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Author: Subject: Hordenine from thermal decarbox of tyrosine
majortom
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Hordenine from thermal decarbox of tyrosine

I have a few grams of 99% + tyrosine and want to make some hordenine (N,N-dimethyltyramine) out of it and I came up with a fairly straightforward synthesis for it.

First the tyrosine would need to be decarboxylated. I was thinking of refluxing it in xylene with a slow stream of nitrogen to prevent oxygen from getting in.

After this was done then I would add a bit of water to the mixture, the unreacted tyrosine is a zwitterion it should be more soluble in water than in organic solvents like xylene, the tyramine is in freebase form and would stay in the organic layer, these would then be separated.

The xylene layer would be refluxed with formalin and formic acid in the Eschweiler-Clarke reaction thus creating N,N-dimethyl tyramine or Hordenine.

Do you think that this would work?
Arrhenius
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Not a chance. Try dissolving tyrosine, or any amino acid for that matter, in water - it doesn't work. Probably miserably insoluble in boiling xylene too. Thermal decarboxylation in this context is sluggish, so you should consult the literature for a real prep - probably copper(II) accelerates it, and Rhodium archives will tell you ketones do. Chose your favorite conditions will probably work for dimethylation. Do your homework if you really want to make it.
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Nicodem
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 Quote: Originally posted by majortom I have a few grams of 99% + tyrosine and want to make some hordenine (N,N-dimethyltyramine) out of it and I came up with a fairly straightforward synthesis for it. ... Do you think that this would work?

No, it would not work. Why would it? You came up with no synthesis and no reference, so this thread should be opened in the Beginners section. Next time make sure you do a literature search to provide a minimum support for for your ideas. Just playing the typical role of the lazy guy who throws anything on a forum for others to digest at his amusement, is not particularly welcome here. We are not a waste bin! Otherwise, welcome anyway.

Refluxing the suspension of tyrosine in xylene would do nothing. The methods of clasical imine mediated decarboxylations of amino acids, which use ketones as catalysts, might not be suitable for tyrosine due to its phenolic functional group. Apart from the dozens methods of fermentation and enzymatic methods for tyrosine decarboxylation that one can find in the literature, there are only a couple of purely chemical transformations mentioned. The must-read-paper on this topic is:
Waser, E. Helvetica Chimica Acta, 8 (1925) 758–773 (DOI: 10.1002/hlca.192500801106)

That this method works was confirmed twice by other researchers. Since the papers are published in rather hard to get journals, I will post their CA’s.:

 Quote: Decarboxylation of amino acids with formation of the corresponding amines and the preparation of the enol form of 2,5-diketopiperazines. Abderhalden, Emil; Gebelein, Fritz. Z. physiol. Chem. (1926), 152 125-31. Journal language unavailable. CAN 20:13073 AN 1926:13073 CAPLUS Abstract Tyramine may be obtained in 95% yield by heating tyrosine to 240°C with 20 parts of Ph2NH and extg. the latter with Et2O. Glycine and alanine yield MeNH2 and EtNH2, resp. dl-Leucylglycine under the same treatment gave 93% of the enol form of leucylglycine anhydride. a-Bromoisobutyryl-a-aminoisobutyric acid, m. 169°C, was prepd. in 80% yield from Me2CBrCOBr and Me2C(NH2)CO2H. On treatment with 25% NH4OH this yielded a-aminoisobutyryl-a-aminoisobutyric acid (I), m. 214-6°C. I is theoretically incapable of forming an enolic anhydride. When heated with Ph2NH it gave 89.7% of the keto form of the anhydride, which sublimes at 260°C. dl-a-Aminobutyryl-dl-a-aminobutyric acid gave 98% of the enolic anhydride, m. 264°C; dl-leucyl-dl-valine 90% of the enolic anhydride, m. 242°C; dl-alanyl-dl-valine 96% of the anhydride, m. 262°C; and dl-leucyl-dl-leucine 93.6% of the enolic anhydride, m. 266°C. Decarboxylation of leucine and tyrosine. Keimatsu, S.; Yamamoto, S. Yakugaku Zasshi (1927), No. 549 946-50. CODEN: YKKZAJ ISSN: 0031-6903. Journal language unavailable. CAN 22:7928 AN 1928:7928 CAPLUS Abstract Waser (C. A. 20, 1067) obtained 90-8% of iso-AmNH2 (I) and tyramine (II) from leucine (III) and tryosine (IV), resp., by using fluorene as a heat carrier. K. and Y. have now found in petroleum (V) the best substitute for fluorene. A mixt. of 150 cc. of V (b. 190-220°C), 20 cc. of the same oil (b. 220-6°C) and 17 g. of III is distd. From the distillate which contains I as the carbonate, 11 g. (97.3%) of I is recovered. For the prepn. of II, a mixt. of 100 cc. of V b. 240-60°C and 20 cc. of the same b. 260-80°C is heated to nearly boiling and 10 g. of IV suspended in a small amt. of V are added in small portions with stirring and during distn. From the distillate, 6.6 g. (68.9%) of II is obtained. The low results were due to the impure raw material used.

