[darkdevil]

Hi,,
I am working on the alkylation of indigo recently. I performed the below reaction:

but I dont get any of my desired product. The mixture did not seem to react. I think it is because of the poor solubility of indigo. I tried to increase the temperature to reflux condition, but then the next morning I obtained a slurry of brown substance that I cannot do any extraction

I suppose the product is a red compound. I tried to react just indigo and the bromodecane (excess) in a sealed container and heated it up to around 200oC. The mixture then turned purple and then red. But when I open the contained, it tured back to the blue indigo slurry. How can I stabilize the red compound??

Thankss

[Archer]

Are you monitoring the reaction with TLC or GCMS?

You could try KOH in DMF or DMSO at room temperature, if this does not work then try heating slowly. You may find your substrate disolves better in these two solvents and KOH is a stronger base.

[darkdevil]

Are you monitoring the reaction with TLC or GCMS?

You could try KOH in DMF or DMSO at room temperature, if this does not work then try heating slowly. You may find your substrate disolves better in these two solvents and KOH is a stronger base.

Hi , Thanks
I tried anhydrous THF and KOtBu with indigo. I can see color change from blue to green that is supposed to be the deprotonation of indigo. I then added alkyl halide, but it seems the reaction does not proceed. If I add an acyl halide in this step I can get the N-acylated indigo cleanly.

[Archer]

Acyl chlorides are always going to be more reactive than alkyl halides so this is not a surprise.

Have you tried a better leaving group, an alkyl iodide for example?

Also with the DMF solvent are you heating this or just letting it stir at room temperature?

[darkdevil]

Acyl chlorides are always going to be more reactive than alkyl halides so this is not a surprise.

Have you tried a better leaving group, an alkyl iodide for example?

Also with the DMF solvent are you heating this or just letting it stir at room temperature?

I havent tried DMF with KOH yet. But I remember I tried DMF and NaOtBu, and it gelled once I added indigo to the mixture. I did not heat it up then.

[Archer]

Sorry, I misread THF as DMF.

Did you apply heat to the reaction in THF?

[darkdevil]

yes i did.  but the reaction doesnt seem to proceed.  i will try to use diglyme as solvent later,  or use an alkyl iodide instead of bromide.
still not sure if temperature or leaving group effect is more dominant to the reaction rate.

[darkdevil]

It seems the reaction works with diglyme solvent
I obtaied an orange red spot at the bottom of TLC plate with eluent hexane:EA=4:1. Since I used an excess of the alkyl bromide. I guess I made a quaternary amine salt that as the orange spot. The organe material dissolves well in water and methanol. I am not going to purify it, instead I started another reaction with idigo : alkyl bromide in exactly 1:2 molar ratios. Let's see if I can get my N-N' diamine indigo.
Will keep this updated.

[darkdevil]

I obtained the same orange material when I used idigo : alkyl bromide 1:2 molar ratios. fo the reaction. The material is water soluble. and insoluble in organic solvents like DCM. I wonder if this is really a quaternary amine salt? I assumed when the first decyl group is added to the secondary amine on indigo, the N atom becomes more nucleophilic. It then attacks another decyl bromide to give an organic insoluble quaternary amine salt. By then, even I used indigo : alkyl bromide 1:2. The final product is still a quaternary amine salt!

Can anyone give me suggestions how can I obtain my desired product?? Thank you so much!

[darkdevil]

Finally, I obtained a monoalkylated product using 2.5 equivalents of alkyl bromide to 1 equivalent of indigo.



But the yield is very low. The choice of solvent is important for this kind of reaction. I am now using 6 equivalents of alkyl bromide, hoping to obtain a bis-alkylated product. Anything I can do to get a higher yield?

[magician4]

in my opinion, your problem results of the fact that you have a case of "vinyloge amide" here:
-NH-C(R)=C(R)-(C=O)-

hence , the -NH- doesn't show that much of amine properties anymore, and therefore the (successfull) reaction with the acylhalide might be understood as a case of imide-formation (which is known to work well with amide/acylhalide combos)

Finally, I obtained a monoalkylated product using 2.5 equivalents of alkyl bromide to 1 equivalent of indigo.

I take it that you checked for the position of the alkylation very thoroughly ? because under the conditions you described , alot more might happen with this system than just N-alkylation...

Anything I can do to get a higher yield?

if my initial analysis was right, this paper (and the "classic methods" referred to therein, too) might be of use for you:
http://www.mdpi.com/1420-3049/4/11/333/pdf


good luck

Ingo

[clarkstill]

A reaxys search reveals only two examples ever of the N-alkylation of indigo dye, which doesn't bode well...

One uses phase-transfer catalysis (NBu4I, aq. NaOH, in benzene) and iodomethane, and the other uses NaH, DMSO.

There are, however, many more examples of acylation, typically with the acid chloride and a pyridine buffer.  Could you take this route, then try to reduce out the carbonyls afterwards?  Maybe some chemoselectivity issues...

[408]

I would not be using KOtBu there.  The acidity of that NH is going to be real low thanks to the H-bond with the carbonyl, meaning at all times the equilibrium will likely favour OtBu- and not indigo-.  So you want to deprotonate it in a way where reverse reaction is not possible.  NaH.  Maybe stoich, maybe slight excess, you will want to experiment.  I like the use of DMSO as well like the paper clarkstill mentioned.  I also would want to use a system where the resultant sodium halide is insoluble for forcing the equilibrium further, so I would use alkyl chloride with a bit of KI added.  Alkyl bromide may work too, but I forget the solubility of NaBr in DMSO.

[darkdevil]

I still could not obtain a higher yield if I changed the alkyl bromide to 6 mole eqvs. using indigo,DMF,and K2CO3 at 160oC

for the vinylogous amide problem... is there a way to make the amine more nucleophilic?? Indigo can be reduced to its leuco form. but it is water soluble and extremely unstable to open atomosphere. The leuco form quickly turns back to indigo when exposed to air.

I wonder if I can perform a two phase reaction while first reduce indigo in water and then add maybe benzene together with alkyl bromide to the aqueous solution? is this possible? and is it a must to use PTC in this kind of reaction?

Another approach is to reduce my N-N' diacylated indigo to tertiary amine 408 suggested. But I havnt done amide reduction before and I am not sure what conditions shall I  use to reduce the amide carbonyl but not the keto group.

Getting frustrated :O

[darkdevil]

in my opinion, your problem results of the fact that you have a case of "vinyloge amide" here:
-NH-C(R)=C(R)-(C=O)-

hence , the -NH- doesn't show that much of amine properties anymore, and therefore the (successfull) reaction with the acylhalide might be understood as a case of imide-formation (which is known to work well with amide/acylhalide combos)

Finally, I obtained a monoalkylated product using 2.5 equivalents of alkyl bromide to 1 equivalent of indigo.

I take it that you checked for the position of the alkylation very thoroughly ? because under the conditions you described , alot more might happen with this system than just N-alkylation...

Anything I can do to get a higher yield?

if my initial analysis was right, this paper (and the "classic methods" referred to therein, too) might be of use for you:
http://www.mdpi.com/1420-3049/4/11/333/pdf


good luck

Ingo

If the successful reaction of indigo with the acylhalide is due to the imide-formation (I assume the gaining of resonance stability), then I would expect the N-arylation of indigo would also be successful?