Post on 09-Feb-2020
Organic seminar
By
Badru-Deen Barry
02/08/17
TRADE-OFF: All Carbon Electrophiles for
Nucleophiles in Ni-Catalyzed Cross
Electrophile Coupling (XEC)
Classical Cross-Coupling Reactions
Conventional
Coupling
Nu + E
Oxidative
Coupling
Nu + Nu
Reductive
Coupling
E + E
Cross Coupling Reagents/Precursors
A. Conventional Cross Coupling Reactions
General Conventional Cross-Coupling Reaction
Mechanism:
Christmann , U.; Vilar, R. Angew. Chem. Int. Ed. 2005, 44, 366
Conventional Method
Advantages High yielding synthetic route for the cross-selective product.
Broad substrate scope.
High functional group tolerance
Mild reaction conditions
Limitations Non-commercial availability of many organometallics and their sensitivity to air and water
Instability of reagents and short shelf-life (e.g. organoboronic acid dimerization).
Sensitivity to air and water.
Toxicity of some metals(e.g. Sn)
Toxicity of organohalides/Formation of PCBs and dioxins.
Additives required to accelerate the transmetallation step (for organoboron and
organosilicon)
General Cross-Coupling Reactions
B. Oxidative Cross-Coupling-Two Nucleophiles
Challenges:
Suitable oxidizing agent to convert the Pd(0) species into a Pd(II) species capable of doing
the double transmetallation
System that will favor the formation of a heterosubstituted intermediate R1-Pd(II)- R2
Pd-Catalyzed Oxidative Nu-Nu Cross-Coupling
Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780
Palladium-Catalyzed Cross-Coupling of Alkylzinc and
Alkynylstannanes
Zhao, Y.; Wang, H.; Hou, X.; Hu, Y.; Lei, A.; Zhang, H.; Zhu, L. J. Am. Chem. Soc. 2006, 128, 15048
Optimization
Csp-M to Csp-M, Csp-M to Csp2 –M, Csp-M to Csp3 –M, Csp2 -M to Csp2 –M, Csp2 -M to Csp3 –M, Csp3 -M to Csp3 –M
as nucleophiles have been reported.
Palladium-Catalyzed Cross-Coupling of Alkylzinc
and Alkynylstannanes
Zhao, Y.; Wang, H.; Hou, X.; Hu, Y.; Lei, A.; Zhang, H.; Zhu, L. J. Am. Chem. Soc. 2006, 128, 15048
Scope
Double Transmetallation
Palladium-Catalyzed Cross-Coupling of Alkylzinc
and Alkynylstannanes
Zhao, Y.; Wang, H.; Hou, X.; Hu, Y.; Lei, A.; Zhang, H.; Zhu, L. J. Am. Chem. Soc. 2006, 128, 15048
Mechanism:
Palladium-Catalyzed Cross-Coupling of Alkylzinc
and Alkynylstannanes
Advantages
Oxidative addition step common to conventional cross-coupling skipped.
High selectivity with good yields for the Csp-Csp3 cross-coupled products
Substrates with β-hydrogens tolerated
Limitations
Use of unstable organometallic reagents as precursors
Toxicity of metal byproduct in the transmetallation step
Need for an oxidant
C. Cross Electrophile Coupling (XEC)
Cross Electrophile Coupling (XEC) – A Field in its
Infancy
Wurtz, A. Ann. Chim. Phys. 1855, 44, 275
Drawbacks:
limited to the efficient synthesis of symmetric alkanes
production of alkenes from side reactions
Suzuki Arylation of an Unactivated Tertiary Alkyl
Bromide
Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc. 2013, 135, 624
limitations with respect to the nucleophile (ortho- and para-substituted aryl-(9- BBN)
reagents generally do not couple in useful yields
Mechanism for the Ni-catalyzed Suzuki Cross-Coupling
Zultanski, S. L.; Fu, G. C. J. Am. Chem. Soc. 2013, 135, 624
Need for More Innovative Reaction Development
1. Use of reagents that exclude use of R – [M]
2. A catalyst system that undergoes facile oxidative addition
Easy accessibility to variable oxidation states: -1, 0, +1, +2, +3, +4
Facile oxidative addition
Radical pathway more readily accessed
Some key features of Ni as a potential candidate
Strategies for Achieving Good Yields of Cross-
Coupling Products in XEC
III. Employ an Excess of One Reagent
I. Electronic Differentiation of Starting Materials - Sequential Oxidative Addition
II. Catalyst-Substrate Steric Matching
Gosmini, C.; Lasry, S.; Nédélec, J.-Y.; Périchon, J. Tetrahedron 1998, 54, 1289.
bipyridine was the only ligand investigated
limited substrate scope.
