Beta-phenyl amphetamine

[Limpet_Chicken]

What is known of beta-phenylamphetamine? Also, beta-phenyl-N-methyl and beta-Ph-N-ethylamphetamine?

Most interested in the primary amine however, since from diphenylacetic acid looks like a two-step reaction, forming a nitrile using diphosphorus tetraiodide in anhydrous carbon disulfide at RT for a couple of hours, then reduction of the nitrile via in-situ formation of STAB, with the nitrile in GAA solution and addition of NaBH4.

I've heard before that B-phenylmethamphetamine is both active, euphoric and long lasting, never heard of
the primary amine being used before, nor beta-phenyl-N-ethylamphetamine.

 

[sekio]

Diphenylacetic acid won't reduce to B-phenylamphetamine via diphenylacetonitrile. You've got to add a carbon.

Also, CS₂ is perhaps the worst solvent ever to work with. How you manage to add a nitrogen with phosphorous and iodine I have no idea.

As for pharmacology, if you have access to old copies of Pharmazie and a working German vocabulary, this may be of use: https://www.ncbi.nlm.nih.gov/pubmed/4783556 or https://www.researchgate.net/public..._a_series_of_diphenylaminopropane_derivatives

In diphenylaminopropane derivatives the substitution of the basic molecule in the amino group by aliphatic residues, benzyl or pyridyl groups leads to a reduction of the acute toxicity and to quantitative and qualitative changes of the pharmacodynamic action pattern. The compounds with the greatest analgetic activity are equal or superior to aminophenazone as regards activity. The introduction of a benzyl or pyridyl group into the molecule causes a loss of analgetic effect, but leads to an increase of the motility promoting effects. The activity of the control substance metamphetamine is reached by none of the derivatives. The anticonvulsive action of these compounds is insignificant. The effect on the blood pressure is not uniform and not very strong. As regards the spasmolytic activity, all water soluble derivatives surpass papaverine several times in vitro as well as in vivo. Pyridyl substituted derivatives attain, among other things, the double spasmolytic activity of the alkyl residue substituted DPA bodies.

 

[Limpet_Chicken]

Meant to say going through an intermediate aldoxime. Since P2I4 will convert aldoximes to nitriles.

Although theres another paper on dehydration-cyanation of carboxylic acids and fuck me if I've just lost it. Can't remember the entirety of the procedure, trying to find the paper again, main thing I remember is that whilst in a pinch carbon tet CAN be used the yields are lowered considerably and its a lot slower, and CS2 seems like its the only really practical solvent to perform the reaction in.

And I have to agree about CS2 being a pain. Difficult to make since it needs passing sulfur vapor through a tube furnace packed with coke at high temperatures, and difficult to buy. Although I think I've just found a place to get a few liters. And going to try the PI3->P2I4 reaction in THF rather than ether, since I don't have much left of either diethyl or diisopropyl ether, so if it can be done either in THF or 1,4-dioxane (which I could make in bulk from antifreeze and conc. sulfuric, and I use plenty ethylene glycol
in freezing mixtures)

The reaction I had in mind is a direct dehydration-cyanation of carboxylic acids to nitriles using P2I4 and ammonium carbonate
in carbon disulfide at room temperature. Been meaning to try it out for MeCN synthesis as a test substrate, I don't actually NEED any acetonitrile, I've already got plenty but from formic acid, ammonium carbonate, red phosphorus, iodine and ether, plus the CS2 for the reaction which of course would be recycled via vac distillation with a water aspirator and cooling bath, nothing difficult.

http://sci-hub.tv/10.1016/j.tetlet.2007.06.108 Quite an unusual reaction, but a 1-pot for nitriles from R-COOH is pretty sweet, no?

And of course the CS2 would be recycled via distillation, I try to recycle all my solvents, and CS2 is going to come over pretty quickly and easily, probably THE easiest solvent to strip, given its low BP.

Edit-scratch the idea of using THF in lieu of EtOEt or iPrOiPr, it'll ring-open THF.

(just found out another interesting trick in P2I4's hat, conversion of glycerine to allyl iodide. Nice.)

 

[sekio]

This is all fine and dandy, what are you going to do with the diphenylacetonitrile afterwards? Make methadone? Reduction will yield B-phenylphenethylamine and not the amphetamine.

