1

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

2

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

3

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

4

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

5

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

6

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

7

DoM Chemistry of Naphthalene-DoM Chemistry of Naphthalene-bis-Diethylamides. First Resultsbis-Diethylamides. First Results

Et2NOC CONEt2Et2NOC CONEt2

TMSTMS4.4 secBuLi4.4 TMEDA / THF

-78*C 4.4 / TMSCl

• Amide steric interactions provides high rotational barriers

•Amides are positioned parallel to each other and perpendicular to the aromatic ring.

Jones, C; Snieckus, V.; Ross, G. unpublished results 2003

50%

8

DoM Chemistry of Naphthalene DoM Chemistry of Naphthalene 1,8-bis-Diethylamide Generalization1,8-bis-Diethylamide Generalization

1. secBuLi /TMEDA/ THF

-78*C 2. E+ Quench

Et2NOC CONEt2Et2NOC CONEt2

EE

• Br2 derivative achieved by Ipsodesilaytion reaction on the bis TMS derivative.

E+ Equiv. % Yeild TMSCl 4.4 50 % DMF 2.2 40 % Br2 Excess 78% a

9

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

10

cj069-0

324 325 326 327 328 329 330 331 332 333 334Da/e0

100

%

328.5

327.5

326.5

325.5

329.5

330.4

331.4

cj069-10

325 326 327 328 329 330 331 332 333Da/e0

100

%

328.3

327.3

326.3

329.3

330.4

331.4

cj069-20

325 326 327 328 329 330 331 332 333 334Da/e0

100

%

328.5

327.3

326.3

330.4

329.5

331.4

cj068-30

325 326 327 328 329 330 331 332 333 334Da/e0

100

%

330.4

328.3

327.3

326.3

329.5

331.4

332.4

cj068-1

325 326 327 328 329 330 331 332 333Da/e0

100

%

328.3

327.3

326.3

330.3

329.3

331.3

cj068-6

325 326 327 328 329 330 331 332 333Da/e0

100

%

328.5

327.5

326.5

329.5

330.4

331.4

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

cj068 blk

324 325 326 327 328 329 330Da/e0

100

%

326.3

325.4

327.3

328.3

M+ Peak at 326

• M+ Peak increases to 328 after addition of SecBuLi and quench with CD3OD

• Time does not increase or decrease the 328 peak

Time 0 10 Min

20 Min 30 Min

1 Hr 6 Hr

M+ Peak at 328

11

cj067-1.1

324 325 326 327 328 329 330 331Da/e0

100

%

328.3

327.3

326.3

329.3

cj067-2.2

325 326 327 328 329 330 331 332 333Da/e0

100

%

328.3

327.3

326.3

330.4329.3

331.4

cj067-3.3

325 326 327 328 329 330 331 332 333Da/e0

100

%

328.3

327.3

326.3

330.4

329.3

331.4

cj067-4.4

325 326 327 328 329 330 331 332 333Da/e0

100

%

328.3

327.3

326.3

330.3

329.3

331.4

cj068 blk

324 325 326 327 328 329 330Da/e0

100

%

326.3

325.4

327.3

328.3

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

M+ Peak at 326M+ Peak at 328

1.1 Eqv 2.2 Eqv

3.3 Eqv 4.4 Eqv

• Number equivalents of s-BuLi do not have an effect on the formation of Mono vs Bis Deuterated product.

12

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%

13

Met+

DMG B(OR)3 MgX2 ZnX2 ClSnR3

CONEt2 OCONEt2 ?OMOM N-Boc x x ?SO2NEt2 x ? ? ?

RLi

DMG

Met+ DMG

XB(OR)2

Pd0

DDooM-Cross Coupling ConnectionsM-Cross Coupling Connections

14

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

Et2NOC CONEt2 Et2NOC CONEt2

BrBr

B(OH)2

Catalyst

BaseSolventReflux 72 hours

RRR

B(OH)2

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

15

AcknowledgementsAcknowledgements

• Dr. Victor Snieckus• Dr. Greg Ross• Dr. Christian Hartung• Dr. Bert Nolte• Dr. Bernd Keller• The Snieckus Group