help reducing 2-nitro-1-phenyl-1-propanol

[starlight]

hi there,

am trying to make some phenylpropanolamine.

Have attempted to reduce 2-nitro-1-phenyl-1-propanol with activated zinc catalyst / ammonium formate as in

Post 370871

(Barium: "2,4-dimethoxyphenylpropanolamine", Novel Discourse).

have failed at this twice now, achieving absolutely crappy yields.

I'm sure this can be sorted out in time, but not wishing to waste the last of my 2-nitro-1-phenyl-1-propanol, I wondered whether a reducing system that I am more familiar with would work.

Can anyone advise whether Red-Al or LAH would reduce the 2-nitro-1-phenyl-1-propanol to 2-amino-1-phenyl-1-propanol? If so then great, as I know how to do these reductions well.

Many thanks.

[Barium]

How did you perform the reduction with Zn/NH4COOH? How did the reaction progress? What did the result look like? Red-Al can be used, no problem. Same with LAH.

[starlight]

Hi Ba,

Can't remember how the first failure was done exactly. The second one however was done pretty much as in your post above except:

- it was scaled up by about a 2.5 molar ratio
- the formate was added in about 6 portions
- the temperature hit 77C

In addition (and maybe this is where my mistake is) after decanting the reaction mixture from the zinc, the zinc in the flask was extracted with 5% HCl in an attempt to make sure all of the free base was removed from the reaction flask. Maybe this made some Zinc Chloride too!.

When the acidic solution of the amine was basified, a voluminous white precipitate formed that was not extracted by the toluene washes (zinc hydroxide?).

Three toluene washes were performed to be sure of extracting all of the free base.

However the yield was down at about 5% so I gave up as the amount of material was too small to bother purifying and too impure (I guess from experience of this reducing system on nitroalkanes) to use.  The reaction product was a yellow oil.

Do you think the HCL extract caused the drop in yields?

[SPISSHAK]

would that be a potential cause of failure?

[Barium]

My guess is incomplete reduction. Many of the aminoalcohols are solids with a mp above 80°C (D-norpseudoephedrine mp 77-78, +/- phenylpropanolamine mp 101-101,5). I also belive that a few of them can be pretty slow to dissolve in toluene. Phenylpropanolamine, however, should be easily soluble in toluene. But remember to saturate the aqueous phase with NaCl in order to push the amine out of solution. Many of them loves to hang out in water.

Reflux the solution for 30-60 minutes after all reactants has been added. This never hurts a reduction like this. Also, it can be a bitch to work blind. Check the reaction progress with TLC to, at least, see when the nitroalcohol is consumed.

My experience with reduction of nitro groups tells me that nothing can be taken for granted. Especially not when reducing aliphatic nitro groups. Some reductions works well with the theoretical, or close to theoretical, amounts of reducing agent. In other cases you need to hit the nitro compound with e.g. 8-10 mol Red-Al/mol nitro to get decent yields.

If you want to try the Zn/formate-system again use excess reactants and apply reflux for a while.

[starlight]

Have a bit more data as well. I tried making the sulfate salt of the PPA by treating an ethereal solution of the PPA with an ethereal solution of H2SO4. First crop of crystals were white (maybe .25g). Second crop yellowish. Attempting to wash the yellowish crystals with acetone produced a dark green acetone solution!!

I did not saturate the aqueous layer with NaCl, so maybe my product was mostly in there!

Still, my next attempt will be with a stronger reducing system that I know how to use to good effect.

Thanks again for the advice.