A great CTH method

[Barium]

Ammonium formate/Pd-C is the most commonly used CTH-system I´ve seen. It has been used to reduce -NO₂ --> NH₂, =NOH --> NH₂ to name a few types of reductions. In the literature the reduction of aromatic nitro groups are far more common than reduction of alphatic nitro groups. This bad for us, since we have more often a far greater interest in reducing aliphatic nitro groups. The ammoium formate/Pd-C system is awesome for aromatics but can be very troublesome for aliphatics.

I´ve over the years had some success with the ammonium formate/Pd-C system for alipahtic nitro groups, in some cases with great yields. But far more often terrible yields. This is even though I´ve used 10 mols formate/mol nitro.    So cursing like mad, I´ve usually ended up using excess Red-Al instead of dirt cheap formate CTH.  

In the literature it´s stated that the different formate salts behave very different as hydrogen donors. Formic acid is usually the poorest donor, sodium formate is better , then ammonium formate (and trialkylammonium formates) and finally the best donor is potassium formate. In

Patent US4792625

potassium formate is used in a CTH procees for various aromatic nitro compounds. I tried this method to make some 2C-H in

Post 326004

(Barium: "Better yields", Novel Discourse) with decent yields (64%). For some reason I completely forgot all about this system until two days ago. This method was now tried with a few nitroalkanes to see how useful it was as a overall CTH method for aliphatic nitro groups.


General method

50 mmol nitroalkane
250 mmol potassium formate
750 mmol water
25-50 ml IPA (depending on how much is needed to get a nice solution)
10%w/w 5%Pd/C (catalyst to substrate)

Add the catalyst to the reaction flask and and wet it with the water. Then add the nitroalkane dissolved in IPA and finally the formate. With good stirring, heat the reaction mixture to about 70°C on a water bath for 1-3 hours. The reaction is over when gas evolution ceases.

Here comes a nice twist.
when the reaction is over one can carefully acidify the solution to pH 2-3, filter off the catalyst and perform the workup as usual.
Or, filter off the catalyst/KHCO₃ and wash it with IPA. Dry the IPA solution with MgSO₄ and distill off the IPA to get the crude amine. Save the filter cake, because when the next batch of the same amine is to be made just dissolve the nitroalkane in IPA, add the filter cake and finally 250 mmol formic acid. Voila, potassium formate regenerated.
Do I need to mention that formic acid is dirt cheap?!

2-Nitro-1-(2,4,5-trimethoxyphenyl)-propane --> TMA-2*HCl 89%
2-Nitro-1-(3,4-ethylenedioxyphenyl)-propane --> EDA*HCl 84%
2-Nitro-1-(2-fluorophenyl)-propane --> 2-FA*HCl 85%
2-Nitro-1-(2,4,5-trimethoxyphenyl)-ethane --> 2,4,5-TMPEA*HCl 85%
2-Nitro-1-(2,4-dimethoxyphenyl)-ethane --> 2,4-DMPEA*HCl 91%
2-Nitro-1-(2,5-dimethoxyphenyl)-ethane --> 2C-H*HCl 89%


I will try this potassium formate CTH system for reduction of imines and oximes. 
Catalytic hydrogenation freak

[Rhodium]

Good, better, great!

Have you tried using this CTH system directly on any nitrostyrenes, eliminating any need for reducing the alkene to the alkane separately, using sodium borohydride?

Also, how many times do you usually recycle your Pd/C, before it loses activity? Is it "safe" to store the catalyst together with the potassium salts for extended periods - it won't decompose or anything?

[Barium]

No I haven´t tried it directly on nitrostyrenes, but I will now when you´ve mentioned it. The filtercake can be stored dampened with water. Add enough water to get a wet slurry and cover it with aluminum foil. The catalyst should not be affected by the potassium salts at all.
The catalyst can be reused at least five times.

Degussa (catalyst manufacturer) claim that a small addition of Fe salt makes Pt and Pd catalysts more efficient for -NO2 reductions. This will also be investigated.


