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

1,8-Naphthalene Diamides.1,8-Naphthalene Diamides.Towards Nerve GrowthTowards Nerve Growth

Factor Inhibitors Factor Inhibitors

Christopher Jones†, Victor Snieckus†, Greg Ross ‡

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

chrisj@chem.queensu.ca

Nerve Growth Factor (NGF)Nerve Growth Factor (NGF)

• Involved in 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 is stimulated in patients suffering from Arthritis pain.

• Inhibition of NGF causes reduction in pain levels.

Ross, G. et al. J. Amer. Chem. Soc, 99 121, 1997

Previously Identified NGF InhibitorsPreviously Identified NGF Inhibitors

N

RO

O

N

O

O

R =

O

OH

NCP 205

HN

OHALE 540

N

O

O

Ar

Ar

EWG

Ar =

R1

Target Molecules

Ross, G. et al. J. Amer. Chem. Soc, 99 121, 1997

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

DMG

E+

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

OCONEt2

O

N

Muchowski, Gschwend 1978

Snieckus, 1983

DMG

Meyers, Gschwend, 1975

CONEt2 Beak, 1977

OMOM Christensen, 1975

SO2NR2 Hauser, 1968

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

CON--Cumyl

SO2N--Cumyl

OCON(Me)-Cumyl

Snieckus, 1999

Ph

DMG

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

Advantages of Directed Advantages of Directed orthoortho Metalation Metalation

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

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

OCONEt2Et2NOCO

PhPh

OMOMMOMO

PhPh

OHOH

PhPh

Ligand for TiCl4

No Cleavageof Carbamate

CH3OH/ 12 N HCl

CH2Cl2

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

SuzukiCross Couple

Double DoM of Naphthalene1,8-bis-Diethylamide

1. s-BuLi /TMEDA/ THF

-78C 2. E+

Et2NOC CONEt2Et2NOC CONEt2

EE

199 TL 6671

E+ E s-BuLi Equiv yld, % TMSCl TMS 4.4 50 CF3CH2I

1 I 4.4 86 DMF CHO 2.2 40 (MeS)2 SMe 2.2 74

Bromo Ipsodesilaytion of Naphthalene-Bromo Ipsodesilaytion of Naphthalene-1,8-dicarboxylic acid bis-diethylamide1,8-dicarboxylic acid bis-diethylamide

CH2Cl2 / Reflux

Et2NOC CONEt2

TMSTMS

Et2NOC CONEt2

BrBrBr2

Colvin, E.W. Silicon in Organic Synthesis. Butterworth: London, 1988

SiR3

E+

R3Si E

-SiR3+

E

+

A

E+ = Br+, I+, NO2+, PhCO+, MeCO+.

General Ipso-substitution Reaction

•Synthesize unconventional substitution

patterns.

•Alternative short route with improved yield.

•Regioselective,clean reaction with mild

conditions.

78%

Mono or Di Deprotonation of NaphthaleneMono or Di Deprotonation of Naphthalenebis-Diethylamide.bis-Diethylamide. What pathway does the What pathway does the

deprotonation follow??deprotonation follow??

CONEt2Et2NOC

secBuLi / TMEDA

THF

CONEt2Et2NOC

CONEt2Et2NOC CONEt2Et2NOC

H

secBuLi / TMEDATHF

CONEt2Et2NOC

E+ QuenchEE

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

•Determined by CD3OD Quench Experiments

Mono vs Bis Incorporation of Deuterium Mono vs Bis Incorporation of Deuterium Monitored by EI Monitored by EI+ + MS over TimeMS over Time

[M+-NEt2] Peak at 254

• [M+-NEt2] Peak (254) diappears after addition of SecBuLi and quench with CD3OD

• Time does not increase or decrease the 256 peak

• Equivalents of base = 4.4

Time 0 10 Min

20 Min 30 Min

1 Hr 6 Hr

[M+2-NEt2] Peak at 256

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?

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

VT NMR Study Naphthalene-1,8-bis-Diethylamide

G2G1

RR

Coalescence of AB System at 368°K

AB System forCH2 of Amides(CH3 decoubled)

Alkyl = Me, CH2Me, CH2Et, CH2Pri, CHME2, CH2Ph

R =Me, COOH, COOMe, H

G1 G2 ΔG‡(kcal/mol) Tc(°K) Ref CONEt2 H 6.7 9.0 94 JOC 4637 COPh COPh 14.7 82 T 3499 COAlkyl COAlkyl 15.1 309 94 JOC 4637 CONEt2 CONEt2 18.2 368

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

B(OH)2

Et2NOC CONEt2 Et2NOC CONEt2

XX

B(OH)2

Catalyst

BaseSolventReflux 72 h

RRR

X = Br, I

Boronic Acid X Base Catalyst Solvent Yield (%) Br Na2CO3 Pd(PPh3)4 DME/H2O 0 Br KF Pd(dba)3 Toluene 0 [(t-Bu)3)PH]BF4 Br K3PO4 Pd(PPh3)4 DMF(Anhyd) 32% I K3PO4 Pd(PPh3)4 DMF(Anhyd) 51%

DMG

RLi

Kinetic orThermodynamic?

Kinetic

RLi

steric relief,product stability

non-productive ONEt2

O

Discovery of New ReactionsRemote Metalation: Close Induced Proximity Effect (CIPE)

Et2NOC CONEt2

10 Equiv LDA

-10°C to rtStir 36 Hours(39%)

CONEt2

O

Orange Colour