Has psychokitty won the OTC safrole contest?

[psychokitty]

Here is that online reference to that microwave demethylation proceedure that I referred to earlier:

http://www.rsc.org/CFmuscat/intermediate.cfm?FURL=/ej/JC/1999/H9901278.PDF

--PK

[startinout]

Thanks for the comments wack-cat/nutter-pussy/schitz-mog, they are appreciated, I have just converted vanillin in piperonal and you would not believe how easy it went, for the safrolly-challenged like myself i think this makes a more realistic route than from eugenol, vanillin is also much cheaper than eugenol (~$555.00 for a 25kg bag of food grade) and you can get it pure so no need to distil. i used the alcl3/pyridine method. I had tried this method on eugenol often and always had difficulty (difficulty as in abject failures)with it, however with vanillin it is a beautiful, simple, extremely scalable process. i even got back the pyridine in the end so you don't need to find buckets of this chemical. My yield was 70% but the paper i followed claims 87% so i might get better at it) A side note does anyone know why pyridine is watched?
Anyhow the KF/DCM(and/or DBrM)/DMF method for the methylation is simple, quick (a 1hr reflux) and scalable.
Anyway I have not taken the piperonal through to the amine yet so this might still be my undoing, although all reports lead me to believe mr shulgin can be trusted, so i am not too concerned. I am doing a 1000g run of the vanillin later next week, i will post my successes/lack of successes up.
And lastly in relation to the demethylation product from eugenol, the difficulty is it is soluble in everything, this combined with the fact that you have all the Alsalt fine powder around makes for any scaling quite difficult. I am however going to try to hydrolyse it next time using 50ª, it might be more soluble in this phase, but who knows.
Anyway the snows falling and I am up for a board, the lab can wait for a few days.


blue always
except for at the start

[psychokitty]

This is good news and congratulations!!! 

As for the issue of going from piperonal to either the safrole or isosafrole or the ketone, there are numerous ways to do it.  You could use a grignard reaction of Mg-ethylbromide in THF to get the 1-3,4-MD-phenylpropanol and then dehydrate it with potassium bisulfate to get isosafrole.  Or you can condense piperonal with nitroethane to get the intermediate nitroalkene, which can be reduced to the ketone any number of ways (dissolving Fe supposedly being the best and cheapest of the lot). 

There are a few untested but very compelling ways to get from the aldehyde to the 1-alkene and, get this, to the epoxide (go figure) that are published in several references that I have.  If someone is willing to get the articles, these may in fact be quite promising.  One article that I have FOR SURE lists piperonal as the starting material, which is then reacted to form a silyl intermediate, which upon hydrolysis, forms safrole.  It looks easy enough, although the yields were somewhere around 48%.  But this is a problem at the hydrolysis phase as the intermediate silyl compound is formed in about 88%yield.  I've never bothered to mention these articles before as I never believed vanillin would be the way to go, but after your last few posts, I've begun to rethink the possibilities.

As for the AlI3 method, isn't this easier than AlCl3/pyridine?  More OTC, I mean?  The reason that I ask is because of it's applicability to vanillin ether hydrolysis, which I believe, yields protocatechualdehyde in about 90% or above.

More later.

BTW, pyridine was once heavily watched because of it's use in converting phenylacetic acid into phenylacetone.  Phenylacetic acid reacted with acetic anhydride catalyzed by pyridine yields P2P.  However, this reaction scheme hasn't been popular since the late 80's.  I doubt pyridine is still much of a hot item.

For those interested, I finally got the French Patent.  Details saved for later.

--PK

[Lilienthal]

Some thoughts on the AlI3 method:

- Excess I2 should possibly be avoided if you have olefinic double bonds in your molecule.
- Al salts / excess Al can be brought into aqueous solution with a small amount of HCl or H2SO4.
- The polyphenolic compounds can be extracted from this solution with three to four ethyl acetate extractions.
- Why not try to substitute I2 with Br2, which is much cheaper on a molar base.

[startinout]

Thanks l-man, good info, I am on the pyridine HCl/microwave trail at present but will come back to the AlI3 method if this also proves frustrating (am worried about adding Cl across the olefin as well as demethylating with the pyridineHCl/microwave method) any thoughts anyone?
Also piperonal steam distills doesn't it???

