(Chief Bee)
12-06-01 13:07
No 245040
      O Leminger's Phenethylamines - posted by Karel
(Rated as: excellent)

Hello, here is translated article from Chemicky Prumysl 22, 553 (1972). I hope Sunlight will be also interested.

A Contribution to the chemistry of alcoxylated b-phenethylamines - part 2, by Otakar Leminger

Some novel alcoxylated b-phenethylamines were prepared by reduction of corresponding w-nitrostyrenes with zinc and hydrochloric acid, at pH<3. Isolation as sulphates and use of simple synthetic method gave yields 70-80 % of theory. This reduction didn't affect the double bond of allyl group, so allyloxy compounds were prepared. All described sulphates were physiologically active; most active seemed to be non-described before 3,5-dimethoxy-4-allyloxy-b-phenethylamine.

A reduction of w-nitrostyrenes [1] was chosen for preparation of b-phenethylamines. Rosemund [2] reduced this compounds in two stages: in first stage with zinc ad acetic acid (pH>3) to form oxime RCH2CH=NOH, in second stage oxime was reduced by sodium amalgam to amine. He isolated only 20 to 25 % of theory, because lot of styrenic polymeres was formed. Spaeth [3] worked analogous to Rosemund and also with low yield. Hey [4] tried electroreduction of some w-nitrostyrene with yield of 47 % of theory. A progress in reduction of w-nitrostyrenes to b-phenethylamines was achieved by use of lithium aluminium hydride, which provided yields 70 % of theory [5,6,7]. Use of complex hydride has some disadvantages, so we reduced w-nitrostyrenes with zinc in (in contrast to Spaeth) mineral acid environment, at pH<3, and formed b-phenethylamine we isolate as sulphate from ethanol, because sulphates of b-phenethylamines are only slightly soluble in cold ethanol. We achieved good yields and work procedure was simple.

We reduced alcoxylated w-nitrostyrenes to corresponding b-phenethylamines with zinc and hydrochloric acid ,the temperature slowly went from 3 deg.C to 20 deg.C. Reaction is described by equation:

w-nitrostyrene + 4 Zn + 9 HCl ---> b-phenethylamine.HCl + 4 ZnCl2 + 2 H2O

Products were isolated as free bases by extraction to benzene. This bases quickly reacted with CO2 in air and were difficult to obtain in analytically pure state, so sulphates were prepared. Sulphates crystallized good and weren't so soluble as hydrochlorides. Prepared b-phenethylamines were identified as chloroplatinates. As an example of this good-yielding readuction the preparation of 3,5-dimethoxy-4- allyloxy-b-phenethylamine is described.

3,5-dimethoxy-4-allyloxy-b-phenethylamine (I)

To ice-cooled and stirred mixture of 42 ml 35 % HCl and 42 ml ethanol were alternately in small portions introduced 5.31 g 3,5-dimethoxy-4-allyloxy- w-nitrostyrene (20 mmol) and 16.5 g zinc powder. Temperature was held at 5 deg.C during this addition, which took 75 min. Mixture was then 1 h stirred at temperature slowly raising from 5 to 10 deg.C and 2 h at 10-12 deg.C. Then 12.5 ml 35% HCl was dropped to mixture during 1 h at 10-15 deg.C. Next 1 h additional 3 g zinc powder were added and stirring was continued 1.5 h at 15-20 deg.C. Remaining zinc was filtered 12 h later and washed with 23 ml water. Clear filtrate was extracted twice with 23 ml benzene to remove non-basic contaminants. Separated water phase was then treated slowly and with cooling with solution 75 g NaOH in 125 ml water; first precipitated Zn(OH)2 finally almost dissolved. Amine was extracted four times 25 ml benzene, united benzene extracts were extracted twice 25 ml water, settled and filtered. Clear slightly yellow filtrate was distilled to remove benzene and then distilled at 10 torr. Amine remained at flask as 4.05 g dense yellow oil (85 %), which solidified on cooling to almost colourless crystals with mp 47 deg.C. Free amine was crystallized from hot n-hexane (1:10) to form snow-white prisms, mp 50-51 deg.C (dried over KOH at 5 torr). Anal. calcd. for C13H19NO3: C, 65.80; H, 8.08; N 5.91. Found: C, 65.95; H, 8.01; N, 5.75.

