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Directed Directed orthoortho Metalation Metalation (DoM) of Naphthalene (DoM) of Naphthalene 1,8-bis(diethylamide):1,8-bis(diethylamide):

Research Towards Nerve Research Towards Nerve Growth Factor InhibitorsGrowth 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.ca7

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Et2NOC CONEt2

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Nerve Growth Factor (NGF)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

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Previously Identified NGF InhibitorsPreviously Identified NGF Inhibitors

N

RO

O

O2N

R =

O

OH

NCP 205

OHALE 540

N

O

O

R2

R1

EWG

R =

H, I, Br, CHO

Target Molecules

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

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Mild Conditions

-78oC 0oC rtTHF or Et2O or DME

Regioselective E+ - Ar SubstComplement

Contiguous SubstitutionPatterns

FG

DMG DMG

DoM

E+

E+

DMG

E1+

E2+

DMG1

DMG2

E+

(m-DMG)

(p-DMG)

Iterative (ring - walk)

DMG1

DMG2

DMG3

(DMG2 > DMG1)

- -

---

--

-

Recent Work1. Kalinin, A.; Snieckus, V. et al. J Org Chem, 2003, 68, 59922. Chauder, B.; Snieckus, V. et al. Org Lett, 2002, 4, 815

Directed Directed orthoortho Metalation Metalation

Original Work1. Gilman et al. J. Am. Chem. Soc. 1939, 61, 106-109.2. Wittig et al. Chem. Ber. 1940, 73, 1197.

OMe OMeRLi

Li

CO2

OMe

CO2H

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DMG

E+

N-COR (R = Ot-Bu, t-Bu)

OCONEt2

O

N

Muchowski, Gschwend 1978

Snieckus, 1983

DMG

Meyers, Gschwend, 1975

CONEt2Beak, 1977

OMOM Christensen, 1975

SO2NR2Hauser, 1968

P(O)(t-Bu)2 Snieckus, 1998

CON--Cumyl

SO2N--Cumyl

OCON(Me)-Cumyl

Snieckus, 1999

DMG

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

Directed Directed orthoortho Metalation (DoM) Reactions Metalation (DoM) Reactions in Organic Synthesisin Organic Synthesis

E+

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Examples of 2,7-substituted Naphthalene 1,8-Examples of 2,7-substituted Naphthalene 1,8-bis(diethylamide)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.

1. sec-BuLi /TMEDA/ THF

-78°C / 45 mins2. Electrophile / -78°C / 45 mins3. Sat. AmCl(aq)

Et2NOC CONEt2Et2NOC CONEt2

EE

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Deprotonation of NaphthaleneDeprotonation of Naphthalenebis-diethylamidebis-diethylamide

CONEt2Et2NOC

secBuLi / TMEDA

THF

CONEt2Et2NOC

CONEt2Et2NOC

secBuLi / TMEDATHF

CONEt2Et2NOC

E+ QuenchEE

E+ = TMSCl, B(OR)3, X2, DMF

secBuLi / TMEDATHF

•Determined by CD3OD Quench Experiments

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• Equilibrium can be seen for 1.1 equivalents

What Role Does the Equivalents of Base Have What Role Does the Equivalents of Base Have on formation of Mono or on formation of Mono or Di AnionDi Anion??

A –StartingMaterial

B –Monoanion

C –Dianion

A B C

1.1 Eqv 2.2 Eqv

3.3 Eqv 4.4 Eqv

Et2NOC CONEt2

Et2NOC CONEt2

-

Et2NOC CONEt2

--

Jones, C.; Snieckus, V. 2003, unpublished results.

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Examples of 2-substituted Naphthalene 1,8-Examples of 2-substituted Naphthalene 1,8-bis(diethylamide)bis(diethylamide)

E+ E Equiv Mono% Bis% SM%

TMSCl TMS 1.1 15 25 38

CF3CH2I I 1.1 24 35 18

1. sec-BuLi /TMEDA/ THF

-78°C / 45 mins2. Electrophile / -78°C / 45 mins3. Sat. AmCl(aq)

Et2NOC CONEt2Et2NOC CONEt2

E

Stephenson, J.; Jones, C.; Snieckus, V. 2003, unpublished results.

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Suzuki-Miyaura Cross CouplingSuzuki-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:

Pd0

Pd2+XR1Pd2+R2R1

R2 B(OH)2BX(OH)2

R1 R2XR1

ReductiveElimination

OxidativeAddition

Transmetalation N. Miyaura et al., Tet. Let. 1979, 3437N. Miyaura, A. Suzuki, Chem. Commun. 1979, 866.

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

Et2NOC CONEt2 Et2NOC CONEt2

XX

B(OH)2

Catalyst

BaseSolventReflux 72 h

RRR

X = Br, I

B(OH)2

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.

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DMG

RLi

Kinetic orThermodynamic?

Kinetic

RLi

steric relief,product stability

non-productive ONEt2

O

Et2NOC CONEt2

10 Equiv LDA

-10°C to rtStir 36 Hours(39%)

CONEt2

O

Orange Colour

Directed Directed Remote MetalationRemote Metalation (DreM): (DreM):Complex Induced Proximity EffectComplex Induced Proximity Effect

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Future WorkFuture Work

Et2NOC CONEt2

I CONEt2

Et2N OB(OH)2

Catalyst

BaseSolventReflux 72 h

R

CONEt2

Et2N OCONEt2

O

5eq LDA

SolventStir 36hrs-10°C to rt

Cyclization of Mono ProductCyclization of Mono Product

Cross Coupling of Mono ProductCross Coupling of Mono Product

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AcknowledgementsAcknowledgements

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

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Questions?Questions?