Sciencemadness Discussion Board - Playing with tyrosine

Playing with tyrosine

tr41414 - 27-6-2007 at 12:30

I just happen to have 100g of quite pure tyrosine (USP, label says 100% !?)... It's one of most easily available aminoacids - can get it in almost any body building store...

There are a few reactions i have in mind:
1-decarboxylation to 4-ho-phenethylamine (ala Trp -> T)
2-methylation to 4-meo-phenylalanine (methylnitrate)
3-oxidation to 4-ho-phenylacetonitrile (wtih TCICA)
4-iodination to 3,5-diiodo-4-ho-phenylacetonitrile (basic iodine)

The only reaction i think will work without any modifications is 1... In rxn 2 Tyr will probably have to be N and COOH protected? Rxn 3&4 are more speculations than anything else, as #3 will probably also result in a ring halogenated product... dunno if product of 4 is right...

smuv - 27-6-2007 at 14:12

You could start from N-acetyl tyrosine. I think (although am not sure) the acetyl group will block N-methylation...if this is so...

1-methylate
2-remove protecting group (amide hydrolysis)
3-decarboxylate
4-halogenate 3,5 positions
5-methoxylate 3,5 (assuming you want to make mescaline)

tr41414 - 28-6-2007 at 00:22

If you look closer, you would see that the reactions i posted are different, all starting from tyrosine... Mescaline is not my ultimate product, but the procedure should be as follows:

- decarboxylation to tyramine
- iodination (halogenation) to 3,5-diiodo-4-oh-phenethylamine
- methylation (also many other analogs can be made by substituting other alochol - IP, P, E, AL) to 3,5-diiodo-4-meo-phenethylamine (don't think it has been tested, but is probably neurotoxic)
- removing the halogen groups (alkoxide + CuI + ultrasound/MW?) if possible directly exchanging them for methoxy

The last two steps could be exchanged to maybe give better yields, but then exclusion of water (when ripping of those Is) would probably be a problem...

SecretSquirrel - 28-6-2007 at 04:20

Quote:

Mescaline is not my ultimate product, but the procedure should be as follows:

If you perform the reaction in your last step, you'll end up with mescaline as your product.

[Edited on 28-6-2007 by SecretSquirrel]

smuv - 28-6-2007 at 13:11

I think we all would be able to help you better if we knew what you wanted to make.

@SecretSquirrel if you look a bit more closely Trxxxx never said he was making mescaline...I just assumed he was

P.S. N-acetyl tyrosine is just as OTC as tyrosine...but now that I have thought about it...I doubt an acetyl group would block the methylation of the amine.

tr41414 - 28-6-2007 at 19:15

@SecretSquirrel: 3,5-diiodo-4-meo-phenethylamine would certainly yield mescaline... but other 4 substitutes should make other phenethylamines... or would there be problems with transetrification (if such thing does exist)?

That acetyl group may do something wierd in the course of decarboxylation or iodination... It may easily be attached on later... I think that methylation of phenol procedes faster in basic environment (and as i said that step is already documented)... the only step into unknown (at least on this substrate) would be exchange of halogen...

would o-methyl or o-alkyl group on tyrosine protect it from getting ring halogenated and would yield p-alkyl-phenylacetonitrile on oxidation using tcica?

PS: will find the references soon...

PainKilla - 28-6-2007 at 21:35

http://www.sciencemadness.org/talk/viewthread.php?tid=3846&a...

smuv - 28-6-2007 at 21:48

Quote:

Originally posted by tr41414
@SecretSquirrel: 3,5-diiodo-4-meo-phenethylamine would certainly yield mescaline... but other 4 substitutes should make other phenethylamines...

This is true...but in you original writeup you metylated the 4 position...Anyhow...I will just assume that you want to make a 3,4,5 alkoxyphenylethylamine.

Quote:

Originally posted by tr41414 I think that methylation of phenol procedes faster in basic environment (and as i said that step is already documented)...

