Bio partnering 2006_final


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Bio partnering 2006_final

  1. 1. PEPPSI  Catalysts and Beyond: Highly Efficient Pd Catalysts for C  C and C  X Bond Formation Aaron G. Maestri, Ph.D. Product Manager - Catalysis Sigma-Aldrich Corporation Presented at the BioParterning Meetings, 2006
  2. 2. Seminar Outline <ul><li>A concise overview of cross coupling and current art </li></ul><ul><li>Introduce PEPPSI  -IPr pre-catalyst </li></ul><ul><li>General interest in sp 3 - sp 3 coupling reactions </li></ul><ul><li>Present proof-of-concept results in Negishi sp 3 - sp 3 couplings </li></ul><ul><li>Demonstrate scope – use in Negishi, Suzuki, Kumada, Heck and Buchwald-Hartwig aminations </li></ul><ul><li>Present preliminary results in Sonogashira, Hiyama, enolate arylation, and Stille reactions </li></ul><ul><li>Utility – easy to use? Produce on scale? Storage? Amenable to larger scale reactions? </li></ul><ul><li>PEPPSI-IPr: conclusions and what’s next </li></ul><ul><li>Introduce an additional Pd cross-coupling catalyst and illustrate the scope of reactivity </li></ul>
  3. 3. How does PEPPSI  reactivity stack up against the best phosphine-based catalyst systems? <ul><li> Phosphine Ligands </li></ul><ul><li> High expense due to multi- </li></ul><ul><li> step syntheses </li></ul><ul><li> Sensitivity to oxidation </li></ul><ul><li> Catalyzed reactions require purification after fouling of the </li></ul><ul><li>product; also usually required in excess relative to Pd </li></ul><ul><li> Chemistry is more developed relative to NHC ligands </li></ul><ul><li> Few phosphine-based catalysts exhibit broad utility * </li></ul><ul><li> N-Heterocyclic Carbene (NHC) Ligands </li></ul><ul><li> Current Literature suggests that the carbene is </li></ul><ul><li> a stronger  -donor than related phosphines making </li></ul><ul><li> the metal more basic/nucleophilic </li></ul><ul><li> Often generate highly robust, air- and water-stable catalysts </li></ul><ul><li> Less stable than the corresponding phosphine - less likely to </li></ul><ul><li>dissociate from the metal thus suppressing  -hydride elimination </li></ul><ul><li> Relatively unexplored methodology – early results suggest great </li></ul><ul><li>things to come </li></ul><ul><li>* It should be noted that Pd(PPh 3 ) 4 is widely applied in catalysis, </li></ul><ul><li>however this complex can suffer from poor long-term stability and </li></ul><ul><li>is now thought to be less (broadly) active than [Pd(0)-NHC systems]. </li></ul>
  4. 4. PEPPSI  is Readily Activated in situ enhance basicity of catalyst Coordinatively saturate the metal Increase the steric environment around the metal
  5. 5. Introducing the Catalyst <ul><li>• Introduction to PEPPSI TM : </li></ul><ul><li>P yridine, E nhanced, P recatalyst, </li></ul><ul><li>P reparation, S tabilization and I nitiation </li></ul><ul><li> or </li></ul><ul><li> PEPPSI </li></ul>• Synthesis : base, PdCl 2 , imidazolium salt, 3-chloropyridine, heat • No glove box, no inert atmosphere, no special handling, no solvent, 3-chloropyridine is distilled off and recycled (kilo-scale)
  6. 6. Alkyl-alkyl couplings. Impossible? <ul><li> Initially, efficient alkyl-alkyl couplings were desired </li></ul><ul><li> Historically plagued by a variety of issues: </li></ul><ul><li> Lack of a docking site on the halide or pseudohalide for the </li></ul><ul><li>metal as we see in allylic and sp 2 system, which means </li></ul><ul><li>oxidative addition is more difficult </li></ul><ul><li> The presence of  -hydrogens can allow for deleterious  </li></ul><ul><li>hydride elimination processes to occur </li></ul><ul><li> Reductive elimination of the two alkyl pieces can be difficult </li></ul><ul><li> Could utilizing NHC based PEPPSI  -IPr technology help overcome these issues? </li></ul>(1) Organ, M. G. Rational catalyst design and its application in sp 3 -sp 3 couplings. Presented at the 230th National Meeting of the American Chemical Society, Washington, DC, 2005; Abstract 308.
