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.
Experimental
Butyrophenone
Synthesis exactly as the acylation described in Post 465794 (missing)
(Kinetic: "2-methylamino-1-phenyl-1-butanone", Stimulants). Yield: 89%.
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
Butyrophenone ("CCCC(=O)c2ccc1c1c2 ")
2-methylamino-1-phenyl-1-butanone4
300mmol 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 MgSO4. 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: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
2-methylamino-1-phenyl-1-butanone ("CNC(CC)C(=O)c2ccc1c1c2 ")
2-methylamino-1-phenyl-1-butanol5
100mmol 2-methylamino-1-phenyl-1-butanone (17.7g)
50mmol NaBH4 (1.9g) in 10ml water containing 25mg NaOH6
Methanol
Acetic acid
DCM
50% NaOH solution
Water
Brine
Magnesium sulfate
To a well stirred solution of the aminoketone in 50ml methanol, cooled to 0oC via an ice bath, was added dropwise a solution of NaBH4 in water, whilst not allowing the temperature to rise above 15oC. 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 precipitatea to form, which was extracted into 100ml then 2x50ml DCM. The combined extracts were washed with 100ml water, 100ml brine, then dried over MgSO4. Removal of the solvent gave a pale solid which was distilled at 134-137oC to give the aminoalcohol as sparkling, waxy white crystals.b
Yield: 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: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
2-methylamino-1-phenyl-1-butanol ("CNC(CC)C(O)c2ccc1c1c2 ")
2-methylamino-1-phenyl-1-butane; Methaephetamine7
80mmol 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. 115oC) 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 MgSO4 and the solvent removed to give the title product as a clear, almost colourless oil.c
Yield: 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 acetonitrile8 will be attempted first.
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
2-methylamino-1-phenylbutane ("CNC(CC)Cc2ccc1c1c2 ")
Acknowledgements
Many 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.
References
1 Post 461403 (https://www.thevespiary.org/talk/index.php?topic=12277.msg46140300#msg46140300)
(Chimimanie: "Ariadne and the Butanamines", Serious Chemistry); Post 470499 (missing)
(Vitus_Verdegast: "phenyl-2-nitrobutene (P2NB) data needed...", Chemistry Discourse)
2 Post 471099 (https://www.thevespiary.org/talk/index.php?topic=11588.msg47109900#msg47109900)
(moo: "Maybe it should be called aephetamine, as in a", Novel Discourse)
3 https://www.thevespiary.org/rhodium/Rhodium/chemistry/iap.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/iap.html)
4 Post 289410 (https://www.thevespiary.org/talk/index.php?topic=7994.msg28941000#msg28941000)
(foxy2: "Methcathinone and ephedrine from propiophenone", Stimulants)
5 Post 433684 (https://www.thevespiary.org/talk/index.php?topic=9857.msg43368400#msg43368400)
(Barium: "You can reduce ketones or aldehydes with ...", Methods Discourse)
6 Post 426052 (https://www.thevespiary.org/talk/index.php?topic=11742.msg42605200#msg42605200)
(Barium: "Novel high-yielding C=C reduction of nitrostyrenes", Novel Discourse)
7 https://www.thevespiary.org/rhodium/Rhodium/chemistry/meth.hi-p.html (https://www.thevespiary.org/rhodium/Rhodium/chemistry/meth.hi-p.html)
8 Post 454897 (https://www.thevespiary.org/talk/index.php?topic=9224.msg45489700#msg45489700)
(Rhodium: "Recrystallization of MDMA.HCl for Purity", Methods Discourse)
Sorry Rhodium. I wasn't sure anybody would care for new challenges so soon so I spared some typing. Here I copied the text and added the references:
“The alpha-methyl group of amphetamine itself can be replaced by allyl, ethyl, or ethynyl groups of electron-donating character, without deleterious effects on centrally-mediated actions [1,2], but replacement by electron-withdrawing groups, such as cyano [3] or trifluoromethyl [4], abolishes amphetamine-like properties.”
[1] Burger, Zimmermann, Ariens (1966), J. Med. Chem. , 9, 469.
