Sciencemadness Discussion Board

3,4,5-trimethoxynitrostyrene reduction fun

mescalaniousmelvin - 26-11-2006 at 12:14

It seems like LAH is not a good option as it goes kaboom, precipiates always clog the stirbar, ether needs to be dry, styrene isn't that soluble in ether, etc, etc.

The best choice would seem to be a nitrostyrene->nitroalkane->amine

Conversion one would happen using NaBH4 in an alcoholic solvent system. The problem here would be the formation of a dimer due to a micheal addition. How would one reduce the risk of this, or avoid it straight out?

The amine is easy enough using Zn/Ammonium Formate.

Biginelli - 26-11-2006 at 13:48

What about NaBH4 in CF3COOH for phase 1?

Ullmann - 26-11-2006 at 15:24

Check this thread for a Al reduction of an homologous nitrostyrene.

It works great..

mescalaniousmelvin - 26-11-2006 at 17:04

^^^^^^^^

What do you think about scale up, what are the consequences of concenterating maybe 2-3e times...Perhaps control the exotherm in an ice salt bath with vigourous stiring?... also the yields are a little low.

I couldn't find any references on this procedure being used to reduce a,b unsat nitro compounds. All I could find was reduction of aliphatic and aromatic nitro compounds.

Also.. was a MP or NMR taken of the product in that synth eto prove it worked?

[Edited on 27-11-2006 by mescalaniousmelvin]

mescalaniousmelvin - 26-11-2006 at 17:18

Quote:
Originally posted by Biginelli
What about NaBH4 in CF3COOH for phase 1?


Seems possible, perhaps h20 might do the trick as well....

Ullmann - 27-11-2006 at 10:22

Quote:
Originally posted by mescalaniousmelvin
^^^^^^^^

What do you think about scale up, what are the consequences of concenterating maybe 2-3e times...Perhaps control the exotherm in an ice salt bath with vigourous stiring?... also the yields are a little low.

I couldn't find any references on this procedure being used to reduce a,b unsat nitro compounds. All I could find was reduction of aliphatic and aromatic nitro compounds.

Also.. was a MP or NMR taken of the product in that synth eto prove it worked?

[Edited on 27-11-2006 by mescalaniousmelvin]


About scaling up:

This was the only attempt done on a 3,4,5 PEA substrate but it was already done on a 2,4,5 alpha-alkylated substrate scaled up five times. The yields usually are in the 70-80% yields for recristallized NS (if the NS is not pure they drop greatly). The reason here for the 50% yield is not because of the reduction but because of the workup : the ammonium acetate salt of the compound is soluble in DCM especially here because the GAA was not removed from the mixture. Some of the product was hence extracted into the three organic washes that were used to take away the rose color from the acidic water layer.

A better workup should or distill the GAA and then extract with a NP solvent to remove the color and continue as described, or basify with lye the post filtration mixture to get rid of GAA by forming sodium acetate, extract the fb in a NP solvent, washes with water, extract with dilute HCl the compound outta the NP, wash once with a NP if there is rose color remaining, basify again and back extract into NP and evaporate to get the fb. It is more lenghty, and i am a lazy chemist and i do not need much product, but it should give a higher yield. If there is much value in the product it would be preferable to use this workup in place of the easiest one i posted.

If it is scaled up to say 100 mmol batch or greater, it is strongly advised a cooling bath (ice) is nearby because the exotherm can be very strong, also one or two efficient condensers must be used then and a big enough RBF should be used (i used a 4 liter three necked RBF for a 150 mmol batch).

I would not go over reducing half a mole of NS by this method, this would be too much exothermic to control and i think the content of the flask would go out like a volcano. Also the amount of hydrogen evolved can be quite important.

I would not concentrate too much this procedure, two or three times may be ok but not more as the solvent refluxing is useful to cool the reaction and control the exotherm and also because the Al sludge at the end could be too hard to stir if less solvent is used. Manual agitation was already needed at two times this concentration. A overhead stirrer (as opposed to magnetic stirrer) could probably be ok to stir the sludge but beware the evolution of hydrogen!

I have heard of several researchers who have used successfully this procedure, and it was a hive favorite soon before it went down. Rhodium has got write ups on this one reduction, and also hyperlab comrades use it quite often, search properly it is well known. IMHO it is the most convenient way to reduce NS, it is cheap and OTC also.

No analysis were done yet on the final amine, bioassays were conclusive... ;)

Good luck,

Dr Ullmann