(Pioneer Researcher)
07-22-02 21:37
No 335851
      MDA and MDMA from CTH reductive amination
(Rated as: excellent)

After Foxy2 posted the CTH reductive amination, we started checking it. We thought about that possibility time ago, but never tried it, but in any case we didn't thought in a water:alcohol system. Our first tests, acording with TLC, where not satisfactoy, but we finally discovered that we were using little of a not very active catalyst. Then we tried it again using the best chemicals, and we found that the reaction works fine for MDA, with the only disadvantage of the use of big amounts of catalyst. I made the research with the help by a friend, it was very appreciated, all was easier.
We started our test using a 10:1 methanol:water solvent because we didn't have at that moment anhydrous chemicals, finally my friend made a test with the 9:1 system and a bigger amount of ketone and it worked similar, probably that difference is not very significant. Accidentally we found as well that ammonium acetate can substitute the ammonium formate as amino group donor, what makes possible use less formate for the reduction.

Here you are what we found in our research (all yields molar ratio):

3 gr ketone, 8.5 gr AA, 3.75 gr AF dissolved in 28 ml 1:10 solution, added 300 mg. of 10 % Pd/C stirred 48 hours (TLC showed completion, but workup was done at 96 hours), 64 %.

3 gr ketone, 9.8 gr AF in 49 ml of 1:10 solution, added 300 mg of 10 % Pd/C, stirred 48 hours, 65 %.

2 gr ketone, 6.9 gr AF in 33 ml of 1:10 solution, added 1.35 gr of 10 % Pd/C (second time used), stirred 16 hours, 81 %. (Pd/C similar to reference)

25 gr of ketone, similar proportions of the reference, full catalyst, 85 %. The higher yield could be explained by less mechanical lost of product and/or the 9:1 solvent system.

Product was checked with mp and bioassayed showing it was the racemic and desired mixture, so the good MDA.

In conclusion, the rxn works as claimed in the reference for MDP2P and probably with other interesting ketones, and yields will depend on the amount and activity of the catalyst. Probably a 20 % weight from ketone of a good catalyst is enough to get the best yields.

As you see yields are very good, and the rxn is very simple, add the ketone and ammonium formate to the solvent, and when it is all dissolved, add the catalyst. With this small amounts we didn't care about to add the catalyst wet, we added it dried at once and we hadn't any accident, but for big ammounts, it is recommendable to take all kind of precautions, but respecting the amount of solvent, we have observed that incresing de solvent volume decrease yields.
Workup was filter and add NaOH solution to release ammonia, then concentrate with the aspirator, add HCl solution, wash, basify, extract, dry and crystallize. May be we could ommit the NaOH addition, but we wanted to be sure that we didn't have ammonia salts contamination in the product.
Temperature was around 20 C, and I would say if room temp is higher, like now in summer, say around 30 C, yields could be not so good. I made a test recently at that temp and the final solution was much darker and TLC was not so good.
Carbonates of ammonia and the amine are formed, and you can see fizzing when adding the HCl solution, or a crystalline mass mixed with the catalyst in the last part of the rxn. I guess that the amine carbonate is more soluble than the ammonia bicarbonate, so may be that crystals doesn't contain amine, but it's not sure. When I observed the crystals, after filtration, I added dilute HCl to the catalyst+crystals in other flask to remove them and filterd the catalyst again adding that solution to the workup.

The chemicals were the best, ketone was 98+ % stored now 4 years in a freezer, what explain the small amounts we used, we don't want to loss that treasure. Ammonium formate, acetate and Pd/C were well branded too. This means that if you use homemade ketone, that can be from 75 to 90 %, the yield will diminish proportionally.

Ammonium formate could be easily homemade, and for this case it seems the best to generate it from aqueous ammonia over solid NaOH (or NaOH and ammonium sulfate) and bubble it into a mixture of methanol, water and formic acid till get a pH of 6-7.

When we tought time ago about a similar rxn to this one, we thought as well in making MDMA. We added a bit of aq methylamine and formic acid to methanol, and then a bit of Pd/C and we observed a clear decomposition of the formate, so we tried the rxn with aq methylamine and formic acid and TLC was very good, then we make a test with 3 gr:

3 gr of ketone, 4.4 ml of 40 % methylamine, 2.4 ml of 98 % formic acid in 30 ml of methanol, 300 mg of Pd/C stirred 48 hours, 83 %.

Yields are better that with ammonium formate using the same catalyst, but the disadvantage is now the use of more methylamine than in the other procedures, TLC tests with less methylamine were not so good. We used and exccess of formic acid to reuse the methylamine forming more reducing agent, but we don't now if it is a good solution or it affects the yields, it's a field to investigate. Unfortunately it is not a very interesting way becuase the problem of the methylamine, but I guess it could be overcome finding a good way to decarboxylate glycine.

I made this research in January, but only communicated it to a few bees, excuse me for delaying so much time these interesting results, but there were reasons to do it. Recently Rhodium sent me a review of the reference in wich they make secondary and tertiary amines using this method.

