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Catalytic Cross-coupling Reactions with Unactivated Alkyl Electrophiles and Alkyl Nucleophiles

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

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  1. Catalytic Cross-coupling Reactions with Unactivated Alkyl Electrophilesand Alkyl Nucleophiles Heng Su 04/11/2008 Department of Chemistry Brandeis University

  2. 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

  3. General Reaction Pattern and Mechanism Activated alkyl electrophiles:

  4. Difficulties of Unactivated Alkyl Substrates M’ = Pd accelerate accelerate

  5. Kumada-type: Dramatic Enhancement by Additive Kochi, J. et al. Synthesis1971, 303 Cahiez, G. et al. Tetrahedron.2000, 56, 2733

  6. 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

  7. 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

  8. 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

  9. Difference in Chemoselectivity Kambe, N. et al. Angew. Chem. Int. Ed.2007, 46, 2086

  10. Kinetic Study and Proposed Mechanism Kambe, N. et al. Angew. Chem. Int. Ed.2007, 46, 2086

  11. Fe Catalyst: Sec-alkyl Electrophiles Chai, C. L. L. et al. Adv. Synth. Catal.2007, 349, 1015

  12. Brief Summary of Kumada-type Cross-coupling

  13. 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

  14. 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

  15. Boronic Acids as Coupling Partners Fu, G.C. et al. J. Am. Chem. Soc.2002, 124, 13662

  16. How do Phosphine Ligands Effect? Fu, G.C. et al. Angew. Chem. Int. Ed.2003, 42, 5749

  17. Sec-Alkyl Electrophiles Fu, G.C. et al. J. Am. Chem. Soc.2007, 129, 9602

  18. Brief Summary of Suzuki-type Cross-coupling

  19. 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

  20. 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

  21. Pd-Catalyzed Coupling Fu, G. C. et al. J. Am. Chem. Soc.2003, 125, 12527

  22. Pd-NHC Catalyst Organ, M. G. etc. Org. Lett.2005, 7, 3805 Organ, M. G. et al. Chem. Eur. J.2006, 12, 4749

  23. Sec-Alkyl Halides as Electrophiles Fu, G. C. et al. J. Am. Chem. Soc.2003, 125, 14726

  24. 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

  25. Radical or Nonradical Pathway? Only C2H6 and C2D6 was observed Vicic, D. A. et al. J. Am. Chem. Soc.2006, 128, 13175

  26. Formal Synthesis of Fluvircinine A1 Fu, G.C. et al. J. Am. Chem. Soc.2008, 130, 2756

  27. Formal Synthesis of Fluvircinine A1: Retrosynthesis Fu, G.C. et al. J. Am. Chem. Soc.2008, 130, 2756

  28. Brief Summary of Negishi-type Cross-coupling Fu, G.C. et al. J. Am. Chem. Soc.2008, 130, 2756

  29. Conclusion

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

  31. Acknowledgement

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