Sciencemadness Discussion Board

oxime reductions

aldol - 21-3-2005 at 02:03

actavation of oximes
can phenyl 2 propanone oxime be reduced in salt form with sodium metal in alcohol
My thoughts were naoh would be formed in the reaction which would basify the oxime anyway, does this slow things down or lower yeilds.
Is this correct ?
the solubility of the salt in alcohol is nil
i think the yeilds would be better in base form could some one verify this
regards aldol

ok, this is the oxime reduction thread

people eater - 25-3-2005 at 00:44

I imagine you could base your work on Sonson's Na reduction of mdp2p oxime or on another oxime reduction mechanism his references describe. You should be able to dry your EtOH with molecular sieves I think?

Step 2. Reduction of the oxime.

3.86g (0.02 mole) oxime was dissolved in 50 ml dry ethanol (fresh 99.5% is OK, otherwise look in Vogel for a procedure for making anhydrous EtOH with Mg and I2) in a two-necked 250ml roundbottomed flask equipped with a condenser, a cork and a stirring magnet. The reaction mixture was heated to reflux, the heat was turned off and 5g elemental sodium was added in such rate that a steady reflux was maintained (make 20-30 pieces and store under hexane). The first additions is conviently kept small. (NOTE: Hydrogen evolution). At the end the reaction was slower so the heating mantle was turned back on to speed things up. The waterwhite, clear postrxn mixture was then slowly treated with 16g H2SO4 in 200ml cold water. The EtOH was removed under vacuum, and the resulting water phase was washed twice with DCM. The aq. phase was made basic by addition of 25% NaOH. The freebase was extracted with 3x30ml DCM. The pooled organic extracts was evaporated under vacuum to constant weight leaving a pale colored residue (3.36g, 94%).

The freebase was dissolved in 20ml IPA, neutralized with 1.6ml HCl and percipitated by the addition of 40 ml Et2O. The crystals was filtered and washed with a small amount of Et2O. Yield: 3.4g of white MDA-HCl. Mp 187.5-188.5°C. (Litt: 187-188°C)

This reduction can also be done in n-BuOH according to [5], and with quite a few NaBH4 reduction systems (NiCl2[6], TiCl4[7], MoO3[8], Co-PC[9], amberlyst-15+LiCl[10], and even with plain NaBH4 in EtOH according to [11]). Adding NaOH to a suspension of Ni-Al is also said to reduce oximes[12] as is SnCl2-Sn-HCl[13].

Different synthesis of oximes starting with nitroalkenes should be looked into, as this could be a good alternative to the existing methods for reducing nitroalkenes. SnCl2 reduces nitroalkenes to oximes under both acidic and basic conditions[14, 15, 16). Zn(BH4)2 in 1,2-DiMeO-ethane does reduce 3,4-MD-phenyl-2-nitropropene to the oxime in good yields [17]. Another promising route is the use of Pb in DMF [18]. This seems to reduce most nitroalkenes to the corresponding oximes.

1. J. Pharm. Sci. 69; 2; 1980; 192-195
2. CA 1955;10595
3. Chem. Ber. 114;12;1981;3813-3830
4. J. Chem. Soc. Perkin. Trans. 2;2;1997;249-256
5. JACS 56, 487 (1943)
6. Chem. Pharm. Bull. 36;1988;1529-1533
7. Synthesis 9;1980;695-697
8. Chem. Ber. 117;2;1984;856-858
9. Angew. Chem. 93;5;1981;477-479
10. Syn. Lett. 4;1999;409-410
11. J. Chem. Soc. Perkin. Trans. 2; 1980; pp83-86 (very sparse information)
12. Aust. J. Chem 34; 1;1981;45-56
13. JACS 67;1945;496
14. Tetr. Lett. 26;49;1985;6013-6014
15. Synth. Commun. 18;7;1988;693-698
16. Heterocycles 24;9;1986; 2581-2586
17. Tetrahedron 48;25;1992; 5317-5322
18. Tetrahedron 48;21;1992; 3313-26 among others

