Mescaline synthesis-lets make it home friendly!

[Oerlikon]

After some research I decided not only to make some Mescaline,but make synthesis of this wonderfull compound much easier and home-friendy and higher yielding.
Fortunately Rhodium,Sciencemadness and even this forum have some pretty neat articles,using very OTC chemicals (with an exception of few) high yielding and home friendly procedures to get precursors.

First,you start from vaniline to get 5-hydroxyvanillin using vanillin,KI,I2,Cu,some solvents,NaOH,H2SO4 and simple reflux.Yields are sufficient and all chemicals very easy to get here.
http://www.erowid.org/archive/rhodium/chemistry/iodovanillin.html
I do understand that I2 might be hard to get in USA but bromination will probably work as good.

Getting  3,4,5-Trimethoxybenzaldehyde  from 5-hydroxyvanillin  is as simple as first step...if you have some dimethylsulfate lying around. This is a pretty nasty stuff which can't be found commericaly here and which I have no suicidal intent to synthesize as long as it needs vacuum distillation! If anyone can help me here to modify this synthesis using  iodmethane it would be great!
http://www.erowid.org/archive/rhodium/chemistry/mmda.mescaline.html

Getting 3,4,5-Trimethoxynitrostirene from 3,4,5-Trimethoxybenzaldehyde is also a well documented and good yielding method.I don't understand use of cyclohexylamine,but avoiding this  nasty,hard to get stuff  will probably reduce yields ,hopefully not too much if it can be substituted by CH3COONa as in second method:
http://127.0.0.1/rhodium/Rhodium/chemistry/345-meo-ns.html
http://www.erowid.org/archive/rhodium/chemistry/mescaline.cathyd.html

Now last step is the real bitch!

There is no even a remote chance for most of us to get all the reagents and apparatus for Pd/H2 high pressure hydrogenation.This is not even an option in my mind,not even using Urushiba catalyst. LiAlH4 and NaBH4 are also out of question,remember,I am trying to make this synthesis VERY simple and cheap so I came up with few other ideas:

3,4,5-Trimethoxynitrostirene to 3,4,5-Trimethoxynitroethane using Fe/HCl or Sn/HCl. Then 3,4,5-Trimethoxynitroethane to mescaline using this method:
http://www.sciencemadness.org/talk/files.php?pid=134331&aid=6176

Since my knowledge on electronic and electro-chemistry is pretty nonexistent I am not sure if it is even possible to reduce –NO2 to –NH2 along with beta carbon using this method. I do know, however,that  reduction of –NO2 to –NH2 is 3 step process that requires 6e- and 6H+ along with 2e- and 2H+ for double bound. Scaling this method up and changing concentration of reagents will also be a big problem for me.

I think this might really work but I need as much help as I can get on the last step and on the methylation.

[pyramid]

Have you ever tried making 5-hydroxyvanillin? It is the worst possible first step to start off this procedure with. No offense to you, but all this information is very old and not very effective.

You can brominate vanillin in high (85-95%) yield using NaBr/GAA and H2O2. The acetic acid can currently be obtained at many places non-suspiciously and the NaBr and H2O2 are OTC.

Currently there are a few places to easily buy sodium metal specifically catering to amateur chemists... The only worthwhile step from 5-bromovanillin is methoxylation. Making the copper salt is OTC, sodium and DMF are not but are easily bought at several places...
It is worth the hassle to get these, because if you try hydroxylation you will just end up back at the drawing board unhappy. Mthoxylation is home friendly, no inert atmosphere is needed except a blast of butane and dry methanol is easily made or bought OTC for some.

For the methylation of syringaldehde I know of no other good methods beside TMP and DMS. I tried a few times with MeI in several solvents with differing bases and never obtained a useful yield.
It is better to make analogues, alkylate with 1-bromopropane,2-bromopropane etc. Or even escaline, all have lower doses than M anyway.

For the nitrostyrene the most OTC way is cold condensation, 60-70% yield. You can use NaOH or KOH..

The last step, reduction, is really one of the simplest of all. Zn/HCl works, don't expect stellar yield though but it is the most OTC.
Next is Al/Hg, obtain a mercury thermometer, make some nitric acid from hardware store chemicals and you are set.
Both are quite OTC, maybe not zinc dust but it can be bought many places non-suspiciously.


Your only problem will be methylation, but in my opinion the other compounds are better anyway and easier to make the benzaldehyde for them(if you do not have suitable methylating agent). Reduction is not as hard as you think, see what I wrote above. It will be even better if you can get some NaBH4.

With sodium and DMF you can also make metaescaline and syringaldehyde/bouringaldehyde opens up many possibilities. Syringaldehyde is a most worthwhile precursor, even with a successful production method for 5-hydroxyvanillin it is not a very useful product.
Hydroxylation is the worst thing to do, it will kill your yield at the first step!! If you even make it work!


