Megatherium (Stranger)
12-22-02 11:19
No 391681
      benzyne + aminopyridine, which N arylated?  Bookmark   

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 frown

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?
12-23-02 00:31
No 391828
      I 've been breaking my head upon this the entire  Bookmark   

I 've been breaking my head upon this the entire day frown ... 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.
(Hive Bee)
12-24-02 03:05
No 392232
      First obstacle...  Bookmark 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)...wink

[Edit: Ooops, 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!
12-24-02 12:00
No 392368
      pyridine -> pyridine-N-oxide -> ...  Bookmark   

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 smile.

Merry christmas smile