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John Stephenson † , Christopher Jones †† , Victor Snieckus ††

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

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John Stephenson † , Christopher Jones †† , Victor Snieckus ††

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  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 8js5@qlink.queensu.ca

  2. Nerve Growth Factor (NGF) • Involved with the neuronal development in the CNS and PNS. • Implicated in Alzheimer’s, epilepsy, stroke and pain. • Production of NGF 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, 9797-9806

  3. Previously Identified NGF Inhibitors Target Molecules Marone, S. and Ross, G. 2000, World Patent No. WO0069829

  4. Directed ortho Metalation • Original Work • Gilman et al. J. Am. Chem. Soc.1939, 61, 106-109. • Wittig et al. Chem. Ber.1940, 73, 1197. 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

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

  6. Examples of 2,7-substituted Naphthalene 1,8-bis(diethylamide) E+ E Equiv Yield (%) CF3CH2I I 4.4 86 TMSCl TMS 4.4 50 DMF CHO 2.2 40 (MeS)2 SMe 2.2 74 Jones, C.; Snieckus, V. 2003, unpublished results.

  7. Deprotonation of Naphthalenebis-diethylamide • Determined by CD3OD Quench Experiments

  8. What Role Does the Equivalents of Base Have on formation of Mono or Di Anion? A B C A – Starting Material B – Mono anion C – Di anion 2.2 Eqv 1.1 Eqv 3.3 Eqv 4.4 Eqv • Equilibrium can be seen for 1.1 equivalents Jones, C.; Snieckus, V. 2003, unpublished results.

  9. Examples of 2-substituted Naphthalene 1,8-bis(diethylamide) E+ E Equiv Mono% Bis% SM% TMSCl TMS 1.1 15 25 38 CF3CH2I I 1.1 24 35 18 Stephenson, J.; Jones, C.; Snieckus, V. 2003, unpublished results.

  10. Suzuki-Miyaura Cross Coupling • Used to form sp2 carbon-carbon bonds • Coupling of an aryl boronic acid with an aryl halide or triflate • Pd(PPh3)4 or Pd(dppf)Cl2 are common Pd0 catalysts • Catalytic cycle of Suzuki cross coupling: N. Miyaura et al.,Tet. Let.1979, 3437 N. Miyaura, A. Suzuki, Chem. Commun.1979, 866.

  11. Suzuki-Miyaura Cross Coupling of 2,7-diHalo Naphthalene 1,8-Bis-Diethylamide Boronic Acid X Base Catalyst Solvent Yield (%) Br K3PO4 Pd(PPh3)4 DMF 32 I K3PO4 Pd(PPh3)4 DMF 51 Jones, C.; Snieckus, V. 2003, unpublished results.

  12. Directed Remote Metalation (DreM):Complex Induced Proximity Effect

  13. Future Work Cross Coupling of Mono Product Cyclization of Mono Product

  14. Acknowledgements • Dr. Victor Snieckus • Chris Jones • Snieckus Group • Family & Friends

  15. Questions?

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