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Negishi Coupling of Secondary AlkylzincHalides with Aryl Bromides and Chlorides

J. Am. Chem. Soc. 2009, ASAP ArticleChong Han and Stephen L. Buchwald

Current Literature: 5/21/09David Arnold

X

R

+R2

R1 ZnBr

R

R2

R1

X = Br, Cl R1, R2 = Alkyl

Cat. Pd(OAc)2

Ligand

THF/Toluene

rt or 60 oC

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Common Strategies Utilized for the Cross-Coupling ofSecondary Alkyl Organometallic Reagents with Aryl Halides

1. Kumada Coupling (1972):

2. Suzuki Coupling (2000):

+MgY Pd or Ni Catalyst

R

R: aryl, vinyl; X = Cl, Br or I; Y = Cl or Br

RX

3. Negishi Coupling:

+M

Pd CatalystX

RR

R: alkyl, hetero-aryl, ether, ester, ketone, nitro...

X: Cl, Br or IM: -B(OH)2, -B(OR)2, -BF3K

+ZnY

Pd CatalystX

RR

R: alkyl, hetero-aryl, ether, ester, ketone, aldehyde...X or Y: Cl, Br or I

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Pioneering Work by Kumada and Hayshi: MechanisticConsiderations for Kumada / Suzuki / Negishi Couplings

* Proper Ligand Selection is Key!J. Am. Chem. Soc. 1984, 106, 158.

LnPd(0)

LnPdII Ph

Br

Me MgCl

Et

Ph

LnPdII

Et

H

Br-Ph

MgClBr

Ph

Me Et

LnPdII H

Ph

Et

Ph

LnPdII

Et

PhEt

Ph Hreductive

elim ination

oxidativeaddit ion

transmetallat ion!"hydrideelimination

insertion

reductiveelimination

reductiveelimination

Br

+MgCl

1% PdCl2 (Ligand)

Ether, rt, 1-24 h

+ +

H

95%5%43%

0%6%19%

0%80%15%

dppf / 1 h

(PPh3)2 / 24 hdppp / 24 h

Desired Catalytic CycleCompeting Pathways

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Kumada Coupling: Catalyst, Ligand and Scope

Br

+MgCl

1 mol % Catalyst

Ether, rt, 1-48 h

+ +

H

A B C

90.890.623194324rtPdCl2 (dppp)2

--885323rtNiCl2 (PPh3)26

--6332923rtNiCl2 (dppp)5

--806524rtPdCl2 (PPh3)24

94.285.840048rtPdCl2 (dppe)3

87.899.0700951rtPdCl2 (dppf)1

Cl-Pd-ClP-Pd-PC (%)B (%)A (%)Time (h)Temp (oC)CatalystEntry

Catalyst Bond Angles, deg% Yield Determined by GC

Pd

Cl

P Cl

P

PhPh

PhPh

Fe99.07

o 87.8o

J. Am. Chem. Soc. 1984, 106, 158.

• Catalyst Screening:

• Use of the PdCl2 (dppf) catalyst successfully suppressed byproducts resulting from β-hydride elimination.• Substrate scope is limited to halide coupling partners compatible with Grignard reagents.

+MgCl

1 mol % PdCl2 (dppf)

Ether, rt, 8-20 h R

OMeCF3

75% 58% 72%

RBr

80% 97%

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Suzuki Cross-Coupling Reactions: Scope and PresentLimitations

• Initial Reports:

B(OH)2

Cl

+

1.5% Pd2(dba)34.5% P(t-Bu)3

3.3 equiv KF

dioxane, 100 oC 75%

B(OH)2+

Br1.0% Pd(dba)2

1.0% Ph5FcP(t-Bu)2

K3PO4

Toluene, 100 oC55% (estimated GC yield)

Mixture of sec- and n-butylaryl products

J. Am. Chem. Soc. 2000, 122, 4020. J. Org. Chem. 2002, 67, 5553.

• Recent Work by Molander:

