Directed ortho Metalation of Naphthalene 1,8-bis(diethylamide): Research Towards Nerve Growth Factor Inhibitors

1
Directed ortho Metalation of Naphthalene
1,8-bis(diethylamide)Research Towards Nerve
Growth Factor Inhibitors

• John Stephenson, Christopher Jones, Victor
  Snieckus
• Department of Chemical Engineering, Queens
  University
• Department of Chemistry, Queens University
• Kingston, ON, Canada. K7L 3N6
• 8js5_at_qlink.queensu.ca

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 Alzheimers,
  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,
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 double DoM Chemistry of 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
7
Deprotonation of Naphthalenebis-diethylamide

• Determined by CD3OD Quench Experiments

8
What Role Does the Equivalents of Base Have on
formation of Mono or Bis?
M-NEt2 Peak at 254
2.2 Eqv
1.1 Eqv
3.3 Eqv
4.4 Eqv
Starting Material
Equilibrium can be seen for 1.1 equivalents
9
Examples of mono DoM Chemistry of Naphthalene
1,8-bis(diethylamide)
E E Equiv Mono Bis SM TMSCl TMS 1.1
15 25 38 (SMe)2 SMe 1.1 ? ? ? CF3CH2I
I 1.1 ? ? ? DMF CHO 1.1 14 35 47
Snieckus, V. Jones, C. Stephenson, J., 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unpublished results.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
• Pd(PPh3)4 or Pd(dppf)Cl2 are common catalysts
• Catalytic cycle of Suzuki cross coupling

11
Suzuki-Miyaura Cross Coupling of 2,7-diHalo
Naphthalene 1,8-Bis-Diethylamide
12
Future Work
Cross Coupling of Mono Product
Cyclization of Mono Product
13
Acknowledgements

• Dr. Victor Snieckus
• Chris Jones
• Snieckus Group