Now, I will present the two of the most information-rich articles regarding novel synthetic methods for the preparation of substituted amphetamines I have ever seen, and they even appear consecutively in the same journal - namely Bull. Soc. Chim. Fr. 130, 450-458 (1993) and Bull. Soc. Chim. Fr. 130, 459-466 (1993). You might already have guessed what the catch is - both articles are written in french.
One of the great things about the Hive is that together, we can accomplish much more than on our own - for example, I do not have the time or energy to translate these articles myself, one of the reasons why, is that I don't speak french. This is scientific literature, and therefore it is relatively easy to guess your way through it, so please let us all translate a small part each.
The articles can be found at the URL's below, and I have scanned them in a high enough resolution for them to be OCR'able, if anybody would want to do it that way:
https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/fenfluramine1.pdf (https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/fenfluramine1.pdf)
https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/fenfluramine2.pdf (https://www.thevespiary.org/rhodium/Rhodium/pdf/archive/fenfluramine2.pdf)
Contents:
Article 1
* Bromobenzene + Mg + CuBr + propylene oxide -> Phenyl-2-Propanol (90%)
The oxirane may be chiral, making the product alcohol chiral too
* Phenyl-2-Propanol + MsCl/TfCl/TsCl + base -> Alcohol sulfonyl ester (80-90%)
* Sulfonyl ester + Alkylamine -> N-alkyl amphetamine (40-60%)
Reaction conditions: Polar aprotic solvent, or alcohol/autoclave
* Phenyl-2-Propanol + Thionyl Chloride -> Phenyl-2-Chloropropane (91%)
* Phenyl-2-Chloropropane + sodium azide -> Phenyl-2-Azidopropane (78%)
* Sulfonyl ester + sodium azide -> Phenyl-2-Azidopropane (78%)
* Phenyl-2-Azidopropane + Pd/H2 -> Amphetamine (67%)
* Phenyl-2-Azidopropane + Triethyl phosphite + HBr -> Amphetamine
* Phenyl-2-Azidopropane + Triethyl phosphite + Dialkylsulfate + HBr -> N-alkyl-Amphetamine (83%)
Article 2
* Bromobenzene + Mg + Allyl chloride -> Allylbenzene (81%)
* Allylbenzene + Base -> Propenylbenzene (94%)
* Propenylbenzene + MCPBA -> Epoxide (78%)
* Epoxide + alkylamine -> Alkylamino alcohol (97%)
* Alkylamino Alcohol + Triethyl Phosphite -> Aziridine (75%)
* Aziridine + Pd/H2 -> N-alkyl Amphetamine (91%)
All of the above epoxide/amino alcohol/aziridine/amphetamine steps seems to be stereoselective!
The substitution of the mesitylate (R)-4b and the tosylate (R)-4a with ethylamine was realised with medium yields always between 40 and 50% in spite of the large number of conditions tested: solvents (DMSO, DMF, ethanol, ethylamine), different dilutions (in proportions from 1 to 5) and temparatures from 50 to 160°C (with different times of contact). With the triflate (R)-4c the yield of the substitution is 60% but under non comparable conditions (-20°C in acetonitrile) because of its higher reactivity. In all cases the non aminated, and thus easily separated, byproducts are mainly the alkenes 9, 10Z and 10E (10E >> 10Z > 9).
It is too bad that this reaction does not proceed more cleanly. But what about post Post 102978 (https://www.thevespiary.org/talk/index.php?topic=6392.msg10297800#msg10297800)
(Ritter: "Re: MDMA via Tosyl Chloride Intermediate?", Chemistry Discourse) (Read also the other posts from the thread). They do the reaction on a primary sulphonate, and it works just fine. OK, I guess that there will be more alkene formed here, because the alkene is in conjugation with the aromatic ring (and hence thermodynamically more stable). But still, it is an easy procedure.
It could be interesting to discuss this reaction with respect to
https://www.thevespiary.org/rhodium/Rhodium/chemistry/mdma.tosylate.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/mdma.tosylate.html)
Siegfried did the SN2 with MeNH2 in MeOH (with a little THF for solubility reasons), and after 5 days stirring at room temperature, the got 50 - 60 % of MDMA.
This is completely in harmony with the findings of that article. The mediocre yield is due to the elimination. I don't think that the aquous MeNH2 procedure of Ritter will give better results. I guess it is just a question of thermodynamics: elemination is somewhat favoured by the formation of the conjugated propenylbenzene :( .
For synthetic reasons, I think it would be better practice to oxidize the P2Pol to P2P, form an imine with MeNH2 & reduce it.
None (http://angelfire.lycos.com/scifi2/lego/journals/26.pdf)
(http://angelfire.lycos.com/scifi2/lego/journals/26.pdf)
DOI:10.1016/S0957-4166(03)00438-5 (http://dx.doi.org/10.1016/S0957%2D4166%2803%2900438%2D5)
The DOI is not working although it is listed in the paper and on the homepage.
