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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, Queen’s University †† Department of Chemistry, Queen’s University

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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, Queen’s University

†† Department of Chemistry, Queen’s University

Kingston, ON, Canada. K7L 3N6

[email protected]


Nerve growth factor ngf
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, 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 double dom chemistry of naphthalene 1 8 bis diethylamide
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%


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 bis
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


Examples of mono dom chemistry of naphthalene 1 8 bis diethylamide
Examples of mono DoM Chemistry Mono or Bis?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.


Suzuki miyaura cross coupling
Suzuki-Miyaura Cross Coupling Mono or Bis?

  • 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:



Future work
Future Work 1,8-Bis-Diethylamide

Cross Coupling of Mono Product

Cyclization of Mono Product


Acknowledgements
Acknowledgements 1,8-Bis-Diethylamide

  • Dr. Victor Snieckus

  • Chris Jones

  • Snieckus Group


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