[zuriel]

Hey everyone, I'm wondering if someone here has any good synthetic advice to offer on this reaction I'm going to try. One of my colleagues in the lab has tried a few things before and they were all fruitless. The reaction itself has been reported before but one of the steps in the reaction involving the addition of the acid chloride in ether solution is problematic since the acyl chloride itself is insoluble in ether.

I've listed the three strategies that have been tried so far. I still think the Grignard route as reported by Kamenskii is the best option but the only item to address here is how to handle the acyl chloride.

Any tips/advice would be invaluable before I set out to try this! 

[kriggy]

Why not use other solvent in acyl chloride reaction?

[zuriel]

THF didn't work either. I guess you need an ether for grignard reactions too no?

Ideally I'd like to be able to use DCM and react both via a FC acylation type set-up. Not sure why it won't work.

[kriggy]

Sure but I was talking about friedel crafts. You said its not soluble in ether so why not try other solvets for this reaction? Or they dont work?

[zuriel]

The problem is the reaction didn't work at all in the case of trying it as any usual indole-3-acylation. I might re-try the acylation reaction again but I'm wondering does anyone have any suggestions as to what else might be useful to look into/ give consideration for? 

[discodermolide]

For the FC reaction try diethylaluminium chloride as the LA, as for solvent try CS₂.

[zuriel]

Thanks for the suggestion discodermolide!

I will get round to trying that soon. I need to order in diethylaluminium chloride.
What I might try in the immediate case is to use an extra equivalent of aluminium trichloride (3 eq. in total), stir this with indole first for 30 min in DCM then add a DCM soln of the freshly prepared acyl chloride and let the setup stir vigorously for 8 hours, checking by TLC every hour.

[discodermolide]

Have a look at this publication:
doi.org/10.1021/cn400035r | ACS Chem. Neurosci. 2013, 4, 1081-1092

[zuriel]

Thanks discodermolide - I've printed a copy of this article and the reference therein. Unfortunately I haven't got the di-alkyl aluminium chloride at hand at the moment so I'll need to order that in first! 

For today I'm just going to bite the bullet and try acylating using about 3 eq. of the Aluminium Chloride.

[discodermolide]

Please, let us know how you get on. Good luck

[zuriel]

So this is the general procedure I decided upon:

Indole-3-acetic acid (1 eq.) was dissolved in DCM and to this was added a very small amount of DMF and oxalyl chloride (5 eq.) – the reaction was kept under nitrogen and was allowed to proceed at 0 degC for 2 hours, after which time both the DCM and oxalyl chloride were removed under reduced pressure.

In the meantime, Indole (1 eq.) was dissolved in DCM and to this was added aluminium trichloride (2 eq). The resulting brown slurry was allowed to stir under nitrogen at 0 degC for 30 mins before a solution of the previously prepared acyl chloride (1.5 eq) was slowly added dropwise to it. The mixture went from brown to a deep black and effervescence was noted. The reaction was then allowed to stir vigorously at RT overnight before being quenched with MeOH, poured over ice, extracted with DCM and the combined DCM extracts being washed with saturated aqueous sodium bicarb, brine and dried before being concentrated to give a dark red solid.

I checked the crude product by TLC and there are two spots and then considerable streaking. Comparing the crude spot with indole and indole-3-acetic acid I can see that the top spot corresponds to indole. There's a possibility that the next spot corresponds to the indole-3-acetic acid methyl ester after the methanol quench.

I'm going to column the crude material later to isolate enough of the second spot in order to NMR it! I'll return soon with more updates