Now, the methylation using the Eschweiler-Clarke method is most probably out of question due to the incompatibility with the phenolic group (reaction of HCHO on the phenolic ortho-positions in the acidic medium of the excess formic acid: Mannich, hydroxymethylations and other tar forming reactions). As far as I know, there is only one paper claiming this is possible using a highly diluted HCOOH in DMF (Journal of Pharmaceutical Sciences, 62 (1973) 2054-2055, can be found in the Wanted references thread). It claims yields around 50%, but in my experience on a 10 mmol scale (for practical reasons I used a lesser dilution) I could only get a 20% yield on a related substrate. Since then I already finished the research contract for which I needed the intermediate and did not bother trying again or optimizing the reaction conditions. Otherwise, a STAB based N,N-dimethylation (see DOI:10.1016/j.bmcl.2005.11.003) is certainly a more efficient approach.
Needless to say, if all this is just about practice rather than the end product, you might as well dibrominate tyrosine to block its reactive ortho-phenolic sites and thus use the normal ketone catalysis for the decarboxylation to 3,5-dibromotyramine (one example of dibromination in 92% yield is in DOI:10.1016/j.bmc.2004.06.030). 3,5-Dibromotyramine should also withstand the normal Eschweiler-Clarke conditions to give 3,5-dibromohordenine. Eventually, this can be debrominated with hydrogenation over Pd-C. Generally, using protecting groups sucks, but if it is about practice, this way you practice more and do some research on the way (with all the pertaining frustrations included).

[Edited on 9/5/2010 by Nicodem]

…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)

majortom
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Quote: Originally posted by Nicodem
 Quote: Originally posted by majortom I have a few grams of 99% + tyrosine and want to make some hordenine (N,N-dimethyltyramine) out of it and I came up with a fairly straightforward synthesis for it. ... Do you think that this would work?

No, it would not work. Why would it? You came up with no synthesis and no reference, so this thread should be opened in the Beginners section. Next time make sure you do a literature search to provide a minimum support for for your ideas. Just playing the typical role of the lazy guy who throws anything on a forum for others to digest at his amusement, is not particularly welcome here. We are not a waste bin! Otherwise, welcome anyway.

Refluxing the suspension of tyrosine in xylene would do nothing. The methods of clasical imine mediated decarboxylations of amino acids, which use ketones as catalysts, might not be suitable for tyrosine due to its phenolic functional group. Apart from the dozens methods of fermentation and enzymatic methods for tyrosine decarboxylation that one can find in the literature, there are only a couple of purely chemical transformations mentioned. The must-read-paper on this topic is:
Waser, E. Helvetica Chimica Acta, 8 (1925) 758–773 (DOI: 10.1002/hlca.192500801106)

That this method works was confirmed twice by other researchers. Since the papers are published in rather hard to get journals, I will post their CA’s.:

 Quote: Decarboxylation of amino acids with formation of the corresponding amines and the preparation of the enol form of 2,5-diketopiperazines. Abderhalden, Emil; Gebelein, Fritz. Z. physiol. Chem. (1926), 152 125-31. Journal language unavailable. CAN 20:13073 AN 1926:13073 CAPLUS Abstract Tyramine may be obtained in 95% yield by heating tyrosine to 240°C with 20 parts of Ph2NH and extg. the latter with Et2O. Glycine and alanine yield MeNH2 and EtNH2, resp. dl-Leucylglycine under the same treatment gave 93% of the enol form of leucylglycine anhydride. a-Bromoisobutyryl-a-aminoisobutyric acid, m. 169°C, was prepd. in 80% yield from Me2CBrCOBr and Me2C(NH2)CO2H. On treatment with 25% NH4OH this yielded a-aminoisobutyryl-a-aminoisobutyric acid (I), m. 214-6°C. I is theoretically incapable of forming an enolic anhydride. When heated with Ph2NH it gave 89.7% of the keto form of the anhydride, which sublimes at 260°C. dl-a-Aminobutyryl-dl-a-aminobutyric acid gave 98% of the enolic anhydride, m. 264°C; dl-leucyl-dl-valine 90% of the enolic anhydride, m. 242°C; dl-alanyl-dl-valine 96% of the anhydride, m. 262°C; and dl-leucyl-dl-leucine 93.6% of the enolic anhydride, m. 266°C. Decarboxylation of leucine and tyrosine. Keimatsu, S.; Yamamoto, S. Yakugaku Zasshi (1927), No. 549 946-50. CODEN: YKKZAJ ISSN: 0031-6903. Journal language unavailable. CAN 22:7928 AN 1928:7928 CAPLUS Abstract Waser (C. A. 20, 1067) obtained 90-8% of iso-AmNH2 (I) and tyramine (II) from leucine (III) and tryosine (IV), resp., by using fluorene as a heat carrier. K. and Y. have now found in petroleum (V) the best substitute for fluorene. A mixt. of 150 cc. of V (b. 190-220°C), 20 cc. of the same oil (b. 220-6°C) and 17 g. of III is distd. From the distillate which contains I as the carbonate, 11 g. (97.3%) of I is recovered. For the prepn. of II, a mixt. of 100 cc. of V b. 240-60°C and 20 cc. of the same b. 260-80°C is heated to nearly boiling and 10 g. of IV suspended in a small amt. of V are added in small portions with stirring and during distn. From the distillate, 6.6 g. (68.9%) of II is obtained. The low results were due to the impure raw material used.

Now, the methylation using the Eschweiler-Clarke method is most probably out of question due to the incompatibility with the phenolic group (reaction of HCHO on the phenolic ortho-positions in the acidic medium of the excess formic acid: Mannich, hydroxymethylations and other tar forming reactions). As far as I know, there is only one paper claiming this is possible using a highly diluted HCOOH in DMF (Journal of Pharmaceutical Sciences, 62 (1973) 2054-2055, can be found in the Wanted references thread). It claims yields around 50%, but in my experience on a 10 mmol scale (for practical reasons I used a lesser dilution) I could only get a 20% yield on a related substrate. Since then I already finished the research contract for which I needed the intermediate and did not bother trying again or optimizing the reaction conditions. Otherwise, a STAB based N,N-dimethylation (see DOI:10.1016/j.bmcl.2005.11.003) is certainly a more efficient approach.
Needless to say, if all this is just about practice rather than the end product, you might as well dibrominate tyrosine to block its reactive ortho-phenolic sites and thus use the normal ketone catalysis for the decarboxylation to 3,5-dibromotyramine (one example of dibromination in 92% yield is in DOI:10.1016/j.bmc.2004.06.030). 3,5-Dibromotyramine should also withstand the normal Eschweiler-Clarke conditions to give 3,5-dibromohordenine. Eventually, this can be debrominated with hydrogenation over Pd-C. Generally, using protecting groups sucks, but if it is about practice, this way you practice more and do some research on the way (with all the pertaining frustrations included).

[Edited on 9/5/2010 by Nicodem]
Phenylalanine

Thank you for the "constructive" criticism. I had actually done a bit of research on decarboxylation of amino acids catalyzed by ketones, However I was unsure of this would apply to tyrosine and did not mention it here. The only thing rhodium had on it was done with tryptamine. As for the Eschweiler-Clarke I knew it was a bit of a temperamental reaction as it is a leuckart variant, however I could not find any specifics as to which substitutes would interfere with it.

