Hi Bees!

Recently my buddy (called SWIA for simplicity) decided to do a CTH reductive amination with ammonium formate, like posted by

Post 335851

(Sunlight: "MDA and MDMA from CTH reductive amination", Novel Discourse)- but as he hadn't other ketones to work with at the moment, he tried it on plain P2P (which was of course homemade, but vac distilled and rather pure), and got decent yields...

Said shortly: CTH reductive amination of 75mmol P2P in 165 ml MeOH/water 9:1 solvent using 36g ammonium formate and 5g Pd/C 10% and 13 hours reaction time yielded ~8.2g amphetamine freebase (molar 80% yield)


Here is what he did:

First, 165ml of 9:1 methanol/water solution were prepared (10% H2O). This was put in a 300ml Erlenmayer together with 36 grams ammonium formate, 10.2ml P2P (which he had put out of the fridge 1 hour ago to warm it to 20°C - density of P2P is 1.0144 g/cm³ at 20°C) and a medium sized stirbar.
This was stirred ~10 minutes at 30°C, until almost all of the salt had dissolved. Then, 4.9 grams of 10% Pd/C were added (before addition SWIA made sure there wasn't much gaseous MeOH in the flask, because he was paranoid about autoignition of >150ml warm methanol   ) and the mixture was stirred violently for a few seconds to mix it thoroughly. The erlenmayer was then plugged with a tissue paper and rxn was stirred for 13 hours at room temp.
After this time, the rxn had become a viscous mud of carbonates, Pd/C and solvent (with a stinging ammonia odor   ).


Now the workup (it surely can be shortened):

First, SWIA added diluted HCl to the rxn (lots of CO₂) until acidic. Then, he vacuum filtered the mixture twice through same filtercake (second time it came through crystal clear) and washed the filtercake three times each with methanol and dil. HCl. The solution+washings were then basified with NaOH(s) and methanol and ammonia were removed by distillation under reduced pressure. After ~40% of the solution had distilled over, SWIA disconnected vacuum, checked the smell of distillation flask and couldn't detect any ammoniacal smell anymore, so he acidified again with HCl and continued distillation (later he neutralized the first ammoniacal fraction with HCOOH and removed the MeOH by distillation, and tiny droplets appeared in the residual water/ammoniumformate mix - probably the unreacted ketone). When residual soln. became slightly milky (lots of salt in there), he stopped distilling.
Everything was cooled, and there were not even traces of unreacted ketone visible, so aequ. NaOH was added until pH 12 was reached - no extraction of acidic soln. was done before. At this point, a slightly pink coloration of the aequous phase was noticed.
When having basified, SWIA extracted with 100, 75 and finally 50ml toluene and gave the last xtraction one night time for separation. The combined toluene extracts were washed with brine, then water, then dried over Na₂SO₄ and the toluene was removed on a water bath under hard vac to yield 9.1ml of a yellow oil, which was dissolved in 40ml dry iPrOH, acidified with ethanolic H2SO4 and the resulting amorph crystals precipitated with dry acetone.
After cooling the mother liquor to below 0°C, the slurry was vacuum filtered, crystals washed with more dry acetone and dried in a dessicator at 50°C to yield 10.9 grams of slightly pink amphetamine sulfate (the pink color is probably amphetamine-p2p-imine. Or maybe just traces of ketone being fucked up by the anhydrous sulfuric, becoming reddish?)


I conclusion I would say, the CTH procedure described by Sunlight works equally good with plain phenylacetone, at least with amm.formate as hydrogen/ammonia donor. Maybe the catalyst load used is an excess (50% w/w catalyst/ketone??), but I'm sure that with lower catalyst amounts (30% w/w) and longer rxn times (like described by Sunlight) it will work equally well. SWIA's catalyst wasn't the best (reused 1x), but still pretty reactive, and gas evolution (which if it ceases is a nice indicator for the end of reduction, too) started 2-3 minutes after addition of Pd/C..