Catalytic hydrogenation freak

[L42L]

It's like every time I look you got some more cool stuff. Saving my Pd/C for the day you bring us a DMT synth. Can't wait to see what happins with the styrene, best of luck!
thanks
lurk

[Barium]

10 g 2,4,5-Trimethoxy-beta-methyl-beta-nitrostyrene (39.5 mmol)
HCOOK (240 mmol)
HOAc (240 mmol)
1 g 5%Pd/C
75 ml EtOH
40 ml water

Everything was mixed except the acetic acid. Gas evolution started immediately, unlike when IPA is used. The reaction mixture was placed in a water bath and heated to 55°C with good stirring. Every now and then during 90 minutes 1 ml acetic acid was added to prevent the bicarbonate to precipitate. If the acetic acid was added in this manner the pH never ever fell below 8, since the potassium acetate is a basic salt. The workup was identical to the previous reaction. The acid extract was saved and isolated to give the ketoxime in a good yield.

The really interesting part was what was recovered from the alkaline extractions. When the solvent was removed no oily amine remained at all despite something showing amine-like behaviour, when the water phase was made alkaline, fell out of solution. Instead it was a white waxy crystalline material. Totally unlike the ketoxime, amine, nitropropene or nitropropane. It was even only very slightly soluble in EtOAc. The suspension in EtOAc was very alkaline so I believe it can actually be N-OH-TMA-2. I added dry HCl/IPA until pH 5 was reached and the waxy solid transformed into a fine crystalline powder.

Yield 3.8 g of 2-(N-hydroxyamino)-1-(2,4,5-trimethoxyphenyl)-propane*HCl (N-OH-TMA-2)??   
Catalytic hydrogenation freak

[Rhodium]

Interesting. Be sure to keep us updated on the analysis of this. An easy route to the N-OH derivatives of phenethylamines opens up a parallell universe of interesting "twins" to popular amines, which are not covered by any laws in most countries.

[Barium]

10 g 2-Nitro-1-(2,4,5-trimethoxyphenyl)-propane (39,2 mmol)
20,5 g HCOOK (roughly 240 mmol) dissolved in 50 ml water
2 g 5% Pd/C (20% w/w)
100 ml EtOH (feel free to substitute this for IPA or MeOH)
14,5 ml HOAc (240 mmol)

The catalyst was added to a 500 ml E-flask equipped with a magnetic stirbar and wetted with 5 ml water. The EtOH was then added followed by the nitropropane and the potassium formate solution. The reaction mixture was stirred and heated to 55°C on a waterbath. When the preciptitated bicarbonate made the mixture difficult to stir the acetic acid was added one milliliter at a time until the salt went into solution again. This procedure was done two times during one hour, at which time the reaction was over.

The catalyst was removed by filtration through celite and saved. The filtrate was colorless with a pH of 12,7. Acetic acid was added until pH 7 was reached and the EtOH removed by distillation in a rotovap (save this because it can be used again as it is). The aqueous solution was made alkaline (pH 13) with NaOH, saturated with NaCl and extracted with 2x50 ml toluene. The combined toluene extractions was dried by azeotropical distillation in the rotovap and the remaining toluene was also distilled away. This left a oil with just a hint of yellow color. 100 ml EtOAc was added to the oil and dry HCl/IPA was added until pH 6,5 was reached. The crystals, which started to form immediately when the HCl was added, was isolated and dried to constant weight.

Yield: 10,1 g (98,5%) TMA-2*HCl as absolutely white crystals. *sniffle*   
Catalytic hydrogenation freak

[Triton]

How does one separate the catalyst from celite?

[Barium]

There is no need to separate the catalyst from the celite at all. Just dump in the filtercake into the reaction vessel for the next reduction. The celite doesn´t disturb anything. When that reaction is over you do not need to add any celite since it is already present.
Catalytic hydrogenation freak

[Ritter]

Hi Barium,

Wow, you sure are doing some fine work here these days, thank you for sharing!!! Congrats on mastering the CTH of nitroalkanes!  I do have a somewhat related  question- you have posted numerous writeups concerning the reduction of the nitroalkane to the amine however you have not said much about the reduction of the nitroalkene to the desired nitroalkane lately.  Have you done any work to improve the NaBH4 reduction of the nitroalkene such as working out a new solvent system or are you still using the same ethyl acetate solvent system described in your very first post on this topic?  In passing, you have also mentioned toluene worked well for the alkene reduction, I'm just wondering what solvent and reaction parameters you prefer after so much experimentation?

