Author Topic: Ring-substituted beta-methoxyphenylethylamines  (Read 3782 times)

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GC_MS

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Ring-substituted beta-methoxyphenylethylamines
« on: March 03, 2003, 02:46:00 AM »
The following article has been requested by one of the more active Bees of this forum: D Lemaire, P Jacob III, AT Shulgin. Ring Substituted beta-methoxyphenethylamines: a New Class of Psychotomimetic Agents Active in Man. J Pharm Pharmacol 37 (1985) 575-577. It appeared to me that only the synthesis part was needed, so that will be the only part I'm presenting right now.

[...]

2-methoxy-2-(2,5-dimethoxy-4-methylphenyl)-ethylamine - A suspension of 2,5-dimethoxy-4-methyl-beta-nitrostyrene (Ho et al 1970) (39 g) in warm methanol (300 mL) was treated with a solution of sodium methoxide (9 g sodium in 150 mL MeOH). After a few minutes (when the solution was complete and nearly colourless) aetic acid (75 mL) was added followed by water (2000 mL) and the reaction mixture was extracted with methylene chloride (3 x 200 mL). The extracts were pooled, and the solvent removed under vacuum to yield an oil which was diluted with a small amount of MeOH and held for 4 h at 0°C. They yellow crystals that formed were removed by filtration, and recrystallized from MeOH to yield 11.1 g of 2-methoxy-2-(2,5-dimethoxy-4-methylphenyl)-1-nitroethane, mp 78-79°C. This intermediate (in anhydrous THF) was added to an ice-cold solution of aluminium hydride (prepared from 96 mL of 1 M LiAlH4 in THF and 2.4 mL 100% sulphuric acid) and brought to reflux for 2h. The excess hydride was destroyed with IPA, and 15% aqueous NaOH was added untill all solids were white and filterable. The filtrate was evaporated to a residual amber oil which was dissolved in methylene chloride and extracted with dilute sulphuric acid. These aqueous extracts were pooled, made basic with 25% NaOH, and re-extracted with methylene dichloride. After removal of the solvent under vacuum, the residue was distilled (0.4 mmHg, 115-128°C) yielding 5.3 g of a colourless oil. This, in IPA (15 mL) was neutralized with concentrated HCl and treated with 70 mL diethyl ether to allow the spontaneous crystallization of the amine as the HCl salt, mp 171-172°C.

2-methoxy-2-(3,4,5-trimethoxyphenyl)-ethylamine - was prepared in a similar manner from 2-methoxy-2-(3,4,5-trimethoxyphenyl)-1-nitroethane (mp 143-144°C) and isolated as the HCl salt, mp 198.5-199.5°C.

2-methoxy-2-(3,4-methylenedioxyphenyl)-ethylamine - was prepared in a similar manner from 2-methoxy-2-(3,4-methylenedioxyphenyl)-1-nitroethane (mp 58-59°C) and isolated as the HCl salt, mp 152-153°C.

2-methoxy-2-(4-bromo-2,5-dimethoxyphenyl)-ethylamine - 4-Bromo-2,5-dimethoxy-beta-nitrostyrene was prepared from 4-bromo-2,5-dimethoxybenzaldehyde (Barfknecht & Nichols 1971) with ammonium acetate in nitromethane (yellow crystals, mp 157-158°C). This nitrostyrene was converted to 2-methoxy-2-(4-bromo-2,5-dimethoxyphenyl)-1-nitroethane (mp 119-120°C) and reduced to the amine as described above. HCl salt, mp 187-188°C.

References:
- CF Barfknecht, DE Nichols. J Med Chem 14 (1971) 370-372
- BT Ho, LW Tansey, RL Balster, R An, WM McIsaac, RT Harris. J Med Chem 13 (1970) 134-135


Rhodium

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Pihkal #14 - BOD
« Reply #1 on: March 03, 2003, 02:11:00 PM »
Ahaa! Nice, this seems to be what's called "BOD" in Pihkal #14... But - Isn't 4-Bromo-2,5-dimethoxy-beta-nitrostyrene supposed to be featured in that article?

