MDP2P from Isosafrole via Epoxide Intermediate

by Osmium



See CA 107:39790k. Isosafrole in acetonitrile + H2O2 in methanol + Na carbonate (pH 8-10.5), temperature 10-45°C, 20h. 94% epoxide. This can be rearranged to MDP2P in about 90% overall yield. Possibly this could also work with straight safrole.

I don't have more info than this CA ref, but I'd try the following:

  1. Prepare a solution of isosafrole in 5 to 10 times the volume CH3CN.
  2. Add a slight molar excess of H2O2 to MeOH (same volume as above), add Na2CO3 until pH is in the desired range.
  3. Place the MeOH solution into a water bath and slowly add the acetonitrile solution of isosafrole, checking the pH.
  4. Stir for a day.
  5. Remove the solvents under vacuum.
  6. Extract the residue with an organic solvent, wash with water, dry if necessary, and evaporate.
  7. Dissolve the residue in 10 volumes ethyl acetate, add a few percent LiI or LiBr.
  8. Reflux for a day.
  9. Wash the solvent with water to extract the Li salts (recycle), dry solvent, evaporate.
  10. Residue should be MDP2P, further purification probably a waste of time.

I have never done that, it's just what I would do if I had a lab and the intent to produce MDP2P via this route. Don't blame me if this doesn't work or explodes into your face.


Ketone from Acetonitrile Epoxidation?

I have no idea if this will work for isosafrole. For all I know it could react with the ring instead of the side chain. If it did for the desired epoxide then it would still need to be refluxed in dilute H2SO4 to form the ketone (as with the performic methods).

"In an alkaline solution hydrogen peroxide reduces the intermediate to the amide with the liberation of oxygen, but at pH 8 no oxygen is evolved and the solution of peroxycarboximidic acid can be used to oxidize an olefin to its epoxide, pyridine to its N-oxide, and aniline to azoxybenzene."

"A low-cost method for epoxidation of cyclohexene is by dropwise addition of 30% H2O2 and NaOH to a stirred mixture of cyclohexene, methanol, and acetonitrile at 60°C, the yield of cyclohexene oxide is 85%"

Radziszewski reaction:

CH3CN + H2O2 ---[NaOH]--> CH3C(NH)OOH ---[H2O2]--> CH3C(O)NH2 + H20 + O2

I guess that the intermediate acid, CH3C(NH)OOH, would need to do a better job than regular peracetic CH3CHOOH in order for this to be sucessful with our favorite olefin.
The reference for this reaction is Payne, Deming, & Williams, J. Org. Chem. Vol 26, p569 (1961)