[Barium]

For most phenylnitropropenes there is no need to use the EtOAc/EtOH system. Instead, to a suspension of the nitropropene in MeOH, EtOH or IPA solid NaBH₄ is added portionwise until the yellow color is completly gone. Then adding twice the volume water and destroying the excess borohydride with acetic acid, distilling off the alcohol and extracting the nitropropane with some NP solvent gives yields in the range 60-95%, depending on the substrate.

Phenylnitroethenes on the other hand needs the toluene/EtOH or EtOAc/EtOH system to give good yields.

I will post a write up on this topic in a little while.
Catalytic hydrogenation freak

[Megatherium]

Are there problems to be forseen when one applies this reaction on thienyl-2-nitropropanes & furoyl-2-nitropropanes?  Isn't the furoyl ring going to be reduced (since the resonance energy of furane is considerably lower than the one of thiophene and benzene).  And with thiophene, is there a risk of catalyst poisioning?

[Rhodium]

The following two articles describe 1) The reduction of nitrostyrenes to oximes and 2) the reduction of oximes to amines, respectively. Both are CTH reactions using Pd/C and Ammonium Formate, and both use alcoholic solvent mixtures. Shouldn't it then be possible to reduce nitrostyrenes to amines in one-pot, using long reaction times and a stronger hydrogen donor like potassium formate?

One trial like this was posteded in

Post 383891

(Barium: "Tested", Novel Discourse) but there was no closure regarding the product identity, and the reaction time was very short - maybe it could benefit from being run overnight or so?


Oximes from Conjugated Nitroalkenes Using Pd/C-Ammonium Formate CTH
G. W. Kabalka, R. D. Pace, and P. P. Wadgaonkar

Synth. Commun. 20(16), 2453-2458 (1990)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/nitroalkene2oxime.cth.html)

Abstract
Conjugated nitroalkenes are readily reduced to the corresponding oximes in good yields using ammonium formate in the presence of palladium. The reactions occur rapidly at room temperature in a solvent system of methanol and tetrahydrofuran.

This article has been mentioned earlier in the following post:

Post 228726

(Cyrax: "Re: Synthesis of amphetamines", Methods Discourse)
____ ___ __ _

Palladium-catalysed Transfer Hydrogenation of Azobenzenes and Oximes using Ammonium Formate
G. K. Jnaneshwara, A. Sudalai and V. H. Deshpande

J. Chem. Research (S), 160-161 (1998)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/cth.oximes.formate.pdf)

Abstract
The reductive cleavage of azobenzenes, including the reduction of oximes to their corresponding amines, has been achieved with Pd⁰ using ammonium formate as hydrogen source.

This article has been mentioned earlier in the following post:

Post 368992

(Rhodium: "CTH Oxime Reduction", Methods Discourse)

[armageddon]

Rhodium, the one-pot nitroalkene->aminoalkane you suggest here could indeed bee a nice shortcut, as it avoids the rather expensive NaBH₄ used for double-bond reduction. SWIM recently tried something similar, but with shorter reaction times (like 45min) and ammonium formate as hydrogen donor (6-7x molar excess), and the results were not very promising, because something like 1% yield    (based on substrate phenyl-2-nitropropene) was obtained. But, as you say, a stronger hydrogen donor like potassium formate and longer reaction times might do the trick in this case. Or perhaps the efficiency of the procedure could be increased by slowly adding formic acid to rxn mixture via dripping funnel. I think this would regenerate in situ the used KCOOH, or would the acid have no time, as it is decomposed directly upon coming in contact with the catalyst? I wouldn't think so, and even if that was the case, HCOOH is a weak hydrogen donor in CTHs AFAIK, like in Zn/HCOOH reactions, so that wouldn't matter at all.
But to achieve simultaneous reduction of the double bond and nitro group, ideal rxn conditions are difficult to realize because alipathic C=C bonds are best reduced at relatively mild temperatures in a moderately polar solvent, whereas NO₂->NH₂ proceeds best at elevated temperatures (100-150°C I think) and anhydrous conditions, with the aid of GAA as cosolvent(according to degussa, no.1 catalyst manufacturer). I think the GAA would somewhat interfer with KCOOH, right? SWIM will still give it a try, using alcohol as solvent, with perhaps a bit of formic, and potassium formate. Rxn temp. will bee maintained at +-70°C, time perhaps 5-6 hours: what do you think? And since SWIM has no KCOOH, he could get it by reacting anhydrous KOH with 99% HCOOH in iPrOH (perhaps with silicagel) under cooling, right?

