Negishi Coupling of Secondary Alkylzinc Halides with Aryl Bromides and Chlorides

R1 X Cat. Pd(OAc)2 R2 Ligand + R2 R ZnBr R 1 THF/Toluene rt or 60 oC R X = Br, Cl R1, R2 = Alkyl

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

Current Literature: 5/21/09 David Arnold

David Arnold @ Wipf Group Page 1 of 12 5/27/2009 Common Strategies Utilized for the Cross-Coupling of Secondary Alkyl Organometallic Reagents with Aryl Halides

1. Kumada Coupling (1972):

MgY Pd or Ni Catalyst RX + R R: aryl, vinyl; X = Cl, Br or I; Y = Cl or Br 2. Suzuki Coupling (2000):

X Pd Catalyst M +

R R R: alkyl, hetero-aryl, ether, ester, ketone, nitro... X: Cl, Br or I M: -B(OH)2, -B(OR)2, -BF3K 3. Negishi Coupling:

X Pd Catalyst ZnY +

R R 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: Mechanistic Considerations for Kumada / Suzuki / Negishi Couplings

Br H 1% PdCl (Ligand) MgCl 2 + + + Ether, rt, 1-24 h

dppf / 1 h 95% 0% 0% (PPh3)2 / 24 h 5% 6% 80% dppp / 24 h 43% 19% 15%

Et Ph Ph

L PdII n Et reductive elimination Br-Ph LnPd(0) Me Et Ph H ins ertion Ph reductive oxidative elim ination addition reductive Ph elimination H L PdII Ph n L PdII Ph n Br Et L PdII H n !"hydride elimination transmetallation Et Et MgClBr Me MgCl

Competing Pathways Desired Catalytic Cycle * Proper Ligand Selection is Key! J. Am. Chem. Soc. 1984, 106, 158.

David Arnold @ Wipf Group Page 3 of 12 5/27/2009 Kumada Coupling: Catalyst, Ligand and Scope

• Catalyst Screening: Ph Ph P Cl Br H o 1 mol % Catalyst 99.07o 87.8 MgCl Fe Pd + + + P Cl Ether, rt, 1-48 h Ph Ph A B C % Yield Determined by GC Catalyst Bond Angles, deg Entry Catalyst Temp (oC) Time (h) A (%) B (%) C (%) P-Pd-P Cl-Pd-Cl

1 PdCl2 (dppf) rt 1 95 0 0 99.07 87.8

2 PdCl2 (dppp) rt 24 43 19 23 90.6 90.8

3 PdCl2 (dppe) rt 48 0 0 4 85.8 94.2

4 PdCl2 (PPh3)2 rt 24 5 6 80 - -

5 NiCl2 (dppp) rt 23 29 3 63 - -

6 NiCl2 (PPh3)2 rt 23 3 5 88 - - 1 mol % PdCl (dppf) MgCl 2 RBr + Ether, rt, 8-20 h R

CF3 OMe 75% 58% 72% 80% 97%

• 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. J. Am. Chem. Soc. 1984, 106, 158.

David Arnold @ Wipf Group Page 4 of 12 5/27/2009 Suzuki Cross-Coupling Reactions: Scope and Present Limitations • Initial Reports: Br 1.0% Pd(dba) Cl 2 1.5% Pd (dba) 1.0% Ph5FcP(t-Bu)2 2 3 B(OH)2 4.5% P(t-Bu)3 + B(OH) 2 + K3PO4 3.3 equiv KF Toluene, 100 oC dioxane, 100 oC 75% 55% (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:

Cl 2 mol % Pd(OAc)2 R1 3 mol % n-BuPAd2

+ R1 BF3K 3 equiv Cs2CO3 R 10:1 toluene/H2O 100 oC, 24 h R R = CH3, OMe, Ac, CO2Me, NO2, CF3, Het-Ar R1 = c-C5H9, i-Pr R1 R1 R1 R1 R1 R1 R1 R1

MeO CO2Et N

R1 = OMe OMe NO2 F Ac CN 87% 88% 82% 89% 89% 77% 51% 0%

Me 78% 77% 1:6 3.5:1 Me i-Pr:n-Pr i-Pr:n-Pr

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

David Arnold @ Wipf Group Page 5 of 12 5/27/2009 Suzuki Cross-Coupling Reactions: Scope and Present Limitations

Cl 2 mol % Pd(OAc)2 • 60 ligands were screened 3 mol % Ligand in parallel. + BF K 3 3 equiv Cs2CO3 • The best 3 were further tested 10:1 toluene/H2O R o against diverse substrates. 100 C, 18 h R R = 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.

David Arnold @ Wipf Group Page 6 of 12 5/27/2009 Negishi Coupling: New Uses for Old Ligands

• Early Reports from Kumada (1984):

Br H 1 mol % PdCl (dppf) ZnCl 2 + + + THF, rt, 20 h

100% 0% 0%

J. Am. Chem. Soc. 1984, 106, 158. • 20 Years Later… the same methodology was applied to the racemic synthesis of bisabolene natural products which are components of many plant essential oils and many have been found to have a range of biological activities.

O MOM O MOM O Rieke Zn B r Br Zn B r 10 m ol % P dCl 2( dppf) HCl + THF THF, reflux , 24 h, 79% 89% O MOM OM OM O (+)- curcuhydroquinone

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

David Arnold @ Wipf Group Page 7 of 12 5/27/2009 Title Paper: Ligand Screening on Problematic Substrates

PCy2

Me2N NMe2

L6 CPhos

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

David Arnold @ Wipf Group Page 8 of 12 5/27/2009 Title Paper: Substrate Scope and Isomeric Product Ratios Employing the CPhos Ligand

PCy2 Me2N NMe2

L6 CPhos

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

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 and heteroaromatic 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 Mechanistic Considerations

PCy2 PCy2 i-Pr i-Pr Me2N NMe2

CPhos i-Pr XPhos

Me Ar Ar

L PdII n Me reductive elimination Br-Ar LnPd(0) Me Me Ar H insertion Ph reductive oxidative elimination addition reductive Ar elimination H L PdII Ar n L PdII Ar n Br Me L PdII H n !"hydride elimination transmetallation Me Me

ZnBr2 Me ZnBr • Since different product ratios are observed between the coupling of i-PrZnBr and n-PrZnBr to the aryl bromide for each ligand, the product ratio of branched to linear products is determined by the relative rates of reductive elimination vs. β-hydride elimination – reinsertion.

David Arnold @ Wipf Group Page 11 of 12 5/27/2009 Conclusion

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

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

• The introduction of the new CPhos ligand has allowed for excellent reaction selectivity for branched vs. linear coupling products by suppressing the undesired β-hydride elimination pathway competitive in these reactions.

PCy2 Me2N NMe2

CPhos

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