GC_MS
(Hive Addict)
03-03-03 02:46
No 413294
      Ring-substituted beta-methoxyphenylethylamines
(Rated as: excellent)
    

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 0C. 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 78-79C. 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, 115-128C) 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 171-172C.

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 143-144C) and isolated as the HCl salt, mp 198.5-199.5C.

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

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 157-158C). This nitrostyrene was converted to 2-methoxy-2-(4-bromo-2,5-dimethoxyphenyl)-1-nitroethane (mp 119-120C) and reduced to the amine as described above. HCl salt, mp 187-188C.

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

Abusus non tollit usum
 
 
 
 
    Rhodium
(Chief Bee)
03-03-03 14:11
No 413424
      Pihkal #14 - BOD     

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
(Hive Addict)
03-04-03 00:38
No 413590
      DOB etc     


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


Abusus non tollit usum
 
 
 
 
    imp
(Newbee)
10-31-03 11:15
No 468014
      How about these possibilities?
(Rated as: excellent)
    

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. frown SWIM has spent more on photocopies than on telephone calls for the entire year... maybe a change in lifestyle is required. crazy
 
 
 
 
    Rhodium
(Chief Bee)
10-31-03 12:18
No 468024
      Zn reduction of oximes     

Zn reduction of oximes: Post 194987 (Rhodium: "Reduction of Imines Using Zinc Powder", Chemistry Discourse)
 
 
 
 
    imp
(Newbee)
10-31-03 12:38
No 468028
      More related...
(Rated as: excellent)
    

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
(Newbee)
11-02-03 18:05
No 468412
      Sulphur analogues of Aminorex & Cathinone     

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.

Lets 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 wink.)

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
(Newbee)
11-03-03 15:46
No 468573
      Phenylnitroalkenes to Oximes using SnCl2
(Rated as: good read)
    

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 (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 (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??
 
 
 
 
    GC_MS
(Hive Addict)
11-03-03 23:17
No 468650
      BOX     

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

I'd actually be more interested in the sulfer analogues of the BOX series, e.g. -methylthio-2C-B or -methylthio-2C-D.

What would be the activities of compounds with a sulfur instead of an oxygen at the beta-oxygen position? What would be the nature of action if there were an alpha-methyl group, making all of these into amphetamine derivatives? Or what about both a sulfur and a methyl group? And what about the isomers that are intrinsic to all of this, the threo- and the erythro- and the D's and the L's? All this is terra incognita, and must someday be looked into. It is chemically simple, and pharmacologically provocative. Someone, somewhere, someday, answer these questions!

PiHKAL, p 492 [#13, BOB: -methoxy-2C-B]

And Shulgin would be happy as well wink.

-Synth. Comm., 18(7), 693-697 (1988)
[Ethyl acetate solvent is excellent for both aldoxime and ketoxime formation. Experimental is already posted by a bee named psychokitty]


Maybe take a look at Rh's page as well: ../rhodium/chemistry /p2p.sncl2.html

18,1g (100mmol) 1-(2-fluorophenyl)-2-nitropropene was added dry in portions to 49,5g (220mmol) SnCl2 x 2 H2O suspended in 75ml EtOAc while the reaction
temperature was kept between 20-40C by a cold water bath. When all nitropropene was added and the color had changed to white (5 min) the EtOAc solution
was transferred to a rb flask containing 250ml water and 50 ml hydrochloric acid. The EtOAc was removed by distillation under diminished pressure and the
aqueous suspension of oxime and tin salts was allowed to stir at 80C for 1 hour. The water phase was now steam distilled to remove the ketone. When no
more oily drops came over the distillate was extracted with DCM. The DCM extracts was dried over MgSO4 and the DCM  removed by distillation leaving a quite
pure ketone as a colorless oil with with a nice aromatic smell.


The obtained oxime, however, can also be reduced to an amine with e.g. Al/Hg (and Zn/AcOH?).

Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".
 
 
 
 
    imp
(Newbee)
11-09-03 19:33
No 469924
      Methylthio- not so easy     

GC_MS, SWIM is somewhat interested in the beta-alkylthio compounds, but unfortunetly it will going to be a lot harder to make the beta-methylthio compounds. Methanethiol boils at 6C, so it is uncertain if we can use the SnCl2 procedure to introduce it to the beta carbon on the aliphatic chain. Furthermore, the beta-ethylthio will likely be a weaker compound, as there are hints that longer chains might abolish the activity that the parent compound would have had (analogous to 2-aminobutanes).

