1-(1,3-benzoxathiol-6-yl)-N-methylpropan-2-amine

[clubcard]

Has anyone come across the title compound? It does turn up on both Reaxys and ChemSpider but with no synthesis. It just turns up in a ligand database. The primary amine (CAS 1895361-23-5) is known.

VSEPR calculations suggest it is as stable as it's benzodioxy counterpart and I'm prepared to bet that it doesn't have the MAOI issues of it's p-MeO & p-MeS counterparts because of it's metabolism. It MAY be neurotoxic (thiophenol) so I wouldn't be keen on trying it but I'm just interested to know why it doesn't seem to have surfaced. It seems likely that the synthesis is rather more involved (enough to stop clandestine producers) but not being controlled under the MoDA (depending on interpretation of the act) but would obviously be covered by the PDA.

I'm not looking at this as a street drug. I'm interested to know if it would be of value in psychotherapy, especially in people suffering from PTSD. I'm sure those blessed with Reaxys can figure out several route - none of them amenable to the 'bucket brigade' or anything outside a well stocked lab.

On reflection, 1-(1,3-benzoxathiol-5-yl)-N-methylpropan-2-amine (primary amine CAS 1891286-82-0) would possibly be the first of class to try on the basis that the me-S is assuredly NOT going to lend any MAOI activity BUT in either case, the thiophenolate moiety is the possible neurotoxic species BUT in the meta position it COULD well undergo oxidation dropping the LogP thus it will exit more gracefully. That the indane rigid analogues are not neurotoxic in animal models fails to convince me. 1 adverse reaction is still 1 too many. Be it acute or chronic - designing benign agents should be first, last and always in medicinal chemistry. It isn't... but it should be.

I'm just wondering if it's seeming absence is toxicity (unlikely), synthetic complexity (possible) and/or lack of stability calculations (Well, the C-S-C-bonds are longer but ring-strain is lower).

BTW - you can throw the IUPAC into any appropriate to view the ligands.... but it's nothing more than an MD ring.... but with an S replacing an O... so certainly close to known agents (a very good thing) but close to other known agents (a bad thing). I presume Dr. Dave has done all of this but I also presume Cayman will steal the idea and attempt to profit from it. Frankly, this latter group is more than happy to supply all and every manner of poisons so if it appears, do NOT presume it IS harmless.

Suspicious - https://www.molinstincts.com/chemic...2-methylpropan-2-amine-cstr-CT1066367990.html

Anyone considering 'sneaking up' on the class might do well to look into 1-(1-benzothiophen-5-yl)propan-2-amine & 1-(1-benzothiophen-6-yl)propan-2-amine in an analogous manner to the self-proclaimed genius behind 'Benzo Fury' who in fact did no more than glance at a patent... and managed to get that wrong for a couple of years. There are 2 kinds of people in the world, those who do the work and those who take credit. I recommend belonging to the former group - there really is far, far less competition. That methedrone turned up on Russian Hyperlab a good 7 years before it was 'invented' is a case in point. Likewise nethiopropamine, ethylphenidate and so on. The Russian guys did all the work....

 

[clubcard]

BTW - placing the S at the meta and para will be of value in analysis of the binding-site(s) since the C-S-C bond-length is longer. The p-thioalkyls from Shulgin's & Nichols's work have seen a fair share of fatalities suggesting that MAOI activity is increased. By placing it at the meta position, that issue can be suppressed but the size and shape of the lipophilic pocket that results in less activity when a -F is appended to the methylene of the methylenedioxy bridge (1-(2-fluoro-1,3-benzodioxol-5-yl)propan-2-amine) MAY reduce activity but it it really is a good test. 3-MeO 4-Me has around the same activity but longer duration than MD bridge suggesting it is the para position that is responsible for serotonin modulation via VMAT-2. If you consider that the addition of the -F produces a chiral centre, I suggest that only 1 enantiomer is as active as it's parent.

This is NOT going to end up being used to circumvent the law but it may provide a safer target for antidepressants and other medications. The S/F compared to O/F lone-pair interaction is of interest. As Dr. Nichols has pointed out - the paperwork to make even tiny amounts puts most researchers off so for them, it may be a research tool. As an aside, O18 converted to F18 would provide a convenient radioligand to watch how VMAT-2 interaction takes place. I seem to recall Shuldin noting that DOI sat in the lungs so maybe the active is a metabolite? I'm also interested in the fact that while 2,5-dimethoxy-3,4-methylenedioxy PEA is a 5HT2a ligand, adding an alpha methyl and resolving the isomers can produce something that is not a ligand and works purely on the monoamine transports. (R) DON was the first thing I thought of, AMT the first thing I tried it with. You will perhaps not be surprised to know that the (S) isomer of AMT is like MDA, not LSD.

