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Cobalt - A History

Cobalt-Catalyzed Cyclopropanations and 2+2+2 Cycloadditions Patrick Levesque Center for Catalysis Research and Innovation Department of Chemistry University of Ottawa Graduate Seminar December 1 st , 2011. Cobalt - A History. 2. Discovered in 1735

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Cobalt - A History

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  1. Cobalt-Catalyzed Cyclopropanations and 2+2+2 CycloadditionsPatrick LevesqueCenter for Catalysis Research and InnovationDepartment of ChemistryUniversity of OttawaGraduate SeminarDecember 1st, 2011

  2. Cobalt - A History 2 • Discovered in 1735 • Used in the preparation of magnetic, wear- resistant, and high-strength alloys. • Cobalt blue (cobalt(II) aluminate, CoAl2O4) can give a deep blue color to glass, ceramics, inks, paints and varnishes. • Cobalt-60 is a commercially important radioisotope • Oxidation states : -1, 1, 2, 3, 4, 5 Cobalt Metal Cobalt, Ontario Cobalt Railway Station 1906

  3. What will be covered 3 • Cyclopropanations • General concepts • Salen ligand based systems • Porphyrin ligand based systems • 2+2+2 Cycloadditions • Mechanism • Review of Literature • Applications in Synthesis

  4. Cyclopropanes 4 In commerciallized drugs In natural products

  5. Co-Catalyzed Cyclopropanations 5 General Catalytic Cycle: • Type of metal carbene? • Reaction intermediates? • Selectivity?

  6. Co-Catalyzed Cyclopropanations 6 Trans cyclopropanation is generally favoured for this reason… But! Cis selectivity can also be achieved. And! The carbene formed is highly influenced by its own substituents as well as the ligands on cobalt. So… multiple mechanisms and transition states are possible.

  7. Metal Carbenes 7 Singlet State (Fischer Type) Triplet State (Schrock Type) Generally higher in energy unless R1 or R2 provides added stabilization (OR, NR2, SR, Halogen)

  8. How do Carbenes React? 8 SINGLET carbenes react in a CONCERTED manner, therefore the rxn is STEREOSPECIFIC TRIPLET carbenes react in a STEPWISE manner, therefore the rxn is STEREOSELECTIVE

  9. The Cobalt Salen Ligand Story

  10. Cobalt Salen Ligand Story 10 Back in 1978… Otsuka, S. et al. J. Am. Chem. Soc. 1978, 100, 3443 Is it possible to design new salen ligands in order to achieve good enantioselectivity and diasterioselectivity?

  11. Towards Trans Selectivity 11 Katsuki, T. et al. Synlett 1995, 825 Katsuki, T. et al. Tetrahedron 1997, 53, 7201 Katsuki, T. Adv. Synth. Catal. 2002, 344, 131 Katsuki, T. et al. Synthesis 2006, 1715 64% ee R1,2,3 =H X= I

  12. Towards Trans Selectivity 12 Katsuki, T. et al. Synlett 1995, 825 Katsuki, T. et al. Tetrahedron 1997, 53, 7201 Katsuki, T. Adv. Synth. Catal. 2002, 344, 131 Katsuki, T. et al. Synthesis 2006, 1715 64% ee R1,2,3 =H X= I R1 =Me/tBu X= I

  13. Towards Trans Selectivity 13 Katsuki, T. et al. Synlett 1995, 825 Katsuki, T. et al. Tetrahedron 1997, 53, 7201 Katsuki, T. Adv. Synth. Catal. 2002, 344, 131 Katsuki, T. et al. Synthesis 2006, 1715 64% ee 73% ee R1,2,3 =H X= I R1 =Me/tBu X= I R2= tBu X= I

  14. Towards Trans Selectivity 14 Katsuki, T. et al. Synlett 1995, 825 Katsuki, T. et al. Tetrahedron 1997, 53, 7201 Katsuki, T. Adv. Synth. Catal. 2002, 344, 131 Katsuki, T. et al. Synthesis 2006, 1715 64% ee 73% ee 75% ee R1,2,3 =H X= I R1 =Me/tBu X= I R2= tBu X= I R3= tBu X= I

