Author Topic: Ketones from Propenylbenzenes via the di-bromides  (Read 14605 times)

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uemura

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Ketones from Propenylbenzenes via the di-bromides
« on: October 22, 2001, 09:40:00 PM »
The following experimental procedures disclose an old, but in the Hive not much -if any- discussed or known approach from the propenylbenzenes to the 2-propanones.

The methods to be shown are easy, do not require any special chemicals and give all high yields in each of the steps from the propenylbenzen to the ketone. Likely not state of the art -the procedures are almost 100 years old-, this write-up gives nevertheless one so-far UNKNOWN clue on the epoxide-ketone re-arrangement mechanism.

The write-up is mainly based on the article of (1) Höring, 'Über die Dibromide aromatischer Propenylverbindungen', Ber 38, 1905, pg. 3464 and the article of (2)  Mannich, 'Studien in der Reihe des Adrenalins', Arch. Phar. Bd 248, 1910, pg. 127. Uemura picked up the essential details from these two papers, some notes are added the end.

It should be noted that the authors have performed the ketone preparation on the anethole and isosafole, but, and this is where it may becomes interesting, it could work for the acid sensitive asarone as well.

Isosafroledibromine  (CH2O2:)C6H3.CHBr.CHBr.CH3
100g Isosafrole is diluted with 100ml petrol ether. Under cooling with ice a solution of 100g bromine in 100ml petrol is added drop wise. If cristals of the Isosafrolebromide are around, some cristals are added to initiate cristallisation when the addition of bromine has finished. The flask is put on ice and the lower part consisting of the dibromide gets solid after some hours.
Yield 203g. The dibromide does not easily cristallize. mp is 52-53DegC. [N1]

Isosafrolebromhydrine (CH2O2:)C6H3.CHOH.CHBr.CH3
100g Isosafroledibromine are dissolved in 300ml acetone, water is added as long as the solution stays clear (appr. 50ml). In addition, 16g of marble pieces (CaCO3) are added to catch up the HBr which is produced by the hydrolyse of the dibromide. Carbon dioxide develops already in the cold. The mixture is heated then 2 hours on a hot waterbath. After 2 hours the aqueous CaBr2 solution is removed and another 40ml water is added. 2 more hours the rxn is heated on a water bath. Then the acetone is removed by destillation. The oily Isosafrolebromhydrine is extracted with ether [N3], the ether solution is washed with water and dried in vacuum. Evap the ether. Yield 98%.
The Isosafrolbromhydrine cannot be destilled in vacuum but will be used as it is for the next step. [N2]

Isosafroleepoxide (CH2O2:)C6H3.CHOCH.CH3
100g Isosafrolbromhydrine are disolved in 100ml alcohol. A solution of 25g KOH in 200ml alcohol is added. Immediately KBr seperates. The alcoholic solution is refluxed on a waterbath to complete the reaction. [N4] Most of the alcohol is then removed by destillion. The solution is poured into water and the Isosafroleepoxide extracted with ether [N3]. Ether solution is dried and evaporated. Yield with respect to the dibromide is 88%.
The Isosafroleepoxide is a colorless, good smelling oil which boils between 143-147DegC under 12mm pressure. [N5]

Piperonyl-acetone (CH2O2:)C6H3.CHOCH.CH3 i.e. Isosafrole-2-propanone
The conversion of the Isosafroleepoxide into the ketone starts when the epoxide is heated to 220 DegC in a flask equipped with a air-cooled condenser. The temperature jumps up quickly to 280DegC. When the exothermic rxn has finished, the mix is refluxed for a short period of time. The first destillation under normal pressure yields a colorless, almost non-smelling oil, which comes over between 280-290DegC. Under 10mm pressure it boils between 149-151 DegC. Yield 80% [N6]

Isosafrole-2-propanone-oxime (CH2O2:)C6H3.CHNOHCH.CH3 [N7]
3g ketone are solved in ethanol, 3g Hydroxylammonumchlorid, solved in a minimum amount of water, are added and the combined solution is make alkaline with concentrated Na2CO3 solution. After standing (hours..) and dilution with water, needles of the oxime seperate. They melt at 87DegC. Recrist. from ethanol or et ether.

