Full MDA Synthesis Starting from Helional

[GhostChemist]

Stage 1. α-methyl-1,3-benzodixole-5-propanal oxime​

The process way presented on Scheme 1.

Scheme 1​

Starting reagents and materials

• 260 g Helional or Ocean propanal (3-(1,3-Benzodioxol-5-yl)-2-methylpropanal CAS 1205-17-0)
• 400 ml EtOH (Ethanol 88%)
• 300-350 ml Na2CO3 (107 g Na2CO3 in 300-350 ml H2O)
• 200-250 ml NH2OH*HCl (141 g NH2OH*HCl Hydroxylamine hydrochloride CAS 5470-11-1)
• 1000 ml H2O
• 5*300 ml DCM
• 900-1000 ml H2O
• 800 ml brine (200-240 g NaCl)
• Flask 2000 ml
• Separating funnels 250 ml and 2000 ml
• Magnetic stirrer
• Vacuum pump
• Heating mantle
• Glasses

Ethanol and Helional. Fig 1

Fig 1​

Helional is placed in a flask and dissolved in EtOH. Fig 2

Fig 2​

Aqueous solutions of sodium carbonate and hydroxylamine hydrochloride are prepared. Fig 3

Fig 3​

When sodium carbonate dissolves, the solutions heat up, and when hydroxylamine dissolves, the solutions cool down. Fig 4​

Fig 4​

The sodium carbonate solution is poured into a 2-liter glass and a hydroxylamine solution is added to it. This causes foaming with the release of carbon dioxide and the formation of free hydroxylamine. Fig 5​

Fig 5​

The resulting hydroxylamine solution is added to the helional solution over 20 hours. Fig 6

Fig 6​

After adding all the hydroxylamine solution, the resulting RM is stirred for 20 hours yet. Fig 7

Fig 7​

After 20 hours, a solid oxime may form. Fig 8

Fig 8​

The liquid part of RM is poured into a separatory funnel for oxime extraction. 800-1000 ml of water and 500 ml of DCM are added. Shake well. The DCM layer is drained and saved. Another 200-250 ml of DCM is added for extraction. The aqueous layer is discarded after extraction. Fig 9​

Fig 9​

500 ml of DCM is added to the oxime in the flask to dissolve it. All of the separated DCM is also added too. Fig 10​

Fig 10​

A saturated solution of sodium chloride in water is prepared in advance. Fig 11

Fig 11​

Distilled water is poured into a separatory funnel and the resulting solution of oxime in DCM is added. The mixture is shaken well. DCM is separated. The aqueous layer is discarded. Fig 12

Fig 12​

Next, the prepared sodium chloride solution is poured into the separatory funnel. DCM is added for washing too. The mixture is shaken well, DCM is separated, the aqueous layer is utilized. Fig 13​

Fig 13​

Anhydrous sodium sulfate is added to the washed DCM for drying. Fig 14

Fig 14​

The dried DCM distilled off. The distillation is initially carried out at atmospheric pressure, reduced pressure is applied at the end of the distillation for complete removal of DCM. Fig 15​

Fig 15​

The resulting oxime is a yellow or yellow-orange oil. Fig 16​

Fig 16​

The oil further crystallizes. Fig 17

Fig 17​

Yield is quantitative 278 g, 99%

Stage 2. α-methyl-1,3-benzodixole-5-propanamide​

The process way presented on Scheme 2.

Scheme 2​

Starting reagents and materials

• 278 g Oxime (α-methyl-1,3-benzodixole-5-propanal oxime)
• 400-500 ml o-Xylene CAS 95-47-6 (Boiling point 144℃)
• 8 g Nickel(II) Acetate Tetrahydrate Ni(OCOCH3)2*4H2O CAS 6018-89-9
• 4500-5000 ml DCM
• 2000-3000 ml H2O
• Flask 2000 ml
• Reflux
• Thermometer
• Separating funnel 2000 ml
• Heating mantle with stirrer
• Glasses
• Schott funnel
• Vacuum filtration kit
• Vacuum pump
• High vacuum grease

200 ml of o-xylene is added to the oxime. Fig 18

Fig 18​

Nickel acetate tetrahydrate is added to a solution of oxime in o-xylene. Fig 19

Fig 19​

The mixture is heated to a gentle boil and kept for 8-10 hours under a reflux condenser at a temperature of 130-140℃. Fig 20​

Fig 20​

After cooling, RM crystallizes. Fig 21

Fig 21​

The cooled RM must be completely dissolved in DCM (4-5 L of DCM). Fig 22​

Fig 22​

1000 ml of water is poured into the separatory funnel. The first portion of the saturated solution of amide in DCM is added and washed. Solid amide in the flask is dissolved with new portions of DCM. Washing is necessary to wash out toxic nickel salts. Washing operations for each portion of DCM are carried out with fresh water. Washing with a sodium chloride solution is recommendable when cleaning very dirty RM, but was not used in this case. Fig 23​

Fig 23​

The washed DCM layer is separated and saved. An additional 200 ml of DCM is added to the aqueous layer to extract the amide. Aqueous layer is discarded. Fig 24​

