Direct β-Functionalization of Carbonyl Compounds

Yijing Dai Jan 08. 2014

Carbonyl Compounds

L.G. Wade, Jr. Organic Chemistry, 5th ed. Prentice Hall, 2002. ISBN 0-13-033832-X

Direct Functionalization of Carbonyl Compounds

Aldehyde & Ketone

●ipso position-Grignard reaction, Wittig olefinations, reductive aminations ●α position-Enolate chemistry (Aldol reaction, Pd-catalyzed α-arylation ) ●β position-?

Carboxylic & Acid & Ester

●ipso position-, Nucleophilic addition, reduction ●α position-Halogenation, Claisen Condensation ●β position-?

Outline

q  Direct β-Functionalization of Ketone and Aldehyde

Ø  Organocatalysis and Photoredox Process

Ø  Palladium-Catalyzed β-Arylation

q  Direct β-Functionalization of Carboxylic Acid and Ester

Ø  Palladium-Catalyzed β-Arylation of Simple Carboxylic Acids

Ø  Palladium-Catalyzed β-Functionalized Esters

Conventional β-Functionalization of Ketone and Aldehyde

α-functionalization

β-functionalization

Conventional approach

Huang, Z.;Dong, G. J. Am. Chem. Soc., 2013, 135, 17747–17750

Outline

q  Direct β-Functionalization of Ketone and Aldehyde

Ø  Organocatalysis and Photoredox Process

Ø  Palladium-Catalyzed β-Arylation (Pd-enolate)

q  Direct β-Functionalization of Carboxylic Acid and Ester

Ø  Palladium-Catalyzed β-Arylation of Simple Carboxylic Acids

Ø  Palladium-Catalyzed β-Functionalized Esters

Three Activation Mode of Organocatalysis

Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.; Wang, W. Nat. Commun. 2011, 2, 211

HOMO Activation

LUMO Activation

SOMO Activation

β-Functionalization Aldehyde by Oxidative Enamine Catalysis

Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.; Wang, W. Nat. Commun. 2011, 2, 211

β-Functionalization of Aldehydes by FBSM

Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.; Wang, W. Nat. Commun. 2011, 2, 211

Oxidative Enamine in Cascade Processes

Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.; Wang, W. Nat. Commun. 2011, 2, 211

Oxidative Enamine in Cascade Processes

Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.; Wang, W. Nat. Commun. 2011, 2, 211

quadruple cascade: oxidation-Michael-Aldol-Dehydration process

Mechanism Study

Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.; Wang, W. Nat. Commun. 2011, 2, 211

Possible Mechanisms

Single electron transfer (SET) pathway

Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.; Wang, W. Nat. Commun. 2011, 2, 211

CAN: Cerium (IV) ammonium nitrate

Standard SET Pathway by MacMillan

Beeson,T. D. ; Mastracchio, A.; Hong, J.; Ashton, K.; MacMillan, D. W. C. Science, 2013, 339, 1593

Possible Mechanisms

Ionic process involving an electron pair transfer

Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.; Wang, W. Nat. Commun. 2011, 2, 211

IBX-mediate oxidation pathway

Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287

Photoredox Activation for β-Arylation of Ketones and Aldehydes

Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W. C. Science, 2013, 339, 1593

Proposed Activation Mode

SET

SET

Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W. C. Science, 2013, 339, 1593

β-Arylation of Different Aldehydes

Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W. C. Science, 2013, 339, 1593

β-Arylation of Different Ketones

Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W. C. Science, 2013, 339, 1593

β-Functionalization of Cyclic Ketones with Aryl Ketones

Petronijević, F. R.; Nappi, M.; MacMillan, D. W. C. J. Am. Chem.Soc., 2013, 135, 18323–18326

Proposed Mechanism

SET

SET

Petronijević, F. R.; Nappi, M.; MacMillan, D. W. C. J. Am. Chem.Soc., 2013, 135, 18323–18326

Scope of the Ketone-Radical Precursor

Petronijević, F. R.; Nappi, M.; MacMillan, D. W. C. J. Am. Chem.Soc., 2013, 135, 18323–18326

Scope of Ketyl Radical Coupling Partner

Petronijević, F. R.; Nappi, M.; MacMillan, D. W. C. J. Am. Chem.Soc., 2013, 135, 18323–18326

Stern-Volmer Quenching Studies for Mechanism

Figure 1. *Ir(ppy)3 emission quenching with benzophenone and enamine 4.

Figure 2. *Ir(p-MeO-ppy)3 emission quenching with acetophenone and enamine 4.

Petronijević, F. R.; Nappi, M.; MacMillan, D. W. C. J. Am. Chem.Soc., 2013, 135, 18323–18326

An Alternative Mechanism for Alkyl-Aryl Ketone

SET

SET

Outline

q  Direct β-Functionalization of Ketone and Aldehyde

Ø  Organocatalysis and Photoredox Process

Ø  Palladium-Catalyzed β-Arylation (Pd-enolate)

Ø  Direct β-Functionalization of Carboxylic Acid and Ester

Ø  Palladium-Catalyzed β-Arylation of Simple Carboxylic Acids

Ø  Palladium-Catalyzed β-Functionalized Esters

Proposed Mechanism

Huang, Z.;Dong, G. J. Am. Chem. Soc., 2013, 135, 17747–17750

Substrate Scope

Huang, Z.;Dong, G. J. Am. Chem. Soc., 2013, 135, 17747–17750

Synthesis of Intermediate for SERT Antagonist

Huang, Z.;Dong, G. J. Am. Chem. Soc., 2013, 135, 17747–17750

Conclusion

Outline

q  Direct β-Functionalization of Ketone and Aldehyde

Ø  Organocatalysis and Photoredox Process

Ø  Palladium-Catalyzed β-Arylation (Pd-enolate)

