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Author: Subject: Phenylethylamines by alkylation of alpha nitroesters

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thumbup.gif posted on 19-1-2009 at 17:49
Phenylethylamines by alkylation of alpha nitroesters

I've found this in some Hive files on an old CD-Rom, so why don't post them!!!!
(this one was posted by lego from the hive).
Step 1: Bromomethylation of benzene

Monatshefte, 1950, 917-920

111,0 dry, finely powdered NaBr is suspended in 50,0 g benzene1, 50,0 ml glacial acetic acid and 27,0 g paraformaldehyde. The mixture is stirred and heated to reflux at 80° C. Over a period of 3 h a mixture of 158,0 g sulfuric acid (d = 1,84 g/ml, 96%) and 80,0 ml glacial acetic acid is added. The mixture is stirred for further 9 h at 80° C, then for 8 h at 80° C without stirring. The reaction mixture was allowed to cool to room temperature and lots of water was added. The formed yellow oil was separated. The aqueous phase was extracted with benzene (feel free to use toluene or xylene), the organic phase and the yellow oil were pooled, treated in usual manner with water, 5% sodium carbonate solution and again with water and dried. After evaporation of solvent the oily residue was destilled at 11 torr (14,7 mbar). The boiling point was 82° C and 95,2 g pure benzylbromide were obtained. Yield: 86,5% (based on benzene).

1 The authors use the same reagent system for the 1,4-bis-bromomethylation of benzene (32,3%), p-bromomethylation of toluene (87%) and bromobenzene (35,2%) and alpha-bromomethylation of napthalene (81%). Other substituted benzenes like 1,4-dimethoxybenzene or 2,6-dimethoxyphenol should also work. Although the yields show drastic differences this should bee no problem as all reagents are very cheap and the procedure can bee performed on a large scale.

Step 2: Benzylbromide --> Methyl 2-Nitro-3-Phenylpropionate

Synth. Comm., 1987, 17(12), 1421-1429 (

Benzyl bromide (1a, 1.8 g1) was added to a stirring solution of methyl nitroacetate (2, 1.21 g) in dimethyl formamide (10 ml) containing benzyl triethyl ammonium chloride2 (TEBA, 0.009 g) and anhydrous KHCO3 (0.5 g) at room temperature.
The reaction mixture was stirred at 60 °C for 16 hrs. DMF was removed under vacuum and the mixture was diluted with water and extracted with ether. Drying and evaporation of the solvent furnished an oil which on vacuum distillation (110°-115 °C/3 mm) yielded pure (TLC) (3a, 1.49 g, Methyl 2-nitro-3-propionate).

In case of 3b and 3c purification was achieved by SiO2 chromatography using EtOAc : PhH (1:9) as eluents.

1 10,5 mmole of any other benzylbromide can bee substituted
Step 3: Decarboxylation

Method A:
JACS, 1955, 77, 5747-5748
3-(2-Nitroethyl)-indole (II). A solution of sodium hydroxide (32.0 g., 0.8 mole) in 64 ml. of water was added to 78.6 g. (0.30 mole) of ethyl alpha-nitro-beta-(3-indole)-propionate ( I ) in 200 ml. of ethanol. The resulting solution was allowed to stand a t room temperature for 44 hours. Solvent was removed under reduced pressure until the flask contained a mass of solid, semi-crystalline material. Ethanol (400 ml.) was added, the mixture was slurried well and the solid was collected on a filter. It was washed with ethanol, then with ether and dried on the filter. The solid was dissolved in 600 ml. of water, the solution was cooled in ice and acidified by slowly adding 20% hydrochloric acid until the pH was between 4 and 5 . Crystalline material began to separate and the flask was cooled at 4° overnight. The light pink crystals were collected, washed with water and dried under vacuum. The yield of 3-(2-nitroethyl)-indole was 47.4 g. (83.27,). Material of analytical purity was obtained from the "practical grade" product described above by dissolving it in 200 ml. of ethanol, treating the solution with charcoal, filtering and adding 95 ml. of warm water to the warm (60°) filtrate. The flask was allowed to cool slowly to room temperature and was then placed in the refrigerator for 2 days. The large, sparkling plates were collected on a filter and washed with two 40 ml portions of 50% ethanol. The product, dried under vacuum, weighed 39.14 g. (68.5%) and melted at 55.5-56.1°. Two months later the melting point of the same material was 68.3-69.2°. It was shown by analysis and infrared spectra that these are dimorphic forms.

Method B:
J. Org. Chem., 1991, 56(16), 4990-4993
Nomenclature overkill (1.13 g, 3.08 mmol), sodium chloride (1.0 g, 17 mmol), and water (0.2 mL, 20 mmol) in dimethyl sulfoxide (15 mL) was heated at 150 °C for 4 h. The solvent was evaporated at reduced pressure, and the black residue was taken up in ethyl acetate and filtered through a small plug of Celite. The filtrate was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to leave a light brown solid. This solid was purified by silica gel chromatography using 1:1 hexanes-ethyl acetate as eluent to give the title compound ae a white solid (0.66 g, 66%).

Edit by Chemoleo: Title

[Edited on 20-1-2009 by chemoleo]
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International Hazard

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[*] posted on 19-1-2009 at 18:01

Just wondering. Exactly how many amphetamine cooking threads do you intend to open?

Sic gorgeamus a los subjectatus nunc.
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International Hazard

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[*] posted on 19-1-2009 at 18:30

Given that there a thread or two on the Hive. Rhodium's, and archives thereof, that many members likely have copies of such, and that much of this is online, what is the point? Are you performing these experiments? Looking for help? Certainly you're not presenting new information, perhaps it might be better to unplug your computer for a few days until the fever and accompanying delirium go away.
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Biochemicus Energeticus

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[*] posted on 19-1-2009 at 19:46

and that much of this is online, what is the point

This could be said for probably 80% of all threads here. So this is NOT a point.

Bluetooth, I suggest you remove the obvious 'drug' angle in the future, to receive a more welcoming response.
This forum is NOT the Hive, nor Wetdreams.
So please conform to the chemical angle we have here, or don't post.

PS thread title edited.
PS2 threads not obviously related to derivatives of the title's subject were left...for now.

[Edited on 20-1-2009 by chemoleo]

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[*] posted on 19-1-2009 at 22:53

Thanks for the bromomethylation procedure!
As for drug related chemistry, i think a-nitropropionic esters can be used as well, this is a good route for MDMA i suppose. Benzodioxol is easily chloromethylated with HCl/CH2O.

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