J. Am. Chem. Soc. 2008, 122, 4020.

Cl

+ BF3KR1

2 mol % Pd(OAc)2

3 mol % n-BuPAd2

3 equiv Cs2CO3

10:1 toluene/H2O

100 oC, 24 h

R

R1

R

R = CH3, OMe, Ac, CO2Me, NO2, CF3, Het-ArR1 = c-C5H9, i-Pr

R1

R1 R1 R1R1

MeO

OMe OMe NO2

CO2Et

R1 =

87% 88% 82% 89% 89%

Me

Me 78%1:6

i-Pr:n-Pr

77%3.5:1

i-Pr:n-Pr

N

R1

F

R1

CN

77% 0%

R1

Ac

51%

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Suzuki Cross-Coupling Reactions: Scope and PresentLimitations

Cl

+ BF3K

2 mol % Pd(OAc)23 mol % Ligand

3 equiv Cs2CO3

10:1 toluene/H2O

100 oC, 18 hR

RR = o-OMe, t-Bu2PPh, 72 h: 57% yield, 1.4:1 i-Pr:n-Pr

R = p-OMe, t-Bu2PPh, 72 h: 79% yield, 8.2:1 i-Pr:n-Pr

• Good Functional Group Compatibility: Alkyl, Aryl, Het-Aryl, Ether, Ester, Ketone, Nitro, and Trifluoromethyl; Does Not Work With Cyano Substituents• Limitations: Moderate Selectivities for i-Pr vs. n-Pr, Sensitive to electronic and steric factors J. Am. Chem. Soc. 2008, 122, 4020.

• 60 ligands were screened in parallel.• The best 3 were further tested against diverse substrates.

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• Early Reports from Kumada (1984):

Br

+ZnCl

1 mol % PdCl2(dppf)

THF, rt, 20 h

+ +

H

100% 0% 0%

• 20 Years Later… the same methodology was applied to the racemic synthesis ofbisabolene natural products which are components of many plant essential oils andmany have been found to have a range of biological activities.

B r Rieke Zn

THF

Br Zn+

OMOM

OMOM

B r 10 mol % PdCl2( dppf)

THF, reflux , 24 h, 79%

OMOM

OMOM

HCl

O

O

89%

(+)- curcuhydroquinone

J. Am. Chem. Soc. 1984, 106, 158.

J. Org. Chem. 2004, 7, 2461.

Negishi Coupling: New Uses for Old Ligands

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PCy2

Me2N NMe2

L6 CPhos

Title Paper: Ligand Screening on Problematic Substrates

• The new CPhos ligand showed excellent conversions and selectivity for thedesired branched products.

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• Excellent yields and selectivities for branched products• Good functional group tolarance

PCy2

Me2N NMe2

L6 CPhos

Title Paper: Substrate Scope and Isomeric Product Ratios Employing the CPhos Ligand

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Title Paper: Substrate Scope Continued

• The optimized reaction works well with sterically hindered, electron deficient andheteroaromatic aryl bromides and chlorides.• Cyclic and acyclic zinc reagents were demonstrated to be good coupling partners.

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LnPd(0)

LnPdII Ar

Br

Me ZnBr

Me

Ar

LnPdII

Me

H

Br-Ar

ZnBr2

Ph

Me Me

LnPdII H

Ar

Me

Ar

LnPdII

Me

ArMe

Ar Hreductiveelimination

oxidativeaddition

transmetallation!"hydrideelimination

insertion

reductiveelimination

reductiveelimination

Mechanistic Considerations

PCy2

i-Pr i-Pr

XPhos

i-Pr

PCy2

Me2N NMe2

CPhos

• Since different product ratios are observed between the coupling of i-PrZnBr andn-PrZnBr to the aryl bromide for each ligand, the product ratio of branched to linearproducts is determined by the relative rates of reductive elimination vs. β-hydrideelimination – reinsertion.

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Conclusion

• The authors have designed a new and efficient catalytic system forNegishi couplings of secondary alkylzinc halides with aryl bromides andactivated chlorides.

• The coupling reaction shows good functional group tolerance andwide substrate scope.

• The introduction of the new CPhos ligand has allowed for excellentreaction selectivity for branched vs. linear coupling products bysuppressing the undesired β-hydride elimination pathway competitive inthese reactions.

PCy2

Me2N NMe2

CPhos

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