'L2Pd

O B

R'L2Pd C

HSoderquist has proposed a µ2-hydroxo-bridged, 4-centered cyclic transition state for thetransmetalation event, which has been shownto proceed with retention of configuration forboth coupling partners.

‡

Soderquist J. Org. Chem. 1998 63 461-470


PdCl2(dppf) is often found to be a superior catalyst for Suzuki cross coupling reactions between boron-alkyl derivatives (possessing β-hydrogens) and vinyl/aryl halides/triflates. This ligand isthought to favor reductive elimination vs. competitive β-hydride elimination for at least tworeasons:

· The bidentate phosphine ligand enforces a cis geometry between the alkyl and vinyl/aryl substituents; this cis geometry is required for reductive elimination

· The large bite angle for this bidentate phosphine ligand results in a smaller anglebetween the alkyl and vinyl/aryl substituents. Recall that minimization of the angle between two metal-bound substituents is thought to promote reductive eliminationevent by increasing orbital overlap:

Suzuki JACS 1989 (111) 314see also Hayashi JACS 1984 (106) 158; Brown Inorg. Chimica Acta, 1994 (220) 249.Danishevsky ACIEE 2001 (40) 4544.

P

P

PhPh

Ph Ph

Fe

dppf, bis(diphenylphosphino)ferrocene

Pd

Cl

Cl

Suzuki: Ligand Effects for Csp3-Csp2 couplings

Me

MeOAc

S

SCO2Me

Me

Br

Me

MeOAc

S

S

Me

CO2Me

Me

MeOH

O

HO

Me

OH

1. 9-BBN-H

2.PdCl2(dppf), K2CO3

dihydroxyserrulatic acid

Urema JACS 1991 113 5402-5410.

M.C. White, Chem 153 Cross-coupling -110- Week of October 1, 2002

Suzuki Couplings: Ligand Effects

Cl B(OH)2

First report of effective Suzuki cross-coupling ofunactivated aryl chlorides:

Fu ACIEE 1998 (37) 3387.

1.5% [Pd2(dba)3]3.6% phosphine

2 eq. Cs2CO3dioxane, 80oC

Aryl chlorides are traditionally unreactive towards Suzuki crosscouplings (recall: I> OTf > Br >>>Cl). This is thought to be duein part to the strength of the Ar-Cl bond (i.e. Ph-X: Cl (96kcal/mol), Br (81 kcal/mol), I (65 kcal/mol)). Reports ofreactivity were limited to reactions using activated substrates (i.e. aryl chlorides with electron withdrawing substituents). The lowcost and high availability of aryl chlorides, however makes themvery attractive substrates. Fu was the first to discover that bulky,electron rich ligands could overcome this reactivity issue.

Room temperature Suzuki couplings with aryl bromides

Br B(OH)20.5% [Pd2(dba)3]

1.2% P(t-Bu)3

3.3 eq. KFTHF, rt

98%OMe

OMe

Chemoselective Suzuki couplings: first example of Pd-catalyzed cross-coupling that demonstrates higher selectivity for aryl chlorides than for aryl triflates

OTf

Cl

B(OH)21.5% [Pd2(dba)3]

3.0% P(t-Bu)3

3.3 eq. KFTHF, rt

95%

OTf

Phosphine % GC Yield

none

BINAP

dppf

Ph2P(CH2)3PPh2Cy2P(CH2)2PCy2PPh3PCy3PtBu3P(o-tol)3

0

0

0

0

0

0

75

86

10

θ

---

---

---

---

---

145

170

182

194

CO v, cm-1

---

---

---

---

---

2069

2056

2056

2066

Bidentate ligands are ineffective. The optimal phosphine toligand ratio is between 1 and 1.5. Both pieces of data suggest that the active catalyst has a single phosphine attached.

Full paper: Fu JACS 2000 (122) 4020.


PdII

P(t-Bu)3

I

T-shaped monomer

164.6o

109.9o

94o

Bulky, electron-rich phosphines

Hartwig JACS 2002 (124) 9346.

