Amphetamines From Nitropropenes
One cannot directly make a methamphetamine from a p-Nitropropene, But who needs 'em anyway when MDA and Benzedrine will do very nicely, thank you. Below is the no-brainer schematic for the conversion:
What goes on in this conversion is that the p-Nitropropene undergoes a catalytic reduction whereby it loses its propene double bond, and the nitro's oxygens get replaced with hydrogens. All this happens in one pot with, usually, just one reaction.
When Strike wrote the first edition Strike considered there to be only one, decent reduction method for the p-Nitropropene. But since then Strike has come across quite a few new ways that make this conversion very, very easy and varied. A lot of the ways were conjured up by one, industrious lab from Tennessee. We'll get to those in a minute. But first let's start off with the basic, default recipe for the reduction of p-Nitropropenes.
METHOD #1: [155, 28 p715]Using the setup in fig. 9, the chemist stirs 55g of LiAIH4 in 200mL THF and adds dropwise to this a mixture of 50g p-nitropropene and 100mL THF from the separa-tory funnel. After addition the solution is refluxed for 24 hours during which time there will be the formation of a lot of white aluminum salt precipitates and the solution will also start to darken. The solution is cooled, 50mL dH20 is added, and the solution is vacuum-filtered. The chemist washes the filter cake with a little extra THF and discards the filter cake. The filtrate is placed in a distillation setup, the THF removed under vacuum and, if desired, the dark MDA/amphetamine oil in the bottom can be distilled over as well to give clear yellow freebase. An alternative cleanup would be to forget about removing the THF and instead adding the solution to 200mL 0.5M H2S04, extracting it with DCM then removing the DCM to get the freebase. Reduction using LiAIH4 gives yields from 60-80%.
The following methods are all the result of one group of scientists: Rajender S. Varma, Laila H. M. Guindi and George W. Kabalka etal. They produced a series of papers in the 1980's that blew the fuck out of nitro compound science. Their methods for reducing p-Nitropropenes are novel and easy. And the best part is that they almost always used our exact precursor (Phenyl-p-nitropropene) as an experimental example. So there ain't gonna be no guessing as to whether their methods are applicable to our precursors. They are!
Although Strike found most of these articles on Strike's own, our good friend and learned scholar Osmium emailed Strike some of the above group's articles and quite a few more that we will get at in just a bit. The following methods can be read about in the original articles in which they were published [49-51], But there is a nice review by the same authors in which a representative example of each of their methods is included . The following were taken from that review. X and speed chemists just substitute an equimolar amount of their respective p-Nitropropene for the one in the methods below. Also, it should be obvious that these reduction methods will work just fine on 2CB and other phenethylamine intermediates.
METHOD #2: "Synthesis of Alkvlamines. General Procedures. Method (A). The synthesis of /3-phenethylamine is representative. A flame dried, nitrogen-flushed, 100 ml flask, equipped with a septum inlet, magnetic stirring bar and reflux condenser was cooled to 0°C. A BH3-THF solution (16 mmol, 9.5 ml of 1.7 M) was injected into the reaction flask via a syringe, followed by the slow addition of a solution of fi-nitrostyrene in THF (4 mmol, 0.6g in 6 ml THF). After the addition, the ice-bath was removed and a catalytic amount (-40 mg) of NaBH4 was added to the stirred reaction mixture by means of a spatula. A moderately exothermic reaction ensued. The reaction was then allowed to proceed for 6 days at 25°C . The reaction mixture was poured on to ice-water mixture (50 ml), acidified with 10% HCI (-20 ml) and then stirred at 60-65°C for 2 h. After cooling to room temperature, the acidic layer was washed with ether (2x50 ml), and then the /3-phenylethylamine was liberated via the addition of aqueous sodium hydroxide. Solid NaCI was added and the product extracted into ether (3x50 ml). The combined ethereal extracts were dried over anhydrous MgS04 and the solvent removed under reduced pressure to yield 0.43 g (88%) of j3-phenylethylamine."
The authors say that the 6 day reaction time at room temp can be accelerated by raising the temperature of the reaction. But they did not specify how much heat or how much time would be reduced.
METHOD #3: The authors next stepped back and considered the cosmic imbalance caused by that 6-day reaction time. The next recipe was what they came up with.
