alchemizt
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Catalysts to help NaBH4 reduce amides
NaBH4 can't by itself reduce amides to amines. But surely there must be a catalytic system that can enable it to do so?
Adding a nickel sale like NiCl2 (nickel chloride) converts it into a nickel boride which is a more powerful reducing agent, but can it reduce amides?
Supposedly nickel borides are ideal for reducing nitro groups to amines. But amides I'm not so sure about.
What other catalysts convert borohydrides into more powerful reducing agents? What about cobalt catalysts? Or copper?
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Niklas
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Borane works well for reducing amides, either make it in-situ from sodiumbrohydride and iodine (https://pubs.acs.org/doi/10.1021/jo00020a052) or make a shelf stable borane source like ammonia-borane complex by reaction sodium borohydride with
ammonium sulfate in THF and filtering off the formed sodium sulfate (http://orgsyn.org/Content/pdfs/procedures/v102p0019.pdf).
Also both nickel chloride and cobalt chloride catalysis can be used to reduce nitriles using borohydride, so I would guess it might work for amides
too (https://erowid.org/archive/rhodium/chemistry/nitrile2amine.n...).
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Lionel Spanner
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+1 for sodium borohydride and iodine - this works at room temperature, and it also works for carboxylic acids.
I have managed to reproduce that reaction, and one key detail the authors don't mention is that the solvent must be dry - if it's not sufficiently
dry, it won't work at all, or the yields will be terrible. I also found that the reaction is not air-sensitive; the intermediate is some kind of boron
compound for sure, but it's not borane itself.
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zed
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Well, it isn't done often, but NaBH4 and Aluminum Chloride, form a complex that will reduce Amides. Yeah, yields aren't great, and expensive solvents
are involved. Typically Glyme or Diglyme. Also. slightly elevated temperatures are required(thus the exotic solvents).
Had an acquaintance that utilized the system to reduce Amides of Indole-3-Acetic Acids, to the corresponding N,N-Di-Alkylamines.
Yields were only in the 30-35% range. And, there was the ever present danger of explosive mishap.
It might be better to utilize appropriate precautions, and perform the reduction via the dreaded reagent.... LiAlH4!
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clearly_not_atara
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Zinc borohydride is a preferred reductant for amides IIRC. ZnCl2 must be anhydrous.
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Keras
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Why not use a Hofmann rearrangement?
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Niklas
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That would shorten the carbon chain by one carbon.
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Keras
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Yeah, but you simply prepare an amide one carbon longer.
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Niklas
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Depending on the substrate that‘s quite a difficulty, going from an Amide to an Amine this way would require one to hydrolize the amide, do an Arndt
Eistert homologisation or something of the kind (requires diazomethane), quench the intermediate ketene with ammonia, and then do the Hoffmann.
If it’s further down into a synthesis maybe changing the overall plan might be an option, but I couldn‘t tell if that‘s viable as we don’t
know the exact substrate.
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Keras
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No, I mean you start from a different material in the first place.
Say, instead of using acetic acid you use propanoic acid.
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zed
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Niklas, what are you trying to make? Be more specific.
Also, I haven't worked with Nickel Boride in a long time, but back in dinosaur days, Nickel Boride wasn't considered a powerful reducing agent.
Nickel Boride was a newly utilized Hydrogenation Catalyst.
Some ground-breaking studies were authored by Brown.
Generally speaking, "powerful reducing agents" are incompatible with water. Such agents glom on to the Oxygen present, and release massive amounts
of Hydrogen.
Generally, that Hydrogen ignites or detonates.
Fun, if you are throwing a pound of Sodium into the ocean. Boom! Fireworks! Not fun, if it happens in your lab.
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Lionel Spanner
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My understanding is that it's less powerful than sodium borohydride as zinc is a softer Lewis acid than sodium. I've come across a paper detailing a
shelf-stable form that can selectively reduce imines in the presence of aldehydes.
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clearly_not_atara
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You are right, it is a little more complicated than that 
https://academic.oup.com/bcsj/article-abstract/64/9/2730/734... | Quote: | | In the presence of a tertiary amine, sodium borohydride (NaBH4) combined with zinc chloride (ZnCl2) showed powerful reducing
properties and carboxylic esters were smoothly reduced to their corresponding alcohols which were not obtained by reduction with NaBH4 and ZnCl2
alone. Tetrahydrofuran (THF) was an efficient solvent, and the effective molar ratio of the reducing agents, NaBH4 : ZnCl2 : tertiary amine, was 2 : 1
: 1. In particular, aminobenzoates such as anthranilic esters, were reduced to aminobenzyl alcohols with high yields without the addition of a
tertiary amine. Further, it was also found that this combination reduced nitro, cyano, and amido groups to their corresponding amino groups.
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