Sciencemadness Discussion Board

n-methyl-3,4-Dihydroxyphenylalanine (orgsyn)

tupence_hapeny - 25-3-2007 at 18:26

Making my first post, one from which my character can be ascertained, is somewhat daunting.

However, I found this synthesis on orgsyn, and apart from one or two chemicals it is well within the reach of the everyday hobbyist:

http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv3...

It is entirely legal to possess and/or make, although the current synthesis may make use of some chemicals I neither want to acquire or own (namely HI). One chemical is seriously not something you would want to order, while another is also not a good idea (Ca.Hg(2?)).

Therefore, I would like some assistance, especially from some of the more knowledgeable persons, on this forum, in order to find a more OTC approach to this interesting, legal molecule.

For instance, I have heard that it is possible to demethylate the vanillin using Lithium Chloride, which is easily prepared from OTC materials (Lithium Carbonate and Chlorine gas) in dimethyl formamide. I therefore seek information on whether DMSO could be substituted for DMF, and if so, what effect this substitution could have on the reaction procedure? (currently works by heating to 150-160C and adding portions of Lithium Chloride over 20 hours). I would also be interested in ascertaining whether this reaction could be performed in a microwave, thus reducing the reaction time.

I would like to know whether the double bond reduction by calcium amalgam could be effectively carried out by use of an aluminium amalgam (given the restrictions upon the use of alkali metals here).:mad:



Thanks

[Edited on 26-3-2007 by tupence_hapeny]

not_important - 25-3-2007 at 19:56

Quote:
...Lithium Chloride, which is easily prepared from OTC materials (Lithium Carbonate and Chlorine gas...


Sounds like an interesting reaction. I've always done it by placing two beakers containing respectively Li2CO3 and water, and tech hydrochloric acid, in a plastic bucket and loosely placing the lid. My way just release CO2, your's look to pump out O2 or a chlorine oxide as well.

There does not appear to be any mention of calcium amalgam in the article you reference.

You can prepare amalgam electrolytically, although perhaps not of sufficient concentration.

[Edited on 26-3-2007 by not_important]

Levi - 25-3-2007 at 21:02

I understood very little of what you said, tupence, but welcome to sciencemadness.

tupence_hapeny - 25-3-2007 at 23:01

Quote:
Originally posted by not_important
Quote:
...Lithium Chloride, which is easily prepared from OTC materials (Lithium Carbonate and Chlorine gas...


Sounds like an interesting reaction. I've always done it by placing two beakers containing respectively Li2CO3 and water, and tech hydrochloric acid, in a plastic bucket and loosely placing the lid. My way just release CO2, your's look to pump out O2 or a chlorine oxide as well.

There does not appear to be any mention of calcium amalgam in the article you reference.

You can prepare amalgam electrolytically, although perhaps not of sufficient concentration.

[Edited on 26-3-2007 by not_important]


The patent it came from makes extensive reference to the need for it to be dry.... (They make the Chloride and dry it in the gas).

They make no reference to calcium amalgam, only to sodium (I chose to use calcium if I do this, I think it requires marginally less mercury (per potential hydrogen) than sodium amalgam:().

Also, with regard to useful aldehydes this could be applied to, could this synthesis be used (minus the demethylation of course) with piperonal? That would be an interesting, substituted phenylalanine...:)

Nicodem - 25-3-2007 at 23:29

Lithium chloride is very hygroscopic and is not easy to dry while it needs to be absolutely dry if the goal is to use it as Lewis acid (same goes for the DMF solvent). Anyway, even if you "heard" that it can be used to demethylate vanillin this still does not mean one can use such a method to substitute the HI demethylation step in that Org. Syn. procedure. The amino acid substrate is something completely different and the LiCl would get quenched by the amino and carboxylic groups. Besides, if your goal is just to play around with amino acids synthesis why you even want to bother with the last step?

Where did you heard that calcium amalgam reduces conjugated electrophilic double bonds like the sodium amalgam used in the procedure? Aluminium amalgam is not particularly useful for the reduction of electrophilic double bonds, but if I remember correctly it can do that on some substrates. I have no idea if it would work on such benzylidenes and besides it would be very, very difficult to work up the reduction due to the acidic phenol group on this particular substrate. CTH reduction systems, for example HCOOK with Pd/C, can be used to reduce electrophilic benzylidene type double bonds (as for example in the reduction of cinnamic acids to phenylpropanoic acids). There are a bunch of other CTH systems used specifically for the reduction of carboxy enamides to amino acid amides, thus suitable to what you want to reduce.

Edit: Any aldehyde without alpha-hydrogens or interfering functional groups can be used instead of vanillin.

[Edited on by Nicodem]

tupence_hapeny - 26-3-2007 at 01:26

Quote:
Originally posted by Nicodem
Lithium chloride is very hygroscopic and is not easy to dry while it needs to be absolutely dry if the goal is to use it as Lewis acid (same goes for the DMF solvent). Anyway, even if you "heard" that it can be used to demethylate vanillin this still does not mean one can use such a method to substitute the HI demethylation step in that Org. Syn. procedure. The amino acid substrate is something completely different and the LiCl would get quenched by the amino and carboxylic groups. Besides, if your goal is just to play around with amino acids synthesis why you even want to bother with the last step?

Where did you heard that calcium amalgam reduces conjugated electrophilic double bonds like the sodium amalgam used in the procedure? Aluminium amalgam is not particularly useful for the reduction of electrophilic double bonds, but if I remember correctly it can do that on some substrates. I have no idea if it would work on such benzylidenes and besides it would be very, very difficult to work up the reduction due to the acidic phenol group on this particular substrate. CTH reduction systems, for example HCOOK with Pd/C, can be used to reduce electrophilic benzylidene type double bonds (as for example in the reduction of cinnamic acids to phenylpropanoic acids). There are a bunch of other CTH systems used specifically for the reduction of carboxy enamides to amino acid amides, thus suitable to what you want to reduce.

Edit: Any aldehyde without alpha-hydrogens or interfering functional groups can be used instead of vanillin.

