1. Catalytic Cross-coupling Reactions with Unactivated Alkyl Electrophiles and 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 / R 2 Zn by Ni/Pd) Conclusion Outlook

3. General Reaction Pattern and Mechanism Activated alkyl electrophiles:

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

5. Kumada-type: Dramatic Enhancement by Additive Cahiez, G. et al. Tetrahedron. 2000, 56, 2733 Kochi, J. et al. Synthesis 1971, 303

6. Alkyl Chlorides as Electrophiles: First Example Kambe, N. et al. Chem. Lett. 2003, 32, 890 Kambe, N. et al. J. Am. Chem. Soc. 2002, 124, 4222

7. Reaction Mechanism and Evidences Kambe, N. et al. Angew. Chem. Int. Ed. 2004, 43, 6180 Kambe, N. et al. J. Am. Chem. Soc. 2002, 124, 4222 Kambe, N. et al. Angew. Chem. Int. Ed. 2003, 42, 3412

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 Fu, G.C. et al. J. Am. Chem. Soc. 2001, 123, 10099 Water is necessary: 1.Non-hydrate salt gave no reaction. 2.Non-hydrate salt + water gave comparable yields Suzuki, A. etc. Chem. Lett. 1992, 691

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. 2008, 130, 2756 R 1 = n-Bu, regioselectivity = 1.9:1 = others, >20:1 Fu, G.C. et al. J. Am. Chem. Soc. 2005, 127, 4594 Fu, G.C. et al. J. Am. Chem. Soc. 2005, 127, 10482

25. Radical or Nonradical Pathway? Vicic, D. A. et al. J. Am. Chem. Soc. 2006, 128, 13175 Only C 2 H 6 and C 2 D 6 was observed

26. Formal Synthesis of Fluvircinine A 1 Fu, G.C. et al. J. Am. Chem. Soc. 2008, 130, 2756

27. Formal Synthesis of Fluvircinine A 1 : 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