TMA-2 by low-pressure catalytic hydrogenation.

[Barium]

100mmol (25.3g) 1-(2,4,5-trimethoxyphenyl)-2-nitropropene, 100ml 99% EtOH, 200mmol AcOH (roughly 12ml) and 760mg 5%Pd/C (3%w/w) was added to a 300ml hydrogenation flask [Note 1]. The vessel was closed and pressurised with argon to three bar 4 times followed by pressurisation with hydrogen to 1 bar and stirring started. The stirring speed was 1500 rpm and the temperature was 19 deg C. Within 2 minutes the hydrogen consumption started and within 20 minutes the temperature rose to 41 deg C and after 1 hour it was 54 deg C. At the two hour point the hydrogen consumption had almost ceased but it was allowed to stir for another hour.

When the reaction was over the vessel was purged with argon (3 times three bar) and then opened. Two teaspoons celite was added and the catalyst was removed by filtration. The filtrate was almost colorless (just a very slight yellow color). The solvents was removed by distillation in a rotovap leaving a light yellow solid cake of  1-(2,4,5-trimethoxyphenyl)-2-propanone oxime weighing 23.2g (97% yield).

23.2g 2,4,5-TMP2P oxime, 100ml 99% EtOH and 4.5g Raney-nickel [Note 2], roughly one and a half teaspoon water wet catalyst (20% w/w catalyst to substrate) was added to a 300ml hydrogenation vessel. The same purging procedure was performed and the vessel was finally pressurised with 1 bar hydrogen. Stirring was started at a rate of 1500 rpm and the temperature was 20 deg C. Within 4 hours the hydrogen consumption had ceased. The temperature never rose above 29 deg C. The vessel was again purged with argon three times and then opened. Three teaspoons celite was added to the reaction mixture and the catalyst was filtered off and rinsed twice with 25 ml EtOH, care being taken that the catalyst never became dry.

The ethanolic solution of the amine was acidified with conc HCl to pH 5.5 and the solvent removed by distillation in a rotovap. To the residue was added 100ml EtOAC and the solvent removed by distillation at  200 mbar. To the residue was added 300ml EtOAc/IPA (70/30). The solution was heated to a gentle boiling and 200 mbar vaccum applied to remove 100 ml solvent. The solution was then allowed to slowly come to room temperature at ampspheric pressure while scratching the walls with a glass rod now and then. Within one hour the solution was a very thick paste of crystals. These was reomoved by filtration, washed once with 100ml dry EtOAc and dried to constant weight.

Yield 24.5g TMA-2 HCl (94% overall yield)

Note 1.
The order of addition should be as follow. Add the dry catalyst first, then the dry substrate and make sure the substrate really covers all the catalyst. Then add the acetic acid followed by the ethanol. By doing it this way there is no need to use an inert atmosphere to avoid ignition since the catalyst is covered by the substrate then wetted by a huge amount of ethanol.

Note 2.
Nickel is chosen over Pd here because if Pd is used, about three moles acid/mol oxime has to be used to minimize side reactions like imine and/or hydroxylamine formation. This can damage the TMA-2 molecule if a strong acid such as sulphuric acid is chosen. With Raney-nickel the acid is not necessary. Furthermore, Pd can be poisoned by amines whereas Ni can´t.

[Ritter]

Much appreciated Barium.  On a side note, the alkene will also reduce nearly quantitatively when using straight ethyl acetate solvent(no added acid necessary) and Pd/C.

What grade of Raney Ni was used and was it a commercial product or made from the alloy?

Do you have any thoughts on a homogenous reduction of the oxime?  The catalysts are very exotic but the danger of pyrophoric nickel is avoided (someone here hates to have to deal with burning nickel ).  Also, Pt black never produces a yield greater than 70% with these types of compounds(solvent: ethanol/HOAc/HCl)

Fantastic job Barium---keep 'um coming!!!!

[Barium]

Hi Ritter

The Raney-nickel was made from the alloy the same day. The temperature of the digestion was never allowed to rise above 60 deg C. This gives in my experience the best activity for low pressure reductions. The ratio of NaOH/Al was 2.5/1

I´ve never done any homogenous catalyst reductions from alkene to oxime or oxime to amine. But what I´ve tried, and this is very interesting, is a reduction of 1-(2,4-dimethoxyphenyl)-2-nitropropene with 5%Pd/C and only water as solvent. At 3 bar H2 and 10 deg C, this gave within 4 hours a mixture of roughly 40% nitroalkane, 55% ketoxime and 5% ketone. The catalyst loading was 5% w/w. I´m curious to see what happens if MeOH, acetone or EtOAc are used as solvents and the temperature is lowered even more. It should be less hydrolysis of the ketoxime at least. But the really interesting part is what happens with the nitroalkane/oxime ratio. This will of course also be tested with some beta-nitrostyrenes.

