MDA Hydrochloride Synthesis From MDP2P
Introduction
This route to MDA isn't anything new. In fact it has been around since 1955. The general overview of the reaction is; 1) Formation of the oxime and 2) reduction of the oxime to the amine. The first step is easily accomplished by reacting the parent ketone with hydroxylamine hydrochloride. Old geezer Shulgin did this with pyridine in a 51% yield. But it can be done with considerably better yields employing plain sodium acetate and methanol.
Equipment and glassware:
- Two-necked round bottom flasks 250 ml;
- Round bottom flask 50 ml;
- Magnetic stirrer;
- Reflux condenser;
- Cold water source;
- Heating plate or mantle;
- Funnel;
- Spatula;
- Glass rod;
- Laboratory scale (0.01 g-200 g is suitable);
- Measuring cylinders 100 ml, 20 ml and 5 ml;
- Beakers 500 ml x2; 250 ml x3; 100 ml x3;
- Pipette;
- Pressure equalized addition funnel 250 ml;
- Laboratory grade thermometer (10 °C to 100 °C) with flask adapter;
- Retort stand and clamp for securing apparatus;
- pH indicator papers;
- Vacuum distillation apparatus or rotovap;
- Vacuum pump;
- Buchner flask and funnel;
- Separatory funnel 0.5 L;
- Ice water bath;
- Vacuum desiccator (optional);
Reagents:
- Sodium acetate trihydrate (CH3COONa • 3H2O) 5.4 g;
- Methanol (MeOH) 20 ml;
- MDP2P 4.5 g;
- Hydroxylamine hydrochloride ([NH3OH]Cl) 2.3 g;
- Distilled water ~165 ml;
- Anhydrous magnesium(or sodium/potassium) sulphate;
- Dry ethanol (EtOH) 50 ml;
- Elemental sodium 5 g (Na) under hexane or gasoline;
- Dichloromethane (DCM) ~190 ml;
- Sodium hydroxide 25% (NaOH) aq solution;
- Isopropyl alcohol (IPA) 20 ml;
- Hydrochloric (HCl) acid 1.6 ml;
- Diethyl ether (Et2O) 40 ml;
Experimental
1-(Benzo[d][1,3]dioxol-5-yl)propan-2-one oxime Synthesis From MDP2P
1. Sodium acetate trihydrate (CH3COONa • 3H2O) 5.4 g and distilled water 4 ml was combined in a 50 ml round bottom flask.
2. The mixture was heated gently with stirring until the acetate was dissolved.
3. MeOH 20 ml was added followed with MDP2P 4.5g.
4. To this reaction mixture, hydroxylamine hydrochloride [NH3OH]Cl 2.3 g there was added and the mixture was refluxed with stirring for 1.5 h.
5. After this period, distilled water 10 ml was added and the heating source was removed. The mixture was allowed to cool in a water bath with the stirring.
6. After returning to room temp, the flask was put into the freezer for ~1 hour.
7. The white crystalline substance was filtered and washed with distilled water 50 ml. The filtrate may turn cloudy as small amounts of product crystallizes.
8. The α-methyl-1,3-benzodioxole-5-propanol oxime product was dried over anhydrous magnesium(or sodium/potassium) sulphate to constant weight. The reaction yield is 4.5g (92%), m.p. 84-85°C. Lit: 84-87°C (H2O/EtOH).
Note: The oxime can also be made in equally good yields with sodium carbonate as the base in 60% EtOH.
2. The mixture was heated gently with stirring until the acetate was dissolved.
3. MeOH 20 ml was added followed with MDP2P 4.5g.
4. To this reaction mixture, hydroxylamine hydrochloride [NH3OH]Cl 2.3 g there was added and the mixture was refluxed with stirring for 1.5 h.
5. After this period, distilled water 10 ml was added and the heating source was removed. The mixture was allowed to cool in a water bath with the stirring.
6. After returning to room temp, the flask was put into the freezer for ~1 hour.
7. The white crystalline substance was filtered and washed with distilled water 50 ml. The filtrate may turn cloudy as small amounts of product crystallizes.
8. The α-methyl-1,3-benzodioxole-5-propanol oxime product was dried over anhydrous magnesium(or sodium/potassium) sulphate to constant weight. The reaction yield is 4.5g (92%), m.p. 84-85°C. Lit: 84-87°C (H2O/EtOH).