3,5-dimethoxy-4-allyloxy-b-phenethylamine sulphate (II)

3.56 g 3,5-dimethoxy-4-allyloxy-b-phenethylamine (15 mmol) were dissoved in 16 ml 96 % ethanol and 1.48 g 50 % H2SO4 (7.5 mmol) were added with stirring and rinsed with 6 ml ethanol. Suspension of crystals was warmed at water bath. After cooling crystals were formed. Product was filtered with suction, washed 15 ml 96 % ethanol and dried at 60 deg. C. Colourless, glistening plates weighed 4.20 g (92 % of theory). Compound II is soluble in hot, slighthly soluble in cold ethanol. Sulphate II is also soluble in water; in ether almost insoluble. Crystallization from hot 96 % ethanol (1:10) provided big glistening thin plates, which after drying over H2SO4 at 5 torr had mp 200-204 deg.C and formula (C13H19NO3)2.H2SO4.2H2O. Anal. calcd. for (C13H19NO3)2.H2SO4 .2H2O: H2O, 5.92; C, 51.30; H, 7.29; N, 4.60; S, 5.27. Found: H2O, 5.79; C, 51.24; H, 7.65; N, 4.87; S, 5.21.

3,5-dimethoxy-4-n-propoxy-b-phenethylamine sulphate (III)
3-methoxy-4-ethoxy-b-phenethylamine sulphate (IV)
3-methoxy-4-allyloxy-b-phenethylamine sulphate (V)
3,5-dimethoxy-4-ethoxy-b-phenethylamine sulphate (VI)

Preparation analogous as (I), free bases were oils, which didn't solidify at room temperature. Sulphates:

III (C13H21NO3)2.H2SO4.2H2O mp 186-188 deg.C
IV (C11H17NO2)2.H2SO4 mp 265-270 deg.C
V (C12H17NO2)2.H2SO4 mp 240-245 deg.C
VI (C12H19NO3)2.H2SO4.2H2O mp 250-255 deg.C

It is recommended to keep given stoichiometry of H2SO4 during preparation of sulphates; excess of H2SO4 gives easily soluble and hardly isolable hydrosulphates.

Physiological activity:
Physiological effects of compounds I-VI were examinated only approximately on my body. Sulphates IV and V in doses 0.1-0.3 g were mild mood-elevators and was also cough calming agents. Compounds I, II, III and VI were much more active. Qualitatively there weren't big difference among them and quantitatively their effect decreased: I > II > III > VI. As an example effect of sulphate II is described. One hour after 20 mg dose per os slight vertigo, light drunkeness and pleasant excitation with locomotion need was observed. Eye perceptions were pricked up, colours seemed to be more warm and objets more plastic. Surroundings was much more interesting than usually. Colourful hallucinations were observed in the dark. Moreover, calming effect to breathing system and some kind of constriction of digestive system was observed. Sleep at night was restless with bumptious fantasies. Even 12 h after medication described effects were present. More serious studies of physiological activity are in contemplation.

Results and discussion:
This experimental work provided that reduction of w-nitrostyrenes with zinc and hydrochloric acid gives yields and quality of b-phenethylamines comparable to use of lithium aluminium hydride. Low yields cited in references had probably this causes: authors reducted with zinc in improper conditions (acetic acid, pH>3) and cooling of the reaction mixture was insufficient, so styrenic derivatives began to polymerize at elevated temperature. They also interrupted the reduction process too soon (we observed minimum 6 h is necessary with good stirring) and didn't always use stoichiometric amount of zinc.


Suitable procedure for producing novel alcoxylated b-phenethylamines was introduced and patented [8]. This compounds could be applicated in psychotherapy.

