Introduction
4-Acetoxy-N,N-dimethyltryptamine (also known as 4-AcO-DMT, 4-Acetoxy-DMT, O-Acetylpsilocin, psilacetin, and "synthetic mushrooms") is a novel lesser-known psychedelic substance of the tryptamine class. It is structurally related to psilocybin and psilocin, the active ingredient in psilocybin mushrooms ("magic mushrooms"). 4-AcO-DMT is thought to produce its effects by binding to serotonin receptors in the brain; however, the precise mechanism is not known.
4-AcO-DMT was first synthesized in 1963 by Albert Hofmann and Franz Troxler as part of a chemical investigation into psilocin analogs. However, it was not tested for psychoactivity during this time. It is unknown when it was first explored in humans. A paper authored by David E. Nichols in 1999 proposed its potential use as an alternative to psilocybin for pharmacological research due to the lower cost of synthesis. Reports of recreational use began to surface shortly after its appearance on the online research chemical market in the 2010s.
4-AcO-DMT was first synthesized in 1963 by Albert Hofmann and Franz Troxler as part of a chemical investigation into psilocin analogs. However, it was not tested for psychoactivity during this time. It is unknown when it was first explored in humans. A paper authored by David E. Nichols in 1999 proposed its potential use as an alternative to psilocybin for pharmacological research due to the lower cost of synthesis. Reports of recreational use began to surface shortly after its appearance on the online research chemical market in the 2010s.
Equipment and glassware:
- 2 L and 1 L Three necked round bottom flasks;
- Retort stand and clamp for securing apparatus;
- Magnetic or top stirrer with heater;
- 250 mL Drip funnel;
- Vacuum source;
- Glass rod and spatula;
- Rotovap machine;
- Reflux condenser;
- Ice-salt and oil bath;
- Laboratory scale (0.001-100 g is suitable) [depends on synthesis load];
- Laboratory grade thermometer (-10 °C to 150 °C) with flask adapter;
- Buchner flask and funnel [Schott filter may be used for small quantities];
- pH Indicator paper;
- Conventional funnel;
- Filter paper;
- Dimethylamine gas kit;
- Hydrogen gas (H2) source;
- TLC kit (optional);
- Vacuum distillation apparatus with Manometer (optional);
- 1 L x1; 500 mL x2; 100 mL x2 Beakers;
- 1 L; 250 mL; 100 mL Measuring cylinders;
- 250 mL Parr hydrogenation bottle [you can use Champagne bottle instead of it];
- Vacuum desiccator (optional).
Reagents:
- 4-Benzyloxyindole (1) 17.5 g, 0.078 mol;
- Diethyl ether (Et2O) 2.05 L;
- Oxalyl chloride 20.3 g, 0.16 moles;
- Dimethylamine anhydrous;
- Dichloromethane (CH2Cl2) ~880 mL;
- Distilled water (H2O) ~700 mL;
- Hexane 375 mL;
- Sodium chloride (NaCl) ~50-100 g;
- Magnesium sulphate (MgSO4) anhydrous ~200 g;
- Methanole (MeOH) ~150 mL;
- Lithium aluminum hydride (LiAlH4; LAH) 8.90 g, 0.234 mol;
- Tetrahydrofuran (THF) 375 mL;
- Dioxane 450 mL;
- Ethyl acetate (EtOAc) ~700 mL;
- Palladium on charcoal 0.25 g 10% ;
- Benzene 50 mL;
- Acetic anhydride (Ac2O) 5 mL, 5.41 g, 5.32 mmol;
- Isopropanol (IPA) 150 mL;
- Toluene 50 mL;
- Absolute (EtOH) ~100 mL.
[3-[2-(Dimethylamino)ethyl]-1H-indol-4-yl] acetate:
Boiling Point: 405.6 °C at 21 torr;
Melting Point: 172-173 °C;
Molecular Weight: 246.31 g/mol;
Density: 1.2±0.1 g/mL;
CAS Number: 92292-84-7.
Procedure
4-Benzyloxyindol-3-yl-N,N-dimethylglyoxylamide (2)
A solution of 4-benzyloxyindole (1) (17.5 g, 0.078 mol) (Biosynth) in anhydrous Et2O (500 mL) was mechanically stirred in a 1 L, 3 necked flasks and cooled in an ice-salt bath to an internal temperature of 0 °C. Oxalyl chloride (20.3 g, 0.16 moles) was added dropwise at a rate that maintained an internal temperature between 0-5 °C. Stirring was continued for 3 h at a temperature between 5-10 °C with a gentle argon sparge to remove evolved HCl. The argon sparge was replaced by a gas inlet tube and a dry ice/acetone condenser. Anhydrous dimethylamine was then bubbled into the reaction with cooling and vigorous stirring until a pH (determined by moist pH paper) between 9 and 11 was achieved. At this time, the orange color of the initial solution had been mostly discharged, and the reaction had the appearance of a slightly off-white slurry with a few flecks of yellow unreacted starting material. Dichloromethane (20 mL) was added to assist solubilization of the unreacted material, and the reaction was stirred for an additional 6 h to yield finally an off white slurry. Et2O (150 mL) was added, and the mixture was cooled to 10 °C. The white solids were collected by suction filtration on filter paper in a Buchner funnel and then were suspended in distilled H2O (250 mL) and stirred for 1 h to remove dimethylamine hydrochloride. The slurry was filtered, and the collected solids were washed on the filter with distilled H2O (3 x 75 mL) and hexane (75 mL) and dried overnight in a vacuum desiccator. The dried product weighed 18.3 g. The organic filtrates and washes were combined, and the solvent was removed by rotary evaporation. The residue was dissolved in CH2Cl2 (100 mL) and the organic solution was washed with distilled H2O (2 x 50 mL) and brine (2 x 50 mL). After drying (MgSO4) the volume was reduced by rotary evaporation. The concentrated residual solution was subjected to flash chromatography over silica gel, first eluting with CH2Cl2 to recover unreacted indole (1.3 g, 7.4%), followed by elution with 10% MeOH in CH2Cl2 to recover 3.3 g of (2). The latter was combined with the initial product to provide a total weight of 21.6 g (85.9%). The crude product was recrystallized from MeOH/EtOAc to give 19.5 g (77%) of 3 with m.p. 152-155 °C (Lit. m.p. 146-150 °C).
4-Benzyloxy-N,N-dimethyltryptamine (3)
A slurry of LiAlH4 (8.90 g, 0.234 mol) in anhydrous THF (100 mL) was prepared in a 2 L, 3-neck flask, previously dried with a heat gun or flame. The flask was fitted with a reflux condenser, mechanical (or magnetic) stirrer, and addition funnel. Anhydrous dioxane (200 mL) was added, and the mixture was heated to 60 °C on an oil bath. 4-Benzyloxyindol-3-yl-N,N-dimethylglyoxylamide (2) (14.5 g, 0.045 moles) was dissolved in a mixture of dioxane (250 mL) and THF (150 mL) and, with rapid stirring, this solution was added dropwise over 1 h. The oil bath temperature was held at 70 °C for 4 h, followed by vigorous reflux overnight (16 h) at an oil bath temperature of 95 °C. Thin layer chromatographic analysis (9:1 CH2Cl2/MeOH silica plates) showed nearly complete reduction. The reaction was heated at reflux for an additional 4 h and then cooled to 20 °C. A solution of distilled H2O (27 mL) in THF (100 mL) was added dropwise, resulting in a gray flocculent precipitate. Et2O (250 mL) was added to assist breakup of the complex and improve filtration. This slurry was stirred for 1 h and the mixture was then filtered with a Buchner funnel. The filter cake was washed on the filter with warm Et2O (2 x 250 mL) and was broken up, transferred back into the reaction flask and vigorously stirred with additional hot Et2O (500 mL). This slurry was filtered, and the cake was washed on the filter with Et2O (150 mL) and hexane (2 x 150 mL). All of the organic filtrates were combined and dried (MgSO4). After the drying agent was removed by filtration, the filtrate was concentrated under vacuum at 40 °C and dried under high vacuum at 0.01 mmHg, leading to crystallization of the residue as a white waxy solid. Recrystallization from EtOAc yielded 12.57 g, (94.8 %) of 4 with m.p. 124-126 °C (lit.4 m.p. 125-126 °C).
4-Acetoxy-N,N-dimethyltryptamine fumarate (4)
In a 250 mL Parr hydrogenation bottle [you can use Champagne bottle instead of it] was placed 0.25 g of 10% palladium on charcoal followed by anhyd sodium acetate (1.50 g, 18 mmol). Benzene (50 mL) was added, followed by acetic anhydride (5 mL, 5.41 g, 5.32 mmol), and (3) (0.50 g, 1.7 mmol). The mixture was shaken under 60 psig (4.14 barr) of hydrogen for 4 h. After the uptake of hydrogen had ceased, the hydrogenation bottle was removed from the apparatus, the mixture was diluted with THF (25 mL), and the catalyst was removed by filtration through a pad of Celite 545. The catalyst was washed repeatedly with isopropanol (3 x 50 mL). The washings and mother liquor were collected separately because of unreacted Ac2O in the filtrate. The mother liquor was concentrated under vacuum to about one half the original volume, then toluene (50 mL) was added. The solution was again concentrated by rotary evaporation. The isopropanol washes were combined with the residue and also concentrated. The residue was then dissolved in anhyd MeOH (50 mL). Fumaric acid (0.198 g, 1.7 mmol) was dissolved in MeOH (10 mL) and added to the stirred methanolic solution of the residue. After stirring for 10 minutes, toluene (50 mL) was added and the solution was concentrated to dryness by rotary evaporation. Absolute EtOH was added to the residue, and a white precipitate of (4) fumarate (0.290 g, 0.8 mmol) formed and was collected by filtration. The filtrate was evaporated, and the residue was dissolved in a minimum amount of MeOH. EtOAc was added and clear crystals began to form. After storing the solution in a freezer at -10 °C, 0.170 g of additional product was collected for a total yield of 0.460 g (74.8%); m.p. 172-173 °C.
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