GC_MS

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DOB etc
« Reply #2 on: March 04, 2003, 12:38:00 AM »

Isn't 4-Bromo-2,5-dimethoxy-beta-nitrostyrene supposed to be featured in that article?




2a = 2-methoxy-2-(3,4,5-trimethoxyphenyl)-ethylamine
2b = 2-methoxy-2-(3,4-methylenedioxyphenyl)-ethylamine
2c = 2-methoxy-2-(2,5-dimethoxy-4-methylphenyl)-ethylamine
2d = 2-methoxy-2-(4-bromo-2,5-dimethoxyphenyl)-ethylamine

[...] The remaining three compounds were explored less estensively [than 2c]. Trials with 2a were discontinued at 180 mg, a level at which there was distinct central awareness, but no definable character of action. With 2b, the physical-to-mental distribution of effects was less desirable than with 2c, but the duration of action was much shorter, about one half that of 2c. The DOB analogue 2d showed the highest potency, and had chronology and a sensory enhancement (in the early part of the experiment) identical to that described above for 2c. However, between the sixth and eight hour, there was the development of tinnitus and a neurological hyperreflexia that discouraged further exploration. [...]

But the only "real" mentioning is to be found in the synthesis description of 2d, which on itself is linked to a J Med Chem article: CF Barfknecht, DE Nichols. J Med Chem 14 (1971) 370-372. If you have access to the article and find it interesting, you are invited to post it ;) For some reason only God knows, my library's J Med Chem collection starts in 1978.

Edit:

Post 453897 (missing)

(weedar: "J. Med. Chem. 14(4), 370-372 (1971)", Methods Discourse)




imp

  • Guest
How about these possibilities?
« Reply #3 on: October 31, 2003, 11:15:00 AM »
SWIM thinks this is related to this thread... A facile procedure for the synthesis of novel beta-alkoxy and beta-alkylthio substituted phenethylamines and ALPHA-METHYLATED phenethylamines. Yes, we can do this on nitropropenes too, making the corresponding beta-alkoxy amphetamines! SWIM has never seen any report of their synthesis or pharmacological activity, only for plain beta-methoxylated phenethylamines. The procedure is so easy and so OTC, anybee can do it...

ref: Chem. Let., pp 243-244, 1985


Reduction of Nitroalkenes with Stannous Chloride in Non-Acidic and Non-Aqueous Medium. Synthesis of a-substituted oximes.

a,B-Unsaturated nitroalkenes are readily reduced by SnCl2.2H2O in alcoholic media to the a-alkoxy oxime derivatives in high yields. In the presence of ethanethiol, the corresponding a-alkylthio oximes are formed.

We have been investigating the potential utility of nitroalkenes for the rapid synthesis of amphetamine derivatives. It was recently reported that functionally substituted aromatic nitro compounds are readily reduced to the corresponding amines by tin(II) chloride in non-acidic media. The mildness of the reaction prompted us to explore the utility of this reagent for the reductions of conjugated nitroalkenes. We wish to report a new, high yield synthesis of a-substituted oximes using SnCl2.2H2O in alcoholic media.

The experimental procedure is straightforward. The alcohol or thiol (15 mL) was added to a mixture of nitroalkene (4 mmol) and stannous chloride (6 mmol) and then the reaction mixture was stirred at room temperature. A mildly exothermic reaction ensued which was accompanied by the disappearance of yellow coloration (nitroalkene). After 20 min, the reaction mixture was carefully poured onto ice. The pH of the solution was adjusted to ~8 via the addition of 5% aqueous sodium bicarbonate and then the product was extracted into ether. The organic phase was washed with brine, dried (MgSO4) and the solvent removed under reduced pressure to yield an essentially pure product. Chromatography on silica gel (5% ether/pet. ether) provided analytically pure samples.



They only try it on 1-phenyl-2-nitroethene and 1-phenyl-2-nitropropene but they generalize all nitroalkenes. Yields were normally in the 85-90% range, with one case at 71%.