How many vietnam vets does it take to change a light bulb



you wouldn't know you weren't there

disclaimer-that joke was not intended to offend any former vietnam veterans, if any were perhaps offended i am very sorry

blue always
except for at the start

[startinout]

Does anyone have any great ideas about how to extract piperonal from DMF without the obv. vac. distill and/or steam distill, the next step would be the knove. condensation with nitroethane if that helps.
tanks guys, you guys rock(et), get it, no, oh well
the punmaster

blue always
except for at the start

[psychokitty]

Extraction of piperonal (my guess):  Dilute DMF solution with water, extract with suitable solvent, separate, wash, then distill off solvent to get the goods.  If the piperonal needs cleaning, then stir solvent layer with saturated bisulfite solution, filter crystals, wash, dry, break up salt with dilute HCl, extract with solvent, and then distill off solvent to get goods.

According to the french patent, there is no stated yields for the eugenol >> allylpyrocatechol conversion.  Only in example 27 "avec un bon rendement".  "Rendement" seems to mean "yields".  Anyone know what "bon" means?  Good?  Either way, pretty vague.

As for that Tetrahedron Letters article detailing the PTC Williamson Synthesis, here's the reference:  1975, v.40, pp.3489.

As for that synthesis of safrole from piperonal:

JOC 1982, 47, 1983-1984.  "[B-(Trimethylsilyl)ethyl]lithium:  A New Reagent for Carbonyl Reductive Vinylation"

--PK

[Scooby_Doo]

Here's another angle on the Eugenol swing donated by the Wizard.

This is a bit of cool cat chemistry if I do say so. May you notice pretty much all of the chems can be easily obtained. Hydriodic acid can be made, check Rhod's site plus old message board for some kick ass OTC methods.
Also the lustful lack of any serious work up until the very end (nice huh).

DISCLAIMER : THE FOLLOWING INFORMATION IS FOR INFORMATIONAL PURPOSES OR ACADEMIC STUDY ONLY. CHECK YOUR LOCAL, STATE AND FEDERAL LAWS, AND PROCURE THE NECESSARY PERMITS BEFORE UNDERTAKING ANY OF THE REACTIONS DESCRIBED BELOW. WIZARD X  SHALL NOT BE HELD LIABLE AND INDEMNIFIED FROM IMPEACHMENT FOR THE USE, MISUSE, INJURY, DEATH, IMPRISIONMENT OR FELLATION DUE TO THE APPLICATION OF THIS INFORMATION.


SYNTHESIS OF ISOSAFROLE FROM EUGENOL

Eugenol, M.W = 164.20 gr/mol; density @ 20 degC = 1.067 gr/cm3

PROCEDURE

Obtain pure eugenol from clove oil which has a boiling point of 255 degC at 760mmHg. With vacuum distillation the boiling point is 123 degC at 12-13mmHg, and 110-111 degC at 5mmHg.

In a 500 ml round bottom flask, cool in ice to 0-2 degC, 100 mls of 57% HI SOLUTION (HYDRIODIC ACID, M.W = 127.93) = 99 grams of HI = 0.774 moles of HI. (B.p 125.5-126.5 deg C/760mm Hg ; Density 1.70 gr/ml ;  55-57%  w/w HI is 0.936 to 0.99 grams of HI per ml).

Add 32.8 grams, ~ 35.0 mls (0.2 moles) of Eugenol to the 100 mls of 57% HI, while the flask is still in the ice. Swirl gently, stopper, place back in the ice and insulate the container holding the ice and place in the fridge compartment for a period of 12 hours. Every 2 hours swirl gently again.

After the 12 hours period, add 1.0 grams of hydroquinone (a polyerisation inhibitor)[NOTE1] and swirl, stopper, remove from the ice to allow it to obtain room temperature. Attach a long reflux condenser and reflux for 2½ hours between 120-130 degC, perfect temperature is 128 degC. After refluxing for the time period allow to cool to room temperature. Dilute with 1 liter of ice cold distilled water and solvent extract with 3 x 100 mls of diethyl ether or petroleum ether and wash once with minimum distilled water 50 mls. Distill the solvent off and the methyl iodide, CH3I, Bp 42.4 degC.[NOTE2] Crystals will form, however some oily residue may or will persist.

