Bombs and Butterflies: TNT ---> TMA-6.

[blasephilomath]

The following is of course only a synthetic outline.  I realize that there are not enough details to actually perform this reaction simply by reading this post.  However, they could easily be looked up for a fee on Beilstein or equivalent I would imagine.

Toluene (or ethylbenzene or cinnamon oil for that matter) is refluxed in HNO3 and H2SO4 to yield (in the case of toluene) 2,4,6-trinitrotoluene which is then reduced with Sn and HCl to 2,4,6-triaminotoluene which then undergoes a diazotization reaction with HNO2 (nitrous acid; made by reacting sodium nitrite with sulfuric acid).  Next, the resulting intermediate is treated with hot, aqueous HCl or H2SO4 (the Sandmeyer reaction, I believe) and
O-trimethylated with either dimethylsulfate or CH3I in MeOH.

The 2,4,6-trimethoxy-1-methylbenzene is then oxidized with KMnO4 to 2,4,6-trimethoxybenzoic acid, reacted with SOCl2, reduced with lithium aluminum tri-tert-butoxide hydride in ether, condensively reduced with EtNO2 and ammonium acetate, and finally reduced with LAH and cyrstallized with HCl and ether to yield TMA-6 hydrochloride.

If the aryltridiazonium ion intermediate is reacted with CuCl or CuBr instead of H2O in hot acid, then 2,4,6-trichloroamphetamine or 2,4,6-tribromoamphetamine, both pharmacological unknowns as far as I know, would result (provided that a minimum of LAH were used in the final reduction so as not to tear off the aromatic halogens). 

Also, it may be possible to use amphetamine instead of toluene as the precursor, provided the the amine be protected (and later deprotected via acid or base hydrolysis) with acetic anhydride, acetyl chloride or even propionyl chloride. 

Again, I'm not exactly sure.  I just know that a lot of people are bored with the same old, same old meth and
mdma, and with acid being as scarce as it seems to be,
TMA-6 would be a welcome diversion IMO.

* * *

Just my 6th cents.

[Vitus_Verdegast]

Toluene (or ethylbenzene or cinnamon oil for that matter) is refluxed in HNO3 and H2SO4 to yield (in the case of toluene) your immediate death in a big kaboom?

(I can imagine the evening news already: 'suspected terrorist blows himself to pieces while trying to make a powerful explosive')  

No offence intended, just adding a small detail to your synthetic 'outline'

[Rhodium]

It is not practical to perform a multiple sandmeyer reaction on a polynitro-aromatic compounds, due to side-reactions such as polymerization etc. Your proposed scheme will more likely than not fail. UTFSE for a similar proposal for the synthesis of Mescaline which was shot down in the Serious Discourse forum a while ago.

[cattleprodder]

Polymerizations occur via a free radical mechanism involving styrenes', allylbenzenes' and propenyl benzenes' side chain double bonds.

Since there is no allyl or propenyl side chain to polymerize in this case, I don't see polymerization as very likely to happen, especially with the
2,4,6-trichloroamphetamine compound.  Using a large excess of H3O+ should decrease the incidence of unwanted azo (R-N=N-R') by products.

Your claim sounds like a scare tactic by the DEA to discourage the successful implementation of this method (which is, after all, their mission I suppose).  Of course, if you can provide published references, then that will be another story altogether.  Sometimes you sound like such a pessimist, Rhosey! 

Also, this would be a good way to convert 2C-H to 2C-B or 2C-C.  That is, 2C-H --> 2C-N --> 2C-A --> 2C-Az --> 2C-B or 2C-C.  It would be especially good for making 2C-C than what is presented in PIHKAL in that no toxic and hard to deal with Cl2 gas would be required. 

At the very least, I think this method merits more research before being dismissed outright.

[Rhodium]

Di/polymerization is possible with almost anything, it doesn't need to be any alkenes involved. The azo byproducts you mention is a good example, imagine a three-dimensional network of -N=N- azo linkages instantly forming between any of the three aromatic nitrogens throughout your solution - possibly very exothermically. 

Do you have any references about azo byproduct minimization using excess acid when hydrolyzing polydiazoaromatics? Do you have any references on tris-diazoaromatics?

I have looked into the use of the sandmeyer reaction for functionalizing 4-amino-phenethylamines, but all references I found on that reaction without any protective group on the aliphatic nitrogen were very old and had no fantastic yields. Theoretically, by adding a carefully measured amount of acid, the aliphatic amine can be protonated selectively over the aromatic one due to their difference in basicity and render the former unreactive to diazotization, but it seems like that is not so easy in practice as it seems. Do you have any references I am unaware of?

I am not aware of myself being pessimistic about any posted suggestion, where I have later been proven wrong and the reaction in question actually did run fine, contrary to my expectations. Usually when I am unsure, I shut up (but the other way around, where I thought a reaction would work, but it actually didn't, has unfortunately happened more than once).

[catastrophe]

How about this way...
1. Brominate 2,5-DMB --> 6-Br-2,5-DMB (%5) there must be a way to increase the yield.
2. ^-OCH3 with CuI in DMF --> 2,4,6-TMB

Anybody got an idea on how to increase the yield in the bromination step to the 6 position instead of the 4?

[cattleprodder]

No, I don't have any references for triazotization (other than an allusion to mono-diazotization in PIHKAL under either DOC or 2CC, I don't remember which), but if I run across one, then I will be sure to try to let you know about it.

As for the bromination of 2,5-DMB, I don't see any easy way to end up with TMA-6 from there.  The energetics just don't seem to agree with that pathway.  Extraction of proanthocyanidin (from grapes), phloroglucinol or phlorizin (both from fruit tree bark) may therefore be the best way to achieve TMA-6 for now.

Didn't someone post a link to a very sophisticated synthesis of dronabinol (delta-9-THC) and other, even more powerful analogues starting from 1,3,5-trichlorobenzene a few years ago?  That would be interesting to review here, as it may very well lead to TMA-6 (that is, psi-TMA) and psi-DOAM as well.

[catastrophe]

Here...

https://www.thevespiary.org/rhodium/Rhodium/chemistry/bromodimethoxybenzaldehyde.html

.

Subsequent fractions gave 1.5g (5%) of 6-bromo-2,5-dimethoxybenzaldehyde (3), mp 102-103°C (EtOH).

SWIM's previous post gave the wrong sequencing on the ring, but the idea still works...
1. 6-bromo-2,5-dimethoxybenzaldehyde
2. methoxide ion in DMF(or EtOAc) with CuI will give the 2,5,6-trimethoxybenzaldehyde (or 2,3,6-tmb; however you want to call it)

As for the bromination of 2,5-DMB, I don't see any easy way to end up with TMA-6 from there.

Seems better(easier) than what you proposed, even if you only get a 2% yield. Sorry if SWIM didn't like your proposed synthesis, it was just too much work. If there was a way to increase the yield in the bromination step, selectivity at the 6 (or 1; however you want to call it) position, then this would great. No formylations, and relatively OTC - if you make the 2,5-DMB and corresponding alkoxides by yourself, which can be done OTC.

[Potter]

see the Proc. Indian Acad. Sci.,1953 A37,¹6, 798-804
and "J. Indian. Chem. Soc." 1962, 39,¹7 439-443

[catastrophe]

You know what, SWIM's idea was for TMA-5 not TMA-6, sorry about that. Just wanted to clarify.