clearly_not_atara
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Conversion of aldehydes to hydrazones with urea?
The idea is to use urea as a "masked" hydrazine, forming an adduct with the aldehyde and then performing the Hoffmann degradation.
First, we can react the aldehyde with urea to form a hemiaminal, and eliminate water to form the enamide (or enurea):
http://www.sciencedirect.com/science/article/pii/S0040402004...
Alternatively, we can convert the alcohol to a vinyl ether, and couple to the amide with palladium, eliminating alcohol, which might be more
efficient:
http://pubs.acs.org/doi/abs/10.1021/ol0494360
In both cases we of course hope for urea to functionalize at only one nitrogen, which means we want to use it in excess. I'm not sure how easy it is
to prefer hemiaminal formation over the alkylidene-bis-urea. It might also be possible to convert the bis-urea adduct to an enamide but I never found
a case where that was done.
From the enurea, a Hoffmann degradation should give an enhydrazine, which rearranges to the hydrazone. This reaction is famous enough that I don't
need to cite it, although references on this particular substrate moiety are lacking.
The primary question is: Orgsyn mentions that water "catalyzes the disproportionation of hydrazones to azines and aldehydes". Obviously this is not
desirable. Some details on the disproportionation are in this paper:
http://pubs.rsc.org/-/content/articlelanding/1966/j3/j396600...
to which I do not have access. It may be possible to degrade the urea in alcohol to a carbamate and transesterify this in acetic acid to yield the
hydrazone. However even these conditions might introduce disproportionation and I'm not sure how severe the problem is.
Anyway, can someone get the paper? :3
EDIT: Reasoning about it, it seems that hydrazone disproportionation starts when the lone pair pyramidal nitrogen attacks the hydrazone carbon, i.e:
R2C=N(H2N + R2C=NNH2 >> R2C=NNHC(R2)NNH2
So disproportionation is promoted in basic conditions and suppressed when the hydrazone is protonated, since the hydrazonium RNNH3+ has no lone pair.
This comports well with the refs I've seen which describe disproportionation accelerating at higher pH. Since the Hofmann degradation is alkaline, we
have to perform the carbamate procedure, but cleaving the carbamates in acetic acid should be okay. Orgsyn produces acetone hydrazone from acetone
azine and hydrazine:
http://www.orgsyn.org/demo.aspx?prep=CV6P0010
It appears that the formation of hydrazine hydrate serves to drive the equilibrium towards hydrazine + azine, since the latter mixture will regenerate
the hydrazone if it is dehydrated and heated. It seems possible that hydrazones dimerize in storage to 1,2,4,5-tetrazinanes, which explains how
acetone hydrazone disproportionates "reversibly" in storage (a phenomenon which befuddles my thermodynamic intuition). It might be necessary to use a
stronger acid than acetic acid, but I hope not.
Anyway, once you get the hydrazonium acetate from the cleavage reaction, I think you should be able to convert this to freebase hydrazone with an
amine base, since IIRC hydrazones are much weaker bases than amines. It seems possible that you might even be able to simply heat it until it loses
acetic acid
[Edited on 6-3-2017 by clearly_not_atara]
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Zandins
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Paper
Here comes the paper:
Attachment: day1966.pdf (402kB)
This file has been downloaded 390 times
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clearly_not_atara
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The original paper discussing Barton's iodination has a procedure for preparation of hydrazones using wet hydrazine with triethylamine and ethanol:
http://pubs.rsc.org/-/content/articlelanding/1962/jr/jr96200...
| Quote: | | ) The aldehyde O (4.64g.) in ethanol (40ml.) and triethyl- amine (15ml.) was refluxed with 64% hydrazine (20ml.) for 30 min. The mixture was poured
into water and the crystalline O-benzylisovanillin hydrazone collected (4.20 g.) |
Intriguingly it appears that ethanol does not promote disproportionation at all and may even discourage it. Perhaps the degradation of a hydrazone
carbamate (by alcoholic enurea Hofmann) may be carried out with a small % of strong acid in ethanol. Hopefully this produces ether as the byproduct
and does not N-alkylate the hydrazone.
[Edited on 6-3-2017 by clearly_not_atara]
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clearly_not_atara
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(apparently I cannot edit this post)
After doing some thinking I think this was a good source of ideas, but I did things backwards. If you can perform the Hofmann on urea and get a
carbazate, why not just... do that?
urea + Br2 + ROH >> carbazate
http://www.sigmaaldrich.com/catalog/product/aldrich/e16503?l... (see I didn't make that name up)
Seems I was wrong about the appropriate deprotection conditions; this paper says acids are bad, but it also says I'm on the right track:
"Hydrazides and hydrazones from carbazates"
It appears they're using fluorenyl. However, this thesis said that a carbazate derived from phenol can be used:
http://www.ruor.uottawa.ca/bitstream/10393/30725/3/Garland_K...
Phenol esters are very easy to deprotect and in fact the paper notes that in some cases it may be deprotected by mere heating. So phenyl carbazate may
be the ticket. Hopefully phenol does not spontaneously react with TCCA.
EDIT: couldn't you just cleave the carbazate to the sodium salt with fused NaOH? Carbamic acids usually won't deprotect until they're protonated after
all. The hydrazone can only cleave or disproportionate after the acid comes off, and the paper above uses ice water for the workup after cleaving Fmoc
with morpholine, so we could get away with a cold bicarbonate solution, maybe? In other words: 1. methyl carbazate + NaOH >> sodium carbazate;
2. sodium carbazate + NaHCO3/H2O >> hydrazone
[Edited on 8-3-2017 by clearly_not_atara]
[Edited on 8-3-2017 by clearly_not_atara]
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CuReUS
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If I am understanding this correctly,the problem here is how to convert the isocyanate from the hoffman to amine(to make the hydrazine) without
hydrolysing the enamide.See this -https://dx.doi.org/10.1002%2F0471264180.or003.07 (pg 282,pg 16/31 in pdf) under "special conditions for the hoffman reaction of higher aliphatic
amides and a,b-unsaturated amides",where they convert the isocyanate to carbamate and then treat that with base to get amine
you could use N-chlorourea to achieve that
[Edited on 9-3-2017 by CuReUS]
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