[Edited on by Nicodem]


Sorry Nicodem,

The idea of using Calcium instead of Sodium was not something I had 'heard' anywhere... It was rather my own poorly thought out idea:( Aside from which , I believe that you're well aware of where I 'heard' about the idea of demethylating vanillin with Lithium Chloride:P

Anyhow, thanks for the information regarding the use of HCOOK (Potassium Formate?), that is weird, I was just reading a host of journal articles on precisely this 'variant' on the leukhardt-wallach(?) reaction yesterday (albeit using formic acid and formamide - also if I remember one used Pt while another used Ni) in conjunction with the reduction of carbonyl groups.

Sorry if my approach to these compounds offends, however, I believe the WOD is both invalid and immoral (given it is utterly impossible for a country to maintain laws which 1/2 of the population breach (or have done) and proclaim itself a democracy:mad:). The sooner we face facts and end this pointless excuse to provide the government (esp. police and the rest of the executive) with the excuse to persecute the people they purport to serve, the better:(

Nicodem - 26-3-2007 at 09:05

I'm not particularly interested in what you heard but in references to what you heard. I'm quite sure any other member who happens to read your post expects exactly the same.

CTH reductions with formic acid salts are not called Leuckart-Wallach reactions - that is a completely different reaction. The CTH acronym stands for "catalytic transfer hydrogenation" and it is essentially the same as the usual catalytic hydrogenation with the difference that instead of H2 another hydride donor is used (cyclohexene, formates, hypophosphites, borohydrides…).

I don't know what all that comments about legislation and war on drugs (assuming WOD means that) has to do with your questions, but if you have an unstoppable urge to post about that, then it would be preferable if you do that in an appropriate section of the forum (Legal and Societal Issues, Whimsy and Detritus seem more appropriate). Not surprisingly this Organic chemistry section is reserved to organic chemistry only.

tupence_hapeny - 26-3-2007 at 20:06

I was not suggesting this transfer hydrogenation (and/or deoxygenation) reaction was a leuckart-Wallach reaction, I was mentioning that there appears to be a great deal of work going into CTH reactions, using the same protocols (albeit with a hydrogenation catalyst) developed for the Leuckart-Wallach reactions (and others, suprising dithionite has been used very succesfully in the same range of L-W reactions as the formate's as a hydrogen donor, so could it be the hydrogen donor here?

http://stratingh.eldoc.ub.rug.nl/FILES/root/VriesJGde/1980/J...

I strangely enough presumed that Methyl-DOPA would be a useful chemical target, one which even the more advanced among us here would be interested in modifying a synthesis of (after all L-DOPA was recently the source of such a lot of interest:D).

Now, that out of the way, let us proceed.

I will avoid all reference to the demethylation reaction (although big tip, it does work). Therefore, All that need be discussed is the (1) reduction of the double bond; (2) hydrolysis of the product with (a) Barium Hydroxide; and (b) Sulphuric Acid. I have stated that I dislike the idea of utilising HI for the demethylation reaction, for legal reasons especially (if it attacks the COOH you will have a SHITLOAD of explaining to do, not least as to why you have a seriously controlled (prohibited) acid and how you used that to 'accidentally' make an even more controlled amphetamine analogue:o).

Now, in order not to upset any one any more, I will suggest that if you wish to carefully reduce the COOH, that you do so carefully and quietly, well away from me . There are any number of methods that you could use, such as HI which will do the quickly although with copious evolution of betraying odours (or so I have heard).

Now, Nicodem... If someone can tell me how the hell I upload files I am more than happy to provide you with some of the refereed articles upon which I have based some of my assumptions (and/or presumptions). Many of them basically describe the use of Leuckart reactants in modified CTH & even Clemmensen type reactions, although I am stumped as to which article I got the reference to calling them Leuckart 'type' reactions. I realise professionals and purists may despise such naming methods, nonetheless, they are effective at describing the mechanism so us less professional and pure 'kitchen kemists', with our limited understanding can decipher how they work.

I do, sincerely, thank you for your interest in broadening the minds of such aspirants as myself and trust me, I ask questions because I do not know, I don't make suggestions because I am sure that they will work, but because with my limited knowledge they might. As to legal & societal issues, you appeared to be seeking some response as to why the interest in the MD version of the same, at least that is how I understood it, if so, honesty is the best policy, wouldn't you agree?

Nicodem - 27-3-2007 at 00:49

I still do not fully understand a lot of your vague talk, but I came to believe that you made quite some terrible confusions:

1.) the end compound in that Org. Syn. procedure is not methyl-DOPA, using the DOPA acronym you could call the product N-methyl-DOPA - thus quite adifferent compound;
2.) neither methyl-DOPA nor this end compound (N-methyl-DOPA) are scheduled in USA (where I assume you live given all the information you gave), however methyl-DOPA is a pharmaceutical compound and as such is bound to FDA rules;
3.) no product or side product arising from the reaction of N-methyl-DOPA or methyl-DOPA with hydrogen iodide is in anyway scheduled or controlled;
4.) you can not reduce the carboxylic group in amino acids to a methyl group with hydrogen iodide, but if you could reduce it (with some other reagent) you would obtain N-methyl-3,4-dihydroxyamphetamine which is fully legal though quite certainly similarly cardiotoxic and vascularly active as 3,4-dihydroxyamphetamine;
5.) reaction differences are based on mechanistical pathways and not on the use of specific reagents like you seem to believe (the Leuckart reaction is mechanistically very different from any CTH reduction even though both can use ammonium formate as reagent) thus calling a CTH reduction as a Leuckart is complete nonsense and only leads to more confusion.

tupence_hapeny - 27-3-2007 at 13:05

Ummm, I do not have any interest in this particular compound for the purpose of making amphetamine derivatives per se... It may be do-able, but at somewhat extraordinary lengths (as with all the other phenylalanine derivatives).

However, I do have a SERIOUS problem with using HI for any HOBBY type reaction... This shit is seriously bad news, leaving aside all of the rather horrific details of the acid itself (like eating glass), it is worth, all by its lonesome a serious custodial sentence, particularly if the prosecution could explain to the Court that it was to be (or was being) used to reduce an 'analogue of a controlled substance'. Quite frankly, unless you have the money to employ serious expert witnesses and brilliant lawyers, YOU ARE FUCKED.

Therefore, I make a suggestion regarding a legitimate synthetic target, I even attempted to phrase the bloody thing appropriately.

