Introduction
Substituted dimethoxyamphetamines (also known as DOx) refers to a class of psychedelic amphetamines originally synthesized and documented by Alexander Shulgin in his investigation of psychoactive phenethylamines in the 1970s. Shulgin later published his findings along with other mescaline-derived compounds in his semi-autobiographical book/organic synthesis reference PiHKAL ("Phenethylamines I Have Known and Loved").
4-Substituted-2,5-dimethoxyamphetamines (DOx) is a chemical class of substituted amphetamine derivatives featuring methoxy groups at the 2- and 5- positions of the phenyl ring, and a substituent such as alkyl or halogen at the 4-position of the phenyl ring. Most compounds of this class are potent and long-lasting psychedelic drugs, and act as highly selective 5-HT2A, 5-HT2B, and 5-HT2C receptor partial agonists. You can find most popular DOx family member syntheses in this topic such as DOB, DOM, DOI, DOC.
4-Substituted-2,5-dimethoxyamphetamines (DOx) is a chemical class of substituted amphetamine derivatives featuring methoxy groups at the 2- and 5- positions of the phenyl ring, and a substituent such as alkyl or halogen at the 4-position of the phenyl ring. Most compounds of this class are potent and long-lasting psychedelic drugs, and act as highly selective 5-HT2A, 5-HT2B, and 5-HT2C receptor partial agonists. You can find most popular DOx family member syntheses in this topic such as DOB, DOM, DOI, DOC.
Procedures
DOB (4) synthesis
1-(2,5-Dimethoxyphenyl)-2-nitropropene (2)
A solution of 10.0 g 2,5-dimethoxybenzaldehyde (1) in 50 mL glacial acetic acid was treated with 6.8 g of nitroethane and 4.0 g of anhydrous ammonium acetate. This mixture was heated on the steam bath for 3 h and then the reagent/solvent was removed under vacuum. The residue was suspended in H2O and extracted with CHCl3. Removal of the solvent from the pooled extracts yielded 11.2 g of an impure 1-(2,5-dimethoxyphenyl)-2-nitropropene (2) which, on recrystallization from 75 mL boiling MeOH, gave 6.7 g of product with a m.p. of 73-75 °C.
A solution of 10.0 g 2,5-dimethoxybenzaldehyde (1) in 50 mL glacial acetic acid was treated with 6.8 g of nitroethane and 4.0 g of anhydrous ammonium acetate. This mixture was heated on the steam bath for 3 h and then the reagent/solvent was removed under vacuum. The residue was suspended in H2O and extracted with CHCl3. Removal of the solvent from the pooled extracts yielded 11.2 g of an impure 1-(2,5-dimethoxyphenyl)-2-nitropropene (2) which, on recrystallization from 75 mL boiling MeOH, gave 6.7 g of product with a m.p. of 73-75 °C.
1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene (2) (2,5-DMP2NP)
2,5-Dimethoxyamphetamine hydrochloride (2,5-DMA) (3)
A solution of 17.0 g of 1-(2,5-dimethoxyphenyl)-2-nitropropene (2) was prepared in 500 mL anhydrous Et2O. This solution was added slowly to a well-stirred suspension of 12.0 g LAH in 700 mL anhydrous Et2O. The mixture was then brought up to a reflux and maintained there for 20 h, cooled with an external ice bath, and the excess hydride destroyed by the cautious addition of H2O. Finally, a total of 500 mL H2O was added, followed by the addition of 300 g potassium sodium tartrate, and sufficient aqueous NaOH to bring the pH above 9. The two phases were separated, and the ether phase dried by the addition of anhydrous MgSO4. [Evaporate ether to get 2,5-DMA free base.] The drying agent was removed by filtration, and the clear filtrate saturated with a stream of anhydrous HCl gas. The formed crystals of 2,5-dimethoxyamphetamine hydrochloride (2,5-DMA) (3) were removed by filtration, washed with anhydrous Et2O, and dried to constant weight of 16.3 g. Recrystallization from EtOH gave an analytical sample with a m.p. of 114-116 °C. The hydrobromide salt is melted at 129-131 °C.