1. Leminger, O.: Chem. prum. 22, 496 (1972).
2. Rosemund, K. W.: Ber. dtsch. chem. Ges. 42, 4780 (1909).
3. Spaeth, F.: Monatshefte fuer Chemie 40, 135 (1919).
4. Hey, P.: Quart. J. Pharm. Pharmacol. 20, 129 (1947); CA 41, 6879 (1947)
5. Ramirez, F. A., Burger, A.: J. Am. Chem. Soc. 72, 2781 (1950).
6. Benington, F., Morin, R. D., Clarke, L. C.: J. Am. Chem. Soc. 76, 5555 (1954); J. Org. Chem. 23, 1979 (1958).
7. v. Bruchhausen, F., Aguilar Santoz, Schaefer, C.: Arch. Pharm. 293, 785 (1960); CA 55, 3635g (1961).
8. Leminger, O.: PV 3870 z 25.5.1971.
9. Creighton, R. H., Mc Carthy, J. L., Hibbert, H.: J. Am. Chem. Soc. 63, 312 (1941).

My note:

Ref. 1 contains Reimer-Tiemann formylation of 2,6-dimethoxyphenol to form syringaldehyde in 33 % yield, alkylation of phenolic groups with alkyl iodides in 67-81 % yields and condensation of intermediate benzaldehydes with nitromethane in ethanolic KOH in 55-67 yields.


(Hive Bee)
12-06-01 14:06
No 245071
      Re: O Leminger's Phenethylamines - posted by Karel  Bookmark   

Wished all contributions would be so clear and comprehensive. Saved and filed in Uemuras library. Thanks Rhodium!
Carpe Diem
(Chief Bee)
12-06-01 14:08
No 245074
      Re: O Leminger's Phenethylamines - posted by Karel  Bookmark   

Don't thank me, thank Karel. I just moved his post from the "wanted references" thread to the main forum so it would get more attention.
(Chief Bee)
01-08-03 13:52
No 396477
      Otakar Leminger Online  Bookmark   

Now also available in HTML at ../rhodium/chemistry /leminger.html
(Official Hive Translator)
01-08-03 15:58
No 396513
      Awesome!  Bookmark   



Sincerely Yours,
(Hive Bee)
01-09-03 01:51
No 396629
      test  Bookmark   

Physiological effects of compounds I-VI were examinated only approximately on my body.

By Karel or by the author of the article? I assume it's the author of the article. Should be done more by nowadays scientists... :) Looks interesting indeed. /me grabs Zn powder

Ave Hive, synthetisandi te salutant!
(Hive Bee)
01-09-03 02:01
No 396631
      Oh yes!  Bookmark   

The 4-allyloxy-3,5-dimethoxy-PEA and 4-EtO-3-MeO-PEA are highly interesting for their mood-elevating properties IMHO. I wouldnīt spit on the other ones either. wink
Yes Leminger tasted them himself, as any psycopharmacologist with a sense of decency would.

Catalytic hydrogenation freak
(Hive Bee)
01-09-03 03:00
No 396642
      Well, mood-enhancers are catching my attention  Bookmark   

Well, mood-enhancers are catching my attention lately, and I'm most interested in testing some of them, to see how exactly they change my social behaviour. And I agree with you that every decent psychopharmacologist should taste his products, though I'm "worried" about how today's Scientist would react. Amazed? Surprised? Upset? Generally, there still is a severe lack of essential pharmacokinetical data, even for MDMA. And if there is a person out there who receives approval to do human testing with drugs, the tests are performed in 'dull rooms'. Imagine doing MDMA having nothing to focus on. How do they call that, rape?

Ave Hive, synthetisandi te salutant!
(Hive Bee)
01-09-03 04:06
No 396650
      Rape  Bookmark   

I canīt even begin to undestand the suffering of the poor souls whoīve had high doses LSD and other heavy psychedelics administred in a clinical setting. Bad trip is not the right word for it. Terror is more appropriate! Personally Iīd rather be butt-fucked without lube. shocked

And I agree with you that every decent psychopharmacologist should taste his products, though I'm "worried" about how today's Scientist would react. Amazed? Surprised? Upset?

The idea of forcing another living being to take a compound you wouldnīt dare taking yourself just because you want some cllinical data makes me absolutely furious. Those scientists are  no better than Dr. Mengele. Thatīs what I tell each and every one of them too. Mnay of them becomes very upset when I tell them that I taste my own stuff. So? I sleep well at night anyway.