Barium, I am very interested: have you already tested your potassium formate CTH on imines? If this would work, I bet it would be possible to get methamphetamine by reducing phenylacetone with Pd/C with in situ methylamine generation from nitromethane, similar to Al/Hg nitromethane reductions. As far as I understand, Al/Hg is capable of reducing both ketones and nitroalkanes, the former reacting with amines to give imine intermediates which are protonated, the latter being straight hydrogenated. And Pd/C is also capable of reducing ketones to amines with an amino group donor like ammonium acetate/formate, besides of being of great use for nitro->amine reductions (phenyl-2-nitropropanes or nitromethane, giving the corresponding amphetamines or methylamine)..
Perhaps a good route for bees without access to methylamine and much better than having to deal with hg salts! The great disadvantage of al/hg nitromethane reactions.. ..together with painful workups!!
The only question left would be if palladium/charcoal is capable of reducing imines. If this works, one could react p2p with amm.formate, a pd/c catalyst and slow addition of nitromethane, or perhaps P2P and CH₃NO₂ premixed and calculated amounts added to Pd/C and LOTS of NH₄COOH... Work to bee done!

Thanks, A

[Barium]

So far I have not seen a CTH-system capable of selectively reduce the C=C bond in a phenylnitroalkene. To succeed with this a catalyst with high affinity for the C=C bond and a very very low, or no affinity at all for the nitro group must be used. A catalyst with such properties are to be found among the homogenous family. With every hydogen donor I have seen so far, combined with Pd, the nitro group is reduced to a hydroxylamine. This gives a hydroxylenamine since the double bond is still intact and the hydroxylenamine tautomerizes immediately to the oxime.

Aliphatic oximes are kind of tricky to reduce further. Aromatic oximes on the other hand are really easy to reduce. In the articles above all the oximes are aromatic. Not even Kabalka have presented a CTH system which reduces aliphatic oximes.

[armageddon]

First of all, thx for your quick response Barium!

So to speak, Pd/C is NOT capable of simultaneous reduction of double bonds AND alipathic nitro groups, since it prefers attacking the NO₂ group, leaving something like C₆H₅CH=C(CH₃)NHOH, which in turn tautomerizes to phenylacetone oxime before the catalyst has time to attack the f***ing double bond.

But still I think pd might bee useful in that case, I think of

Post 335851

(Sunlight: "MDA and MDMA from CTH reductive amination", Novel Discourse)where sunlight successfully reduced ketones with an amino group donor, formic acid and pd/c (methink), and all those old writeups about al/hg oxime reductions

https://www.thevespiary.org/rhodium/Rhodium/chemistry/alhg.oxime.html

where the only difference to normal ketone al/hg's is the acidic, aequous environment. To repeat it: Al/Hg and Pd/C both are capable of reducing ketones and nitro groups to their amino derivatives, and I don't understand why pd/c should let oximes unaffected whereas al/hg would reduce them!? It would bee just too nice and easy..
Oh, not to forget: zinc and formic (or was it HCl) reduce nitropropenes to P2Ps and amphetamines (minor), and I think ("nose chromatography", SWIMs only method of analysis ) that pd/c does something similar to nitrostyrenes, as SWIMs Xperiments showed amphetamine was produced in minor amounts (he got ~150mg sulfate), accompanied with strong p2p smell. Perhaps Pd/C acts similar to Zn/H+? But it also works on ketones, so why should styrenes give something useless (styrene->ketone->amine)?