I should have looked up tyrosines solubility instead of just assuming it was soluble in water as it was a zwitterion, I had borrowed the xylene idea from some of rhodium's stuff on tryptophan. Its solubility is around 40 mg/ 100 ml. Could I use Phenylalanine instead which would avoid the problems with the phenolic hydroxyl group and which has a considerably higher solubility of almost 3 gram/100 ml. Of course this would produce the homologue of hordenine N,N-dimethylphenethylamine.
Arrhenius
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Researching a topic does not mean reading the Rhodium archive. Start by buying March's Organic Chemistry (a $60 comprehensive textbook on applying synthesis). Second, access the primary scientific literature. Chances are your local library doesn't have this, so you should go to a college or university. If you really cannot do this, then search for papers using google/google scholar and read the abstract. If you find things pertaining to your chemistry, you can request papers in the references section of the forum (or see if they're already there). Sandmeyer International Hazard Posts: 784 Registered: 9-1-2005 Location: Internet Member Is Offline Mood: abbastanza bene  Quote: Originally posted by Arrhenius Researching a topic does not mean reading the Rhodium archive. What do you mean? To my mind it depends on the topic. majortom Harmless Posts: 26 Registered: 8-5-2010 Member Is Offline Mood: No Mood  Quote: Originally posted by Arrhenius Researching a topic does not mean reading the Rhodium archive. Start by buying March's Organic Chemistry (a$60 comprehensive textbook on applying synthesis). Second, access the primary scientific literature. Chances are your local library doesn't have this, so you should go to a college or university. If you really cannot do this, then search for papers using google/google scholar and read the abstract. If you find things pertaining to your chemistry, you can request papers in the references section of the forum (or see if they're already there).

I think it constitutes qute a good start, If you dont have apphiliations with universities they will not let you into their libraries, As far as doing searches on the web for scientific papers, goood luck getting anything more than the abstract unless you are willing to pay \$200 + for a subscription to the journal it is in! Not all of us have the kind of resources that would allow that kind of research.
JohnWW
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I have uploaded March's Organic Chemistry to my rapidshare.com account, and posted the link for it in the References section under Organic Chemistry books.
majortom
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 Quote: Originally posted by JohnWW I have uploaded March's Organic Chemistry to my rapidshare.com account, and posted the link for it in the References section under Organic Chemistry books.

Have not read marsh's, I allways heard vogel's was the standard, although my introduction was through "introduction to organic chemistry," an anchient 70's book, it was pretty comprehensive for the time though at 400 + pages. I cant recal the author('s) names
zed
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Might be able to diazotize and replace the amino function on Tyrosine, with a halogen.

Thereafter, reaction with dimethylamine, should produce the N,N-Dimethyl tyrosine.

Provided the phenolic OH doesn't interfere.

If the OH doesn't interfere, and you get the desired product, then you merely need to decarboxylate the N,N-Dimethyl tyrosine. Though this might not be simple as it sounds.

Such decarboxylations usually proceed through an imine intermediate. Since no imine can be formed from the tertiary amino function, decarboxylation might be more difficult than usual. Oh, it's do-able; bacteria...or their enzymes.....can do anything! It's just that such procedures are a little more arcane than most of us are accustomed to.

Another possibility, might be oxidizing tyrosine to the phenylacetaldehyde via the keto-acid or keto-ester. Thereafter, reductive amination with Dimethyamine, should produce your desired product.

It's better to start with a foundation based on published reference material. Since you would prefer not to spend a hundred years, working out the details of the best experimental procedures to follow, it is wise to rely on the discoveries of those that have gone before us.

As for your assertions regarding University Libraries....Generally speaking, if you assume a civilized appearance, you can walk right in, and make yourself at home. Most people have no problem gaining admission.

Research on the WEB can be frustrating, but it can also be very rewarding. Patents are very accessible, and some altruistic journals have made their past contents available.....completely free! Organic Synthesis, is one such. The best of the best.

[Edited on 7-6-2010 by zed]
Methansaeuretier
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What about dimethlyation with Zn/formaldehyde and decarboxylation of the methylated tyrosine? Zn should not harm the OH-Group

Ref. for dimethylation of Amino Acids with Zn, aq. formaldehyde and NaH2PO4 is in Attachment

Attachment: 96730940_2807.pdf (98kB)

[Edited on 7-6-2010 by Methansaeuretier]
Globey
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Quote: Originally posted by Sandmeyer
 Quote: Originally posted by Arrhenius Researching a topic does not mean reading the Rhodium archive.

