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Directed Directed orthoortho Metalation of Naphthalene Metalation 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.ca

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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

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Previously Identified NGF InhibitorsPreviously Identified NGF Inhibitors

N

RO

O

O2N

R =

O

OH

NCP 205

HN

OHALE 540

N

O

O

Ar

Ar

EWG

Ar =

R1

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

OMe OMeRLi

Li

CO2

OMe

CO2H

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

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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 double DoM Chemistry Examples of double DoM Chemistry of Naphthalene 1,8-bis(diethylamide)of Naphthalene 1,8-bis(diethylamide)

1. sec-BuLi /TMEDA/ THF

-78°C 2. Electrophile

Et2NOC CONEt2Et2NOC CONEt2

EE

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%

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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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Starting Material

1.1 Eqv 2.2 Eqv

3.3 Eqv 4.4 Eqv

• Equilibrium can be seen for 1.1 equivalents

[M+-NEt2] Peak at 254

What Role Does the Equivalents of Base Have What Role Does the Equivalents of Base Have on formation of Mono or Bis?on formation of Mono or Bis?

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Examples of mono DoM Chemistry Examples of mono DoM Chemistry of Naphthalene 1,8-bis(diethylamide)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.

1. sec-BuLi /TMEDA/ THF

-78°C 2. Electrophile

Et2NOC CONEt2Et2NOC CONEt2

E

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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

• Pd(PPh3)4 or Pd(dppf)Cl2 are common catalysts

• Catalytic cycle of Suzuki cross coupling:

Pd0

Pd2+ XR1Pd2+ R2R1

R2 B(OH)2BX(OH)2

R1 R2

XR1

ReductiveElimination

OxidativeAddition

Trans-metalation

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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

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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

Solvent

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