Abstract: Abstract—Regioselective addition of aryl lithium to commercially available (S)-(+)-propylene oxide provides the corresponding (S)-aryl-2-propanol. The (R)-amphetamine is obtained by conversion of the alcohol to the tosylate followed by azide displacement and hydrogenation. Mitsunobu conversion of the alcohol to the (R)-bromide followed by azide displacement and hydrogenation affords the (S)-amphetamine.
[...]
Experimental
4-Bromo-2,5-dimethoxytoluene 6b
To a solution of 2,5-dimethoxytoluene (100 g, 0.657 mol) and NaOAc (56.6 g, 0.690 mol) in HOAc (400 mL) in a 1000 mL three necked, round bottomed flask equipped with N2 inlet, magnetic stirrer, and addition funnel was added Br2 (110 g, 0.688 mol), dropwise. The solution changed from clear to yellow and eventually to dark orange. After stirring for 20 min the reaction was quenched with a solution of saturated NaHSO3 and the mixture was extracted with CHCl3 (3×500 mL). The combined organic extract was dried over Na2SO4 and concentrated to a yellow solid. Recrystallization from hot EtOAc/hexane gave 6b as a white crystalline solid; mp 90°C (lit.3 91°C)
(2',5'-Dimethoxy-4'-methylphenyl)-2-propanol 9b
To a solution of 4-bromo-2,5-dimethoxytoluene 6b (20 g, 0.087 mol) in dry THF (700 mL) in a 1000 mL round bottomed flask equipped with N2 inlet at ?72°C was added a solution of 2.0 M n-BuLi in pentane (43 mL, 0.086 mol). After stirring for 10 min, propylene oxide 8 (2.51 g, 0.043 mol) was added. Stirring was continued for 10 min and BF3·Et2O (9.22 g, 0.065 mol) was added. The reaction was allowed to stir for 15 min. It was then quenched with satd NH4Cl and extracted with Et2O (3×250 mL). The combined organic extract was dried over Na2SO4, filtered, and evaporated to dryness leaving a residual oil. Treatment with MeOH resulted in a white ppt. The ppt was separated by filtration and discarded, and the MeOH filtrate was evaporated to dryness leaving brown crystals. Purification by column chromatography (SiO2; hexane:EtOAc 5:1) afforded 9b (7.67 g, 84%) as white powdery crystals: mp 80–81°C (lit.9 80.5–81.5°C)
(2',5'-Dimethoxy-4'-methylphenyl)-2-propyl tosylate 10b
A mixture of 9b (1 g, 0.005 mol), p-toluenesulfonyl chloride (1 g, 0.005 mol), and pyridine (20 mL) was prepared while stirring a 1000 mL round-bottomed flask, in an ice bath. The mixture was transferred to the freezer and after 48 h crystals had formed. The reaction mixture was poured over ice, forming a white solid which was filtered, washed with hexanes and water, and dried under vacuum to give 10b (1.56 g, 90%): mp 99–100°C
(2',5'-Dimethoxy-4'-methylphenyl)-2-propyl azide 11b
After stirring overnight in a round bottomed flask, a mixture of 10b (1 g, 0.003 mol) and NaN3 (0.75 g, 0.012 mol) in DMF (20 mL) was taken up in water and extracted with Et2O. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to give 11b (640 mg, 95%) as a light brown oil.