Or you could adapt Antibody2's Al/Hg/AcOH reduction of mdp2p oxime-


In a 4l beaker with mag stirring, 0.75 moles of activated Al (19.5g) [1] is added to 1l 95% EtOH and 100mls dH2O, followed by 0.33 moles oxime of MDP-2-P (65g) [2],and 3 moles HOAc (180g). The Rxn is heated to 60C and heat removed. There follow three additions of 0.75 moles of activated Al at 30 minutes, 1 hour, and two hours. Temperature was maintained at 60C by placing beaker in a cold water bath as necessary. There is a vigourous evolution of hydrogen as the rxn progresses, care must be taken the rxn vessel does not overflow. An additional 150mls 95% EtOH and 15mls dH2O is added at 2hours. At 3 hours the rxn is a viscous gel which has stopped the stir bar. An additional 300mls 95% EtOH and 30mls dH2O is added . The rxn was allowed to stir until it has returned to room temperature, during which time 1 l of 15M NaOH was prepared and cooled. The rxn vessel was placed in a cold water bath and the basic solution was added slowly over 20 minutes, with care being taken the tempertaure did not rise above 60C. 500g of NaCl was added, much of which precipitated after stirring. 500mls toluene is added with stirring. The toluene/EtOH/amine layer is separated and decanted into 750mls of dH2O, causing the EtOH to migrate to the aqueous layer. The toluene layer is separated and the aqueous/alcoholic layer is extracted 2 times with 250mls toluene. The pooled toluene extracts are washed once with 400mls dH20 and once with 400mls brine, then dried through MgSO4 and gassed w/ dry HCl gas, furnishing 54g MDA HCl (0.267 moles, 81%) .

1. Activated by refluxing in 19.5g Al in 800mls of 50/50 dH2O/MeOH, with 1g Hg2Cl2 for 15 minutes, the mercuric solution was decanted, and Al was washed once with 400mls 95% EtOH, which was also decanted. Same mercuric solution was used for all four activations.
2. Prepared according to Sonson's instructions


You can simply amalgamate the aluminum in situ for convenience and 1g of Hg salt would be huge overkill I think. HgI2 is easily prepared by briefly stirring .5g Hg, .66g I2, 1-2ml MeOH. it can be used immediately or allowed to evaporate to a uniform red powder. Conc h2so4 is the best for getting the post amalgam grap out of yer flask. If you use toluene/xylene for extraction, you have to add enough water (with base) to make the acqueous layer denser than the toluene/xylene, or it won't separate properly. With this in mind it's idiot-proof, persuming your oxime is as good as ours. Not that we ever had p2np, but p2np should easily hold up to the conditions that its ring-substituted relatives can.

I want details of those NaBH4/metal reductions...
Spin up some dmmdaaaaahhhh...

mick - 12-4-2005 at 12:26

If sodium in ethanol is a good reducing agent for oximes let me know.
I have seen a 100 gal pot full of an oxime detonate when it was over heated.


How hot ?

xwinorb - 20-10-2006 at 14:08

SWIX has some oxime, he is thinking about reducing it with Al-Hg in MeOH plus AcOH. Chromic recipe.

I would like to know if this is a lot more exhotermic, than, let's say, more customary Al-Hg reductions. I use Hot Bags foil, a bit thicker than Reynold's Heavy Duty.

Reflux plus cooling OK ? In a 2 l BF.

I am planning to use aproximately 20 g of ketoxime. Oxime made from PMK ( MDP2P ) and hydroxylamine.


xwinorb - 25-10-2006 at 17:33

My small contribution to this topic :

SWIX tried it, used 15 g of oxime. Exothermic under control, but would not scale up or use thinner foil.

Done ( most of foil consumed, no longer exothermic ) in three hours.

Basified, filtered, extracted with toluene. Filtration long, difficult, did several times. Will try to let is settle next time.

After A/B, got 2.5 g of a certain PEA. Nice, dry, powdery, white. Biossayed OK. Subjectively also clean, nice.

Would appreciate any suggestions about how to improve yield ( aprox 20 %, taking into account that oxime effective weight was guessed at was at 10.71 g. Still a bit wet and with impurities, oxime yield more than 100 % ).



Sandmeyer - 28-10-2006 at 17:35

Damnit, why not go to the crystal meth forum and "discuss" the "science" of mixing 3 reagents ad infinitum overthere?

There you can post all the possible parameters in the known universe that can influence your reaction. People that are unfortunately not on methamphetamine get bored by such posts in org chem forum, so show some understanding.

