ForbesMcKinley
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Secondary from primary amine for non-horrible cost, ideally without imine racemization
Hey scimad,
Working on 1-phenyl-N-propylpentan-2-amine from 1-phenylpentan-2-amine. Making the latter starting with 1-nitrobutane via kornbluth from
1-bromobutane and sodium nitrite, then forming 1-phenyl-2-nitropent-1-ene from benzaldehyde and 1-nitrobutane with catalytic ethylenediamine, then
reducing to 1-phenylpentan-2-amine with hydrazine hydrate/zinc.
The end goal is specifically (R)-1-phenyl-N-propylpentan-2-amine. I figure dutch resolution with (R,R)-tartaric acid is the right way to go about
this.
I could resolve 1-phenylpentan-2-amine, then take a chirality-preserving approach for forming the secondary amine and hopefully avoid forming an
intermediate imine, probably via the propanamide (acylation to N-(1-phenylpentan-2-yl)propanamide with propionic anhydride & triethylamine, then
reduction with LiAlH4 or maaaybe Borane-THF (or DMS so it doesn't die in a day and take a billion hours reflux)?). Re-racemization of the primary
amine is probably a lot easier because basically amide reduction requires harsh conditions with expensive reagents and overall sucks, plus resolution
and racemization easier.
I figure if I'm not worried about preserving chirality, I could just reduce with propionaldehyde and NaBH4 I think? Downside is resolution and
re-racemization of the secondary amine is probably a good bit harder, but NaBH4/propionaldehyde is a helluva lot cheaper than the stronger reducing
agents I'd need in the propanamide route. If I'm lucky and conditions are very fast and mild there's a chance it only epimerizes a bit but seems
unlikely.
Running catalytic or transfer hydrogenation seems annoying and expensive too; maybe the raney nickel approach but might take harsh conditions and be
slow. There have been some recent papers on silanes (i think polymethylhydrosiloxane?) and zinc/salts for amide reduction but don't quote me on that.
I'm not aware of any good transfer hydrogenation approaches without noble metal catalysts; I looked at an iron-zeolite method that used isopropanol as
the donor but the mentioned catalyst was pretty dang pricey.
I could have messed up something here, or missed something, or not thought of something that applies and would make this a lot easier. I'm fairly new
so if I did something stupid please let me know  I'd appreciate whatever thoughts
y'all have.
[Edited on 5-2-2025 by ForbesMcKinley]
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clearly_not_atara
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I remember reading that furfural forms particularly stable imines with most amines. However, I've never actually seen a procedure where someone forms
the furfural imine, alkylates it, and then hydrolyzes the iminium to get a secondary amine. Still, I think it's an interesting possibility, since
furfural is relatively cheap.
The same method is often mentioned using benzaldehyde, which is similar, although the imines are not quite as stable.
There is also this:
https://patents.google.com/patent/US6423871B1/en
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ForbesMcKinley
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Gotcha, yeah furfural route might be a good option. If I'm understanding you right basically amine and anhydrous furfural forms imine, add propyl
bromide/chloride, probably under mildly basic conditions, then hydrolyze? I have no idea what sort of epimerization I could expect here ngl.
Cesium hydroxide seems like an interesting choice. My rough read is I can expect ballpark 85-89% yield from their examples and run around 1
equivalent CsOH; sound about right? Would like to potentially run this synthesis a few times and cesium isn't super cheap so might try to recover.
Vaguely think I might be able to bubble CO2 through CsBr solution, heat to destroy other bicarbonates, then treat with CaOH2 to recover CsOH solution?
Might be totally off-base. Molecular sieves amount seems crazy off; 500mg/1.7mmol implies over a kg for a larger synthesis.
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ForbesMcKinley
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This might be of interest in case anyone runs across this in future: https://pubs.acs.org/doi/10.1021/ol201351a
Looks like it provides decently selective and cheap N-alkylation in a TEMPO-BIAB system. Non-activated alcohol is oxidized to an aldehyde which
reacts to generate imine and reduce via NaBH4/NaBH(OAc)3. Yields are solid but it uses 2-3 equivalents of the amine which is a pain, since in this
case I have to synthesize the starting primary amine so that's my limiting factor from a cost perspective. Still, might be useful to someone working
with a bulk chemicals-type amine that doesn't need to be synthesized in-house.
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