One might be able to start from the beta-ethylthio compound, hydrolise, apply amine protection, methylate the free thiol, then deprotection. A bit involved. 

SWIM really liked the idea of a methylaminorex sulphur analogue. But since people don't seem to be interested in it, then have people considered 4-ethylaminorex?... 2-amino-4-ethyl-5-phenyloxazoline. It should be realized through cyclization of 1-phenyl-2-aminobutanol with cyanogen. It probably would be less potent than methylaminorex, but that's not what SWIM is interested in. Perhaps halo-ethylaminorex compounds wouldn't be as toxic as the methyl counterparts... that would be very interesting.

How the hell can no one be interested in 2-amino-4-methyl-5-indolyloxazoline? An aminorex analogue of a tryptamine, that just sounds sexy. No? Pffft, fine. 

Sorry, but SWIM is not the biggest of Shulgin fans... SWIM would prefer not to discuss their reasons.
 
 
 
 
    GC_MS
(Hive Addict)
11-11-03 01:06
No 470143
      Beta-thio PEA analogues     

Well, I'd say you could synthesize the beta-thio PEAs in two different ways (probably more, but these are the ones I have in mind right now):

- reaction of RS- with a nitrostyrene. In case of MeSH, you should work at low temperatures.
- reaction of a benzaldehyde, RSH and MeNO2 (or others) to yield a 1-phenyl-1-thio-2-nitroethane.

If MeSH has a low boiling point, working at low temperatures or constantly bubbling in generated MeSH might be a solution, no?

Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".
 
 
 
 
    Vitus_Verdegast
(Hive Addict)
11-12-03 05:35
No 470467
      Translation of Ber., 93, pp 32 (1960)
(Rated as: excellent)
    

Here is the translation of the synthesis posted in Post 468028 (imp: "More related...", Methods Discourse):


alpha-Methoxy-alpha-phenyl acetone oxime:
To a suspension of 80 g 2-Nitro-1-phenylpropene (1) in 100 ccm methanol was dripped in slowly, over 90 min., a solution of 116 g tin(II)chloride in 60 g hydrochloric acid and 60 ccm methanol with stirring and cooling.The mixture was allowed to stir for an additional half an hour at ambient temperature, diluted with 750 ccm water and the
precipitating oil was extracted with ether. The ethereal extract was washed 3 times with dil. HCl, once with a tartaric acid solution, and once with water, and the ether was evaporated in vacuo, yielding a crystalline mass, after cooling and scratching the residue with a glass rod. This was sucked dry on clay.
The raw product (66 g) was dissolved in a solution of 25 g potassium hydroxide in 100 ccm water, this was diluted with 500 ccm water, treated with activated carbon, filtered and slowly acidified by adding a 20% AcOH solution dropwise with cooling. The crystalline oxime IIa precipitates from solution, they were filtered off on a Buchner, washed with water, and dried on clay (ton ?). Yield: 58 g (66% theoretical), mp. 59-61C (from petroleum ether).

Consult the Hive psychiater (http://www.geocities.com/eric_vornoff/index.htm)
 
 
 
 
    Rhodium
(Chief Bee)
11-12-03 06:08
No 470471
      Clay     

At least in earlier times, it was common to dry crystals by spreading them on a porous ceramic surface.
 
 
 
 
    Manichi
(Stranger)
11-12-03 19:22
No 470584
      5-phenyl-2-amino-thiazolin-4-one: inactive     

Imp: Has anyone ever considered novel sulphur analogues of aminorex and cathinone?

I have considered the pemoline thio analogue, and according to Bull. soc. chim. Fr. 1963 (5) 1018-1022 it is inactive when you replace the O in the ring of the pemoline by the sulfur atom.

I dont known about thio-4-MAR analog, but pemoline and 4-MAR are strikingly similar and then i would not expect much of thio-4-MAR neither. Beside that a quick search on the thio-4-MAR analog yielded only a few refs on antiviral and antifungicide activity, nothing of stimulant activity.

frown ...sorry for the disapointment.
 
 
 
 
    imp
(Newbee)
11-12-03 23:28
No 470612
      Thanks Manichi!     

...sorry for the disapointment.

No, this is not disappointment at all! It is good that we found out, thank you.

Yes, 2-amino-5-phenylthiazoline-4-one is very close to pemoline and 4-mar. Although it is not 100%, we can probably say with some confidence that they will be inactive. Thank you for clearing this up.

What about the thione analogues wink?

Okay, SWIM has one more idea for you! SWIM promises this is the last one... Please anyone answer!...

