Synthesis of Phenethylamines by Catalytic Hydrogenation of Nitrostyrenes

10% Palladium on charcoal, 3 atm H₂^1a

As shown in Scheme 1, the nitrostyrene (3) was obtained by the reaction of 4-methoxy- 2,3-methylenedioxybenzaldehyde^1b,c (2) with MeNO₂. lt was reduced to the amine (4) hydrochloride by catalytic hydrogenation in a MeOH and 1N HCl mixture over 10% Pd/C catalyst with a yield of 67%. Because of the insolubility of 3 in solvents commonly used for catalytic hydrogenation, this method for the reduction of nitrostyrene (3) on a larger scale could not be applied. Alternatively, the reduction could be done with LiAlH₄ in dry THF.

Scheme 1

a) MeNO₂, AcONH₄/AcOH, 100°C. b) H₂, 10% Pd/C in MeOH, aq. 1 N HCl, rt. c) LiAlH₄/THF, 80°C.

Experimental

General

TLC was carried out on precoated silica gel 60 HF₂₅₄ plates (Merck). Silica gel 60 (230-400 mesh, ASTM, Merck) was used for column chromatography.

4-Methoxy-2,3-methylenedioxy-β-nitrostyrene (3)^1c

4-Methoxy-2,3-methylenedioxybenzaldehyde^1b,c (2) (4.49 g; 24.9 mmol), MeNO₂ (3.3 mL; 61 mmol), AcONH₄ (1.94 g) in AcOH (20 mL) were heated at 100°C for 3 h under argon. After cooling, the reaction mixture was poured into cold H₂O (150 mL). The crystalline precipitate was filtered, washed with H₂O and dried to give fine yellow crystals: 4.65 g (83%); mp 156.2-159.8°C (MeOH) (lit.^1c 155°C (dec.))

IR (KBr)	1640s, 1620s, 1595, 1515s, 1500s, 1450s, 1445s, 1335s, 1290s, 1270s, 1205, 1175, 1110s;
¹H-NMR (CDCl₃)	7.87 (d, J = 13.5, 1H), 7.76 (d, J = 13.5, 1H), 6.92 (d, J =8.7, 1H), 6.60 (d, J =8.7, 1H), 6.12 (s, 2H), 3.96 (s, 3H);
¹³C-NMR (CDCl₃)	148.4 (s), 146.8 (s), 137.3 (s), 135.6 (d), 134.0 (d), 125.7 (d), 108.3 (d), 107.2 (s), 102.4 (t), 56.6 (q);
CIMS (NH₃)	241 (100, [M+NH₄]⁺), 224 (6, [M+1]⁺), 223 (6, M^+·)

2-(4-Methoxy-2,3-methylenedioxyphenyl)ethylamine (4)

Catalytic reduction: Nitrostyrene (3) (0.5 g; 2.24 mmol) was dissolved in MeOH (150 mL). To this solution aq. 1N HCl (11 mL, 5 equiv.) and Pd/C (10%, 0.1 g) were added. This was continuously shaken overnight under a H₂ atmosphere (50 psi). After filtration over Celite®, the solution was evaporated to dryness to yield a brownish yellow solid. Treating this solid with CH₂Cl₂ gave a colorless precipitate which was filtered and dried to give 4·HCl (0.35 g, 67%); mp 215.8-216.3°C (MeOH-Et₂O).
Reduction with LiAlH₄: LiAlH₄ (1.2 g; 31 mmol) was suspended in dry THF (110 mL), and then heated to reflux under N₂. To this refluxing suspension, the solution of nitrostyrene (3) (1.14 g; 5.1 mmol) in dry THF (20 mL) was added dropwise during 2 h and refluxed for 3 h under N₂. After cooling, sat. aq. sodium potassium tartrate solution was added and the mixture extracted with Et₂O (6x30 mL). After drying of the organic phase (Na₂SO₄), it was evaporated to dryness to give a dark yellow oil, which was purified by acid/base treatment: 0.7 g (72%).

IR (KBr)	3400 (br), 3130 (br), 3050s, 1645, 1505, 1450, 1405s, 1290, 1275, 1170, 1140, 1090, 1050
¹H-NMR (CD₃OD)	6.62 (d, J = 8.6, 1H), 6.49 (d, J = 8.6, 1H), 5.88 (s, 2H), 3.78 (s, 3H), 3.08 (t, J =7.4, 2H), 2.82 (t, J = 7.4, 2H);
¹³C-NMR (DMSO-d₆)	146.9 (s), 142.9 (s), 134.9 (s), 122.9 (d), 108.2 (d), 101.4 (t), 56.6 (q), 38.7 (t), 26.9 (t);
CIMS (NH₃)	196 (100, [M+1]⁺), 195 (19, M^+·)

5% Palladium on charcoal (K-type), 1 atm H₂²

As a typical example, the preparation of 3,4-methylenedioxy-β-phenethylamine is described.

In a 30-mL side-arm flask equipped with a magnetic stirring bar were placed 3,4-methylenedioxy-β-nitrostyrene (0.500 g, 2.59 mmol), 5% palladium on charcoal (K-type) (0.533g, Pd 0.26 mmol), 12 M HCl (0.5 mL), and ethanol (10 mL). The reaction mixture was stirred at 0°C for 3 h under a hydrogen atmosphere (1 atm). The catalyst was removed by filtration through celite and the solution washed with CH₂Cl₂ (3x20 mL). The aqueous layer was neutralized with aqueous ammonia solution (28%, 5 mL) and extracted with CH₂Cl₂ (4x20 mL). The combined organic layers was dried over Na₂SO₄. Evaporation of the solvent gave 0.303 g of product, or 71%.

The yield of mescaline from 3,4,5-trimethoxy-β-nitrostyrene was 65%.

Palladium Black, 1 atm H₂³

A suspension of 3 g 3-methoxy-4,5-dihydroxy-ω-nitrostyrene in 80 ml AcOH with simultaneous introduction of H₂ was added to vigorously shaken mixture of 3 g Pd black in 65 ml AcOH and 2 ml konc. H₂SO₄, previously saturated with H₂ during 30 min. When absorption calculated amount of H₂ finished, catalyst was filtered off, AcOH removed in vacuo, and resulting oil cooled until starting of crystallisation. Deposited crystals filtered and washed directly on the filter with 15 ml acetone. Yield of amine bisulphate is 2 g (52%), mp 107-108°C (from water).

Palladium Black, 1 atm H₂⁴

A suspension of 15 g Pd black in 175 ml AcOH was saturated with H₂ under vigorous shaking during 30 min. Then 7.5 ml of conc H₂SO₄ (d=1.84) in 25 ml of AcOH was added and saturation with H₂ was continued at another 15 min. After saturation of catalyst, with simulaneous introduction of H₂, was added suspension of 25g 2-hydroxy-3-methoxy-ω-nitrostyrene in 75 ml AcOH in small portions during 3 hrs. After absorption of the calculated amount H₂ the reaction was complete. From filtrate after removing Pd solvent was distilled off, crystalline residue treated with 50 ml of AcOEt and filtered. Sulphate was dissolved in minimum quantities of water (25 ml), and basefied with aq. NH₃, deposited base was filtered off and air-dried. Yield of 2-hydroxy-3-methoxy-phenethylamine 16.4 g (76%), mp 112°C.