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
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
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)
Aminations Reactions - Introduction
This work :
Types of amination reactions :
• Buchwald-Hartwig
• Nucleophilic
• Electrophilic
• C-H amination
Arene Aminations Reactions
• Nucleophilic (via benzyne)
Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 3832
• 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.
Ideal Amination Reaction
Amination reactions typically need preactivation of either arene of amine
Ideal reaction : no preactivation needed !
Arene Aminations Reactions
• C-H amination
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.
• Control of the site selectivity :
• Steric bias
• Electronic bias
• Directing group
• Mostly ortho to the DG or on the primary C-H bond.
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
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.
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.
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.
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
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.
Meta-Substituted Arenes
Larrosa : Ortho arylation et decarboxylation
Yu : Electron deficient arene only
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
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.
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
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
Proposed Mecanism
Optimization
Control Reactions
Substrate Scope
b
25 mol % tri(2-furyl)phosphine, 2.0 equiv of amine and 3.0 equiv of Cs2CO3 were used.
Substrate Scope - Homodimerization
Electron poor substrate are good oxidant
Electron poor phosphine decreases the formation of unwanted dimerization product
Scope - Part 2
•
Mono-addition is very difficult to control.
Scope Part 3 : Amine
•
nBuNHOBz do not couple under these condition
Other Results
•
Aryl bromide (weaker oxidant)
•
Scale up
Deuteration Studies
P70S6 Kinase Inhibitor
Retrosynthetic analysis:
Synthesis :
Hartwig :
Murphy, J. M.; Liao, X.; Hartwig, J. F., J. Am. Chem. Soc. 2007, 129, 15434.
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