Synthesis of 2C-D

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2,5-Dimethoxy-4-methylbenzyl Chloride1

Sodium borohydride (42 g, 1.1 mol) was added to a suspension of 2,5-Dimethoxy-4-methylbenzaldehyde (180 g, 1 mol) in i-PrOH (2000mL) The resulting mixture was refluxed for 2.5 h. The solvent was removed in vacuo and the residue partitioned between H2O and Et2O. The ethereal solution was washed (H2O, saturated brine) and chilled (ice H20), and 500 ml of 12 N HCl was added with good stirring. Stirring was continued, without cooling, for 1 h. The two layers were separated and the aqueous layer was extracted with Et2O. The combined ethereal solutions were washed (H2O, saturated brine), dried (Na2SO4), and concentrated to give 189 g of beige crystals. Recrystallization from petroleum ether (bp 100-115 °C) gave 2,5-Dimethoxy-4-methylbenzyl Chloride (138 g, 69%), mp 60-67°C. By boiling down the petroleum ether mother liquors, a second crop (about 30 g) of material was obtained.

2,5-Dimethoxy-4-methylbenzyl Chloride3

Gaseous hydrogen chloride was bubbled into a well-stirred mixture of 200ml of 35% formaldehyde, 100 ml of concd. hydrochloric acid and 400 ml of dioxane for 15 min at such a rate that the temperature of the mixture remained between 55-60°C with no external heating. To this mixture 152g (1.0 mole) of 2,5-dimethoxytoluene was added, dropwise, over a period of 20 min, while the temperature was maintened between 55-60°. When the addition was completed, the passage of hydrogen chloride was stopped. The mixture was cooled and poured into 2 L of ice water and 300 ml of ethyl ether. The aqueous layer was extracted twice more with 250 ml portions of ether. The combined ether extracts were washed with cold water until the washings were neutral to litmus, then dried with anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was distilled through a 4-in Vigreux column to give 110-130g (55-65%) of colorless liquid, bp 144-153°C/14-16 mmHg, which solidified on cooling. Recrystallization from CH3CN gave white crystals, mp 61.5-62.5°C.


To a suspension of 0.7 g (14 mmol) of NaCN in 6 ml of anhydrous DMSO was added, dropwise, with stirring a solution of 2.0 g (10 mmol) of 2,5- Dimethoxy-4-methylbenzyl Chloride in 6 ml of anhydrous DMSO. A slight exothermic effect was noted. The mixture was stirred for 2.5 h at ambient temperature and then poured into H20. The product was extracted out with Et2O; the combined extracts were washed with H2O and with saturated brine and dried (Na2SO4). The solvent was evaporated to give a solid which was recrystallized from petroleum ether (bp 100-115°C) to give 1.3g (68%) of 2,5- Dimethoxy-4-methyl-phenylacetonitrile, mp 65-66°C.

2,5-Dimethoxy-4-methylphenethylamine Hydrochloride (2C-D)1

To a stirred solution at room temperature of 5.0 g (26.3 mmol) of the 2,5-Dimethoxy-4-methyl-phenylacetonitrile in 100 ml of anhydrous THF was added, at a moderate rate, 158 ml (158 mmol as BH3) of B2H6 in THF solution. The solution was stirred and refluxed for 16.5 h. The reaction mixture (some solid had separated) was cooled (0°C) and cautiously decomposed with 50 ml of 6 N HCl. The resulting mixture was poured onto cracked ice and an excess of dilute NaOH solution; the oily product was extracted out with Et2O. The combined extracts were washed with H2O and then with saturated brine and dried (MgSO4). The solvents were removed under reduced pressure and the salt of the product was formed with HCl(g) in EtOH. The solution was evaporated to dryness and the residue was recrystallized from i-PrOH. Colorless crystals of 2C-D.HCl (3.80 g, 62%), mp 214-215.5°C, were obtained.


2,5-dimethoxytoluene (45 g) was dissolved in dry tetrachloroethane (450 mL). Oven dried zinc cyanide (80 g) was added and the mixture stirred vigorously at room temperature while a continuous stream of dry hydrogen chloride was introduced. After 1 hour, the brown mixture was thoroughly cooled at 0°C and 72 g of anhydrous aluminium chloride was added. Hydrogen chloride was passed into the mixture for an additional 2 hours, maintaining the temperature at 65-70°C. Additional dry zinc cyanide (40 g) was then added, while continuing introduction of the dry gas for an additional 2 hours. Further zinc cyanide (40 g) was added again and introduction of the gas was continued for an additional 4 hours. Sulfuric acid (550 ml, 2.5 N) was added slowly to the cooled mixture, which was then allowed to stand overnight at room temperature. The mixture was slowly heated to the boiling point and then steam distilled. The organic solvent came over first and was collected separately; this was followed by the whitish title aldehyde (42.1 g, 79% yield), which was crystallized from ethanol giving a crystalline white product, mp 85°C.

An alternative synthesis of 4-methyl-2,5-Dimethoxybenzaldehyde from 2,5-dimethoxytoluene can be found here.


A mixture of 5.4 g (30 mmoles) of 2,5-Dimethoxy-4-methylbenzaldehyde, 2.5 g of NH4OAc, 2.5 ml of CH3NO2, and 25 ml of benzene was refluxed for 20 hr, during which time H2O was azeotroped with a Dean-Stark tube. After cooling, the resulting solution was washed successively with 2x25ml H2O, 2x25ml saturated aqueous NaHSO3 and 2x25ml H2O. The benzene layer was dried (Na2SO4) and evaporated in vacuo leaving 6.0 g (90%) of a yellow solid, mp 111-112°. Recrystallization from Benzene-Heptane (1:2) gave 5.3 g (79%), mp 118-119°C. This melting point remained unchanged upon another recrystallization.

2,5-Dimethoxy-4-methyl-phenethylamine (2C-D)2

To a stirred suspension of 3.0 g (80 mmoles) of LiAlH4 in 50 ml of THF was added a solution of 4.4 g (18 mmoles) of 2,5-dimethoxy-4-methyl-beta- nitrostyrene in 50 ml of THF. The mixture was refluxed for 1 hr, cooled in ice, and treated with a mixture of H2O and THF to decompose excess LiAlH4. The resulting mixture was filtered and the filter cake was extracted with THF. The combined THF solution was evaporated in vacuo leaving 3.7g of oily product. A solution of this oil in 25 ml of Et2O was treated with Et2O-HCl to precipitate 3.4 g (83%) of the hydrochloride salt, mp 200-203°. Recrystallization from EtOH gave 1.8 g, mp 212-213°C. Addition of Et2O to the filtrate yielded 750 mg, mp 211-213°C. The total yield was 62%. In a separate run distillation of free amine yielded 59% of a liquid, bp 95-105°C (0.15 mmHg).


[1] J. Med. Chem. 19, 1400-1404 (1976)
[2] J. Med. Chem. 13, 134-135 (1970)
[3] J. Org. Chem. 25, 1453-1454 (1960)
[4] J.Heterocycl.Chem. 17, 563-569 (1980)