Catalytic hydrogenation freak
(Pioneer Researcher)
01-09-03 10:18
No 396714
      I didn't see this post  Bookmark   

I didn't see this post until a few weeks ago using TFSE, I was very susprised for that. Now thanks Rhodium for your interest, I hope I can try the same procedure (with methanol) soon with 2,5 DMNE, it's a bit different from the variations I've tried.
I've oberved that the work up volume could be reduced by concentrating the solution and adding aq. NH3 till pH > 11.
(Hive Bee)
01-19-03 07:00
No 399690
      mescaline  Bookmark   

I tried it for mescaline (so now you also know what Post 397753 (GC_MS: "3,4,5-trimethoxynitrostyrene", Newbee Forum) was needed for wink.
Haven't calculated yields yet (sulfate crystals recrystallized from water are still drying), but I estimate i'm somewhere in the 50s% (from the nitrostyrene to the recrystallized sulfate salt). Not bad for a first try wink.

Ave Hive, synthetisandi te salutant!
(Hive Addict)
01-19-03 07:13
No 399693
      Hey, congrats. At what scale did you do it?  Bookmark   

Hey, congrats. At what scale did you do it? 20-50 mmol?

Catalytic hydrogenation freak and the sluttiest slut of all sluts
(Hive Bee)
01-19-03 07:17
No 399696
      *  Bookmark   

I used 4 g of the nitrostyrene. Another one programmed during this week, with at least 10 g of the nitrostyrene.

Ave Hive, synthetisandi te salutant!
(Hive Addict)
01-19-03 07:26
No 399699
      well  Bookmark   

That sounds great how 'bout a writeup for the benefit of all?
And Rhodium thank you for the reference and literature, an interesting parallel can be drawn between phenylethylamines that elavate the mood and the 3,4 substitutions due to the structural akin to dopamine which is one of my therories as to ecstacy is so euphoric.
(Hive Bee)
01-19-03 07:47
No 399703
      *  Bookmark   

I did exactly the same as in the translated article.

Ave Hive, synthetisandi te salutant!
(Hive Addict)
01-19-03 19:09
No 399800
      Yields  Bookmark   

yes, but what were your yields?
(Pioneer Researcher)
01-20-03 07:47
No 399901
      Good news  Bookmark   

These are good news, this way is tested and it works satisfactorily. I've got with this procedure, not exactly the same that Karel posted but based in russian patent, from 54 to 75 % yield of amine from 2,5 DMNS, the more Zn used and the more purity grade, the more yield. In regard to the 3,4,5 TMNS rdxn it was posted by a bee about a 50 % yield too time ago. I'll try the Karel's post procedure soon, I'll post the reuslts and may be we can start to publish the communications about the Zn in the Method Discourse Forum.
(Hive Bee)
01-21-03 11:56
No 400235
      yield  Bookmark   

Yield of mescaline as a sulfate is 51%. Two important notes: it was my first try, so yields will be higher if I try it next time (impossible that yield are good from the first time, at least in my case), and I performed 2 recrystallizations. This is probably not necessary, but I wanted to obtain a product as pure as possible. And I achieved my goal very well. GC/MS analysis of an acidic extraction of some crystals gave an absolutely blank chromatogram (aside the peak of 1 phtalate, which originates from the solvent). This is a very good omen! Throw in the Zn, gather your HCl and synthesize your Divine Candy! Next time (tomorrow?), I'll throw in some HgCl2 (thinking of 10%). Shouldn't hurt the yield... And I'm going to check an alkaline extraction with GC/NPD, maybe MS.

Ave Hive, synthetisandi te salutant!
(Hive Bee)
01-21-03 18:12
No 400323
      WOW! This Is Potentially One Of The Most  Bookmark   

significant developments to be posted here! Almost every compound listed in Pihkal required Lithium Aluminum Hydride reduction for final step. This would certainly make life much simpler. I would suggest the use of high purity Zinc (99.99%+)
for the best results. Amazing!!
(Hive Bee)
01-21-03 23:46
No 400378
      Indeed, but...  Bookmark   

Admitted it has a great potential, it is a shame that the method does not work for nitropropenes. A few posts can be found on that topic using TFSE. When I tried, I obtained a mixture of both the phenylacetone and the amphetamine. All by all, there seemed to be much more ketone then amine.