Nicodem - 28-10-2006 at 23:08

Interestingly, such fixations are not characteristic only of meth users. I knew a researcher in the academia who managed to stick for years doing research on the same reaction involving 3 reagents changing all kind of parameters ad infinitum. Nobody ever managed to understand what the point of his work was. Even now I suspect he was just one of those guys without any imagination whatsoever that simply got the simplest idea on how to waste time in producing useless information and still get paid a decent salary. From then on, I got the feeling that there are a bunch of people like him in the academia, just less radical perhaps.

Organikum - 29-10-2006 at 07:00

Read a paper posted on the Hive times ago, a scientific one which very much pointed out how little understood the chemistry of HI actually is, formation and decomposition with for example H2SO4 or H2O2, electrolytic and in special the dependance on concentration and conditions.

Thats the funny thing about chemistry, actually nothing is really understood, reaction mechanisms are a big joke if not referring to simple intermediates and overall thats no science with a working theory but just some empiric data obscured by inconclusive nomenclatura.

Has the advantage that even the amateur can with simple means discover new ways. Needs a lot of luck though - it´s quite non-intuitive too.

But on topic here: Well thats really covered, people should read the writeups, thats why they were made. Or ask something new maybe.

xwinorb - 30-10-2006 at 20:57

In my latest post, I mean the corresponding amphetamine, not the PEA.

Sorry for the mistake, and also for not stating everything clearly.

I think the low yield relates to the oxime purity, everything else looks OK.

[Edited on 31-10-2006 by xwinorb]

haribo - 28-11-2006 at 08:38

Anyone with a Hive backup should look at Labrats Zinc/Nickel couple for the reduction of oximes. It's nicer to the enviroment than using mercury salts. It is smelly since you do the reaction in conc. NH4OH but it's easy, simple & referenced.

Organikum - 21-5-2007 at 11:03

Anybody tried this? Does it require strict anhydrous conditions? Does it work in EtOH or IPA?


Nicodem - 21-5-2007 at 11:17

There was some discussion about the method using Mg from the same authors:

kmno4 - 4-12-2007 at 03:38


I have found an article with described procedure of reduction of some oxime to amine. But conditions are strange (to me):
oxime+ dry THF + Al(Hg)
According to:
....C-N=OH + 3H ->....C-NH2 + H2O
Al + 3H2O -> Al(OH)3 + 3H (simplified, of course)
, for each molecule of oxime two molecules of H2O are needed.
Am I right or I overlooked something and guys from article are right ? Is THF a H-donor ??

In attachment page from cited article with this procedure.

Attachment: Page from jo00015a026.pdf (79kB)
This file has been downloaded 1384 times

Vogelzang - 20-9-2009 at 05:58

from Chemische Berichte


Eine alkololische Lösung von 9.4 g Phenylacetoxim wurde nach un nach mit 500 g 2 1/2 pCt. Natriumamalgam versetzt und die Flüssigkeit durch Zugiessen von Eisesssig stets angesäuert. Ueberschreitet die Temperatur der Lösung nicht 20º, so ist bei dem Zusatze der ersten Hälfte des Amalgams nur eine geringe, beim Hinzufügen der zweiten Hälfte aber eine lebhafte Wasserstoffentwicklung wahrzunehmen.
Die gelb gefärbte Flüssigkeit wurde nach der Reduction von dem Alkohol durch Eindampfen befreit und der Rückstand mit Wasser erwärmt. Ungelöst blieb etwas unverändertes Oxim; das Filtrat schied auf Zugabe von Kalilauge ein aufschwimmendes braun gefärbtes Oel ab, das nach dem Trennen mittels Aether fractionirt wurde. Farbloses Liquidum vom Siedepunkt 197-198º bei 725 Druck.
Ausbeute 7.5 g vom destillirten Amin, was etwa 90 pCt. der theoretischen Menge entspricht.
Das Phenyläthylamin wurde in die Acetyl- und Benzoylverbindung übergeführt und diese mit Phosphorpentoxyd zu den Dihydroisochinolinderivaten condensirt.

