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Author: Subject: n-methyl-3,4-Dihydroxyphenylalanine (orgsyn)
Sandmeyer
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[*] posted on 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]




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tupence_hapeny
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[*] posted on 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]




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[*] posted on 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.




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tupence_hapeny
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[*] posted on 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.




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[*] posted on 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 607 times





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[*] posted on 7-4-2007 at 09:25


Do you mind explaining what is so interesting in that paper? I'm all ears.
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[*] posted on 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?




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[*] posted on 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?
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[*] posted on 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)
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[*] posted on 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




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[*] posted on 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.
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[*] posted on 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




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[*] posted on 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.
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