I. Electronic Differentiation of Starting Materials
The Ni-catalyzed electrochemical and chemical coupling of aryl with pyridyl/pyrazinyl
I. Electronic Differentiation of Starting Materials:
Sequential Oxidative Addition
Qian, Q.; Zang, Z.; Wang, S.; Chen, Y.; Lin, K.; Gong, H. Synlett 2013, 24, 619
Reductive Cross-Coupling of Aryl Halides for Csp2-Csp
2 Bond Formation
Electronic Differentiation of Starting Materials
[Csp2-Csp
2] Bond Formation
Qian, Q.; Zang, Z.; Wang, S.; Chen, Y.; Lin, K.; Gong, H. Synlett 2013, 24, 619
without Bu4NI 53%
2b instead of 2a, without Bu4NI 48%
3b instead of 2a, without Bu4NI 36%
DMF instead of DMA, without Bu4NI 39%
NiBr2 and 2b instead of NiI2 and 2a, without Bu4NI 35%
2b instead of 2a, 100 mol% MgCl2, without pyridine, without Bu4NI n.d
i-Pr-Pybox 3b instead of 2a, without Bu4NI trace
Model Reaction:
Electronic Differentiation of Starting Materials
Qian, Q.; Zang, Z.; Wang, S.; Chen, Y.; Lin, K.; Gong, H. Synlett 2013, 24, 619
Synthesis of Unsymmetrical Biaryl Compounds [Csp2-Csp
2]
Qian, Q.; Zang, Z.; Wang, S.; Chen, Y.; Lin, K.; Gong, H. Synlett 2013, 24, 619
Heteroaromatic Halides as Substrates
Synthesis of Unsymmetrical Biaryl Compounds [Csp2-Csp
2]
Elimination of an in-situ Negishi Process
1. King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc., Chem. Commun. 1977, 683.
2. Qian, Q.; Zang, Z.; Wang, S.; Chen, Y.; Lin, K.; Gong, H. Synlett 2013, 24, 619
Synthesis of Unsymmetrical Biaryl Compounds [Csp2-Csp
2]
How about a Kumada!!!
Proposed Ni(I) /Ni(III) and Ni(0)/Ni(II) Catalytic Cycle
Qian, Q.; Zang, Z.; Wang, S.; Chen, Y.; Lin, K.; Gong, H. Synlett 2013, 24, 619
Synthesis of Unsymmetrical Biaryl Compounds [Csp2-Csp
2]
Synthesis of Unsymmetrical Biaryl Compounds
[Csp2-Csp
2]
Formation of unsymmetrical biarlys from electronenriched aryl halides and aryl halides
No organometallic reagents involved.
