Lego
(Stranger)
03-04-03 06:51
No 413690
      Red. amination with Zn/iPrOH and mol. sieves
(Rated as: excellent)
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Reductive amination with Zn/iPrOH and molecular sieves


Eur. J. Org. Chem. 1998, 1271-1273

Abstract: A ketone is treated with a primary amine to form an imine in iPrOH in the presence of molecular sieves and HOAc. This amine is reduced to the amine with Zn in good yield.

Keywords: Reductive amination, zinc, acetic acid, isopropylalcohol, isopropanol, IPA, molecular sieves, imine, ketone, primary amine


The abstract of this article has been posted at the Hive before, but not the exact method. See Post 164964 (not existing) and Post 108765 (dormouse: "Red. Amin. with molecular sieves and Zn/IPA  -Feck", Novel Discourse).



The authors tried to synthesize III from I and II via reductive amination. Common methods like NaBH3CN, NaBH(OAc)3, LAH failed for this target compound.

Experimental: 1.00 g (5.43 mmol) ketone I and 1.00 g(5.40 mmol) amine II were dissolved in 10 ml of absolute isopropanol and dried with molecular sieves 3 for 1 h at RT. 1.00 ml (17.5 mmol) glacial acetic acid were added unter N2 atmosphere and the reaction mixture refluxed for 6 h. The oil bath was then removed and 870 mg (13.3 mmol) Zn dust was added in portions over a period of 5 min. After 5 min the reaction mixture became solid. It was partly dissolved with 15 of isopropanol. The solids were removed by filtration and washed with methanol until the filtrate was colorless. The solvent was evaporated (50C, 30 Torr) and the residue dissolved in 20 ml 2 M NaOH solution and 10 ml CH2Cl2. The phases were separated and the aqueous one extracted with 10 ml CH2Cl2. The combined organic phases were washed with 5 ml of brine, dried with MgSO4 and the solvent evaporated (40C, 30 Torr.). The crude oil was dissolved in 0.5 ml of CH2Cl2 and 20 ml of tert-butyl methyl ether and washed with 2 M NaOH solution (15 x 5 ml). The organic phase was washed with brine and dried with MgSO4. After evaporation of the solvent and drying the residue under oil-pump vacuum, 1.35 g (3.82 mmol, 70%) BDMPA III were obtained as pale-yellow viscous oil.

I











Molecule: a1 ("O=C(c1ccccn1)c2ncccc2")




II











Molecule: a2 ("NC(c1ccccn1)c2ncccc2")




III











Molecule: a3 ("N(C(c1ccccn1)c2ncccc2)C(c3ncccc3)c4ccccn4")




Comments by Lego: iPrOH was purchased from a standard chemical supplier and was not dried further.
Maybe the amount of acetic acid may be reduced if primary amines like methylamine are used because the authors assume pyridyl groups to act as a 'proton sponge' inhibiting the protonation of the intermediate carbinol amine.
The authors did not use any other high boiling alcohol, may be 1-butanol may also work or even better. The amine II was prepared from the corresponding oxime with Zn/NH3, see Post 413177 (Lego: "Reduction of ketoximes with Zn/NH3", Novel Discourse)




The candle that burns twice as bright burns half as long
 
 
 
 
    Sunlight
(Pioneer Researcher)
03-04-03 09:06
No 413719
      I'm working in it right now !!!  Bookmark   

I've been working in a similar procedure since a few days ago!!!. Thinking that Zn seems to reduce almost everything, I thought it could  well reduce the hemiaminal formed in the addition of ammonium formate and ketone in alcohol containing water, as well as the imine. I started the tests, and I've observed that the ketone  (MDP2P) dissappears completely using both ammonium formate or ammonium acetate with methanol containing or not water. I made a lot of tests and better results were obtained when the rxn is performed at about 60 C for 3-4 hours. Respect to methylamine I made a test and it seemed to work the same.
I have been very excited getting similar TLC's to the CTH reductive amination, but today I've done finally a rxn in a workable scale, and the isolated product is not the amine, but a curious white gum that is soluble in methanol and in concentrated HCl. I wonder if first it is reduced to the amine and then the amine forms some kind of Zn complex, and it it could be reverted by acidification before the workup.
When the Zn dust is added, even at room temp, it forms a grey suspension, and after about five minutes, it forms an aglomeration of solids that slow reacts with the ammonium salts. TLC at this moment shows a clear spot in the place of the amine /that could be the amine or not) and other byproducts . If the rxn is let to work hours, specially if hot, all the spots dissappear, and there's only a short tongue coming up from the bottom of the plate. What the hell can be it, a polymer, a Zn complex ... ?
 
 
 
 
    hermanroempp
(Hive Bee)
03-04-03 13:08
No 413778
      Re: Zinc complex  Bookmark   

I'm not quite sure, but I bet you're on the right way with the assumption that a Zn-complex has formed. Decomposition of the Zn-complex can be performed with aqueous NaOH (10% in water) and subsequent steam distillation. Compare with Vogel's 3rd, p. 828 ff under "quinoline".
Amines are notorious for forming complexes with Zn...wink

Quidquid agis, prudenter agas et respice finem!
 
 
 
 
    Sunlight
(Pioneer Researcher)
03-04-03 13:36
No 413786
      Thanks  Bookmark   

Thank you for your interest. In the workup I tried adding NaOH solution without success, I guess that that product can be anything. I need to explore it more times to see if there's something useful there.