I admittadly know little about methyl nitrate, but for common methylation agents such as DMS and methyl halides, the amine must be protected.

I think you are taking an indirect route to these compounds.

I beleive a more direct route would be:

1. Bromate 3,5 positions (Br2 in AcOH)
2. Hydroxylate (is that a word) I beleive Cu dust in NaOH does this. This would form 3,5 hydroxytyrosine
3. Oxidize to nitrile
4. Alkylate 3,4,5 positions while making sure conditions are not harsh enough to hydrolize nitrile.
5. Reduce Nitrile to Amine

[Edited on 28-6-2007 by smuv]

SecretSquirrel - 28-6-2007 at 23:17

Quote:

Originally posted by smuv

@SecretSquirrel if you look a bit more closely Trxxxx never said he was making mescaline...I just assumed he was

I know that. He said he does not want to make mescaline, but then he said:

Quote:

removing the halogen groups (alkoxide + CuI + ultrasound/MW?) if possible directly exchanging them for methoxy

And that would most certainly yield mescaline.

[Edited on 29-6-2007 by SecretSquirrel]

smuv - 29-6-2007 at 10:26

Good call...I guess I didn't read his post very closely.

tr41414 - 29-6-2007 at 15:28

Depending on that 4-alkyl group (it's made in step 3; the substrate must be acetyl protected

) the product could be just about anything

Would transetrification (if that does exist) be an issue?
I would suggest not to put out mescaline... After all we are doing mostly chemistry and not drugs

PS: The oxidation of Tyr to Dopa using persulfate is also interesting, although yields are a bit low (20%)

[Edited on 29-6-2007 by tr41414]

smuv - 29-6-2007 at 17:08

Quote:

Originally posted by tr41414
I would suggest not to put out mescaline... After all we are doing mostly chemistry and not drugs

You are the one mentioning neuro-toxicity. Mescaline analogues (which you are making) are still drugs.

Quote:

Would transetrification (if that does exist) be an issue?

I dont really understand what you mean by this, could you be a little clearer when exactly this would occur. I see no carboxylic acid involved to form an ester with.

Quote:

PS: The oxidation of Tyr to Dopa using persulfate is also interesting, although yields are a bit low (20%)

Dopa can also be produced electrochemically. Which may be of interest.

Oh I now think an acetyl group is not sufficiently bulky to block alkylation of the amine. You would need to use a more stericly hindering group.

tr41414 - 30-6-2007 at 01:09

Banana peels can also be used as drugs

So, dont even dare to talk about growing bananas

If you read properly i said transETRIFICATION (without s), but now i don't think such thing does exist... I'm still searching for proper ketone (MEK and acetone in turpentine just seem to boil) for that decarbox... will be buying some spearmint oil soon

maybe also phorone would work? (hmm... but on the second tought it will probably form the piperidone ring around our amine)

PS: can one not just oxidise some pinene to get the ketone? but i only found refs. on pb acetate oxidation

kmno4 seems to do some unwanted cleaveing...

[Edited on 30-6-2007 by tr41414]

smuv - 30-6-2007 at 03:50

Transeterfication? Transtherfication? At any rate, i've never heard of it but could see it occuring under certain conditions.

Why are you considering decarboxylating already...how are you going to protect your amine? Why are you even decarboxylating the amine. You can convert Directly from the amino acid to nitrile without decarboxylation. Also your step, where you Halogenate p-methoxy phenylacetylnitrile will proceed with shitty yeilds as I would expect the nitrile to hydrolize under these conditions (forming either an amide or carboxylic acid).

To do things the way you want to do them you should change your order:

1. Bromate 3,5 positions (Br2 in AcOH)
2. Williamson ether synthesis to alkylate 3,5 positions
3. Convert to nitrile w/ tcca and NaOH in water
4. Alkylate 4 position of nitrile
5. reduce nitrile to amine

The only step I am not sure about is the 4th, common reagents for alkylation might play with the nitrile...but I I'm not sure.

