negishi coupling of secondary alkylzinc halides with aryl …ccc.chem.pitt.edu/wipf/current...

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

David Arnold @ Wipf Group of 12 5/27/2009

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


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


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


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%


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%


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.


• 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


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.


• 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


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.


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



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.


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


negishi coupling of secondary alkylzinc halides with aryl …ccc.chem.pitt.edu/wipf/current...

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