Al/Hg on ketoximes

[Chromic]

In AB2's and Chromic's writeups they use 10 eq AcOH and Al... also 10 eq of NaOH to 1 eq Al to basify. Has anyone had success using less hydroxide or less AcOH/Al while still getting yields in the 80s?

I've heard of 7.5 eq NaOH to Al, and that seems to work just fine. Standard Al/Hg's, a la B.S. etc with imines use 3.3 eq's Al to ketone... would a good yield still come about if just 3.3 eq's of Al to ketoxime were used? If MDOH.HCl was made, how could one, qualitatively, tell the difference? Does any one here have some suggestions?

[pHarmacist]

If MDOH.HCl was made, how could one, qualitatively, tell the difference? Does any one here have some suggestions?

MDOH hydrolyses into the prim. amine in vivo, so there shouldn't bee any qualitative difference, afaik...

[Chromic]

In

Post 298425

(Antibody2: "Al/Hg/HOAc Oxime redxn", Methods Discourse) AB2 writes that MeOH doesn't work. Then he writes about using MeOH to make MDOH. I kinda think this was just some sloppy chemistry? I've seen MDA from a MeOH system before. I'm very tempted to try this with just 5 eq Al in wet MeOH, no acid. Thoughts?

It appears like we really need more peer review going on with our chemistry.

[cublium]

Cub has had some MDOH and he has had some MDA aswell.MDA.HCl's mp was around 182-183 C and MDOH.HCl turned purple upon heating over 120C,don't ask why.
Both worked the same.MDA probably oxidises to MDOH in body.

[Rhodium]

MDOH freebase is a solid, while MDA freebase is a liquid.

[Antibody2]

In AB2's and Chromic's writeups they use 10 eq AcOH and Al... also 10 eq of NaOH to 1 eq Al to basify. lets be clear about this, It was Ab2 s write up, Chromics was a knock off. CHECK THE DATES!

Has anyone had success using less hydroxide or less AcOH/Al while still getting yields in the 80s?
The amount of NaOH has absolutely dick all to with the yeild, Using XS NaOH makes for better extraction seperation especially when using EtOH. this crap really belongs in the newbee forum

  I've heard of 7.5 eq NaOH to Al, and that seems to work just fine. Standard Al/Hg's, a la B.S. etc with imines use 3.3 eq's Al to
   ketone the ratios of NaOH/Al have ABSOLUTELY NOTHING TO DO WITH ratios of Al/ketone

would a good yield still come about if just 3.3 eq's of Al to ketoxime were used? i doubt it, but then again i don't feel compelled to fix things that work just fine. 7.5 equivalents of Al/HOAc is the lowest I've seen without drops in yeild.

If MDOH.HCl was made, how could one, qualitatively, tell the difference? Does any one here have some suggestions? MDOH freebase will leave a frosty coating all over your redxn vessel [edit] and you can partially crash it out of toluene with refridgeration

AB2 writes that MeOH doesn't work. Then he writes about using MeOH to make MDOH. I kinda think this was just some sloppy chemistry? I said the best yeilds were with EtOH not that MeOH didn't work

I've seen MDA from a MeOH system before. I'm very tempted to try this with just 5 eq Al in wet MeOH, no acid. Thoughts? flushing your ketoxime down the toilet would save you time. NO ACID - NO AMINE - PERIOD! but some people need to fuck-up all on their own, be my guest.

It appears like we really need more peer review going on with our chemistry. yah! i should have kept it a secret instead of sharing it with ungrateful cocksuckers like you! Bear in mind smarty pants that before i posted that redxn (that you had sweet fuck all to do with btw) the only other oxime redxn (other than hydrogenation)  involved sodium metal in anhydrous EtOH - try buying that at your local hardware store

[Antibody2]

it isn't 7.5 equivalents of NaOH based on the Al, it is 5 equivalents, and considering the amount of sodium acetate formed in the basification (it will stop the stirbar!!!) you need help to extract that mess.

you want to try with 3.3 equivalents of Al, be my guest. Have you considered the amount of Al consummed reacting with the H20? In case you are using the same math you used to calculate NaOH ratios, let me tell you the H20 ratio is almost 15% of solvent volume(HOAc excluded). A whole lot more water in this reaction than in the BS synth.

what? you think no water? well yes that can be done (proved it reducing DMMDA2), but it is there for a reason, it isn't gratuitous, but i'll let sherlock figure that one out for himself.

