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MDP2P from isosafrole
via the dibromide, bromohydrin and epoxide

Including Thermal Rearrangement of the Epoxide to MDP2P

Written by Uemura

HTML by Rhodium

The following experimental procedures disclose an old, but at the Hive not much - if anything - 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 two articles by Höring1 and by Mannich2. 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.


Isosafroledibromide (CH2O2:)C6H3.CHBr.CHBr.CH3

100g Isosafrole is diluted with 100ml petrol ether. Under cooling with ice a solution of 100g bromine in 100ml petroleum ether is added dropwise. If crystals of the Isosafrolebromide are around, some crystals are added to initiate crystallisation 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 crystallize. mp is 52-53°C.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 neutralize the HBr which is produced by the hydrolysis of the dibromide. Carbon dioxide develops already in the cold. The mixture is heated then 2 hours on a hot water-bath. 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 distillation. The oily Isosafrolebromhydrine is extracted with etherN3, the ether solution is washed with water and dried in vacuum. Evap the ether. Yield 98%. The Isosafrolbromhydrine cannot be distilled 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 etherN3. 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 143-147°C under 12mm pressure.N5

3,4-Methylenedioxyphenyl-2-propanone, (CH2O2:)C6H3.CHOCH.CH3 i.e. MDP2P

The conversion of the Isosafroleepoxide into the ketone starts when the epoxide is heated to 220°C in a flask equipped with a air-cooled condenser. The temperature jumps up quickly to 280°C. 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 280-290°C. Under 10mm pressure it boils between 149-151°C. Yield 80%N6

Isosafrole-2-propanone-oxime (CH2O2:)C6H3.CHNOHCH.CH3N7

3g ketone are solved in ethanol, 3g Hydroxylamine Hydrochloride, dissolved 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 87°C. Recrist. from ethanol or diethyl ether.


  1. Hörig uses ether instead of petroleum 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-bromohydrine the Höring approach with pieces of marble should work better, since the HBr is removed as 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. buffered peracetic 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 peracid 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 61-62°C and with a mp of 72-74°C.


  1. Höring, 'Über die Dibromide aromatischer Propenylverbindungen', Chem. Ber. 38, 3464 (1905)
  2. Mannich, 'Studien in der Reihe des Adrenalins', Arch. Pharm. 248, 127 (1910)