SYNTHESIS: A solution of 76.6 g 2,5-dimethoxyaniline in 210 mL H2O containing 205 mL fluoroboric acid was cooled to 0 °C. with an external ice bath. There was then added, slowly, a solution of 35 g sodium nitrite in 70 mL H2O. After an additional 0.5 h stirring, the precipitated solids were removed by filtration, washed first with cold H2O, then with MeOH and finally Et2O. Air drying yielded about 100 g of the fluoroborate salt of the aniline as dark purple-brown solids. This salt was pyrolyzed with the cautious application of a flame, with the needed attention paid to both an explosion risk, and the evolution of the very corrosive boron trifluoride. The liquid that accumulated in the receiver was distilled at about 120 °C at 20 mm/Hg, and was subsequently washed with dilute NaOH to remove dissolved boron trifluoride. The product, 2,5-dimethoxyfluorobenzene, was a fluid, straw-colored oil that weighed 7.0 g.
To a vigorously stirred solution of 40.7 g 2,5-dimethoxyfluorobenzene in 215 mL CH2Cl2 cooled with an external ice bath, there was added 135 g of anhydrous stannic chloride. There was then added, dropwise, 26 g of dichloromethyl methyl ether at a rate that precluded excessive heating. The reaction mixture was allowed to come to room temperature over the course of 0.5 h, and then quenched by dumping into 500 g shaved ice containing 75 mL concentrated HCl. This mixture was stirred for an additional 1.5 h. The separated organic layer was washed with 2×100 mL dilute HCl, then with dilute NaOH, then with H2O and finally with saturated brine. Removal of the solvent under vacuum yielded a solid residue that was recrystallized from aqueous EtOH yielding 41.8 g 2,5-dimethoxy-4-fluorobenzaldehyde with a mp of 99-100 °C.

A solution of 2.5 g 2,5-dimethoxy-4-fluorobenzaldehyde in 15 mL acetic acid containing 1 g nitromethane was treated with 0.2 g anhydrous ammonium acetate, and heated on the steam bath for 4 h. After cooling, and following the judicious addition of H2O, crystals separated, and additional H2O was added with good stirring until the first signs of oiling out appeared. The solids were removed by filtration, and recrystallized from acetone to give 2.0 g of 2,5-dimethoxy-4-fluoro-beta-nitrostyrene with a mp of 159-162 °C.

To a suspension of 2.0 g LAH in 200 mL cool anhydrous Et2O under an inert atmosphere, there was added a THF solution of 2.0 g 2,5-dimethoxy-4-fluoro-beta-nitrostyrene. The reaction mixture was stirred at room temperature for 2 h and then heated briefly at reflux. After cooling, the excess hydride was destroyed by the cautious addition of H2O, and when the reaction was finally quiet, there was added 2 mL of 15% NaOH, followed by another 6 mL of H2O. The basic insolubles were removed by filtration, and washed with THF. The combined filtrate and washes were stripped of solvent, yielding a residual oil that was taken up in 10 mL of IPA, neutralized with concentrated HCl, and the generated solids diluted with anhydrous Et2O. The white crystalline 2,5-dimethoxy-4-fluorophenethylamine hydrochloride (2C-F) was recrystallized from IPA to give an air-dried product of 0.5 g with a mp of 182-185 °C.

DOSAGE: greater than 250 mg.

DURATION: unknown

QUALITATIVE COMMENTS: (with 250 mg) Even at 250 milligrams, the effects were slight and uncertain. There may have been some eyes-closed imagery above normal, but certainly not profound. At several hours there was a pleasant lethargy; sleep was completely normal that night.

EXTENSIONS AND COMMENTARY: A number of graded acute dosages were tried, and it was only with amounts in excess of 100 milligrams that there were any baseline disturbances at all. And at no dose that was tried was there any convincing indication of believable central effects.

The three-carbon amphetamine analogue of 2C-F would quite logically be called DOF (2,5-dimethoxy-4-fluoroamphetamine). It has been prepared by reaction of the above benzaldehyde with nitroethane (giving 1-(2,5-dimethoxy-4-fluorophenyl)-2-nitropropene, with a melting point of 128-129 °C from ethanol) followed by LAH reduction to DOF (the hydrochloride salt has a melting point of 166-167 °C, after recrystallization from ether/ethyl acetate/ethanol). 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.

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