CS Activation COPPERCATALYZED CC COUPLING OF THIOL ESTERS AND BORONIC ACIDS UNDER AEROBIC CONDITIONS

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C-S ActivationCOPPER-CATALYZED C-C COUPLING
OFTHIOL ESTERS AND BORONIC ACIDS UNDER AEROBIC
CONDITIONS

• Prokopcova, H. and Kappe, C. O.
• Angew. Chem. Int. Ed. 2008, 47, 2-5.
• Institute of Chemistry
• Karl-Franzens University
• Graz, Austria
• Presenter Masayuki Wasa
• Group meeting, April 3rd, 2008.

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Traditional Suzuki-Miyaura type
Cross-Coupling Rxn.
Miyaura, N. Suzuki, A. J. Chem. Soc., Chem.
Commun. 1979, 866.

• Advantages
• Mild reaction condition.
• High functional group tolerance.
• Broad availability of starting materials.
• Boronic acids are commercially available, air
  and moisture stable, and have relatively low
  toxicity.

• Limitations
• Preparation of C-halogen directing group.
• Basic condition.
• Expensive palladium catalysts.

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C-H Activation Approach from the Yu Group
Chen, X. Goodhue, C. E. Yu, J.-Q.J. Am. Chem.
Soc. 2006, 128, 12634.
1)
Giri, R. Maugel, N. L. Li, J. J. Wang, D.-H.
Breazzano, S.P. Saunders, L. B. Yu, J.-Q.J.
Am. Chem. Soc. 2007, 129, 3510-3511.
2)
Wang, D.-H. Wasa, M. Giri, R. Yu, J.-Q.J. Am.
Chem. Soc. 2008, Accepted for publication.
3)
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Another Pathway C-S Activation.Pd-catalyzed
C-C cross-coupling protocol for synthesis of
ketones from thiol esters and boronic acids
Liebeskind, L. S. Srogl, J. Am. Chem. Soc. 2000,
122, 11260-11261. Emory University, Georgia.
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Mechanism

• Oxidative addition of Cu(I)-bound thiol ester to
  the Pd(0) catalyst.
• Cu(I)-carboxylate polarizes the Pd-S bond through
  Cu(I) coordination to the S center.
• 2) Cu(I)-carboxylate activates the trivalent
  boron center.

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3 Notable advantages of Liebeskind-Srogl reaction
Unlike the traditional Suzuki-Miyaura
cross-coupling reaction-where the presence of
base is essential-the nonbasic conditions in this
protocol can tolerate the involvement of
base-sensitive starting materials and products.
1)
2) Has matured enough to be applicable in total
synthesis.
Org. Lett. 2007, 9, 2993-2995.
Org. Lett. 2006, 8, 1613-1616.
3) Second-generation Liebeskind-Srogl reaction is
copper-catalyzed.
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3 Pitfalls of Liebeskind-Srogl reaction

• Requires
• Catalytic amount of Pd
• A stoichiometric amount of Cu(I) carboxylate
• Strictly anaerobic reaction conditions

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BreakthroughNovel Cu-catalyzed aerobic
cross-coupling of thiol esters with boronic acids.
Villalobos, J. M. Srogl, J. Liebeskind, L. S .
J. Am. Chem. Soc. 2007, 129, 15734-15735.

• Major improvements
• Cu-catalyzed no need for Pd
• Aerobic conditions

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Mechanism
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Novel discovery and limitations

• Discovery
• A novel coupling reaction templated by a higher
  oxidation state Cu species (in contrast to
  conventional addition/transmetalation/
• reductive elimination pathway).
• 2) Extraordinary level of chemoslectivity.

• Limitations
• Requires
• Use of specifically funtionalized thiol esters.
• A sacrificial equivalent of boronic acid.

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Thank you for your attention!