You want to use MeOH? it can work, but your work-up will not be the joy that it is with EtOH or IPA. The post basification soup will not be as easy to extract. More emulsions (sodium acetate again).

I'm not saying my synth can't be improved or optimized but i'm damned if i'll accept insults like "sloppy chemistry" from some puke who can't even get his math straight.

[Antibody2]

and what do i get? whining.

did you ever try making MDA with NaBH4? or via leukart? or via nitropropene? There is a learning curve with all those pain in the ass reactions and even then they are still flaky sometimes. My reaction, a newbeee can get a 80% the 1st time!!!

[sYnThOmAtIc]

I though you two were friends?

Oh well I don't mean to piss you off antibody. I love that synth. I was oh so hoping somebody would come up with a better way of reducing that stuff without trying to make or buy sodium metal..

Oh and what it so bad about making mda from nitropropene intermediate? Other than lowsy yields, it is fairly simple.

Weren't the yields your reduction of the oxime like 88%? So what is to improve? Its al/hg simplicity with an oxime super high fucking yield of mda.  Only the sodium metal reduction compares in yields and still is so far from comparison in ease and availability. But hey if you got it use it right?

[Chromic]

Personal attacks aside, AB2's procedure is a beautiful discovery of something that was before thought impossible (the simplicity of an Al/Hg for reducing ketoximes). Adding all the Al at the first as I do, is a nice tweak to the procedure.

I said it to AB2, I'll say it again. I'm a nit-picking fuck who wants to optimize and make this procedure as efficient as possible, without hurting yields. A recent analogous example--the work I repeated from the French ref with GABA said to use 100g GABA / 1L. That observation made by the French chemists was invaluable. Without it, I would have been lost. But I got that to like 100g / 240ml. The yields do not change, the volumetric efficiency nearly quadrules and everything is great. Optimizing a synthesis is not a newbie question--it's discourse on an established method of drug synthesis.

[Antibody2]

Other than lowsy yields kinda says it all, but once upon a time it also used to require the use of ethers

Chromic - optimization is one thing, flattering even. the cheap shots were disappointing and some of the comments/queries of the original post ill considered.

[Herr_Ovalmeister]

Bull. Soc. chim. has and article about Al(Hg) reduction of oximes in it.  Log in as everybee2, password allbees at

http://briefcase.yahoo.com

and go to

http://briefcase.yahoo.com/beefiles2001

.  Its in the Al(Hg)-oximes folder  (BullsocchimFr1934 file).  If you don't have the DejaVu reader on your computer already you can install it by downloading and running the  DjVuSolo3_1-noncom.exe file in the DejaVu program folder.  Its best not to install the DejaVu browser plug-in (DjVuWebBrowserPlugin.exe, not in the folder) because it doesn't seem to work with multi-page files and interferes with downloading multi-page files.

[Antibody2]

but i don't think there is much new there, the reductions they describe are similar to the ones using THF that Rhodium has on his site. (none of them run on our precursers)

for anybee who doesn't read french, they do their reduction in refluxing ether and oddly eneough they add their water dropwise during the reduction with caveats about too fast an addition rate stopping the amlgamation.

[Herr_Ovalmeister]

Here's a partial translation of page 854.  Maybe someone else can finish it.


Bull. soc. chim. France (5)1, (1934)
Page 854

Mode of operation (4):  to a three neck flask with a reflux condenser, mechanized agitator and dropping funnel is introduced at first the necessary quantity of aluminum sheets of 3/10 mm thickness.  Cover with water and small quantity of 10% solution of NaOH.  When the metal is visibly attacked, decant and wash several times with water.  Introduce some 4% HgCl₂ solution.  Becomes cloudy.  Wash metal with water several times, then alcohol.  Add 1/10 mole oxime in 150-200 cm³ ether.  Turn on mechanical agitator.  The release of hydrogen is regular (smooth?)….. and may cause ebullition of the ether.

When the reaction is vigorous/lively water is added through the dropping funnel.  The success of the operation depends on the rate of introduction.  Too high a rate of H₂O addition quenches the reaction………..

When all of the amalgam is transformed:  which takes about 6 to 8 hours……….

The contents of the flask is introduced into (transferred to) a round bottom flask surmounted by a long tube and is maintained on a double boiler for a short time at the temperature of the ebullition of ether.  Strain out aluminum residue, wash with ether, combine ether extracts, evaporate……..