  7. 7. PEPPSI  -IPr Exhibits Broad Utility in C–C and C–X Bond Forming Reactions
  8. 8. PEPPSI  Results in the Negishi Reaction: sp 3 -sp 3 couplings Organ, M. G. et al. Chem. Eur. J. 2006 , 12 , 4749.
  9. 9. Negishi Couplings – Extending PEPPSI  -IPr Versatility  sp 2 – sp 3 :  sp 3 – sp 2 : Organ, M. G. et al. Chem. Eur. J. 2006 , 12 , 4749.
  10. 10. Negishi Couplings – Execution of the Full Reaction Scope  sp 2 – sp 2 : Organ, M. G. et al. Chem. Eur. J. 2006 , 12 , 4749.
  11. 11. PEPPSI  Results in the Suzuki Reaction  sp 2 – sp 2 : Organ, M. G. et al. Chem. Eur. J. 2006 , 12 , 4743.
  12. 12. PEPPSI  Results in the Buchwald- Hartwig Amination Reaction • Alkyl amines readily transformed; anilines not so well Organ, M. G. et al. manuscript in preparation.
  13. 13. Extending PEPPSI  Reactivity in the Buchwald-Hartwig Amination Reaction • Aryl chlorides only • All reactions complete at room temperature Organ, M. G. et al. manuscript in preparation.
  14. 14. Kumada-Tamao-Corriu Coupling • Coupling works well at room temperature Organ, M. G. et al. Chem. Eur. J. 2006 , Accepted.
  15. 15. Kumada-Tamao-Corriu Coupling: Exploiting PEPPSI  ’s High Activity  First room temperature tetra ortho substituted cross coupling reported of any kind  Sequential Coupling Chemistry Organ, M. G. et al. Chem. Eur. J. 2006 , Accepted.
  16. 16. PEPPSI  Competition Experiment • PEPPSI- IPr is very reactive relative to other known strong catalysts in the literature
  17. 17. Heck-Amination Sequence - PEPPSI  Exhibits Robust Microwave Behavior • Yields > 75%, small library of 20 indoles prepared
  18. 18. Sonagashira Coupling – is PEPPSI  Versatile? • 1° Alkyl Centers: • 2° Alkyl Centers:
  19. 19. Enolate Arylation – Extending PEPPSI  Utility Under Mild Conditions
  20. 20. Hiyama Coupling • Note that the reaction of silanol and their respective Sodium salts are efficiently promoted in this reaction. • The Silanoates are available as a convenient solid that can be stored and dispensed directly into the reaction
  21. 21. What About Scale-up?? • Buchwald-Hartwig on Scale • Work Up • 1) filter thru Celite, 2) extract into acid, 3) titrate until basic 4) back extract into ether, 5) dry and remove solvent 26.5 G! 10 G! • Suzuki on Scale 10 G! • Kumada on Scale
  22. 22. Pd(AmPhos) 2 Cl 2 : A Highly Efficient, Air-Stable Catalyst for the Heteroaryl Suzuki Reaction
  23. 23. Conclusions <ul><li>Extremely stable to air and moisture </li></ul><ul><li>Commercialized on kilo scale </li></ul><ul><li>Improved or comparable activity to known Pd </li></ul><ul><li>catalysts (Buchwald, Nolan) </li></ul><ul><li>High performance in various reaction paradigms </li></ul><ul><li>Many reactions occur at room temperature </li></ul><ul><li>No need for additional ligands  one-component catalyst </li></ul><ul><li>Competitive pricing (per mole basis vs. Pd(PPh 3 ) 4 ) </li></ul><ul><li>Preliminary data also suggests that PEPPSI TM is effective in couplings that historically prove challenging for Pd catalysis, i.e., the coupling of nitrogen and sulfur-containing compounds </li></ul><ul><li>Three results illustrated that PEPPSI TM -catalyzed reactions scale well </li></ul><ul><li>PEPPSI TM behaves well in microwave conditions, while many Pd catalysts do not </li></ul><ul><li>Innovative PEPPSI  website including ordering information: </li></ul>Discover how Sigma-Aldrich’s PEPPSI  Technology can add value to your discovery and process design. Visit