Восстановление нитростиролов борогидридом натрия и алюминием.

Эта реакция была предложена и проверена знаменитым американским юхимиком Spitball'ом, который сейчас к нашему величайшему горю находится в американской федеральной тюрьме, и будет находиться там ещё минимум 16 лет. Давайте пожелаем ему всего самого хорошего.

Протекает она в две стадии, первая - восстановление нитростирола до соответствующего нитроэтана борогидридом натрия в метаноле. Вторая - восстановление нитроэтана в амин каталитическим переносным гидрированием (используется палладиевый катализатор, однако скелетный никель тоже годится для гидрирования).

Обе реакции протекают с высокими выходами, поэтому в настоящее время она наиболее популярная в среде наших менее стеснённых в средствах иностранных коллег.

Процедура:

1. Sodium borohydride reduction of 2,5-dimethoxynitrostyrene

а) Оригинал (от Beaker'a).

Into a dry 2L RBF flask equipped with a stir bar was added 400mL of anhydrous ethanol(If you can't get anhydrous ethanol, use anhydrous IPA. DO NOT USE METHANOL!!!). The rxn was cooled to 0C in an ice/water bath and 36.2g of sodium borohydride was added(slight H2 evolution). A pressure-equalized addition funnel was charged with a pre-made saturated solution of 50g 2,5-dimethoxynitrostyrene in THF(about 600mL) and attached to the flask. A piece of tubing was attached to the top of the addition funnel and run outside to vent the hydrogen that is will evolve during the course of the reaction. While maintaining the ice/water bath, slowly(reaction is exothermic, so go slowly) all of the bright yellow nitrostyrene solution(refill the addition funnel if necessary) was added to the sodium borohydride solution over the course of ~90 min (Note: gas will evolve over the course of the addition. It is H2. Be careful). After the addition is complete, the rxn was allowed to stir for an additional 10 min and then poured into a 4L erlenmeyer containing 1L of H2O and a 3" stir bar (H2 evolution). While stirring, 250mL GAA (Heavy H2 evolution) was carefully added (one could use 400 mL 31.45% HCl). The quenched reaction mixture was divided into three portions. In a 2L sep funnel, each portion was combined with 500mL Et2O(or toluene) and 500mL brine. The funnel was shaken and the aqueous(bottom) layer was discarded. The organics were washed with 3 additional 500mL portions of brine. This was repeated with the other two portions. The organics were combined, dried over MgSO4, filtered and the solvent evaporated to give a clear yellow oil. Yield - 47.0g of crude 2,5-dimethoxynitroethane

б) Усовершенствованный вариант (без ТГФ) от Barium'a.

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. Donґt 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.

2. Catalytic Transfer Hydrogenation of Crude 2,5-dimethoxynitroethane

The crude product of the previous step was dissolved in 400mL MeOH and placed in a 1L RBF equipped with a stir bar. In a separate beaker away from all combustible materials, 1g of 10% Pd/C was carefully wetted down with MeOH and the resulting slurry transferred to the rxn flask. To the rxn flask was added 62g ammonium formate. The flask was equipped with a reflux condensor, a piece of tubing was attached to the top of the condensor, and the end of the tubing was submenged in a container of water (this works to exclude O2 from the rxn while allowing the evolving CO2 to escape). The rxn was gently refluxed for 24 hr.(CO2 evolution), cooled, filtered through celite to remove the Pd/C, and the solvent evaporated. The residue was taken up in 150 mL of Et2O (or toluene) and 300 mL of H2O and the pH adjusted to >12 with 20% NaOH. The mixture was transfered to a sep funnel, shaken, and separated. The aqueous layer was extracted with 2 x 100 mL portions of Et2O (or toluene). The combined organics were dried over MgSO4, filtered, and gassed with HCl (2CH x HCl is partially soluble in DCM, so don't gas in that solvent). The resulting white crystalline solids were filtered, washed with Et2O, and allowed to air dry to give 2CH Hydrochloride. Yield - 43.8g (94%) of 2CH Hydrochloride

Примечание 1 - ещё один пример catalytic transfer hydrogenation Вы можете найти здесь.

Примечание 2 - полученный в шаге 1 фенилнитроэтан может также быть восстановлен в амин алюминиевой амальгамой или цинком в серной кислоте. Весьма вероятно, что каталитическое гидрирование на никеле Урушибары также сработает хорошо.

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