Easy and high yielding BH4 / CTH reduction of nitrostyrenes
After 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 (https://www.thevespiary.org/talk/index.php?topic=11742.msg45017900#msg45017900)
(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 KBH4(25% excess) in IPA/water exactly1 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 KOH2. 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 75oC while stirring. Evolution of hydrogen was noted around 50oC. 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 MgSO4, 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 H2SO4 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 8) !
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.
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
Accounting the 7 grams of water used in preparing the potassium formate solution (388 mmole), the water from the neutralisation (250 mmole), and the water from 13,5 grams of a 85 g formic acid / 100 g solution (112 mmole) ( <- which would be logical since it contains 250 mmol formic acid), we have exactly 750 mmol water :) 8)
I wonder, is there any particular reason why an water to formate ratio of 3 is prefered? In the patent Patent US4792625 (http://l2.espacenet.com/dips/viewer?PN=US4792625&CY=gb&LG=en&DB=EPD)
, it seems that the reaction goes (initially) faster at a ratio of 2,66.
I 'm sorry to bother you with a question about this futiliy, since the reaction works most beautifully. Probably the formate to water ratio doesn't matter that much (cfr.: Post 384333 (https://www.thevespiary.org/talk/index.php?topic=12193.msg38433300#msg38433300)
(Barium: "Dare I say quantitative yield", Novel Discourse)).
Great work !!! :) ;) .
I wonder, is there any particular reason why an water to formate ratio of 3 is prefered? In the patent Patent US384333, it seems that the reaction goes (initially) faster at a ratio of 2,66.
The ratio 2.5-3 has in my experienced proven to be the best yielding one. To much water definately fucks up the reaction! The water to formate ratio is very important to get right - otherwise yields and reaction times will go to heck...
bad boy - now i gotta sleep!!
After sleeping with the patent under my pillow & clearing the THC out of my head, I realised that the reaction consumes in fact 150 mmole of water.
50 mmol nitroalkane
250 mmol potassium formate
750 mmol water
250 HCOOK + 250 H2O --> 250 H2 + 250 KHCO3
50 -NO2 + 150 H2 --> 50 -NH2 + 100 H2O
________________________________________
50 -NO2 + 250 HCOOK + 150 H2O --> 100 H2 + 50 -NH2 + 250 KHCO3
I guess this more or less explains the rate of the reactions of Patent US4792625 (http://l2.espacenet.com/dips/viewer?PN=US4792625&CY=gb&LG=en&DB=EPD)
. Theoretically, the minimum water to formate ratio would be 150 / 250 (which would consume all the water from the medium).
The ratio 2.5-3 has in my experienced proven to be the best yielding one. To much water definately fucks up the reaction!
Then, the reaction not only consumes water ..., too much produces a hangover :-[ :) . Thank you for clarifying this point, Bandil.
The more I think about this reaction, the more I 'm impressed with this CTH.
EDIT: I screwed up the ref. to the patent in my previous post due to the partying (it has been corrected now <-- the screw-up was that I made a US patent out of Barium 's post :-[ ).
Now I have to iron it (the patent, not the pillow ;) )
Bandil wrote
There - the final HTML work is done and shipped off. Hopefully it will be online soon
I'm still looking forvard to read it.