Actually, the IUPAC spat out by Chemoffice looks wrong. 1-(2-fluoro-1,3-benzodioxol-5-yl)propan-2-amine suggests an -F on the benzene ring when in fact it's on the methylene spacer. I'm pretty certain it has been synthesized. I know 1-(2,2-difluoro-1,3-benzodioxol-5-yl)propan-2-amine (CAS 910393-51-0) has been reported on by Trachsel et al. ('Synthesis of Fluoro Analogues of 3,4‐(Methylenedioxy)amphetamine (MDA) and Its Derivatives' Biochemistry and Diversity - Volume3, Issue3 March 2006 Pages 326-336. Free here -

https://docslide.net/download/link/...ogues-of-34-methylenedioxyamphetamine-mda-and

Tell me I'm not on my own here, please?

Oh, and of course, taking LSD as your prototype, you will see that the 7 position of the indole overlays the para position of the PEA class. The indole's nitrogen overlays the 2-MeO which is why 5-MeO indoles have so much more affinity. It seems that while 7-methyl results in an MDA-like compound (if you stick to the (S)) but larger groups are not 5HT2a ligands... although I'm not certain that anyone has actually made 5-MeO 7-Br and so forth. The NBOMe class is a non-rigid LSD conformer. the O of the methoxy overlays the =O of the amide and thiophene & furan rings substitute for the anisole showing that the N,N-dimethyl, N-sec-butyl & (S,S) 2,4-dimethylazetidine are space-filling. It's just an extra hydrogen-bond acceptor that increases the lysergamide's affinity... sorry if this is all known but I'm feeling strangely isolated :-D

 

[sekio]

1-(2-fluoro-1,3-benzodioxol-5-yl)propan-2-amine suggests an -F on the benzene ring when in fact it's on the methylene spacer.

Because the compound is a benzodioxole the ring is numbered differently, c.f. napthalene vs phenyl.

I'm kind of suprised that there are no benzoxazoles or other heteroaromatic analogs of MDx out there.

 

[Hodor]

I presume Dr. Dave has done all of this but I also presume Cayman will steal the idea and attempt to profit from it. Frankly, this latter group is more than happy to supply all and every manner of poisons so if it appears, do NOT presume it IS harmless.l

Cayman? As in Cayman chemical?
Last I checked these people make actual "research chemicals", i.e. standards for chromatography, antibodies for immunoassays, etc... they're not a dodgy RC vendor. I don't think people looking to use or sell recreational drugs are going to have them synthed by a major American company that has to comply with US regulations, and charges hundreds of dollars for a few miligrams of product.

 

[Hodor]

Because the compound is a benzodioxole the ring is numbered differently, c.f. napthalene vs phenyl.

I'm kind of suprised that there are no benzoxazoles or other heteroaromatic analogs of MDx out there.

Shulgin did make 4-T-MMDA-2, which showed at best a threshold level of activity at 25mg.

However, based on the descriptions in PIHKAL I would assume the base compound MMDA-2 to be more of a psychedelic than a releasing agent (being essentially a cyclized analogue of TMA-2), so it probably says little about the potential applicability of a benzoxathiol group in an empathogen.

 

[clubcard]

Hodor - yes, Cayman Chemicals sell bulk. I know this because I know people who have ordered bulk.

I feel a fool for not noting this compound. Was it in Pihkal? I haven't owned a copy for 20 years. Well, it shows that the scaffold is stable and in all likelihood, the 1-(1,3-benzoxathiol-5-yl)-N-methylpropan-2-amine will be an entactogen. Of course, you need to build the (fluoro)methylene bridge as the aldehyde does not appear to be commercially available.

There is a company in the UK that sells the unsubstituted phenylnitropropenes in HUGE bulk. The guy knows it is legal but is under no illusion as to the utility. I know he just keeps 1 tonne in stock and when he needs more, he has a RT aldehyde -> nitroalkene route using NaOH to drive it. The smart money stops at the nitro-alcohol (he will supply), reduces with NaBH4 and makes a ring.... evidently 'the smart money' does not exist as in 30 years, he's has 1 5Kg order!

That is what frightens me. People with literally no idea of potential risks are producing novel agents and being all surprised when people die. 'Serotonia' aka p,4-dimethylaminorex (Dr. Zee's killer RC) is a SRI & an MAOI so as risky as 4MTA. Without the 4-methyl, it ISN'T an MAOI (Dr. Dave confirmed) so a 2:1 mix of p-Me:m-Me aminorex is MDMA++ by which I mean the best bits of MDA & MDMA at 125mg (higher MW). More euphoric and more defined body-rushes. All I know is that everyone who tried it said it beat MD(M)A. Dr. Dave has that and indeed the entire QSAR. It isn't doing me any good so let the expert use the data or at least not waste time characterizing a known agent. The MD doesn't work, BTW, but the p-Me m-MeO does.... but T1/2 is too long. Those methyls are sacrificial moieties. MAO oxidizes & then non-specific blood-enzymes form the gluconate........

Just so everyone knows.

BTW - KOCN doesn't work and BrCN is not good to work with at scale. NaHNCN does the cyclization admirably and quantitatively but it cannot be stored and making for use requires some kind of REAL chemist this the bucket-brigade will not find this information of use.

I may mention synthetic routes in the negative i.e. WHY the stuff won't turn up.