[Ritter]

I´m curious to see what happens if MeOH, acetone or EtOAc are used as solvents and the temperature is lowered even more.

From experience, a nearly quantitative yield of oxime will result with some traces of ketone.

[ChambeRed]

Great work barium,this is the kind of work that attracted me to the hive in the first place,thanks for your hard work!.Swim isn't equipped to perform pressure reactions but bee assured that this post has been bookmarked and the day will come many hardworking moons from now that swim will dig up this post and dream. barium a true soilder.
Bee's don't die,we just multiply.

[Ritter]

Hi Barium,

I'm familiar with most techniques for generating active Raney Ni from the alloy, however I have found that the sundry preparations in the literature have their own individual caveats.  Many refs make it sound like such a fickle process that the slightest mistake will result in an inactive catalyst.

Would you be so kind as to provide us with a detailed writeup on exactly how the active nickle used in your experiments was generated--it will be so nice to have a tried-and-true procedure in our archives!!!!! 

Thanks again Ba!!!!!!

[Barium]

Ritter Sir, your wish is my command  

Preparation of Raney-nickel

Dissolve 37g NaOH in 250ml water in a 500ml flask and cool it down to room temperature. Place this flask in a cooling bath and with good stirring add 20g powdered 50/50 Ni/Al alloy in portions of 1-2g. Do not add this alloy too quick or it will boil over due to heavy gas evolution. Keep the temperature of the reaction between 50-55 deg C by heating or cooling the reaction flask as necessary. When all the alloy has been added apply constant heating at 50 deg C for another hour with gentle stirring. Decant off most of the the liquid and add 250ml water and stir for a couple of minutes, decant and repeat 15-20 times. When the pH of the water is 8-8.5 the washing is completed. Transfer the catalyst to a flask and keep it covered with water. It remains very active for about one week. The activity then drops over time. Freshly prepared it contains about 100ml H2/g catalyst. 

Catalytic hydrogenation freak

[madprosr]

swim has UTFSE to no avail.
he pulls beta-asarone at 180C with his shitty compressor. might it suffice for ketone?
maybe with TFE paste instead of tape on the joints...
he would like to apply the o2 wacker due to its simplicity (and rumored 66% theoretical).
but what will happen if ketone with tmp1p contamination is reacted with hydroxylamine?
what about in the leukart or raney-nickel reductions?
anybody successfully recrystallize the ketone or ketoxime? RC, you've wacked it...
anybody attempt the NaI complex yet???
hopefully someday swim will have data for the bees. lovin' you barium. tma-2 is dandy?
"one way or another, sooner or later, this darkness has got to give"

[Rhodium]

According to my references, 2,4,5-trimethoxyphenyl-2-propanone can be distilled at 174°C/15 mmHg, or 115-120°C/0.5mmHg. It's mp is 44-46°C.

If your vacuum can pull asarone over at 180°C, it gives you a shittier vacuum than an aspirator... I don't think all of your ketone will distill unharmed through there (I guess your bp will be ~200°C), so expect a loss of 25-50%. The boiling point of asarone ketone at standard pressure is 290°C (and gives a very low yield) according to uemura.

Please try the asarone wacker, recrystallization of the oxime should remove TMP1P contamination.

[madprosr]

Using plumbing TFE paste to seal the joints, the pump now pulls water at 36C!
Much better than the PTFE tape. Maybee now distilling tmp2p is a possibility. Will distil asarone again soon. Bad news, previously water-white distilled asarone turned yellow after just 4 days in the fridge. Glassware was thoroughly cleaned too.    

what solvent is reccommended for asarone ketoxime recrystallization?
hexane, toluene, IPA, IPA/EtOAc? must IPA be dry?

swim is presently better able to acquire the chems for peracetic oxidation followed by the leukart. Unfortunately H2SO4 is all he has for glycol/epoxide rearrangement. No-one has posted yields yet for this method? Maybe he can find LiI or MgBr2 yet...

[catastrophe]

Barium, in your first hydrogenation, why is the nitropropene not reduced to the amine in the first place? SWIM noticed you used a smaller amount of catalyst, and no strong acid to prevent a Micheal addition.
Perhaps Adam's catalyst would be a better choice.

[Barium]

IPA is a good solvent for asarone ketoxime recrystallization. Just follow the directions given by MadMax.
Catalytic hydrogenation freak

[Barium]

A nitropropene will never give yields of amine like this if you shoot directly for the amine. Well, actually there are methods, but you would need very ugly reaction conditions. You do not want to play with those, believe me. So instead I gave you this method which give very good yields and only calls for super-easy conditions.