[Chromic]

>NO ACID - NO AMINE - PERIOD!

We'll see if I should have just flushed the ketoxime. My question will be answered shortly.

[Chromic]

175ml MeOH, 35ml H2O, 100mg HgCl2, 11.5g Al. Stirred about 15 minutes. Then 16.4g crunchy white isosafrole ketoxime was added (it did not all dissolve?). Reacted until all foil was gone (lightly refluxed around 2hr point until end of rxn, at which point all ketoxime did dissolve). Basified with 60g NaOH in 135ml water. Extracted with toluene, washed with 10% NaOH, filtered toluene, washed again with 10% NaOH. Titrated with HCl until pH 4. Evaporated water. 12.7g white MDA before IPA recrystallization. (69%)

I must say that the yields aren't the 83% I got before with the 10 eq AcOH and 10 eq Al--but then again only 5 eq Al was used (so this could explain the lowered yield).

[Antibody2]

well I'm surprised to hear it, because neither of the following two refs worked on the oxime of MDP2P. Ab2 wasn't the only one for whom they failed. but if it worked as you say without an acid in alcohol, then i guess its time to eat some crow

JACS 111, 6228 (1989)
To a solution of the oxime (24.6 mg, 0.521 mmol) in 10% H2O-THF (30ml) were added aluminum amalgam, which was prepared from 0.25g of granular aluminum and 2% HgCl2 (0.1ml) in 10% H2O-THF (0.5ml). The reaction mixture was stirred for 3h at room temperature. 3ml conc NaHCO3 was added, and the reaction mixture was filtered and the filter cake washed with ethyl acetate. The filtrate was diluted with water and
extracted with ethyl acetate. The extracts was washed with brine, dried over MgSO4 and concentrated in vacuo to give 20.34 mg (85%) of the desired amine as an oil.



JOC 56(15), 4706 (1991)
A solution of the oxime (11g, 19 mmol) in 250ml dry THF was treated with aluminum foil (5g, 190 mmol) that had been cut into small pieces and immersed successively in 2% aqueous HgCl2, distilled H2O and THF. The dark gray suspension was stirred for 12h at room temperature, at which time TLC revealed the absence of starting material. The suspension was filtrered and concentrated to yield 7.8g (75%) of the product amine as a light yellow oil.

[hypo]

> Ab2 wasn't the only one for whom they failed.

yep, they failed for a (foaf)**5 too (with PMP2Poxime though).
ab2's method then worked with the same batch of oxime.

but note that
*) the man's lab technique was much worse then (not that it's good now).
*) he never had luck with THF systems.

all i can say: very strange.
(i remember you did the reaction with different acids, and only
the AcOH one worked well!?)

[Antibody2]

the THF solvent system did work eventually but it required HOAc

Post 250280

(Antibody2: "Complete synthesis of DMMDA-2 and DMMDMA-2", Methods Discourse), but the yeild was nothing to brag about, and THF is no fun to work with.

(i remember you did the reaction with different acids, and only  the AcOH one worked well!?) i have a theory on why the HCl didn't work as well as HOAc,and it was beacause the HCl was a strong enough acid to react directly with the Al forming alot AlCl3 before the oxime was ever reduced, while the HOAc wasn't a strong enough acid to form an Al salt, not quickly anyways, otherwise the rxn mixture would have been basic at the end of the rxn not still acid.

So i think when HCl was used as the acid in short order it was the same as if no acid was used, which gave the reduced yeilds consistent (or lower) with what Chromic just posted. Thats my theory, for whatever it is worth.

[Chromic]

Perhaps the difference between the two of us trying it could be the external heat I applied? Perhaps the acetic acid consumes the foil fast enough to raise the temperature, and hydrochloric acid too quickly for it to matter? Just a thought.

Did you apply external heat when you tried it without acid? Was all the foil consumed? (I've learned that if the foil is not completely consumed it's a terrible sign for an Al/Hg)

Now my next question is a terrible question. Was it the lack of acid or the reduced amount of foil that dragged down the yield ~10%? (or was it a sort of sloppy workup, where the rxn mix was only extracted 1x with toluene, or was it because I used less base... oh no, sorry guys. there's more small, tiny riddles to be solved) Well, at least we know that the acid isn't necessary for an Al/Hg reduction of ketoximes.

Amines: 1
Acids: 0