It seems like there is no great benefit from anhydrous conditions anymore, unless one wants to squeeze out the highest possible yield.
1-(2,4-dimethoxyphenyl)-2-propanone, 250 mmol
Methylamine HCl, 375 mmol
NaOH, 375 mmol
Sodium borohydride, 290 mmol
Aliquat 336, 5 mol%
Toluene
Water
To a solution of the ketone in 100 ml toluene was added a solution of 25,3 g methylamine hydrochloride in 30 ml water followed by dropwise addition of 15 g NaOH dissolved in 40 ml water while stirring the mixture violently. The addition of NaOH was allowed to take five minutes so the liberated methylamine had time to react with the ketone instead of being pushed out of solution. When the addition was complete the mixture was stirred for another hour at room temperature. The aqueous layer was then separated and discharged.
To the toluene solution of the imine was added 4,8 g (12 mmol, roughly 5 mol%) Aliquat 336 followed by a solution of 11 g sodium borohydride in 35 ml water containing 25 mg NaOH
1 in one portion. The mixture was violently stirred
2 for one hour at 35° by slight warming. The residual borohydride was destroyed by addition of diluted acetic acid until gas evolution ceased and the aqeous layer separated and discharged. The toluene solution was extracted with 3x100 ml 10% HCl and the extracts combined, washed with 50 ml toluene and saturated with NaCl.
The aqueous solution was then made alkaline with NaOH until pH 14 was reached and extracted with 2x50 ml toluene. The combined toluene extractions was washed once with water and once with brine, and then dried over MgSO
4. The solvent was removed at 40° @ 80 mbar leaving a slightly yellow oil weighing 48 g (92%). The hydrochloride was made by dissolving the free base in 250 ml EtOAc and adding 5N HCl/IPA until pH 4 was reached. Sparkly crystals formed immediately and was removed by filtration and dried to constant weight. Yield 45g 2,4-dimethoxy-N-methylamphetamine hydrochloride (2,4-DMMA)
1. NaOH is added to avoid the decomposition of sodium borohydride in water.
2. The stirring should powerful enough to create a emulsion. This allows the surface area of the two phases to be as large as possible, which means better contact and short reaction time.
CommentsI'm sure about 0,5 molar equivalents sodium borohydride is sufficient. The large amount used here was actually due to a miscalculation on my side.
My firm belief is that the
in situ liberation of methylamine is more effective than using a premade 40% aqueous solution. The addition of NaOH to MeAm HCl, using the concentrations above, makes a nearly saturated solution of NaCl at the same time. This kicks out the methylamine from the aqueous phase and forces it into contact with the ketone. If a premade 40% solution is used the amine is much more prone to stay in where it is, thus less of the target imine is formed.