1. First Directed ortho Metalation (DoM) of 1,8-Naphthalene Diamides. Towards Nerve Growth Factor Inhibitors Christopher Jones†, Victor Snieckus†, Greg Ross ‡ † Department of Chemistry, Queen’s University, Kingston, ON, CANADA K7L 3N6 ‡ Department of Physiology, Queen’s University, Kingston, ON, CANADA K7L 3N6 chrisj@chem.queensu.ca

2. Nerve Growth Factor (NGF) Involved in the neuronal development in the Central Nervous System and Peripheral Nervous System. Nerve Growth Factor is implicated in Alzheimer’s, epilepsy, stroke and pain. Production is stimulated in patients suffering from Arthritis pain. Inhibition of NGF causes reduction in pain levels. Ross, G. et al. J. Amer. Chem. Soc, 99 121, 1997

3. Previously Identified NGF Inhibitors Target Molecules Ross, G. et al. J. Amer. Chem. Soc, 99 121, 1997

4. Directed ortho Metalation (DoM) Reactions in Organic Synthesis E+E+ Hartung, C, Snieckus, V. Modern Arene Chemistry, Wiley-VCH, Weinheim. 2002, 330

5. Advantages of Directed ortho Metalation Recent Work 1. Kalinin,A.; Snieckus, V. et al. J Org Chem, 2003, 68, 5992 2. Chauder, B.; Snieckus, V. et al. Org Lett, 2002, 4, 815

6. Previous Work Involving 2,7-Disubstituted 1,8-Naphthalene Systems Wuest, J et al Organometallics, 1996,15, 1296

7. Double DoM of Naphthalene1,8-bis-Diethylamide 1 99 TL 6671

8. Bromo Ipsodesilaytion of Naphthalene- 1,8-dicarboxylic acid bis-diethylamide Colvin, E.W. Silicon in Organic Synthesis. Butterworth: London, 1988 General Ipso-substitution Reaction Synthesize unconventional substitution patterns. Alternative short route with improved yield. Regioselective,clean reaction with mild conditions. 78%

9. Mono or Di Deprotonation of Naphthalene bis-Diethylamide.What pathway does the deprotonation follow?? Mono or Di Deprotonation of Naphthalene bis-Diethylamide. What pathway does the deprotonation follow?? Determined by CD 3 OD Quench Experiments

10. Mono vs Bis Incorporation of Deuterium Monitored by EI + MS over Time [M + -NEt 2 ] Peak at 254 [M + -NEt 2 ] Peak (254) diappears after addition of SecBuLi and quench with CD 3 OD Time does not increase or decrease the 256 peak Equivalents of base = 4.4 Time 010 Min 20 Min30 Min 1 Hr 6 Hr [M +2 -NEt 2 ] Peak at 256

11. What Role Does the Equivalents of Base Have on formation of Mono or Bis? Starting Material 1.1 Eqv 2.2 Eqv 3.3 Eqv 4.4 Eqv Equilibrium can be seen for 1.1 equivalents [M + -NEt 2 ] Peak at 254

12. VT NMR Study Naphthalene-1,8-bis-Diethylamide Coalescence of AB System at 368°K AB System for CH 2 of Amides (CH 3 decoubled) Alkyl = Me, CH 2 Me, CH 2 Et, CH 2 Pr i, CHME 2, CH 2 Ph R =Me, COOH, COOMe, H

13. Suzuki - Miyaura Cross Coupling of 2,7 – diHalo Naphthalene 1,8-Bis-Diethylamide