Quite frankly, if I wanted to use any part of this reaction to produce the compounds you impute, I would reductively aminate potassium pyruvate with methylamine (instead of ammonia as in these two patents):

http://www.freepatentsonline.com/4149012.html
http://www.freepatentsonline.com/3972921.html

And then perform the Akabori synthesis using vanillin and n-methyl-d,l-alanine, reducing this sucker with HI (I2/H3PO3) to achieve both the demethylation and reduction of that pesky OH in one pot (as mentioned elsewhere using hydroquinone to retard polymerisation). Then methylation using MeI2/Br2/Cl2... Apart from Methylamine (which even I can reach), entirely OTC, and fairly cheap so crap overall yields wouldn't matter.

So, having (hopefully) established that my interest in the title compound is not connected with the synthesis of banned substances, may we proceed?

No, I do not believe that the naming of reactions is dependant upon (or even necessarily related to) the reagents involved. I simply happened to note (as even a perfunctory search will demonstrate) that others, much more qualified than myself, were describing the formate CTH as a Leuckart type reaction. This made it a great deal easier for me to grasp the mechanics behind the reaction in this instance, so I thought to adopt that usage. Perhaps in order to resolve this debate, it is time for me to demonstrate my ignorance in full (bearing in mind I have no training in chemistry that will take some time, patience please)

I personally understand (although my understanding of the mechanics of such reactions is unfortunately still somewhat vague) the reaction to proceed by virtually the same mechanism as a catalytic leuckart (albeit without the amine). Apart from that part of the reaction which forms the imine (normally formamide/methylformamide), the LW is simply a transfer hydrogenation of a carbonyl type compound from a formate hydrogen donor, giving CO2 and whatever group was attached to the (now reduced) carbonyl. I believe this to be right, so if I am wrong, please advise me where and how this theory is wrong - that is not a challenge but a request.

Eclectic - 27-3-2007 at 13:51

I think you are confusing HI with HF. AFAIK, HI does not eat glass, although is is very corrosive to metals. While watched, and regulated as far as sale goes, is HI actually illegal to possess and use for any purpose other than reducing ephedrine and pseudophedrine and phenylpropanolamine to various amphetamines? No drug precursor and reductant=no illegal drugs.

tupence_hapeny - 27-3-2007 at 20:49

Here, Hyroiodic/Hydriodic acid is certainly prohibited. Possession of more than 0.1g is an indictable offence, and serves as grounds from which to infer intent to manufacture amphetamines. Whether or not the material it is being used to reduce is 'technically' an amphetamine matters very little, particularly as you having been in possession of it, are on a hiding to nothing with the jury from the start, so whether they will believe your version of what you were doing over the version put before them by both police witnesses and the prosecutor. You will require the use of a VERY EXPERIENCED & QUALIFIED professor in organic chemistry, who is unlikely to wan't to be involved, in order to convince the jury that the chemical structures are not the same and not able to be, with the materials on hand, turned into illicit drugs. This will be an uphill battle, and success is not guaranteed, quite frankly, juries are 'normal' people with no knowledge of chemistry, but with the same fear of the unknown as has been instilled into all of us from birth, the fact that police and the government believe you are guilty puts you behind the 8-ball big time.

PS So SWIM 'imagined' the etching caused by hot, concentrated HI? Perhaps this etching is similar to the effect of concentrated HCl on gold over time? You know, HCl does not affect gold, right? Yet concentrated HCl will attack it over time, high heat and concentrations make acids and bases do things that they may not do normally, that doesn't mean it doesn't happen.

Nicodem - 28-3-2007 at 01:53

All that off topic legalistic bullshit in the Organic chemistry section makes me highly upset. Please stop with that crap! Who do you try to fool anyway? Do you seriously believe that nobody noticed that you confused everything you could confuse and you actually thought that amino acid might be in anyway a useful precursor to illegal drugs? Your unstoppable off topic diversions into the legal aspects of prohibition and the presumed illegality of hydrogen iodide possession is nothing but an expression of your bad consciousness and an apologism to your greed just as demonstrated by your "swimming". Please grow up or if you are unable to mature then just move over to WetDreams. And meanwhile try not to spread misinformation like that crap about acids properties and hydrogen transfer in the Leuckart reaction. Don't get me wrong, it is not that I'm upset because of your ignorance, that is fully comprehended, I'm upset because you consider this forum's members plain suckers.

[Edited on by Nicodem]

not_important - 28-3-2007 at 09:25

Another way to get dry LiCl is to make it via conventional wet methods, dry it at 100 C or so, mix with ammonium chloride, and heat while removing gasses with a slight vacuum, and finally a higher vacuum to get all the NH4Cl. The detailed procedure is in an early Inorganic Synthesis, used to make anhydrous lanthanide chlorides (or bromides). Works for non-volatile halides - alkali, alkaline earth, and lanthanide metals, manganese, and a few others; not for Al, Zn, and so on.

tupence_hapeny - 28-3-2007 at 20:43

Nicodem,

So having just stated that HI is illegal here, you would suggest I state that I had noticed the effect of the same substance on glassware, given that just such an admission would be, in fact, nothing less than a veritable admission to having taken part in an ACTUAL illegal act?

I am sure that nothing would please me more, however and unfortunately, I am utterly incapable of doing so, for as I mentioned, the person who may or may not have taken part in the commission of an ACTUAL illegal act was somebody other than me.

Not_important,

Thanks for that, it would be useful not to have to work with dry gasses, one of my all time pet hates.

tup

[Edited on 29-3-2007 by tupence_hapeny]

As to the etching of glass by HI, I think I may have discovered the reason why...

HI generated by the reaction between orthophoric acid and Iodide will generally be accomplished by use of orthophosphoric acid generated by the 'wet process' (calcium phosphate + sulphuric acid = calcium sulphate and phosphoric acid), one of the contaminants of which is hydroflouric acid:

http://en.wikipedia.org/wiki/Phosphoric_acid

Similarly to that produced by reaction of cheap, hypophosphorus acid (and phosphorus acid) derived from the salts, as these are made by (in one approach) heating a dry mixture of carbon (charcoal) and absorbed phosphoric acid to white heat and generating phosphorus, which is collected in water (which is turned into the acid) and forms a slurry which is reacted with calcium carbonate. The phosphite and hypophosphite salts being separated from the phosphate salts by dissolving in water:

http://www.freepatentsonline.com/4379132.html

There doesn't appear to be any means utillised of separating out the calcium flouride (from the contaminant in the original absorbed acid or the precipitant), so some of this will remain in the salts - which will also be in the acid generated (H2PO2/H3PO3) from them, so contaminating any HI generated therefrom.

