Pyridine CH Functionalization Organic Pedagogical Electronic Network The

Pyridine C–H Functionalization Organic Pedagogical Electronic Network The Sarpong Lab University of California, Berkeley 2014

Ubiquity and Importance of Substituted Pyridine Derivatives Pharmaceutical Agents: Bioactive Natural Products:

Approaches to Functionalize Pyridines 1 - Nucleophilic Addition to Activated Pyridines Nucleophilic substitution with halopyridines (SNAr) Organometallic addition / oxidation Bull, J. A. ; Mousseau, J. J. ; Pelletier, G. ; Charette, A. B. Chem. Rev. 2012, 112, 2642.

Approaches to Functionalize Pyridines 2 - Metallation of pyridines / Addition of electrophiles Bull, J. A. ; Mousseau, J. J. ; Pelletier, G. ; Charette, A. B. Chem. Rev. 2012, 112, 2642.

Approaches to Functionalize Pyridines 3 - Transition-Metal Mediated (or Catalyzed) Functionalization of Pyridines Cross-Coupling of Pseudonucleophilic Pyridines Direct C-H Functionalization Bull, J. A. ; Mousseau, J. J. ; Pelletier, G. ; Charette, A. B. Chem. Rev. 2012, 112, 2642.

Grand Challenge: Control of the Regioselectivity – Direct C(2)-H Functionalization 1 – Regioselectivity relying on proximity of the metal (Pyridine Nitrogen as Directing group) Using stoichiometric amounts of early transition metals 1 1. (a) Durfee, L. D. ; Rothwell, I. P. Chem. Rev. 1988, 1059. (b) Sadimenko, A. P. Adv. Heterocycl. Chem. 2005, 88, 111. (c) Jordan, R. F. ; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778. 2. (a) Fagnou, K. et al J. Am. Chem. Soc. 2009, 131, 3291. (b) Sun, H. -Y. ; Gorelsky, S. I. ; Stuart, D. R. ; Campeau, L. -C. ; Fagnou, K. J. Org. Chem. 2010, 75, 8180. (c) Tan, Y. ; Barrios-Landeros, F. ; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 3683. (d) Bull, J. A. ; Mousseau, J. J. ; Pelletier, G. ; Charette, A. B. Chem. Rev. 2012, 112, 2642.

Grand Challenge: Control of the Regioselectivity – Direct C(2)-H Functionalization 2 – Regioselectivity relying on Bond Dissociation Energies Pd-catalyzed Direct CH Arylation of Pyridine N-Oxides 2 1. (a) Durfee, L. D. ; Rothwell, I. P. Chem. Rev. 1988, 1059. (b) Sadimenko, A. P. Adv. Heterocycl. Chem. 2005, 88, 111. (c) Jordan, R. F. ; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778. 2. (a) Fagnou, K. et al J. Am. Chem. Soc. 2009, 131, 3291. (b) Sun, H. -Y. ; Gorelsky, S. I. ; Stuart, D. R. ; Campeau, L. -C. ; Fagnou, K. J. Org. Chem. 2010, 75, 8180. (c) Tan, Y. ; Barrios-Landeros, F. ; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 3683. (d) Bull, J. A. ; Mousseau, J. J. ; Pelletier, G. ; Charette, A. B. Chem. Rev. 2012, 112, 2642.

Grand Challenge: Control of the Regioselectivity – Direct C(3)-H Functionalization 1 – Regioselectivity relying on p-basicity of pyridines (C-3 is the most p-basic position) 1 - Ligand driven isomerization (electron rich and hindered) - C 3 is most electron rich, Pd is thus closer to C 3 in the p-donor form (directs CMD) 1. (a) Ye, M. ; Gao, G. -L. ; Yu, J. -Q. J. Am. Chem. Soc. 2011, 133, 6964. (b) Yu, J. -Q. et al. , J. Am. Chem. Soc. 2011, 133, 19090. 2. Guo, P. ; Joo, J. M. ; Rakshit, S. ; Sames, D. J. Am. Chem. Soc. 2011, 133, 16338.

Grand Challenge: Control of the Regioselectivity – Direct C(3)-H Functionalization 2 – Regioselectivity relying on Bond Dissociation Energies (with EWG as ‘Directing’ groups) 2 1. (a) Ye, M. ; Gao, G. -L. ; Yu, J. -Q. J. Am. Chem. Soc. 2011, 133, 6964. (b) Yu, J. -Q. et al. , J. Am. Chem. Soc. 2011, 133, 19090. 2. Guo, P. ; Joo, J. M. ; Rakshit, S. ; Sames, D. J. Am. Chem. Soc. 2011, 133, 16338.

Grand Challenge: Control of the Regioselectivity – Direct C(4)-H Functionalization 1 – Regioselectivity relying on Bond Dissociation Energies (with EWG as ‘Directing’ groups) 1 1. 2. 3. Guo, P. ; Joo, J. M. ; Rakshit, S. ; Sames, D. J. Am. Chem. Soc. 2011, 133, 16338. (a) Wei, Y. ; Kan, J. ; Wang, M. ; Su, W. ; Hong, M. Org. Lett. 2009, 11, 3346. (b) Wei, Y. ; Su, W. J. Am. Chem. Soc. 2010, 132, 16377. Murphy, R. A. ; Sarpong, R. Org. Lett. 2012, 14, 632.

Grand Challenge: Control of the Regioselectivity – Direct C(4)-H Functionalization 2 – Regioselectivity relying on substrate bias All other positions blocked 2 Intramolecular example 3 Regioselective C(4)-H Functionalization of pyridine without substrate bias is still a challenge… 1. 2. 3. Guo, P. ; Joo, J. M. ; Rakshit, S. ; Sames, D. J. Am. Chem. Soc. 2011, 133, 16338. (a) Wei, Y. ; Kan, J. ; Wang, M. ; Su, W. ; Hong, M. Org. Lett. 2009, 11, 3346. (b) Wei, Y. ; Su, W. J. Am. Chem. Soc. 2010, 132, 16377. Murphy, R. A. ; Sarpong, R. Org. Lett. 2012, 14, 632.

Problems Please provide a reasonable mechanism that accounts for the observed regioselectivity, and explain what type(s) of approach was used to control this regioselectivity (a) (b) (c) (d) 1. García-Cuadrado, D. ; Braga, A. A. C. ; Maseras, F. ; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066. 2. Mousseau, J. J. ; Bull, J. A. ; Ladd, C. L. ; Fortier, A. ; Sustac Roman, D. ; Charette, A. B. J. Org. Chem. 2011, 76, 8243. 3. Ye, M. ; Gao, G. -L. ; Yu, J. -Q. J. Am. Chem. Soc. 2011, 133, 6964. 4. Godula, K. ; Sezen, B. ; Sames, D. J. Am. Chem. Soc. 2005, 127, 3648.

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