Route for aromatic substitution on pyridine

[Bandil]

In the attempt of creating some new anti-psychotics, i need some advice from the chemistry masters  

I have a 4-chloro-3-amino-pyridine and I have some trouble with an aromatic substitution of the chloro in the 4. position. I know 4-chloro is very reactive in substitution because of different resonance stuctures of the pyridine ring, but it's too reactive in this case unfortunately. I'm using a R-C-N^--C-R nucleofile and it has to be less reactive than an imine NH nucleofile( ^-N=C=(RR). Perhaps using some dynamic reaction conditions, such as low temperatures (-78 ^oC).

I just nead some advice for some inferior leaving groups for this synthesis, I was pondering using a methoxygroup. A bromo group or other halogens are not useable as they can make a metal-halogen exchance (I'm using a Li-salt of mopholine so halogens aren't possible).

Any suggestions would be greatly appreciated!

Happy living in spring time to all of you people   !

Kind regards
Bandil

[Nicodem]

Could you please explain a little more. I dont understand exactly so correct me if I'm wrong. If your reaction is 4-chloro-3-amino-pyridine with the N-Li-morpholine then you have to know that the 3-amino group on the pyridine has a much lower pKa than morpholine and the most probable result of such a rection would be the self condenstion of two or more molecules of 4-chloro-3-amino-pyridine (meaning you get something like tar). I think you can't avoid this unless you protect the amine function, but not with just any protection (N-acetylation would make it even more acidic!).

[Bandil]

I understand your concern... I have thought of it prior to this    No need to worry about this issue, as it's a triple substituted amine in the 3. position, so no basic hydrogens on this amine.

Sorry I didn't mention it, guess i have friday fever allready  

Regards
Bandil

[Nicodem]

In such case I don't know what goes wrong. Maybe your base is way to strong and causes a side rxn (the hydride exchange at the position two yielding 2-hydroxy-pyridine products or something).
It might be worth trying to avoid an extremly strong base like N-Li-morfoline and try to refluxs your chloropyridine in excess morpholine for a day or two (or better yet to follow the rxn with TLC). So, using morpholine as a solvent, base and nucleophile at the same time. Adding some K2CO3 might help a little.

[lugh]

This article from JACS 76 3527 (1954) provides a means for substitution at the 4 position: