Aqueous NaBH4 Reductive Amination of Phenylacetones

Freifelder stated a long time ago that phenylacetone + aq.methylamine -> N-methylimine which is hydrogenated to N-methylamphetamine. The wet enviroment doesn´t disturb the imine formation. Yet when bees here want to make MDMA they tend to choose anhydrous conditions. In particular in the borohydride reduction of the imine to amine.

I decided to challenge this:

10g 2-fluorophenylacetone (65mmol) was dissolved in 50ml toluene and to this was added a solution made of 10.6g (130mmol) ethylamine HCL and 5.25g NaOH in 50ml water. The mixture was vigorously stirred at room temp for 2 hours. The aqueous phase was then removed and the toluene phase was transferred to a 250ml rb flask containing 1.9g NaBH4 (50mmol), 25ml water and 15ml EtOH and the mixture was vigorously stirred for a further 2 hours at room temp. Diluted hydrochloric acid was then added dropwise until pH2 was reached, the phases was separated and the toluene phase was extracted twice with 20ml 5% HCL and then discarded. The combined aqueous phases was made strongly alkaline with 50% aq NaOH and extracted twice with 50ml toluene. The toluene extracts was dried over MgSO4 and stripped of solvent in a rotovap. The residual yellow oil (nasty smell) was dissolved in 50ml EtOAc and dry HCL in IPA added until pH4 was reached. The white crystals was isolated and dried to constant weight. Yield 8.9g (40.9mmol,62.9%) N-ethyl-1-(2-fluorophenyl)-2-aminopropane hydrochloride

A few further tests were conducted, varying the reaction conditions:

    A      B   C    D   E

1   EtNH2  1h  0.5  1h   52%
2   EtNH2  2h  0.5  1h   55%
3   EtNH2  1h  1    1h   56%
4   EtNH2  2h  1    3h   73%
5   MeNH2  1h  0.5  1h   55%
6   MeNH2  2h  0.5  1h   56%
7   MeNH2  1h  1    1h   49%
8   MeNH2  2h  1    3h   78%

A. Amine used
B. Time for imine formation in hours
C. Molar equivalents NaBH4 to substrate
D. Imine reduction time
E. Yield of N-alkyl-2-Fluoroamphetamine HCl