-------------------------------------------------------------------------------- Reductions of Nitroalkenes Using Zinc and Aluminum Amalgam -------------------------------------------------------------------------------- Comptes Rendus 213: 304 ('41) - Translation by Labrat Amongst the reduction methods used in organic chemistry, there are many methods using Zn. The zinc is used, either in metal form, or associated with other metal in the form of a couple: Zn-amalgam (BER 46: 1837 ('13), Zn-Cu, Zn-Pd and Zn-Pt are described in the literature. The couple Zn-Ni has not received attention by chemists. The Zn-Ni couple is only active in the presence of base: ammonia or hydroxide ions. We've used ammonia as base in most cases. Preparation of the couple: One can obtain this easily by treating a ammoniacal solution of a nickel salt, e.g. the sulfate, with powdered zinc. The nickel is reduced and releases hydrogen, while the zinc is transformed into the oxide, which dissolve slowly in the ammoniacal solution. In some cases it's necessary to remove the ionised nickel, either because it'll form an insoluble complex with the substance to be reduced, or because one wants to replace the ammonia with sodium/potassium hydroxide. We've realised the hydrogenation of several functional groups in this work: Oximes, isonitrosoketones ------------------------- The ketoximes are reduced to the corresponding primary amines. Phenethylamine and amphetamine were obtained starting from methylphenylketoxime and methylbenzylketoxime. The isonitrosoketones are reduced to aminoalcohols. We cite the case wherein isonitrosoacetophenone is reduced to beta-phenylethanolamine. Nitriles -------- Benzyl cyanide is reduced to phenethylamine. Reductive amination of ketones ------------------------------ If a commercial solution of ammonia is used (with added alcohol to solubilise the ketone), one obtains a moderate yield of the corresponding amine. Cyclohexanone gives a 60-70% yield of cyclohexylamine. Methylbenzylketone is transformed in the same way to phenylisopropylamine. -------------------------------------------------------------------------------- Ann.Pharm.France 7: 733('49) - Translated by Labrat 2,3-dimethoxyphenethylamine ---------------------------- We've prepared this substance by direct reduction of the nitrostyrene with zinc amalgam in hydrochloric acid. Water is added to 24 g of the nitrostyrene until the total volume is 650 ml. Add 100 ml concentrate HCl and 10 ml of a 5% solution of HgCl2. Add with vigorous stirring in small portions 46 g powdered zinc, amalgamated with 33 ml 5% HgCl2 solution. With every addition of Zn, 15 ml concentrated HCl is added. The temperature is not allowed to rise over 35 C. After complete disappeared of the nitrostyrene, one filters the unreacted zinc and concentrates the acidic solution in vacuo. Add NaOH/H20 solution until the precipitated zinc redissolves and extract several times with ether. The ethereal solutions are washed and dried over Na2SO4. The ether is evaporated and the residue is fractionated to give 60% amine. -------------------------------------------------------------------------------- On the reductive amination of P2P, using MeNO2 as the source of methylamine: Yakugaku Zasshi; 77; 1957; 310; Chem.Abstr.; 1957; 11278; 2-MeCH:CHC6H4OMe (52g) in 400ml AcOH treated portionwise with 200g. Pb3O4 stirred 1 hour at 40 degrees, the solution treated with a small amount of H2O, AcOH removed in vacuo, the residue extracted with Et2O, the Et2O residue with 500ml 20% H2SO4 refluxed 3 hrs, and the end product with EtO2 gave 24g 2-MeOC6H4CH2COMe (I), I (32.8g) in 19g MeNO2 and 100ml EtOH added dropwise to 30g Al-Hg in 500ml EtOH, refluxed 2-3 hours, the Al(OH)3 and EtOH removed, the residue acidified with HCl, washed with Et2O, made alkaline with NaOH, and the end product extracted with Et2O gave 29g 2-MeOC6H4CH2CH(NHMe)Me. -------------------------------------------------------------------------------- Excerpt from Monatsh. Chem. 79 (1948) pp72-77 Direct reduction of the nitro compound to the amine: 1g 2,3-dimethoxy-beta-nitrostyrene was dissolved in a mixture of 10ml HOAc, 10ml EtOH and 10ml H2O by gentle heating, and 2g fine Al turnings were added. The reduction started after the addition of some HgCl2 and was completed by heating on a warm water bath after standing for two hours at room temp. Workup was done in an analogous manner to the oxime (apparently filtration, solvent removal under vacuum and an acid-base extraction). 