I presume that the HI generated from RP would be free of this impurity, so this would be the reason why the various reactions differ.



[Edited on 29-3-2007 by tupence_hapeny]

Nicodem - 29-3-2007 at 03:45

I can work with concentrated aqueous HI any time I want without worrying about any legal consequences. You should find the paragraph of the law saying that working with HI is illegal before making such assumptions based on rumors. If such a paragraph truly exists it would mean that perhaps thousands of chemists are criminals, but what is naive is that you seem to believe that the law is the same all over the world. Anyway, there are so many threads on these issues in the "Legal and Societal Issues" section of the forum that I can only consider this discussion as extremely off topic here.

Aqueous HI does not etch glass – actually it is even sold in glass bottles. You seem to have it mixed up with the etching of the glass that happens with the hot H3PO4 (at >120°C H3PO4 attacks glass and ceramics quite notably and above 150°C where it starts to dehydrate to pyrophosphoric acid it is able to dissolve your flask in some hours). Hydrogen fluoride on the other hand attacks glass already at room temperature and quite more efficiently due to the very favorable thermodynamics of the Si-F bond over the Si-O bond (since glasses are amorphous metallic silicates).

tupence_hapeny - 29-3-2007 at 20:39

A quick look at the legislative changes made post-2004 in the majority of jurisdictions, from which hobbyists contributing to this board would come from, will demonstrate that HI is a prohibited substance. You (obviously as a result of your employment?) may have access to HI, and frankly I wouldn't doubt it, however, this does not mean that it is a particularly 'usable' chemical for most amateurs (especially here, as in this jurisdiction there is not even any allowance for researchers to have it, it is simply verboten).

I honestly did not consider the effect of the hot phosphoric acid, thank you. I think that this may serve as a valuable demonstration of the potential differences that can occur as the result of using 'non-Lab Grade' (or even tech) reagents.

In relation to the nature of HI, so could it be purified by feeding some powdered silica to the reaction? On the assumption that the more finely divided sillica will react with the phosphoric (or even pyrophosphoric acid) before it eats too much of the glassware (it should also remove the HF)?

This may be of some significant utility, as the industrial process for hydrogenation of carbohydrates to hydrocarbons uses distillation to remove the HI from the H3PO4 generated by the reaction between phosphorus acid and iodide. This would be good as the industrial processes for making the phosphorus require phosphoric acid to be mixed with sillica, so the removal of it from its end use would be a step in the regeneration of it, elegant is good...

So, back to the title reaction, the double-bond can be reduced with potassium formate and formic acid... I take it an excess of at least one of the two would be necessary? Do you have any links to articles, etc. describing the reaction? I have some, but they don't go into the reduction of double bonds, only specific functional groups.

[Edited on 30-3-2007 by tupence_hapeny]

Nicodem - 30-3-2007 at 01:12

Quote:
Originally posted by tupence_hapeny
So, back to the title reaction, the double-bond can be reduced with potassium formate and formic acid... I take it an excess of at least one of the two would be necessary?

Formic acid itself can not be efficiently used in CTH reductions, only its deprotonated form, the formate anion, can be used as a so called hydride donor. The mechanism for the "hydride donation" requires intramolecular beta-hydride elimination from an L-M-O-CO-H intermediate where M is palladium or other appropriate transition metal and L any ligand - thus only formate salts work appropriately since HCOOH itself is unable to coordinate well with the metal. This intermediate usually decomposes to MH2 (if L=H) and CO2 as side product (similar but specific mechanisms go on also with other hydride donors like hydrazine, cyclohexene, hypophosphates, isopropanol…). Thus the reducing hydride species is usually exactly the same as in normal hydrogenations except that it is formed from beta-hydride eliminations as opposed to the insertion of the metal in the H-H sigma bond (the point is mainly in making the use of the Parr apparatus and H2 unnecessary). You do not need to know all that about the mechanism since organometallic chemistry of transition metals is way beyond the scope of this thread, but as you can already see the mechanism is completely different from the mechanism of the Leuckart reaction (the mechanism of the Leuckart is discussed in Tetrahedron, 19 (1963) 1789-1799; J. Am. Chem. Soc., 70 (1948) 1187-1189; J. Am. Chem. Soc., 70 (1948) 1422-1424 and several other papers; as you can see it no hypothesis of its mechanism ever calls for an organometallic intermediate).

Some relevant CTH reductions papers and reviews:
Synthesis, (1988) 91-95 (DOI: 10.1055/s-1988-27478) and references therein.
http://www.erowid.org/archive/rhodium/chemistry/cth.cinnamic...
Tetrahedron Letters, 41 (2000) 7847–7849 (DOI:10.1016/S0040-4039(00)01365-4).
the "Reduction of the double bond in conjugation to carbonyl moiety" section in http://www.erowid.org/archive/rhodium/chemistry/cth.af.revie...
…and many, many other papers you can find for yourself by searching using the several publisher's search engines.

Only an experiment can confirm you beyond any doubt weather any CTH method for the reduction of electrophilic conjugated double bonds might work efficiently for your specific case.

PS: I can easily order hydriodic acid, just like anybody else in my country, if I would ever happen to need it. No need to ask my employer to do so.

Edit: I disagree that the majority of contributors to this forum are from the jurisdiction of Texas, USA or any such cowboy jurisdiction. Perhaps the scientific level of this forum is not particularly high, but I don't think it so bad as to call for such harsh conclusions.

[Edited on by Nicodem]

tupence_hapeny - 30-3-2007 at 03:20

Nicodem,

Thank you. I am currently reading like mad in order to understand how and why the reaction works. I do appreciate the input.

