Author Topic: benzyne + aminopyridine, which N arylated?  (Read 2678 times)

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Megatherium

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benzyne + aminopyridine, which N arylated?
« on: December 22, 2002, 11:19:00 AM »
I 've kind of a hard nut to crack.

4-aminopyridine is a ambident nucleophile.  And furthermore, the pyridine ring sucks the 4-amino free electron pair into the aromatic ring, making the pyridine nitrogen even more nucleophilic.  I suspect that with this compound, there is a tautomeric equilibrium, similar to the one between 4-hydroxypyridine  <--> 4-pyridone ... which complicates things even more  :(

The objective is to arylate the 4-amino group, but my concern a the side reaction in the 1-position ...

Which reaction do you think will occur?  Would a benzyne type reaction be just fine, or would it be better to do a coupling with the Pd type catalysts?

Megatherium

  • Guest
I 've been breaking my head upon this the entire
« Reply #1 on: December 23, 2002, 12:31:00 AM »
I 've been breaking my head upon this the entire day  :(  ... and I 've concluded that the 4-aminopyridine coupling with an arylhalide isn't such a good idea after all.

It would probably be better to convert the substrate to 4-bromopyridine using the Sandmeyer reaction & consequently couple this to an arylamine using a Pd catalyst such as  Pd2(dba)3.

I 've not much experience with the Sandmeyer ... is there any reason why this reaction shouldn't work on a 4-aminopyridine?  I 've never seen an example where the aromatic was a pyridine ring ... 
I 'd really like an oppionion on the Sandmeyer.

hermanroempp

  • Guest
First obstacle...
« Reply #2 on: December 24, 2002, 03:05:00 AM »
..to overcome would be the synth of 4-bromopyridine. Simple bromination of pyridine won't work, since pyridine is deactivated (in regard of electrophilic aromatic substitution, of course) in the 2-, 4-, and 6-position, SAE reaction is possible only in 3- and 5-position. Nucleophilic substitution can be achieved on 2-, 4-, and 6-position, the 2-position is clearly preferred. Cicibabin reaction (the reaction of pyridine with sodium amide) yields almost exclusively 2-aminopyridine.
Back to the 4-bromopyridine, how do you want to synthesize that compound?
I'd say forget it, go straight for the 4-aminopyridine by oxidising pyridine to pyridine-N-oxide (activating the aromat), nitrating it with strong mixed acid (HNO3 + H2SO4) to get 4-nitropyridine-N-oxide and reducing the latter compound to 4-aminopyridine with hydrogen/Raney-Ni in acetic acid/acetic acid anhydride.
Now to the Sandmeyer...should work if a diazonium compound forms. Diazonium compounds can be formed even from aromats with strong deactivating groups (e.g. a nitrated or sulfonated aminobenzene), so the Sandmeyer should work, at least theoretically....(never did it myself on pyridines)... ;)

[Edit: Ooops, misunderstood...you already want to go that route:
pyridine -> pyridine-N-oxide -> 4-nitropyridine-N-oxide -> 4-aminopyridine -> 4-bromopyridine (via Sandmeyer)
Answer is still the same, should work...]

Quidquid agis, prudenter agas et respice finem!

Megatherium

  • Guest
pyridine -> pyridine-N-oxide -> ...
« Reply #3 on: December 24, 2002, 12:00:00 PM »
pyridine -> pyridine-N-oxide -> 4-nitropyridine-N-oxide -> 4-aminopyridine -> 4-bromopyridine (via Sandmeyer)

Yup, that 's what I had in mind.  Sorry that my post wasn't very clear.  Anyhow, thanks for your advice.  I needed confirmation for this route.  You 've just made my day  :) .

Merry christmas  :)