Sciencemadness Discussion Board - Synthesis of dopamine from protocatechualdehyde

Synthesis of dopamine from protocatechualdehyde

Melgar - 12-7-2016 at 15:20

Disclaimer: I'm trying to synthesize dopamine, because I think it would be an interesting synthesis, not because I'm trying to use it as a drug or something.

I'm actually starting with protocatechualdehyde, and I can think of at least three routes:

1. Reduce it to the alcohol, react that with HBr, react that with cyanide, then reduce that to the amine.

2. React the aldehyde with cyanide to get the cyanohydrin, reduce that to the amine, lop off the beta hydroxyl group somehow, if whatever reduction method I used hasn't done it already.

3. Nitroaldol reaction with nitromethane. Dehydrate to get the nitrostyrene, then reduce the nitro group to an amine. IIRC, there would be tautomerism between the imine and the amino alkene forms, and the imine would be reduced more easily.

You'll probably notice that all these routes call for lots of reductions. That's because I just made a bunch of aluminum/galinstan alloy, and it's proven to be an extremely effective reduction reagent. I've successfully reduced aliphatic nitro groups to amines easily enough, and now I'm ready for something more challenging. Alcohols and water both work as solvents, though I'd worry about using isopropyl alcohol, being that aluminum isopropoxide might just convert all your ketone groups into secondary alcohols. I'm also interested in trying the reduction with nickel and copper salts, to see if and how much that affects reactivity.

I may be able to do Raney nickel now too, although I'm not sure if I'd be able to melt nickel with just a propane torch. I have at least five grams of nickel nitrate though, so I'm sure I can figure something out from there.

edit: I'm having trouble finding references doing anything like this though, mostly because there isn't really a point. All the references I've found are either from Rhodium, or describe the biological enzymatic route.

[Edited on 7/12/16 by Melgar]

Crowfjord - 12-7-2016 at 16:12

Formation of the nitrostyrene and reduction reduction with aluminum amalgam is tried and true, probably your best bet.

Do you have a plan to isolate the end product? Regular acid-base extraction will prove difficult, if possible. Dopamine will be soluble is the aqueous phase under both acidic and basic conditions due to the aromatic hydroxyl groups. Perhaps the picric acid salt would have a low enough solubility to isolate, similar to the way Ramirez and Burger isolated their phenolic amines .

Cryolite. - 12-7-2016 at 16:20

While we're at it, why not methyleneate the catechol with DCM in DMSO and use nitroethane instead of nitromethane

The nitroaldol condensation is probably your best bet here-- this is the route utilized to make most of the phenethylamines in PiHKAL. There is an abundance of information on this reaction and the catalyst used, and although yields tend to be slightly on the low side (~60%) the reaction is rather straightforward to run and easier than the competing methods. Chemplayer actually has a video on a reaction very similar to the one you are proposing here (https://www.youtube.com/watch?v=qySLcGIIDGM -- they use vanillin instead of protocatechualdehyde)

As for the reduction of the nitrostyrene formed, there are again many routes of synthetic value here. Shulgin used lithium aluminum hydride in his book, but this is out of the reach of most amateurs. A better route is to use aluminum amalgam (al/ga should work well too-- there is a writeup of this for the reduction of 1-phenyl-2-nitroprop-1-ene to amphetamine on the rhodium mirrors, with yields of about 60%. In addition, http://www.sciencemadness.org/talk/viewthread.php?tid=4889 claims a similar reduction of nitrostyrenes to the corresponding amine with zinc in hydrochloric acid. Most of the information on such reductions was on the hive and on Rhodium's site, for pretty obvious reasons.

[Edited on 13-7-2016 by Cryolite.]

[Edited on 13-7-2016 by Cryolite.]

Melgar - 12-7-2016 at 22:29

Quote: Originally posted by Cryolite.

While we're at it, why not methyleneate the catechol with DCM in DMSO and use nitroethane instead of nitromethane

Well, for one thing, I have no nitroethane and more nitromethane than I know what to do with.

Quote:

Maybe I should try this with vanillin first, seeing as I got lucky with the aldehyde and would have a hard time finding more. I only have 20g as it is. Also, I've never had much luck with the Henry reaction. If weak bases are supposed to be the best catalysts, then why are so many done with potassium hydroxide? When I've done it with sodium or potassium hydroxide, it always just turned darker and darker reddish-brown, until it was obviously not what I wanted. I used dimethylaminoethanol a few times, and that seemed to fail on me. I'd like to be able to do the reaction both ways, and be able to get the amine and the amino alcohol on reduction, but I still haven't figured out what conditions produce the nitroalkene, and which ones the nitroalcohol. I'm pretty sure I read that it had to do with whether a primary, secondary, or tertiary amine was used, but now I can't find that reference. For some reason, most references that describe what base to use either don't explain anything, or use some ridiculously complex base in order to make the reaction stereoselective, which I don't care about anyway, since dopamine isn't chiral.

Quote:

As for the reduction of the nitrostyrene formed, there are again many routes of synthetic value here. Shulgin used lithium aluminum hydride in his book, but this is out of the reach of most amateurs. A better route is to use aluminum amalgam (al/ga should work well too-- there is a writeup of this for the reduction of 1-phenyl-2-nitroprop-1-ene to amphetamine on the rhodium mirrors, with yields of about 90%. In addition, http://www.sciencemadness.org/talk/viewthread.php?tid=4889 claims a similar reduction of nitrostyrenes to the corresponding amine with zinc in hydrochloric acid. Most of the information on such reductions was on the hive and on Rhodium's site, for pretty obvious reasons.