  15. Towards Trans Selectivity 15 Katsuki, T. et al. Synlett 1995, 825 Katsuki, T. et al. Tetrahedron 1997, 53, 7201 Katsuki, T. Adv. Synth. Catal. 2002, 344, 131 Katsuki, T. et al. Synthesis 2006, 1715 64% ee 73% ee 75% ee 83% ee R1,2,3 =H X= I R1 =Me/tBu X= I R2= tBu X= I R3= tBu X= I R3 =tBu X= Br

  16. Towards Trans Selectivity 16 Katsuki, T. et al. Synlett 1995, 825 Katsuki, T. et al. Tetrahedron 1997, 53, 7201 Katsuki, T. Adv. Synth. Catal. 2002, 344, 131 Katsuki, T. et al. Synthesis 2006, 1715 93% ee 64% ee 73% ee 75% ee 83% ee R1,2,3 =H X= I R1 =Me/tBu X= I R2= tBu X= I R3= tBu X= I R3 =tBu X= Br R3= OMe X= Br

  17. Scope of Trans Cyclopropanation 17 Scope seems limited… Katsuki, T. et al. Synthesis 2006, 10, 1715

  18. Trans Selectivity – Optimal Results 18

  19. The Cobalt-Salen Ligand Story 19 Back in 1978… Otsuka, S. et al. J. Am. Chem. Soc. 1978, 100, 3443 Is it possible to design a ligand that will provide good enantioselectivity and exclusively the cis product?

  20. Towards Cis Selectivity 20 * * Katsuki, T. et al. Synthesis 2006, 10, 1715 96% ee R1 = -(CH2)4- R2= Ph (R) catalyst No NMI

  21. Towards Cis Selectivity 21 * * Katsuki, T. et al. Synthesis 2006, 10, 1715 96% ee 98% ee R1 = -(CH2)4- R2= Ph (R) catalyst No NMI R1 = -(CH2)4- R2= Ph (R) catalyst

  22. Towards Cis Selectivity 22 * * Katsuki, T. et al. Synthesis 2006, 10, 1715 96% ee 98% ee -99% ee R1 = -(CH2)4- R2= Ph (R) catalyst No NMI R1 = -(CH2)4- R2= Ph (R) catalyst R1 = -(CH2)4- R2= Ph (S) Catalyst Slow RXN

  23. Towards Cis Selectivity 23 * * Katsuki, T. et al. Synthesis 2006, 10, 1715 96% ee 98% ee 0% ee 99% ee R1 = -(CH2)4- R2= Ph (R) catalyst No NMI R1 = -(CH2)4- R2= Ph (R) catalyst R1 = -(CH2)4- R2= Ph (S) Catalyst Slow RXN R1 = H R2= Ph

  24. Towards Cis Selectivity 24 * * Katsuki, T. et al. Synthesis 2006, 10, 1715 95% ee (trans) 96% ee 98% ee 0% ee 99% ee R1 = -(CH2)4- R2= Ph (R) catalyst No NMI R1 = -(CH2)4- R2= Ph (R) catalyst R1 = -(CH2)4- R2= Ph (S) Catalyst Slow RXN R1 = -(CH2)4- R2= Me (R) Catalyst R1 = H R2= Ph

  25. Scope of Cis Cyclopropanation 25 Scope seems limited… Katsuki, T. et al. Synthesis 2006, 10, 1715

  26. The Cobalt-Salen Ligand Story 26 Pushes R group forward Causing steric bulk Pushes styrene to turn anticlockwise b/c of steric repulsion Steric interaction with the phenyl of the substrate… induces cis selectivity Ester prefers to sit here (pocket). More bulk = slower rxn time but similar enantioselectivity. Opposite enantiomer = enantioselectivity is inverted BUT slower reaction time b/c 2’ phenyl blocks substrate approach Modified XRay from Ir-Salen complex: Katsuki, T. et al. J. Am. Chem. Soc., 2008, 130, 10327

  27. The Cobalt-Salen Ligand Story 27 Steric interaction with Ph of styrene is greater than the one with R Causes less steric interraction with the Ph of styrene Ester prefers to sit here (pocket) Approach is more traditional, causes trans selectivity Modified XRay from Ir-Salen complex: Katsuki, T. et al. J. Am. Chem. Soc., 2008, 130, 10327

