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Author: Subject: Caffeine to theacrine?
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[*] posted on 1-9-2021 at 07:39
Caffeine to theacrine?

Theacrine is a CNS stimulant compound of the methylxanthine class which, in comparison to the closely related caffeine, produces longer-lived but overall milder and somewhat qualitatively different effects. Due to its longer duration and milder offset it has been gaining some popularity as an alternative to caffeine.

I began wondering whether it might be possible for the amateur chemist to achieve theacrine starting from the relatively inexpensive caffeine. While the resemblance to a mere shower thought is uncanny, I figured it might be a good idea to extend the topic to everyone here in case there's valuable discussion to be had. As far as I'm aware, synthetic theacrine has not been documented, and I would like to familiarize myself with the ostensibly excellent reasons for this.

It is believed that the most commonly known biosynthetic pathway proceeds from caffeine to theacrine via 1,3,7-trimethyluric acid.


1,3,7-trimethyluric acid <-> Theacrine

An area of interest toward the synthetic manipulation of the caffeine molecule is born of the desire to examine relatively stable silver complexes with antimicrobial properties as potential treatments against respiratory pathogens. One such compound is the bis(N-heterocyclic carbene)-silver acetate complex, whose preparation involves a kind of exhaustive methylation of caffeine which results in the formation of an imidazolium halide. I don't know enough to determine outright whether this could be of any use, but here it is all the same:

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Godrick VanHess

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[*] posted on 1-9-2021 at 08:32

It has been synthesized before. If you dig deep enough you probably can find a pathway from caffeine over multiple articles although it doesn't look like anyone directly made it from caffeine in the literature.

For synthesizing threacrine directly from caffeine it seems easy to do. First Reference uses KOH in water to directly add an OH to the 8 position which should be easy enough to oxidize directly to threacrine. Second reference does an intramolecular addition of a connected alcohol to that position on a related molecule. The third reference uses CrO3 in acetic acid to oxidize the alcohol on 2-hydroxyimidazolidine-4,5-dione to an ketone. Personally I think jones reagent would be worth a try as an oxidant.

Short of it is I think it is certainly possible to make easily from caffeine.

1.) Konstantinchenko, A. A.; Morkovnik, A. S.; Pozharskii, A. F.; Tertov, B. A. Khimiya Geterotsiklicheskikh Soedinenii (1985), (12), 1694-5


3.) Journal of Organic Chemistry (1986), 51(23), 4483-5

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[*] posted on 1-9-2021 at 09:35

Well, I did a SciFinder search and found NO clear references to its synthesis, and the only examples that were provided were a couple Chinese patents by the same people (not very promising). They essentially claim to make it by exhaustively methylating uric acid with typical methylating agents. So here's a link to that if you want to poke around in it:

The only other source that makes it was this:
Screen Shot 2021-09-01 at 11.27.22 AM.png - 201kB
I can't find the full text. That snippet is all I've got.

I also found this promising article though, which claims the oxidation of caffeine to 1,3,7-trimethyluric acid in 70% yield, using acetonitrile as the solvent, and a whole variety of possible oxidants, with PEG-300 (widely available) as a surfactant to facilitate the reaction:

So, if that oxidation works as stated, and it's possible to methylate the resulting 1,3,7-trimethyluric acid, that should get you there in two steps.

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Godrick VanHess

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[*] posted on 1-9-2021 at 10:37

Found the paper synthesizing theacrine electrochemically starting from caffeine (See Ref. 1). They reference Ref. 2 for the synthesis of 9-methylcaffeinium iodide.

That being said, I would go with Texium's idea, seems a lot more straight forward.


2.) J. Med. Chem. 2006, 49, 23, 6811–6818

[Edited on 1-9-2021 by Godrick VanHess]

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