2,5-Dimethoxy-4-methylamphetamine hydrochloride 5b
To a solution of 11b (640 mg, 2.7 mmol) in MeOH (20 mL) in a Parr flask was added 10% Pd/C catalyst (60 mg) and the mixture was rocked under 40 psi H2 for 12 h. The catalyst was removed by filtration through a Celite pad and the filtrate was evaporated to dryness. The residual solid was taken up in Et2O and HCl gas was allowed to bubble through. No solids formed. The Et2O was evaporated and the residual solid was taken up in a minimal amount of MeOH; Et2O was added dropwise. The crystals that formed overnight were filtered, washed with Et2O, and dried to yield 5b (400 mg, 60%): mp 188–190°C (lit.12 184–185°C)
(S)-(2',5'-Dimethoxy-4'-methylphenyl)-2-propanol (S)-9b
A solution of 6b (33 g, 0.143 mol) in freshly distilled THF (1000 mL) in a 2000 mL round bottomed flask was cooled to ?72°C. To the chilled, stirring solution was added a solution of 2.0 M n-BuLi (71 mL, 0.142 mol) dropwise. After 10 min, S-(?)-proplyene oxide (S)-8 (5 mL, 0.072 mol) was added, followed by BF3·Et2O (13.6 mL, 0.107 mol). After stirring for 15 min the reaction was quenched with saturated NH4Cl and extracted with Et2O (3×400 mL). The combined organic extract was dried over Na2SO4, filtered, and evaporated to dryness. The residue was taken up in MeOH, causing a white precipitate to form. The ppt was separated by filtration and discarded, and the MeOH was evaporated to dryness. The residual solid was recrystallized from hot EtOAc/hexanes several times. Evaporation of the combined mother liquors afforded a brown oil which, when eluted through a silica column (hexanes:EtOAc 4:1), afforded additional (S)-9b, which was combined with the previously recrystallized batches. A further recrystallization from hot EtOAc/hexanes yielded pure (S)-9b (13.00 g, 74%): mp 90-92°C,
5.7. (S)-(2',5'-Dimethoxy-4'-methylphenyl)-2-propyl tosylate (S)-10b
A mixture of (S)-9b (9.88 g, 0.048 mol), p-toluenesulfonyl chloride (10.8 g, 0.057 mol), and pyridine (200 mL) was prepared while stirring in a 1000 mL round bottomed flask, in an ice bath. The mixture was transferred to the freezer and after 48 h crystals had formed. These crystals were removed by filtration and washed with hexanes. The volatiles were evaporated from the combined filtrate and washings and the residual liquid was poured over ice. Since no solid was formed, the mixture was extracted with CHCl3. After drying over Na2SO4 and evaporation of the solvent, the residue was triturated with hexanes to afford a white solid which was filtered, washed with hexane and water, and dried under vacuum to give (S)-10b (13.2 g, 77%): mp 77–78°C
(R)-(2',5'-Dimethoxy-4'-methylphenyl)-2-propyl azide (R)-11b
After stirring overnight, a mixture of (S)-10b (12 g, 0.035 mol) and NaN3 (8.96 g, 0.138 mol) in DMF (200 mL), in a round-bottomed flask, was treated with H2O and extracted with Et2O. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to give (R)-11b (7.4 g, 91%) as a light brown oil.
(R)-(-)-2,5-Dimethoxy-4-methylamphetamine hydrochloride (R)-5b
To a solution of (R)-11b (7.3 g, 0.032 mol) in MeOH (200 mL), in a Parr flask, was added 10% Pd/C catalyst (600 mg) and the mixture was rocked under 40 psi H2 for 12 h. The catalyst was removed by filtration through a Celite pad and the filtrate was evaporated to dryness. The residual solid was then taken up in CHCl3 and extracted with 1 M HCl. The combined extract was basified with NaOH and extracted with CHCl3. After drying over Na2SO4, the solvent was evaporated and the residual solid was taken up in Et2O. Treatment with HCl gas followed by evaporation of the solvent resulted in a solid hydrochloride salt. The solid was taken up in a minimal amount of MeOH and Et2O was added dropwise. Crystals formed overnight, which were filtered, washed with Et2O, and dried under vacuum to yield (R)-5b (5.3 g, 70%): mp 198–200°C (lit.1 204–205°C)
S-(-)-2,5-Dimethoxy-4-methylamphetamine (S)-5b
To a solution of (S)-(2',5'-dimethoxy-4'-methylphenyl)-2-propanol (S)-9b (0.4 g, 0.002 mol) in dry THF (5 mL) was added triphenylphosphine (1 g, 0.004 mol) and CBr4 (1.26 g, 0.004 mol). After stirring overnight the solids were removed by filtration and the filtrate was evaporated to dryness. The residual oil was taken up in DMF, sodium azide (0.5 g, 0.008 mol) was added and stirring was continued overnight. The reaction was quenched with H2O and the mixture was extracted with CHCl3. The organic extract was dried and evaporated to dryness. The residue was dissolved in EtOH, treated with 10% Pd/C and shaken under 40 psi of H2 overnight. The catalyst was removed by filtration and the solvent was evaporated to near dryness. The residue was taken up in H2O and the pH was adjusted to 7. After washing with Et2O the pH was adjusted to 11 and the solution was extracted with CHCl3. The organic extract was dried over Na2SO4 and evaporated to dryness.
GC analysis showed the product to be (S)-5b of 97% optical purity.