Edit: Ullmann at SM posted an OTC variant of methoxylation using molecular sieves, check it out.

[Oerlikon]

I heard about bromination but never found detailed work-up on it,unlike the method I mentioned above (iodination).
In above mentioned link,yields are consistently documented to be over 70%,so I don't know how it can "get old".
Remember,different chemicals are differently availabe OTC arround the world.
I have and can get things like DMF,p.a. grade MeOH only,GAA,NaBr,Na,I2,H2O2,Cu powder,CuSO4,Zn,Hg,HgCl2,even vanilline can be imported w/o problem.
But things like syringaldehde,mol sieve,NaBH4...theare is no way! maybe in USA,but here...NO!

I am not interested in any analogues apart from mescaline,not at all.
What does DMF and Na have to do with above procedure?!
What about that cold condesation,I am not familiar with those methods but there are two references I posted that claim to have 70%+ yields.
If you have any refferences on procedures you mentioned plese share them here,thanks on advice but I can't do the whole procedure based on the few words.
What is a SM? Sciencemadness.org!?

[pyramid]

I think you are misunderstanding me.
I gave you a different route to mescaline through syringaldehyde.
The DMF and sodium have everything to do with actually making the syringaldehyde.
Look on lambdasyn.org for the vanillin bromination, I have given you enough info to find and research further for yourself. All the routes and info you need is online, I need not repeat it here in detail.

It is old, because there are now much better methods.
So, syringaldehyde you make yourself from the bromovanillin... I only mentioned the mol sieves and NaBH4 as yet another alternate method for particular steps.

Apparently all the chemicals you need vbeside the methylating agent are available to you, so what is the problem?
Yes, sciencemadness.
It sounded like you wanted the most OTC way to the nitrostyrene, if it does not yield high enough for you then you need to make other catalysts or buy them.
So your only problem now is the methylation. I don't know what you can do here beside the methyl methane sulfonate posted at SM.

Please read my post above more carefully, search sciencemadness, hyperlab, versuchschemie, lambdasyn etc etc for info on every single procedure needed that i mentioned!

In the Rhodium archive there is an example of cold condensation of 2,5-dimethoxybenzaldehyde with base. Just use the same general procedure for the 3,4,5-. I believe on hyperlab even there is an actual example of someone who used it. It works and no exotic catalyst is needed. It is also very fast and gives a clean product.
Of course, if other reagents are available for you, then just pick what you want to use beside that. I was just giving what i know to be some of the most OTC methods.

[Oerlikon]

NOW I have the refferences! Thanks,will do so and come back to discuss it after some research.

[redcat]

on forming syringaldehyde from bromo-vanillin, would using a NaOH/NaOMe solution suffice or would the hydroxide be a strong enough base to substitute the ring significantly?

[heisenberg]

on forming syringaldehyde from bromo-vanillin, would using a NaOH/NaOMe solution suffice or would the hydroxide be a strong enough base to substitute the ring significantly?

If you use NaOMe you will get syringaldehyde, if you use NaOH you will get 3,4-dihydroxy-5-methoxybenzaldehyde.

[pyramid]

If there is alot of NaOH and you try the methoxylation the reaction will fail, the conditions aren't even the same.

Redcat, are you talking about NaOMe solution made from anhydrous EtOH and NaOH, with mol sieves? If you get this to work please post your experience as I really want to hear about this. I've heard it works but have never seen an actual example.

[redcat]

yea thats what I was talking about, but I dont really have any way of knowing if it works.  the melting point only differs by 20C so it would be hard to determine that way.

also on a side note, would it be feasible to condense the syringaldehyde with nitromethane and THEN alkylate the phenol? or must the alkylation be before the condensation?

[redcat]

another quick question:
I noticed that all the lab procedures for the methoxylation step use DMF as a solvent.  would any other polar aprotic solvent work like ethylacetate or DMSO?

[Oerlikon]

DMF is not that hard to find.Look at the art shops,modeling shops etc. it's u sed as special kind of paint remover that doesn't damage plastic or something like that.
I still don't get why original method using I instead of Br from Rhodium doesn't work according to pyramid?
They have pretty straight up procedures and yields look great on paper. I would like to heard/read from someone who actually tried it.

Unfortunately I won 't even start this in at least a year,mehylation is unsolvable problem for now.
I can get liters of acetanhydride and many other chemicals that are next to impossible to got where most
of you live but decent reducing or methylating agent...no way!

