[swordlord]

As showned in my attached pic，4-hydroxypyridine(4HP)  has a resonance structure which sort of acts as an amide. So, if i wanna esterify the hydroxyl of 4HP from a carboxylic acid chloride, how can this happen as you know the acid chloride may also reacts with the amide H.

[Fry]

Deprotonate the alcohol with a base to make it more nucleophillic? Although you can draw resonance structures that are able to toss negative charge on the amine, oxygen is more electronegative. May work..

[Rico]

First of all those structures you have drawn is not resonance forms, but tautomeric forms, that is two molecules in a rapid equilibrium.
Second, that is a very good question. Im pretty sure that acylation will happen at nitrogen since it is more nucleophilic than oxygen (even though it is less electronegative).
My first thought was to acylate the N-oxide, but this will probably just happen on the oxygen attached to the nitrogen instead. I dont know, maybe it will work!
My second thought was to make the ester-product by a nucleophilic aromatic substitution of the 4-halogen substituted N-oxide (see attached jpeg-file). The 4-halogen substituted N-oxide can then be made from 4-pyridone.
This route includes more synthetic steps, but it is probably necessary to obtain the right product.

I Hope my ideas will help you.

[Rico]

A little addition to my post above: Maybe the nucleophilic aromatic substitution can be done directly on the 4-halogen pyridine. This will shorten the synthesis very much, since the oxidation and reduction steps will not be necessary.
The reason why i wanted the N-oxide was to make the nitrogen posetively charged and therefore making the the substrate a better electrophile.

[swordlord]

thanks rico
what you posted really enlightens me a lot.
however, i have a paper on hand(J. Med. Chem. 2007, 50, 1850-1864), in which they just employed a traditional way of doing the esterification:

"General Procedure for the Preparation of Pyridinyl Esters:
To a solution of carboxylic acid (2 mmol, 1.0 equiv) in DCM (5
mL) at rt was added thionyl chloride (0.4 mL, 1.3 equiv) and a
catalytic amount of DMF (2 drops). After 20 h of stirring, the
solvent was removed in vacuo to afford the acyl chloride product.
A solution of the acyl chloride in DCM (5 mL) was added dropwise
to a solution of pyridinyl alcohol or amine (1.0 equiv) and pyridine
(0.18 mL, 1.1 equiv) in DCM (5 mL) at 0 °C. After 3 h of stirring,
the solvent was removed in vacuo. The residue was diluted with
H2O and extracted with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, and then concentrated in
vacuo. Purification of the crude product by flash chromatography
on silica gel afforded the product as a solid in 43-90% yield."

i really wonders how they made that happen. maybe only experiment itself will tell.
thanks again!

[Fry]

Rico, I was talking about the nucleophilicity of the resultant alkoxide. It is MUCH greater than even a tertiary amine, a phenoxide will win.

Also, swordland.. Is it possible that maybe the reason for the correct acylation under normal conditions is the fact that the resulting pyridinium ion cant stabilize its positive charge? Look how close the positive charge in the pyridine ring is to the carbonyl carbon in the acetyl group...

[Rico]

Fry, i see what you mean. But if you treat 4-pyridone (which is the most abundant tautomer of the two) with base then the nitrogen will get deprotonated, forming a stablilized anion. This anion is the same as the one that will get formed if 4-hydroxypyridine is deprotonated on oxygen (see resonance forms in jpeg attached). In this anion the negative charge is distributed in some degree on both the nitrogen and the oxygen, of course depending on electronegativity. I believe that this situation corresponds to comparing the nucleophilicity of amides (bases formed by deprotonating amines) and alkoxides, and then the nitrogen will be the best nucleophile. 

[Rico]

Swordlord, if you look in the paper you see that all the substrates they have used is 3-hydroxypyridines and these molecules don't have tautomeric forms like the 2- and 4-hydroxypyridines have the tautomeric forms 2-pyridone and 4-pyridone, respectively. I honestly don't think that this procedure will get you anywhere with 4-pyridone, but maybe its worth a try. You might get both acylated products, and then the question is, is these two products separable 

[Fry]

Ill take your word for it then

[lavoisier]

The 'books' say that:

A) 2- and 4- hydroxypyridines exist almost entirely in the carbonyl tautomeric form, therefore they are better named 'pyridones'
B) AcCl in Et2O acetylates 4-pyridone at the nitrogen first, then the product can equilibrate in DCM at room temperature to a 1:1 mixture with 4-acetoxypyridine
C) the sodium salt of 4-pyridone can be silylated at the oxygen with TMSCl, but the alkylation selectivity depends on reacton conditions (and I'm afraid that the same is true for acylation)

Conclusion: either you find for a specific literature method describing the conditions for a selective O-acylation, or you protect the nitrogen as suggested.

But actually, if and when you've formed the product, you may find that it's not very stable, and it equilibrates to the N-acylated stuff. If you look in chemical suppliers' websites, you can't find any 4-acyloxypyridine with unsubstituted nitrogen (even the simplest ones), which seems to suggest that these products are unsuitable for long-term storage.

I don't know what you need these substances for; however, if they are meant to be intermediates, I would suggest you to choose something more stable (and remember that if you want to improve the O/N selectivity you should aim for atoms that bind oxygen preferentially, e.g. phosphorus and silicon).