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One-Pot Amphetamine Synthesis from Phenylacetonitrile,
Methylmagnesium Iodide and Sodium Borohydride

Written by Rhodium

 

The alkylation of benzyl cyanide (phenylacetonitrile) with methylmagnesium iodide affords a complex salt of Phenyl-2-iminopropane, which is directly reduced to racemic amphetamine using sodium borohydride. No attempt is made to isolate the intermediate as it easily hydrolyses to phenylacetone and ammonia at neutral or acid pH. The inverse alkylation of acetonitrile with benzylmagnesium chloride yields the same intermediate imine complex, which of course can be reduced in the same fashion as described below.

Experimental1

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 82-85C at 13 mmHg), yield about 10 grams (~75% of theory).

Further articles on Grignard alkylation of substituted phenylacetonitriles:

A Study and Identification of Potential By-Products of Sibutramine
G.O. Reddy, M.R. Sarma, B. Chandrasekhar, J. M. Babu, A.S.R. Prasad, and C.M.H. Raju
Org. Proc. Res. Dev. 3, 488-492 (1999)

Abstract
In the synthesis and process development of sibutramine (9), the isolation and characterization of two potential by-products namely heptane dinitriles (4a-b) and bis-cyclobutyl alkylamine (10) have been studied. The key steps in the synthesis of sibutramine which have contributed to the formation of above by-products are cycloalkylation of 4-chlorophenyl acetonitrile (1) and tandem Grignard reduction on 1-(4-chlorophenyl)-cyclobutylcarbonitrile (3).

Novel diacid accelerated borane reducing agent for imines
Zhi-Hui Lu, Nandkumar Bhongle, Xiping Su, Seth Ribe and Chris H. Senanayake
Tetrahedron Letters 43, 86178620 (2002)


Abstract
A remarkable effect of diacids in modulating the reactivity of borane has been discovered. This novel
process provides a rapid and excellent access for reduction of a variety of imines with different functionalities.

New resolution approach for large-scale preparation of enantiopure didesmethylsibutramine (DDMS)
Zhengxu Han, Dhileepkumar Krishnamurthy, Q. Kevin Fang, Stephen A. Wald and Chris H. Senanayake
Tetrahedron: Asymmetry 14, 35533556 (2003)


Summary
The unoptimized reaction was originally performed by Grignard addition to 1-(4-chlorophenyl)-1-cyclobutylcarbonitrile 2 in toluene at 9095C for 18 h, followed by reduction using 3 equiv. of NaBH4 in iso-propanol under refluxing for >20 h, and the reaction was quenched with water to furnish the product.

After a series of experiments an optimum procedure was established, which uses the addition of i-BuMgCl to 2 at >105C for 2 h, followed by quenching with methanol. The imine intermediate 3 was reduced using one equivalent of NaBH4 at 025C for 1 h. An efficient quenching process was identified by adding the reaction mixture to a 2 M HCl aqueous solution at 0C, which generated a homogeneous reaction mixture that can be easily stirred. After work-up, this optimized process afforded a crude racemic 1b in toluene with excellent yield (>95%). The optimized experimental conditions proved highly desirable for large-scale production (see below).

Experimental

A 1 L three-necked round-bottomed flask was charged with 1-(4-chlorophenyl)-1-cyclobutyl- carbonitrile (50.0 g, 261 mmol) and toluene (150 mL), followed by iso-butyl magnesium chloride (395 mL, 1.0 M in MTBE), and the resulting mixture was distilled until the internal temperature reached 105C. After stirring at that temperature for 2 h, the mixture was cooled to 0C and methanol was added slowly (295 mL), followed by sodium borohydride (10.4 g, 1.06 equiv.) portion-wise. The resulting mixture was stirred at rt for 15 min and was added to a 2N HCl solution (330 mL) slowly, stirred for 15 min and the phases were separated. The aqueous phase was extracted with toluene (300 mL), the combined organic phases were distilled to remove methanol, and then washed with aqueous NaOH solution (1.5 M, 100 mL) and water (100 mL) twice. The resulting organic phase was heated to 5060C, followed by an addition of D-tartaric acid (40.0 g) in water (80 mL) and acetone (40 mL) slowly. The reaction mixture was azeotrope distilled until the internal temperature reached 92C and then cooled to ambient temperature in 12 h. The slurry was filtered, and the wet cake was washed with MTBE (100 mL) and dried at 4045C under reduced pressure to afford (RS)-DDMSD-Tartrate (100.5 g) in 95.8% yield.

References

  1. Procedure Adapted from the Synthesis of #49 in J. Am. Chem. Soc. 109, 3378-3387 (1987)