[zuriel]

Hi folks,

Just starting my research PhD now and loving it so far.
Currently trying to get this reaction to work though.

I want to form the oxoacetic acid derivative of 7-azaindole. So far I know that I need to dissolve the 7-aza in diethyl ether react it with glyoxyl carbonate. It's the next part I'm having trouble with though.

Following a colleague's thesis - his method of preparation of the oxoacetic acid derivative of 7-aza with a METHYL group on the 1 position involves first forming the acid chloride of the 1-methyl-7-azaindole then removing the diethyl ether under reduced pressure - suspending the crude in acetone and adding an aqueous KOH soln. This is left stir at RT for 14 hours and then acidified to pH 2 using HCl (aq) to give the oxoacetic acid which crashes out as a white ppt.

I'm wondering should I just use a milder base in the case of 7-azaindole being my starting material? So far everything is good up until I acidify the crude mix and there's no ppt. I haven't gotten an NMR of my crude yet but I have a gut feeling it went wrong somewhere.

Any suggestions would be appreciated! Thanks!

PS- writing this in a hurry so if you have any questions/need clarifications please ask.

[discodermolide]

I'm afraid I am a little confused by your post.
What is the structure of a 1-methyl-7-azaindole acid chloride?

Anyway why should you expect a ppt, one case is the 7-methyl derivative the other  non-substituted, why would you expect them to behave the same way?

[zuriel]

Hey discodermolide, sorry I rushed my earlier post.

Attached, the structure of 1-methyl-7-azaindole oxoacetic acid.
I'm wondering, after I treat the crude acid chloride with KOH should I just bring to neutral pH as opposed to pH 2?

My colleagues acidification step in the work up threw me off a bit really. Most papers where I searched for making the acid chloride derivative of 7-azaindole involved using aluminium trichloride and/or forming ionic liquids. That's why my colleague methylated the 7-azaindole making the molecule itself more reactive thus making the format'n of the acid chloride much more versatile. 

[discodermolide]

If you hydrolyse with KOH you will get the potassium salt, therefore I would take the pH down to around 2. If there is no crystallisation then extract the product out with DCM.

[Dan]

I'd recommend starting with literature concerning C3 acylation of your starting material (not the methyl derivative).

e.g. "An Effective Procedure for the Acylation of Azaindoles at C-3" Journal of Organic Chemistry, 2002, 67, 6226-6227 Link

[OC pro]

This one worked well for me some years ago on a substituted indole compound.

http://pubs.acs.org/doi/abs/10.1021/ol005841p

[zuriel]

Thank you all very much for your advice! 
I am going to have a look at those papers now.

[zuriel]

Just one other question. I keep seeing aluminium trichloride cropping up in papers. I am trying to acylate without having to resort to using that (it's a bit messy in the lab). I noticed a paper once that quoted the preparation of the oxoacetic acid derivative of 7-azaindole by reacting 7-azaindole with oxalyl chloride in THF at RT. Can anyone see why this would have a reason NOT to work or be a viable route?

[OC pro]

Could work but you could see N-alkylation. At least you can give it a try. Seems to be simple enough. However, if handled carefully and with a good working technique AlCl3 is no prob at all. It reacts slowly with water - no hazard.

[zuriel]

Thanks for the suggestions guys! I really appreciate the help.