Synthesis of DOB with NaBH4 and Al/Hg

Synthesis of DOB with NaBH4 and Al/Hg by Iudexk

Procedure

2.84g [75mmol] NaBH4 and 1g silica gel was added to 30mL anhydr IPA and cooled to 0C in an ice/salt bath. A solution of 4.15g [18.6mmol] 2,5-dimethoxyphenyl-2-nitropropene in 25mL t-Bu-O-Me was then added dropwise with stirring at a rate such that rxn temp. did not exceed 5C. Stirring was then continued at room temp. for 6hrs. The rxn mixture was acidified by the slow addition of 50mL 32% HCl. 100mg HgCl2 was then added and dissolved. 3.011g [112mmol] aluminium foil was then added slowly. After all Al had disappeared, rxn mixture was filtered, tBu-O-Me/IPA evaporated, to give red aq. layer, which was washed w/DCM, some of the red coloring being removed, DCM extracts perfectly clear. This was then basified, extracted w/DCM, DCM washed w/H2O, dried over MgSO4 and evaporated to yield 1.205g 2,5-DMA as a pale yellow oil. This oil was dissolved in 7.6mL GAA, and under sitrring 1.135g Br2 in 2.5mL GAA was added dropwise over 4mins. The rxn mixture was left to stir for 3hrs, poured into 125mL H2O, washed w/tBu-O-Me, basified and extracted w/DCM. The DCM was evaporated [forgot to add boiling chip, flask overboiled, some of product lost] to give an amber oil, which was dissolved in 75mL Et2O and gassed w/HCl [CaCl2 H2SO4] under stirring. Flask was put in a freezer for 1hr, then filtered [filtrate pH=5.5] andd air-dried to yield 0.69g 2,5-dimethoxy-4-bromoamphetamine hydrochloride as a white crystalline powder.

Notes

1. .5g silica gel would have the same effect and not be such a bitch to stirring.
2. When washing the DOB.HCl/H2O w/tBu-O-Me, a huge emulsion is formed, which could bee avoided by the addition of 50mL or so conc. aq. NaCl, or possibly by washing w/Et2O instead.
3. If using Al from Al pie plates (thicker), much less molar excess (~4x) would bee needed.

Bioassay of product, which I am currently bioassaying as I type this, is fucking unbelievable [nice]

A similar procedure, by Dr Gonzo:

10g of 2,5-dimethoxy-beta-nitropropene was placed in a 300 ml beaker with magnetic stirbar and 250 ml methanol, and stirred for a few minutes to dissolve as much as possible. Sloooowly… 50 mg at a time… 2.2 g NaBH4 was dropped into the sirring solution, with moderate effervescence with every addition. Addition of all the NaBH4 took less than 30 minutes. After a little bit more stirring, 50 ml 20% HCl was added SLOWLY – if there’s any hydride left, it will bubble vigorously. About 300 mg HgCl2 was added and allowed to dissolve (still stirring) for a couple of minutes. Shredded kitchen aluminum foil was added, around half a gram at a time, allowing the foil to react mostly away before the next portion was added, in order to keep the reaction rate and temperature down. Several grams of Al were used, and the reaction was declared finished when all color was gone and when the chemist thought enough Al had been added. About 500 ml dH2O was added (in a new beaker), and then it was basified with 10% NaOH until the sludge turned from solution -> gel -> granules. This was allowed to settle, then the usual gut-wrenching Al/Hg workup was done, with multiple dilutions, extractions, etc. When the final DCM extractions were vacuumed off, 5.5 ml of impure presumed 2,5-dimethoxyamphetamine freebase (not analyzed, just hoped to be right) was left. Yield: approximately 60%. A drop of freebase produced crystals with the usual ether/IPA/HCl system.

This reaction was also run on straight phenyl-beta-nitropropene, except in absolute ethanol and not methanol. Use MeOH! EtOH yields are poor. Anyway, 16g phenyl-beta-nitropropene was reduced to amphetamine freebase, which was then crystallized with 93% H2SO4 in 99% IPA. Yield: 3.5-4g amphetamine sulfate. Bioassaying the product thoroughly kicked the asses of the experimental subjects, and also produced extreme euphoria, most likely due to the joy of having completed a successful synthesis.

Osmium Comments:

Gonzo’s workup is not very good. When he’s done with the Al/Hg part he dilutes it with water. The product is still in solution, because the whole mother is still acidic. Then he dilutes it with water, and starts basifying it with NaOH. This precipitates the Al hydroxides and freebases the product at the same time. Bad idea, because the Al sludge will effectively absorb the organic, non-water soluble oil and render it inaccessable for further solvent washes.

I’d rather dilute it with some more MeOH, and then start adding the NaOH. This will precipitate the Al just like before, but the MeOH will not be sufficiently diluted to crash out the freebase. It is still soluble in the watery MeOH and filtration will hopefully yield a bigger portion of the product, because the Al sludge will not absorb so much of it. That should give you a better yield, with less solvent washes of the Al hydroxides.