Aromatic vs aliphatic bromination of butyrophenone

[Kinetic]

Using Psycho Chemist's writeup on

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

as a basis, I would like to attempt the synthesis of phenyl-2-(N-methylamino)butane; replacing propiophenone with butyrophenone, and ammonia solution with methylamine solution (For non-chemist bees, its a methamphetamine analogue; methamphetamine is phenyl-2-(N-methylamino)propane). However, the first step involves adding bromine to the butyrophenone solution.

In the UK, the desired product, phenyl-2-(N-methylamino)butane, is currently uncontrolled. However, if some of the bromine happens to add to the aromatic ring (either mono or poly-bromination), the product becomes a scheduled compound.

How much more favourably will the bromine add to the aliphatic alpha-position, rather than the aromatic ring? Obviously adding more then 100% calculated would be asking for trouble. Would adding maybe 98% be more sensible?

The reaction scheme will look something like this:

1.Add bromine to butyrophenone as above link
2.Add alcoholic methylamine solution instead of alcoholic ammonia solution
3.Reduce cathinone analogue to ephedrine anlogue using Sodium Borohydride.
4.Reduce using HI/red phosphorus, to give 1-phenyl-2-(N-methylamino)butane
5.Vacuum distillation of freebase, acid base extraction etc...

And if the ring is at all brominated, will the HI/red phosphorus reduction completely remove the bromine, as it does iodine in a properly run reduction?
I'd thought of adding some magnesium turnings to the final product just in case, to form a Grignard of any left over bromine. This could be hydrolysed to guarantee complete removal of Bromine.

Any thoughts, and would the final Grignard idea be necessary? I promise when I have the money, there will be a full writeup, and also a running commentry of the experience if I see fit (inspired by altair's recent escapades   ).

[Rhodium]

If you add 1 equivalent of bromine, really slowly and as a dilute solution, you will get almost all side-chain bromination. Distillation or recrystallization of the intermediates and final product will totally ensure that no ring-brominated byproduct makes it through.

Grignard reactions aren't possible on molecules with amine functions.

If you add pyrrolidine instead of methylamine to the bromoketone, I promise you a much more interesting  stimulant.

[Kinetic]

Thankyou for your quick response Rhodium.
If magnesium was added to the brominated product however (if any did remain), surely this would deprotanate water rather than the amine? Thinking of pKa's... Isn't water about 15, whereas an amine is about 35? What I meant for this suggestion was to make a Grignard without bothering to dry the solvent, or even with some water added, to immediately hydrolyse any formed ArMgBr to product. Drone mentions this somewhere for removing the Bromine from Bromocriptine.

As it happens, I am currently working on a similar synthesis using pyrrolidine, but with a longer side chain. Unfortunately it isn't my synth so it must remain secret!
If I remember correctly, prolintane has the structure you recommend I make, but with a pentyl chain. Will the butyl be more potent? I thought that with pyrrolidine as the amine function, a longer chain was more favourable, or is this just when beta-ketones are involved? I'm interested in my original synthesis because of the activity of methyl-J, and also from the very few reports such as

Post 242352

(Rhodium: "Re: Designer Drugs Directory", Serious Chemistry) on phenyl-2-aminobutane , but do you think that phenyl-2-pyrrolidinylbutane [hope my IUPAC is correct] will be more interesting than phenyl-2-(N-methylamino)butane? This may be very interesting, because adding ring substituents to phenyl-2-pyrrolidinylpropane would result in more legal analogues (sadly all substituted phenyl-2-pyrrolidinylbutanes would be controlled); these may be active because of the pyrrolidine function! Sorry this has gone a bit off topic, but this area really interests me!

[Rhodium]

If water is present you would get no grignard reaction at all...

The compounds mentioned in Designer Drugs Directory are 1-phenyl-3-aminobutanes, not 1-phenyl-2-aminobutanes.

Do you think that phenyl-2-pyrrolidinylbutane will be more interesting than phenyl-2-(N-methylamino)butane?

Oh yes. I do not have exact potency data available right now though.

[Kinetic]

From the above link;

Among the stimulants are  alpha-PEA, 4-methyl-alpha-PEA, diphenyl-2-pyrrolidinyl-methanol* (2-5mg), N,N-dimethylamphetamine (25-40mg), phenyl-2-aminobutane (20-40mg), 4-methylaminorex with the double bond reduced* (10-25mg), (2-hydroxyethyl)-amphetamine and 4-fluoromethamphetamine.

