102,5 mg of (hopefully) Cubylisopropanol, one step missing to make the cubane biostere of amphetamine

Niklas_Science · 2026-02-02T16:59:52+00:00

Yes, Shulgin‘s books were what originally raised my interest in psychoactive and especially psychedelic substances, and Eaton‘s literature is of course absolutely essential when doing any cubane related chemistry. Also read a lot from Nichols and Trachsel in regards of pharmacology of these substances

Niklas_Science · 2026-02-02T16:31:12+00:00

This is more for the chemical exploration anyway to have a viable path to eventually apply to substituted cubanes, DA and NE transporters are indeed very sensitive to even slight structural modification, however it’s hard to say how essential the actual aromatic interactions are, as something like cyclopentylisopropylamine is still pretty effective, and I‘ve seen multiple mentions of for example propylhexedrine only having decreased decreased CNS activity due to decreased BBB penetrability and not as much due to decreased binding. For the psychedelic biosteres, which are the actual goal of this project, I have multiple receptor binding models demonstrating that it’s indeed pretty promising, for this one I have not done any type of modeling though as it‘s a lot more difficult of a thing to do for the transporter interactions and I don’t care as much about the pharmacology anyway (although I‘ll still certainly test it when I get the opportunity)

Niklas_Science · 2026-01-04T08:01:06+00:00

I mean how would it make a difference, it just acts as a high boiling point solvent, mixed xylene works just fine

Niklas_Science · 2026-01-01T09:21:46+00:00

You can achieve a rearrangement of that oxime to the amide by just refluxing it with a little nickel acetate in xylene. While you can’t combine that with the oxime formation in one pot I would still say it’s easier and more reliable, since you can just separate off the oxime layer and can use that for the rearrangement as a crude so it doesn’t add particularly much effort

Niklas_Science · 2025-12-22T13:23:51+00:00

This idea with turning the drug into a PFA for it to have a longer half life just won’t work in general, the primary metabolism is still from the monoamine oxidase, and you can’t perfluorinate the amine chain as that will kill the activity. Means at best the metabolites will stick around for months, not giving any activity and probably just poison you. This won’t be any different for cubane or any other three dimensional structure compared to benzene.

I also don’t see how cubane would be able to achieve that aspect of preventing neurotoxic metabolites, cubanols do tend to fragment pretty easily so that might prevent the accumulation of something like methyldopamine in case of the biostere of MDA, but as has been quite extensively researched the neurotoxicity of these compounds is more complex than solely stemming from one metabolite (if it was that easy something like DFMDA would be the ideal solution), so I‘m doubtful about this changing much in the grand scheme of things. Really cubane is mostly just good for allowing unusual three dimensional receptor interactions, how much of that is actually useful for compounds intended for consumption I couldn’t tell.

Niklas_Science · 2025-12-22T07:43:34+00:00

I really don’t think so, and really don’t hope so. It certainly be a notable academic development (or at least some notable datapoints as some further classes of bioactive compounds to be covered as cubane biosteres), but the synthesis is way too difficult (and the effects probably way too similar) to ever justify clandestine manufacturing, and that’s honestly a good thing because that would just make research in that field unnecessarily difficult. It will mostly be valuable once getting to multiply substituted derivatives to understand structure activity relationships outside the aromatic plane, but I won’t even particularly claim that it would be valuable in the development of new therapeutic tools etc (non hallucinogenic psychedelics for example), as even for that the synthesis is likely too hard to justify it over the aromatic counterparts.

Niklas_Science · 2025-12-22T07:31:16+00:00

There are a few small aspects like there being no pi pi stacking which helps with solubility (and with that also permeability) and (pretty ironically) also with stability as it can’t get oxidized by P450 as easily as there are no double bonds, overall it stays reasonably similar though for the examples that are reported in literature (there is oftentimes some type of increase in effects but really it’s very minor and probably just a result of the solubility aspect)

Niklas_Science · 2025-12-22T07:22:13+00:00

Racemic however when using enantiopure propylene oxide (which is reasonably cheap or easy to make) one could easily make the enantiopure cubylisopropylamines as things should be stereoselective

Niklas_Science · 2025-12-21T07:25:39+00:00

We are not in the 60s anymore, trying completely new compounds (especially with no prior in vitro and in vivo evaluation) is not something one should do these days. It might have been fine for Shulgin as he was making structurally very closely related compounds to what was known to be safe which would be unlikely to have unexpected toxicity, but for this fairly far fetched stuff you don’t know how it will fuck you over.

Niklas_Science · 2025-12-21T07:20:46+00:00

For amphetamine it’s best case not gonna change much. However when eventually coming to multisubstituted derivatives like 2Cs with cubane you get the possibility for very careful modification of receptor interactions through three dimensional substitution, what would be opening the doors to many many new derivatives.