(perhaps Kabalka didn't try to reduce oximes, if he did: was anything ever published? something where he states oximes cannot be reduced by pd/c and hydrogen donors? The fact that one researcher (although being VERY competent) didn't confirm the possibility of such a reaction is NO PROOF of its impossibility in general, I think    Show me a published statement like "according to our experiment, its impossible" and I will believe it, but if everyone just thought everything was impossible because his favourite researcher didn't work on the subject, noone would EVER discover anything new, right?   )

And still I'm left with an important question: would Pd/C work on amphetamine methylimine (obtained by reacting p2p w/methylamine, in situ or in an extra reaction?) and produce methylamphetamine by hydrogenating the =N to NH ? Remember Pd/C does reduce nitroalkanes to their amines, hence also nitromethane->methylamine. SWIM thinks this could turn out to become a easy onepot meth synth without mercury salts or high pressure involved... perhaps it would bee just TOO easy that way and is therefore not possible   ...

Any comments are welcome!!

Greetz A

[hest]

There have been some effort to try to make this work here at the hive, but with no luck at all.
Iff you try and work up the product by A/B you end up with the oxime, with smel's aminelike and give some flufy material with ether HCL but it's not the amphetamine(phenetylamine). The problem is the conjugation beetwen the dob.bond and the nitrgroup. Only solution is to red. the dob.bond with NaBH4 and then CTH of the nitrogroup.


As you say, this way would bee to easye *lol*.

[josef_k]

There have been some effort to try to make this work here at the hive, but with no luck at all.

What about this then:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/nitropropene.cth.txt

Very large amount of catalyst though.

[armageddon]

Hmm, I just read a very interesting analysis done by GC_MS (great work!!! THX a lot!) on Zn/HCOOH reductions of nitropropanes obtained by NaBH₄ reduction of nitrostyrenes (UTFSE for posts by GC_MS containing "reanalysis nabh4 zn/hcooh"), some P2P impurities were present and he too assumed that unreacted nitropropene (insufficient NaBH₄ was used) was reduced to phenyl-aminopropene, being tautomerized and hydrolized to P2P. He also concluded this had to be minimized because of P2P amphetamine condensation by-products...
Yet another reason why nitropropene->aminopropane reductions won't work with pd/c. Even if some of the nitropropene got reduced to nitropropane, there would be enough aminopropene formed to give mainly ketone-amine condensation products in the end, right? But on the other hand, there is a procedure by Sunlight (see my above post) that uses Pd/C,  ammonium formate at room temp. and long, long rxn times (16-48h) to go from the ketone to the amine (using MDP2P as substrate, yielding MDA), wierd!

Anyway, the easiest, highest yielding and least dangerous (LAH,THF,hydrogen/pressure,HgCl₂-not needed anymore !) method to reduce nitrostyrenes to their amphetamines is borohydride reduction, followed by hydrogenation with either Zn/formic acid or Pd/C and some formic acid salt (or again NaBH₄) - yields are on the high side: 60-90% depending on the nitroalkene substrate are achieved in each reduction step, often there is even no need to work up the intermediate product - and everything can be applied to almost any known nitrostyrene! Already easy enough, dare I say hest!   And it gets better: borohydride is being researched as future fuel replacement in fuel cell cars, that means availability will surely become better within the next years   ! poor pigs, might I say!

Still noone who has tried to reduce imines with pd/c? Seems as if SWIM will have to figure it out by himself..

Greetz A

[Barium]

Sunlights work to reductively aminate MDP-2-P with in situ generated ammonia from ammonium formate shows that notoriously sensitive imines are reduced in good yields with Pd. Pd can of course also be used with molecular hydrogen under pressure. A way to improve yields in CTH reductive aminations and alkylations would possibly be to swap Pd for Pt. Perhaps doped noble metal catalysts or doped Raney catalysts would be even better.