Pd(dba)2 + 1 P(t-Bu)3Pd0 PO

t-Bu

t-Bu

t-Bu

Ph

Ph14e-

I

dba

dba

PdII

P(t-Bu)3

I

M.C. White, Chem 153 Cross Coupling -112- Week of October 1, 2002

Suzuki: Ligand Effects for Csp3-Csp3 couplings

n-DecBr

9BBNn-Hex

n-Decn-Hex

4 % Pd(OAc)28% ligand

1.2 eq. K3PO4THF, rt

+

Ligand % GC Yield

BINAP

dppf

P(OPh)3P(n-Bu)3PPh3AsPh3P(2-furyl)3PCy3P(i-Pr)3PtBu3P(o-tol)3


Suzuki: Ligand Effects IIBuchwald Ligands (commercially available from Strem).General features: electron rich and bulky. Buchwald speculates thatthe electron rich nature of the phosphines promotes oxidative addition and tight binding to the metal (prevents Pd black formation).Moreover, the steric bulk of the ligand promotes reductiveelimination. Subtle feature: o-phenyl may be oriented such thatπ-interaction with the metal occurs. It is not clear why this feature isimportant.

PCy2

Me2N

Pt-Bu2

Me2N

PCy2 P(t-Bu)2

1 2

3 4

Cl B(OH)2

Room temperature Suzuki cross-coupling of unactivated aryl chlorides:

1.5% Pd(OAc)23.0% 4

3 eq. KFTHF, rt

92%

Suzuki Csp2-Csp3 Coupling

Cl0.5% Pd(OAc)2

1.0% 4

3.3 eq. KF

THF, 65oC

C6H14

83%CO2Me

CO2Me

B nC6H14

Exceptionally high TON

B(OH)2O

Br

Pd(OAc)2 : 4 (1:2)

3.3 eq. KF

100oC

100,000,000 TN in 24h*

O

Ph

Note: only observed for this substrateBuchwald ACIEE 1999 (38) 2413.Buchwald JACS 1999 (121) 9550


Cl

Cl

Cl

MeO2C

Me

Me

Me

(HO)2B

(HO)2B

(HO)2B

OMe

MeO2C

Me

Me

Me

OMe

General conditions

Pd2(dba)3 (1.5 mol%)

L (3.0 mol%)

Cs2CO3 (2 equiv.)

dioxane, 80 oC, 1.5 h

+

+

+

99% yield

91% yield

89% yield

Nolan J. Org. Chem. 1999 64 3804-3805.

N N

Me

Me

Me

Me

Me

Me

Nucleophilic N-heterocyclic carbenes (imidazol-2-ylidenes): these so called "phosphine mimics" do not dissociate fromthe metal center, and thus an excess of ligand is not requiredto prevent agregation of the catalys to yield the bulk metal.

L =

generated in situ from the corresponding Cl salt

Suzuki: An alternative to phosphines


Suzuki: the “TlOH effect”

O

ORZOCOHN

O

O

O

RO OR

OR

O

O

OR

RO

RO

YO

OY

OY

OR

O

OR

OR

OR

OR

RO

OOR

OR

O

OR

RO

I

(HO)2B

+75

76

7576

R = CH2PhOMe(p)Y = Si(Me)2(t-Bu)Z = CH2CH2Si(Me)3

P

O

(MeO)2

Conditions Yield

KOH, 70 oC, 18 h

Pd(PPh3)4

Base

0 %

TlOH, rt, 25 min 63%

Further studies demonstrated that with TlOH, this coupling can be achieved almost

instantaneously even at 0 oC, allowing its application to substrates with fragile functional

groups as well as with large molecular weights.Kishi, JACS. 1987, 109, 4756-4758.

M.C. White, Chem 153 Cross-Coupling -116- Week October 1, 2002

Suzuki: TlOH vs. TlOEt

Roush, Org. Lett. 2000, 17, 2691-2694.

TlX source Yield

TlOEt

TlOH (10% stock solution)

The use of TlOEt in place of TlOH has advantages in terms of commercial availability, stability, and ease of use. Roush and coworkers found that thallium(I) ethoxide promotes rapid Suzuki cross couplings for a range of vinyl- and arylboronic acids with vinyl and aryl coupling partners in good to excellent yields.

