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 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? |
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Megatherium (Stranger) 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 ... 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. |
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hermanroempp (Hive Bee) 12-24-02 03:05 No 392232 |
First obstacle... | Bookmark | ||||||
..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! |
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Megatherium (Stranger) 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 . Merry christmas |
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