Fluoroamphetamine (4-FA and 2-FA) synthesis without INCB precursores

[G.Patton]

Introduction

​

In this topic I want to represent synthesis of 4-Fluoroamphetamine (4-FA). Feature of this synthesys is that it almost doesn't take forbidden by INCB (International Narcotics Control Board) precursores. Nitroethane can be synthesized by yourself (see links). Here is total synthesis from 4-chlorobenzaldehyde, but you can simplify your way with buying 4-fluorobenzaldehyde.

4-Fluoroamphetamine is subjectively very similar to amphetamine, but with some effect on the serotonin release, probably making the effects have a touch of MDMA-like action. Receptor interaction data suggests that racemic p-fluoroamphetamine is 2/3 as potent as d-amphetamine, probably suggesting that the racemic versions of both drugs are almost equipotent. This seems to be an interesting analog of amphetamine for use as a stimulant, and probably the yet untested 4-fluoro-methamphetamine is too. The synthesis of 2-Fluoroamphetamine proceeds similarly. It has a more pronounced stimulating effect than 4-FA, in which MDMA effects predominate. 2-Fluoroamphetamine is a good alternative to amphetamine, just a little higher dosage. These substances are not included in the lists of prohibited substances of the INCB convention, but are analogues or derivatives under many local laws.​

General​

The reaction is pretty straight-forward for a compound like this, but there are a few differences. The first step is the Henry condensation of 4-fluorobenzaldehyde with nitroethane, which goes in moderate yield with n-butylamine as catalyst under reflux. Using ethylenediammonium diacetate as catalyst at room temperature results in a miniscule yield. The yield is better if the reaction mixture is cooled in the freezer before filtering. Another variation would be to perform the reaction in 100ml of refluxing toluene instead of isopropanol, and using a Dean-Stark trap to separate the formed water in the reaction which would drive the reaction forward. It is however unknown how well that technique would work, the yields did not improve by using ethylamine as the catalyst and drying the reaction mixture over molecular sieves.

In the second reaction step, the intermediate nitropropene is reduced with Lithium Aluminum Hydride, but in this instance an unconventional procedure is used. Instead of adding the nitroalkene to the LAH solution, a LAH solution is added dropwise to a solution of the nitroalkene. This is done to minimize side-reactions. Excess LAH may dehalogenate the fluorine atom from the substrate, forming regular amphetamine, which is not what we want. By using this addition sequence, it is ensured that the nitroalkene is always in excess, and not the LAH.

Another way of reducing the nitroalkene to the amphetamine is to perform the reaction in two steps, first reducing the double bond with sodium borohydride, and then reduce the remaining nitro group to an amine using Zinc/Formic Acid.

Also I have to mention that 2- or 4-FP2NP can be reduced by Al/Hg method quite well as in the amphetamine synthesis.

Difficulty Rating: 5/10
​

Equipment and glassware:​

• 500 mL Four-neck flask fitted with thermometer, anchor stirrer and reflux condenser with bubble counter;
• 2 L Round bottom flask (RBF);
• Magnetic stirrer with heating plate;
• Retort stand and clamp for securing apparatus;
• Laboratory scale (0.01-500 g is suitable);
• Buchner flask (2 L) and funnel (or small Schott filter);
• Rotary evaporator;
• Vacuum source;
• 2000 mL x1; 250 mL x3; 500 mL x3; 100 x2 Beakers;
• Glass rod;
• HCl dry gas apparatus;
• Reflux condenser;
• Laboratory grade thermometer (50 °C to 250°C) with flask adapter;
• 1 L Erlenmeyer flask;
• Distillation apparatus;
• 1 L Separatory funnel;
• Boiling chips;
• Measuring cylinders 100 and 500 mL;

Reagents:​

• 140 g, 1 mol of 4-chlorobenzaldehyde;
• 58 g, 1 mol Potassium fluoride (KF);
• 5 g Nitrobenzene;
• 7.98 g Tetrakis(diethylamino)phosphonium bromide;
• ~50 mL Chlorobenzene;
• 30 g, 0.4 mol Nitroethane;
• 20 mL Isopropanol (IPA);
• 1 mL N-butylamine;
• ~100 mL Methanol;
• 600 mL Tetrahydrofurane (THF);
• 7.6 g, 0.2 mol Lithium aluminum hydride (LAH; LiAlH4);
• ~150 mL Distilled water (H2O);
• 7.5 mL Sodium hydroxide 15 % aq (NaOH);
• 250 mL Petroleum ether or DCM;
• 50 mL 0.1M Hydrochloric acid (HCl);
• 25 % Ammonia solution (NH4OH);
• ~100 g Magnesium sulphate (MgSO4) anhydrous;
• Dry HCl gas;