You can try adding a strong acid and Adams catalyst, but you won´t get anything but the oxime anyway. There Michael´s addition is not a problem since the C=C doublebond isn´t attacked. But hey, feel free to improve it. I´d be the first one to cheer you  
Catalytic hydrogenation freak

[catastrophe]

Hydrogenation of Oximes
-----------------------
Hydrogenation of oximes can give rise to primary, secondary or tertiary amines, hydroxylamines or imines. Acetylation of the oxime facilitates hydrogenation. Rhodium is the preferred catalytic metal for formation of primary amines, generally resulting in substantially less secondary amine product than palladium. Platinum or palladium is generally preferred for partial hydrogenation of oximes to hydroxylamines or imines. Formed imines are rarely isolated.

Reduction of oximes occurs under mild reaction conditions with platinum group metal catalysts (5 to 100ºC, 1 to 10 atmospheres H2 pressure). Acidic solvents or solvent systems are recommended to minimize reaction rate inhibition caused by the amine product(s). Primary amine formation is favored by the use of acidic solvents or ammonia to minimize reductive coupling reactions

[catastrophe]

SWIM always thought that Pd/Pt catalyts were used because they gave complete saturation of the molecule, but according to the ref. above and Barium, they don't.

So how does one know if hydrogenation of a nitrostyrene will yield an oxime or an amine? SWIM has read numerous papers on reductions of nitrostyrenes to amines using solvent/strong acid/catalyst(Pd or Pt) substrates. Will the use of a strongly acidic media yield primary amine, and not the oxime?
Possibly not using the acid inhibits hydrogenation, causing only partial saturation and leaving the amino-carbon double bond? With further saturation SWIM would bet there would also be some hydroxylamine product too, but those are also yummy.

So bottom line, if partial saturation occurs we will have at least oxime,
R-CH=N-OH, which can give a variety of products with continued hydrogenation...

1. R-CH2-NH2 + H2O
2. R-CH2-NH-OH
3. R-CH=NH + H2O

1 is great, 2 is acceptable, but 3 nobody wants.

Will higher pressures(4-5 bar), more catalyst, and more time(24h) help complete saturation of the starting alkene? SWIM wants an elegant one-pot nitrocompound --> amine, not a series of dual stage partial hydrogenations. (Barium's is a special case, because it involved and acid-sensitive molecule)

Skita and Keil, Ber. 65, 424 (1932) describes reductions of nitriles, oximes, and nitrostyrenes to amines using platinum catalysts. So why are there so many conflicting reports!

Can somebody please help SWIM out?

[hest]

SWIM wants an elegant one-pot nitrocompound --> amine,

So do wee, but most of the eksperiment dosen't work. Noone have reduced the nitropropen to the propylamine in one step. (atleast not in high yeld). So this is actual a big step in the right direction. Im working with the plain nitropropen right now, to see how an non-activated nitropropen react's.

[Barium]

If you UTFSE and check Rhodium´s site you´ll find several reports of nitrostyrene to amine reductions. But all of them are very low-yielding, or if nice yields are produced they require shitloads of catalyst. This problem have been attacked during many years. So far no-one has ever come up with a one-pot, high-yielding, low catalyst loading and low-pressure reduction.

20% w/w Raney-nickel and 100-150 bar will give you 50-70% yield of amine from a nitropropene. There´s your one-pot reaction.
Catalytic hydrogenation freak

[catastrophe]

Thanks for the responses, SWIM found some more articles detailing nitrostyrene to amine reductions. Apparently the use of a strong acid favours amine production, but as Barium said, they are no where near the yields that he was able to obtain (usually in the 60-70% range). They also required much higher pressures.

Barium, will your oxime synthesis(GAA/ethanol/Pd) work for all nitropropenes with such good results? Is it also good for nitroethenes(this would be great)? SWIM gathers from your remarks that the real point of the synthesis was the reduction of the oxime using raney-nickel, and low pressures. But SWIM took the entire package as excellent.

Bees, this is a really great synthesis, everybody must really take another look at it and bask.

Thanks

[Barium]

Yes strongly acidic enviroment is favorable for amine formation. But there are a few drawbacks with the acidity as well. Since water will be present some of the oxime will be hydrolyzed to ketone. This ketone both can and will react with the product amine forming an imine which will be reduced to amine. This last amine is not what we want and will just contaminate the product. it will also tag along the A/B workup and end in the final product if distillation isn´t part of the workup. Nickel cannot be used with strong acids.

Yes most nitropropenes will form ketoximes with the H2/Pd-C/GAA/EtOH-system, except those with aromatic halogens. Ritter reported that the GAA isn´t necessary, EtOAc/Pd gives oximes in nearly quantitative yields.
Catalytic hydrogenation freak

[catastrophe]

Thanks very much Barium. Could you recommend some literature/journals SWIM might be able to read about nitrostyrene reductions via CTH?