Author Topic: The preparation of AET  (Read 3224 times)

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starlight

  • Guest
The preparation of AET
« on: June 03, 2004, 06:46:00 PM »
One of Glennon's papers suggests that AET shows stimulus generlization to MDMA in experimental animals. It was considered a worthwhile pursuit to determine whether this held true for a human subject.

1-(3-indolyl)-2-nitrobutene
85ml acetic acid, 8ml acetic anhydride, 5g ammonium acetate, 14.4g (100mmol) indole-3-carboxaldehyde and 20ml (220mmol) nitropropane were put in a 250ml erlenmeyer with condenser attached. The reaction contents were stirred and kept at 85-90°C for three hours (using an oil bath)

The heat source was removed, the flask was cooled, and 100ml of water was added. The flask was then left overnight, after which the whole lot was vacuum filtered. The solids so obtained were recrystallized twice from ~100ml EtOH to give 8.9g 1-(3-indolyl)-2-nitrobutene as shiny orange crystals (40% yield based on the indole-3-carboxaldehyde used).

1-(3-indolyl)-2-nitrobutane
8.5 g (40 mmol) 1-(3-indolyl)-2-nitrobutene was added during 30 minutes to a solution of 1.9 g (50 mmol, 1,25 mol eq.) sodium borohydride in 25 ml water and 50 ml IPA.

The reaction ran a lot slower than with a phenyl-2-nitrobutene or phenyl-2-nitropropene. It was assumed that this was due to the low solubility of the substrate in IPA/H20 (it is also pretty insoluble in toluene - a Red-Al reduction was considered but the solubility in toluene at room temp is close to zero - THF cosolvent is called for here).

After all the substrate was added, the solution was stirred for another 2 hours, by which time only a slight yellow color remained to the solution (starting material is orange).

At this point 50% acetic acid was added dropwise until the effervescence subsided. NaCl was poured in until no more dissolved and stirred vigorously for five minutes. The reaction was then vacuum filtered to remove the insolubles.

The filtrate separated into an upper yellow alcoholic layer, and a lower aqeous layer. The aqeous layer was discarded. The IPA layer was used in the next reaction. It was assumed from the color change that this stage of the reaction had worked nicely (looked like any other nitrobutene/nitropropene reduction to the nitrobutane/nitropropane).

The solution of 1-(3-indolyl)-2-nitrobutane in IPA was left overnight before conducting the next reaction.

1-(3-indolyl)-2-aminobutane
40ml of IPA was added to the IPA layer from the previous reaction. 0.6g of 10% Pd/C was added to the IPA layer and then the mixture was stirred.

In another beaker 3.6 ml of water was mixed with 13.2 g of 85% KOH. 10.8 g of 85% HCOOH was dripped in to the KOH/H2O.

The potassium formate/H2O was poured into the Nitrobutane/IPA flask and the mixture was heated to 75C while stirring. Evolution of hydrogen was noted around 40C. Throughout the course of this CTH (2.5 hours), the effervescence kept stopping and would restart on the addition of more catalyst. About 3ml of GAA were added during the course of the reaction to keep it a nice consistency. In all about 2g of 10% Pd/C were added (in the end addition of more catalyst did not cause any further hydrogen evolution and the reaction was considered to be over.

The reaction mixture was vacuum filtered and the filtercake was rinsed with a little IPA. The final filtrate was light yellow in color.

The filtrate was saturated with table salt and filtered. The lower aqeous layer/NaCL slurry was discarded and the IPA stripped at atmospheric pressure.

The result was about 9g of Orange/Brown tar which was insoluble in 5% HCl.

Something went wrong in this last reduction. Would you expect 1-(3-indolyl)-2-nitrobutanes/nitropropanes to reduce with CTH normally?

Why did the catalyst stop working and need supplementing? - is this catalyst poisoning? CTH has worked properly on phenyl-2-nitropropanes for the same research lab.

Do trypatmines have a habit of forming tar when compared to phenethylamines?

Oh, and lastly does anyone here have first hand experience of the activity of the desired product?

Rhodium

  • Guest
?-ethyl-tar
« Reply #1 on: June 03, 2004, 08:14:00 PM »
Do trypatmines have a habit of forming tar when compared to phenethylamines?

Yes, most definitely. Purification through flash chromatography (or short-path high-vac distillation) very often has to be performed to get something which can be crystallized as a salt.

Oh, and lastly does anyone here have first hand experience of the activity of the desired product?