Fig 24​

The DCM layer is dried over anhydrous sodium sulfate. Fig 25

Fig 25​

The dried DCM is distilled off. At first, distillation is carried out at atmospheric pressure. At the end, vacuum distillation is used to completely remove DCM. Fig 26

Fig 26​

After DCM distilled off and cooling RM, amide crystals is formed. Fig 27

Fig 27​

The crystals are filtered out on a vacuum filter. Fig 28

Fig 28​

The amide crystals are quickly washed with a portion (50-70 ml) of DCM. Fig 29

Fig 29​

The amide is dried. Yield is 165 g or 59.4%. Fig 30

Fig 30​

Stage 3. MDA​

The process way presented on Scheme 3.

Scheme 3​

Starting reagents and materials

• 150 g α-methyl-1,3-benzodixole-5-propanamide
• 3000 ml H2O
• 159 g NaOH in 500 ml H2O
• 745 ml NaClO (Sodium hypochlorite solution CAS 7681-52-9) with active chlorine 13%
• 2000-2500 ml DCM
• 800-1000 ml H2O
• 1000-1200 ml 5-7% aqueous HCl
• Flask 5000 ml
• Ice 2-3 kg
• Reflux
• Glasses
• Magnetic stirrer with heater
• Separating funnel 2000 ml

A solution of alkali in water is prepared before synthesis and cooled to +5℃. Fig 31

Fig 31​

The amide is poured in to a 5000 ml flask and 3000 ml of distilled water is added. Fig 32​

Fig 32​

The suspension of amide and water is cooled to 0-5℃ while stirring. Fig 33​

Fig 33​

The alkali solution is added in portions over 30 minutes. Fig 34

Fig 34​

A sodium hypochlorite solution with a chlorine activity of 13% is pre-cooled to +5℃. Fig 35​

Fig 35​

The activity of chlorine in sodium hypochlorite is determined by density. Fig 36​

Fig 36​

Next, sodium hypochlorite is added to the RM. The RM is stirred for 1-2 hours. Fig 37​

Fig 37​

RM is heated to a temperature of 70-75℃ and stirred for 1.5-2 hours. All solid amide should turn into oil. That is, RM from suspension should completely turn into emulsion. (When taking a sample of oil, the sample should not give needle-shaped crystals when cooling, since this indicates the presence of unreacted amide). RM pH≥10. Fig 38​

Fig 38​

1000 ml of DСM is added to the cooled RM. DСM is not utilized! Fig 39

Fig 39​

The aqueous layer of RM is poured into a separatory funnel and extraction is carried out with several portions of DCM. Fig 40​

Fig 40​

All DСM solutions are combined. Fig 41

Fig 41​

The resulting DCM layer with a total volume of 2000-2500 ml is washed with 800-1000 ml of water. Fig 42​

Fig 42​

The washed DCM layer is dried over sodium sulfate. Fig 43​

Fig 43​

Further extraction of the MDA with an aqueous solution of 5-7% hydrochloric acid is used. Aqueous hydrochloric acid is poured into the funnel, then DCM. The mixture is shaken well. The aqueous layer should always be slightly acidic. Fig 44​

Fig 44​

A small portion of aluminum oxide is added to the separated aqueous layer containing the MDA hydrochloride and mixed well. Fig 45​

Fig 45​

The solution is filtered through a paper filter. Fig 46

Fig 46​

The filtered solution is evaporated until crystallization. Fig 47

Fig 47​

The resulting crystals are transferred to a filter. 125 ml of petroleum ether are added. Fig 48

Fig 48​

The crystals are carefully ground on a filter with a pestle. Fig 49

Fig 49​

The solvent is removed by vacuum. Fig 50

Fig 50​

Next, the crystals are ground in a mortar with a small portion of DСM. Fig 51

Fig 51​

The mixture is filtered. Fig 52​

Fig 52​

The washed product is transferred to a mortar and ground into powder again. Then ground in a mortar continues with the addition of fresh DCM and ethanol (1:1). The procedure is repeated 3-4 times. Fig 53​

Fig 53​

The resulting mixture is filtered and additionally washed with DCM. Fig 54

Fig 54​

The resulting powder is dried on a filter. Fig 55

Fig 55​

The authenticity of MDA is proven by a qualitative reaction with gallic acid (a solution of 0.05 g of gallic acid in 10 ml of 80-94% sulfuric acid). The appearance of a green color indicates the presence of MDA. Fig 56​

Fig 56​

Yield of MDA hydrochloride is 70%

!!!!!!!!Further purification of MDA hydrochloride will be show in the next topic and video!!!!!!!​

 

[Mo0odi]

Thank you
On this work

 

[bigbadbear]

great

 

[Rabidreject]

Bravo! I heard about this synthesis on a podcast a while ago now. It’s a really cool one. Nicely done indeed.
I would try this but I’m already wasting too much time on MDA, of which I’m not a huuuge fan.
Love the chemistry tho!