Ave Hive, synthetisandi te salutant!
(Hive Bee)
01-22-03 01:58
No 400398
      My experience  Bookmark   

I've tried the Zn/HCl on 2,5-DMNS with and without HgCl2, with no success.
Didn't want to wait for lab grade Zn to be delivered so I used ground up battery casing instead. I suspect that this was my source of failure.
I plan to try with lab Zn next time.

Mountain Boy
(Pioneer Researcher)
01-22-03 06:04
No 400420
      2CH  Bookmark   

I've done several times the 2,5 DMNS rdxn, and it works always and really it is very simple. Better control temp around 10-15 C (russian patent say 25/30) and waht is really important is to keep the acid concentration >5 % of total wight of rxn. I've got only low yields when I bought a sep funnel and I confused the scale of the funnel, I added less acid during a important part of rxn ( a bit soned may be ?).  You'll get always a decent to good yield using 3-6 part of Zn to nitro, with the correct amount of acid.
It seems that doesn't matter solvent volume or temperature if it is <25-30, I've done it at -5 C and different volumes and yields were more or less the same, directly propotioned with the Zn amount. My tip is to work between 5-15 degrees, specially in the first stage, till the nitro dissappears, the  rxn is very exhothermic.
(Pioneer Researcher)
02-10-03 15:44
No 406397
      Test done
(Rated as: excellent)

I tried the Zn HCl reduction posted by Rhodium - Karel with 2,5 DMNS. I made slight changes to make the rxn more comfortable to me and correcting an excess of Zn over acid that was present in the first half of the original procedure, that is not necessary due not all the Zn reacts (like usually happens). Anyway these changes can't produce significative changes in the final result.

10 grams fo 2,5 DMNS were powdered in a coffee grinder, then 1 gram of the powder was put in a flask with 110 ml of denatured 96 % ethanol and 120 ml of 36 % HCl, and the suspension was cooled to 0 C in an ice salt bath. To the coffee grinder was added 25 grams of Zn powder and it was mixed together with the nitrostyrene in order to make an homogeneous mixture for the additions. The mixtured powder was added to the alcohol/aq.HCl solution in small portions in one hour, caring to prevent excesive fizzing, and the temperature was < 5 C. Then in half hour more were added 13 grams of Zn powder more, and the temperature was let to rise 10 C, and then it was let stirring 1 hour more with  temperature between 10-15 C. Finally, it was added 24 ml of HCl and 9 grams of Zn powder in one hour at about 15 C, and it was let stirring at room temperature for 16 hours.
The solution was filtered and the Zn was washed with 60 ml of water. The Zn was dried and it weighted 10.3 gr, more than a 20 % unreacted.
The filtrate was washed twice with 50 ml of toluene, then added with cooling to a solution of 206 gr of NaOH in 344 ml of water, what promoted the formation of an alcoholic layer and the aqueous hydroxide layer (almost all dissolved). It was transfered to a 1 liter separatory funnel and the alcoholic layer was separated, then the aqueous layer extracted twice with 60 ml of toluene and then with 40 ml of toluene. The extracts were washed twice with 60 ml water, then with brine and finaly with NaOH solution (to remove the rest of hydroxides), dried over 12 gr of KOH, filtered, then crystallized to afford 6.1 gram of off white 2CH HCl, 59 % yield.

It's a easy procedure, and yields are quite good. I've done similar tests and yield seem to depend more on the quantity of reacted Zn than other conditions such as solvent amount or even temperature. In this particular case, the initial concentration of acid is high, so the temperature was kept low (<5 C) but there was undesirable fizzing. The problem is the work up, it is not readily scalable for that reason, but this procedure is very elegant, and everything is done with a 1 liter separatory funnel. If you want more yield, you should add more Zn and more acid, then the work up will be bigger.

In my first tests I used a not very pure Zn, then I got a 54 % with a 5.5:1 Zn:nitro w/w, but then I bought a 97 % pure Zn, and yields were better. A 50 % + is always sure.