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Author: Subject: 3,4,5-trimethoxy-beta-nitrostyrene synthesis
yogi
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[*] posted on 29-12-2004 at 13:34
3,4,5-trimethoxy-beta-nitrostyrene synthesis


Im looking for synthesis routes for 3,4,5-trimethoxy-nitrostyrene.
The more routes the better. Can anyone help? i know of the spath method mentoined by the MIA Rhodium, but that dates back to the 1919, and also offline.
There must be better ways...

[Edited on 29-12-2004 by yogi]
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Joeychemist
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smile.gif posted on 29-12-2004 at 13:54
This should help


3,4,5-Trimethoxy-beta-nitrostyrene


"The following components were placed in a one-necked 1000ml conical flask equipped with a Dean-Stark water trap (capacity about 30ml): 3,4,5-trimethoxybenzaldehyde (98.1 g, 0.5 mol), dimethylammonium chloride (81.5 g. 1 mol), nitromethane (300ml), toluene (300ml) and anhydrous potassium fluoride (4.36 g, 75 mmol). This mixture was vigorously refluxed with stirring for 5 h. The reaction flask was cooled down, then fitted to a rotary evaporator to order to remove the volatiles by gradual heating under reduced pressure. To the tepid residue (~55°C), chloroform (125 ml) and 0.2 M HCl (400 ml) were added. The mixture was heated on the water bath until complete dissolution. Then the flask was stored overnight in a refrigerator (-5°C). A crystalline solid was filtered out by suction, carefully rinsed with water and thoroughly dried in a vacuum oven. The filtrate was poured into a separatory funnel, the layers were separated and the aqueous phase was extracted with chloroform (3x100 ml). The organic extracts were combined then evaporated to give a crude oily material, which was chromatographed over silica gel (400g, eluent dichloromethane-ethyl acetate, 95:5). After removal of the solvent, the resulting solid and the previously separated product were recrystallized together from isopropanol: yield 99.2g (83%); mp 125.5-126.5°C (allotropic change at 121-121.5°C)."
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Rosco Bodine
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[*] posted on 29-12-2004 at 14:07


There is a much easier way . Heat your nitromethane up and dissolve into it your trimethoxy benzaldehyde , adding some denatured alcohol if necessary for all to go into solution . Add a few ml of butylamine , seal the vessel and incubate it for several days . A layer of water will separate and float on top the mixture . When the layer of water ceases to increase , the reaction is finished . On cooling the nitrostyrene will crystallize and may be filtered . If it is the amphetamine analogue of mescaline which is your intended end product and a better investment of time , then substitute nitroethane for the nitromethane , and your intermediate product will be a nitropropene instead of a nitrostyrene .
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yogi
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[*] posted on 29-12-2004 at 14:17


Rosco, do you have refs for that incubatioin method?
Also at what temps to incubate? what atmpspheric conditions are needed? etc.. etc...
a ref would be very nice :)
thankx for all the info guys.
This place is starting to feel like a nice home for this refuge bee....
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Rosco Bodine
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[*] posted on 29-12-2004 at 14:29


The method is journal published but I don't have the citation handy . One reference was in regards to an electrochemical reduction of methlyenedioxyphenylnitropropene to MDA , in an acetic acid and alcohol electrolyte with a small amount of HCl ,
in a porous cup with water cooled lead sheet cathode , surrounded by an anolyte
of dilute H2SO4 and a sheet lead anode .
I can confirm the method works for the condensation of piperonal and nitroethane . Also can confirm the method works for plain benzaldeyde and nitroethane . The method is general so I'm sure it is referenced several places .

BTW ,
The iron / HCl reduction of the phenylnitropropylene to the phenylacetone is 90% efficient but requires superb mixing equipment , rapid reversing counter-rotational stirrer to keep the iron filings in suspension and the reaction mixture emulsified while the phenylacetone product steam distills .

[Edited on 29-12-2004 by Rosco Bodine]
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trilobite
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[*] posted on 29-12-2004 at 14:39


Never forget PIHKAL.

http://www.erowid.org/library/books_online/pihkal/pihkal096....
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yogi
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[*] posted on 29-12-2004 at 14:45


u r of great help Rosco.
Have you heard of the simple condensation of a benzeldehyde in nitromethane with ammonium acetate as a catalyst? It seems also as good., though again refluxing of the volatile nitromethane is needed.
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trilobite
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[*] posted on 29-12-2004 at 14:53


But that's why you should be refluxing it under a condenser and not evaporating in an open flask.
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Rosco Bodine
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[*] posted on 29-12-2004 at 15:06


Any time you see lithium aluminum hydride and ether , understand that you can get the thing you are trying to make with less complication than trying to avoid trouble obtaining such reagents as are highly suspect and highly watched , as well as damn expensive .

