1 Directed ortho Metalation (DoM) of Naphthalene 1-8-bis-diethylamide: Research Towards Nerve Growth Factor Inhibitors John Stephenson †, Christopher Jones.

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Presentation transcript:

1 Directed ortho Metalation (DoM) of Naphthalene 1-8-bis-diethylamide: Research Towards Nerve Growth Factor Inhibitors John Stephenson †, Christopher Jones ††, Victor Snieckus †† † Department of Chemical Engineering, Queen’s University †† Department of Chemistry, Queen’s University Kingston, ON, Canada. K7L 3N6

2 Nerve Growth Factor (NGF) Involved with 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 of protein is stimulated in patients suffering from Arthritis pain. Inhibition of NGF causes reduction in pain levels. Shamovsky, et al. J Am Chem Soc, 1999, 121,

3 Previously Identified NGF Inhibitors Target Molecules Marone, S. and Ross, G. 2000, World Patent No. WO

4 Recent Work 1. Kalinin, A.; Snieckus, V. et al. J Org Chem, 2003, 68, Chauder, B.; Snieckus, V. et al. Org Lett, 2002, 4, 815 Directed ortho Metalation Original Work 1.Gilman et al. J. Am. Chem. Soc. 1939, 61, Wittig et al. Chem. Ber. 1940, 73, 1197.

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

6 Examples of double DoM Chemistry of Naphthalene 1,8-bis(diethylamide) E + EEquiv% Yield CF 3 CH 2 II4.486% TMSClTMS 4.450% DMFCHO2.240% (MeS) 2 SMe2.274%

7 Examples of mono DoM Chemistry of Naphthalene 1,8-bis(diethylamide) E + EEquivMono%Bis%SM% TMSClTMS1.1?%?%?% (SMe) 2 SMe1.1?%?%?% CF 3 CH 2 II1.1?%?%?% Snieckus, V.; Jones, C.; Stephenson, J., 2003, unpublished results.

8 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

9 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 What Role Does the Equivalents of Base Have on formation of Mono or Bis?

10 Suzuki-Miyaura Cross Coupling Background slide, perhaps containing: Coupling of an aryl boronic acid with an acryl halide Oxidative cycle: oxidative add, transmetalation, reductive elim ? Or other suggestions

11 Suzuki-Miyaura Cross Coupling of 2,7-diHalo Naphthalene 1,8-Bis-Diethylamide

12 Future Work Cyclization of Mono Product Cross Coupling of Mono Product

13 Acknowledgements Dr. Victor Snieckus Chris Jones Snieckus Group