[2] Shamano, Hitchens, Goldstein, Beiler (1968), Arch. int. Pharmacodyn. Ther. , 172, 251.
[3] Pinder, Burger, Ariens (1970), Arzeim.-Forsch. , 20, 245.
[4] Pinder, Burger (1967), J. Pharm. Sci., 56, 970.
I very much recommend this book (Hallucinogenic agents). There are even more info on the side chain modifications for the psychedelics. I was so inspired by a modification that I’m planning a new project: phenoxyethylamines and phenoxyisopropylamines. Some of the phenoxyethylamines were found active hallucinogens in animal test. The one shown below was twice as potent as mescaline in some EEG tests on cats, but I’m still searching for the original studies (very old and inaccessible publications). Maybe the phenoxyisopropylamines would be even more potent. They must be so extremely easy to prepare starting from various phenols. There are some hints from Medline for the possibility that phenylthioisopropylamines may also posses some activity, even thought the homoamphetamines (Ar-(CH2)2-CH(NH2)-Me) are essentially inactive (the DOM homologue was found to be 100times weaker and others even much less active).
Molecule: (https://www.the-hive.ws/forum/faq.pl?Cat=#applet)
a hallucinogenic phenoxyethylamine ("c1(cc(c(cc1Cl)Cl)OC)OCCN")
If anybody can find and post them, these are the refs for the phenoxyethylamines:
Julia, M. and de Rosnay; European Journal of Medicinal Chemistry, 4 (1969), 334.
Julia, M. and de Rosnay; European Journal of Medicinal Chemistry, 5 (1970), 337.
(European J. of Med. Chem. stil had the title Chim. Ther. in those times)
Rougeul, A.; Laval. med., 40 (1969), 37.
Rougeul, A. and Verdaux, J.; Rev. Can. Biol., 31 (1972), 49.
Nicodem, you always provide very interesting and novel info...
They must be so extremely easy to prepare starting from various phenols.
Indeed, they are extreamly easy to prepare. A word of caution. There is some structural similarity to chlorophenoxy herbicides, for instance 2,4-D - (2,4-dichlorophenoxy) acetic acid - a very (neuro)toxic pesticide.
http://www.epa.gov/ttn/atw/hlthef/di-oxyac.html (http://www.epa.gov/ttn/atw/hlthef/di-oxyac.html)
2,4-D is a herbicide used on a number of crops. At high concentrations it affects the central nervous system (CNS) in humans, with symptoms including stiffness of arms and legs, incoordination, lethargy, anorexia, stupor, and coma. 2,4-D is also an irritant to the gastrointestinal tract and skin in humans. Chronic (long-term) oral exposure to 2,4-D results in effects on the blood, liver, and kidneys in animals. Several human studies have suggested an association between exposure to 2,4-D (and other herbicides) and an increased incidence of tumor formation. However, it is not clear whether this represents a true association, and, if so, whether it is specifically related to 2,4-D. Some studies have reported increased incidences of tumors in orally exposed animals. EPA has not classified 2,4-D as to its human carcinogenicity.
But, who knows, amines might be harmless...
Selective monoamine oxidase inhibitors. Compounds derived from phenethylamine and 1-phenoxy-2-aminopropane.
Y. Kumar, L. Florvall, et. al.
Acta. Pharm. Suec. 20, 349 (1983) (https://www.thevespiary.org/rhodium/Rhodium/pdf/maoi-amphetamines.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/maoi-amphetamines.pdf)
Abstract
4-Alkoxyphenylalkylamines (1-10). 3- and 4-trifluoromethylphenethylamines (11-14) and 1-phenoxy-2-aminopropanes (15-22) were synthesized and tested for monoamine oxidase (MAO) inhibitory effects in vitro and after oral administration in vivo with particular attention to any selective effect on the A form of MAO. The compounds were, to varying degree, more potent in inhibiting the deamination of 5-hydroxytryptamine (5-HT) than phenethylamine. i.e. they are preferential MAO-A inhibitors. The most potent compounds in vitro were 3-(4-ethoxy-2-methylphenyl)-1-methylpropylamine (10) and 4-ethoxy-2-methylphenethylamine (2) in the 4-alkoxyphenylalkylamine series, 2-fluoro-4-trifluoromethylphenethylamine (13) in the trifluoromethylphenethylamine series and 1-(2-bromo-4-methylphenoxy)-2-aminopropane (21) in the phenoxy-2-aminopropane series. After oral administration to rats all the compounds were poor inhibitors of 5-HT deamination in brain slices. However, after intraperitoneal injection to mice, compounds 3, 10 and 4-methoxyamphetamine were quite potent in potentiating the 5-hydroxytryptophan syndrome in mice and in protecting MAO-A in the mouse forebrain against being irreversibly inhibited by phenelzine.