So if we want to make the compound BOB in pihkal, we take 4-bromo-2,5-dimethoxynitroethene, dissolve it in some MeOH and add a dash of SnCl2. Isolate the beta-methoxylated aldoxime then reduce to the amine (4-bromo-2,5,beta-trimethoxyphenethylamine). For the beta-ethoxylated compound, we just perform the reaction in EtOH instead.
Now if we wanted to make a new and potentially VERY interesting compound, we use the procedure on 4-bromo-2,5-dimethoxynitropropene and make the ketoxime, then reduce to form the 4-bromo-2,5,beta-trimethoxyamphetamine!

And what about 1-(4-bromo-2,5-dimethoxyphenyl)-1-(m)ethylthio-2-ethylamine?

Anybody have good refs. for a mild zinc mediated reduction of oximes? Something that wouldn't hydrolyse the methoxyl group to form the phenylpropanolamine analog (ooooohhhh, how about oxidation to substituted cathinones? - are there any reports on 4-bromo-2,5-dimethoxycathinone?) And what about some substituted aminorex compounds? SWIM's receptors are salivating at the possibilities.

Using this to prepare 4-bromo-2,5-dimethoxyphenylpropanolamine might be better than

Post 460135

(Bandil: "Synthesis of 4-bromo-2,5-dimethoxy-PPA", Methods Discourse)
.

Edit: Just calculated that SWIM has spent upwards of $200 worth of drug-related photocopies at the library so far this year.  :(  SWIM has spent more on photocopies than on telephone calls for the entire year... maybe a change in lifestyle is required.  ::)  

Rhodium

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Zn reduction of oximes
« Reply #4 on: October 31, 2003, 12:18:00 PM »
Zn reduction of oximes:

Post 194987 (missing)

(Rhodium: "Reduction of Imines Using Zinc Powder", Chemistry Discourse)

imp

  • Guest
More related...
« Reply #5 on: October 31, 2003, 12:38:00 PM »
Firstly, thank you Rhodium. Secondly, SWIM has a large collection of papers using SnCl2 as a reducing agent. Mostly for nitroalkene --> oximes...

SnCl2 + nitroalkene in acetone ---> oxime (65-75% yields)
SnCl2 + nitroalkene in AcOEt ---> oxime (90% + yields)
Na2SnO2(aq) + nitroalkene ---> oxime (70-90% yields)

Varma & Kabalka are the authors for all of them. They have done so much work on amphetamine synthesis using very accessible reducing agents (SnCl2, CrCl2). If anyone is interested SWIM can post the papers.

Now back to the topic, SWIM also dug up some German refs detailing an almost identical beta-methoxy substitution...

ref. Ber., 93, pp 32 (1960)

Uber die Reduktion von Nitroolefinen mit Zinn(II)-Chlorid

a-Methoxy-a-phenyl-aceton-oxim : Einer Suspension von 80 g 2-Nitro-1-phenyl-propen-(1) in 100 ccm Methanol lieB man unter Ruhren und Kuhlung eine Losung von 116 g Zinn(II)-chlorid in 60 g Salzsaure und 60 ccm Methanol langsam im Laufe von 90 Min. zutropfen. AnschlieBend wurde noch 1/2 Stde. bei Raumtemperatur weitergeruhrt, dann mit 750 ccm Wasser verdunnt und das dabei ausfallende Ol mit Ather ausgeschuttelt. Die ather. Losung wurde dreimal mit ver. Salzsaure, dann mit Weinsaurelosung und Wasser gewaschen und das Losungsmittel i. Vak. entfernt. Der Ruckstand erstarrte beim Kuhlen und Anreiben mit dem Glasstab zu einem Kristallbrei. Dieser wurde abgesaugt und auf Ton getrocknet. Das Rohprodukt (66 g) wurde in einer Losung von 25 g Kaliumhydroxyd in 100 ccm Wasser gelost, nach dem Verdunnen mit 500 ccm Wasser mit Kohle behandelt, filtriert und aus dem Filtrat durch langsames Eintropfen von 20-proz. Essigsaure unter Kuhlung das Oxim IIa in kristalliner Form ausgefallt. Die Kristalle wurden abgesaugt, mit Wasser gewaschen und auf Ton getrocknet. Ausb. 58 g (66% d. Th.). Schmp. 59-61 (aus Petrolather).

imp

  • Guest
Sulphur analogues of Aminorex & Cathinone
« Reply #6 on: November 02, 2003, 06:05:00 PM »
Can somebody translate that above? Flippie, are you around? - you did an excellent job last time.