"Synthesis of Alkvlamines. General Procedures. Method (A). The synthesis of /3-phenethyiamine is representative. A flame dried, nitrogen-flushed, 100 ml flask, equipped with a septum inlet, magnetic stirring bar and reflux condenser was cooled to 0°C. Sodium borohydride (9.5 mmol, 0.36 g) was placed in the flask followed by sequential addition of THF (13-15 ml) and BF3-Et20 (12 mmol, 1.5 ml) at 0°C. After the addition, the ice bath was removed and the contents were stirred at room temperature for 15 min. The solution
of fi-nitrostyrene in THF (2 mmol, 0.3g in 5 ml THF) was then injected dropwise into the reaction flask via a syringe and the reaction mixture refluxed on an oil bath for 5.5 h. After cooling to room temperature, the reaction was quenched by careful addition of water (25 ml), the mixture acidified (1N HCI, 25 ml), and then heated at 80-85°C (oil bath) for 2 h. After cooling to room temperature, the product was isolated (75%) as described in method A [from above, folks]."
METHOD #4: The last one from this review . The authors found that reduction occurred using some spacey sounding catalyst called lithium triethylborohydride. But something interesting occurred in the process. The catalyst reduced the nitro group and all to give only a small amount of the predicted amphetamine. But it also stuck one its ethyls on the nitrogen to give a majority product of N-ethylamphetaminel
That means that this method is a neat little way one can get the ever lovely MDEA (Methylenedioxyethyl amphetamine, the softer cousin of X). Strike hears you asking "So if one uses lithium tri-methvlborohvdride can one get methamphetamine out of that nitro group?". Good question. Unfortunately the answer is no. The authors say "Interestingly, N-alkylated products were not produced when other alkylborohydhdes were used." Fair enough. Here's the recipe:
"Reduction of Nitrvalkene with Lithium Triethylborohydride (Su-perhydride) and borane. General Procedure. The reduction of ¡3-methyl-j3-nitrostyrene [a.k.a. Phenyl-p-nitropropene, folks] with su-perhydride (LiEt3BH) and borane (BH3) is representative. Into a flame dried, nitrogen-flushed, 100 ml flask, equipped with a septum inlet, magnetic stirring bar and reflux condenser was added a solution of LiEt3BH (10.5 mmol, , 10.5 ml) via a syringe, followed - 140 -
by the addition of a solution of j3-methyl-fl-nitrostyrene (7mmol, 1.4 g in 5 ml of THF). After the addition, the reaction mixture was stirred at room temperature for 1h. Excess BH3THF (23 mmol, 28 ml) was then added and heated at 60-70°C for 15 h. The mixture was poured into ice water and acidified to pH 2. The mixture was stirred and heated at 60-65°C for 2 h and then cooled to room temperature. The acidic water layer was washed with ether (3x30 ml) to remove N-hydroxylamphetamine. The pH was then adjusted to 10 and the product extracted into ether (3x30 ml) and dried (MgS04). The solvent was removed under reduced pressure to yield 0.73 g (64%) of N-ethylamphetamine. The hydrochloride salt was prepared and recrystallized from an ether/ethanol (20:1) mixture."
METHOD #5: Contributed by Osmium . The paper reads (at least to Strike) that this reduction method can work to reduce the formyl intermediate made in the Leuckart reaction directly into MDMA instead of needing to hydrolyze to MDA with HCI (don't ask). For this reaction one substitutes an equimolar amount of p-Nitropropene for the 3,4-dimethoxybenzylcyanide in the representative experimental below:
"NaBH4 (4.56g, 120mmol) was added to a solution of Me3SiCI (26.04g, 240mmol) in THF (100mL) and the mixture refluxed for three hours under argon. A solution of 3,4-dimethoxybenzylcyanide (10g, 56.4mmol) in THF (50mL) was then added over the course of 10min. The solution was refluxed for a further 10h. After cooling, 100mL MeOH were cautiously added and the volatiles removed in vacuo. The residue was taken up in dilute HCI and washed with ether. The aqueous solution was treated with excess dilute NaOH and then repeatedly extracted CH2CI2. The organic extracts were combined, dried over Na2S04, and the solvent evaporated to afford 2-(3,4-dimethoxyphenyl)ethylamine. Yield = 9.16g (90%)."
The authors caution that "MeSiH is formed. It should therefore be ensured that this volatile silane (b.p. ~10°C) can escape from the reaction vessel.''
Continue reading here: Bromosafrole Phenylisopropylbromide
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