Ortho vs Ipso: Site-Selective Pd and Norbornene-Catalyzed Arene C−H Amination Using Aryl Halides

1. Ortho vs Ipso: Site-Selective Pd and Norbornene-Catalyzed Arene C−H Amination Using Aryl Halides Zhe Dong and Guangbin Dong J. Am. Chem. Soc. 2013, 135, 18350-18353. Anne-Catherine Bédard Charette Literature Meeting February 5th 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 This work : Types of amination reactions : • Buchwald-Hartwig • Nucleophilic • Electrophilic • C-H amination

5. AreneAminations Reactions • Nucleophilic (via benzyne) • Electrophilic (nitrogen source is oxidized) Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 3832 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.

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

7. AreneAminations 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 : GuangbinDong • Types of areneamination reactions • Catellani reaction • Meta-substituted arene • The paper • Challenges and Optimization • Proposed Mechanism • Substrate scope • Mechanism investigation • Conclusion

9. Catellani Reaction Norbornene-mediated ortho C-H functionalization. • 1985.: reaction of norbornene with bromobenzene Marta Catellani Pr University of Parma • 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 Palladium (IV) intermediate Potential for meta substituted arene 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.

11. Catellani Reaction 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 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.

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 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. Maimone, T. J.; Milner, P. J.; Kinzel, T.; Zhang, Y.; Takase, M. K.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 18106.

14. Meta-Substituted Arenes Larrosa : Ortho arylation et decarboxylation Electron deficient arene only Yu : 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

15. Meta-Substituted Arenes Yu : Meta-direction removable template Gaunt : 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.

16. Meta-Substituted Arenes : Nitrogen Substituent Lautens : Hartwig : 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

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 Cs2CO3 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 • 1st 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