2-(4-Fluorophenyl)-1-methylethylamine:
Boiling point 215 °C at 760 mm/Hg;
Molecular Weight: 151.2 g/mole (base);
Density: 1.042 g/cm3;
CAS Number: 459-02-9 (base)​

Procedure​

​

4-fluorobenzaldehyde From 4-chlorobenzaldehyde (2)​

140 g (1 mol) of 4-chlorobenzaldehyde (1), 58 g (1 mol) of potassium fluoride, 5 g of nitrobenzene and 7.98 g of tetrakis(diethylamino)phosphonium bromide (phase transfer catalyst) [TDPB] are placed in a 500 mL four-neck flask fitted with thermometer, anchor stirrer and reflux condenser with bubble counter. The mixture is subsequently heated while stirring to 190 °C and allowed to react for 20 hours. After the reaction is complete, the reaction mixture is allowed to cool, dissolved in chlorobenzene, insoluble constituents are filtered off and the product (4-fluorobenzaldehyde) (2) is purified by fractional distillation under reduced pressure. Yield 77 %, with a selectivity of 93 %.​

​

4`-Fluorophenyl-2-nitropropene (3)​

4-Fluorobenzaldehyde (2) (24.8 g, 0.2 mol), nitroethane (30 g, 0.4 mol), 20 mL of isopropanol and 1 mL n-butylamine were heated under reflux for 5 h in the same flask. The reaction mixture was allowed to cool to room temperature overnight while crystallization occured. The crude yellow product was filtered and recrystallized from a minimum of hot methanol to afford 20 g (55 %, 0.11 mol) of pale yellow crystals (3) (m.p. 64-66 °C).​

​

4`-Fluoro-amphetamine (4)​

Lithium aluminum hydride (7.6 g, 0.2 mol), dissolved in 200 mL THF was added dropwise to a stirred solution of 4-fluoro-phenyl-2-nitropropene (3) (18.1 g, 0.1 mol) in 200 mL dry THF and the mixture was allowed to stir at room temperature for 4 h in 2 L RBF. The excess hydride was decomposed by the careful addition of 7.5 mL water, 7.5 mL 15 % NaOH and finally another 22.5 ml of water. The mixture was filtered with suction, and the filter cake washed with 2 x 100 mL warm THF. The THF was removed under vacuum, and the crude residue dissolved in 100 mL petroleum ether and extracted with 3 x 50 mL 0.1M HCl. The combined acidic fractions were basified with 25 % ammonia (NH4OH) and the crude product extracted with 3 x 50 mL petroleum ether, the pooled extracts dried over MgSO4 and the solvent evaporated under vacuum. The residue was distilled twice to afford 8 g (52 %) of 4-fluoro-amphetamine as a colorless liquid, b.p. 78 °C at 10 mmHg (lit 95-96 °C/17 mmHg, 96 °C/19 mmHg), m.p. (HCl salt) 152-154 °C. The hydrochloride salt (4) can be prepared by dissolving the freebase in ten times the volume of petroleum ether, and passing through dry HCl gas until no more crystals separate.​

​

 

[maloo]

Very detailed write up. Thank you.

You mentioned a tweak to 2nd stage addition to prevent liah4's tendency to dehalogenate the fluorine atom. Is there a similar concern with the al amalgum if choosing the al/hg method?

 

[G.Patton]

Very detailed write up. Thank you.

You mentioned a tweak to 2nd stage addition to prevent liah4's tendency to dehalogenate the fluorine atom. Is there a similar concern with the al amalgum if choosing the al/hg method?

malooHello. You can use Al/Hg way for 4'-F-P2NP reduction as described here:

https://chemistry.mdma.ch/vespiary/4-FA%20al%20hg%20recipe.pdf

Moreover, NaBH4 reduction also can be used.