../rhodium/pdf /redamin.cth-pd.pdf

May be me and them were working at the same time in the rxn of not primary amines.

We made recently a homemade catalyst to see if it could work. We thouhgt about an OTC an easy way, first we got activated charcoal from a pet shop, it was powdered with a cofee grinder, and then purified by heating it at 80 C one hour at half with 10 % HCl, filtered and dried, then PdCl2 was diluted in a HCl solution, the purified charcoal was added and then we added grindered aluminium slowly, at 40-60 C, we used about 1 gr for 140 mg of PdCl2 but probably much less is enough, (HCl was added if not rxn). Finally it was filtered and washed extensively with water and dried. The I compared his activity with a new commercial one by adding the same amount of both catalysts in two flasks containing the same amount of diluted formate. My catalyst worked, but not so well like the other (a 50 % ?). I forgot the idea of making a comparative test with both catalysts, but after a week in wich the homemade catalyst was in an open dish in a closed armchair (exposed to air), I thought that the lack of activity could be compensated by doubling the amount of catalyst, I tested the catalysts again and my catalyst had lost a lot of activity (10 % of the other ?) so I forgot the idea.
I've made different homemade catalysts for CTH rdxns and my homemade catalyst always gave poor yields. I used formaldehyde and NaBH4, and now Al, and results seem similar. I believe now that the question is the support that has been always the same, and as you understand is very primitive. I tried pharmaceutical C from capsules, but it so thin that can't be filtered. May be that's the key, find a good activated carbon to get a enough good catalyst.

Have a nice summer.
(Hive Bee)
07-23-02 13:37
No 336110
      Wow  Bookmark   

Absolutely great work Sunlight. Just great!!laughlaughlaugh

You beat me on this one. Id scribbled something similar down on my to do-list.
I bet one can increase the yields equal to regular hydrogenation. Probably not in the case of primary amines, but almost certainly with secondary amines. If one buy the catalyst from the manufacturers directly the catalyst will have a very high activity. This is sometimes not the case when catalysts are bought from supply houses, because they can have been on the shelf for years, and the activity decreases with time.

Raney Nickel or Urushibara Nickel can also be used in this type of CTH. Aqueous enviroment does not complicate anything. Nickel catalysts will not reduce =O to -OH as can be the case with Pd.

Id also try this with Rh/C and 5%Pd/5%Rh/C.
(Pioneer Researcher)
07-23-02 18:22
No 336154
      Ni catalyst  Bookmark   

Someone with experience with Ni catalysts should try this rxn. I made a initial test by precipitating Ni from NiCl2 with aq NH3, and it didn't decompose the formate, but I've not experience with it.
(Hive Bee)
07-25-02 09:41
No 336869
      re: Catalyst  Bookmark   

  I posted info on pd/c catalysts here a few weeks ago... it appears you did not do an acid prewash on your homemade catalyst... pore size seems to be a factor as well in Pd/C catalysts

  here's the post... Post 334044 (ClearLight: "Effects of carbon activation on Pd", Methods Discourse)

Infinite Radiant Light - THKRA
(Pioneer Researcher)
07-25-02 13:27
No 336911
      I read your post  Bookmark   

And that's the reason I think now that the probelm is in the carbon. The acid wash I made is the standard I know read with HCl, not with phosphoric acid. Good info, thanks.
07-29-02 23:49
No 338662
      25 g scale-up question  Bookmark   

"25 gr of ketone, similar proportions of the reference, full catalyst, 85 %. The higher yield could be explained by less mechanical lost of product and/or the 9:1 solvent system."

This mean that you use 25 g ketone, 16.9 g 10% Pd/C, and how many mL 9:1 methanol/water? I try to read ref, but have no experience, don't know which part to take numbers from.
07-30-02 04:34
No 338752
      methanol+ Pd/C = fire  Bookmark   

Please bee careful with combining methanol and Pd/C. During filtration it will very often start burning (a big no-no with all the solvent around). Better use ethanol or add more water (?).
(Hive Bee)
08-01-02 14:35
No 339796
      Just started one  Bookmark   

I choosed 4-fluorophenylacetone as my test substrate.

100mmol (15.2g) 4-fluorophenylacetone
1mol (63g) ammonium acetate
1.5g 5%Pd/C of a really good quality, bought directly from the manufacturer.
140ml 9:1 EtOH:water

Gas evolution started within 1min after the catalyst was added. After 30min its bubbling like a newly opened soda can. Now I leave it stirring for 24h.

Youll have the results tomorrow.
(Hive Bee)
08-01-02 16:55
No 339814
      4-fluorophenylacetone  Bookmark   

Man where (general idea of course) can you get that stuff?
Sounds like it could make something very interesting.
BTW I don't think that will work, your supposed to use the formate not the acetate.
I don't think that the acetate salt will decompose to any appreciable amount of free hydrogen.
(Pioneer Researcher)
08-02-02 03:21
No 339999
      Ammonium formate  Bookmark   

Barium, it's the formate, not the acetate wich decomposes with Pd/C releasing H2, is it a mistake when writing ? You have used a 50 % of Pd metal (I used a 10 % w/w of 10 % Pd/C to get a 60+%).
(Hive Bee)
08-02-02 15:59
No 340207
      Brainfart....*proottzzz*  Bookmark   

Of course silly me meant ammonium formate...God Im stupid!!
I used ammonium formate nothing else.