Getting back to beta-substitutions, do you think a beta-methyl group on the aliphatic chain would be an active compound? Something like 1-phenyl-1-methyl-2-aminoethane, or 2-phenyl-3-aminopropane. That is strange looking!

SWIM can propose a relatively simple synthesis for it, but does anyone think this will have any activity? Vitus, Manichi, Rhodium, Chimimanie, ... anyone?

Edit: Ooops, almost forgot blush... Thank you very much for the translation Vitus!
 
 
 
 
    GC_MS
(Hive Addict)
11-13-03 00:52
No 470618
      Ring-substituted beta-methylthioPEAs
(Rated as: good read)
    

Here are some fragments from an article to get you started in the field of -alkylthiophenethylamines.

Rates of reaction of n-butanethiol with some conjugated heteroenoid compounds

CE Lough, DJ Currie, HL Holmes. Can J Chem 46 (1968) 771-774

Abstract - The reaction of substituted 3-benzal-2,4-pentanediones, ethyl benzalacetoacetates, diethyl benzalmalonates, benzalmalonamides, cinnamalmalonitriles, -nitrostyrenes and -nitropropenylbenzenes with excess n-butanethiol go essentially to completion in 20% aqueous ethanolic solution buffered to pH 7. The second order rate constants derived from the reactions of meta- and para-substituted derivatives correlate well with Hammett constants. The nature and conformation of the functional group cis to the phenyl group determines the extent to which ortho substituents hinder the reaction.

Introduction

Aliphatic and/or aromatic thiols have been added to benzalacetone [1], benzalacetophenone [2-10], -nitrostyrene [11-13], 3-benzal-2,4-pentanedione [1], and ethyl benzalacetoacetate [1] but no attempt was made to demonstrate that the adducts of the latter two compounds arose by 1,4-addition to the conjugated system. Moreover, no record could be found of the isolation of an adduct arising from the addition of a thiol to the conjugated system of a cinnamonitrile with a second functional group on the &alfa; carbon atom. In some instances, reaction proceeds without a catalyst [3,4,9] but in general, catalysts such as dry hydrogen chloride [7,8], piperidine [1,2,7,8,10], or sodium ethoxide are employed.
The 1,4-addition of thiophenol to -nitrostyrene, in the presence of piperidine, has been demonstrated [12] by reduction of the nitro group of the adduct (1) to 2 and the preparation of the hydrochloride of 2 from thiophenol and 3. At least in the case of the hydrogen chloride catalyzed reaction of ethanethiol and thiophenol to benzalacetophenone some 1,2- as well as 1,4-addition occurs [2,7,8].
This paper describes some related aqueous solution reaction and although excessive -eliminations occur when thiol adducts are treated with strong base [5], such eliminations are unlikely in solutions buffered to pH 7 when excess thiol is present.

Ph-CH=CH-NO2 + Ph-SH ---> Ph-CH(-SPh)CH2-NO2 -[Zn/HOAc + HCl]-> Ph-CH(-SPh)CH2-NH2.HCl

Ph-CHCl-CH2-NH2 + Ph-SH ---> Ph-CH(-SPh)CH2-NH2.HCl

Experimental

[...] The butanethiol addition reactions were run in 80% aqueous buffer (pH 7)-20% EtOH (v/v) at 25C and followed by UV spectroscopy [15] and the insolubility of the adducts required that these reactions be run in very dilute solution.

References

1 S Ruhemann. JCS 87 (1905) 17
2 W Davey et al. JCS (1957) 1015
3 BH Nicolet et al. JACS 57 (1935) 1098
4 RL Frank et al. JACS 68 (1946) 2104
5 BH Nicolet et al. JACS 53 (1931) 3066
6 BH Nicolet et al. JACS 54 (1932) 1998
7 T Posner. Ber Deutsch chem Ges 34 (1901) 1395
8 T Posner. Ber Deutsch chem Ges 35 (1902) 808
9 F Kipnis et al. JACS 71 (1949) 3554
10 S Ruhemann et al. JCS 87 (1905) 461
11 RL Heath et al. JCS (1947) 1477
12 LF Cason et al. JACS 73 (1951)142
13 A Mustafa et al. JACS 77 (1955) 3860
14 RF Silver et al. Can J Chem 45 (1967) 1001




Voila, this should be enough to get you started in the library. wink

Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".
 
 
 
 
    SPISSHAK
11-13-03 08:30
      I know this is irrelavent but,
(Rated as: insignificant)
    
 
 
 
    GC_MS
(Hive Addict)
01-16-04 01:58
No 482787
      Problems with BOB...     

