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Catalytic Cross-coupling Reactions with Unactivated Alkyl Electrophiles and Alkyl Nucleophiles. Heng Su 04/11/2008 Department of Chemistry Brandeis University. Outline. Introduction General reaction pattern and mechanism Difficulties for unactivated alkyl substrates

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catalytic cross coupling reactions with unactivated alkyl electrophiles and alkyl nucleophiles

Catalytic Cross-coupling Reactions with Unactivated Alkyl Electrophilesand Alkyl Nucleophiles

Heng Su

04/11/2008

Department of Chemistry

Brandeis University

outline
Outline
  • Introduction

General reaction pattern and mechanism

Difficulties for unactivated alkyl substrates

  • Several Reaction Types

Kumada type (RMgX by Mn/Cu/Ni/Pd)

Suzuki type (RBR’2 by Pd/Ni )

Negishi type (RZnX / R2Zn by Ni/Pd)

  • Conclusion
  • Outlook
general reaction pattern and mechanism
General Reaction Pattern and Mechanism

Activated alkyl

electrophiles:

kumada type dramatic enhancement by additive
Kumada-type: Dramatic Enhancement by Additive

Kochi, J. et al. Synthesis1971, 303

Cahiez, G. et al. Tetrahedron.2000, 56, 2733

alkyl chlorides as electrophiles first example
Alkyl Chlorides as Electrophiles: First Example

Kambe, N. et al. J. Am. Chem. Soc.2002, 124, 4222

Kambe, N. et al. Chem. Lett.2003, 32, 890

reaction mechanism and evidences
Reaction Mechanism and Evidences

Kambe, N. et al. J. Am. Chem. Soc.2002, 124, 4222

Kambe, N. et al. Angew. Chem. Int. Ed.2003, 42, 3412

Kambe, N. et al. Angew. Chem. Int. Ed.2004, 43, 6180

alkyl fluorides as electrophiles
Alkyl Fluorides as Electrophiles

Kambe, N. et al. J. Am. Chem. Soc.2002, 125, 5646

Kambe, N. et al. Angew. Chem. Int. Ed.2007, 46, 2086

difference in chemoselectivity
Difference in Chemoselectivity

Kambe, N. et al. Angew. Chem. Int. Ed.2007, 46, 2086

kinetic study and proposed mechanism
Kinetic Study and Proposed Mechanism

Kambe, N. et al. Angew. Chem. Int. Ed.2007, 46, 2086

fe catalyst sec alkyl electrophiles
Fe Catalyst: Sec-alkyl Electrophiles

Chai, C. L. L. et al. Adv. Synth. Catal.2007, 349, 1015

suzuki type phosphine did make differences
Suzuki-type: Phosphine did Make Differences

Suzuki, A. etc. Chem. Lett.1992, 691

  • Water is necessary:
  • Non-hydrate salt gave no reaction.
  • Non-hydrate salt + water gave comparable yields

Fu, G.C. et al. J. Am. Chem. Soc.2001, 123, 10099

alkyl chlorides and sulfonates as electrophiles
Alkyl Chlorides and Sulfonates as Electrophiles

Fu, G.C. et al. Angew. Chem. Int. Ed.2002, 41, 1945

Fu, G.C. et al. Angew. Chem. Int. Ed.2002, 41, 3910

boronic acids as coupling partners
Boronic Acids as Coupling Partners

Fu, G.C. et al. J. Am. Chem. Soc.2002, 124, 13662

how do phosphine ligands effect
How do Phosphine Ligands Effect?

Fu, G.C. et al. Angew. Chem. Int. Ed.2003, 42, 5749

sec alkyl electrophiles
Sec-Alkyl Electrophiles

Fu, G.C. et al. J. Am. Chem. Soc.2007, 129, 9602

negishi type styrene additive
Negishi-type: Styrene Additive

Knochel, P. et al. Angew. Chem. Int. Ed.1995, 34, 2723

Knochel, P. et al. Angew. Chem. Int. Ed.1998, 37, 2387

replace diorganozinc by organozinc halide
Replace Diorganozinc by Organozinc Halide

Knochel, P. et al. Angew. Chem. Int. Ed.1998, 37, 2387

Knochel, P. et al. J. Org. Chem.2002, 67, 79

pd catalyzed coupling
Pd-Catalyzed Coupling

Fu, G. C. et al. J. Am. Chem. Soc.2003, 125, 12527

pd nhc catalyst
Pd-NHC Catalyst

Organ, M. G. etc. Org. Lett.2005, 7, 3805

Organ, M. G. et al. Chem. Eur. J.2006, 12, 4749

sec alkyl halides as electrophiles
Sec-Alkyl Halides as Electrophiles

Fu, G. C. et al. J. Am. Chem. Soc.2003, 125, 14726

enantioselective negishi cross coupling
Enantioselective Negishi Cross-coupling

Fu, G.C. et al. J. Am. Chem. Soc.2005, 127, 4594

Fu, G.C. et al. J. Am. Chem. Soc.2005, 127, 10482

R1 = n-Bu, regioselectivity = 1.9:1

= others, >20:1

Fu, G.C. et al. J. Am. Chem. Soc.2008, 130, 2756

radical or nonradical pathway
Radical or Nonradical Pathway?

Only C2H6 and C2D6 was observed

Vicic, D. A. et al. J. Am. Chem. Soc.2006, 128, 13175

formal synthesis of fluvircinine a 1
Formal Synthesis of Fluvircinine A1

Fu, G.C. et al. J. Am. Chem. Soc.2008, 130, 2756

formal synthesis of fluvircinine a 1 retrosynthesis
Formal Synthesis of Fluvircinine A1: Retrosynthesis

Fu, G.C. et al. J. Am. Chem. Soc.2008, 130, 2756

brief summary of negishi type cross coupling
Brief Summary of Negishi-type Cross-coupling

Fu, G.C. et al. J. Am. Chem. Soc.2008, 130, 2756

outlook
Outlook
  • Unactivated tertiary alkyl chlorides as electrophiles
  • Tertiary alkyl boron compounds as nucleophiles
  • Enantioselective cross-coupling of unactivated electrophiles