  28. The Cobalt Porphyrin Ligand Story

  29. Cobalt Porphyrin Ligand Story 29 In 2003… Zang, P. et al. J. Org. Chem. 2003, 68, 8179

  30. Cobalt Porphyrin Ligand Story 30 The year after… To show the strength of this catalyst… one example?? Zang, P. et al. J. Am. Chem. Soc. 2004, 126, 14718

  31. Cobalt Porphyrin Ligand Story 31 3 years later, a reaction scope is published! Zang, P. et al. J. Org. Chem. 2007, 72, 5931

  32. Cobalt Porphyrin Ligand Story 32 In the same year: electron deficient alkenes. Zang, P. et al. J. Am. Chem. Soc. 2007, 129, 12074

  33. Cobalt Porphyrin Ligand Story 33 Ligand modification, different diazo compound. Zang, P. et al. J. Am. Chem. Soc. 2008, 130, 5042

  34. Cobalt Porphyrin Ligand Story 34 Two years later, acceptor/acceptor diazo compounds Large Scope, method seems very general. Zang et al. J. Am. Chem. Soc. 2010, 132, 12796

  35. Cobalt Porphyrin Ligand Story 34 If alkenes work, why not alkynes? Zang, P. et al. J. Am. Chem. Soc. 2011, 133, 3304

  36. Cobalt Porphyrin Ligand Story 36 If intermolecular reactions work, why not try intramolecular ones? Fairly large scope, a lot of functional group tolerance Zang, P. et al. J. Am. Chem. Soc. 2011, 133, 15292

  37. Cobalt Porphyrin Ligand Story 37 Before the story ends, here are a few cool uses for the compounds we’ve seen… Zang, P. et al. J. Am. Chem. Soc. 2011, 133, 3304 Zang, P. et al. J. Am. Chem. Soc. 2011, 133, 15292 Zang, P. et al. J. Am. Chem. Soc. 2011, 133, 15292

  38. Resumé of Cobalt Porphyrin Story 38

  39. Cobalt-Catalyzed [2+2+2] Cycloadditions

  40. 2+2+2 Mechanism 40 3 alkynes = Catalytic Process Aubert, C. et al. J. Am. Chem. Soc. 2006, 128, 8509

  41. 2+2+2 Mechanism 41 1 alkene = Stoichiometric Process Aubert, C. et al. J. Am. Chem. Soc. 2007, 129, 8860

  42. [2+2+2] Cycloadditions 42 • With 3 Alkynes • With 2 Alkynes + 1 Double Bond • With Alkynes + Nitriles • Asymmetric Variants • Applications in Synthesis

  43. Benzene Derivatives - Selectivity 43 The simplest 2+2+2 would be that of acetylene… No problem! Almost as simple: symmetrical alkynes, again…No problem! When it comes to multiple, unsymmetrical alkynes… 38 possible outcomes!

  44. Strategies for Achieving Selectivity 44 Higher Three Tethers Two Tethers Probability of Success One Tether Wing-it! Lower

  45. Winging-it… or sort of! 45 A few Examples that do not offer much challenge in terms of selectivity… Siebert, W. et al. Eur. J. Inorg. Chem. 2000, 1177 Goswami, A. et al. J. Org. Chem. 2005, 690, 3251

  46. Winging-it…Sort of! 46 More challenging examples: Cheng, C. et al. Chem. Commun. 2005, 4955

  47. One Tether 47 Okamoto, S. et al. Org. Lett. 2006, 8, 1439 Tacke, R. et al. Organometallics2007, 26, 4835

  48. Two Tethers 48 SHOW XRAY HERE! Stary, I et al. Angew. Chem. Int. Ed. 2008, 47, 3188

  49. Two Tethers – Disposable Silyls 49 M. Malacria et al. Org. Lett. 2004, 6, 1519.

  50. 2 Alkynes + Double Bond 50 Aubert, C. et al. Angew. Chem. Int. Ed. 2005, 44, 7114 Aubert, C. et al. Angew. Chem. Int. Ed. 2005, 44, 7114

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