Has anyone ever considered novel sulphur analogues of aminorex and cathinone? As a basic example say we wanted to make 1-phenyl-1-ethylthio-2-aminopropane (beta-ethylthioamphetamine). So we use the SnCl2 procedure to make the oxime and then apply a bit more of a rigourous reduction procedure like the one used in pihkal BOHD. This will, should, cause hydrolysis of the ethylthio group on the beta-carbon to form the free thio phenylpropanolamine analogue, 1-phenyl-1-thio-2-aminopropane. Now we can cyclize to form the aminorex compound, 2-amino-4-methyl-5-phenylthiazoline.

Let’s not forget

Patent GB793965

, which is also a good route to these analogues. Extend this idea to ring-substituted amphetamines, and some yummy things are possible... 2-amino-4-methyl-5-(4-thiocyanato-2,5-dimethoxyphenyl)thiazoline.

Are there any -SH to =S oxidation procedures to form the thione analogue of cathinone? How about starting from cathinone or methcathinone - can't we replace the =O directly? Dissolve cathinone in HCl saturated ethanol then bubble in H2S...

R2C=O + H2S --HCl--> R2C=S + H2O

Is anybody actually interested in these ideas? SWIM will go to the library just for curiosity sake, but if everyone is just interested in methamphetamine and MDMA then SWIM doesn't want to waste time. If people are actually interested then SWIM will search much harder for relevant articles.

Mmmmmmm, just imagine the possibilities... indole to 3-(2-nitropropenyl)indole via DMANP (see rhodium's), and then follow the reaction scheme to form 2-amino-1-(3-indolyl)propanol. From here we make the aminorex and cathinone analogues 2-amino-4-methyl-5-indolyloxazoline and 3-(2-aminopropionyl)indole. How about the sulphur analogues 2-amino-4-methyl-5-indolylthiazoline and 2-amino-1-(3-indolyl)propan-1-thione?

(Sorry if there are any nomenclature issues, SWIM tried to be consistent... maybe that should have been 2-amino-1-(3-indolyl)propanone  ;) .)

Of course the ultimate goal of all this is to create new states of drug-induced psychedelic euphoria. High can never really be high enough!

imp

  • Guest
Phenylnitroalkenes to Oximes using SnCl2
« Reply #7 on: November 03, 2003, 03:46:00 PM »
As requested, here are more refs for this type of reaction... (SWIM doesn't want to type them, but can scan them this week IF REQUESTED!)

-Synth. Comm., 18(7), 693-697 (1988)

Post 494625 (missing)

(Rhodium: "Nitroalkene reduction with Tin(II) - full articles", Novel Discourse)

[Ethyl acetate solvent is excellent for both aldoxime and ketoxime formation.]

-Chem. Ind., pp. 735 (1985)
[Acetone solvent. Unsuitable for aldoxime formation, but excellent for ketoxime]

-Tet. Lett., vol. 26, No. 49, pp. 6013-6014 (1985)

Post 494625 (missing)

(Rhodium: "Nitroalkene reduction with Tin(II) - full articles", Novel Discourse)

[SnCl2 + NaOH (aq) --> Na2SnO2 (aq). Again, gives excellent yields with ketoximes, but is unsuitable for aldoximes]

Other
-----
-Tet. Lett., vol. 25, No. 8, pp. 839-842 (1984)
[This uses SnCl2 to selectively reduce aromatic nitro groups in an EtOH slurry with very high yields (always >90%)

-Synth. Comm., pp. 1325 (1985)
[Uses CrCl2 for nitroalkene --> oxime]

Come people, what do you think about the sulphur analog idea SWIM posted above??