In a 1 liter round bottom, reflux reaction flask, add the following.
A volume of 300 mls of ethanol is added to the crystal residue of 3,4-dihydroxy-1-propenylbenzene, 3,4(HO-)C6H3-CH=CH-CH3 and the 3,4-dihydroxy-1-(1-iodo)phenylpropane, 3,4(HO-)C6H3-CHI-CH2-CH3 and hydroquinone. Another 1.0 grams of hydroquinone is added and mixed together.[NOTE1] A solution of 22.44 grams (0.4 moles) of potassium hydroxide, KOH, in 200 mls of 50/50 distilled water/ethanol is made. The potassium hydroxide solution is then added with stirring to the above 3,4-dihydroxy-1-propenylbenzene, 3,4(HO-)C6H3-CH=CH-CH3 and the 3,4-dihydroxy-1-(1-iodo)phenylpropane, 3,4(HO-)C6H3-CHI-CH2-CH3 residue-ethanol solution. The combined mixture is then gently refluxed with stirring on a hot-water bath or steam bath for 1 hour.[NOTE3]

Add a solution of 53.58 grams (0.2 moles) of diiodomethane, ICH2I (M.W = 267.9 gr/mol), in 150 mls of ethanol and continue refluxing for 2 hours.[NOTE4] Strip all ethanol solvent under vacuum distillation, and add 400 mls of distilled water. Solvent extract with ether 2 x 100 mls. Keep the water layer as it contains unreacted 3,4-dipotassiumoxy-1-propenylbenzene, 3,4(KO-)C6H3-CH=CH-CH3.[NOTE5] The ether/isosafrole solution mixture is washed once with distilled water, and under careful vacuum distillation the isosafrole is distilled at 179.5 degC at 100 mmHg or 135.6 degC at 20 mmHg.
[NOTE6]



[NOTE1] hydroquinone oxidizes in air and in solutions exposed to air rapidly. Keep the flask well closed and protected from light.

[NOTE2] the solution contains a mixture of methyl iodide, CH3I ;
3,4-dihydroxy-1-propenylbenzene, 3,4(HO-)C6H3-CH=CH-CH3 and the
3,4-dihydroxy-1-(1-iodo)phenylpropane, 3,4(HO-)C6H3-CHI-CH2-CH3 and hydroquinone.

[NOTE3] at this stage the 3,4-dihydroxy-1-(1-iodo)phenylpropane, 3,4(HO-)C6H3-CHI-CH2-CH3 will be converted to 3,4-dihydroxy-1-propenylbenzene, 3,4(HO-)C6H3-CH=CH-CH3 and 3,4-dipotassiumoxy-1-propenylbenzene, 3,4(KO-)C6H3-CH=CH-CH3.

[NOTE4] methanol can be used in all cases, instead of ethanol. At this stage the main product is isosafrole. Dibromomethane, BrCH2Br can also be used.

[NOTE5] add dilute HCl until slightly acidic and solvent extract to obtain the 3,4-dihydroxy-1-propenylbenzene, 3,4(HO-)C6H3-CH=CH-CH3.

[NOTE6] propenylbenzene, C6H5-CH=CH-CH3, are susceptible to polyerisation, influenced by acids. Both isosafrole and safrole can be steam distilled.



TESTS

3,4-dihydroxy-1-propenylbenzene; 3,4(HO-)C6H3-CH=CH-CH3, in an alcoholic solution develops a deep green-blue colour on treatment with 2 % alcoholic ferric chloride solution.

Eugenol : In a cold saturated aqueous solution of ferric chloride, gives a turbid grayish-yellow colour. With 2 % alcoholic ferric chloride solution, a blue colour, which fades to grey-yellow colour in 15 minutes. An intense purple-black colour develops when reacted with 48 % hydrobromic acid at 2 degC.

Safrole and Isosafrole : an intense red to scarlet red colour develops when dissolved in concentrated sulphuric acid.

[startinout]

the method has a crap yield (I performed it last week), i think the problem is with the methylation reaction, it only goes well with polar aprotic solvents (DMF/DMSO/ethacet if you are desperate).
I will try a revised method next week which still utlilses the first step but after the ether removal i will use KF/DMF/DIM instead of the etOH/KOH, then after recovery will boil up the mix with KOH ala elusis style to transform all to isosafrole, will post results, my yield from that method was about 7% (crude prod) and removing the ethanol took far too long for that measely quantity. Not to be discouraging just warning others off, also HI is not fun to work with, either to buy (expensive!!!!!), to make (nasty!!!!!!!!!) or to have split all over your gentitals (ouch that burns).
Anyway may have some good news for all soon after a little vac distill this afternoon.
caio

blue always
except for at the start

[Scooby_Doo]

Hhmm that looks like a whole lot of pain. 7% that's really shit. Well hopfully the methylation is the fuck up. Which isn't too much to ask considering every methylation I ran into either used polar-aprotic or autoclaves and years to get it to run.