Differences in electron properties between the coupling partners impacted the high coupling
efficiency
Summary
Limitations
Limited to OMe as the phenyl electron enriching group
Strategies for Achieving Good Yields of Cross-
Selectivity in XEC
III. Equal Substrate Reactivity: Employ an Excess of One Reagent
I. Electronic Differentiation of Starting Materials - Sequential Oxidative Addition
II. Catalyst-Substrate Steric Matching
II. Catalyst/substrate Matching – [Csp2 – Csp
3] Bond Formation
Shrestha, R.; Dorn, S. C. M.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 751
Three approaches to conjugate addition
Catalyst/substrate Steric Matching [Csp2 – Csp
3]
Shrestha, R.; Dorn, S. C. M.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 751
Ni-Catalyzed Reductive Conjugate Addition to Enones
Optimization
Ni-Catalyzed Reductive Conjugate Addition to
Enones [Csp2 – Csp
3]
Shrestha, R.; Dorn, S. C. M.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 751
Aryl Halide Electronic Effects
Ni-Catalyzed Reductive Conjugate Addition to Enones
Shrestha, R.; Dorn, S. C. M.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 751
Ligand/Catalyst Sterics
Catalyst-Substrate Steric Matching: Ni-Catalyzed
Reductive Conjugate Addition to Enones [Csp2 – Csp
3]
Shrestha, R.; Dorn, S. C. M.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 751
Mechanism
Catalyst-Substrate Steric Matching: Ni-Catalyzed Reductive
Conjugate Addition to Enones [Csp2 – Csp
3]
Three electrophilic reagents
Substrate and ligand sterics complement each other
Summary
Shrestha, R.; Dorn, S. C. M.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 751
Catalyst-Substrate Matching -Csp3-Csp3 Bond
Formation
Nickel-catalyzed Cross-Coupling of Unactivated Alkyl Halides using
Bis(pinacolato)diboron as Reductant -
Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci., 2013, 4, 4022
Nickel-catalyzed Cross-Coupling of Unactivated Alkyl Halides
using Bis(pinacolato)diboron as Reductant
Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci., 2013, 4, 4022
Coupling of Unactivated Alkyl Halides using Bis(pinacolato)diboron as Reductant
Coupling of secondary with primary alkyl bromides
Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci., 2013, 4, 4022
Proposed Catalytic Intermediates for Conjugate
Addition
Nickel-catalyzed Cross-Coupling of Unactivated Alkyl Halides using Bis(pinaco-
lato)diboron as Reductant - Csp3-Csp3 Bond Formation
Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci., 2013, 4, 4022
Radical Process
Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci., 2013, 4, 4022
alkyl radical intermediate generated during the course of coupling
Nickel-catalyzed Cross-Coupling of Unactivated Alkyl Halides using bis(pinac-
olato)diboron as Reductant - Csp3-Csp3 Bond Formation
Coupling of Unactivated Alkyl Halides using bis(pinac- olato)diboron as Reductant - Csp3-Csp3 Bond Formation
Xu, H.; Zhao, C.; Qian, Q.; Deng, W.; Gong, H. Chem. Sci., 2013, 4, 4022
Mechanism
Coupling of Unactivated Alkyl Halides using bis(pinac-
olato)diboron as Reductant - Csp3-Csp3 Bond Formation
Safer and easier synthetic route with bench-stable and readily available substrates
Need for organometallics is eliminated
Conclusions
Strategies for Achieving Good Yields of Cross-
Selectivity
3. Employ an Excess of One Reagent
1. Electronic Differentiation of Starting Materials - Sequential Oxidative Addition
2. Catalyst-Substrate Steric Matching
III. Excess of one Reagent - (Csp3-Csp
3) Bond
Formation
Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett., 2011, 13, 8
Nickel-Catalyzed Reductive Cross-Coupling of Unactivated Alkyl Halides
Challenges– Cross-Coupling vs Homocoupling
Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett., 2011, 13, 8
Nickel-Catalyzed Reductive Cross-Coupling of Unactivated Alkyl Halides
Substrate Scope and Selectivity Determining Factor
Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett., 2011, 13, 8
Nickel-Catalyzed Reductive Cross-Coupling of Unactivated Alkyl Halides
Coupling of cyclic 2o alkyl bromides with 1o alkyl halides
Yu, X.; Yang, T.; Wang, S.; Xu, H.; Gong, H. Org. Lett., 2011, 13, 8
Nickel-Catalyzed Reductive Cross-Coupling of Unactivated Alkyl Halides
Nickel-Catalyzed Reductive Cross-Coupling of
Unactivated Alkyl Halides
Selectivity induced by using an excess of one organohalide coupling partner.
Summary
Nickel-Catalyzed Reductive Cross-Coupling of Unactivated Alkyl Halides
Summary
Csp2 – Csp
2 bond formation via electronic differentiation
Csp2 – Csp
3 bond formation by matching catalyst/ligand and substrates
Csp3 – Csp
3 bond formation by using an excess of one reagent
Utility of readily available, easy-to-handle and stable starting materials
Acknowledgement
Dr. Robert E Maleczka
Dr. Xuefei Huang
Faculty of the Chemistry Department
The Maleczka Group: Susanne Miller,Chathurika Jayasundara, Jonathan Dannatt, Fangyi
Shen, Damith Perera, Jose Montero
Zheng Li, Shuang, Aliakbar, Saeedeh
Thank You