0.58g was obtained after distillation at 1mmHg, 80-110° air bath temperature. From that 0.67g of the picrate was obtained. -------------------------------------------------------------------------------- Posted on the Hive 980815 by Zorohustra In this dream I dreamed that I tried Eleusis's "Proposed nitro -> amine reduction for general use" (which can be found at Rhodium's outstanding page, check it out!). 13g of GOOD phenyl-2-nitropropene was dissolved in 150ml Glacial Acetic Acid in a 500ml 3-neck RB. 55g of tech. Zinc powder was "purified" as in Vogel's 5:Ed. (washing with 10% HCl, then dH2O, followed by acetone). The dry and pure Zinc was slowly added to the nitropropene solution, while stirring at 700rpm. When ~2/3 of the Zinc had been added the solution turned "rust-red". When all the Zinc had been added the temperature was 80C. The solution was still stirred at 700rpm, the goal was to heat it to 100C, but it became 106C, at which point it boiled(?!). The solution was no longer "rust-red", the Zinc was again gray and the solution appeared to be light-pink/red (observed by stopping the stirring for a while). The stirrer speed was increased to 1100rpm and the solution was held like this for another 30min (total time ~45min). The solution is now light yellow, with some colorless foam. "Perhaps I have made P2P instead the chemist thought." (I think I've read in March that it can be made with Zn/HOAc). 60ml 37% ACS hydrochloric acid is put into the additionfunnel and added over perhaps 20min, no spectacular reaction at all. 1-2 hour later another 20ml hydrochloric acid is added, can't hurt I mean. The solution is now near colorless, its decantated from unreacted Zinc, the solution dumped into 1000ml cool dH2O, the Zinc washed with 100ml dH2O. The solution was washed with 3*60+50ml DCM (500ml sep. funnel ;). Then basified with NaOH solution until pH 10-11, then extracted with 3*70+50ml DCM. The solvent was removed by destillation, leaving VERY LITTLE of "something", 15ml anhydrous acetone was added and 2-3 small drops of 98% sulfuric acid, crystals percipitated. But we are talking about a yield in the 100mg range… The chemist dumped it all out, being more of a curios chemist then a desperate speedhead. The washings was also stripped from solvent by destillation and then dumped into a satured bisulfitesolution, but no crystals formed. Hmm, IF this reaction can give an acceptable yield this is at least NOT the way to get it, there is really not much to do then but to try with lower temperature, but I am not motivated. -------------------------------------------------------------------------------- Zn/Hg Nitrostyrene reduction To suspension 1.5 g of 5-bromo-1,3-dimethoxy-omega-nitrostyrene in 20 ml of aqueous MeOH (1:1) was added 4.5 g. HCl (d=1.19) and 0.3 ml 5% aqueous HgCl2 soln. Under stirring this was reduced with 5 g. of Zn dust, previosly amalgamated with 0.3 ml 5% HgCl2 soln, adding Zn in portions at 30-35°C during 30 min. After addition completing, the reaction mass was heated to 45-50C and kept at this temp under stirring during 30 min. Unreacted Zn was removed, filtrate basified with 10% NaOH untill all deposited Zn(OH)2 was dissolved. Base was extracted with toluene (3x50 ml), solvent ditilled off in vacuo, and residue dissolved in 10 ml CH3OH, and treated with saturated soln of picric acid - yield 2.0 g picrate, 83% Ref: Zh. Org. Khim 35, 720 (1965) -------------------------------------------------------------------------------- Zorohustra: I have earlier dreamt about several more traditional approaches of the old, but still useful (I hope ;) Clemmensen reduction of phenylnitropropens, these dreams have all turned out fruitless. The following is a modification and in this dream there was product, even thou the yield was low. This is my dream: 60g Zinc powder was mixed with 5g HgCl2 and carefully stirred until homogenous, about 100ml d water was added and then slowly 4ml of concentrated hydrochloric acid was added, the temperature rose to about 50C and the amalgamation was finished within 5 minutes. The water was removed by filtration and the amalgam was washed with MeOH. The amalgam was placed in a 1000ml 3-neck RB flask containing 140ml MeOH, the mixture was magnetically stirred and 70ml of concentrated hydrochloric acid was slowly added, the temperature rose to about 65C. A condenser