Shulgin's synthesis of 4-Bromo-2,5-dimethoxyphenethylamine (2c-b):
A 100g solution of 2,5-dimethoxybenzaldehyde, in 220 g of nitromethane, was treated with 10g of ammonium acetate anhydrous, and heated in a steam bath for 2.5 hours, stirring it from time to time. The deep red reaction mixture was separated from the excess nitromethane under vacuum, and the residue crystallized spontaneously.
This raw nitrostyrene was purified by spraying it into Isopropyl Alcohol. It was then filtered and air-dried, and 85g of 2,5-dimethoxy-β-nitrostyrene were obtained, in the form of a yellow-orange product, with a purity suitable for the next step. A new purification can be achieved by recrystallization in boiling IPA.
In a 2L round-bottomed flask, equipped with a magnetic stirrer and placed in an inert atmosphere, 750ml of tetrahydrofuran anhydrous (THF) were added, which contained 30 g of lithium-aluminium hydride. Then 60 g of 2,5-dimethoxy-b-nitrostyrene were added in THF solution. The final solution presented a dirty yellow-brown color, and was kept at reflux temperature for 24 hours.
After letting it cool, the excess hydride was destroyed by adding IPA, drop by drop. Then 30 ml of 15% NaOH was added to convert the inorganic solids into a filterable mass. The reaction mixture was filtered and the filter cake was washed, first with THF and then with MeOH (methanol).
The mother liquors and washes were combined and separated from the vacuum solvent, and the residue was suspended in 1.5 ml of H2O. It was then acidified with HCl, washed with 3×100 ml of CH2Cl2, strongly alkalized with 25% NaOH, and re-extracted with 4×100 ml of CH2Cl2.
The combined extracts were separated from the solvent under vacuum, which resulted in 26 g of an oily residue, which distilled at 120-130 ºC, at 0.5 mm/Hg, which obtained 21 g of a white oil, 2,5-dimethoxy-phenylethylamine (2C-H), which traps carbon dioxide from the air very easily.
To a solution, under vigorous agitation, of 24.8 g of 2,5-dimethoxyphenylethylamine in 40 ml of glacial acetic acid, 22 g of elemental bromine (Br2) dissolved in 40 ml of acetic acid were added. After about two minutes, solids began to form and the release of quite a bit of heat. The reaction mixture was allowed to reach room temperature again, filtered, and the solids were washed, in moderation, with cold acetic acid.
This was hydrobromide salt. There are many complicated forms of salts, both polymorphous and hydrate, that can make the isolation and characterization of 2C-B dangerous. The safest route is to form the insoluble hydrochlorinated salt by means of the free base. The entire mass of the wet salt with acetic acid was dissolved in temperate H2O, alkalized at least up to pH 11 with 25% NaOH, and extracted with 3×100 ml of CH2Cl2.
Solvent removal provided 33.7 g of residue, which distilled at 115-130 °C, at 0.4 mm/Hg. The white oil, 27.6 g, was dissolved in 50 ml of H2O containing 7.0 g of acetic acid. This clear solution was vigorously stirred and treated with 20 ml of concentrated HCl. Then the immediate formation of the anhydrous salt of 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) occurred. This mass of crystals was separated by filtration, washed with a little H2O, and then with several portions of 50 ml of Et2O (diethyl ether). After drying it completely in the air, 31.05 g of fine white needles were obtained, with a f.p. of 237-239 ºC. When too much H2O is present at the time of adding the final concentrated HCl, a hydrated form of 2C-B is obtained. Hydrobromide salt melts at 214.5-215 ºC. It was observed that the acetate salt had a f.p. of 208-209 ºC.
A 100g solution of 2,5-dimethoxybenzaldehyde, in 220 g of nitromethane, was treated with 10g of ammonium acetate anhydrous, and heated in a steam bath for 2.5 hours, stirring it from time to time. The deep red reaction mixture was separated from the excess nitromethane under vacuum, and the residue crystallized spontaneously.
This raw nitrostyrene was purified by spraying it into Isopropyl Alcohol. It was then filtered and air-dried, and 85g of 2,5-dimethoxy-β-nitrostyrene were obtained, in the form of a yellow-orange product, with a purity suitable for the next step. A new purification can be achieved by recrystallization in boiling IPA.
In a 2L round-bottomed flask, equipped with a magnetic stirrer and placed in an inert atmosphere, 750ml of tetrahydrofuran anhydrous (THF) were added, which contained 30 g of lithium-aluminium hydride. Then 60 g of 2,5-dimethoxy-b-nitrostyrene were added in THF solution. The final solution presented a dirty yellow-brown color, and was kept at reflux temperature for 24 hours.
After letting it cool, the excess hydride was destroyed by adding IPA, drop by drop. Then 30 ml of 15% NaOH was added to convert the inorganic solids into a filterable mass. The reaction mixture was filtered and the filter cake was washed, first with THF and then with MeOH (methanol).
The mother liquors and washes were combined and separated from the vacuum solvent, and the residue was suspended in 1.5 ml of H2O. It was then acidified with HCl, washed with 3×100 ml of CH2Cl2, strongly alkalized with 25% NaOH, and re-extracted with 4×100 ml of CH2Cl2.
The combined extracts were separated from the solvent under vacuum, which resulted in 26 g of an oily residue, which distilled at 120-130 ºC, at 0.5 mm/Hg, which obtained 21 g of a white oil, 2,5-dimethoxy-phenylethylamine (2C-H), which traps carbon dioxide from the air very easily.
To a solution, under vigorous agitation, of 24.8 g of 2,5-dimethoxyphenylethylamine in 40 ml of glacial acetic acid, 22 g of elemental bromine (Br2) dissolved in 40 ml of acetic acid were added. After about two minutes, solids began to form and the release of quite a bit of heat. The reaction mixture was allowed to reach room temperature again, filtered, and the solids were washed, in moderation, with cold acetic acid.
This was hydrobromide salt. There are many complicated forms of salts, both polymorphous and hydrate, that can make the isolation and characterization of 2C-B dangerous. The safest route is to form the insoluble hydrochlorinated salt by means of the free base. The entire mass of the wet salt with acetic acid was dissolved in temperate H2O, alkalized at least up to pH 11 with 25% NaOH, and extracted with 3×100 ml of CH2Cl2.
Solvent removal provided 33.7 g of residue, which distilled at 115-130 °C, at 0.4 mm/Hg. The white oil, 27.6 g, was dissolved in 50 ml of H2O containing 7.0 g of acetic acid. This clear solution was vigorously stirred and treated with 20 ml of concentrated HCl. Then the immediate formation of the anhydrous salt of 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) occurred. This mass of crystals was separated by filtration, washed with a little H2O, and then with several portions of 50 ml of Et2O (diethyl ether). After drying it completely in the air, 31.05 g of fine white needles were obtained, with a f.p. of 237-239 ºC. When too much H2O is present at the time of adding the final concentrated HCl, a hydrated form of 2C-B is obtained. Hydrobromide salt melts at 214.5-215 ºC. It was observed that the acetate salt had a f.p. of 208-209 ºC.