A solution of 17.0 g of 1-(2,5-dimethoxyphenyl)-2-nitropropene (2) was prepared in 500 mL anhydrous Et2O. This solution was added slowly to a well-stirred suspension of 12.0 g LAH in 700 mL anhydrous Et2O. The mixture was then brought up to a reflux and maintained there for 20 h, cooled with an external ice bath, and the excess hydride destroyed by the cautious addition of H2O. Finally, a total of 500 mL H2O was added, followed by the addition of 300 g potassium sodium tartrate, and sufficient aqueous NaOH to bring the pH above 9. The two phases were separated, and the ether phase dried by the addition of anhydrous MgSO4. [Evaporate ether to get 2,5-DMA free base.] The drying agent was removed by filtration, and the clear filtrate saturated with a stream of anhydrous HCl gas. The formed crystals of 2,5-dimethoxyamphetamine hydrochloride (2,5-DMA) (3) were removed by filtration, washed with anhydrous Et2O, and dried to constant weight of 16.3 g. Recrystallization from EtOH gave an analytical sample with a m.p. of 114-116 °C. The hydrobromide salt is melted at 129-131 °C.
2,5-Dimethoxy-4-bromoamphetamine (DOB) (4)
To a well-stirred solution of 1.95 g of the free base of 2,5-dimethoxyamphetamine (2,5-DMA) (6) in 12 mL glacial acetic acid, there was added 1.8 g elemental bromine dissolved in 4 mL acetic acid over the course of 5 min. The slightly exothermic reaction was allowed to stir for 3 h, and then added to about 200 mL H2O. The cloudy solution was washed with 2 x 100 Et2O, made basic with aqueous NaOH, and extracted with 3 x 100 mL CH2Cl2. Evaporation of the solvent from the pooled extracts gave about 3 mL of a pale amber oil, which was dissolved in 250 mL anhydrous Et2O and saturated with anhydrous HCl gas. The fine white crystals of 2,5-dimethoxy-4-bromoamphetamine hydrochloride (7), DOB, were removed by filtration, Et2O washed, and air dried. These weighed 1.7 g and had a m.p. of 195-196 °C. Recrystallization from IPA brought this up to 207-208 °C.
To a well-stirred solution of 1.95 g of the free base of 2,5-dimethoxyamphetamine (2,5-DMA) (6) in 12 mL glacial acetic acid, there was added 1.8 g elemental bromine dissolved in 4 mL acetic acid over the course of 5 min. The slightly exothermic reaction was allowed to stir for 3 h, and then added to about 200 mL H2O. The cloudy solution was washed with 2 x 100 Et2O, made basic with aqueous NaOH, and extracted with 3 x 100 mL CH2Cl2. Evaporation of the solvent from the pooled extracts gave about 3 mL of a pale amber oil, which was dissolved in 250 mL anhydrous Et2O and saturated with anhydrous HCl gas. The fine white crystals of 2,5-dimethoxy-4-bromoamphetamine hydrochloride (7), DOB, were removed by filtration, Et2O washed, and air dried. These weighed 1.7 g and had a m.p. of 195-196 °C. Recrystallization from IPA brought this up to 207-208 °C.
2,5-dimethoxy-4-bromoamphetamine hydrochloride (7) (DOB)
DOM (3) synthesis
1-(2,5-Dimethoxy-4-methylphenyl)-2-nitropropene (2)
To a solution of 54.9 g 2,5-dimethoxy-4-methylbenzaldehyde (1) (see the recipe for 2C-D for its preparation) in 215 g glacial acetic acid there was added 19.5 g anhydrous ammonium acetate and 30.6 g nitroethane. This mixture was heated for 3 h on the steam bath, the reaction mixture was cooled in a wet ice bath, allowing the spontaneous formation of yellow crystals. As much H2O as possible was added (just short of a persistant cloudy oily character) and after a few additional h standing, the crystalline 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene (2) was removed by filtration and recrystallized from boiling acetic acid. The yield, after drying to constant weight, was 28.3 g and the m.p. was 87-88 °C.