OTBDPS

O

Me

Me

I

TBSO

Me HO B(OH)2

Me Me

TBDPSO

TlX, Pd(PPh3)4THF, H2O

OTBDPS

O

Me

Me

TBSO

Me

OTBDPS

Me Me

OHReagent age

--- 83%

1 month old 71%

TlOH (10% stock solution) 5 month old 50%

TlOH (from solid)) 12 month old 52%

The presence of water does not appear to be necessary for effective cross couplings with Pd(PPh3)4/TlOEt, challenging the assumption that TlOH is an obligatory intermediate

I

CO2Me

t-BuO2C CO2t-Bu(HO)2B OH

Pd(PPh3)4, TlOEt

THF/H2O : 3/1 97% yieldTHF (anhydrous) 92% yield

CO2Me

t-BuO2C CO2t-Bu

HO

M.C. White/M.S. Taylor Chem 153 Cross-Coupling -117- Week of October 1, 2002

Suzuki : Formation of Hindered Aryl-Aryl Bonds

OMe

B(OH)2O

ONCO2t-Bu

N

O

TfO

NCO2t-Bu

N

O

Pd+

P

P

NCO2t-Bu

N

O

OMeO

O

OMeO

O

NCO2t-Bu

N

O

PdP P

Pd(dppf)Cl2, K3PO4THF, 65°C

1:1 mixture of atropisomers Intermediate en route to Diazonamide A

Pd0(dppf)

OTf -

Pd0(dppf)oxidative addition

63%

OMe

B(OH)2O

O

transmetalation


The aryl triflate used in this coupling is highly hindered as a result of the oxazole substituent in the 3-position of the indole. The ability toreliably couple such an electrophile to a similarly hindered 2-substituted arylboronic acid highlights the utility of the Suzuki cross-coupling forthe formation of challenging bonds. Furthermore, the tolerance of lactone, protected indole, and the Lewis basic oxazole functionality is notable.

Vedejs OL 2000 (2) 1033.

M.C. White/M.S. Taylor Chem 153 Cross-Coupling -118- Week of October 1, 2002

Suzuki: reliable method for late-stage macrocyclization

O O OO

B

O

O

O

O OTBS

O O

I

OTBS

TBS TBS PdCl2(MeCN)2

OO OO

B

O

O

O

O OTBS

O OPd

OTBS

TBSI

Ph3AsAsPh3

TBS

Pd(Ph3As)n Pd(Ph3As)n

OO OO

O

O

O

O OTBS

Pd

OTBS

TBSAsPh3

AsPh3TBS

O O OO

O

O

O

O OTBS

OTBS

TBS TBS

Ph3As, AgO, THF Desilylation yields Rutamycin b.

70%

oxidative addition reductive elimination

transmetalation

Demonstration of the utility of the Suzuki coupling as an efficient macrocyclization method.Spiroketal, ketone, and enone functionalities are all well tolerated. The efficiency of this reaction compares well with more conventional methods such as macrolactonization or olefination. (Notethat in this case, the corresponding Stille macrocyclization was not successful)

White, J. Org. Chem. 2001, 66, 5217.


Hydroboration/Suzuki coupling sequence sets a new stereocenter and effects macrocyclization

O

I

OMe O

OMOM

OPMB

O

I

OMe O

OMOM

OPMB

BR2

O

Pd

OMe O

OMOM

OPMB

PP

I BR2

BH

O

OMe O

OMOM

OPMB

O

Pd

OMe O

OMOM

OPMB

P P

1. 9-BBN, THF

2. (dppf)PdCl2 (20 mol%)

Benzene / H2O, NaOH

80°C, 12 h (48%)

Synthetic studies towards Salicylihamide A

Pd0(dppf)

Pd0(dppf)hydroboration

oxidative additiontransmetalation


The well-documented diastereoselectivity of hydroboration reactions with 1,1-disubstituted olefins provides an opportunity to control stereochemistry as part of the coupling strategy. Alternative cyclization via macrolactonization is rendered difficult in this instance by the bulky ortho-substituted carboxylic acid.

Maier, Org. Lett. 2002, 4, 13, 2205.

Documents

C-C Bond Formation - Harvard Universitysites.fas.harvard.edu/~chem153/lectures/week3.pdfhalides. Reactivity of aryl halide: P Ni (II) PCl Cl X n-BuMgBr (2 eq) 0.7 mol% Ph 2 Ph 2 X%