Yes, such descriptions can be read in

None

(http://www.erowid.org/library/books_online/tihkal/tihkal11.shtml)


starlight

  • Guest
Yes, most definitely.
« Reply #2 on: June 03, 2004, 11:50:00 PM »
Yes, most definitely. Purification through flash chromatography (or short-path high-vac distillation)

Somehow I don't think that would have helped in this case. If you have a ball of brown tar that won't even partially dissolve in HCl I think the game is pretty much over really.

Thanks for the TiKAL Ref. I had looked at those, but was wondering if anybody here had first-hand experience.

Another attempt will be made.

Lilienthal

  • Guest
Maybe you have formylated your tryptamine?
« Reply #3 on: June 04, 2004, 12:22:00 AM »
Maybe you have formylated your tryptamine?

starlight

  • Guest
maybe
« Reply #4 on: June 04, 2004, 12:28:00 AM »
Unless somebody here has had good success with CTH of similar compounds, then maybe another reduction system should be tried.

Barium

  • Guest
Oh the agony
« Reply #5 on: June 04, 2004, 05:35:00 PM »
Use a metal hydride or another strong reducing agent when reducing the nitroalkane. I have had very little luck using Pd with indoles. I think it has to do with the poisoning effect of the indolic nitrogen. After all it is a secondasry amine and amines are notorious poisons for Pd. What pussles me though is that even in a strongly acidic solution the Pd is still poisoned.

Throughout the course of this CTH (2.5 hours), the effervescence kept stopping and would restart on the addition of more catalyst.

This is exactly the same pattern I have seen in most trials with all kinds of indoles. I'm leaning more towards the use of Urushibara or Raney nickel is this reduction since they are not poisoned by any amine.


starlight

  • Guest
don't try the condensation as described above
« Reply #6 on: June 16, 2004, 01:06:00 AM »
I'm afraid that it does not work as advertised.

I'm ashamed to admit it but the nitrobutene created in the reaction sequence above was not pure by any means. No TLC was performed which would have indicated as much. The correct product has since been isolated and is much closer to yellow in color.

Now, it seems that the first challenge is getting good enough yields of a pure product in the nitrobutene condensation.

First off - the above experimental states that the reflux time is 3 hours. This is a mistake, it should say 6 hours. Even after 6 hours there is loads of unreacted aldehyde left with the above reagent ratios.

A similar trial was conducted with methylamine acetate in IPA. After 6 hours all of the initial aldehyde was gone and some product was formed, but a load of dark polymeric crap as well (reaction temperature ~80c).

Next trial will be with methylamine acetate and a lower temperature/shorter time. When a replicable method with a decent yield has been found it will be posted.

kjb1891

  • Guest
AET, AMT, etc
« Reply #7 on: June 17, 2004, 08:17:00 PM »
I have a question regarding a possibly easy synth for AET. Here's Hest's microwave synth for AMT:

500mg indole-3-carboxaldehyde was mixed with 1g nitroethane and 50mg amm.acetate. The mixture was nuked with 150W for 2min, and then rextalised from methanol.
Yeald: >90%

Do you think using the same process but using nitropropane instead of nitroethane might result in AET rather than AMT? What would you come up with if you used nitrobutane or nitromethane?

starlight

  • Guest
the reaction will work
« Reply #8 on: June 18, 2004, 05:29:00 PM »
The reaction you are suggesting with nitropropane will work, although yields are likely to be significantly lower than with nitroethane.

A recent trial using 20mmol methlyamine acetate in 50ml of IPA with 100mmol Indole-3-carboxaldehyde and 110mmol nitropropane held at 55-56C for 7 hours seems to have worked a treat (full writeup to follow when yields have been measured). Recrystallization from 40% EtOH works really well.

Nitromethane would make tryptamine. Nitrobutane is probably not worth worrying about as the chain will be too long to work well probably.

starlight

  • Guest
Satisfactory condensation method
« Reply #9 on: June 22, 2004, 04:29:00 PM »
Well, the yields aren't stellar, but this does work to create a pure product:

Preparing Methylamine Acetate in IPA
2.63g (40mmol) 85% KOH was dissolved in 50ml Hot IPA. To this was added 2.3ml GAA. 2.72g (40mmol) of MeAm.HCL (40mmol) was dissolved in 60ml Hot IPA. The two hot solutions were mixed in a cold flask and allowed to cool. A voluminous precipitate of KCL formed that was vacuum filtered off.

1-(3-indolyl)-2-nitrobutene
55ml of the methylamine acetate in IPA solution made above was put in a 250ml erlenmeyer flask with 14.4g (100mmol) Indole-3-carboxaldehyde and 9.9ml (110mmol) 1-Nitropropane. A condenser was attached to the flask and the stirred mixture was heated on a waterbath at 55-56C for 7 hours.

The flask was removed from the condenser and the reaction contents filtered. The filter retained a yellow powder, and the filtrate was an orange liquid. Cold distilled water was added to the orange liquid, which caused the separation of a red oil. This oil crystallized overnight to give dirty orange crystals.

The light yellow powder retained in the filter above was recrystallized from 40% EtOH to give 4g of bright, shiny orange crystals that were vacuum filtered off (indistinguishable in color and form from 1-(2,5-DimethoxyPhenyl)-2-nitropropene). Cold distilled water was added to the mother liquor which resulted in the precipitation of bright yellow, fluffy crystals. These were saved for the moment.

The dirty orange crystals that resulted from the crystallization of the red oil above were recrystallized three times from 50% IPA. This recrystallization is somewhat tricky. It is necessary to heat the solvent to 55-60C in order to dissolve the nitrobutene, but not hot enough to dissolve the impurities (orange/brown colored crystalline impurities). The solvent then needs to be vacuum filtered whilst hot and crystals allowed to form. After the third recrystallization, these crystals will be bright yellow and fluffy like the ones described above.

Both sets of bright yellow fluffy crystals are then recrystallized from 40% EtOH to give 3g pumpkin orange, needle-like crystals like those described above.

Total yield - 7g or 33%

starlight

  • Guest
Sensitive molecule - beware
« Reply #10 on: June 24, 2004, 04:37:00 PM »
7 g (34 mmol) 1-(3-indolyl)-2-nitrobutene was added during 25 minutes to a solution of 1.6 g (42.5 mmol, 1,25 mol eq.) sodium borohydride in 17.5 ml water and 35 ml IPA.

After all the substrate was added, the solution was stirred for another 2 hours, by which time only a slight yellow color remained to the solution (starting material is pumpkin orange).

At this point 50% acetic acid was added dropwise until the effervescence subsided. NaCl was poured in until no more dissolved and stirred vigorously for five minutes. The reaction was then vacuum filtered to remove the insolubles.

The filtrate separated into an upper yellow alcoholic layer, and a lower aqeous layer. The aqeous layer was discarded. The IPA layer was added to 150ml of cold distilled water. The mixture so formed was white, opaque with no visible crystals. This mixture was extracted with 2x30ml of toluene (the toluene took on a yellow color). The toluene containing the suspected product was washed once with water and once with brine, dried with MgSO4, and then the toluene was removed at rotovap. This left ~1g of a brown oil that still smelt of toluene. This crystallized on cooling to form tan crystals in a brown liquid. The crystals were filtered off and weighed 0.3g

Most of the product was still obviously in the aqueous layer (held there by IPA/traces of toluene - should have used brine for the separation!). Another 400ml of cold distilled water was added to the still white aqueous layer and it was left overnight. In the morning, the precipitate was vacuum filtered from the now clear solution to yield a further 5.3g of cream/tan colored crystals. The filtrate was now discarded.

In total 5.6g crude 1-(3-indolyl)-2-nitrobutane were recovered which means a yield of ~78%.

The next day it was attempted to dissolve this nitrobutane in around 150ml of toluene. Most of it dissolved (not all), but the solution was a bit brown in color to indicate a pure product. Recrystallization was decided upon. unfortunately the process of rotovapping the toluene off with a bath temperature of 66C caused the toluene solution to turn a deep red color (decomposition). Petroleum ether was added to the toluene solution, and this caused about 3.5g of a brown substance to fall out of solution (the decomposed intermediate). The solution was now a yellow color.

So the moral of this story is: don't heat a toluene solution of 1-(3-indolyl)-2-nitrobutane otherwise it will decompose and ruin your intermediate.

The yellow petroleum ether/toluene solution may be usable or may not be. When the research lab reports back I will post further results.

starlight

  • Guest
given up for the time being
« Reply #11 on: June 24, 2004, 07:36:00 PM »
Well, all the carboxaldehyde / nitrobutene / nitrobutane is gone as is many, many hours of messing about.

I think it's time to call this one a day and move onto something easier for a few weeks until the appetite for the challenge has returned.

SWIM is sick of the smell of indoles!!

indole_amine

  • Guest
maybe this helps
« Reply #12 on: September 26, 2004, 09:24:00 AM »
In this paper, they reduce indolyl-nitroalkanes with nickel boride/hydrazine hydrate, rather than Pd/C.

And they prepare their intermediate nitro compound via a method similar to the one Starlight used - but deprotonate the nitroalkane beforehand, and thus get the indolylnitroalkane directly without having to reduce anything with NaBH4...



(abstract and title are mentioned here:

Post 448477

(hest: "AMT in the MW oven", Tryptamine Chemistry)
)


indole_amine