Ø  Direct β-Functionalization of Carboxylic Acid and Ester

Ø  Palladium-Catalyzed β-Arylation of Simple Carboxylic Acids

Ø  Palladium-Catalyzed β-Functionalized Esters

Transition-Metal-Catalyzed C-H Functionalization

Jazzar, R.; Hitce, J.; Renauda,A.; Sofack-Kreutze,J.; Baudoin, O. Chem. Eur. J. 2010, 16, 2654 – 2672

Shang, R.; Ilies, L.; Matsumoto, A..; Nakamura, E. J. Am. Chem. Soc. 2013, 135, 6030−6032

Outline

q  Direct β-Functionalization of Ketone and Aldehyde

Ø  Organocatalysis and Photoredox Process

Ø  Palladium-Catalyzed β-Arylation (Pd-enolate)

Ø  Direct β-Functionalization of Carboxylic Acid and Ester

Ø  Palladium-Catalyzed β-Arylation of Simple Carboxylic Acids

Ø  Palladium-Catalyzed β-Functionalized Esters

Direct β-Functionalization of Carboxylic Acids

This coupling reaction provides the first example for carboxyl-directed Pd-insertion into sp3 -β-C-H bonds in simple aliphatic acids

R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano, L. B. Saunders, J.-Q. Yu, J. Am. Chem. Soc. 2007, 129, 3510 – 3511

Three Coordination Modes of Pd(II) with Carboxylic Acids

Chen, X.; Engle, K. M.; Wang, D.; Yu, J. Angew. Chem. Int. Ed. 2009, 48, 5094 – 5115

Proposed Mechanism

Outline

q  Direct β-Functionalization of Ketone and Aldehyde

Ø  Organocatalysis and Photoredox Process

Ø  Palladium-Catalyzed β-Arylation (Pd-enolate)

Ø  Direct β-Functionalization of Carboxylic Acid and Ester

Ø  Palladium-Catalyzed β-Arylation of Simple Carboxylic Acids

Ø  Palladium-Catalyzed β-Functionalization of Esters

Pd-Catalyzed α or β-Functionalization of Carboxylic Esters

A. Renaudat, L. Jean-Grard, R. Jazzar, C. E. Kefalidis, E. Clot, O. Baudoin, Angew. Chem. 2010, 122, 7419 – 7423

Initial Study

A. Renaudat, L. Jean-Grard, R. Jazzar, C. E. Kefalidis, E. Clot, O. Baudoin, Angew. Chem. 2010, 122, 7419 – 7423

Ligands Study

A. Renaudat, L. Jean-Grard, R. Jazzar, C. E. Kefalidis, E. Clot, O. Baudoin, Chem. Eur. J. 2012, 18, 1932 – 1944

Ligands Study

A. Renaudat, L. Jean-Grard, R. Jazzar, C. E. Kefalidis, E. Clot, O. Baudoin, Chem. Eur. J. 2012, 18, 1932 – 1944

Electronic Effect Study

A. Renaudat, L. Jean-Grard, R. Jazzar, C. E. Kefalidis, E. Clot, O. Baudoin, Chem. Eur. J. 2012, 18, 1932 – 1944

Proposed Mechanism

A. Renaudat, L. Jean-Grard, R. Jazzar, C. E. Kefalidis, E. Clot, O. Baudoin, Chem. Eur. J. 2012, 18, 1932 – 1944

DFT Calculation

Gibbs free energy (kcal  mol−1) diagram for the α- and β-arylation pathways (L=PCy3, Ar=2-fluorophenyl).

A. Renaudat, L. Jean-Grard, R. Jazzar, C. E. Kefalidis, E. Clot, O. Baudoin, Angew. Chem. 2010, 122, 7419 – 7423

Kinetic Study

A. Renaudat, L. Jean-Grard, R. Jazzar, C. E. Kefalidis, E. Clot, O. Baudoin, Chem. Eur. J. 2012, 18, 1932 – 1944

Deuterated Experiments

A. Renaudat, L. Jean-Grard, R. Jazzar, C. E. Kefalidis, E. Clot, O. Baudoin, Chem. Eur. J. 2012, 18, 1932 – 1944

β-Functionalization of β’-Keto Esters

Leskinen, M. V.; Yip, K.; Valkonen, Arto,; Pihko, P. M. J. Am. Chem. Soc. 2012, 134, 5750−5753

Indol Scope

Leskinen, M. V.; Yip, K.; Valkonen, Arto,; Pihko, P. M. J. Am. Chem. Soc. 2012, 134, 5750−5753

β’- Keto Ester Scope

Leskinen, M. V.; Yip, K.; Valkonen, Arto,; Pihko, P. M. J. Am. Chem. Soc. 2012, 134, 5750−5753

Mechanism Investigation

Leskinen, M. V.; Yip, K.; Valkonen, Arto,; Pihko, P. M. J. Am. Chem. Soc. 2012, 134, 5750−5753

Conclusion

Acknowledgement

Dr. Wulff Dr. Xuefei My group members: Wenjun, Xin, Xiaopeng and Yubai Fangyi and Jun

THE END