Recently there have been a number of discussions on butanamines:
1 both the amphetamine analogue 2-amino-1-phenylbutane, or
aephetamine2, and also the methamphetamine analogue 2-methylamino-1-phenylbutane, or
methaephetamine.
2 Until now, no synthesis of the latter had been published at the Hive.
The four step procedure below begins with benzene, and proceeds via the 'butanamine methcathinone' analogue, the synthesis of which has been posted, although a modified version follows. The reduction of this gives the ephedrine analogue, finally undergoing a standard HI/P reduction to give the title product.
The method as stands has little use for ring substituted amines because of HI's ability to cleave aromatic ethers. Notable exceptions are active compounds which don't contain alkoxy groups; the use in the initial acylation step of either fluorobenzene/propionyl chloride to give 4-fluoromethamphetamine as the final product, or indane/propionyl chloride to give the untested [?] 'indanylmethamphetamine', or N-methyl IAP.
3 The combination of benzene/propionyl chloride will of course produce racemic methamphetamine, although propiophenone is extremely cheap, and purchasing this would be a nice way of cutting out a step.
ExperimentalButyrophenoneSynthesis exactly as the acylation described in
Post 465794 (missing)
(Kinetic: "2-methylamino-1-phenyl-1-butanone", Stimulants).
Yield: 89%.
Molecule:
Butyrophenone ("CCCC(=O)c2ccc1c1c2 ")
2-methylamino-1-phenyl-1-butanone4300mmol butyrophenone (44.5g, 43.5ml)
310mmol bromine (49.5g, 15.9ml)
~750mmol methylamine as a 30% aq. solution (85ml)
330mmol 37% HCl (27ml diluted to 300ml)
DCM
Toluene
Sodium bicarbonate solution
Water
50% aq. NaOH solution
Magnesium sulfate
The bromine was added a well stirred solution of the butyrophenone in 100ml DCM, dropwise over 15 minutes. Stirring was continued for a further 15 minutes, then the solution was washed with 100ml water and 3x100ml sodium bicarbonate solution.
The almost colourless organic layer was placed back in the flask, and aqueous methylamine was added over 10 minutes. Stirring was continued for 4 hours after addition.
a The solution was washed with 3x200ml water, then extracted into 3x100ml dilute HCl. The combined acidic extracts were washed with 2x100ml toluene, then cooled and basified to pH 11 with ~16ml NaOH solution. The liberated freebase was extracted into 3x50ml DCM, and the combined extracts were washed with 2x100ml water then dried over MgSO
4. The solvent was cautiously removed,
b to leave the product as a clear yellow oil.
Yield: 38.7g (219mmol, 73%)
aThe exothermic reaction rose to reflux, and had cooled to room temperature by this time.
bA low temperature ensures minimal thermal decomposition of the aminoketone freebase.
Molecule:
2-methylamino-1-phenyl-1-butanone ("CNC(CC)C(=O)c2ccc1c1c2 ")
2-methylamino-1-phenyl-1-butanol5100mmol 2-methylamino-1-phenyl-1-butanone (17.7g)
50mmol NaBH
4 (1.9g) in 10ml water containing 25mg NaOH
6Methanol
Acetic acid
DCM
50% NaOH solution
Water
Brine
Magnesium sulfate
To a well stirred solution of the aminoketone in 50ml methanol, cooled to 0
oC via an ice bath, was added dropwise a solution of NaBH
4 in water, whilst not allowing the temperature to rise above 15
oC. The clear solution quickly became turbid, and the initial yellow colour faded to almost white. The reaction was stirred with ice bath cooling for half an hour after addition, then at room temperature for a further hour. Acetic acid was then added until fizzing ceased, then all was poured into 200ml water. NaOH was added to bring the pH to 12, causing a voluminous creamy white precipitate
a to form, which was extracted into 100ml then 2x50ml DCM. The combined extracts were washed with 100ml water, 100ml brine, then dried over MgSO
4. Removal of the solvent gave a pale solid which was distilled at 134-137
oC to give the aminoalcohol as sparkling, waxy white crystals.
bYield: 14.8g (83mmol, 83%)
aThe amount of precipitate was unprecedented, and far more than the amounts formed with similar borohydride reduction attempts (either DCM/water/PTC (67%), or aminoketone HCl/water (88%, but messy)). It is know that in methanol, cathinones racemise, presumably via an enolate intermediate. Maybe in this case the borohydride is instead reducing the double bond of the enolate, hence affecting the stereochemistry of the product: ephedrine is soluble in water whereas pseudoephedrine is much less so.
bNone of which made it to the receiving flask, and were very difficult to scrape from the condenser.
Molecule:
2-methylamino-1-phenyl-1-butanol ("CNC(CC)C(O)c2ccc1c1c2 ")
2-methylamino-1-phenyl-1-butane; Methaephetamine780mmol 2-methylamino-1-phenyl-1-butanol (14.3g)
130mmol red phosphorous (4.0g)
260mmol HI as a 57% aq. solution (34ml)
85mmol 37% HCl (7ml)
50% NaOH solution
Methanol
Ether
Water
Magnesium sulfate
A well stirred solution of the aminoalcohol in 40ml methanol was treated with HCl.
a After stirring for 10 minutes, all volatiles were removed under vacuum. The HI and phosphorous were added in one batch, and the reaction heated to reflux (approx. 115
oC) for 36 hours. The reaction mixture was then cooled, diluted with 200ml water and filtered. The solution was washed with 60ml toluene,
b then basified to pH 12 with NaOH. The pale, clear freebase was extracted with 2x50ml ether, and the combined extracts were washed with 2x100ml water, dried over MgSO
4 and the solvent removed to give the title product as a clear, almost colourless oil.
cYield: 9.9g (76%)
aUse of the freebase instead of a salt will lead to a lower yield even if an extra equivalent of HI is added, as it effectively reduces the concentration of free HI to ~43%, assuming the density remains the same.
bThis was due to a toluene shortage, 2x100ml toluene is recommended.
cThis will be dissolved in IPA, neutralised with HCl, and precipitated with ether. Undesirable aziridines/iodo compopunds etc. will be removed by recrystallisation: methanol/ether, or boiling acetonitrile
8 will be attempted first.
Molecule:
2-methylamino-1-phenylbutane ("CNC(CC)Cc2ccc1c1c2 ")
AcknowledgementsMany thanks to Nemo_Tenetur, wherever he is, for providing excellent information which got me into clandestine chemistry in the first place, and whose synthesis of a Pyrovalerone analogue the first two steps were based upon. It also goes (almost) without saying to thank Rhodium and all the other Mods, since I wouldn't have been able to post any of this without the wonderful Hive.
References1 Post 461403
(Chimimanie: "Ariadne and the Butanamines", Serious Chemistry);
Post 470499 (missing)
(Vitus_Verdegast: "phenyl-2-nitrobutene (P2NB) data needed...", Chemistry Discourse)2 Post 471099
(moo: "Maybe it should be called aephetamine, as in a", Novel Discourse)3 https://www.thevespiary.org/rhodium/Rhodium/chemistry/iap.html
4 Post 289410
(foxy2: "Methcathinone and ephedrine from propiophenone", Stimulants)5 Post 433684
(Barium: "You can reduce ketones or aldehydes with ...", Methods Discourse)6 Post 426052
(Barium: "Novel high-yielding C=C reduction of nitrostyrenes", Novel Discourse)7 https://www.thevespiary.org/rhodium/Rhodium/chemistry/meth.hi-p.html
8 Post 454897
(Rhodium: "Recrystallization of MDMA.HCl for Purity", Methods Discourse)