BTW, here is my post on the legal issues regarding amateur chemistry in Australia at the present time:

http://www.sciencemadness.org/talk/viewthread.php?tid=8228

You may notice that I have taken advantage of the opportunity to place it in the appropriate forum.

tup

tupence_hapeny - 30-3-2007 at 18:56

Now, sorry about the double post, but I don't feel comfortable with editing after the end of the same day (seems dishonest somehow). Anyhow, with relation to the demethylation I have found some fleeting references in old boards on the use of NMP (n-methylpyrolidone) as a substitute for pyridine with AlCl3. On a search of this board I have found a 1999 patent (originally posted by CherrieBaby: http://www.sciencemadness.org/talk/viewthread.php?tid=1369&a...) for the methylation of bezodioxoles using NMP and dihalomethane:

http://www.freepatentsonline.com/5936103.html

With regard to the substitution of the pyridine, I refer amongst others to this:

http://www.erowid.org/archive/rhodium/chemistry/allylcatecho...

Which while not using NMP this paper does substitute the pyridine with pet.ether. I also found other references to the demethylation of eugenol and vanillin (there appears to have been a great deal of interest in this subject over the years?). Some of the chemistry appears sound, and some just plain dangerous, however, there is even a vague reference to the potential of NMP (although the author seems to believe that an organic base is necessary which pet-ether ain't so it can't be):

http://www.synthetikal.org/hiveboard/arch/forum/topic/topic_...

(NB Another reference by Wizard X to the use of HI for demethylation, seems he was right all along (btw as per the orgsyn version of the title compound, use of Acetic Anhydride will obviate the need for hydroquinone, for those here that are simply perverse).

Finally, a reference to a book which is kinda famous to some people here, I won't mention the name of the same as I bumped into a massive bitch session on this board about the current use (misuse?) of the name of the same by another board:

http://designer-drug.com/pte/12.162.180.114/dcd/chemistry/tc...

This also goes into a number of specific approaches to the demethylation of eugenol/vanillin.

The reason I suggest NMP is basically the reason advanced by the author of the patent cited by CherrieBaby. It is a high boiling bipolar aprotic solvent, which does not break down at 200C, or form nasty smelly mercaptan like DMSO. It is also freely available as a paint stripper (actually as a GBL substitute) in anything up to 220L drums and beyond for stuff all. Basically if AlCl3 and petroleum ether work I see no reason why, especially given my dislike for ether, this wouldn't.

I am aware however, that this is a topic that has been argued to death, so I would expect that others have other ideas as to whether or not it will work.

With regard to the reduction of the double bond, Nicodem, I am trying to avoid Pd as I just noticed that Palladium chloride is also banned here. Is there any way around this, such as for instance a dissolving metal reaction (although mercuric chloride (HgCl2) is banned mercury chloride (Hg2Cl2) is not - easier to make - doesn't work so easily, quickly or well).

Please understand me, I don't intend to BREAK the law, just to give the bastard a mighty stretch (I think the time has come).

BTW Here is a paper that describes the demethylation of vanillin in 92% yield using nitrobenzene and Aluminium Bromide:

Jayne Thesis

[Edited on 31-3-2007 by tupence_hapeny]

2nd Edit

The reason I ask about dissolving metal reaction (namely clemenson type - Zn/Hg) is due to this article which suggests that the formate method of transfer hydrogenation was developed as an alternative to Wolf/Kischner & Clemmenson reactions:

http://www.erowid.org/archive/rhodium/chemistry/cth.carbonyl...

[Edited on 31-3-2007 by tupence_hapeny]

Nicodem - 31-3-2007 at 05:48

Confusing lots of stuff again? It is getting a habit already. :)

The US5936103 patent is about methylenation where NMP is only a solvent most appropriate due to its high dielectric constant (thus promoting SN2 substitutions). It has nothing to do with demethylations! (You seem to have confused methylenations with demethylations all over your last post.)
Pyridine can not be used for demethylations. Instead certain pyridinium salts can be used since they are both acids and solvents (they are so called ionic liquids at the reaction temperature). Usually pyridine hydrochloride is used (being the cheapest) like in the example of eugenol demethylation you referred to. The other reason for using pyridine salts instead of the usual strong acids otherwise used (like AlCl3, AlBr3, AlI3, BBr3, BCl3, HBr, HI and so on) is in that they are less harsh and some other functional groups can survive where they otherwise would not (like the double bond in eugenol if HBr was to be used). So there is no such thing as "substitute the pyridine with pet.ether" for the simple reason that neither pyridine nor petrol ether can be used as reagents for demethylations. The first can not be used at all (since it is a base) while the second is just an inert solvent, thus appropriate for the use of AlCl3 as the acid reagent for demethylation.
Quote:
With regard to the reduction of the double bond, Nicodem, I am trying to avoid Pd as I just noticed that Palladium chloride is also banned here.

Like I already said, chances are that aluminium or zinc amalgam can reduce this double bond, but I would certainly not bet on it.
Quote:
Please understand me, I don't intend to BREAK the law, just to give the bastard a mighty stretch (I think the time has come).

And you want to do that by synthesizing a useless amino acid? You could have at least chosen to make some methyl-DOPA instead, so that you will have some medicine in case you get Parkinson's. :P

tupence_hapeny - 31-3-2007 at 06:20

Sorry, may not have been real clear... I'm still trying to get the hang of writing this stuff properly. No, I didn't think that the NMP was anything other than a solvent, however, I have constantly run into the suggestion here, there and everywhere that a strong organic base is necessary (in addition to the lewis acid) in order to demethylate vanillin and eugenol. My point in relation to petroleum ether (also not suggesting that it was a reagent, merely a solvent) was that if it works and is not a strong, organic base (when used in conjunction with a lewis acid) in this reaction - there is no real reason why NMP would not. I do however grovel in shame in relation to the misuse of pyridine instead of pyridine hydrochloride - that was not intentional - merely an oversight and not meant to mislead (in fact, given the widespread knowledge of, for instance the microwave demethylation, I would be rather suprised if it could).

The making of a 'useless amino acid' is precisely what I intend to make Sir... I am currently sueing police where I am and have ABSOLUTELY no intention of making anything stronger as I confidently expect a visit immediately a 'chemical' smell is noticed. I need to be able to assert in Court that I was ONLY making a 'useless amino acid' moreover, via a synthetic route which was (1) viable; and (2) completely legal. I assume you of all people will be able to understand my purpose in doing so?

tup

EDIT: PS Nicodem, I appear to have missed something on my first glance at your post, you say that the double bond from eugenol would not survive demethylation using a lewis acid.... What precisely would happen to it?

