Megatherium (Hive Bee)
05-17-03 02:24
No 433631
      Synthesis of beta-amino-butan-2-one?  Bookmark   

It should be possible to prepare this compound by the following Mannich reaction:
acetone + formaldehyde + NH4Cl --> CH3-CO-CH2-CH2-NH2

I need a lab procedure for the synthesis of this compound.  What is the correct name of this compound?  I searched in the US patent office for 4-amino-butan-2-one, but I found nothing frown.
(Official Hive Translator)
05-17-03 03:24
No 433634
      ?  Bookmark   

I always had an impression (though never knew for sure) that Mannich worked only with secondary amines, no?

I am mistaken here, then why not prepare all sorts of cathinones via this route (and why then g o the trouble of synthing 1st a bromoderivative etc.)?

(Hive Bee)
05-17-03 03:42
No 433635
      I think most of the Mannich reactions are done  Bookmark   

I think most of the Mannich reactions are done with secundary amines to prevent further reaction.  If it is done with NH4Cl, the R-CO-CH2-CH2-NH2 can react futher to (R-CO-CH2-CH2)2NH, which can on its turn react with CH2O and R-CO-CH3 to form (R-CO-CH2-CH2)3N.  An example of a "double" Mannich reaction on methyl amine is the synthesis of tropinone (Robinson, J Chem Soc (1917) p 762).

Further, a possible side reaction is that upon heating, ammonia is eliminated yielding a vinyl ketone (in this case CH2=CH-CO-CH3).

I am no specialist in the very versatile Mannich chemistry.  Advice is highly appreciated.
(Official Hive Translator)
05-17-03 08:45
No 433661
      Well,  Bookmark   

Well, in this case i see a fair chance that one could prepare N-monoalkyl cathinones in this fashion: say, ethyl or t-butyl (Assholium said once smth about this pattern being quite active although his saying was probably theoretical)

Anyhow, this is a good way to make tertiary cathinones (like N-diethylamino) and their elongated side-chain analogues. I have a specific proc for this rxn somewhere, can post if interested.

(Hive Addict)
05-17-03 12:07
No 433685
      Yes  Bookmark   

The t-butylamino cathinones are indeed worth a closer look. So are the diisopropylamino cathinones..*hint hint* wink

(Hive Bee)
05-17-03 20:14
No 433741
      Did someone say cathinones?  Bookmark   

If I'm not mistaken, a Mannich on a propiophenone will give the wrong cathinone isomer, i.e. that with the amine on the terminal carbon, which is why we're stuck with the bromoketone intermediatefrown. It's such a shame that lovely smelling propiophenones have to be converted into such nasty lachrymators to get to the final product.

According to Beilstein, the nomenclature for 4-aminobutan-2-one is correct. For such a simple molecule it's quite difficult to synthesise, precursor wise; there are no references for the Mannich on acetone given. The best way seems to be starting from methyl vinyl ketone; react it with phthalimide in ethyl acetate in the presence of sodium methoxide. See Chem.Abstr.; 57; 1962; 8555. The yield isn't given I'm afraid. The yield is given, however, for what looks like an extremely easy cleavage of the phthalimido group to give the HCl salt of 4-aminobutan-2-one; heat in aqueous HCl for 24 hours, yield 99%smile. See Monatsh.Chem.; 132; 2; 2001; 279 - 294 for the procedure, or a very similar one is given in J.Med.Chem.; 28; 1; 1985; 9-12.

My next point (and the real reason for making this post) is to ask Barium for more information on his t-butylamino and N,N-diisopropylamino cathinones. What were the ring substituents, and how long was the alpha-alkyl chain? MPPH, a Pyrovalerone analogue with a hexanophenone chain, is active at around 20-50mg if I recall correctly. Best check with Nemo_Tenetur though..

It'd be interesting to hear if anyone has tried the larger N-substituents on the shorter chain propiophenones.
(Hive Bee)
05-17-03 20:35
No 433746
      Thanks you for those refs., Kinetic.  Bookmark   

Thanks you for those refs., Kinetic.

An example of the Mannich reaction for the synthesis of
4-diethylamino-butan-2-one is given in Organic Syntheses, CV 4, 281.  But this is not exactly what I am looking for.
(Hive Bee)
05-17-03 21:13
No 433752
      More refs!  Bookmark   

[Quick note: When I said the yield wasn't given for one of the reactions in my prevoius post, I meant it wasn't given in the abstract I have. I'm sure it will be given in the full journal article]

Since you're looking at patents, take a look at Patent DE933339, which is apparently (I can't read German..) for the transformation of 4-dimethylamino-butan-2-one to N-(3-oxo-butyl)-phthalimide, which can then be cleaved to the primary amine HCl in 99% yield as given above. I can't see why it wouldn't work on the diethyamino-butan-2-one. An alternative method to the same phthalimide intermediate can be found in Chem.Abstr.; 1951; 2935.

It looks like the Mannich doesn't work with primary amines, since all the references to your compound go via other routes, using a 2 or 3 step synthesis.

Edit: Had to mention that there is a one-step route; from 4-amino-but-2-ene, via a Wacker oxidation! It's a shame 4-amino-but-2-ene isn't readily available.
(Hive Bee)
05-18-03 00:44
No 433788
      The German patent is great :-) .  Bookmark   

The German patent is great smile.

In example 1 they make a quaternary ammonium salt of 1-dimethylamino-3-butanone by reaction with dimethyl sulfate.  They heat it subsequently, hence I think the methyl vinyl ketone is generated in situ by a Hofmann elimination (or Hofmann elimination takes place after the kalium salt of phtalimide is added and the reaction mixture is heated further).

This in situ generation of the methyl vinyl ketone is rather good news, due to its toxicity.  A downside is that one needs di(m)ethyl amine to do the initial Mannich reaction like described in Org Syn CV4 p 281, so using the methyl vinyl ketone straight away will save conciderable synthetic effort.

Thank you very much for those great references.  A wave for Kinetic smile, the bee who found a nice solution (in one single day) for this not so trivial synthesis of this simple looking compound.

Very good work smile.

Could a german speaking bee please translate the "Beispiel I" from the patent?