Anise Oil as Precursor for Phenylethylamine Designer Drugs of the 2C-X FamilyDieter Waumans, Noël Bruneel, Jan Tytgat41st International TIAFT meeting, Poster #104
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https://www.thevespiary.org/rhodium/Rhodium/pdf/anethole.2c-b.pdf)
IntroductionAnethole is the main component of anise oil and can be used in the (clandestine) synthesis of 4-methoxy(meth)amphetamine (PM(M)A). It has now been found that anethole can be used as precursor for other phenylethylamines (PEAs) as well. The finding is exemplified for 4-bromo-2,5-dimethoxyphenylethylamine (2C-B)
Synthesis Of 2,5-DimethoxybenzaldehydeA: Anisaldehyde from anethole via oxidative cleavage: 20 g anise oil was suspended in a mixture of 150 mL water and 30 mL conc. sulfuric acid; addition of 55 g sodium bichromate at such a rate that the temperature did not exceed 40°C. The reaction mixture was extracted with 4 x 125 mL toluene and the solvent evaporated. The residual oil was vacuum distilled to yield 9.1 g anisaldehyde.
B: O-formyl-4-methoxyphenol: 6 mL anisaldehyde was dissolved in 75 mL dichloromethane (DCM). A mixture of 12 g hydrogen peroxide and 10 mL conc. formic acid was added over 30 min. The reaction mixture was gently refluxed for 21 h.
C: 4-methoxyphenol: Evaporating the solvent from reaction mixture B and taking up the residue in 100 mL aqueous NaOH (20%) (25 mL MeOH as co-solvent) yielded 4.1 g 4-methoxyphenol as a white crystalline product after the usual work-up and purification steps.
D: Reimer-Tiemann formylation of 4-methoxyphenol: 124.1 g 4-methoxyphenol was dissolved in NaOH solution (320 g NaOH in 400 mL water). In total, 161 mL chloroform was added. The usual work-up and steam distillation yielded 109.8 g of a clear yellow oil that did not solidify upon standing at room temperature (GC/MS: 94% 2-hydroxy-5-methoxybenzaldehyde).
E: Methylation of 2-hydroxy-5-methoxybenzaldehyde: The yellow oil from D was used without further purification. A 250 mL RB flask was charged with 100 mL acetone, 14 g anhydrous potassium carbonate and 10 g 2-hydroxy-5-methoxybenzaldehyde; the mixture was brought at reflux temperature and 11 g dimethyl sulfate was added. The reaction was continued for 4 hours. The solvent is evaporated and the crude end product crystallized in cold water. Recrystallization from EtOH/water yielded 8.3 g 2,5-dimethoxybenzaldehyde (GC/MS: 98%+ 2,5-dimethoxybenzaldehyde)
Synthesis of 4-Bromo-2,5-Dimethoxyphenylethylamine (2C-B) A: 2,5-dimethoxylphenyl-2-nitroetheneA 250 mL RB flask was charged with 16.6 g 2,5-dimethoxybenzaldehyde, 1.6 g NaOAc and 50 mL nitromethane. Refluxing for 4h yielded 14.4 g of the corresponding nitrostyrene after recrystallization.
B: 2,5-dimethoxyphenyl-2-nitroethane5.0 g of 2,5-dimethoxylphenyl-2-nitroethene was added to a solution of 4.0 g sodium borohydride in 100 mL isopropanol. This yielded 4.2 g of a yellow oil after decomposition of the excess borohydride followed by the usual work-up (B).
C: 2,5-dimethoxyphenylethylamine (2C-H)The 2,5-dimethoxyphenyl-2-nitroethane was dissolved in 100 mL isopropanol with 8 molar equivalents Zn and 3.5 molar equivalents HOAc (relative to amount of Zn). This yielded 2.0 g of 2,5-dimethoxyphenylethylamine as a faintly yellow oil (C).
D: 4-Bromo-2,5-dimethoxyphenylethylamine Hydrochloride (2C-B.HCl)The obtained amine was brominated following Shulgin’s method to yield 2.1 g 2C-B as the hydrochloride salt (D).
ConclusionIt is possible to synthesize phenylethylamine derivatives different from PMA and PMMA using anethole as precursor. The total yield of 2,5-dimethoxybenzaldehyde from anethole varies between 15-25%. The total yield of 2C-B from 2,5-dimethoxybenzaldehyde amounts to ca 20% (using easily procurable compounds).