[Edited on 1-4-2007 by tupence_hapeny]

Sandmeyer - 31-3-2007 at 13:39

Quote:
Originally posted by Nicodem
Where did you heard that calcium amalgam reduces conjugated electrophilic double bonds like the sodium amalgam used in the procedure? Aluminium amalgam is not particularly useful for the reduction of electrophilic double bonds, but if I remember correctly it can do that on some substrates. I have no idea if it would work on such benzylidenes and besides it would be very, very difficult to work up the reduction due to the acidic phenol group on this particular substrate. CTH reduction systems, for example HCOOK with Pd/C, can be used to reduce electrophilic benzylidene type double bonds (as for example in the reduction of cinnamic acids to phenylpropanoic acids). There are a bunch of other CTH systems used specifically for the reduction of carboxy enamides to amino acid amides, thus suitable to what you want to reduce.

Edit: Any aldehyde without alpha-hydrogens or interfering functional groups can be used instead of vanillin.

[Edited on by Nicodem]



MeOH/Mg is also effective for this sort of reduction... If someone can get this paper: http://www.ingentaconnect.com/content/ben/coc/2004/00000008/...


Magnesium in Methanol (Mg / MeOH) in Organic Syntheses

Authors: G. H. Lee1; I. K. Youn1; E. B. Choi1; H. K. Lee1; G. H. Yon1; H. C. Yang1; C. S. Pak1

Source: Current Organic Chemistry, Volume 8, Number 13, September 2004, pp. 1263-1287(25)

Abstract:

Magnesium in methanol(Mg / MeOH) system is an extremely versatile, efficient, economical and convenient reducing agent for various reactions useful for organic synthesis such as reductive cyclization, reductive elimination, reductive cleavage, reduction of a conjugated double bond, desulfonylation, and reduction of various functional groups. This comprehensive review is intended to highlight the use of Mg / MeOH in each of these organic transformations.

PainKilla - 31-3-2007 at 14:16

Quote:
Originally posted by Sandmeyer
Quote:
Originally posted by Nicodem
Where did you heard that calcium amalgam reduces conjugated electrophilic double bonds like the sodium amalgam used in the procedure? Aluminium amalgam is not particularly useful for the reduction of electrophilic double bonds, but if I remember correctly it can do that on some substrates. I have no idea if it would work on such benzylidenes and besides it would be very, very difficult to work up the reduction due to the acidic phenol group on this particular substrate. CTH reduction systems, for example HCOOK with Pd/C, can be used to reduce electrophilic benzylidene type double bonds (as for example in the reduction of cinnamic acids to phenylpropanoic acids). There are a bunch of other CTH systems used specifically for the reduction of carboxy enamides to amino acid amides, thus suitable to what you want to reduce.

Edit: Any aldehyde without alpha-hydrogens or interfering functional groups can be used instead of vanillin.

[Edited on by Nicodem]



MeOH/Mg is also effective for this sort of reduction... If someone can get this paper: http://www.ingentaconnect.com/content/ben/coc/2004/00000008/...


Magnesium in Methanol (Mg / MeOH) in Organic Syntheses

Authors: G. H. Lee1; I. K. Youn1; E. B. Choi1; H. K. Lee1; G. H. Yon1; H. C. Yang1; C. S. Pak1

Source: Current Organic Chemistry, Volume 8, Number 13, September 2004, pp. 1263-1287(25)

Abstract:

Magnesium in methanol(Mg / MeOH) system is an extremely versatile, efficient, economical and convenient reducing agent for various reactions useful for organic synthesis such as reductive cyclization, reductive elimination, reductive cleavage, reduction of a conjugated double bond, desulfonylation, and reduction of various functional groups. This comprehensive review is intended to highlight the use of Mg / MeOH in each of these organic transformations.


Attachment: 14259790.pdf (208kB)
This file has been downloaded 14242 times


tupence_hapeny - 31-3-2007 at 21:31

Thanks Sandmeyer and PainKilla, all research is gratefully accepted.

Now back to that bloody double bond,

Would the Zinc/Nickel couple, as is according to this paper, capable of reducing the double bond in cinnamic acid to hydrocinnamic acid (the respective structures are as shown in this electroreductive synthesis from Orgsyn), reduce this double bond?

Tup

PS I have to edit in order to make my links work

PPS Also note that the orgsyn synthesis referred to in this post makes use of an electrolytic process to generate sodium amalgam in situ (unfortunately needing sulphuric acid which would fuck up this one) and is suitable for the reduction of other compounds which can be reduced by sodium amalgam

[Edited on 1-4-2007 by tupence_hapeny]

Sandmeyer - 1-4-2007 at 00:57

Mg/MeOH is very simple and OTC, numerous references describe the reduction of the functional group you want to reduce with this system. By the way, there are much better (easier, more OTC, cheaper) routes to MDMA, a route that requires around 10 steps to such a simple compound is not a good one...

[Edited on 1-4-2007 by Sandmeyer]

tupence_hapeny - 1-4-2007 at 03:58

Yeah, I read that article, however, like anything else that has even been considered over the last ten years, magnesium metal is unfortunately 'verboten' in this neck of the woods. Take heed everybody, we appear to be in front of you in this regard - the legislatures will ban EVERYTHING that is even remotely connected to this hobby, while somewhat hypocritically bemoaning the lack of interest amongst youth to take up the hobby. That being said, if I could 'legally' use it to reduce that bloody double bond - I believe that it would be a great alternative to Zn-Ni (which requires, after all, aqueous ammonia - stinky).

I chose to start with this compound because it is (1) legal; and (2) structurally similar to more interesting compounds. As I have pointed out earlier, the orgsyn procedure provides verification, if it were needed, of the validity of Wizard X's proposed use of HI to demethylate eugenol (subject of course to Nicodem's suggestion that the double bond may do something weird).