was fitted, as well as an addition funnel. The temperature of the amalgam/MeOH mixture was held at 50C with external heating. Meanwhile, 15g of really pure 1-phenyl-2-nitropropene and 200ml MeOH was mixed, the solution heated until boiling, to solve the crystals. The hot solution was added to the addition funnel and over just 15 minutes the whole 200ml was introduced into the RB. The solution boiled hard and the temperature rose to 70C, all while stirring at 1100rpm. The solution was left boiling for another 2 hours. The workup was quite a mess and in retrospect I can say that the best thing to do, probably, is to make the solution basic with 10% NaOH solution, filter, remove MeOH, extract whit DCM, skip back-extraction and let the distillation be the only cleanup. Anyhow, after distillation the yield of amphetamine freebase was ~4ml, that was collected at 125C with aspirator "vacuum". Tips how to increase the yield are very welcome, preferable from a Clemmensen dreaming bee, the refs always claim 60-70% yield, but that is just not my experience.. -------------------------------------------------------------------------------- Lone Ranger: Can you use a two phase system to incrase yields? The use HCl/zinc amalgam and a toluene layer can be helpful in preventing an immpossible to seperate complex forming with the zinc. JACS, vol 58, 1438 -------------------------------------------------------------------------------- Osmium: Basifying with strong NH3 avoids precipitation of Zn(OH2) in the workup. -------------------------------------------------------------------------------- Dreamer: Yesterday i had a dream, i tried to reduce P2NP (phenyl-2-nitropropene) to amphetamine with amalganated Al. I amalganated 20gr of Al. To this 20gr Al i added 0.1 mol P2NP in 150ml Tetrahydrofuran (YES, tetrahydrofuran with his peroxides). The 150ml didn't cover the foil in the 1l Flask and i added another 150ml :). I putted the condensor on the flask and all was immersed in ice cold water!! (very important) Then i added slowly, in 10ml steps 100ml of a solution of (100ml 31% HCl and 50ml H2O), i didn't have 25% HCl. The reaction TE climbed to 50°. To keep up the generation of bubbles i added after 45 min the last 50 ml of HCl slowly in 10ml steps. The whole mixture colled down to 20° and i let stand everything over night. Next day i made all very basic through slowly addition of 50% NaOH (~100ml). When i saw that with the addition of NaOH generated other bubbles,so i let everything stand again for 4h. Then i filtered the whole solution with a Buchner funnel, which was quite tedious because the grey shit is plugging (that should be "verstopfen" in english, http://www2.echo.lu/edic/ is a really good page for someone, who didn't follow english lessons at school) the filter paper. Well, after 2h all was filtered. I extracted with 3*75ml with a mixture of Chloroform and DCM (because once i recovered DCM i poured it to chloroform --> errors of a computerfreak, which is playing the chemist), i washed with 500ml of 10% NaOH (maybe an error, if amphetamine dissolves in diluted NaOH, a lot of the product could be loosed, is this true ?) the solvents where recovered and a red oil was the result. Now i made the sulfate salt instead of the HCl salt, because the sulfate is not so soluble in water (1part in 8.8parts of H2O). I added 2ml of the oil to 20ml of ether and a few drops of 96% H2SO4, i got amorphic crystals. I tried with 20ml den. 90° ethanol, again only amorphic crystals, maybe to many impurities, so one should distill the amphetamine freebase at 102°(13) under vaccuum. I couldn't, because my vaccum setup exploded a week ago. (while heating a mixture under vacuum i didn't realize, that the water trap of my vacuum hose was damaged, so the pressure in the glass of my vacuum distillation setup, which was not fixed, growed, pushed the glassware out of the ground joints, ...,) So i poured the last ~10-12ml of red oil to the amorphic crystals in a 30ml 90% den. ethanol. I added a little bit of 96% H2SO4. I waited 1min and i got a dense red-white mass. Remembering eleusis's acetone wash of mdma, i poured 100ml of acetone into the mass, a lot of crystals separated out. Everything seemed ok, but when i tried to add more acetone i mixed up the 95% H2SO4 with the acetone (same color of the flask :(() and i poured 5ml of 96% H2SO4 in the Acetone, den. Ethanol and Amphtamine Sulfate. There was a lot of fizzing