Notes:
1: Hörig uses ether instead of pet ether for the bromation. The dibromide is used as it is for the next step.
2: Mannich adds the calcium carbonate during the rxn. For the preparation of the corresponding asarone-bromihydrine the Höring approach with pieces of marble should work better, since the Hbr is removed when it's produced.
3: Any other non-polar solvent should also be fine.
4: No duration specified by Höring.
5: There are of course other methods around to get to the epoxide, e.g. per-acetic methods or oxidation with H2O2 in MeCN/MeOH.
6: The conversion can also be performed by mixing the Isosafroleepoxide with GAA and adding some drops of H2SO4. But the main interesting point is, the epoxide does not explode but re-arranges into the ketone!!!! And: No need for Li-salts and ethyl-acetate for the rearrangment. Just use HEAT The per-acid method will not likely work for asarone.
7: This is more for information. Oximes may however also be reduced to the amine, there are examples on the chief bees site. The anethole-oxime comes in a two isomeric variants with mp 61-62DegC and with a mp of 72-74DegC.

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uemura

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #1 on: October 22, 2001, 10:56:00 PM »
Yes,
they had to heat it up to start the epoxide->ketone re-arrangement which anyway heats the whole stuff up even more. Then they destilled it under normal pressure. A vaccuum destillation after the conversion has seized should even get a more clean product.
Again, if just heat allows the rearrangement from epoxide to ketone, this would be optimal for asarone, since acid catalysed rearrangements (e.g. in GAA) may not work in this case.
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psychokitty

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #2 on: October 23, 2001, 05:15:00 AM »
I could swear that I once read that they used a catalytic amount of sulfuric acid to rearrange the epoxide to the ketone.

uemura

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #3 on: October 23, 2001, 10:44:00 AM »
The author Hoering was aware of that. He wrote: 'to get the epoxide any traces of acid must be avoided otherwise conversion to the ketone may take place.' His main interest was not an efficient way for ketone production, but to put the emphasis on the 'intramolecular transition of atoms' which seemed to be a hot issue at this time.
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megamole

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #4 on: October 23, 2001, 11:17:00 AM »
Can't epoxides be rearranged using a lithium catalyst, like LiBr or LiI?

Rhodium

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #5 on: October 23, 2001, 12:56:00 PM »
That too. Any lewis acid does the job.

uemura

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #6 on: October 23, 2001, 12:59:00 PM »
Yes, this is the 'standard' way of re-arrangement. Refluxing the epoxide in ethylacetate with LiBr or LiJ. Unfortunately Uemura got two different products when he applied this for the asarone-epoxide he got from the H2O2 epoxidation in MeCN/MeOH. This is why he is still seeking for other routes to the ketone.
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PrimoPyro

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #7 on: October 23, 2001, 04:00:00 PM »

That too. Any lewis acid does the job.



Rhodium, could you use aluminum chloride (AlCl3)? And if so, would the hydrated form be suitable? I'm referring to the hydrate produced upon addition of muriatic to Al foil.

                                                  PrimoPyro


I collect synthetic drug precursers. Aren't you jealous? Member: C_F and pyrotek FanClubs  8)

Rhodium

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #8 on: October 23, 2001, 05:04:00 PM »
The problem with many of the stronger lewis acids (such as AlCl3) is that they are likely to rupture the methylenedioxy ring. That's why the less strong LiI is preferred for isosafrole epoxide rearrangement.

