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Improved NaBH4 reduction of nitrostyrenes to phenylnitroalkanes

by Barium
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Call me a sissy but I like to avoid ethers anytime I can. And now Ive found a way of avoiding THF in a otherwise good procedure.

2,5-Dimethoxynitrostyrene is reduced by sodium borohydride to 1-(2,5-dimethoxyphenyl)-2-nitroethane. A reduction which has given many people gray hair prematurely. In theory it is simple and straightforward, but in practice it can be a great way to make tar.

Beaker found a method (my guess is from Synthetic Communications, 886-887, 1985.) and modified it slightly. The authors tried 1,4-dioxane, THF, various mixtures of MeOH, EtOH or i-PrOH and said ethers, as well as the not too good chloroform/IPA/sillica gel. Beaker settled for THF since it is more readily avalible than 1,4-dioxane which the authors choosed. It seems like neither the Indian authors or Beaker tried ethyl acetate. I did!

Reduction of 2,5-dimethoxy-beta-nitrostyrene to 1-(2,5-dimethoxyphenyl)-2-nitroethane

In a two-neck 250ml rb flask with a egg shaped stirbar containing 40ml EtOAc and 10ml denaturated EtOH(1), 3.63g (95mmol) commercial NaBH4 is added in one portion. The flask is immersed in a 10C cooling bath. A 4-bulb Allihn condenser(2), with cold tap water running through it, is inserted in the central neck and a thermometer in the side neck. Let the temperature drop to 15C and start add 5g (24mmol) 2,5-dimethoxy-beta-nitrostyrene in 0.5g portions to the borohydride suspension. Keep the temperature between 20-30C during the addition, which takes some 15 minutes. When all nitrostyrene has been added allow the reaction mixture stir for another 20 minutes.

Add 50ml cold water to the reaction mixture and stir for a couple of minutes. Transfer the mixture to a 500ml separation funnel and remove the bottom aquoeous layer(3). Add another 50ml portion of cold water, shake, allow to separate and remove bottom layer. Add a third portion of 25ml cold water and dropwise 50% aq. acetic acid untill gas evolution ceases. One might need to shake it now and then to bring the aqueous layer in contact with some borohydride still remaining on the walls. When no more gas is evolved add 50ml brine, shake, let separate and remove the bottom layer. Now you will have a bright yellow solution of the phenylnitroalkane in some wet EtOAc, dry with some MgSO4 and strip off the solvent to give a yellow oil. Yield 4.94g (98%) 1-(2,5-dimethoxyphenyl)-2-nitroethane, purity 97% (HPLC).

(1) If possible choose ethanol not denaturated with ketones. However the small content of acetone, MEK or other ketones does not interfer with the reaction since they are reduced before the nitrostyrene is added. The ketone content in regular denaturated ethanol is normally between 4-5%. If the only option is a ketone denaturation, calculate how much borohydride will be consumed and make the necessary correction. Sodium borohydride reacts with the alcohol to form the corresponding alkyloxyborohydride, which is the actual reducing agent. Ethanol reacts and forms mono-, di- or tri-ethoxyborohydride more easily than IPA (steric hindrance or not acid enough?). MeOH reacts too good with borohydride to be useful here.

(2) The reason for using a condenser is to minimise the loss of solvent carried along by the evolved hydrogen.

(3) This solution contains quite a bit of unreacted borohydride. Dont just throw it down the drain. Kill the borohydride with some aq. acid first.

The above method has been used up to 0.2 mol scale without complications. I have also tried the same reaction with toluene instead of EtOAc, and it seems to work just as fine. The only drawback is that more toluene than EtOAc is needed, about 50% more, because the nitronate intermediate REALLY comes out as it is formed.

Another try, using less NaBH4

5g (23,9mmol) 1-(2,5-dimethoxyphenyl)-2-nitroethene was added in portions to 1,1g (28,7mmol, 1,2eq) NaBH4 in 50ml toluene and 10ml EtOH. The reaction was kept at 20C by immersion in a cold water bath. When 2/3 had been added the temperature did not rise so fast after each addition so the remaining 1/3 of the nitrostyrene was added in one portion. After about one hour the solution had only a very pale yellow color. 20ml water was added, this caused a lot of bubbling and a white solid fell out of the solution. Diluted acetic acid was added dropwise until gas evolution ceased. Solid NaCl was added to the reaction flask and everything was strirred for 5min. The two phases was poured into a sep funnel, leaving some undissolved NaCl behind. The bottom aquoeous layer was removed and the toluene layer was washed with 2x 100ml water, dried with MgSO4 and the solvent removed in a rotovap leaving a pale yellow oil. Yield 4,7g (92,8%) 1-(2,5-dimethoxyphenyl)-2-nitroethane.


The same procedure was used to make 1-(3,4,5-trimethoxyphenyl)-2-nitroethane from 3,4,5-trimethoxy-beta-nitrostyrene. The only difference was that I allowed the temperature to rise to 45C when 2/3 of the nitrostyrene had been added. Otherwise the reaction would have taken a long time due to the poor solubility of the substrate in the solvent. Will try again with toluene as solvent. The following amounts was used;

  • 23,9g (0,1 mol) 3,4,5-trimethoxy-beta-nitrostyrene
  • 15,2g (0,4 mol) NaBH4
  • 200ml EtOAc
  • 40ml EtOH

Yield 23,5g (97,5%) phenylnitroalkane as a colorless solid. Purity 98% by HPLC


4,15g NaBH4 stirred happily in 50ml EtOAc and 10ml EtOH at 15C. 5g 1-(2-fluorophenyl)-2-nitropropene was added in small portions. Be careful here! The first 250mg or so caused a violent bubbling, much more than the earlier ones. The temp rose 8C from that small portion. Wierd! 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. Kept on adding happily, but kept a close eye on the temp. When 2/3 was added, another 10ml EtOH had to be added. Paste again! The total amount of EtOH added was 30ml. This will cause a problem in the workup since it will carry the ester and some product over to the water phase. This time I destroyed the borohydride with dropwise addition of diluted acetic acid to the rxn vessel. When this was done, 100ml toluene was added together with 50ml brine. The solvent layer washed two times with water, once again with brine, dried and stripped of solvents in a rotovap.

Yield; 4,3g (84,9%) 1-(2-fluorphenyl)-2-nitropropane as a clear yellow oil. Purity; 97% (HPLC)


25,3g (100mmol) 1-(2,4,5-trimethoxyphenyl)-2-nitropropene was added portionwise to a suspension of 11,4g (300mmol) NaBH4 in 150ml AcOEt and 43,2ml (1,2mol) EtOH @ 20-25 deg C. An ice-water bath needed to cool the reaction mixture. The addition took 25 minutes. It was the allowed to stir at room temp for an additional 20min. Excess borohydride was destroyed with diluted acetic acid. When gas evolution ceased 100ml toluene and 150ml brine was added. The organic phase was washed twice with water (2x100ml) and once again with 100ml brine. The solvent was dried with MgSO4 and stripped off in a rotovap. The residue solidified to a clear yellow cake. This cake was dissolved in 150ml MeOH which gave a bright yellow solution. To this solution 500ml ice-cold water was added. This gave in 5min a thick slurry of colorless fluffy crystals which were filtered off and dried.

Yield 23,7g (92,9%) 1-(2,4,5-trimethoxyphenyl)-2-nitropropane