I'll forget the Grignard idea, as it seems unnecessary anyway. I'll have to check up on the legal status of phenyl-2-pyrrolidinylbutane first, but it sounds interesting! I don't think it's controlled over here, but it's best to be sure . I may actually try both, since I have both pyrrolidine and methylamine handy (downstairs actually)... It may take me a couple of months but I promise a writeup when I finally get it done! If you can find any references for phenyl-2-pyrrolidinylbutane, I'd be most grateful. The Hive needs new drugs...
Edit: In my previous post I said that all ring substituted phenyl-2-pyrrolidinylbutanes are controlled; in fact, as far as I am aware, they are all presently uncontrolled.

[Rhodium]

Here's something:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/cathinine.txt

[Nemo_Tenetur]

1-Phenyl-2-(pyrrolidin-1-yl)butan-1-one is not as pleasant nor as strong as APP. After prohibition of alpha-pyrrolidinopropiophenone (APP) in the year 1998 I've synthesized and evaluated the butan-1-one analog. Yes, of course, it's a stimulant but it can not compete with APP. As a rule of thumb, lenghtening of side chain increases the activity (see, for example, prolintane or pyrovalerone), but the butan-1-one was not accepted as a substitute for APP. Activity in lab rats does not always equals activity in human lab rats.

[Osmium]

Ring bromination will not be an issue if you work without a catalyst (e.g. iron powder), and maybe at elevated temperature.
I'm not fat just horizontally disproportionate.

[Kinetic]

There have been a few posts about methylone recently, and I have been reading up on ring substituted cathinone analogues. I would like to attempt the synthesis of both methylone and beta-keto 2C-B, due in no small part to their current legal status in the UK...

The simplest theoretical way I can think of making them is by bromination of the substituted propiophenone/acetophenone in a way analogous to that of butyrophenone/propiophenone, ie simply adding 1 equivalent of bromine to either of them, with acetic acid as the solvent. However, I have a feeling that adding bromine to 2,5-dimethoxyacetophenone may result in the bromine adding to the 4-position in the ring. Will this happen? In PIHKAL, no heat is required to brominate 2C-H in acetic acid, although it's ring is slightly more activated due to the aliphatic group in the 1-position rather then 2,5-dimethoxyacetophenone's carbonyl.

I also seem to remember reading (although I can't find it now) that adding bromine to MDA will result in ring bromination. Would adding 1 equivalent of bromine result in ring bromination of 3,4-methylenedioxypropiophenone over alpha-carbon bromination?

[Regis]

According to the literature, bromination of butyrophenone will definitely brominate at the alpha position ONLY.   Same thing goes for 2,5-dimethoxy- and 3,4-methylenexioxy- acetophenone and propiophenone.  As far as I have read, none of the a-bromination reactions of acylophenones have been accompanied by significant nuclear bromination.  The ONLY exception is the aqueous methanol oxone/NaBr reaction which seems to indicate that nuclear bromination occurs with "electron-rich" aromatic systems (but there were no substituted acylophenones provided as examples; only acetophenone and propiophenone).  But this seems to only be an exception.  As a rule of thumb, acyl groups are deactivating.  This is why the Friedel-Crafts acylation reaction works so well.  Once one deactivating acyl group is present on the benzene ring, no more similar groups can add on.  This is why during a-bromination of acylophenones, nuclear bromination does not occur.  I've seen so many examples of this in the literature that I can almost say that it is an indisputable fact.

Bromine in methanol solvent is reported to work much better than in acetic acid for the a-bromination of acylophenones.  For more general information and/or a detailed explanation, read the thread wherein I provide a general review of oxone reactions.  It was posted about a month or so ago.  Use the Hive searh engine and the keywords "oxone" and "NaBr" and my username, Regis.  In it is a reference to a Brittish Patent (or US Patent; I don't remember) that specifically details the bromination of various ring substituted acylophenones using Br in methanol solvent.  A copy of the patent is available from ep.espacenet.com

As for formation of arylaminoketones using the bromination/hexamine technique, I have recently made a few suggestions in this area.  See my post under the "The Most Interesting CTH Reaction Ever Documented?" thread located in the Novel Discourse forum.

Hope this has been of some help.  Feel free to ask any questions that you may have.

[Kinetic]

Thanks Regis, that was the kind of answer I was looking for; well written, and exactly what I wanted to hear!
I was worried that the activating methoxies/methylenedioxy ring would be enough to override the deactivating acyl group, and cause unwanted bromination. As it seems this doesn't happen, I'll have to give the synthesis a try as soon a I can (or as soon as I get the chemicals...). A full writeup is promised if I ever get as far as the final product!