Greetz A

This is from "Mann, Frederic George - Practical Organic Chemistry" page 361:

Section 13. Ketones. C:0. (cf. Tables IX, X, 541-542)

Acetone, ethyl methyl ketone, diethyl ketone; acetonphenone, benzophenone (and their nuclear-substituted derivatives). Cyclohexanone.

Physical properties: (...insignificant...)

GENERAL REACTIONS.

1. Alipathic ketones containing the CH₃CO- group restore the colour very slowly to Schiff's reagent:
    other ketones have no reaction.
2. Form phenylhydrazones, 2,4-dinitrophenylhydrazones and semicarbazides. (Many oximes are too
    soluble for ready isolation.)
3. Ketones containing the CH₃CO- group give the iodoform reaction. (For other compounds which
    give this test, see p. 91.)
4. Ketones containing the CH₃CO- group give
   (a) a red coloration with alkaline sodium nitroprusside
   (b) a violet coloration with m-dinitrobenzene and sodium hydroxide
5. Certain ketones give bisulphite addition compounds.
6. Do not reduce ammoniacal AgNO₃ or Fehling's solution (distinction from aldehydes)."


Well I don't know what made the unreacted ketone turn violet/pink after H₂SO₄ addition, but it's an explanation for the pink aequous phase after basifying with NaOH...
(and I think the ketone is responsible for the coloration of the final sulphate salt, too...)

Or maybe the acetone is involved in some way, too?

Greetz A

Hi Bees!

This time my friend SWIA wanted to check if other alcohols could be substituted for methanol. He decided to use exactly the solvent proportions given in the original paper that Sunlight discovered time ago (

"A modified palladium catalysed reductive amination procedure"

(https://www.thevespiary.org/rhodium/Rhodium/pdf/redamin.cth-pd.pdf)).
The proportions used are 9:1 MeOH/H2O solvent system, 10x molar excess NH₄COOH to ketone - but SWIA wanted to change something, so he tried using EtOH (denatured with 1% pthalic acid diethyl ester) as alcohol, and this time he tried it with a catalyst load of 30% w/w...

First, 49mmol P2P (6.5ml; prewarmed to room temp.) were dissolved in 128ml den.EtOH. Then were added 14.3ml H₂O and 28.7g ammonium formate and the mixture was stirred at 30°C for about 10 minutes (until almost all salt had dissolved). Next, 1.8g 10% Pd/C were added (reused for the ?th time, but thoroughly cleaned and reactivated by boiling it in dil.HCl, then aequ.NaOH, then MeOH, washed with H2O to neutrality and air dried at 50°C) and everything was stirred at maximum RPM for a few seconds. Gas evolution started IMMEDIATELY, so the flask was plugged with tissue paper and left to stir at low speed. After 2.5 hours, carbonates became visible...

That's all he told me so far, will ask SWIA about his results and post them as soon as I happen to see him...

Greetz A

I only applied tha scientific paper that was posted here in the Hive, and it's in Rhodium's page. Your finding is excellent becuase it verifies that this procedure will work more or less the same with the most interesting ketones, and opens and easy way to get compounds such as TMA2 from corresponding ketones.

Hi!

Yes sunlight, that's a nice aspect of this CTH...  

But SWIA told me that after 7 hours rxn time with EtOH:H20 solvent the rxn mixture had become too viscous to continue stirring (at least too viscous to stir without splattering everything up the sidewalls of the flask) - and after having spilled a good part of product (be careful with adding dil. HCl to carbonates/catalyst, CO2 evolution can be very vigorous!   ) the yield amounted to 2 grams freebase (very pure this time, almost colorless), giving 2.5 grams of the sulfate salt (30% yield)...

I think the formed carbonates/bicarbonates are less soluble in ethanol, and therefore it is no suitable solvent in this case.

Interesting was the fact that SWIA tried to keep everything "as aequous as possible" during workup (less NaOH, less HCl - less salt) and used a bit more water - and guess what, after removal of ammonia and while reducing the volume of the now acidified soln. the remaining ketone simply steam distilled over - under vacuum...