To a solution of 54.9 g 2,5-dimethoxy-4-methylbenzaldehyde (1) (see the recipe for 2C-D for its preparation) in 215 g glacial acetic acid there was added 19.5 g anhydrous ammonium acetate and 30.6 g nitroethane. This mixture was heated for 3 h on the steam bath, the reaction mixture was cooled in a wet ice bath, allowing the spontaneous formation of yellow crystals. As much H2O as possible was added (just short of a persistant cloudy oily character) and after a few additional h standing, the crystalline 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene (2) was removed by filtration and recrystallized from boiling acetic acid. The yield, after drying to constant weight, was 28.3 g and the m.p. was 87-88 °C.
2,5-Dimethoxy-4-methylamphetamine hydrochloride (DOM) (3)
Method A
A suspension of 9.5 g LAH in 750 mL well stirred anhydrous Et2O was held at reflux under an inert atmosphere, with the return of the condensed solvent passing through a Soxhlet thimble containing 9.5 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene (2). After the addition of the nitrostyrene was complete, the stirred suspension was maintained at reflux for an additional 4 h, then cooled to room temperature and allowed to continue stirring overnight. The excess hydride was destroyed by the addition of 750 mL 8% H2SO4, cautiously, until the hydrogen evolution ceased, then at a speed that allowed the formed solids to disperse. The phases were separated, the aqueous phase washed once with Et2O, treated with 225 g potassium sodium tartrate, and finally made basic (pH >9) with 5% NaOH. This was extracted with 3x150 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was 9.6 g of a clear oil which spontaneously formed crystals with a mp of 60.5-61 °C from hexane. These solids were dissolved in 150 mL anhydrous Et2O, and saturated with anhydrous HCl gas. After standing at room temperature for 2 h, the crystalline 2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM) (3) was removed by filtration, washed with Et2O, and air dried to constant weight. There was obtained 8.25 g of glistening white crystals that had a m.p. of 190.5-191.5 °C. The sulfate had a m.p. of 131 °C.
Method B
The above nitrostyrene may also be converted to the final amine product through the intermediary of the corresponding phenylacetone. To a well stirred suspension of 10.4 g powdered iron in 20 mL glacial acetic acid held at reflux temperature, there was added 4.9 g 1-(2,5-dimethoxy-4-methylphenyl)-2-nitropropene (2) as a solid. Refluxing was continued for 2 h and then all was filtered through wet Celite. After washing with 300 mL H2O followed by 300 mL Et2O, the combined filtrate and washes were separated, and the aqueous phase extracted with 2 x 100 mL Et2O. The organic phase and extracts were combined and washed with 2 x 100 mL saturated K2CO3 and the solvent was removed under vacuum, yielding a reddish oil weighing 3.3 g. This was distilled at 111-115 °C at 0.5 mm/Hg to give a pale green solid. After recrystallization from benzene, there was obtained 2.8 g 1-(2,5-dimethoxy-4-methylphenyl)-2-propanone as white crystals with a mp of 57-59 °C. This ketone has also been described as a pale-yellow oil with a bp of 115-118 °C at 0.4 mm/Hg. A solution of 0.7 g 1-(2,5-dimethoxyphenyl-4-methyl)-2-propanone in 20 mL MeOH was treated with 6.0 g ammonium acetate, 0.3 g sodium cyanoborohydride, and 3 g Linde 3 A molecular sieves. The mixture was stirred overnight, the solids removed by filtration, and the filtrate dissolved in 100 mL H2O. The solution was acidified with dilute H2SO4, and washed with 2 x 25 mL CH2Cl2. The aqueous phase was made basic with aqueous NaOH, and the product extracted with 2 x 25 mL CH2Cl2. The solvent was removed under vacuum, and the residue distilled (at 160 °C at 0.2 mm/Hg) to give a colorless product which was dissolved in 3 mL IPA, neutralized with concentrated HCl, and diluted with 50 mL anhydrous Et2O. There was obtained 0.18 g of 2,5-dimethoxy-4-methylamphetamine hydrochloride (3) (DOM) as a white solid with a m.p. of 187-188 °C.
The optical isomers of DOM have been prepared in two ways. The racemic base has been resolved as the ortho-nitrotartranilic acid salt by recrystallization from EtOH. The (+) acid provides the (+) or "S" isomer of DOM preferentially. Also, the above-mentioned 1-(2,5-dimethoxy-4-methylphenyl)-2-propanone can be reductively aminated with optically active alpha-methyl benzylamine with Raney Nickel. This amine is isolated and purified by recrystallization of the hydrochloride salt. When optically pure, the benzyl group was removed by hydrogenolysis with palladium on carbon. The m.p. of either of the optical isomers, as the hydrochloride salts, was 204-205 °C.
The optical isomers of DOM have been prepared in two ways. The racemic base has been resolved as the ortho-nitrotartranilic acid salt by recrystallization from EtOH. The (+) acid provides the (+) or "S" isomer of DOM preferentially. Also, the above-mentioned 1-(2,5-dimethoxy-4-methylphenyl)-2-propanone can be reductively aminated with optically active alpha-methyl benzylamine with Raney Nickel. This amine is isolated and purified by recrystallization of the hydrochloride salt. When optically pure, the benzyl group was removed by hydrogenolysis with palladium on carbon. The m.p. of either of the optical isomers, as the hydrochloride salts, was 204-205 °C.
DOI synthesis
N-(1-(2,5-Dimethoxyphenyl)-2-propyl)phthalimide (3)
A mixture of 14.8 g phthalic anhydride (2) and 19.5 g of 2,5-dimethoxyamphetamine (1) (2,5-DMA) (see DOB synthesis above) as the free base was heated gradually to about 150 °C with an open flame. A single clear phase was formed with the loss of H2O. After the hot melt remained quiet for a few moments, it was allowed to cool to about 50 °C and then diluted with 100 mL of hot MeOH. The solution was stirred until homogenous, seeded with product, and then cooled in an ice bath to complete the crystallization. After removal of the product by filtration, washing sparingly with MeOH, and air drying, there was obtained 24.6 g of N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide (3) as off-white crystals, with a m.p. of 105-106 °C.
N-[1-(2,5-Dimethoxy-4-iodophenyl)-2-propyl]phthalimide (4)
To a solution of 2.0 g N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide (3) in 15 mL warm acetic acid which was being vigorously stirred, there was added a solution of 1.2 g iodine monochloride in 3 mL acetic acid. This was stirred for 2 h at about 40 °C during which time there was a definite lightening of color, but no solids formed. The reaction mixture was poured into 600 mL H2O, which produced a reddish glob floating in a yellow-orange opaque aqueous phase. The glob was physically removed, dissolved in 30 mL boiling MeOH which, on cooling in an ice bath, deposited off-white crystals. These were removed by filtration, washed with MeOH, and air dried to give 1.5 g of N-[1-(2,5-dimethoxy-4-iodophenyl)-2-propyl]phthalimide (4) as fine white crystals with a slight purple cast. The m.p. was 103-105.5 °C and the mixed mp with the starting non-iodinated phthalimide (m.p. 105-106 °C) was depressed (85-98 °C). Extraction of the aqueous phase, after alkalinification, provided an additional 0.15 g product.
To a solution of 2.0 g N-(1-(2,5-dimethoxyphenyl)-2-propyl)phthalimide (3) in 15 mL warm acetic acid which was being vigorously stirred, there was added a solution of 1.2 g iodine monochloride in 3 mL acetic acid. This was stirred for 2 h at about 40 °C during which time there was a definite lightening of color, but no solids formed. The reaction mixture was poured into 600 mL H2O, which produced a reddish glob floating in a yellow-orange opaque aqueous phase. The glob was physically removed, dissolved in 30 mL boiling MeOH which, on cooling in an ice bath, deposited off-white crystals. These were removed by filtration, washed with MeOH, and air dried to give 1.5 g of N-[1-(2,5-dimethoxy-4-iodophenyl)-2-propyl]phthalimide (4) as fine white crystals with a slight purple cast. The m.p. was 103-105.5 °C and the mixed mp with the starting non-iodinated phthalimide (m.p. 105-106 °C) was depressed (85-98 °C). Extraction of the aqueous phase, after alkalinification, provided an additional 0.15 g product.
2,5-Dimethoxy-4-iodoamphetamine hydrochloride (DOI)
A solution of 0.75 g N-(1-(2,5-dimethoxy-4-iodophenyl)-2-propyl)phthalimide (4) in 10 mL EtOH was treated with 0.3 mL of hydrazine hydrate, and the clear solution was held at reflux on the steam bath overnight. After cooling, there was a crystallization of 1,4-dihydroxyphthalizine that started as small beads but finally became extensive and quite curdy. These solids were removed by filtration and had a mp of about 340 °C (reference samples melted over a five to ten degree range in the area of 335-350 °C). The filtrate was dissolved in 100 mL CH2Cl2 and extracted with 2 x 150 mL 0.1 N HCl. The aqueous extracts were washed once with CH2Cl2, made basic with 5 % NaOH, and extracted with 3 x 100 mL CH2Cl2. Removal of the solvent under vacuum gave 0.5 g of a colorless oil, which was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas. There was obtained, after filtration, and air drying, 0.35 g of 2,5-dimethoxy-4-iodoamphetamine hydrochloride (5) (DOI) as white crystals that melted at 200.5-201.5 °C. This value did not improve with recrystallization.
A solution of 0.75 g N-(1-(2,5-dimethoxy-4-iodophenyl)-2-propyl)phthalimide (4) in 10 mL EtOH was treated with 0.3 mL of hydrazine hydrate, and the clear solution was held at reflux on the steam bath overnight. After cooling, there was a crystallization of 1,4-dihydroxyphthalizine that started as small beads but finally became extensive and quite curdy. These solids were removed by filtration and had a mp of about 340 °C (reference samples melted over a five to ten degree range in the area of 335-350 °C). The filtrate was dissolved in 100 mL CH2Cl2 and extracted with 2 x 150 mL 0.1 N HCl. The aqueous extracts were washed once with CH2Cl2, made basic with 5 % NaOH, and extracted with 3 x 100 mL CH2Cl2. Removal of the solvent under vacuum gave 0.5 g of a colorless oil, which was dissolved in 300 mL anhydrous Et2O and saturated with anhydrous HCl gas. There was obtained, after filtration, and air drying, 0.35 g of 2,5-dimethoxy-4-iodoamphetamine hydrochloride (5) (DOI) as white crystals that melted at 200.5-201.5 °C. This value did not improve with recrystallization.
Acetone-washed crude DOI*HCl (5)
DOC synthesis
A solution of 6.96 g 2,5-dimethoxyamphetamine hydrochloride (1) (2,5-DMA) (see DOB synthesis above) in 250 mL H2O was made basic with aqueous NaOH and extracted with 3 x 75 mL CH2Cl2. After removal of the solvent from the pooled extracts under vacuum, the residual free base was dissolved in 36 g glacial acetic acid and, with good stirring, cooled to 0 °C with an external ice bath. There was then added, with a Pasteur pipette, 3 mL of liquid chlorine (Cl2) [or gaseous bubbling Cl2, which can be made by Kipp's apparatus]. The generation of HCl was evident, and the reaction was allowed to stir for an additional 3 h. The mixture was then poured into 300 mL H2O and washed with 3 x 100 mL Et2O. The aqueous phase was made basic with NaOH and extracted with 3 x 150 mL CH2Cl2. After removal of the solvent from the pooled extracts, the residue was dissolved in Et2O and saturated with anhydrous HCl gas. There was the formation of a heavy oily precipitate. The ether supernatant was decanted, and the residue was intimately mixed with 200 mL of fresh anhydrous Et2O. Everything set up as an off-white crystalline mass weighing 2.3 g. This was dissolved in 12 mL of boiling MeOH and diluted with 230 mL boiling Et2O. The clear solution was quickly filtered to give a clear, pale amber mother liquor, which soon started depositing lustrous white crystals. After filtering, Et2O washing, and air drying to constant weight, there was obtained 1.4 g of 2,5-dimethoxy-4-chloroamphetamine hydrochloride (1) (DOC) From the mother liquors (from the original HCl saturation) an equal amount of product could be obtained by exploiting the acetone insolubility of the hydrochloride salt of the product. The published m.p. of this salt, from acetone/EtOH, is 187-188 °C. A sample of this hydrochloride salt, prepared from the amino analogue via diazotization and eventual hydrolysis of an acetylated precursor, was recrystallized from EtOH/ether and had a m.p. of 193-194.5 °C.
2,5-dimethoxy-4-chloroamphetamine hydrochloride (1) (DOC)
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