Maybe someone else could check up on my (so, so) chemistry.

tr41414 - 30-6-2007 at 04:01

it is much simpler to decarboxylate and not go the nitrile / reduction way (that would be more useful - worth the effort - if one would be interested in amphetamine analogs: nitrile -> p2p)... tcica would probably halogenate and decarboxylate/oxidise the tyr to nitrile in one step...

halogens on the phenyl ring are not as good leaving groups, so conditions will have to be pretty harsh...

smuv - 30-6-2007 at 04:21

The only reason to create the nitrile is to avoid protecting the amine. Plus decarboxylations are a bitch and usually require fairly harsh conditions.

Quote:

tcica would probably halogenate and decarboxylate/oxidise the tyr to nitrile in one step...

Quote:

halogens on the phenyl ring are not as good leaving groups, so conditions will have to be pretty harsh.

Yes (I think i have seen a Cu(I) catalyzed reaction with sodium methoxide in dmf or something like that) but its possible...anyhow I am just correcting your original proposed synthesis...by creating something that has a higher chance of working out while still sticking to your original outline.

[Edited on 30-6-2007 by smuv]

tr41414 - 30-6-2007 at 07:50

According to Chem Pharm Bull 23, 2179 (1975): Tyrosine >-Cl2-> 3,5-Dichloro-4-hydroxyphenylacetonitrile

For decarboxylation diphenyl ether, aniline, p2p, acetophenone and probably also most other not-to-reactive ketones can be used... User urushibara has attempted pressurized acetone decarboxylation @200-250C which seemed to work :cool:

So i will probably do some nanoscale experiments with empty CO2 bombs... till i get my spearmint oil...

Oxidation to nitrile followed by a NaBH4 reduction is alternative to thermal decarboxylation...

Quote:

Ref. found by Foxy2

Synthesis of 3,5-diiodo-4-methoxyphenethylamine
Jatzkewitz, Horst; Noeske, Hans Dietrich
(Hoppe-Seyler's Zeitschrift für physiologische Chemie) Hoppe-Seyler's Z. physiol. Chem. 287, 43-6 (1951)
Journal written in Unavailable. CAN 49:4568 AN 1955:4568

Abstract
The synthesis of 3,5-diiodo-4-methoxyphenethylamine (I) is described.
I is used to study the effect of biogenic amines on the action of mescaline. To 14 g. tyramine-HCl in 23 cc. H2O and 46 cc. N NaOH, 11.8 g. iodine in alk. KI soln. (contg. 20 g. KI, 160 cc. H2O, and 46 cc. N NaOH) is added dropwise with stirring, maintaining constant alky. The soln. is filtered and acidified with excess H2SO3, giving 12 g. crude 3,5-diiodotyramine-HI (II), yellow leaves (from H2O) m. 232-4°C (decompn.).
II (12 g.) treated with the calcd. amt. of hot Na2CO3 soln. gives 6 g. free base (III), pale yellow, m. 188-90°C.
III (2 g.) boiled 10 sec. with 5 cc. Ac2O and dild. with H2O gives 1.75 g. N-acetyl-3,5-diiodotyramine (IV), colorless plates, m. 139-40°C.
IV (6 g.) (crude) in tetrahydrofuran is methylated with 60 cc. ethereal CH2N2 dild. with 40 cc. CHCl3, washed twice with 5% NaOH and H2O, dried and the solvent removed, giving 5.2 g. N-acetyl-3,5-diiodo-4-methoxyphenethylamine (V), needles, m. 138-40°C.
V 3.8 g. is refluxed 5 hrs. with 19 cc. HCO2H, 14 cc. HCl, and 14 cc. H2O., evapd. in vacuo and dried with EtOH and C6H6, the residue extd. with three 15 cc.-portions of abs. C6H6 gives on evapn. of the solvent 3.4 g. crude I.HCl. The pure compd. m. 213-15°C. The salt dried in Et2O over anhyd. K2CO3, on removal of solvent and crystn. from petr. ether gives I, colorless leaflets, loses its crystal structure at 41-3°C, and m. 55-7°C.

