Call me a sissy
but I like to avoid ethers anytime I can. And now I´ve 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 ethylacetate. I did!!....
In a two-neck 250ml rb flask with a egg shaped stirbar containing 40ml EtOAc and 10ml denaturated EtOH(1), 3.63g(95mmol)NaBH4 is added in one portion. The flask is immersed in a 10 deg C 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 15 deg C and start add 5g(24mmol)2,5-dimethoxy-
beta-nitrostyene in 0.5g portions to the borohydride suspension. Keep the temperature between 20 and 30 deg C 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 sine 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.
(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. Don´t just throw it down the drain. Kill the borohydride with some aq. acid first.
This method has been used up to 0.2 mol scale without complications.