[pyramid]

I did not say iodination did not work, rather hydroxylation is a waste of reagents if you can even get it to yield something.
It is better in all ways to brominate(NaBr/KBr, H2SO4, GAA, H2O2 like on lambdasyn) because it is cheap and very easy, much cheaper than using I2 or iodide salts.
I have tried the iodination, and the hydroxylation several times(also tried with bromovanillin). I am saying it is not the best option and minuscule yields of the hydroxyvanillin were obtained each time, it DOES NOT work as said on paper unfortunately. You can obtain some yield, but it is very bad about 20%...

But Oerlikon if you find it hard to believe the method on Rhodium does not work well at all, by all means try it for yourself!

There have been some people getting it to work on Hyperlab but it is large scale and still not the best option. If you can get sodium etc then use the methoxylation it is 100% better. Plus when you change your mind about not making analogues you can make the other compounds easily  

Also, maybe you can try methylation with methyl bromide. I'm not saying it will work, but if you make syringaldehyde you could try it on a small scale. It would be really excellent if that worked.

I think DMF is the only suitable solvent for methoxylation, you will be able to find it.

And I do not know why you would want to methylate after condensation (I don't know if this is even possible). You have to methylate anyway, so why not syringaldehyde and obtain pure 3,4,5-trimethoxybenzaldehyde?

[Oerlikon]

As I said many times,different things are differently available OTC arround the globe!
I can get iodine and it's salt easier and Iodine is much better leaving group.
One and only methylation agent I can get is methyl iodide and it doesn't work in this case.

I clearly misunderstood you. Of course,in this case methoxylation is hydroxylation and methylation of 5th position in one step. My fault!
Now I just need to find methylation that works for 4th position...

[redcat]

Alkylation after the condensation (before reduction) would be advantageous if one were making analogues.  rather than alkylation 3 times, condensing 3 times, and reducing 3 times, it would only be necessary to condense once, alkylate 3 times, and reduce 3 times.
also, what kind of product name would the DMF be under?

[pyramid]

I don't understand...
There is only the 4-position on syringaldehyde to alkylate. If you want an analogue, you just use respective alkyl bromide/iodide and reflux in DMF with K2CO3.
For example 4-propyl you just use 1-bromopropane and reflux with above conditions until starting material is consumed...yield is always high.
Then you go on as usual.

Edit: now I see what you mean by 3 times. I do not believe it is even worth it to try alkylating after the condensation. For one i do not know if it works and have never seen it tried, and you might as well do 3 more steps...it is not much work really those alkylations are easy. Plus you get more experience aka FUN!
But really just in my mind if you already have the respective alkylating agent, the syringaldehyde and solvent/base I would just alkylate and do it that way as usual.

[redcat]

thanks for the advice,
if its as easy as you say, then I guess its no big issue

do you think NMP would work as a substitute to DMF?
it seems easier to acquire and has a similar polarity.

BP is a bit higher, but not really that much.

[Sedit]

One and only methylation agent I can get is methyl iodide and it doesn't work in this case.

     This is not true, There is a reference posted somewhere on this site here that speaks of using Ammonium Methylsulfate to Methylate Phenols. This should apply fine here as well even though I have never heard first hand home chemist use of it.

     AMS can be made very simply by refluxing Sulfamic acid in Methyl alcohol in dry condition and good stirring. On cooling large pure crystals of AMS can be filtered off and stored in a dry environment to prevent hydrolysis. The synthesis can be performed in an afternoon and a pound could be made cheep as chips. Its also much less toxic then MeI and many other methylation reagents.

[POSEIDON]

If anyone can help me here to modify this synthesis using  iodmethane it would be great!
Look this link ,
http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0418

and use methyl iodide

[andreas]

I remember there was a 1930s electrochemical reduction of some aldehyde ... maybe 2,5dmb maybe not, thru to mesc.
I remember something of note in the experiment : they got some custom made porcelain basin to do it in , I think instead of using a salt bridge they used a molecular sieve porcelain wall.

Ah, it is called electromesc.txt on someplace.

Edit: Here is the original text you are talking about http://127.0.0.1/Rhodium/Rhodium/chemistry/electromesc.txt - Palladium

[redcat]

One and only methylation agent I can get is methyl iodide and it doesn't work in this case.

     This is not true, There is a reference posted somewhere on this site here that speaks of using Ammonium Methylsulfate to Methylate Phenols. This should apply fine here as well even though I have never heard first hand home chemist use of it.

     AMS can be made very simply by refluxing Sulfamic acid in Methyl alcohol in dry condition and good stirring. On cooling large pure crystals of AMS can be filtered off and stored in a dry environment to prevent hydrolysis. The synthesis can be performed in an afternoon and a pound could be made cheep as chips. Its also much less toxic then MeI and many other methylation reagents.

what would be an appropriate way of drying the AMS? simple vacuum filtration?
after the crystals are stored, what kind of solvent is necessary for the methylation?
is it just a simple reflux for a few hours or is it more complex?