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Directed Directed orthoortho Metalation (DoM) of Metalation (DoM) of
Naphthalene 1-8-bis-diethylamide:Naphthalene 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
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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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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 ?% ?% ?%
(SMe)2 SMe 1.1 ?% ?% ?%
CF3CH2I I 1.1 ?% ?% ?%
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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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
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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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Suzuki-Miyaura Cross CouplingSuzuki-Miyaura Cross Coupling
• Background slide, perhaps containing:
• Coupling of an aryl boronic acid with an acryl halide
• Oxidative cycle: oxidative add, transmetalation, reductive elim
? Or other suggestions
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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
B(OH)2
Et2NOC CONEt2 Et2NOC CONEt2
XX
B(OH)2
Catalyst
BaseSolventReflux 72 h
RRR
X = Br, I
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Future WorkFuture Work
Et2NOC CONEt2
I CONEt2
Et2N OB(OH)2
Catalyst
BaseSolventReflux 72 h
R
CONEt2
Et2N OCONEt2
O
10eq 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