BottlenecksGhost (Stranger)
05-14-03 15:26
No 433137
      Can benzophenone be used in Knoevenagel rxn?  Bookmark   

Does anyone have any information of benzophenone having been used in Henry/Knoevenagel or other active methylene condensations with nitroalkanes, esters, etc.?

If one could form the nitroalkenes in the conventional way, I was thinking it might be usable as a stepping-stone for elaboration to methadone, dipipanone or similar analgesics.

When benzophenone is boiled hard with nitromethane and aq. dimethylamine, the solution slowly yellows and finally reddens. When filtered, a red oil is retained in the filter, but it does not crystallize.

In any case, benzophenone seems much less reactive than benzaldehydes, and does not form a soluble addition complex with sodium bisulfite after stirring overnight.

If benzophenone can be used in base-catalyzed condensations with nitroalkenes, another difficulty seems to be the enamines. Enamines are traditionally made from aldehydes, and most ketones are not very reactive. And in the case of acetone, I have seen no report of enamines having been made from it. However, I was thinking that one could maybe make an enamine from ethyl acetoacetate (there is a ref on Orgsyn:, and then decarboxylate the resulting carboxylic acid condensation product.

General idea:


Molecule: benzophenone (" O=C(c1ccccc1)c2ccccc2 ")

Benzophenone + 1-nitropropane (Henry rxn) ->

Molecule: (2-nitro-1-phenylbut-1-enyl)benzene (" CCC(=C(\c1ccccc1)c2ccccc2)\[N+]([O-])=O ")

Molecule: acetone enamine (" O1CCN(C(=C)C)CC1 ")

2-nitro-1-phenylbut-1-enyl)benzene + acetone morpholine enamine (Michael addition, acidification) ->

Molecule: 5-nitro-4,4-diphenylheptan-2-one (" C(C(c1ccccc1)(c2ccccc2)C([N+]([O-])=O)CC)C(C)=O ")

5-nitro-4,4-diphenylheptan-2-one + dimethylamine (Michael addition) ->

Molecule: 2-Dimethylamino-4,4-diphenyl-5-nitrohept-2,3-ene (" C(/C(c1ccccc1)(c2ccccc2)C([N+]([O-])=O)CC)=C(/C)N(C)C ")

2-Dimethylamino-4,4-diphenyl-5-nitrohept-2,3-ene + sodium borohydride (reduction) ->

Molecule: 2-Dimethylamino-4,4-diphenyl-5-nitroheptane (" C(C(c1ccccc1)(c2ccccc2)C([N+]([O-])=O)CC)C(C)N(C)C ")

2-Dimethylamino-4,4-diphenyl-5-nitroheptane + (1.) NaOH, (2.) HCl (Nef reaction) ->

Molecule: methadone (" C(C(c1ccccc1)(c2ccccc2)C(=O)CC)C(C)N(C)C ")

(Hive Bee)
05-14-03 15:50
No 433141
      Looks nice  Bookmark   

I don't have any specific information on benzophenone at the minute, but according to the Merck Index, Knoevenagel reactions should work on ketones as well as aldehydes. It isn't surprising that benzophenone isn't too reactive; the steric interference must be huge in comparison to benzaldehyde. As for the bisulfite adduct, in the thread beginning with Post 431312 (synthesys: "Would MDP1P pass the bisulfate test?", Newbee Forum), both GC-MS and terbium say '1-ones' won't give addition complexes in the way aldehydes and '2-ones' do.

There are dozens of catalysts to try for the Knoevenagel, and it's often hard to pick one which fits the substrate using anything other than trial and error. Maybe methylamine could work, as it seems to be a rather generic catalyst.

It'll be very interesting to see how you get on, and I'm especially interested in that first