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 ChemistryNatural Product Total Synthesis

Since sept 2011 : published 15 independent papers•4 ACIE (1 VIP)•6 JACS (3 most read)

Aminations Reactions - Introduction

Types of amination reactions :

•Buchwald-Hartwig

•Nucleophilic•Electrophilic •C-H amination

This work :

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, 7652Campbell, 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

Ideal Amination ReactionAmination reactions typically need preactivation of either arene of amine

Ideal reaction : no preactivation needed !

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.

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

Marta CatellaniPr University of Parma

Norbornene-mediated ortho C-H functionalization.

• 1985.: reaction of norbornene with bromobenzene

BrPd(PPh3)4, tBuOK

anisole, 80-105oC 65%

BrPd(PPh3)4, tBuOK

anisole, 80-105oC

F

F

F F

F1 : 3

• 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

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

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 norbornene24-27 kcal/mol

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

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 tBuBrettPhosIntra vs intermolec mechanism still being investigated.

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

Meta-Substituted ArenesYu :

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

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 :

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 oxidantElectron 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 InhibitorRetrosynthetic 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