Reductive amination of Propiophenone

[phase_dancer]

I am interested in reductively aminating propiophenone (1-Phenyl-1-propanone) via either methyl man’s or Osmium’s procedures. I seem to remember something once mentioned about reduction of the imine (methylamination) not being as favorable as for P2P or MDP2P but I used TFSE and couldn’t find anything.  

Should it be OK to substitute a molar equivalent of propiophenone in either of the above methods?

[Rhodium]

I believe that any method that works for MDP2P or P2P will work on Propiophenone - the question is rather why you want to do it. The resulting amine is rather inactive.

[phase_dancer]

Thanks Rhodium. I'm aware the compound is inactive, and in fact it is my reason for wishing to prepare it. As my lecturer has some doubts as to the effectiveness of reductive amination using using Al/Hg, this is to be a simple (no permit required) way of assessing the procedure before employing it in more serious applications.

I wondered whether the ability to form the imime may be influenced by the position of the ketone relative to the ring i.e. C1 rather than C2 due to difference in conjugative effects of neighboring groups. If yes, would this be likely to influence further reduction and therefore amounts of P1Pol produced?

[Rhodium]

Benzaldehyde imines are far more stable than phenylacetaldehyde imines. Why wouldn't the same relationship be present with the corresponding methyl ketones?

Can't you just dig up some literature references for your lecturer instead?

[zorohydride]

I actually saw this amine offered in one of the Sigma Aldrich catalogs and was being sold as a standard for Schedule 1 'Drugs of abuse', go figure. From what I have been able to glean, you want to do the Al/amalgum RDXN which would be done with an XS of amine in a hydroalcoholic soln. If you are attempting this method for propiophenone, there will be some trouble due to the aromatic ring pulling the reactivity of the ketone [hindered] unlike the 2 position which is quite reactive. When you do react a ketone in the "2" position via the aforementioned method, be sure to add enough alcohol to get a clear soln., have at least a 3 molar XS of amine, and let your soln. sit for a 24 hr minimum prior to adding the amalgum foil. Xperience has taught us that the rxn proceeds much cleaner and with higher yields and less 'glop' to clean out afterwards. For hindered amines there is only one method that I like and it's inexpensive and not labor intensive. Set up a reflux with a Barret water trap and an Allihn condenser with a one molar soln of ketone and 1.05M of amine in Xylene and a few crystals of p-TSOH-H2O. If the RXN goes well you will collect ~18mL of H2O in the trap and trapped the 'imine' intermediate in the xylene. Reflux off the xylene at 80 C using a water aspirator to get the imine; you can leave some xylene behind. Dissolve the cooled imine soln. in 99% IPA and slowly add .30 M of NaBH4 with stirring and mild heating after the complete addition. Slowly add H2O [1 mL every 5 min] and the borohydride complex will break down and the RDXN complete. There are other methods like NaBH3CN but that is now inferior to Na[OOCCH3]3BH; the former is poisonous and the latter is expensive. My method is inexpensive and will work for your situation plus you get a near theoretical yield of trapped intermediate; it's all downhill from there. I didn't get into too much detail but I think you will sort it out.

[Rhodium]

zorohydride: In your 24h imine formation scenario, are you against the use of aqueous amine solutions?

According to

Barium

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/redamin.aqueous.nabh4.html), the yield won't increase beyond what is achieved from letting the imine form for ~2h, at least not when water is present.

[zorohydride]

I am not at all bothered by the use of water in the aluminum amalgum RDXN. It used to bee that the favored amine was a 40% aqueous solution. In fact, it is necessary to have water in the RDXN RXN as a source of hydrogen. When the amine and the ketone are admixed, I merely suggest that [1] enough alcohol such as IPA be added to get a clear solution in one phase so the ketone and amine can react and most importantly that [2] that solution bee allowed to sit for at least 24 hours prior to adding the aluminum so the amine and ketone can react. I am being redundant to stress a point because the RXN goes cleaner with a much higher yield and a lot less aluminum 'glop' to clean up afterwards. I have done some ahnydrous RDXN's, but not with Al/Hg, but with STAB above. I hope that I have clarified my procedure. I have heard anecdotal reports where amine/alcohol/ ketone soln. was set up in stoppered bottles for weeks and yields were high; I found a 24 hour window was most suitable and this could probably been less. I never did a time vs yield study; usually, when you find a method that works and works repeatedly, it's worth discussing.

[phase_dancer]

zorohydride: thanks for the tips. A longer imine formation time shouldn't be a problem.

Rhodium: yeah, I've tried that. I'll present the above reasoning and see what he makes of it.

Cheers  

[josef_k]

the question is rather why you want to do it. The resulting amine is rather inactive.

Are you sure this amine is inactive? I remember shulgin said something about the MDA analogue with the amine moved to the carbon next to the phenyl ring was atleast somewhat active.
And I believe in an old post you made about the book designer drugs directory, the book claimed that alpha-phenethylamine was active. This amine is just another methyl group on that compound.

[Rhodium]

I didn't say it was completely devoid of any activity, just "rather inactive". Designer Drugs Directory tells us that -PEA "show a very weak CNS stimulating action (about 5-7 fold weaker than amphetamine)".

The MDA analog (designated ALPHA in Pihkal) still gives a weak effect at ~150mg, see the following Pihkal quote:

The benzylamine counterpart (as if one were to move the amine function from the beta-carbon to the alpha-carbon of the three carbon chain of the amphetamine molecule) is alpha-ethyl-3,4-methylenedioxybenzylamine or 1-amino-1-(3,4-methylenedioxyphenyl)propane, ALPHA. The hydrochloride salt has a mp of 199-201°C. At low threshold levels (10 milligram area) there were eyes-closed "dreams" with some body tingling. The compound was not anorexic at any dose (up to 140 milligrams) and was reported to produce a pleasant, positive feeling. It is very short-lived (about 3 hours).