(S)-2,5-Dimethoxyphenyl-2-propanol (S)-9c
To a solution of 1-bromo-2,5-dimethoxybenzene 6c (43.41 g, 0.200 mol) in dry THF (700 mL) in a 1000 mL three necked round bottom flask equipped with an N2 inlet and cooled to ?72°C was added a solution of 2.0 M n-BuLi in pentane (100 mL, 0.200 mol). After stirring for 10 min, (S)-propylene oxide (S)-8 (6.00 g, 0.103 mol) was added. Stirring was continued for 10 min and BF3·Et2O (21.29 g, 0.15 mol) was added. After stirring for 15 min the solution was quenched with saturated NH4Cl and extracted with Et2O (3×250 mL). The combined organic extract was dried over Na2SO4, filtered, and evaporated to dryness leaving an oil with a precipitated solid. The solid was filtered off, washed with MeOH and discarded. The oil was again evaporated, dried in vacuo and purified by column chromatography (SiO2; hexane:EtOAc 5:1). The fractions that contained the product were evaporated and recrystallized from EtOAc/hexane yielding (S)-9c (13.60 g, 67% yield) as clear colorless needle crystals. The chiral purity of the product was determined to be 100% by GC analysis of a diastereomeric mixture obtained by derivatizing with menthyl chloroformate (MCF). The compound had mp 56–57°C
(S)-2,5-Dimethoxyphenyl-2-propyl tosylate (S)-10c
To a solution of (S)-2,5-dimethoxyphenyl-2-propanol (S)-9c (10.19 g, 0.052 mol) in pyridine (70 mL) in a 1000 mL round bottomed flask was added p-toluenesulfonyl chloride (11.88 g, 0.062 mol) while stirring in an ice bath. The flask was then transferred to the freezer and left for three days. The flask was full of crystals, which were collected by filtration. The pyridine solution was washed with a cold biphase of aqueous 3% NaOH and CHCl3. The CHCl3 layer was drawn off and washed with cold aqueous 2% HCl. The CHCl3 layer was dried over MgSO4 and evaporated to an oil. The oil was then recrystallized from EtOAc and hexane yielding (S)-10c (10.38 g, 57% yield) as white crystals.
(R)-2,5-Dimethoxyphenyl-2-propyl azide (R)-11c
To a solution of (S)-2,5-dimethoxyphenyl-2-propyl tosylate (S)-10c (10.17 g, 0.029 mol) in DMF (80 mL) was added sodium azide (7.55 g, 0.116 mol) and the solution was stirred for 5 days. TLC indicated complete conversion. The mixture was taken up in water and extracted with Et2O (3×300 mL). The Et2O layers were combined and washed with H2O to remove excess DMF. The aqueous layer was backextracted with Et2O (200 mL). The combined organic extract was dried over Na2SO4, filtered, and evaporated to give (R)-11c (6.19 g, 96% yield) as a clear light yellow colored oil.
[/b](R)-2,5-Dimethoxyamphetamine (R)-5c
To a solution of (R)-2,5-dimethoxyphenyl-2-propylazide (R)-11c (6.19 g, 0.028 mol) in MeOH (200 mL) was added 10% Pd/C (0.65 g) and the slurry was hydrogenated at 40–45 psi overnight. The catalyst was removed by filtration through celite and the MeOH was evaporated to leave (R)-5c (5.42 g, 100% yield) as a clear light yellow colored oil.
GC analysis indicated 98% enantiomerically pure (R)-5c.
(R)-4-Iodo-2,5-dimethoxyamphetamine (R)-5d
To a solution of (R)-2,5-dimethoxyamphetamine (R)-5c (5.42 g, 0.028 mol) in EtOH (100 mL) was added I2 (14.10 g, 0.066 mol) and Ag2SO4 (17.32 g, 0.066 mol) and the reaction mixture was allowed to stir overnight. The precipitated yellow solid was collected by filtration and the EtOH evaporated. The solid residue was dissolved in CHCl3 and washed with aqueous 5% NaOH (250 mL). The aqueous layer was extracted with CHCl3 (2×300 mL) and the organic layers were combined and washed with H2O. The organic layer was then dried over Na2SO4, filtered, and evaporated down to a purplish brown solid (8.45 g). Column chromatography (SiO2, 8% EtOH/CHCl3) gave (R)-5d (4.31 g, 48% yield) as an off white solid.
(R)-4-Iodo-2,5-dimethoxyamphetamine (R)-5d hydrochloride
Treatment of a CHCl3 solution of (R)-5d (6.29 g, 0.020 mol) with HCl/MeOH, followed by evaporation of the solvent gave a solid that was recrystallized using MeOH/Et2O. The white crystals were collected and washed with Et2O giving R-5d hydrochloride
(5.50 g, 0.015 mol, 79% yield): TLC single spot using UV visualization Rf 0.72 (chloroform:methanol:ammonium hydroxide (80:18:2)), mp 222–223°C (lit.6 218–219°C)
Logically rather than moderating my posts, the whole thread should be removed,.
Your off topic posts are still visible if you click the post title, which you would know if you'd really read the FAQ :P This thread was started on the topic of a novel route to substituted amphetamines, not the travails of an OTC chemist, so it won't bee closed on your demand ;D As far as your problems in vacuum distillation, the Europeans who created the science of organic chemistry, and their Greek and Arabic predecessors didn't know about borosilicate glass, or of companies that would provide such equipment, they made it themselves 8) There's considerable information available here and on Rhodium's page on scientific glassblowing, perhaps you should spend more time studying what's available here, instead of trying to run the place ;)