PS: could anyone fetch the articles and attach them please?

smuv - 30-6-2007 at 10:06

See Synlett 2004, (12) 2180-2184. I am not saying your ref is crap...the conditions just are different

using a pressure vessel to decarboxylate defies Le Chatelier's principle.

This is interesting though...according to that ref the acetyl group protects just fine...thats good to know

dr. nick - 1-7-2007 at 04:19

Quote:

... I'm still searching for proper ketone (MEK and acetone in turpentine just seem to boil) for that decarbox... will be buying some spearmint oil soon maybe also phorone would work? (hmm... but on the second tought it will probably form the piperidone ring around our amine)

Hoping not to bother you too much with my inadequate knowledge, but as i'm interested in anything from amino acids, too, i wonder if it shouldn't work like the decarboxylation of phenylalanine - with Cyclohexanol and Cyclohexanon and so on ... ?

also, even if that's "drugs" again first things that comes to mind for me from tyrosine are opiat/opioides (->biochemistry poppies). but probably that's too far out.

Anyway, very informative thread, thanks!

tr41414 - 1-7-2007 at 05:52

I think that decaboxylation should go well with cyclohexanon, but it is said that cycloxexEnone works much, much better... for the price i will pay for 50ml of essential oil here, 1l could be had from india :mad:

is there really no easy way to oxidise pinene to the ketone?

Decarbox. is one-way-only-reaction, so there is no equilibrium, but i agree with you that the last few CO2-s will be less happy to fly of... The problem might be sideproducts (acetone selfcondensation, or even something with our amine) and some unreacted aminoacid...

Opiates? You mean fentanyl analogs? These would probably be legal and probably quite powerful (i don't think 4-oh would be active, but 4-meo almost surely)... the phenethyl group can be exchanged, also aniline can be exchanged for another amine to lower / change the potency... You should take a look at phenylethanolamine and PPA... ala drone's OTC fentanyl

dr. nick - 1-7-2007 at 12:04

Quote:

Opiates? You mean fentanyl analogs?

ah, i see - pretty interesting! and no, i didn't have anything special in mind, it was just that i believe to remember the biosynth of morphin was somehow outgoing from thyrosine ...

so you think there might be a way to something like that from thyrosine??
ohoho! pretty interesting indeed

wonder if i might find something on it somewhere!

thanks!

tr41414 - 2-7-2007 at 03:18

the fentanyl was just a guess, as it is an opiate and is not too hard to synth... synthesis of morphine - derivates are very complicated...

yes... the biosynth http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/alkaloid/mo... essentialy starts from tyrosine, but it is a looooong way there (involving around 20 enzymes, some have not even been determined yet)... but one could try doping the poppies... even more viable way would probably be to make poppy cell culture, add some more advanced precursors and somehow try to extract the product from live culture, to have it produce more

it also seems many animals (also humans) are able to produce morphine from tyrosine, but reports are somewhat confusing

...

dr. nick - 2-7-2007 at 09:17

yes, i'm reading this and that on cell culture the last time - interesting field, for lots and lots of interesting compounds (not only drugs

), also the idea of doping poppies is good. gonna try to get the stuff one needs for analgetics tlc first, but it's complicated for someone new to this (at least to me) and not really cheap ...

as talking on stuff like that now anyway i hope i didn't make this thread go totally ot, but one thing i want to mention before i stop - there where some hints on an corey-fuchs synth to morphin from phenylalanine in 10% yeild, if it's true. ok, not tyrosine, but hey ...
couldn't find much on it, and of course it's way beyond everything possible to me even if i wanted to do something like that.

tr41414 - 4-7-2007 at 05:52

10% yield ??? that's a whole lot... couldn't find anything on your procedure... but as said before it won't go without more than 20 step procedures and exotic reagents (probably hard to find but obivously not watched, as nobody uses them

