Negishi Coupling of Secondary Alkylzinc Halides with Aryl Bromides and Chlorides
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1 Negishi Coupling of Secondary Alkylzinc alides with Aryl Bromides and Chlorides X X = Br, Cl 2 1 ZnBr 1, 2 = Alkyl Cat. Pd(OAc) 2 Ligand TF/Toluene rt or 60 o C 1 2 J. Am. Chem. Soc. 2009, ASAP Article Chong an and Stephen L. Buchwald Current Literature: 5/21/09 David Arnold David Wipf Group Page 1 of 12 5/27/2009
2 Common Strategies Utilized for the Cross-Coupling of Secondary Alkyl Organometallic eagents with Aryl alides 1. Kumada Coupling (1972): X 2. Suzuki Coupling (2000): MgY Pd or Ni Catalyst : aryl, vinyl; X = Cl, Br or I; Y = Cl or Br X M Pd Catalyst 3. Negishi Coupling: : alkyl, hetero-aryl, ether, ester, ketone, nitro... X: Cl, Br or I M: -B(O) 2, -B(O) 2, -BF 3 K X ZnY Pd Catalyst : alkyl, hetero-aryl, ether, ester, ketone, aldehyde... X or Y: Cl, Br or I David Wipf Group Page 2 of 12 5/27/2009
3 Pioneering Work by Kumada and ayshi: chanistic Considerations for Kumada / Suzuki / Negishi Couplings Br MgCl 1% PdCl 2 (Ligand) Ether, rt, 1-24 h dppf / 1 h (P 3 ) 2 / 24 h dppp / 24 h 95% 5% 43% 0% 6% 19% 0% 80% 15% Et L n Pd II Et ins ertion L n Pd II reductive reductive!"hydride Et L n Pd II Et reductive elim ination L n Pd(0) oxidative addition transmetallation Br- L n Pd II Br Et Et MgClBr MgCl Competing Pathways * Proper Ligand Selection is Key! Desired Catalytic Cycle J. Am. Chem. Soc. 1984, 106, 158. David Wipf Group Page 3 of 12 5/27/2009
4 Kumada Coupling: Catalyst, Ligand and Scope Catalyst Screening: Br MgCl 1 mol % Catalyst Ether, rt, 1-48 h Fe P Cl Pd P Cl o 87.8 o A B C % Yield Determined by GC Catalyst Bond Angles, deg Entry Catalyst Temp ( o C) Time (h) A (%) B (%) C (%) P-Pd-P Cl-Pd-Cl 1 PdCl 2 (dppf) rt PdCl 2 (dppp) rt PdCl 2 (dppe) rt PdCl 2 (P 3 ) 2 rt NiCl 2 (dppp) rt NiCl 2 (P 3 ) 2 rt Br MgCl 1 mol % PdCl 2 (dppf) Ether, rt, 8-20 h O 75% 58% 72% Use of the PdCl 2 (dppf) catalyst successfully suppressed byproducts resulting from β-hydride. Substrate scope is limited to halide coupling partners compatible with Grignard reagents. CF 3 80% 97% J. Am. Chem. Soc. 1984, 106, 158. David Wipf Group Page 4 of 12 5/27/2009
5 Suzuki Cross-Coupling eactions: Scope and Present Limitations Initial eports: B(O) 2 Cl 1.5% Pd 2 (dba) 3 4.5% P(t-Bu) equiv KF dioxane, 100 o C 75% B(O) 2 Br 1.0% Pd(dba) 2 1.0% 5 FcP(t-Bu) 2 K 3 PO 4 Toluene, 100 o C 55% (estimated GC yield) Mixture of sec- and n-butylaryl products J. Am. Chem. Soc. 2000, 122, J. Org. Chem. 2002, 67, ecent Work by Molander: Cl BF 3 K 1 = C 3, O, Ac, CO 2, NO 2, CF 3, et-ar 1 = c-c 5 9, i-pr 1 = O 2 mol % Pd(OAc) 2 3 mol % n-bupad 2 3 equiv Cs 2 CO 3 10:1 toluene/ 2 O 100 o C, 24 h O O NO 2 87% 88% 82% 89% 89% CO 2 Et 1 N F Ac CN 77% 51% 0% 78% 1:6 i-pr:n-pr 77% 3.5:1 i-pr:n-pr J. Am. Chem. Soc. 2008, 122, David Wipf Group Page 5 of 12 5/27/2009
6 Suzuki Cross-Coupling eactions: Scope and Present Limitations 60 ligands were screened in parallel. The best 3 were further tested against diverse substrates. Cl 2 mol % Pd(OAc) 2 3 mol % Ligand BF 3 K 3 equiv Cs 2 CO 3 10:1 toluene/ 2 O 100 o C, 18 h = o-o, t-bu 2 P, 72 h: 57% yield, 1.4:1 i-pr:n-pr = p-o, t-bu 2 P, 72 h: 79% yield, 8.2:1 i-pr:n-pr Good Functional Group Compatibility: Alkyl, Aryl, et-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, David Wipf Group Page 6 of 12 5/27/2009
7 Negishi Coupling: New Uses for Old Ligands Early eports from Kumada (1984): Br ZnCl 1 mol % PdCl 2 (dppf) TF, rt, 20 h 100% 0% 0% J. Am. Chem. Soc. 1984, 106, 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. B r ieke Zn TF Br Zn O MOM B r 10 m ol % P dcl 2 ( dppf) TF, reflux, 24 h, 79% O MOM Cl 89% O O MOM OM OM O ()- curcuhydroquinone J. Org. Chem. 2004, 7, David Wipf Group Page 7 of 12 5/27/2009
8 Title Paper: Ligand Screening on Problematic Substrates 2 N PCy 2 N2 L6 Cos The new Cos ligand showed excellent conversions and selectivity for the desired branched products. David Wipf Group Page 8 of 12 5/27/2009
9 Title Paper: Substrate Scope and Isomeric Product atios Employing the Cos Ligand PCy 2 2 N N 2 L6 Cos Excellent yields and selectivities for branched products Good functional group tolarance David Wipf Group Page 9 of 12 5/27/2009
10 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 Wipf Group Page 10 of 12 5/27/2009
11 chanistic Considerations PCy 2 2 N N 2 i-pr PCy 2 i-pr Cos i-pr Xos Ar Ar L n Pd II insertion Ar L n Pd II Ar reductive reductive!"hydride L n Pd II Ar reductive ZnBr 2 L n Pd(0) oxidative addition transmetallation L n PdII Ar Br 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 vs. β-hydride reinsertion. Br-Ar ZnBr David Wipf Group Page 11 of 12 5/27/2009
12 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 Cos ligand has allowed for excellent reaction selectivity for branched vs. linear coupling products by suppressing the undesired β-hydride pathway competitive in these reactions. PCy 2 2 N N 2 Cos David Wipf Group Page 12 of 12 5/27/2009
Negishi Coupling of Secondary Alkylzinc Halides with Aryl Bromides and Chlorides
Negishi Coupling of Secondary Alkylzinc Halides with Aryl Bromides and Chlorides The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation
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