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by William Schulz Bechara

14 MARCH 2014. by William Schulz Bechara. Charette/Collins Literature Meeting April 8 th , 2014. Controlling Site Selectivity in C-H Functionalization. Catalyst-based control. Substrate-based control. a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012 , 45 , 936.

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by William Schulz Bechara

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  1. 14 MARCH 2014 by William Schulz Bechara Charette/Collins Literature Meeting April 8th, 2014

  2. Controlling Site Selectivity in C-H Functionalization Catalyst-based control Substrate-based control a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.

  3. Directing Groups in Substrate-Based Control With Pd Monodentate Bidentate Tridentate a) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. c) Colby, D. A.; Tsay, A.-S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. d) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. e) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.2010, 132, 3965. f) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726. g) Shi Chem. Sci. 2013, 4, 3712.

  4. Catalytic Manifolds in Pd-Catalyzed C-H Functionalization Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788.

  5. Jin-Quan Yu • Education : • East China Normal University - Shanghai, China : 1982 - 1987B.Sc. in Chemistry - Top 5% of national examination for admission to SIOC • Shanghai Institute of Organic Chemistry (SIOC) - Shanghai, China : 1987 - 1988Coursework for M.Sc. degree • Guangzhou Institute of Chemistry - Guangzhou, China : 1988 - 1990M.Sc. in Chemistry with S.D. Xiao • University of Cambridge - Cambridge, UK :1994 - 1999Ph.D. in Chemistry with Jonathan Spencer • University of Cambridge - Cambridge, UK :1999 - 2003Junior Research Fellow (JRF) of St. John's College • Harvard University - Cambridge, MA, USA : 2001 - 2002Postdoctoral Fellow, supervisor: E.J. Corey • Academic Positions : • University of Cambridge - Cambridge, UK • Royal Society Research Fellow : 2003 - 2004 • Brandeis University - Waltham, MA, USA • Assistant Professor of Chemistry : 2004 - 2007 • Scripps Research Institute - La Jolla, CA, USA • Associate Professor of Chemistry : 2007 – 2010 • Professor of Chemistry : 2010 – 2012 • Frank and Bertha Hupp Professor of Chemistry : 2012 - present 20 (or 16) years of academic studies!!

  6. Pd(0)-Catalyzed Intermolecular Arylation of C(sp3)-H Bonds Wasa, M.; Engle, K. M.; Yu, J.-Q.J. Am. Chem. Soc.2009, 131, 9886.

  7. Pd(II)-Catalyzed Olefination of C(sp3)-H Bonds Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc.2010, 132, 3680.

  8. Key Features of the Weak Coordinating “N-ArF” DG Auxiliary - Low pKa : Faster deprotonation. Lower pKa is instrumental for the presence of a larger population of the reactive deprotonated amide. - Weak coordination : EWG group coordinated to the N center pushes the hybridization toward a N(sp2) center and weakens the coordination to the Pd center (relative to other N(sp3)). - PES (potential energy surface/DFT studies) of the reaction is slightly flatter in presence of ArF compared to fully H-substituted. Reductive elimination step is slightly more favorable. - Weak coordination has been successfully exploited to control the reactivity and selectivity of Pd-cat. C-H functionalization. Figg, T. M.; Wasa, M.; Yu, J.-Q.; Musaev, D. G.J. Am. Chem. Soc.2013, 135, 14206.

  9. Synthesis of Unnatural Chiral a-Amino Acids Can one apply the Pd(II)-catalyzed C-H activation for the b-functionalization of Alanine based SM?

  10. Synthesis of Unnatural Chiral a-Amino Acids General Limitations - Long reaction time - Di-arylation - Low yields - Different N-Aux for mono- or di-arylation - Racemization - Limited to electron-rich Ar-X - No one-pot di-arylation with 2 different substituents a) Chen, K.; Hu, F.; Zhang, S.-Q.; Shi, B.-F. Chem. Sci.2013, 4, 3906. b) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.-J.; Shi, B.-F. Angew. Chem. Int. Ed.2013, 52, 13588. c) Tran, L. D.; Daugulis, O. Angew. Chem., Int. Ed.2012, 51, 5188.

  11. Pd-Catalyzed Arylation of Primary C(sp3)-H Bonds  Substituted pyridine ligands can match the weak coordination of the amide auxiliary (CONHArF) a) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216. b) M. Wasa et al., J. Am. Chem. Soc. 2012, 134, 18570.

  12. Pd-Catalyzed Arylation of Primary C(sp3)-H Bonds He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216. *Gram-scale reaction.

  13. Pd-Catalyzed Arylation of Primary C(sp3)-H Bonds He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216. *Gram-scale reaction.

  14. Determination of Enantiomeric Purity He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  15. Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds • Better yields using electron-donating 2-alkoxylpyridines. • The conformation of the lone pairs on the oxygen atom (in L10) is rigidified to favor p-conjugation with the pyridine ring. a) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216. b) M. Wasa et al., J. Am. Chem. Soc.2012, 134, 18570.

  16. Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  17. Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  18. Pd-Catalyzed Arylation of Secondary C(sp3)-H Bonds He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  19. Synthesis of Amino Acids via Sequential C(sp3)–H Arylation in One Pot He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  20. Synthesis of Amino Acids via Sequential C(sp3)–H Arylation in One Pot He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  21. Ligand-Enabled C(sp3)–H Arylation With Heteroaryl Iodides He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  22. Synthesis of N-Fmoc-Protected Unnatural Amino Acid He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  23. C(sp3)–H Olefination of Alanine Derivatives (PdII/Pd0) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  24. Unnatural a–Amino Acid Elaboration He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  25. Crystallography of Primary C(sp3)–H Activation Intermediate He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  26. Crystallography of Secondary C(sp3)–H Activation Intermediate He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  27. Catalytic Reactivity of Intermediates A and B - TFA is required for this transformation, presumably to facilitate the dissociation of one of the pyridine ligands. He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.l Homs, A.; Yu, J.-Q. Science.2014, 343, 1216.

  28. Intramolecular Kinetic Isotope Effect

  29. Proposed Mechanism for Pd(II)/Pd(IV) Catalysis CsF or AgCO3 help scavenge the I from Pd by forming clusters* * M. Wasa et al., J. Am. Chem. Soc.2012, 134, 18570.

  30. Future Work - These rare and valuable C(sp3)–H insertion intermediates (A and B) provide a promising platform for further kinetic and computational study of elementary steps in a well-defined manner.

  31. Thank YouQuestions?

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