I used 1.5g 5%Pd/C wich is 10%w/w to the substrate.
(Hive Bee)
08-03-02 00:33
No 340329
      Not bad  Bookmark   

The reaction was allowed to run for 28 hours. When I started workup the reaction mixture was thick from precipitated ammonium cabonate/bicarbonate. I acidified to pH 3.5 with diluted HCl then added couple of teaspoons of celite, stirred and filtered off the catalyst. Then I extracted with 2x50ml toluene basified to pH 12.5, saturated with NaCl, extracted again with 2x50ml toluene, washed the extractions with 50ml water and finally with 50ml brine. When the solvent had been dried over MgSO4 and striped in a rotovap there was roughly 8g of a slightly yellow oil which had a quite strong but oherwise typical amine smell.
50ml EtOAc was added then 5N HCl/IPA dropwise until pH 5 was reached. No crystals. Another 150ml EtOAc added and the solution was heated on a waterbath to 60 deg C. Pressure was reduced to 250 mbar and the solvent was slowly distilled off untill until there was a slight cloudiness appearing. Distillation was then stopped and the flask and contents was allowed to slowly cool to room temp. Right before it reached room temp the solution solidified in a matter of seconds. 200ml ice cold EtOAc was added and the crystals was filtered off and dried leaving 7.3g 4-fluoroamphetamine HCl as bright white crystals.

The toluene extracts from the first acid solution was dried and solvent removed leaving 6.1g 4-fluorophenylacetone.  
(Chief Bee)
08-03-02 01:48
No 340353
      You recovered the P2P?  Bookmark   

You recovered the P2P? Are you sure it wasn't reduced to the alcohol? Otherwise, it seems great! You had no problems with ammonium carbonate clogging the condenser?
(Hive Bee)
08-03-02 18:25
No 340617
      I didnt use a condenser.  Bookmark   

I didnt use a condenser. I just used a 500ml E-flask. When everything was added I flushed the flask with argon and covered it with aluminum foil. There was no ammonium salts on the sides of the flask the next day. But the solution was thick from preciptaded salts.

I steam distilled the recovered ketone and got 5.4g back with a purity of 96% by HPLC. So most of it is recoverable. Nice!
(Pioneer Researcher)
08-04-02 15:06
No 341093
      Pd/C amount and condenser  Bookmark   

Barium, if you put 15 gr of ketone and 1.5 gr of 5 % Pd/C you used a 10 % w/w of 5 % Pd/C, not 10 % Pd/C, what means half Pd metal, so in fact half catalyst, what would explain that 40 % yield instead of the 60+ % we got using a 10 % of 10 % Pd/C.
Rhodium, what I've seen is that the ammonium bicarbonate is a problem in the condenser only when refluxing, I didn't use a condenser in this rxn, only a tissue paper to isolate partially the rxn, it makes an atmosphere of ammonia and CO2 inside the flask that should be enough.
(Hive Bee)
08-04-02 16:09
No 341103
      Yes, you used approx.  Bookmark   

Yes, you used approx. 0,0014mol Pd/mol ketone and I used approx. 0,0007mol Pd/mol ketone. Im going to try some variations of this procedure, while keeping my lower catalyst loading. Im a bit conservative when it comes to that particular matter. This is probably from being spoiled by regular catalytic hydrogenations. I will also try raney nickel and a few other catalysts.

(Hive Bee)
08-05-02 11:32
No 341578
      Yes!  Bookmark   

  Raney would be very interesting, please let us know what you find out!

Infinite Radiant Light - THKRA
(Chief Bee)
08-05-02 12:12
No 341594
      Raney-Ni with hydrazine hydrate is a no-no here, ...  Bookmark   

Raney-Ni with hydrazine hydrate is a no-no here, and will just make the hydrazine analog of the amphetamine, right?

Most PEA/Amphetamine hydrazines are known MAO inhibitors, and many very toxic).
(Hive Bee)
08-05-02 13:21
No 341615
      Hydrazine?  Bookmark   

Who said anything about hydrazine? I would not use it as a hydrogen donor, ever. There are many just as good hydrogen donors but way, way less toxic and nasty.
(Chief Bee)
08-05-02 20:34
No 341735
      RaneyHydrazine  Bookmark   

I'm eager to use RaNi/N2H4 for something, as I have too much of both (the RaNi is one month past expiry date, it's an aqueous suspension)... I was just hoping anyone would say I was wrong in my guessing so that this could be a reaction where I could use it...
(Hive Bee)
08-06-02 11:41
No 342039
      Since hydrazine in precense of raney nickel would ...  Bookmark   

Since hydrazine in precense of raney nickel would be decomposed to hydrogen and ammonia. I bet it could possibly be used here too. The oldest bottle of raney nickel I still have is now four years old. Just to test the activity I used it for a reductive amination 6 months ago. It was no problem to use it.