For those who may be interested in that sort of thing, the reaction between vanillin and creatine, taking place in a melt (without solvents) may translate to some who might consider the use of an akabori between vanillin and n-methyl-d,l-alanine (in fact, I even provided patents as to the reductive amination used to make alanine - heres another (needs formylation):

http://orgsynth.org/orgsyn/prep.asp?prep=cv1p0021

To make the 4-methyl-3-hydroxyl-ephedrine, then using HI (provided they feel comfortable in doing so, it being against the law and all) to reduce the substituted ephedrine and demethylate it in one pot - making 3,4-dihydroxy-d,l-methamphetamine and then proceeding to methylate the same, perhaps even using one of the approaches that have been flogged to death... (Even perhaps that one I referenced on the previous page using NMP as solvent)

However, I reiterate my original statement, this topic is not designed to result in a precursor for MDMA, I simply want to work out a method by which I can work around the restrictions upon our hobby at present, in order to produce the title compound. Not to do anything with it, simply to be able to say that I made the bloody thing. As I say, one could imagine my research being put to a bad use, yet I can hardly to be held responsible for such things, can I (Well at least, not yet).

tup

Postscriptum I suggest the above, I have neither the training or the knowledge to state categorically that it would work. In fact, in order for the suggested route to MDMA to work (1) The Akabori (sans solvent) would have to work (as per Akabori himself with benzaldehyde & n-methyl-d,l-alanine = d,l-ephedrine & d,l-pseudo); (2) HI would have to reduce ephedrine (and I believe that to be likely); (3) HI would have to demethylate the substituted ephedrine; (4) the methyl group would have to bond to the 3,4 positions rather than anywhere else; and (5) a decent reductive amination of either pyruvate or bromopropionic acid would have to be worked out (I can find nothing on the synthesis of n-methyl-alanine itself).

[Edited on 1-4-2007 by tupence_hapeny]

Nicodem - 1-4-2007 at 10:24

I had no time to reply to some previous posts though I wanted to, so…
Quote:
Originally posted by tupence_hapeny
No, I didn't think that the NMP was anything other than a solvent, however, I have constantly run into the suggestion here, there and everywhere that a strong organic base is necessary (in addition to the lewis acid) in order to demethylate vanillin and eugenol.

Bases have nothing to do with it and besides NMP is certainly not a strong organic base. Actually it is not even a base given that is only somewhat more basic than water which is otherwise considered neutral (the pKa of protonated NMP is about 0, while that of protonated water is -1.7). Anyway, for acidic demethylations you need strongly acidic conditions in the presence of at least moderate nucleophile. Strong acids are not going to be strong at all if they are put together with a strong organic base. You can utmost combine a strong acid with a very weak base to obtain a weak acid like pyridine hydrochloride but then the loss in acidity will have to be compensated by higher reaction temperatures. For example, concentrated hydrobromic acid is quite perfect, since it is strong enough to protonate the Ar-O-Me oxygen while the bromide anions are nucleophilic enough for an SN2 substitution with the so protonated Ar-O-Me, thus leaving you with Ar-OH and MeBr. Depending on the substrate, this can usually happen even bellow 100°C, but if instead of HBr you would want to use pyridine hydrobromide you would need to compensate the less acidic media by using a higher temperature (150°C or more). When your reaction mechanism requires two excluding conditions to meet (high acidity vs. strong nuclephilicity) it is all about push and pool to get it optimal.

Quote:
The making of a 'useless amino acid' is precisely what I intend to make Sir... I am currently sueing police where I am and have ABSOLUTELY no intention of making anything stronger as I confidently expect a visit immediately a 'chemical' smell is noticed. I need to be able to assert in Court that I was ONLY making a 'useless amino acid' moreover, via a synthetic route which was (1) viable; and (2) completely legal. I assume you of all people will be able to understand my purpose in doing so?

No, I of all people have no clue what you are up to. But that is not important because I'm not particularly interested either. However, I do find lawyers and other such greedy persons highly annoying and to avoid at all cost. Moreover, a lawyer abusing of organic chemistry is a nightmare come true for me. Nevertheless I'll respect your interest in law as long as you respect my interest in organic chemistry.
Quote:
EDIT: PS Nicodem, I appear to have missed something on my first glance at your post, you say that the double bond from eugenol would not survive demethylation using a lewis acid.... What precisely would happen to it?

I did not say that eugenol would not survive a demethylation using a Lewis acid. After all you even have literature examples where very strong acids like AlCl3 or AlI3 are used. I only said that pyridine hydrochloride is less harsh to certain functionalities that would not survive some other reagents. It is obvious that reagents are always selected in consideration of the functional groups on the substrate. Obviously you will not choose a reagent that reacts with alkenes at the required reaction conditions if your goal is to demethylate an alkene like eugenol. For example, strong acids with nucleophilic anions or in the presence of other nucleophiles (like certain solvents) are out of play with eugenol. For example, in the literature example of demethylation of eugenol with AlCl3, there are used 1.85 equivalents of this reagent in relation to eugenol. As you see this is just slightly less than required to coordinate with the OH and MeO groups of eugenol, but not enough to coordinate with the Pi bonds of the alkene function. Thus the minimum required is used. If instead 3 equivalents would be used, the excess AlCl3 would coordinate with the least basic function in eugenol, the double bond, making it a highly electrophilic carbocation and this would lead to polymerization into the so called "crap" (one of the most common products in organic chemistry, yet still a mystery to its identity). So not only one needs to consider the reagent to use, but just as importantly the amount needed and the conditions required. Of course, besides using strong acids there are other methods of demethylation of phenyl methyl ethers, so one can actually choose non-acidic reagents were it to be that a functional group on the substrate is simply incompatible with any acid at all. Unfortunately such wide choice of compatible reagents is not always possible in many organic transformations and one is forced to use all kind of tedious by-passes to avoid such synthetical dead ends. Your substrate is an amino acid and thus many demethylation methods become either useless or need to be modified accordingly.

PS: It might help you immensely in understanding these things if you would read about elementary organic chemistry as much as you do about law. Furthermore reading about organic chemistry might even clear up your confusions that are confusing me so much. You would be surprised at the wonderful books you can find in a library. These things are many times better explained in books than I could ever explain you myself given that I'm not skilled in pedagogy, English is not my native tongue and these reactions are not my specialization.

tupence_hapeny - 2-4-2007 at 06:21

Ahhh, yes.... But where will the majority of amateur chemists in this country be without a lawyer that is willing to try to understand what the fuck they were up to, instead of simply advising them to plead guilty in order to avoid a heavier sentence via acceptance of the police evidence overtop of that of my clients?

