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Directed Directed orthoortho Metalation (DoM) of Metalation (DoM) of

1,8-Naphthalene diethylamides:1,8-Naphthalene diethylamides:Research Towards Nerve Research Towards Nerve Growth Factor Inhibitors.Growth Factor Inhibitors.

John Stephenson, Christopher Jones†, Victor Snieckus†

†Department of Chemistry, Queen’s University, Kingston, ON, CANADA K7L 3N6

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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

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Previous Work Involving 2,7-Disubstituted Previous Work Involving 2,7-Disubstituted 1,8-Naphthalene Systems1,8-Naphthalene Systems

Wuest, J. et al. Organometallics, 1996, 15, 1296

OCONEt2Et2NOCO OCONEt2Et2NOCO

tert-BuLi, THF

-95°C, TMSCl84% yield

Br2CCl487% yield

TMSTMS

OCONEt2Et2NOCO

BrBr

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Steric Interference With 1,8-Steric Interference With 1,8-bis(bis(diethylamide)diethylamide)Naphthalene SystemNaphthalene System

OONN

OO

1

TMSTMS <N

O

N

O

2

TMSTMS

X-ray structure of 2,7-bis(TMS)shows steric interference fromdiethylamide groups

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Previous Examples of DoM Chemistry Previous Examples of 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

4.4 50%

2.2 40%

Snieckus, V.; Jones, C., 2003, unpublished results.

(CH3)2N

H

O

H

O

Si(CH3)3Cl Si(CH3)3

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

E+ E Equiv % Yield

2.2 75%

4.4 86%

Snieckus, V.; Jones, C.; Stephenson, J., 2003, unpublished results.

MeS S

Me

CF3CH2I

SMe

I

1. sec-BuLi /TMEDA/ THF

-78°C 2. Electrophile

Et2NOC CONEt2Et2NOC CONEt2

EE

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Bromo Ipso-DesilylationBromo Ipso-Desilylation

Snieckus, V.; Jones, C.; Stephenson, J., 2003, unpublished results.

1. sec-BuLi /TMEDA/

THF / -78°C 2. (iPrO)3B3. NH4Cl(aq)/pinacol

Et2NOC CONEt2

BrBrEt2NOC CONEt2

BBO

OO

O

Metal-Halogen ExchangeMetal-Halogen Exchange

Br2/CH2Cl2

Reflux78% yield

Et2NOC CONEt2

TMSTMS

Et2NOC CONEt2

BrBr

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Research with Sulfonamide AnalogsResearch with Sulfonamide Analogs

1. NaNO2, H2SO4

2. SO2, Fe2+

NH2 SO3H HO3S SO2H

Cu2+, O2

HO3S SO3H

Desire to build a larger library of 2,7-substituted 1,8-naphthalene derivatives.

NH2 SO3H

NH S

1. (Boc)2O/THF

2. PCl5/DCM3. NHEt2/NEt3/DCM

N

O

OO

O

Research direction for New Year

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AcknowledgementsAcknowledgements

• Dr. Victor Snieckus• Chris Jones• Snieckus Group