[Edited on 13-7-2016 by Cryolite.]

In that case, it's probably safe to assume my aluminum/galinstan reduction has a good chance of working, at least with modifications. It'll be the first thing I try anyway.

Quote:

Do you have a plan to isolate the end product? Regular acid-base extraction will prove difficult, if possible. Dopamine will be soluble is the aqueous phase under both acidic and basic conditions due to the aromatic hydroxyl groups. Perhaps the picric acid salt would have a low enough solubility to isolate, similar to the way Ramirez and Burger isolated their phenolic amines .

Strong acid ion exchange resin (water softener resin). Evaporate the solution of the hydrochlorides. Separating bases will depend on what base I use.

clearly_not_atara - 12-7-2016 at 23:07

Actually, methylenating the catechol could be nice if you find it's causing you problems -- catechols can polymerize by oxidation and react readily with electrophiles, possibly including nitroalkenes. Methylenedioxy compounds are easily destroyed with common reagents including HBr, and no MeBr is produced.

Trouble is, protocatechualdehyde is a poor substrate for methylenation. It's less reactive than other catechols here. It might work with an amidine base in acetonitrile, or the KOH/DMSO system. See "The Methylenation of Catechols".

In any case, the Henry reaction is the way to go. Since you're looking at a terminal nitrostyrene, Zn powder + HCl reduction is good (this is less effective for internal nitrostyrenes).

CuReUS - 13-7-2016 at 02:15

http://ci.nii.ac.jp/els/110003626905.pdf?id=ART0004133549&am...
the authors use vanilin(maybe because its more easily available than protocatechualdehyde),do a henry reaction followed by a reduction and then use a novel(and nice

) method for the O-dealkyaltion.

Nicodem - 13-7-2016 at 12:45

Quote: Originally posted by Melgar

1. Reduce it to the alcohol, react that with HBr, react that with cyanide, then reduce that to the amine.

2. React the aldehyde with cyanide to get the cyanohydrin, reduce that to the amine, lop off the beta hydroxyl group somehow, if whatever reduction method I used hasn't done it already.

3. Nitroaldol reaction with nitromethane. Dehydrate to get the nitrostyrene, then reduce the nitro group to an amine. IIRC, there would be tautomerism between the imine and the amino alkene forms, and the imine would be reduced more easily.

Option 1 obviously cannot work.
Option 2: Protocatechualdehyde cyanohydrin can be formed (there are literature examples), but the direct hydrogenation to reduce the benzylic alcohol and the nitrile at the same time would most likely require some O-acylation first.
Option 3: There is no point in doing a Henry reaction followed by dehydration, particularly on such a sensitive substrate. Protocatechualdehyde can undergo a Knoevenagel condensation with nitromethane to give the 3,4-dihydroxy-beta-nitrostyrene directly (several literature examples). This could be hydrogenated directly to dopamine hydrochloride, thus bypassing the isolation of the unstable dopamine.

Why did you open a thread on this topic without even reviewing the prior art syntheses? It makes it appear like you are wasting us time.

Loptr - 13-7-2016 at 16:18

I don't see it as a waste of time, after all, this is the beginnings section. Nicodem does have a point though, and it would be best to attempt a known procedure, and if you have issues to then get help with troubleshooting. It's best, especially with such a small amount of reagent, to attempt an already peer reviewed procedure.

Anything else is speculating and naval gazing from our perspective. Experiment when you can, follow someone else when you can't.

Cryolite. - 13-7-2016 at 17:07

According to https://www.google.com/patents/WO2007020381A2?cl=en , vanillin cyanohydrin can be directly reduced with H2 + Pd/C at 5 bar to 3-methoxy-4-hydroxy-phenethylamine. I'm not sure how much more sensitive protocatechualdehyde is than vanillin, but it's at least some evidence that direct hydrogenation is at least possible.

CuReUS - 14-7-2016 at 09:01

Quote: Originally posted by Nicodem

Quote: Originally posted by Melgar

1. Reduce it to the alcohol, react that with HBr, react that with cyanide, then reduce that to the amine

.
Option 1 obviously cannot work.

why not ?
protocatechualdehyde to 3,4-dihydroxybenzyl alcohol -http://www.znaturforsch.com/ab/v58b/s58b1220.pdf
In case there is a chance of unwanted side reactions due to HBr,the benzyl alcohol can be directly converted to the cyanide
http://pubs.acs.org/doi/abs/10.1021/jo00327a034
the reduction should be straight forward -http://pubs.acs.org/doi/abs/10.1021/jo00067a033

Quote: Originally posted by Nicodem

Protocatechualdehyde can undergo a Knoevenagel condensation with nitromethane to give the 3,4-dihydroxy-beta-nitrostyrene directly (several literature examples)

could you please provide one such example.

[Edited on 15-7-2016 by CuReUS]

stoichiometric_steve - 20-7-2016 at 15:59

Quote: Originally posted by Nicodem

Why did you open a thread on this topic without even reviewing the prior art syntheses? It makes it appear like you are wasting us time.

My thoughts exactly, seems like an unfavourable combination of logorrhea with little scientific effort.

[Edited on 21-7-2016 by stoichiometric_steve]