Chemistry is no longer a science that can be practiced without legal advice and or assistance - even if only with regard to avoiding patent infringements or prosecuting the same. In any event, I am busily reading up on the chemistry, however, most of what is available online (and my alma mater doesn't have chemistry - so no online access via the library) is somewhat over my head, apart from that that has been attached and explained at length on Rhodium, etc. I have in many instances simply sought to understand the relative reaction mechanisms (or sought to have them understood) and then sought other means of attaining the same ends.

tupence_hapeny - 7-4-2007 at 08:24

BTW,

Nicodem here is why I called this product methyldopa, although I foolishly left out the n bit. If you read this article you will see why a synthetic route, which this author spent much time and effort on reaching by another route, appealed to me:

http://www.biochemj.org/bj/027/0054/0270054.pdf

tup

[Edited on 8-4-2007 by tupence_hapeny]

Attachment: Synthesis of 3,4-dihydroxy-phenyl-n-methylalanine.pdf (478kB)
This file has been downloaded 685 times


Nicodem - 7-4-2007 at 09:25

Do you mind explaining what is so interesting in that paper? I'm all ears.

tupence_hapeny - 7-4-2007 at 11:50

You didn't notice that an eminent scholar tried and failed repeatedly on the way to a compound which can now be made via a veritable cookbook style, step-by-step approach? That these failures helped him to understand how the chemistry worked? Presumably the failures occurred because, in part, he had not been taught the, what is now, elementary chemistry necessary to predict that these things wouldn't & couldn't work?

I take it that you also didn't notice that he made it in the end?

What, I wonder, would you say to someone making precisely those mistakes, for precisely the same reasons, today?

Nicodem - 8-4-2007 at 06:50

What you talk is general to all ancient papers and applicable to all of the good old authors (though I just hate the Biochemical journal papers due to the low quality experimental data in comparison to the old ACS or RSC publications). Indeed the ancients were much more advanced in practical chemistry than today's chemists while today we are more advanced in understanding the mechanistics of chemical reactions. As consequences we can easily develop the most surprising chemical transformations of which the ancients could only dream, but our students are nearly not able to perform as well in laboratory practice as it used to be the case several decades ago. But that what progress is about, to rely on the tedious work of our ancestors. However, I still do not understand why is just that specific paper supposed to be interesting and to what purpose?

tupence_hapeny - 8-4-2007 at 07:13

Yet, as is well known, I am unable to access the 'basic' material of which you speak, so I must learn by the mistakes of myself and others...

Do you honestly mean to say that you cannot not see anything in that paper that may help me (and others) to understand the mechanics of this and other similar problems? Or at least, to allow us to find out what (even if we don't understand 'why') will and won't work?

I was recently reading up on phenylserine and dihydroxyphenylserine, and remember thinking to myself that if the glycine was n-methylated then we would basically get this compound. Lo and behold, I find a paper where somebody else tried precisely that, and failed, and then not only explained why but also found a synthesis that worked by n-acetylating the glycine to form the azlactone.

By the way, as to the reduction of the double bond, how do you think a yeast based process would work (given that yeast will reduce the double-bond in cinnamic acid):

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv7p0215

However, and this may suprise you, I prefer the old papers - because they at least admit to trying things that didn't work - which helps others avoid those same mistakes.

tup

I have edited this to include a PDF file on the use of yeast to reduce double bonds in nitrostyrenes.


[Edited on 9-4-2007 by tupence_hapeny]

Attachment: yeast.nitrostyrene.reduction.pdf (86kB)
This file has been downloaded 887 times


tupence_hapeny - 24-5-2007 at 11:19

BTW,

As regards the benzyl-creatinine:

1. could the ketone be removed via a Wolf-Kishner reaction?

(a) If so, will the cleavage of the azlactone still take place?

(b) what will be the post cleavage result?

2. Could the ketone be reduced to an alcohol by any of the known methods?

(a) If so, will the cleavage of the azlactone still take place?;

(b) what will be the post cleavage result?

I 'think' that the 'Wolf-Kishner' would work and that the result would be reduction of the ketone to the alkane, however, I am fairly confident that the cleavage would still take place, however, I am unsure as to what would be the result (either an alcohol or an alkane).

What is less sure, is what the other methods of reducing ketones, which proceed to an alcohol (which I assume would work as the cleavage appears to need fairly drastic conditions) will result in - post cleavage... An alcohol sure, but what will it become post-cleavage? Or perhaps, should it just be removed prior to affecting the cleavage (easier said than done, but anyway)?

tup

Nicodem - 24-5-2007 at 11:31

Huh...?
I lost you already at the point 1. Are you talking about N-methyl-3,4-dihydroxyphenylalanine from the Org. Syn. entry or is this about some other compound? There is no ketone group anywhere in that molecule and equally none in the synthesis intermediates.

tupence_hapeny - 25-5-2007 at 03:59

I was pointing to the first product, the one resulting from the reaction between vanillin and creatinine... I was actually in two minds as to whether that C=O bond is reduceable, - however, I have found that by proceeding on the assumption that something 'iffy' will work is the surest method of gaining information on this board...

So, my question is whether the C=O bond is reduceable, and if so how hard would it be?

Obviously this would differ depending upon whether it reacts as an amide still despite hanging, exposed, off the cyclic creatinine ring...

Even if it does, perhaps all would not be lost, as according to an 'Indian - Letters' article (which I know you love) Hydrazinium monoformate in conjunction with Raney Nickel will reduce nitriles to amines - so obviously it will reduce amides.

All questions without answers,

tup

Nicodem - 25-5-2007 at 08:32

You are confusing lactams/amides with ketones. Of course lactams can be reduced to amines (with LiAlH4) but reducing that carbonyl selectively without affecting the other groups is near to impossible.
Quote:
Originally posted by tupence_hapeny
Hydrazinium monoformate in conjunction with Raney Nickel will reduce nitriles to amines - so obviously it will reduce amides.

Would you mind stop posting misinformation! Obviously, if a reduction method works for nitriles it is no damn guaranty it will reduce amides! Get yourself a damn schoolbook about basic organic chemistry already.