Here's my translation/interpretation:

An alcoholic solution of 9.4 g phenylacetoxime was gradually added to 500 g of sodium amalgam and the liquid was kept acid by addition of glacial acetic acid. The temperature stayed under 20º. When the first half of the amalgam was added there was little reaction, but after the second half of the amalgam was added there was a vigorous production of hydrogen.
The yellow colored liquid was freed from the alcohol after the reduction by evaporation and the residue was warmed in water. Unreacted oxime remained undissolved. The filtrate when treated with KOH produced a brown oil (floating on top), after separation of ether medium (extracted with ether?). Colorless liquid bp 197-198º at 725 pressure.
Yield 7.5 g of distilled amine, about 90 % theoretical corresponding amount.
The phenylethylamine was converted to the acetyl and benzoyl derivatives and condensed to dihydroisoquinoline derivatives using phosphorus pentoxide.

manimal - 23-9-2009 at 16:59

Weygand says that most reagents suitable for the reduction of nitros are suitable for the reduction of oximes. Tin/HCl would affect the desired reduction, unless there's a specific reason that it won't that I'm overlooking.

zed - 2-10-2009 at 13:33

Phenyl-2-Propanone Oximes, are not as easily reduced as Phenylacetoximes.

Tin/HCl would be unlikely to reduce a P2P Oxime.

In fact, Heinzelmann, used such a reduction (Fe/HCl), to produce a P2P Oxime, from a Nitro-Propenyl-Benzene.

I'm assuming you aren't actually interested in the manufacture of amphetamine itself, nor in the manufacture methamphetamine. So, that would place your interest in the synthesis of primary amines, like MDA, DOB, and such. Somewhat less odious endeavors than meth manufacture. And, possibly even legal in your jurisdiction.

There are several reasonable approaches to this problem, assuming you wish to avoid the Leuckart reaction.

The first, is direct reduction of Nitro-olefin to Amine via Metal Hydride.

As we discussed in an earlier thread, NaAlH4 is easily produced, via the high pressure hydrogenation of Sodium and Aluminum, in a toluene solvent, using tri-ethyl-aluminum as a catalyst. TriethylAluminum is pyrophoric, making it
somewhat difficult to handle, but overall, the procedure is very do-able.

The resulting NaAlH4, may be used in place of LiAlH4, or it may be converted to
that material.

A second approach, involves reductive amination of a P2P with Pt/H2 and Benzylamine. The reduction first produces an N-Benzyl- Amphetamine, which upon further reduction, undergoes hydrogenolysis, to produce the unsubstituted amphetamine, plus toluene. Benzyl being an excellent "leaving" group.


There is another approach, a Japanese procedure, that involves high pressure hydrogenation, of the Nitro-Olefin, in the presence of Ammonium Acetate, and Raney Nickel. Reported yields are ~65% Amine.

I have heard negative reports, regarding the efficacy of the procedure.
This reduction may proceed (if it actually does proceed), via reduction to oxime, transamination, and reduction of resulting imine. Leaving an unreduced hydroxylamine acetate, as a by product.

Vogelzang - 6-10-2009 at 15:26

The experimental section of the attached article has a process for reduction of P2P oxime with Na-Hg.

Attachment: JCS1930p18-21-Hey.pdf (257kB)
This file has been downloaded 1297 times

entropy51 - 6-10-2009 at 15:38

Quote: Originally posted by Vogelzang  
The experimental section of the attached article has a process for reduction of P2P oxime with Na-Hg.

Why would anyone smart enough to be a chemist want to do that? It would be a felony on every continent except Anarctica, wouldn't it?

Vogelzang - 6-10-2009 at 15:55

What if you worked for Smith, Klein and French and had a DEA license to make it? Its used in diet pills and for ADHD.

entropy51 - 6-10-2009 at 16:23

Quote: Originally posted by Vogelzang  
What if you worked for Smith, Klein and French and had a DEA license to make it? Its used in diet pills and for ADHD.

I'm sure SKF will be eternally grateful to you if they forget how to make it and need to come to ScienceMadness to remember how to make it!

Vogelzang - 7-10-2009 at 12:10

I hit the jackpot. Now that entropy's blook pressure is raised I'll post this link.