)

And for "doping" cacti would probably be much better subjects than poppies, I also think cultivating cactus cells would be simpler (a bit less differentiated)... But you won't get any opiates from cacti

we should not get too off-topic here, so back to tyrosine & friends

hehe... i really like these aminoacids as they can be made (as we found out not so easily) into so many interesting things... hmm... not that happy anymore about that high pressure acetone decarboxylation (any leak might result in a big boom)... what about decarboxylation in glycerol (higher BP, seen it done somewhere)? or maybe using camphor as a catalyst?

dr. nick - 4-7-2007 at 09:25

yes, amino acids are really cool - i always find new uses every time i start to chase again

my only practical experience with it was the phenylalanin decarboxylation a la rhodium and it worked. pretty frustrating i did never find anything to do with the yeilded ß-pea

also tried it with turpentine and paraffin and some other strange stuff, forgot, but as i managed to do it the reported way i forgot it for a while. maybe time to start again. it's really fascinating, somehow. never tried with acetone and so on since i can't prevent it from evaporating - the proceedure seems to take some more time as mentioned at rhodium, but maybe just because i have only inferior material available (cyclohexanone from some special thinner, and so on)

got some l-arginine and want to try to decarboxylate it the same way as the phe (right abbrev?) since i found something really interesting on fatty acid amides ... if i ever proceed i'll report!

tr41414 - 4-7-2007 at 12:26

Nice reference: http://www.jbc.org/cgi/reprint/62/3/725

seems there is no easy way to tyramine with high yield... have tried gliceryn and doesn't seem to do anything but dissolve tyrosine... it was only 1 min run and temp was around 250C, then it starts to boil... the funny thing is that the thermomether, when removed from testtube does fume a lot (now that i think it may be from water in air and glycerin -> it's used as artificial fog for special effect

) and smelled of burned peanuts which was probably acrolein (wow, a bit toxic)...

Hmm... the biosynthesis sounds like a fun project, but ordinary Saccharomyces cerevisiae (according to www.biochemj.org/bj/069/0210/0690210.pdf) only produce tyrosol, so one would probably have to use some kind of lactic acid bacteria (which can be found in certain "bioactive" foods

)...

smuv - 4-7-2007 at 13:54

And I point out once again...if you plan to make the nitrile...it can be done in one step from the amino acid with TCCA under very mild conditions with high yields. There is no need to decarboxylate.

see Synlett 2004: 2180-2184

dr. nick - 5-7-2007 at 13:08

@smuv:

interesting thing, too - read about it with phenylalanine, but do you know any possibility to separate the product without vakuum destillation?

btw.: on more dumb question what is the nitrile of tyrosine? or maybe even arginin? forgive my ignorance, i just don't get it ...

thanks!

smuv - 10-7-2007 at 22:59

Based upon the synlett procedure referenced earlier, I would say that the crude ether extracted product should be pure enough to proceed forward with; I say this mainly because the yields are very high for this reaction and also any unreacted phenylalanine will stay in the strongly acidic aqueous phase (if you follow the workup highlighted at the end of the article).

The nitrile of tyrosine would be 4-hydroxyphenylacetonitrile
" arginin " 1-(3-cyanopropyl)guanidine although I do not expect that to be attainable via the method we are talking about (I think the guanidine group will react as well with the hypochlorous acid)

dr. nick - 11-7-2007 at 11:56

thanks!

and: damned, this thread doesn't help much to get fentanyls out of my mind - especially when thinking of decarboxylation, a mannich as mentioned elsewhere with another amine instead of aniline and reaction of the product with acetic anhydrid or even acetic acid instead of propionic anhydride (as also mentioned elsewhere) - with a decent testing method this would be fun for years, even for kitchen chemists ... *arrrr, get off my mind, evil amino acid possibilities, you're so off topic* ...