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

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

3. Various Approaches to Functionalize Pyridines 1 - Nucleophilic Addition to Activated Pyridines Nucleophilic substitution with halopyridines (S N Ar) Organometallic addition / oxidation 2 - Metallation of pyridines / Addition of electrophiles 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.

4. Grand Challenge: Control of the Regioselectivity – Direct C(2)-H Functionalization 1. (a) Durfee, L. D.; Rothwell, I. P. Chem. Rev. 1988, 88, 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. Using stoichiometric amounts of early transition metals 1 1 – Regioselectivity relying on proximity of the metal (Pyridine Nitrogen as Directing group) 2 – Regioselectivity relying on Bond Dissociation Energies 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. Pd-catalyzed Direct CH Arylation of Pyridine N-Oxides 2

5. Grand Challenge: Control of the Regioselectivity – Direct C(3)-H Functionalization 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. 1 – Regioselectivity relying on  -basicity of pyridines (C-3 is the most  -basic position) 1 - Ligand driven isomerization (electron rich and hindered) - C3 is most electron rich, Pd is thus closer to C3 in the  -donor form (directs CMD) 2 – Regioselectivity relying on Bond Dissociation Energies (with EWG as ‘Directing’ groups) 2 2. Guo, P.; Joo, J. M.; Rakshit, S.; Sames, D. J. Am. Chem. Soc. 2011, 133, 16338.

6. 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. Guo, P.; Joo, J. M.; Rakshit, S.; Sames, D. J. Am. Chem. Soc. 2011, 133, 16338. 2. (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. 3. Murphy, R. A.; Sarpong, R. Org. Lett. 2012, 14, 632. 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…

7. Pyridine C–H Functionalization Problems 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. 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) (c) (b) 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. (d)