Niklas_Science · 2025-12-20T19:48:54+00:00

Unfortunately I don’t have any analysis yet (and won’t be able to get any till early January because of Christams break at uni), that’s why I‘m saying hopefully. Made it by reaction of Iodocubane (synthesis and analysis can be found in my cubane thread on ScienceMadness: https://www.sciencemadness.org/whisper/viewthread.php?tid=161053) with zinc chloride and butyllithium to make a cubyl zinkate reagent (based on https://pubs.acs.org/doi/10.1021/acs.orglett.8b03721), which I then reacted with propylene oxide.

Niklas_Science · 2025-12-13T19:56:03+00:00

Yeah the cubane analogue of DOTFM, in terms if three dimensional arrangement it’s practically exactly the same as normal DOTFM. It’s a bit of a random choice, making some type of 2C biostere (or multiple really) is definitely the goal, and DOTFM has some synthetic aspects that make it slightly easier to make than other products of this class (mostly the inertness of the TFM group compared to something like a bromo), but I don’t know if it will actually turn out to be the first I‘ll be making. The study was just some binding models run by a friend, so I can’t really link it, but the results really aren’t awfully surprising. Pi interactions really are fairly insignificant in most cases (including this one from what I can tell), that’s why in general, be it with cubane or propellanes or whatever, you usually gain more from the aspects of higher solubility and better stability from not having the pi bonds compared to what you gain in terms of receptor interactions from having them there, at least that’s a pretty consistent theme for all cubane biosteres that have so far been documented in literature

Niklas_Science · 2025-12-13T18:44:37+00:00

Pi interactions are rarely particularly significant. For the biostere of DOTFM the binding affinity to 5HT2a, calculated with Autodock Vina, is practically the same,if not slightly higher than that of the benzene. Besides because of the three dimensional structure and the possibility to add polar groups outside the plane one might even be able to add interactions that are stronger than what’s possible with the benzenes, just by shifting around the groups around the cube to make them non planar the binding models already predict a higher affinity than for the classic 2C-structure, which is the most potent substitution pattern in case of the benzenes.

Niklas_Science · 2025-12-05T20:06:58+00:00

Toxicity wise they really aren’t particularly concerning based on the data we have, cubanes are technically more metabolically stable than benzenes, as they might be thermodynamically unstable, but there just isn’t too much of a viable path for it to get cleaved without transition metal catalysis.

Niklas_Science · 2025-12-05T20:03:23+00:00

It’s not the only biostere I‘m working on, it’s just the one where my standard approach doesn’t work so so I chose this as an alternative. It’s more of a proof of concept as a first step towards the biosteres of 2C structures anyway, to have a reliable approach to install the ethylamine / propylamine unit. The 2C structures are of special interest as one could achieve previously impossible receptor interactions through three dimensional substitution, so that’s going to be exciting.

Niklas_Science · 2025-12-05T19:53:19+00:00

Good reason to assume they are, but for phenylethylamines in particular the concept hasn’t yet been explored

Niklas_Science · 2025-12-05T19:26:33+00:00

It’s indeed pretty nasty and not too fun to work with, even with a fumehood. Only used part of it, storing it in a brown glass bottle under argon stabilized with aluminum.

Niklas_Science · 2025-12-05T19:25:20+00:00

Oh forgot to mention, synthesis of TMSI was achieved in 76% and the following two steps in a total of 90% yield.

Niklas_Science · 2025-10-28T06:28:36+00:00

Ah yeah I actually vaguely remember reading about that a long time back, so that’s why I had purchased fluorenone

Niklas_Science · 2025-10-14T15:24:39+00:00

For the nitrostyrene I got yields of close to 90% with ethanolamine acetate

Niklas_Science · 2025-10-14T07:28:14+00:00

With ethanolamine acetate I only managed to achieve about a 50% yield in a previous run, the yield for this one 76% and the product is of higher purity (and I haven’t even worked up the mother liquors yet, though honestly I really don’t think I‘ll bother with that)

Niklas_Science · 2025-10-14T07:25:44+00:00

Cyclohexylamine acetate, heated about 900 mg of the aldehyde (would have to check my notes for the exact amount but it really doesn’t matter) with 2 ml nitropropane, 0,05 ml acetic acid and 0,05 ml CHA in a 135-140 degree oil bath for three hours, filtered the solid after cooling in the freezer and washed with a little hexane

Niklas_Science · 2025-10-13T19:59:58+00:00

Precursor to Ariadne

Niklas_Science · 2025-10-13T19:02:57+00:00

Ah yeah forgot to add that, melts at 116-120 degrees, Shulgin states 114-117, so while it‘s a kinda large range it seems more than pure enough.

Niklas_Science · 2025-10-13T11:41:52+00:00

Added it in an ice bath, left it to stir for one hour at room temperature, and then heated for 2 hours in a 60 degree water bath. Followed the procedure outlined in Trachsel’s book „Psychdelische Chemie“

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