Sciencemadness Discussion Board - 1-(3-bromo,4-methoxyphenyl)-2-nitroethene reduction

1-(3-bromo,4-methoxyphenyl)-2-nitroethene reduction

enima - 27-7-2005 at 00:39

I'm trying to reduce
1-(3-bromo,4-methoxypheny)-2-nitroethene to the appropriate phenethylamine. The purpose of this reaction is to familiarize myself with reductions.

The nitroethene was made from anisaldehyde followed by brominating using NBS. The yields on the bromination was around 80%. This was followed by a condensation of nitromethane using the hendry reaction and cyclohexamine. The nitrostyrene was recrystallized in IPA.

The problem I have run into is the reduction. Which is the best route to reduction that could be implemented while keeping the bromine attached.

I know the aluminium mercury amalgam is able to do this however mercury salts would prefferably be avoided (besides amalgams seem to be very messy compared to other reduction methods).

I was originally planning on doing a reduction of the double bond with NaBH4 followed by a catalytic tranfer hydrogenation. The NaBH4 does not reduce the halogen but the CTH does. (according to what I have read).

Can anyone provide a reduction method? help would be appreciated.

[Edited on 27-7-2005 by enima]

[Edited on 27-7-2005 by enima]

Nicodem - 27-7-2005 at 01:25

Quote:

Which is the best route to reduction that could be implemented while keeping the bromine attached.

It is very hard to dehalogenate an arylbromide like this one. Mostly only Pd, Pt and similar noble metal catalyst with hydrogen do this under harsh conditions as well as LiAlH4 if the temperature is not held very low.
It is very hard to reduce the double bond of a 2-aryl-nitroethane without causing the polymerisation (the formed nitroalkane adds on the double bond of the nitroalkene due to basic media). The reaction works efficiently only on 2-aryl-nitropropenes and higher homologues.

The best option is the Leminger's method using Zn/HCl/EtOH.

enima - 27-7-2005 at 13:04

Nicoderm, I have reduced 4-methoxyphenylnitroethene using NaBH4 and CTH, the reduction works well. The NaBH4 reduction is biphasic. (The reduction method has been posted by Barium @ the hive.)

My success with the Leminger reductions have not been very successful 1g-3g from 10g of starting material. The NaBH4 and CTH reduction of the 4-methoxyphenylnitroethene yielding 90% and 80% respectively.

I was thinking about using a Zn/Formate salt reduction, what do you think of this?

transformer - 28-7-2005 at 17:35

When it comes to reducing 4-fluoro-phenyl-2-nitropropane with Pd/C HCOOK normal reflux conditions with IPA definately do not cause dehalogenation.

As a side not Zn/Formate has often not been so successful for nitro reductions if you do not purify your nitroalkene.

Zinc/HCl always does the trick just make sure to activate your zinc, take time to add the HCl slowly and have a fair ammount of conc NaOH around to redisolve the zinc hydroxides during the post workup.

[Edited on 29-7-2005 by samsung]

enima - 28-7-2005 at 21:16

Thanks samsung, I think I will try the CTH reduction.

transformer - 29-7-2005 at 01:54

np

Also if you are unsure about the purity of your 1-(3-bromo,4-methoxypheny)-2-nitroethene it is advisable to isolate and recrystalize this intermediate before proceeding with the Pd/C reaction to get those high yields.

I have repeatedly observed moderate to poor yields when the isolated IPA layer from a post aq IPA/NaBH4 reduction was directly used in the Pd/C reduction.

Sandmeyer - 2-8-2005 at 02:30

enima, it seems strange that you got that bad yields from Zn/HCl, did you do it exactly as in the Leminger paper?

praseodym - 2-8-2005 at 05:50

I was thinking of a few methods which can be done...

Firstly, is it possible to do an electrochemical reaction as in reduction of the compound at electrodes?

Secondly, i guess that a strong oxidiser such as LiAlH4 can be used.

But i think the most effective way of doing it is by using NaBH4, EtOAc and EtOH. I think this is the way you should do it:
1) Add NaBH4, EtOAc and EtOH together and stir well.
2) Add, in small portions, the nitroethene. When 1/3 had been added the suspension turned to a thick white paste which had to be diluted with more EtOH. So another 10ml EtOH was added. Keep a close eye on the temp because the reaction could be quite violent.
3) When 2/3 was added, another 10ml EtOH had to be added.
4) This will cause a problem in the workup since it will carry the ester and some product over to the water phase.
5) Destroy the borohydride with dropwise addition of diluted acetic acid to the rxn vessel.
6) Add toluene together with brine.
7) Wash the solvent layer two times with water, once again with brine, dried and stripped of solvents in a rotovap.

I believe this will help you in the reduction reaction.

joe_aldehyde - 2-8-2005 at 05:55

Quote:

Originally posted by samsung
np

how did you purify the nitroalkane? the only method i could think of was to dissolve it in dilute NaOH to yield the nitronate salt, other organic impurities ought to stay in the organic layer.

praseodym - 2-8-2005 at 06:55

I wouldnt say that my method is 100% pure but its purity will be somewhere at the 97% range. I think purification could be done, in this case, by HPLC but i am still not very sure about that.

enima - 2-8-2005 at 07:46

Pd/C CTH will reducce the bromine group, it does so partially. (it reduces Cl - I).

