Christopher Jones † , Victor Snieckus † , Greg Ross ‡
description
Transcript of Christopher Jones † , Victor Snieckus † , Greg Ross ‡
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
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%