Or
'Moderately Optimistic About Cathinones'
Firstly, thanks Nicodem for the interesting refs you have so far given on the phenoxyethylamines (POEAs?), and for the modifications to the alpha- side chain. You saved me some time and money as I had considered making alpha,alpha,alpha-trifluoromethamphetamine via reductive amination of the corresponding ketone, which I had hoped to make from the Grignard reaction between benzylmagnesiumbromide and trifluoroacetic anhydride.
Now to cathinones:
Because of their legal status and ease of preparation, I've tried a few cathinone analogues over the past 1.5 years. Although in general they have been somewhat of a disappointment, I still think some of them are worth trying. I have tried the following, in chronological order:
1-(4-methylphenyl)-2-(pyrrolidin-1-yl)-hexan-1-one (MPPH)
2-methylamino-1-phenyl-1-butanone
4-methylmethcathinone
4-fluoromethcathinone
4-methoxymethcathinone
Methylone
Alpha-pyrrolidinylpropiophenone
MPPH is highly active and rather potent (20-50mg recommended dose), but in me, the side effects of paranoia were too great. However this was the first drug I ever made, and knowing of the negative effects impurities can have on experiences, it would be unfair to blame the 'crash' and the paranoia on the drug itself, as they may have been in part due to my inexperience with the synthesis.
After multiple failures with the acylation of benzodioxole, I decided to try acylating toluene, which led to my discovery of 4-methyl methcathinone's effect. The bioassay can be found in Post 424046 (https://www.thevespiary.org/talk/index.php?topic=11604.msg42404600#msg42404600)
(Kinetic: "Next morning...", Novel Discourse).
I wasn't particularly surprised to find 4-methoxymethcathinone inactive, but was rather more upset to discover 4-fluoromethcathinone was as good as inactive too. Until Bandil's recent thread which confirmed 4-fluoro-4-MAR didn't live up to his expectations (nor mine, as I made some by a different route and tested it just after him), I had worried that I may have actually tried 1-(4-fluorophenyl)-2-methylaminoethanone, as I keep my acetyl and propionyl chloride next to one another in my shed. I can never be entirely sure what I made, but I'm certain enough to not want to waste my time performing the synthesis again.
After finally managing to acylate benzodioxole with a mixture of propionic acid/trifluoroacetic anhydride, I was disappointed by methylone itself, but I suspect this was due to my overly high expectations of it. I had hoped it would substitute for MDMA but in me it doesn't. Because of this I only made it the once, though I will try it again this summer in a different set and setting; last summer when I tried it I wasn't feeling too good about myself. Unlike on ecstasy, even with high doses of methylone taken in a nightclub, I couldn't completely lose the self consciousness which is so overwhelming in my everyday life. I suppose that's why I like ecstasy so much.
I didn't enjoy alpha-pyrrolidinylpropiophenone at all, though others I have spoken to have recommended it. Some of it's negative effects in me can be found in Post 449770 (https://www.thevespiary.org/talk/index.php?topic=11196.msg44977000#msg44977000)
(Kinetic: "Yes", Newbee Forum).
I'm still interested in trying the N-unsubstituted methylone analogue, which I suppose could be made by treatment of MDP1P first by bromine and then by 1eq. sodium azide; the resulting azidoketone (which should be formed in almost quantitative yield, from experience) would be reduced to the aminoketone by either CTH or Zn/ammonium chloride. The use of azidoketones is also the basis for my proposed 'novel route to amphetamines'.