1. O RTHO VS I PSO : S ITE -S ELECTIVE P D AND N ORBORNENE -C ATALYZED A RENE C−H A MINATION U SING A RYL H ALIDES Zhe Dong and Guangbin Dong J. Am. Chem. Soc. 2013, 135, 18350-18353. Anne-Catherine Bédard Charette Literature Meeting February 5 th 2014

2. Outline Introduction The author : Guangbin Dong Types of arene amination reactions Catellani reaction Meta-substituted arene The paper Challenges and Optimization Proposed Mechanism Substrate scope Mechanism investigation Conclusion

3. Guangbin Dong BS, Peking University, China, 2003 PhD, Stanford University, 2009 (Trost) Postdoc, California Institute of Technology, 2011 (Grubbs) Assistant Prof. University of Texas at Austin (2011) Research Interests : Catalytic Reaction Development Organometallic Chemistry Natural Product Total Synthesis Since sept 2011 : published 15 independent papers 4 ACIE (1 VIP) 6 JACS (3 most read)

4. Aminations Reactions - Introduction Types of amination reactions : Buchwald-Hartwig Nucleophilic Electrophilic C-H amination This work :

5. Arene Aminations Reactions Nucleophilic (via benzyne) Electrophilic (nitrogen source is oxidized) Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7652 Campbell, M. J.; Johnson, J. S. Org. Lett. 2007, 9, 1521. Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 3832

6. Ideal Amination Reaction Amination reactions typically need preactivation of either arene of amine Ideal reaction : no preactivation needed !

7. Arene Aminations Reactions C-H amination Control of the site selectivity : Steric bias Electronic bias Directing group Mostly ortho to the DG or on the primary C-H bond. Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806. Kantak, A. A.; Potavathri, S.; Barham, R. A.; Romano, K. M.; DeBoef, B. J. Am. Chem. Soc. 2011, 133, 19960.

8. Outline Introduction The author : Guangbin Dong Types of arene amination reactions Catellani reaction Meta-substituted arene The paper Challenges and Optimization Proposed Mechanism Substrate scope Mechanism investigation Conclusion

9. Catellani Reaction Marta Catellani Pr University of Parma Norbornene-mediated ortho C-H functionalization. 1985.: reaction of norbornene with bromobenzene p-fluoro-bromobenzene leads to two isomeric products in the same conditions Catellani, M.; Chiusoli, G. P. Organomet. Chem. 1985, 286, C13–C16.

10. Catellani Reaction Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119. Motti, E.; Rossetti, M.; Bocelli, G.; Catellani, M. J. Organomet. Chem. 2004, 689, 3741. Palladium (IV) intermediate Potential for meta substituted arene

11. Catellani Reaction Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119. Motti, E.; Rossetti, M.; Bocelli, G.; Catellani, M. J. Organomet. Chem. 2004, 689, 3741. De-insertion of the norbornene is a reversible step Catellani propose that the reduction in steric hindrance at the Pd is the driving force for the reaction Ring strain in norbornene 24-27 kcal/mol

12. Outline Introduction The author : Guangbin Dong Types of arene amination reactions Catellani reaction Meta-substituted arene The paper Challenges and Optimization Proposed Mechanism Substrate scope Mechanism investigation Conclusion

13. Meta-Substituted Arenes Maimone, T. J.; Milner, P. J.; Kinzel, T.; Zhang, Y.; Takase, M. K.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 18106. Electron rich aryls give higher ratio of the meta product It was shown that the fluorating agent is 11, a modified tBuBrettPhos Intra vs intermolec mechanism still being investigated.

14. Meta-Substituted Arenes Larrosa : Cornella, J.; Righi, M.; Larrosa, I. Angew. Chem. Int. Ed. 2011, 50, 9429. Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc, 2009, 131, 5072 Ortho arylation et decarboxylation Yu : Electron deficient arene only

15. Meta-Substituted Arenes Yu : Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature. 2012, 486, 518. Phipps, R. J.; Gaunt, M. J. Science, 2009, 323, 1593. (Mech Cu) Chen, B.; Hou, X.-L.; Li, Y.-X., Wu, Y.-D. J. Am. Chem. Soc. 2011, 133, 7668. Gaunt : Meta-direction removable template

16. Meta-Substituted Arenes : Nitrogen Substituent Lautens : Wilhelm, T.; Lautens, M. Org. Lett. 2005, 7, 18. Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F., J. Am. Chem. Soc. 2002, 124, 390 Hartwig :

17. This Paper - Challenges Oxidant need to provide the amine Be stronger than aryl halide to avoid homo-Catellani reaction Not too strong to avoid destruction of NBE or Pd(0) catalyst Reductant need to be orthogonal to the oxidant

18. Proposed Mecanism

19. Optimization

20. Control Reactions

21. Substrate Scope b 25 mol % tri(2-furyl)phosphine, 2.0 equiv of amine and 3.0 equiv of Cs 2 CO 3 were used.

22. Substrate Scope - Homodimerization Electron poor substrate are good oxidant Electron poor phosphine decreases the formation of unwanted dimerization product

23. Scope - Part 2 Mono-addition is very difficult to control.

24. Scope Part 3 : Amine nBuNHOBz do not couple under these condition

25. Other Results Aryl bromide (weaker oxidant) Scale up

26. Deuteration Studies

27. P70S6 Kinase Inhibitor Retrosynthetic analysis: Synthesis : Hartwig : Murphy, J. M.; Liao, X.; Hartwig, J. F., J. Am. Chem. Soc. 2007, 129, 15434.

28. Conclusion Arene-amination reaction at the ortho (vs ipso) position of the halide 1 st C-N bond forming Catellani reaction Complementary to the Buchwald-Hartwing amination Future work Expanding the scope to aryl bromides Mechanistic studies on the C-N bond formation