Note: The oxime can also be made in equally good yields with sodium carbonate as the base in 60% EtOH.
MDA Hydrochloride Synthesis From 1-(Benzo[d][1,3]dioxol-5-yl)propan-2-one oxime
9. α-Methyl-1,3-benzodioxole-5-propanol oxime 3.86g (0.02 mole) was dissolved in 50 ml dry ethanol (fresh 99.5% is OK) in a two-necked 250 ml round bottom flask equipped with reflux condenser, a cork and a stirring magnet anchor.
10. The reaction mixture was heated to reflux, the heat was turned off and elemental sodium 5 g (Na) was added in such rate that a steady reflux was maintained [make 20-30 pieces and store under hexane, NOT on air].
11. The first additions is conveniently kept small. [Note: Hydrogen evolution!].
12. At the end, the reaction became slower so the heating mantle was turned back on to speed reaction up.
13. Then, an aqueous-white, transparent reaction mixture was slowly treated with H2SO4 16 g in cold water 200 ml.
14. The EtOH was removed under vacuum and the resulting water phase was washed twice with DCM 2 x 50 ml.
15. The aq. phase was made basic by addition of 25% NaOH aq solution.
16. The freebase was extracted with DCM 3 x 30 ml.
17. The pooled organic extracts was evaporated under vacuum to constant weight leaving a pale colored residue (3.36 g, 94%).
18. The freebase was dissolved in IPA 20 ml, neutralized with HCl acid 1.6 ml and percipitated by the addition of Et2O 40 ml. 19. The crystals was filtered and washed with a small amount of Et2O. MDA hydrochloride yield is 3.4g of white product, m.p. 187.5-188.5°C. (Lit: 187-188°C).
10. The reaction mixture was heated to reflux, the heat was turned off and elemental sodium 5 g (Na) was added in such rate that a steady reflux was maintained [make 20-30 pieces and store under hexane, NOT on air].
11. The first additions is conveniently kept small. [Note: Hydrogen evolution!].
12. At the end, the reaction became slower so the heating mantle was turned back on to speed reaction up.
13. Then, an aqueous-white, transparent reaction mixture was slowly treated with H2SO4 16 g in cold water 200 ml.
14. The EtOH was removed under vacuum and the resulting water phase was washed twice with DCM 2 x 50 ml.
15. The aq. phase was made basic by addition of 25% NaOH aq solution.
16. The freebase was extracted with DCM 3 x 30 ml.
17. The pooled organic extracts was evaporated under vacuum to constant weight leaving a pale colored residue (3.36 g, 94%).
18. The freebase was dissolved in IPA 20 ml, neutralized with HCl acid 1.6 ml and percipitated by the addition of Et2O 40 ml. 19. The crystals was filtered and washed with a small amount of Et2O. MDA hydrochloride yield is 3.4g of white product, m.p. 187.5-188.5°C. (Lit: 187-188°C).
Conclusion
This reduction can also be done in n-BuOH and with quite a few NaBH4 reduction systems (NiCl2, TiCl4, MoO3, Co-PC, Amberlyst-15/LiCl, and even with plain NaBH4 in EtOH). Adding NaOH to a suspension of Ni-Al is also said to reduce oximes as is SnCl2-Sn-HCl.
Different synthesis of oximes starting with nitroalkenes should be looked into, as this could be a good alternative to the existing methods for reducing nitroalkenes. SnCl2 reduces nitroalkenes to oximes under both acidic and basic conditions. Zn(BH4)2 in 1,2-DiMeO-ethane does reduce 3,4-MD-phenyl-2-nitropropene to the oxime in good yields. Another promising route is the use of Pb in DMF. This seems to reduce most nitroalkenes to the corresponding oximes.
Different synthesis of oximes starting with nitroalkenes should be looked into, as this could be a good alternative to the existing methods for reducing nitroalkenes. SnCl2 reduces nitroalkenes to oximes under both acidic and basic conditions. Zn(BH4)2 in 1,2-DiMeO-ethane does reduce 3,4-MD-phenyl-2-nitropropene to the oxime in good yields. Another promising route is the use of Pb in DMF. This seems to reduce most nitroalkenes to the corresponding oximes.