 

[polymath]

Having more than one aromatic ring in a stimulant molecule would certainly give a lot of possibilities for ring-substituted derivatives... For example, connect the phenyl groups of desoxypipradrol with an extra alkylene bridge to prevent them from rotating (or do the rings in a diphenylmethyl group have a lot of room for rotation even without that?) - the effect on NET and DAT binding would depend on the conformation in which the molecule has to approach those proteins for binding.

 

[adder]

You can go from a nitrile to a ketone with a Grignard reagent. But why not try converting the carboxylic acid directly to the corresponding methyl ketone with methyllithium? Red phosphorus, iodine, CS2, sounds more messy.

 

[Limpet_Chicken]

Actually, Adder, RP and iodine aren't used directly, rather, they are used in a separate step to the reaction itself, a disproportionation reaction of phosphorus triiodide in dry ether, to create an entirely separate reagent used in the synthesis of the nitrile, diphosphorus tetraiodide, which is capable of dehydration of a carboxylic acid directly to a nitrile in combination with ammonium carbonate, at room temperature and simple stirring in anhydrous CS2 with high yields. The P2I4 is formed, and then isolated from the solvent, and used in CS2, although prepared in ether.

And actually it was the diphenylethylamine which was the target to begin with, someone else somewhere else suggested the result would be the beta-phenylamphetamine, and I couldn't see where the extra carbon was going to be coming from, considering that this particular nitrile formation isn't a case of cyanide addition, elongating a carbon chain by C1.

The plan is, rather, eschweiler-clarke on the diphenylethylamine to lefetamine. A lot less messy than anything involving alkyllithium or grignard reagents. And no schlenk technique required. Just reduction of the nitrile to the amine and Eschweiler-Clarke methylation that de facto avoids any quaternization since the tert.amine can't go and form another iminium species and overalkylate, when the dimethylated amine is exactly what is desired.

Which isn't to say alpha- or beta-phenyl (meth/eth-)amphetamines wouldn't be a future target. This was mostly because of confusion, thinking 'where the hell is that extra carbon going to come from), although don't let it stifle discussion on the properties of sidechain-phenylated amphetamines.

I'm guessing the confusion on the part of the other speaker evolved because most cyanation reactions involve addition of extraneous cyanide, and dehydration of a carboxylic acid directly to a nitrile is a rather unusual reaction, with P2I4 being a relatively neglected and not too well known reagent. In this case, the cyano group carbon comes not from an additional x-CN but from the carbon of the carboxylic acid itself, thus not extending the carbon chain.

 

[adder]

Yes, I know PI3 would be prepared in a separate step and then P2I4 generated from it. It seems pretty straightforward no matter how you choose to make it, but inert gas and exclusion of water are required for best yields here IMO, you have to either generate PI3 first from RP and iodine or from PCl3 with KI. Though PCl3 is probably not an easy chemical to come by. Anyway, PCl3, PI3, P2I4 will all fume upon contact with moisture in air and will degrade upon contact with oxygen too, PCl3 for instance slowly degrades even if stored under argon from contact with small quantities of water depositing oligomeric yellow solids on the bottle cap. Storing any of the three without inert gas will not work and weighing P2I4 out in the air without being able to flush vials with nitrogen or argon is not going to be nice either, getting yields reported in the original article will be impossible. Hence I thought of direct methylation of the carboxylic acid if inert gas is required anyway, methyllithium can be generated in situ and used right away in the way Grignard reagents are usually prepared and used when the scale does not justify buying ready solutions. Alternatively the synthesis of the ketone intermediate may be tried with acetic anhydride. Basically, all the chemistry of phenylacetic acid theoretically has potential application here. But that's all irrelevant if you really want just beta,beta-diphenylethylamine.

 

[sekio]

Lefetamine is an alpha-phenylphenethylamine, not a beta-phenylphenethylamine (fig.1), and is thereby inaccessible from diphenylacetic acid... you could easily get to it from 2,3-diphenyl-propanoic acid via the diphenylpropanamide, a Hofmann degradation (preferably with NaOCl instead of Br₂), & alkylation. (fig.2)

fig.1:

fig.2: