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Synthesis of 4-Fluoro-2,5-Dimethoxyamphetamine (DOF)

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[DOF] has been prepared by reaction of [2,5-dimethoxy-4-fluorobenzaldehyde] with nitroethane [...] followed by LAH reduction to DOF [...]. Animal studies that have compared DOF to the highly potent DOI and DOB imply that the human activity will be some four to six times less than these two heavier halide analogues. As of the present time, no human trials of DOF have been made.

- Alexander Shulgin, in Pihkal1


While the above statement at first might sound disappointing, due to the wording about "the human activity will be some four to six times less", it is actually quite encouraging, as the data actually implies that DOF should be an active psychedelic somewhere in the same dosage range as 2C-B (as DOB/DOI are active at 1-3mg, and animal tests indicate that DOF is 6-8 times weaker, it still gives an activity range of 6-24mg!).

Isn't the above quote very enticing? We here have a substance which is very similar to the otherwise very interesting DOB/DOI/DOM/2C-B/2C-I family of psychedelics, but one which has still to this date not undergone any known human trials. Who will be the first to taste it and report back what it really was like? Will you?

Synthetic Overview

2-Fluorohydroquinone is prepared in moderate yield by oxidation of o-fluorophenol with potassium persulfate in aqueous NaOH, followed by acid hydrolysis of the intermediate p-hydroxyphenyl potassium sulfate. The product is subjected to flash chromatography followed by recrystallization from chloroform to remove ~35% unreacted o-fluorophenol (can be recycled) and a small amount of cis,cis-2,4-hexadienedioic acid formed through over-oxidation.

The 2-fluorohydroquinone is methylated with dimethyl sulfate in aqueous NaOH to afford 2,5-dimethoxyfluorobenzene, which upon Friedel-Crafts formylation with α,α-dichloromethyl methyl ether with tin(IV)chloride as catalyst leads exclusively to 2,5-dimethoxy-4-fluorobenzaldehyde. Condensation of the aldehyde with nitroethane under standard conditions gives the corresponding nitroalkene, which in turn is reduced by etheral LiAlH4 to give 2,5-Dimethoxy-4-Fluoroamphetamine Hydrochloride (DOF·HCl) in high yield.

An alternative route1 to 2,5-dimethoxyfluorobenzene involves diazotization of 2,5-dimethoxyaniline in the presence of aqueous fluoroboric acid, followed by pyrolysis of the precipitated diazonium fluoroborate salt, but unfortunately that method only gives ~10% yield.




o-Fluorophenol (11.3 g, 0.100 mol) was dissolved in 400 ml of 6% aqueous NaOH. Solid potassium persulfate (27 g, 0.10 mol) was added to this stirred solution in several portions over 10 min. The dark mixture was stirred overnight at room temperature, then concentrated to about a third of its original volume on the rotary evaporator. The solution was neutralized with concentrated HCl and extracted once with 200 ml of ether. The aqueous solution was acidified with 100 ml of concentrated HCl, boiled for 1 hr, then concentrated to ca. 50 ml on the rotary evaporator.

Addition of 200 ml of acetone precipitated the inorganic salts, which were removed by filtration. The filtrate was taken to dryness on the rotary evaporator and the dark residue, dissolved in acetone, was added to 15 g of silica gel. The solvent was removed and the material was added to a column of 100 g of silica gel packed in hexane. The column was eluted with 10% acetonitrile in chloroform, taking 75-ml fractions. Fractions 5-20 contained 5.3g (41%) of product, showing a single spot on TLC. Further purification could be effected by dissolving the material in boiling chloroform (60 ml/g), concentrating the solution to about a third of its original volume, and cooling in an ice bath to give white plates: mp 122-123°C.

The ether extract of the aqueous reaction solution was concentrated to an oil (4.0g) which was identified as mostly unreacted o-fluorophenol by its 1H-NMR spectrum (6.6-7.3 ppm, complex multiplet). A small amount of white solid was noted in the oil. Crystallization of the material from 30 ml of acetone gave 0.2 g of white crystals, identified as cis,cis-2,4-hexadienedioic acid: mp 199°C.


To a mechanically stirred solution of crude 2-Fluorohydroquinone (48.9 g, 0.3 mol) in 90 mL of EtOH was added 220 g (1.74 mol) of Me2SO4, and the mixture was cooled in an ice bath. A solution of NaOH (75 g, 1.88 mol) in H2O (155 mL) was added at such a rate that the internal temperature remained at 20-30°C. Following the addition, the stirred mixture was heated to 65-70°C for 0.5 h and then cooled and extracted twice with Et2O. The combined extracts were washed with H2O, dried (anhydrous MgSO4), and filtered. Evaporation of the solvent gave an oily residue, which was distilled in vacuo to yield 29 g of pure 2,5-dimethoxyfluorobenzene, by 119-121°C (40 mm) (44%, based on 2-fluorophenol not recovered).


A solution of 2,5-dimethoxyfluorobenzene (40.7 g, 0.26 mol) in CH2Cl2 (215 mL) was cooled in an ice bath to 5-6°C. Under vigorous stirring, 135g (0.52 mol) of SnCl4 was added, followed by the dropwise addition of dichloromethyl methyl ether (26 g, 0.27 mol) at a rate which maintained the internal temperature below 10°C. The reaction mixture was allowed to warm to room temperature during 30 min with continued stirring and then was poured into a mixture of 500 g of ice and 75 mL of concentrated HCl, and the green solution was stirred for 1.5 h. The CH2Cl2 layer was separated and washed with 2x100 mL of 10% HCl, H2O, 10% NaOH, H2O, and finally with saturated brine. After the CH2Cl2 layer was dried over anhydrous Na2SO4 and the solvent was evaporated, the residue was recrystallized from EtOH containing a small quantity of H2O to yield 41.8 g (87.5%) of 2,5-dimethoxy-4-fluorobenzaldehyde, mp 99-100°C, 2,4-dinitrophenylhydrazone, mp 219-220°C.


A mixture of 2,5-dimethoxy-4-fluorobenzaldehyde (41.3 g, 0.219 mol), NH4OAc (4 g), and 110 mL of nitroethane was heated at reflux for 4 h and allowed to cool to room temperature. The solid product deposited was collected: yield 35.2 g of yellow prisms, mp 128-129°C, and a second crop of 11.6 g, mp 127-128°C, to give a total yield of 88.5%. The analytical sample was recrystallized from EtOH as yellow needles: mp 128-129°C.

2,5-Dimethoxy-4-Fluoroamphetamine Hydrochloride (DOF·HCl)2

To a stirred and cooled (ice bath) mixture of LiAlH4 (28 g, 0.7 mol) in dry Et2O (600 mL) was added gradually a solution of 1-(2,5-Dimethoxy-4-fluorophenyl)-2-nitropropene (36.2 g, 0.15 mol) in THF (250 mL). After the addition, the mixture was stirred at room temperature for 1.5 h, heated at reflux for 15 min before cooling, and hydrolyzed with 28 mL of H2O, followed by 25 mL of 2 N NaOH and then 75 mL of additional H2O. After the inorganic precipitate was removed by filtration, the Et2O-THF was evaporated in vacuo to a residual oil, which was further dried by four evaporations with 15- to 20-mL portions of dry benzene. The oil was taken up in dry Et2O and treated with sufficient ethereal HCl to give a distinctly acid reaction to moist pH paper. The colorless precipitated hydrochloride was collected and washed thoroughly with dry Et2O: yield 32.5g (87%); mp 160-162°C. Recrystallization from Et2O-EtOAc-EtOH afforded 30.8 g (82%) of DOF·HCl, mp 166-167°C.



  1. Pihkal #26, 2C-F
  2. R. A. Glennon, et. al., J. Med. Chem. 25, 1163-1168 (1982)
  3. W. Baker and N.C. Brown, J. Chem. Soc., 2303 (1948)
  4. A.E. Feiring & W.A. Sheppard, J. Org. Chem. 40(17), 2543 (1975)