BTW , refluxing nitromethane is not safe .

[Edited on 29-12-2004 by Rosco Bodine]
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trilobite
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[*] posted on 29-12-2004 at 15:16


Then there's the cold way of doing the Knoevenagel condensation where the benzaldehyde is dissolved in the nitroalkane, some amine catalyst added, and the mixture kept in a stoppered bottle for a couple of weeks pipetting the formed water out from the bottle now and then. However, I haven't got any details and 3,4,5-trimethoxybenzaldehyde is known to be the picky one.


Rosco: Are you implying that distilling nitromethane is not safe? That's known to not be true as many people have distilled their nitromethane in the past.
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Rosco Bodine
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[*] posted on 29-12-2004 at 15:25


Quote:
Originally posted by trilobite
Then there's the cold way of doing the Knoevenagel condensation where the benzaldehyde is dissolved in the nitroalkane, some amine catalyst added, and the mixture kept in a stoppered bottle for a couple of weeks pipetting the formed water out from the bottle now and then. However, I haven't got any details and 3,4,5-trimethoxybenzaldehyde is known to be the picky one.
You need to incubate the mixture like I said , 60 C is good .

Quote:

Rosco: Are you implying that distilling nitromethane is not safe? That's known to not be true as many people have distilled their nitromethane in the past.
Nope , I'm not implying anything , I'm saying it straight out , and I knew I'd get an argument . Anybody who want's to reflux and distill the stuff is welcome . I have too , and I'll never do it again because of the autooxidation potential for explosion in distilling a monopropellant which sooner or later catches up with you when you did not plan on it .
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trilobite
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[*] posted on 29-12-2004 at 16:33


I'm not looking for an argument. This is a matter of theory vs. practice, theoretically it can happen, in practice people really do seem to get away with it. It's something you could argue over forever, quite pointless. However, I can explain my point of view.

In those chemistry boards which are not involved with explosives but the chemistry this thread deals with, the concensus among respected people has been that nitromethane can be distilled safely, as numerous people have done so, that's all. Maybe it can be different if glassware/nitromethane/whatever is contaminated with the right material and you distill to dryness or something. I'm not the person to ask about materials that sensitize nitromethane, I know that microscopic glass spheres can do that though.
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yogi
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[*] posted on 29-12-2004 at 16:47


I belive nowadays fiddling with nitromethane if possible should be avoided. Technology has evolved a great deal in the last years, and new ways to make anything are popping up like mushrooms after the rain.
Still I accept that while refluxing nitromethane and the likes *could* be dangerous, it is often used and with no dire consequensces.
On the topic at hand - relfuxing with nitromethane is possible, but patience is a virtue, and I like rosco's view.
So ne way, to make a long story short, i believe some1 will try to incubate the Benzeldehyde with nitromethane in the future and report it :)
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Rosco Bodine
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[*] posted on 29-12-2004 at 16:58


Let me put it this way . Just because something has a boiling point and can be distilled doesn't necessarily mean that it is a benign material under distillation conditions . Isopropyl nitrite and methyl nitrate can also be distilled , probably nitroglycerin as well , and even though you can get your glass really clean and your vacuum high , sooner or later you are going to get a big and loud surprise .
It is that way with nitroparaffins too . I have seen it happen . It is simply a matter of time .
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[*] posted on 29-12-2004 at 17:03


Does anyone know of NM exploding during distillation? I haven't heard of this happening.



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Darkfire
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[*] posted on 29-12-2004 at 20:18


Keep the temps under control and youll be fine, a vacume could help. Ive never had a problem at atmospheric pressure.



\"I love being alive and will be the best man I possibly can. I will take love wherever I find it and offer it to everyone who will take it. I will seek knowledge from those wiser and teach those who wish to learn from me.\" Duane Allman
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enima
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[*] posted on 3-1-2005 at 14:57


Well, there are sooo many wonderful routes...
where to begin?

lets go for the benzaldehyde first.
here are a few methods.

1. Vanillin
a. brominate with NaBr/Oxone, or a NH4Br /H2O2 system for aromatic rings, should have nice high yields.
b. react with NaOH in N2 env to produce the 5-hydroxyvanillin and then react with 2 molar of trimethylphosphate (TMP)
b-ii . do a nucliophillic substition of the 5-bromo with NaOCH3 and then perform a alkylation with 1 molar of TMP and a base.


