1 First Directed First Directed ortho ortho Metalation (DoM) of Metalation (DoM) of 1,8-Naphthalene Diamides. 1,8-Naphthalene Diamides. Towards Nerve Growth Towards 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 [email protected]
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Christopher Jones † , Victor Snieckus † , Greg Ross ‡
First Directed ortho Metalation (DoM) of 1,8-Naphthalene Diamides. Towards Nerve Growth Factor Inhibitors. Christopher Jones † , Victor Snieckus † , Greg Ross ‡ † Department of Chemistry, Queen’s University, Kingston, ON, CANADA K7L 3N6 - PowerPoint PPT Presentation
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First Directed First Directed orthoortho Metalation (DoM) of Metalation (DoM) of
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.
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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