Novel One Pot Amphetamine synth from BzCN, MeMgI and NaBH4

Introduction

The alkylation of benzyl cyanide (phenylacetonitrile) with methylmagnesium iodide affords Phenyl-2-imino- propane, which is directly reduced with NaBH4 without isolation of the intermediate to give racemic amphetamine. The same procedure with Benzylmagnesium chloride and acetonitrile will yield the same intermediate imine, which of course can be reduced in the same fashion as done in this document.

Procedure

A solution of MeMgI was prepared in the usual manner from methyl iodide (15g, 0.105 mol) and clean Mg turnings (30g) in 200ml dry THF, and the solution was added slowly with good stirring to a cooled solution of (11.7g, 0.1 mol) benzyl cyanide in 150ml dry THF in a dried 1000ml round-bottomed flask. The reaction mixture was stirred at room temp for two hours and then cooled in an ice-bath. The solution was diluted with 150ml of dry methanol and NaBH4 (9.5g, 0.25 mol) was added in portions during 30 minutes, and the reaction mixture was stirred for another hour. The reaction mixture was concentrated under vacuum and the residue dissolved in 200ml water and acidified with concentrated HCl. The solution was washed with 2x50ml DCM, made basic through the addition of 25% NaOH, and extracted with 3x75ml DCM. The pooled organic extracts was dried over MgSO4, filtered and the solvent evaporated under vacuum. The oily residue was then vacuum distilled to give racemic amphetamine as a clear oil (bp 82-85°C at 13 mmHg).

Yield 10.8g (80% of theory).

Reference: JACS 109, 3378-3387 (1987) Procedure adapted from the synthesis of #49.