(at least he concentrated everything until no more oily drops came over, and upon extracting the acidic residue absolutely NOTHING was recovered)

So: use methanol, and after basifying (and removal of ammonia by distillation) acidify and steam distill to recover ketone...

Greetz A

IMHO the best work up is to add water to dissolve the most bicarbonates presents in the flask, then filter and wash the Pd/C with methanol and water (and then with NaOH solution and water), then concentrate the solution, add water and HCl and wash, basify and extract to crystallize.
If the pH goes too acidic or too basic in the extractions sometimes a white polymer is formed that need filtration.
Acidifying before concentration gives a dark solution, but concentrating it as it is, just with water removes ammonia and CO2, so there's not evolution of CO2 when adding HCl to wash. It's more clean.

Well this kind of workup sounds alot easier! But isn't amphetamine volatile with steam? I would guess that if the distillation is stopped at the right point, only CO2 and NH3 would come over (giving LOADS of ammonium carbonate in the condenser ) - but how determine the right time to stop concentrating? I am afraid that a small amount of amine freebase could be steam distilled!? (maybe not with higher substituted amphs, but in this case)

The polymer is not nice if it happens, but only forms above pH 13 (I think), so basifying to pH 11-12 is the solution..

SWIA tells me he got very clean amine with concentrating while acidic, too - maybe dark coloration is more a problem with higher substituted amines (I would guess).

Greetz A

Evaporation is made with the help of vaccum, with an aspirator, so NH3 and CO2 goes through the drain. Concentration is enough when you see a milky colour in the solution, even drops of oil, it means that there's not enough methanol to keep in solution the organics, the main part is water. Then is enough to add water and acidify, wash, then basify and extract.

Hi!

Sunlight: Seems like SWIA will have to clean his aspirator from his thick dust layer (he HATES that thing - but your workup is just less time-consuming)...

Perhaps Sunlight and I am not the only bees posting in this thread *lol*    - it would be very nice if some other bee would try this procedure on, let's say, asarone ketone (or any other propiophenone besides MDP2P and P2P)?

This would be VERY interesting! And I see no reason why 2,4,5-triMeO-P2P should not work as good as the tested ones...

Greetz A

Hi bees!

SWIA told me that adding a bit formic 99% mostly solved the carbonate problem for him. Perhaps one could use a bit less water if this is done, helping imine formation (just an idea).

Or what about forming the imine under anhydrous conditions with ammonium acetate, then add formic acid/water and do a cth?

C'mon, I want to see reports on TMA-2 made via this CTH...  

Greetz A

Water is necessary in this rdxn, it doesn't work if it is not present. It is probably because the rdxn doesn't take place from the imine, but from teh previous intermediate hemiaminal. Read the scientific paper in Rhodium's page.
I tried it with a mixture of ammonium acetate for amination and ammonium formate as hydrogen donor for the CTH, and it works too with may be a little less yields.

Hi!

In case you read my above post trying to explain the pink coloration of the salt obtained from this CTH - forget it, I think here lies the truth:

https://www.thevespiary.org/rhodium/Rhodium/pdf/forensic/amph.impurities-7.pdf

...will do a bit research to find out if the imine impurities analyzed in above article are responsible for the color - did I mention that the impurities also have a really nice odor, resembling that of strawberries?  

Sunlight: OK so forming the imine first is out - thought it could be of advantage, but apparently you also thought that once...

A

When doing bigger batches it is advised to boil the used catalyst (after CTH) in dil.HCl/IPA for ~45 minutes - the solution after filtering off the Pd/C has a deep reddish color, it appears that something similar to leuckart hydrolysis happens (maybe there are formylamphetamine/Pd complexes formed during CTH reductive aminations, dunno).

Basifying/extracting should show what causes the coloration, and even if neither ketone nor amine are isolated - hey, your catalyst is a *LOT* cleaner than before...

Greetz A