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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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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

nerve growth factor ngf
Nerve Growth Factor (NGF)
  • Involved with the neuronal development in the NS.
  • 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

previously identified ngf inhibitors
Previously Identified NGF Inhibitors

Target Molecules

Marone, S. and Ross, G. 2000, World Patent No. WO0069829

directed ortho metalation
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

directed ortho metalation dom reactions in organic synthesis
Directed ortho Metalation (DoM) Reactions in Organic Synthesis

E+

Hartung, C, Snieckus, V. Modern Arene Chemistry, Wiley-VCH, Weinheim. 2002, p. 330

examples of 2 7 substituted naphthalene 1 8 bis diethylamide
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Jones, C.; Snieckus, V. 2003, unpublished results.

deprotonation of naphthalene bis diethylamide
Deprotonation of Naphthalenebis-diethylamide
  • Determined by CD3OD Quench Experiments
what role does the equivalents of base have on formation of mono or di anion
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Jones, C.; Snieckus, V. 2003, unpublished results.

examples of 2 substituted naphthalene 1 8 bis diethylamide
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.

suzuki miyaura cross coupling
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.

suzuki miyaura cross coupling of 2 7 dihalo naphthalene 1 8 bis diethylamide
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. 2004, unpublished results.

suzuki miyaura cross coupling of 2 7 dihalo naphthalene 1 8 bis diethylamide1
Suzuki-Miyaura Cross Coupling of 2,7-diHalo Naphthalene 1,8-Bis-Diethylamide

Boronic Acid X Base Catalyst Solvent Yield (%)

I K3PO4 Pd(PPh3)4 DMF quantitative

Stephenson, J.; Jones, C.; Snieckus, V. 2004, unpublished results.

future work
Future Work

Separation of products with Me2S2

and DMF quenches

Other electrophiles

Cyclization of Mono Product

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