and the crystals disappear !???!!! WHY ?WHY ?WHY ? Does acetone react with conc. sulfuric acid or ethanol and did one of these reaction byproducts destroy my amphetamine sulfate? Recovering the other crystals from ether gave 1 gr of brown-white with acteone washed crystals. I don't know how high the yield is, maybe around 50%.I am sure that i can improve this reduction, because i was really imprecise. When i used tetrahydrofuran there where two layers. Is it ok if there are two layers with the P2NP in the organic layer, without an alcohol, that dissolves P2NP even in the water layer? Would it raise the yield if i add some Alcohol? Could it be that in such a reduction with amalganated Al the solvent is reduced too (acetone, methyl ethyl ketone -->in denaturated ethanol) and reduces the reduktion power of the reaktion? It is impossible for me to get methanol and pure isopropylalcohol without acetone (i can get tetrahydrofurane or ethyl ether like distilled water, but so funny it sounds no mathanol and 1l pure isopropyl alcohol costs like 95% ethanol). Is there a possibility to eliminate all chemicals beside methanol and ethanol, and what does denaturated 1°category mean? If the TE of such a reduction is kept low, will this reduction work for MD-P2NP and is it possible to make a sulfate salt of MDA with a low solubity in water too? -------------------------------------------------------------------------- Sunlight (01-21-99): Al/Hg and acetic acid reduction of 2,5-DMNS to 2C-H Recently I was dreaming about to reduce 2,5 dimethoxy nitrostyrene to the amine 2C-H with Al/Hg and acetic acid. I waited about 50-60 % but I got only 35%. Yields are not good, but Shulgin reports 40% in 2C-B and 50% in 2C-H with LAH, so might be interesting to avoid buy/use LAH. Proportions I use : 1 nitro (grams) 10 acetic acid (ml) 15 ethanol 96 (ml) 5 water (ml) The reaction must be carried at about 60 C, becuase then the nitro is dissolved. Some tips are: - Put the HgCl2 in the reaction, then add the Al squares at a rate enough to keep the temp around 60, and add till the orange colour disappear. About the double weight of nitro will be enough, may be less. - Filter before add NaOH solution, if not the great amount of sodium acetate formed complicates filtration, even crystallize in the flasks. Filter and wash the cake with water, and then add NaOH. -------------------------------------------------------------------------------- Zn/Hg reduction of 3-Br-4,5-MD-NS to 3-Br-4,5-MD-PEA 53 g (0.22 mole) 3-Bromo-4,5-methylenedioxynitrostyrene and amalgamated Zink (prepared from zinc powder (200g) and HgCl2 (20g)were suspened in EtOH 2 L). Under vigorous stirring, conc HCl was added portionwise into the above mixture until the yellow coloring of the reaction mixture disappeared. After the decoloration was completed, the reaction mixture were further stirred for 30 min. An excess Zn/Hg was filtered off; EtOH was removed in vacuum. Yield 32g (46.7%) Tomitza et al, Chem Pharm Bull 16, 217-226 (1968) -------------------------------------------------------------------------------- Dr Gonzo (04-14-99) - NaBH4 + Al/Hg reduction of 2,5-DMP2NP to 2,5-DMA 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. -------------------------------------------------------------------------------- Piglet NH2OH.HCl is readily available from photography supply. And a better reduction using the Zn/Ni couple has been posted by labrat. Claims to reduce imines to amines (ketone in 80% methanol saturated with NH3 at about 60-70%, yields higher from oxime, the side-product being hydroxylamine (boo hoo!), the freebase of which is a solid. It's active as MDA. If you really want MDA, put it right back into the next batch being reduced! Search for Labrats post (it IS there, I just havn't got the time) and then here are some details. (I use the sulphate). NiSO4 + 6 NH3 --> Ni(NH3)6SO4 Zn + H2O --> ZnO + H2 ZnO + 4 NH3 --> Zn(NH3)4(OH)2 Pour off the NH3 solution, add your oxime in 80% v/v Methanol solution, add 3 moles of NaOH and slowly add the Zn in portions (if it overheats, cool under running water) until it's all added, heat for 90 minutes, cool, filter (wash filtrate into mother liquor). Neutralize, extract, remove solvent (yielding the hydroxylamine as solid) or simply make salt as you see fit (IE a mix of MDA/MDOH). 2 NaOH + Zn -->Na2[ZnO2] + 2H --------------------------------------------------------------------------------