I have been looking at a raney nickel CTH which selectively reduces the NO2 group leaving the Br intact.
It is very mild and selective. Anyone know how to make raney nickel?

Sandmeyer, I did, the reduction is tedious requring continuous addition of nitrostyrene and zinc to an hcl solution, the temps were kept to what the paper specified. (This was attempted a few years ago). This proceedure also does not scale very well.

praseodym, thanks for the double bond reduction, I have been using bariums reduction which has been faily successful (DCM is used instead f EtOAc, mainly for accessibility reasons along with a PTC Aliquatt 336) What EtOH are you using denatured or 95% w/ h20?

[Edited on 2-8-2005 by enima]

joe_aldehyde - 2-8-2005 at 08:36

HPLC, praseodym? why not something even more complicated

i just don't happen to have the equipment handy...

sparkgap - 2-8-2005 at 08:41

...and lithium aluminum hydride is no oxidizer either, praseodym...

Sigh...

sparky (~_~)

enima - 2-8-2005 at 08:59

yea LAH will also dehalogenate the aromatic.

transformer - 2-8-2005 at 16:57

Quote:

Originally posted by joe_aldehyde

how did you purify the nitroalkane? the only method i could think of was to dissolve it in dilute NaOH to yield the nitronate salt, other organic impurities ought to stay in the organic layer.

crystalize out the recovered oil and then recrystalizing from a suitable solvent, often IPA seems to work

praseodym - 3-8-2005 at 06:06

Quote:

...and lithium aluminum hydride is no oxidizer either, praseodym...

Sigh...

sparky (~_~)

Oops, that was a typographical error on my part. Sorry for that mistake. What i wanted to type was that a strong reducing agent such as LiAlO4 can be used.

praseodym - 3-8-2005 at 06:09

I was very tired when i was typing that, hence that mistake made. Not offended, right, sparkgap?

Apologies

enima - 3-8-2005 at 06:32

lol, no one is offended

the problem with LAH is that it WILL dehalogenate the ring which is what I'm trying to prevent. There is a nice paper in synthetic communications where Raney Nickel is used in a CTH to selectively reduce nitro groups. Carbonyl groups are not reduced, neither halogens. All is required is formic acid, IPA for the solvent.

I found the article while searching on google, it can be found at a hive mirror.

"Selective Reduction of Nitro Compounds
Using Formic Acid and Raney Nickel
Synth. Commun. 30(16), 2889-2895 (2000)"

Link

[Edited on 3-8-2005 by enima]

praseodym - 3-8-2005 at 06:41

So does formic acid work on the reduction of 1-(3-bromo,4-methoxypheny)-2-nitroethene?

enima - 3-8-2005 at 07:13

the C=C bond will have to be reduced first with NaBH4. Formic acid as the hydrogen donor should be able to reduce the nitroalkane to the amine, leaving the bromine intact.

Raney Nickel is the catalyst. I wonder if Urushibara could do the same job? I suppose the only way to find out is to test it.

joe_aldehyde - 4-8-2005 at 06:06

Quote:

Originally posted by enima
the C=C bond will have to be reduced first with NaBH4.

under these conditions, how does one minimize the possibility of polymerization? large volume of solvent, huge excess of borohydride?

praseodym: formic acid will work in conjunction with Pd/C or Raney Ni, i've been told by a former hive member that there is a certain trick to improve yields in CTHs: use 1eq. KCOOH instead of HCOOH and add 3 eq. HCOOH during reaction, eliminating the precipitation of K2CO3 (this applies when using Pd/C, i'm pretty sure that it works with Ra-Ni,too).

transformer - 4-8-2005 at 17:29

Quote:

Originally posted by joe_aldehyde

under these conditions, how does one minimize the possibility of polymerization? large volume of solvent, huge excess of borohydride?

Yes, silica in combination with a 4 molar exces of borohydride seems to minimize dimer formation.

praseodym - 4-8-2005 at 23:05

Quote:

Originally posted by samsung
Yes, silica in combination with a 4 molar exces of borohydride seems to minimize dimer formation.

How does silica with borohydride help to minimise dimer formation? Does it act as a Mw control agent in this case??

transformer - 5-8-2005 at 02:50

During the NaBH4 reduction the highly polar and negativeley intermediate is formed on the protic insoluble silica gel and will accept a proton before it has the chance to undergo a michael addition.

For more information check out this paper: ns.nabh4-silicagel.pdf

dextro - 20-10-2006 at 10:02

Quote:

Originally posted by samsung
During the NaBH4 reduction the highly polar and negativeley intermediate is formed on the protic insoluble silica gel and will accept a proton before it has the chance to undergo a michael addition.

For more information check out this paper: ns.nabh4-silicagel.pdf

the link doesn't work anymore. has someone a new one or further informations about the use of silica in this reaction ?

thx

[Edited on 1-21-2011 by Polverone]