2. Starting with anisaldehyde, dibrominate the molecule using a really strong system, the FeCl3 (20% molar), NBS (2molar) 1 molar of the anisaldehyde in a CH3CN solvent, stir for a few hours. Evaporate solvent.

b. React with 2 molar of NaOCH3 to do the nucliophillic substition.

3. Starting with elemicin, react with KOH at 140-150C to produce the isoelemicin.
b. React with KMnO4 to produce the benzaldehyde.

From here you can proceed with the typical hendry condensation using an amine, methylamine, butylamine, cyclohexamine in IPA or someother solvent, equal molar amount of nitromethane (maybe 10% extra) and reflux for 5-6 hours.

Recrystallize and you have you product.

Sorry I do not have the time to go into detail, if you would like a more detailed description on any one of the proceedurees feel free to ask. the 3,4 are the safest routes as methylating agents are carcinogenic.
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Darkfire
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[*] posted on 3-1-2005 at 15:41


From the TMBA with NM MeNH2 NaOH and an HCl dehydration works very well, from begining to filtering your product is less than an hour. No reflux or anything.



\"I love being alive and will be the best man I possibly can. I will take love wherever I find it and offer it to everyone who will take it. I will seek knowledge from those wiser and teach those who wish to learn from me.\" Duane Allman
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[*] posted on 3-1-2005 at 15:53


enima: Do you have a reference for 1b? The mono-methylation of syringaldehyde with TMP to TMBA is shown in US4453017, but I was always unsure if TMP is strong enough to di-methylate 5-hydroxyvanillin directly to TMBA, like DMS can do.



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[*] posted on 4-1-2005 at 00:16


Quote:
2. Starting with anisaldehyde, dibrominate the molecule using a really strong system, the FeCl3 (20% molar), NBS (2molar) 1 molar of the anisaldehyde in a CH3CN solvent, stir for a few hours. Evaporate solvent.

b. React with 2 molar of NaOCH3 to do the nucliophillic substition.


Dibromination of anisaldehyde usually is a slow reaction. What they usually do is to dibrominate p-hydroxybenzaldehyde and methylate after the alkoxylation step. Also, it is better to use more than 2 molar alkoxide. Generally, a 3 to 4-time molar excess per bromine is advisable.

For the Henry condensation reaction of 3,4,5-trimethoxybenzaldehyde with nitromethane, I suggest the procedure written out by Shulgin in PiHKAL. It works as described.
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enima
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[*] posted on 4-1-2005 at 11:41
example of alkylation with tmp


In a three-neck flask (capacity 100 ml) equipped with a mechanical stirrer and reflux condenser, 5.00 g (0.033 mol) of vanillin and 5.00 g (0.036 mol) of anhydrous potassium carbonate were placed and the mixture was heated under a nitrogen atmosphere to 85° C. The mixture was a clear to amber melt of vanillin with carbonate in suspension. To this mixture was added 5.00 ml (0.043 mol) of trimethyl phosphate over about 5 minutes while maintaining the reaction temperature below 125° C. The mixture was maintained at about 80° C. for one hour and then cooled to 40° C. The mixture was poured into 20 ml water and extracted two times with 20 ml of methylene chloride. The combined extracts were dried over anhydrous potassium carbonate, filtered, and concentrated to give 5.4g (99%) of veratraldehyde as a pale oil.

-----------
*keep in mind you need double the tmp amount for your the two hydroxy groups.
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[*] posted on 4-1-2005 at 16:56


Btw, anyone know the best method to reduce the nitrostyrene to the corresponding ethylamine? CTH/Catalyst(Pd/C) or Al/Hg? Which one has the best result, and also a work-up or a good link would be very welcome.
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Darkfire
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[*] posted on 4-1-2005 at 17:22


Hg/Al is the simpler and more easily acessible choice for a small scale synth.

Borohydride to open up the double bond and catalitic hydrogenation to the ethylamine is higher yeilding, and better for a large scale synth.




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enima
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[*] posted on 6-1-2005 at 14:36
Al/Hg gives good yields.


There is an article on rhodium (mirror) which has a nice reduction of a nitrosytrene using Al/Hg around 70% yield, for personal use, I'd recommend this.

The trick is to let the Al/Hg type reductions to run until all the al is consume, add heat and reflux if necessary, it seems to also improve yields.
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Rosco Bodine
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[*] posted on 6-1-2005 at 22:13


It would be my personal recommendation to steer away from the trimethoxy whatevers and look with more interest at the MDA , MDMA type compounds which are generally more "user friendly" on terms of the benefit versus risk category .
Trimethoxy compounds are persistent psychomimetics , along with being psychedelics , whereas the methylenedioxy group is more easily metabolized and doesn't have the potential legacy effects afterwards involving little problems like long term persistent insanity for example :D
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