[zuriel]

Hey everyone!

I'm looking for some advice here, please. I don't want to go trying lots of stuff before hearing some pointers first! I'm trying to make 7-Azaindole-3-acetic acid. Ideally I want to end up with a benzenesulfonyl protected 7-aza-3-acetic acid but even reaching the stage where I have the acid in a nice solid form would be great.

I've attached a PNG scheme of what I'm doing at the moment. The structures I've marked in red I can make on a large scale. At the moment I'm checking out two routes to the acetic acid. I either take the glyoxylate ethyl ester through a silane reduction before hydrolysis with 4 equivalents of LiOH, or I acidify the potassium glyoxylate salt to afford the glyoxylic acid which I take through a Wolff Kishner reduction.

In both cases there's a pH adjustment necessary and, with the 7-Aza nucleus in place I need to get to a pH of about 5 in order to avoid protonation of the pyridine nitrogen.

In both cases I get a poor yield of product - and disregarding certain impurities, I can see by NMR analysis that I have formed the acid - just not in a quantity that I would have hoped for in order to bring it through to the final protection.

I'm wondering does anyone have any ideas on what other reaction routes I could try? I'm conscious about 7-azaindole not being the cheapest starting material ever and I'm also conscious of the fact that I need to have this acid on a fairly reasonable scale (3g for protection ideally).

Thanks in advance to anyone who can help and, if I manage to try any suggestions that work - I'll acknowledge the users input! 

Thanks Everyone (PS- if you need any specific details on experiments, please let me know - I tried to keep this as concise as possible).

[Babcock_Hall]

I am not following you.  In the rightmost column, you show a protonation step with HCl.  How is it that the carboxyate will become protonated but not the pyridine-like nitrogen?

[zuriel]

If you dissolve the salt in water and adjust the pH to about 5 the free acid crashes out nicely. Now, the pyridine nitrogen MAY have been protonated, but as far as the crude NMR is concerned it seems to agree with what you may expect for the acid. I haven't examined that compound fully yet, like I said, I'm open to suggestions before I examine any of those routes further. 

[kriggy]

Why dont you use just bromoacetic acid? or some derivate of it?
Please note that Im not professional nor graduate student but Im not realy sure why are you using the ester you do. I thought that the 3 position of indole is electron rich so it reacts easily with electrophiles.

[408]

Why dont you use just bromoacetic acid? or some derivate of it?
Please note that Im not professional nor graduate student but Im not realy sure why are you using the ester you do. I thought that the 3 position of indole is electron rich so it reacts easily with electrophiles.

This is what I am thinking as well.  Although a carboxylic acid will not be good with AlCl3, so something like ethylchloroacetate, AlCl3, and the heterocycle.  Or is the reason you acylate with the given reagent for specificity reasons?

[zuriel]

Indole is easily acylated at the 3 position but 7-azaindole is particularly unreactive at this position. I use a paper by Zhang et. al which details an efficient acylation method for 7-azaindole using 3-5 equivalents of aluminium trichloride and an excess of the acylating agent.

[Babcock_Hall]

The pK_a of pyruvic acid, an alpha-ketoacid, is 2.5.  If this is a good model, then at a pH of 5, it is fully ionized.  My only knowledge about substituted pyridine pK_a values comes from nicotinamide and isonicotinamide, both of which have values in the vicinity of 3.5.  But suppose your pK_a is 5 or even higher.  Then if the nitrogen protonates, one will have a zwitterion. 

[TheUnassuming]

Can you tell what the unwanted products are in your first reaction?  I'm assuming your starting materials from the first reaction are purchased?  If so, especially with something sensitive like ethyl chlorooxoacetate you might want to check to make sure its still clean and pure.  If they are still good then trying the ethylchloroacetate or other reagents is probably a good call.

[zuriel]

The only side product from the first reaction, after an aqueous work up, is the structure whereby the chlorine of the ethylchloroacetate is replaced by an OH. The other side products include aluminium salts and some starting material but these are easily separated on a column.

I'm going to actually try the acylation reaction with the ethyl bromoacetate. If I'm being honest I really never thought of using it! It certainly would be very useful if I could cut down on my number of synthetic steps.

Babcock_Hail, if I ended up with a zwitterion then what do you suggest would be the best way to isolate it in solid form?

[Babcock_Hall]

Others may have better answers than I do.  However, if it is being isolated from water, then I would try adjusting the pH to be near the isoelectric point.

My experience with nicotinic and isonicotinic acids is that they are somewhat soluble in dichloromethane but somewhat more soluble in DMF.  I am not sure whether that information will be helpful or not.

[zuriel]

It's certainly helpful! Thanks for your input.

Most journals I notice, dealing with 7-azaindole, normally adjust the pH to 5. The Wolff Kishner reduction works. After aqueous workup, I layer an organic solvent and adjust the pH to 5-7 - the only issue is the mediocre yield and the carrying over of diethylene glycol into the organic solvent.

I guess I just need the best advice on which way to go in order to make this material in a concise, reproducible manner.