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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
David Arnold @ Wipf Group Page 1 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
David Arnold @ Wipf Group Page 2 of 12 5/27/2009
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
David Arnold @ Wipf Group Page 3 of 12 5/27/2009
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%
David Arnold @ Wipf Group Page 4 of 12 5/27/2009
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%
David Arnold @ Wipf Group Page 5 of 12 5/27/2009
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.
David Arnold @ Wipf Group Page 6 of 12 5/27/2009
• 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
David Arnold @ Wipf Group Page 7 of 12 5/27/2009
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.
David Arnold @ Wipf Group Page 8 of 12 5/27/2009
• 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
David Arnold @ Wipf Group Page 9 of 12 5/27/2009
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.
David Arnold @ Wipf Group Page 10 of 12 5/27/2009
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.
David Arnold @ Wipf Group Page 11 of 12 5/27/2009
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
David Arnold @ Wipf Group Page 12 of 12 5/27/2009