Two references have Na/Alc

48. Na/Alc, Figure 3.
Oxime reduction to amphetamine
F.M. Jaeger and J.A. van Dijk, Preparation of 2-phenylisopropylamine. Proc. Acad. Sci. Amsterdam, 44 (1941) 26-40. C.A. 37, 6219 (1943)

49. Na/Alc, Figure 3.
Oxime reduced to amphetamine
W. Leithe, Configuration of ephedrine bases. Berichte 65, 660-666 (1932). C.A. 26: 3495 (1932).

entropy51 - 7-10-2009 at 12:18

I hit the jackpot. Now that entropy's blook pressure is raised I'll post this link
My blook pressure is normally so high that an oxime reduction couldn't make even a bump in it. Nice try, though. My trigger is much less sensitive than that. Besides, most people that use Na amalgam will end up with Hg toxicity. The two or three who could make Na amalgam, that is.

Sedit - 7-10-2009 at 13:38

Its not exactly on topic for this threed(not to far off either I guess) but how would Lithium amalgams perform in reactions that call for Sodium amalgams. Lithium is much easier to get then Sodium and a more powerful reducing agent so I have been curious for sometime about this.

mrhawke - 9-10-2009 at 00:39

Quote: Originally posted by kmno4  

I have found an article with described procedure of reduction of some oxime to amine. But conditions are strange (to me):
oxime+ dry THF + Al(Hg)
According to:
....C-N=OH + 3H ->....C-NH2 + H2O
Al + 3H2O -> Al(OH)3 + 3H (simplified, of course)
, for each molecule of oxime two molecules of H2O are needed.
Am I right or I overlooked something and guys from article are right ? Is THF a H-donor ??

In attachment page from cited article with this procedure.

Hi kmno4,

You are right, the reaction does require a H+ donor, and water would undoubtedly fill this role - even though they used dry THF, the amalgam is prepared in aqueous solution, so there probably would have been some trace of water left to initiate the reaction.

Do note though, and this is where a lot of people see to be confused with the amalgam reductions, is that only the very first step needs to be taken into consideration when talking about the formation of the amine. Yes, it is true that in the course of the reaction, water will react with the aluminium, forming Al(OH)3 (aka Grey Sludge™), but this has nothing to do with the amine (which has already been formed) and is indeed an unwanted side reaction - if it wasn't for the water in the system, the aluminium would be continue to be happily amalgamated indefinitely!

As such, yes, some water is needed to start the reaction going (i.e. for the first three H+ ions!) but as both oxime > amine (as in this case) and imine > amine (as in the n-methyl case) reductions create water as a bi-product, that is all you need; you most certainly do not need the 3 mole equivalents of water per mole of aluminium to create the amine itself.

Vogelzang - 10-10-2009 at 05:03

Here's something by Maurice Moore at Smith, Kline and French on the Leuckart reaction. Its in Dejavu format and can be read using Irfanview (free to download) after installing the plugins. I thought I'd post this here just in case they forgot this.

Attachment: Leuckart301-325.djvu (285kB)
This file has been downloaded 1131 times

[Edited on 10-10-2009 by Vogelzang]

entropy51 - 10-10-2009 at 06:50

Man, that tired old paper on Leuckart has been posted many times, most recently by Sedit in the formamide thread just last summer.

This is the oxime reduction thread. I guess we should rename it to "How many lousy preps do you know for crank?'

No, my blook pressure is not up, I'm just entertained by how you're trying to see how many crank preps you can sneak into a chemistry forum. Really, I am amused. But now that we know you know some lousy preps for crank maybe you can quit cluttering things up with old references that all of us know about already.:P

[Edited on 10-10-2009 by entropy51]

Vogelzang - 10-10-2009 at 12:09

You can see that GSK which includes SKF in a merger has moved up in price recently, no doubt due to the information I posted here on Science Madness.,_Kline_&_French

Vogelzang - 10-10-2009 at 12:19

US 1921424 Medicinal remedy (Smith, Kline and French)
Na + alcohol

US 5300689 Oximation process

JohnWW - 10-10-2009 at 12:26

SKF? If Smith Kline & French use that acronym, they may be violating the trademark of the other SKF company, which makes ball and roller bearings (which I have had to specify from their range in the past, when doing mechanical engineering design work). I think they were originally a Swedish company, and got rich in WW2 by selling large quantities of bearings (the manufacture of which was a trade secret) to both sides. See , , , ,

[Edited on 10-10-09 by JohnWW]

Vogelzang - 10-10-2009 at 13:43