 

[Swirly]

Why not use the method given on The Vesp or here:
https://chemistry.mdma.ch/index/mda.html it seems easier.

Helional or 3-(1,3-benzodioxol-5-yl)-2-methylpropanal to the Helionamide or MMDPPA or 3-(1,3-benzodioxol-5-yl)-2-methylpropanamide

This is a rough sketch from someone's post from The Vesp:

100g Heli run
Mix 400 ml DMSO and 36.93g Hydroxylamine HCL, then add 100g heli and the last 100ml of DMSO.
Heat for 90 minutes at 85-90°C on hotpate with good stirring.
Turn off heating and when temp has gone down to about 70°C, add 15% NaOH solution carefully until pH is about 10, try keep temp around 70-80°C.
Then at 65-70°C start dripping 600ml 30% H2O2 very carefully. The H2O2 is pre-basified to pH 7-7.5 with 15% NaOH, keep a ice-bath ready if temps rise fast to above 95°C and periodically measure the pH to confirm it stays between pH 8-10.
If pH falls below 8 add 15% NaOH till pH is about 10, the temps should be about 80-95°C during the H2O2 addition.
When all 600ml H2O2 has been added continue stir until gas evolution and exothermia had ceased.
When temps have decreased to about 50°C one have 2 choices,
One could pour the content into a large beaker/pyrex dish, put into refrigerator and let it sit overnight to form crystals,
or one could dump it into ice cold water and then immediately vacuum filter the crystals.
I think i go with slow crystallization overnight.
Then vacuum filter the crystals and wash them on the funnel with distilled water.
Re-crystallization from water if it seem needed.

Then a Hofmann rearrangement of Helionamide with NaDCC (sodium dichloroisocyanurate) to MDA freebase.

Here is someone else's outline also from The Vesp:

Chemicals:
7.28g NaDCC dihydrate (~29 mmol)
400ml 10% NaOH
10.90g helionamide (~53 mmol)

Procedure and observations:
The entire 7.28g of sodium dichloroisocyanurate dihydrate was added to 400ml of warm 10% NaOH. I made the mistake of not crushing the little granules into a powder as before. If you're going to attempt this, crush the NaDCC into a fine powder. After nearly an hour of heating there was still a cloud of very fine precipitate visible in the beaker.
Then the helionamide was added in portions (no exotherm was observed, so it would probably be possible to just dump it in).
The mixture was heated to 70C and then to 90C. Total heating time was about 2 hours. The reaction was monitored by TLC on silica (eluent: 7:3 ethyl acetate/hexane, visualized by permanganate. UV works very poorly here in my experience.).

There wasn't much CO2 evolution - I'd say none, really. Maybe it was all immediately absorbed by the hydroxide and that's why I couldn't see bubbles. TLC was helpful.
A decision was made to hold the RM off-heat, but on stirrer and with a watchglass on top for the entire night (~9h). After letting the mixture stand a thin layer of brown-yellow oil could be seen on coalescing on top. The reaction mixture had a characteristic smell of something trying to smell bad but not doing too good of a job at it

. I'd describe it as warm helional that had gone bad.

The reaction mixture was filtered to remove the fine precipitate and the yellow mother liquor was extracted using 3x40ml of DCM. The extracts were red/orange in color. The DCM extracts were extracted using 90ml of water to which 10ml of conc. HCl was added. This mixture was added in 4 portions and the extracts were yellow. This was then basified using first potassium carbonate and then sodium hydroxide. You could as well probably just use sodium hydroxide - the basicity created by the carbonate wasn't enough to fully precipitate the amine freebase.
The mixture was put in fridge and a couple large globules of red oil could be seen on the bottom. The basified mixture was extracted once again with 3x30ml DCM, dried over magnesium sulfate and the DCM was mostly stripped with help of some warm water and a fan.

When the mixture was concentrated to around 20ml it was poured into a 25ml RBF and heated up over a steam bath to draw off any remaining DCM.

Then the oil was vacuum distilled (140C, ~1mbar, remember - first vacuum, then heat! There will be a lot of bumping as some DCM will always remain and has to be first drawn off by the pump - use the gas ballast to remove it from the oil or it will kill your pump). The crude oil weighed 6g and after the distillation it was around 5g. Pure phenylethylamine freebases are colorless - and the distillate was indeed colorless. In the boiling flask there remained red goop that had a smell similar to that of the freebase.

The freebase was taken up in ~20ml of IPA, acidified using 3 pipettefuls of conc. HCl and the salt spontaneously precipitated out as thick crystals after addition of some anhydrous acetone.

The salt was filtered and washed with plenty of acetone. After drying the final yield of very pure (blindingly white!) MDA hydrochloride is around ~50%. The converesion to salt is nearly quantitative, but remember to collect the second crop from the washings (I forgot about it and lost ~500mg of the product).

I have not gotten around to MDA but I would for sure go with this method instead of the older "2 dogz" synth outlined here.

 

[Anarchy Labz]

Thank you for this synthesis! Will there be a video on it?

 

[HIGGS BOSSON]

Yes, we edit video