I have attempted a few syntheses of BOB but have encountered some problems, problems which I'd rather not like to encounter frown.

Shulgin used 4-bromo-2,5-dimethoxybenzaldehyde as direct precursor, and not 2,5-dimethoxybenzaldehyde. I had in mind to make 2,5-dimethoxynitrostyrene, which I reacted with NaOMe. Reduction of the nitro functional group is straightforward, and all what would be left to do was bromination to obtain BOB as end product. However, things didn't run as smooth as I hoped for. When reacting 2,5-dimethoxynitrostyrene with NaOMe, the end product is a mixture of 1-(2,5-dimethoxyphenyl)-1-methoxy-2-nitroethane and 2,5-dimethoxynitrostyrene, even when using a royal excess of NaOMe. Purification is not straightforward... I'd have to apply fractional distillation to a small amount of product.

It seems I have to synthesize the 4-bromo-2,5-dimethoxybenzaldehyde myself now. Maybe Shulgin encountered the same problems, which pushed him into choosing the pathway via the brominated benzaldehyde? Or maybe I am overlooking something obvious? Anyone else with experience in this synthesis?

And yes, the nitrostyrene was pure.

Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".
 
 
 
 
    GC_MS
(Hive Addict)
02-24-04 02:38
No 490780
      1-(4-bromo-2,5-dimethoxyphenyl)-2-nitroethene
(Rated as: good read)
    

Some information for those who might be interested in BOB...

I have performed the synthesis of the nitrostyrene la Shulgin with NH4OAc as catalyst and MeNO2 as solvent and reagent. The colour evolution is very similar to the reaction of 2,5-dimethoxybenzaldehyde and MeNO2 using the same reaction conditions. Only that the reaction takes longer (due to the deactivating role of Br).

Recrystallization has been attempted with MeOH and IPA, but both solvents failed miserably. Toluene on the other hand, did a magnificent job. So if you are planning on synthesizing 1-(4-bromo-2,5-dimethoxyphenyl)-2-nitroethene, just use toluene. The nitrostyrene has a magnificent yellow colour, like most of the nitrostyrenes.

Advanced clitoris massage specialist. 32 years of experience. PM me for a "sample".
 
 
 
 
    Nicodem
(Hive Bee)
03-17-04 12:42
No 495783
      beta-alkoxy-PEA paper
(Rated as: excellent)
    

A paper on preparation (with no pharmacology) of beta-alkoxy-phenylethylamines. However, it also contains some interesting chemistry for possible application to DOI and 2C-I preparation (phenylnitroethanes can be iodinated with I2/Ag+ on ring position 4!):



The preparation of potentially psychoactive beta-alkoxyphenethylamines.
Milton Aillon Torres, Bruce Cassels and Marcos Caroli Rezende
SYNTHETIC COMMUNICATIONS, 25(8), 1239-1247 (1995).

Excerpt: As part of our interest in structure-activity relationships of psychotomimetic phenethylamines and their interactions with serotoninergic receptors, we describe In the present communication the preparation of a series of substituted p-alkoxyphenylethylamines.

The real drug-problem is that we need more and better drugs. J. Ott
 
 
 
 
    Ganesha
(Stranger)
03-19-04 11:41
No 496172
      Good find, Nicodem!     

Too bad there is nothing on (psycho)pharmacology. Do you think that you can get reference # 1 and if possible even # 2 cited in the above paper?

Thanks! tongue

'I' am a crowd, obeying as many laws As it has members. Chemically impure Are all 'my' beings.
 
 
 
 
    Rhodium
(Chief Bee)
03-19-04 14:34
No 496200
      Here is the experimental part from Ref #1:     

Some Fluoro and Nitro Analogs of TMA-2 and MMDA-2
Synth. Commun. 24(3), 417-426 (1994) (../rhodium/chemistry /fluoronitro.html)

The Hive - Clandestine Chemists Without Borders
 
 
 
 
    Nicodem
(Hive Bee)
03-31-04 10:13
No 498315
      Full paper of Ref #1
(Rated as: excellent)
    

Some fluoro and nitro analogues of hallucinogenic amphetamines.
Aida Neira Jara, Milton Aillon Torres, Bruce Kennedy Cassels and Marcos Caroli Rezende
Synth. Commun. 24(3), 417-426 (1994)

Abstract: The preparation of the fluoro and nitro analogues (2)-(5) of the hallucinogens 2,4.5-trimethoxy- and 2-methoxy-4,5-methylenedioxy-amphetamine is described.

The real drug-problem is that we need more and better drugs. J. Ott