Easy and high yielding BH4 / CTH reduction of nitrostyrenesAfter much work with the CTH reduction i finally managed to get a pretty decent yield in an easy way! This first succesfull substrate was para-fluoro-(phenyl-nitropropene), but many will follow shortly.
Here is how it goes:
BH4 reduction:The following method was used:
Post 450179
(Barium: "Improvement", Novel Discourse), but please note:
a) Barium made a typo, switching the amount of IPA and water in the writeup. Please correct this prior to trying it out.
b)After finished reduction, 80% acetic acid is used to quench the remaining borohydride. Simply drip it in till the mixture stops fizzing.
7.4 g pF-P2NP (40.9 mmole) was added portionwise to a suspension of 2.8 g KBH
4(25% excess) in IPA/water exactly
1 as Barium described. After five minutes everything was added, the whole suspension was allowed to stirr for 30 mins. At this time 80% acetic was added dropwise till the fizzing subsided. Non-iodized table salt was poured in untill no more dissolved and stirred heavily for a minute or two. This was filtered through a small funnel to remove the borates + salt, and rinsed with a little IPA. The filtrate separated into an upper alcoholic layer(slighty yellow), and a lower aqeous layer (clear). The aqeous layer was discarded. The IPA layer was used without further fuzz in the following reaction.
CTH reduction:The following amounts where used. The amount of the nitropropane can simply be switched with the amount of nitropropene used, as the first reduction is so high yielding.
50 mmol nitroalkane
250 mmol potassium formate
750 mmol water
25-50 ml IPA (depending on how much is needed to get a nice solution)
10%w/w 5%Pd/C (catalyst to substrate)
The IPA layer from the previous reaction was topped of with +20% more to make it a little more dilute. 0.7 g of 5% Pd/C was added to the IPA layer and stirred heavily.
In another beaker 7 mL's of water was made into a slurry with 14 g's of
dry KOH
2. While stirring like a madman, 13.5 g 85% HCOOH was dripped in (caution: very exothermic). Do the math yourself on how much water to add. You get water from: the neutralization of the two acids, the water in the formic acid, the KOH and perhaps the Pd/C if you use prewetted.
The potassiumformate mixture was poured into the nitro/IPA flask in one portion. The whole lot is heated to 75
oC while stirring. Evolution of hydrogen was noted around 50
oC. A few mL's of 80% acetic acid was added now and then, when the mixture got too "lumpy" (4 mLs was used in total). After two hours the hydrogen evolution had subsided and the reaction was deemed over.
The black slurry was filtered twice through filter paper (first time alot of black sludge came through, but simply use the same filter as before as a "plug" for the second filtering). The filtercake was rinsed with a little IPA to get all the goodies with it. The final filtrate was almost colourless. After saving the filtrate, the filtercake was washed with water a few times and saved in the "used 5% Pd/C pile".
The almost-clear filtrate was saturated with table salt and filtered (the Pd/C filtercake can actually be re-used here and THEN cleared up with water). The lower aqeous layer was yet again discarded and the IPA stripped at atmospheric pressure.
The yellowish oil residue weigthed 6.5 grammes. This was dissolved in dilute hydrochloric acid and washed twice with 15 mL's DCM, giving a nearly colourless solution (perhaps a tint of green/yellow?). The aqeous layer was basified and extracted with 3*20 mL DCM. The DCM was dried with a tiny bit of MgSO
4, filtered and stripped. This left 4.5 grammes of a clear oil (p-F-amphetamine). The yield the total reduction is 72% with very easy steps in between
.
The p-F-amphetamine was dissolved in IPA, and precipitated with
a precisely half molar amount of H
2SO
4 dissolved in IPA. This was added in a thin stream and when the whole mess was unstirrable it was filtered and the filtrate titrated with the acid again. Yield of the sulfate salt was quantitative (95%+), which is good enough for me
!
Conclusion:Yeah! With a little practice the reduction from the nitropropene to the amphetamine can be done in about five hours total. The yields are really good, and reaction conditions are mild. It does not seem to bother the reactions, that the same IPA is used throughout the scheme.
Pretty slick dare i say!
Notes:1) Potiassium borohydride was used as it was the closest container. The sodium version works exactly the same (except the different molar weight of course).
2) If using the regular 15% water KOH, please compensate for the additional water in your calculations.