John Stephenson † , Christopher Jones †† , Victor Snieckus ††
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Directed Directed orthoortho Metalation Metalation (DoM) of Naphthalene (DoM) of Naphthalene 1,8-bis(diethylamide):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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Et2NOC CONEt2
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Nerve Growth Factor (NGF)Nerve Growth Factor (NGF)
• Involved with the neuronal development in the CNS and PNS.
• Implicated in Alzheimer’s, epilepsy, stroke and pain.
• Production of NGF 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
OHALE 540
N
O
O
R2
R1
EWG
R =
H, I, Br, CHO
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
Original Work1. Gilman et al. J. Am. Chem. Soc. 1939, 61, 106-109.2. Wittig et al. Chem. Ber. 1940, 73, 1197.
OMe OMeRLi
Li
CO2
OMe
CO2H
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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 2,7-substituted Naphthalene 1,8-Examples of 2,7-substituted Naphthalene 1,8-bis(diethylamide)bis(diethylamide)
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
Jones, C.; Snieckus, V. 2003, unpublished results.
1. sec-BuLi /TMEDA/ THF
-78°C / 45 mins2. Electrophile / -78°C / 45 mins3. Sat. AmCl(aq)
Et2NOC CONEt2Et2NOC CONEt2
EE
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Deprotonation of NaphthaleneDeprotonation of Naphthalenebis-diethylamidebis-diethylamide
CONEt2Et2NOC
secBuLi / TMEDA
THF
CONEt2Et2NOC
CONEt2Et2NOC
secBuLi / TMEDATHF
CONEt2Et2NOC
E+ QuenchEE
E+ = TMSCl, B(OR)3, X2, DMF
secBuLi / TMEDATHF
•Determined by CD3OD Quench Experiments
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• Equilibrium can be seen for 1.1 equivalents
What Role Does the Equivalents of Base Have What Role Does the Equivalents of Base Have on formation of Mono or on formation of Mono or Di AnionDi Anion??
A –StartingMaterial
B –Monoanion
C –Dianion
A B C
1.1 Eqv 2.2 Eqv
3.3 Eqv 4.4 Eqv
Et2NOC CONEt2
Et2NOC CONEt2
-
Et2NOC CONEt2
--
Jones, C.; Snieckus, V. 2003, unpublished results.
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Examples of 2-substituted Naphthalene 1,8-Examples of 2-substituted Naphthalene 1,8-bis(diethylamide)bis(diethylamide)
E+ E Equiv Mono% Bis% SM%
TMSCl TMS 1.1 15 25 38
CF3CH2I I 1.1 24 35 18
1. sec-BuLi /TMEDA/ THF
-78°C / 45 mins2. Electrophile / -78°C / 45 mins3. Sat. AmCl(aq)
Et2NOC CONEt2Et2NOC CONEt2
E
Stephenson, J.; Jones, C.; Snieckus, V. 2003, unpublished results.
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Suzuki-Miyaura Cross CouplingSuzuki-Miyaura Cross Coupling
• Used to form sp2 carbon-carbon bonds• Coupling of an aryl boronic acid with an aryl halide
or triflate
• Pd(PPh3)4 or Pd(dppf)Cl2 are common Pd0 catalysts
• Catalytic cycle of Suzuki cross coupling:
Pd0
Pd2+XR1Pd2+R2R1
R2 B(OH)2BX(OH)2
R1 R2XR1
ReductiveElimination
OxidativeAddition
Transmetalation N. Miyaura et al., Tet. Let. 1979, 3437N. Miyaura, A. Suzuki, Chem. Commun. 1979, 866.
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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
Et2NOC CONEt2 Et2NOC CONEt2
XX
B(OH)2
Catalyst
BaseSolventReflux 72 h
RRR
X = Br, I
B(OH)2
Boronic Acid X Base Catalyst Solvent Yield (%)
Br K3PO4 Pd(PPh3)4 DMF 32
I K3PO4 Pd(PPh3)4 DMF 51
Jones, C.; Snieckus, V. 2003, unpublished results.
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DMG
RLi
Kinetic orThermodynamic?
Kinetic
RLi
steric relief,product stability
non-productive ONEt2
O
Et2NOC CONEt2
10 Equiv LDA
-10°C to rtStir 36 Hours(39%)
CONEt2
O
Orange Colour
Directed Directed Remote MetalationRemote Metalation (DreM): (DreM):Complex Induced Proximity EffectComplex Induced Proximity Effect
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Future WorkFuture Work
Et2NOC CONEt2
I CONEt2
Et2N OB(OH)2
Catalyst
BaseSolventReflux 72 h
R
CONEt2
Et2N OCONEt2
O
5eq LDA
SolventStir 36hrs-10°C to rt
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• Family & Friends
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Questions?Questions?