What do you mean? To my mind it depends on the topic.

One good thing about March is that, up to about just before it goes to pre-edit, it contains most the latest journal methods being discussed. What a great preview. Also enjoyed "Survey of Organic Synthesis, 1& 11", Of course, there are some methods almost never spoken of for fear they are far too easy to accomplish. Such as a couple OTC aminos in a pot and viola, mU agonist,
Methansaeuretier
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 Quote: Originally posted by Methansaeuretier What about dimethlyation with Zn/formaldehyde and decarboxylation of the methylated tyrosine? Zn should not harm the OH-Group Ref. for dimethylation of Amino Acids with Zn, aq. formaldehyde and NaH2PO4 is in Attachment

I was interested if this work for any arylaminoacids. I just tried it... about 1 g of 4-Methoxyphenylalanine dissolved in about 50ml tap water together with 4-5g KH2PO4 and heated in a microwave until everything dissolvend, cooled back to room-temperature (a little backup sample was saved for TLC) and mixed some mls 35% formaldehyde and a half teaspoon of zinc dust with it. Now, 20h later, still stiring the mixture, I made a TLC and now there are two spots instead of the one of the backup-sample!.
The second -new- spot is still very little and slightly transparent but clearly visible on UV-detection.. the new stuff is much less mobile in the same eluent (1/3 ).

So it seem that it works, but needs a very long reaction time. Actually I don't know how to find out if it's dimethylated or monomethylated or something completely different.

I used about MeOH/25% NH4OH 4:1 as eluent and "Alugram Sil G/UV254" as layer. Detection via UV light 254nm

Maybe it may work better and faster with additional potassium formiate as hydrogen donor together with KH2PO4 and also washing of the Zn dust with 2M HCl may increase reaction time too...

I would like to scan the layer, but my Canon scanner does not support 254nm and my (mobile phone) camera is very poor

[Edited on 22-6-2010 by Methansaeuretier]
Nicodem
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 Quote: Originally posted by Methansaeuretier I was interested if this work for any arylaminoacids. I just tried it... about 1 g of 4-Methoxyphenylalanine dissolved in about 50ml tap water together with 4-5g KH2PO4 and heated in a microwave until everything dissolvend, cooled back to room-temperature (a little backup sample was saved for TLC) and mixed some mls 35% formaldehyde and a half teaspoon of zinc dust with it. Now, 20h later, still stiring the mixture, I made a TLC and now there are two spots instead of the one of the backup-sample!. The second -new- spot is still very little and slightly transparent but clearly visible on UV-detection.. the new stuff is much less mobile in the same eluent (1/3 ).

It is unlikely that the N-methyl or N,N-dimethyl derivative would be "much less mobile" on TLC. On the contrary, I would expect it to be slightly more mobile. I never used alumina TLC plates and such extremely polar eluents, so I might be wrong for whatever reason.

 Quote: Maybe it may work better and faster with additional potassium formiate as hydrogen donor together with KH2PO4 and also washing of the Zn dust with 2M HCl may increase reaction time too...

Potassium formate is not hydrogen donor unless there is present a metal catalyst able to decompose it via beta-hydride elimination. Needless to say, zinc is not able to do that.

PS: I take it that you are aware that N,N-dimethyl alpha-amino acids can not form imines and thus can not be decarboxylated by any of the ketone catalysed decarboxylation methods.

…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)

Methansaeuretier
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 Quote: [quote=180711&tid=13829&author=Nicodem] It is unlikely that the N-methyl or N,N-dimethyl derivative would be "much less mobile" on TLC. On the contrary, I would expect it to be slightly more mobile. I never used alumina TLC plates and such extremely polar eluents, so I might be wrong for whatever reason.

I've thown a second eye on the layer... the potential N-Methyl derivate dot is nearly 2 mm above the educt on all 2 TLC I made with this eluent... may be only a coincidence but I'll try to use another eluent to get a better dissolution.

 Quote: PS: I take it that you are aware that N,N-dimethyl alpha-amino acids can not form imines and thus can not be decarboxylated by any of the ketone catalysed decarboxylation methods.

Argh, fuck, I've overseen that. What about diphenylmethane or copperchelate!? They should work, right?

[Edited on 23-6-2010 by Methansaeuretier]

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