Ritter

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #9 on: October 24, 2001, 06:50:00 PM »
Since lithium iodide is a prevalent reagent in this thread, SWIM thought he'd pass on his experience synthesizing it.  The reaction is very elementary, a simple metathesis reaction between lithium chloride and sodium iodide does the trick.  Simply dissolve equimolar portions of LiCl(anhydrous if possible but not necessary) and NaI in separate portions of anhydrous methanol and combine the solutions.  Precipitation starts immediately and chilling the vessel in crushed ice accelerates the displacement.  The ppt can be difficult to isolate through standard vacuum filtration so SWIM has found that doing the rxn. in test tubes then spinning them down in a centrifuge produces nice compact pellets of anhydrous LiI.  This synth was posted on the Hive many years ago and I'm fairly sure it is no longer in the database.  Anhydrous LiI is a DEA watchlist item so you are best off making it yourself.  Lithium chloride is commonly used for making solder fluxes and ordering it attracts no unwanted attention.

Rhodium

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #10 on: October 24, 2001, 07:25:00 PM »
Great! Have you used the LiI for this expoxide transformation? Yields?

Osmium

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #11 on: October 24, 2001, 10:05:00 PM »
I thought NaCl was insoluble in MeOH?

sunlight

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #12 on: October 24, 2001, 10:32:00 PM »
Merck:
Methanol usually is a better solvent than ethanol, dissolves many inorganic salts, e.g., sodium iodide 43%, calcium chloride 22%, ammonium nitrate 14%, copper sulfate 13%, silver nitrate 4%, ammonium chloride 3.2%, sodium chloride 1.4%.

IudexK2

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #13 on: October 25, 2001, 01:56:00 AM »
So in the recent article posted in the chem forum where they reflux the dibromo-compound with 85% KOH, are they actually refluxing the epoxide to turn it into a p2p?

Masquerade

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #14 on: October 25, 2001, 04:12:00 AM »
Lithium Hypochlorite and acide hydrochloric give lithium chloride.
Lithium Hypochlorite and acetone/butanone give lithium acetate/propanoate and chloroform.
Lithium Acetate and acide sulphur give lithium hydrogen sulphate.
Useful??

uemura

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #15 on: October 25, 2001, 03:02:00 PM »
Bees,
now having an easy way to get LiJ, the conversion with Ethylacetate seems to be easy. But Uemura still would like to find out, why the H2O2/MeCN epoxidation followed by conversion with LiBr/EtAc worked fine for anethol but not for asarone.
Any idea????
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Rhodium

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #16 on: October 25, 2001, 05:25:00 PM »
Which step failed? The epoxidation or the isomerization?

Ritter

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #17 on: October 25, 2001, 08:41:00 PM »
Osmium,
d'oh, your right, the supernatant contained the lithium iodide.  Its been a long time.

Rhodium,
Have never run the epoxide rearrangement with LiI.

otto

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #18 on: October 25, 2001, 11:06:00 PM »
Hi uemura,

>Again, if just heat allows the rearrangement from epoxide >to ketone, this would be optimal for asarone, since acid >catalysed rearrangements (e.g. in GAA) may not work in >this case.

in the Houben-Weyl a 80% yield is given for the thermal rearrangement from asarone epoxide to the ketone. dont know the exact volume, page etc. though.

otto

uemura

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Re: Ketones from Propenylbenzenes via the di-bromides
« Reply #19 on: October 26, 2001, 09:21:00 AM »
Bingo...
Thousend thankxs Otto!!! Uemura has access to all the 30+ volumes of the Houben-Weyl in his preferred library. If you find the ref. posting will be appreciated. Uemura will translate and post as soon as he found it.

To Rhod: It's not completely clear which step failed. At the time he did the anethol/asarone epoxidation rxn Uemura was reluctant to destill the epoxides because he was not sure how stable the expoxides would be. The anethol run as described by Osmium gave a reasonable bisulfite compound at the last step without purification (i.e. destillation). The asarone-"ketone" gave none! So Uemura vacuum destilled the 8-10ml (say) and got two fractions, a green oil first, which cristallised after some days and a smaller amount of oil, which also cristallised later on in the flask (together with some brown polymerised? stuff). Because of the small yield of material no further investigation have been performed at this time.
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