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Author: Subject: aldehyde bisulfite adduct to acid azide
karlos³
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[*] posted on 29-6-2018 at 03:14
aldehyde bisulfite adduct to acid azide


Hey, so I do have a problem and I would really greatly appreciate if someone could give me some tangible advice on that problem.

I want to do a modification of the albright-goldman-oxidation of a bisulfite adduct of an aldehyde.
Normally, that would give when the reaction is quenched with a nucleophile, either ammonia/amines for an amide, an ethyl/methyl alkoxide to give an ester, or aqueous K/Na carbonate to give an acid.

My problem here is now, that I want to change the used nucleophile to sodium azide instead, to hopefully give the acid azide directly.
I am relatively sure that it would work, but I do not know for certain?

And, the second problem related to this is, due to the usually careful conditions in which an acid azide is synthesised from an acid chloride(i.e. cold, around ~5°C, careful addition of the azide to the acid chloride/vice versa), so I am very hesitant to try this simply out.

Could somebody give me some really tangible tips here?
If this would work, and under which conditions it should proceed for an ideal outcome?

As the reagents I would want to use, some are either very precious/hard to get/expensive or dangerous(the NaN3 respectively).
Of course I will try to follow the reaction on a tlc-plate, but since the used reagents are a bit special, I would really like to get some useful advice before I am stuck with an only half-reacted toxic soup :(

Thank you really a lot, for anyone who could help me out here :)
The paper is attached where the idea is based on

(props to those who brought me on this great idea, you will read it and I thank you a lot! :D)

Attachment: aldehyde to amide ac2o bisulfite.pdf (185kB)
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wildfyr
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[*] posted on 29-6-2018 at 08:26


I'll have to think more on on the actual functional group conversion (though it seems reasonable), but the reason the acid azide is treated so carefully (and often, not isolated at all) is that it will undergo a Curtius rearrangement. Curtius rearrangement is the highly exothermic process of an acyl azide spontaneously converting into an isocyanate+N2 gas. Depending on the nature of the groups attached, this can happen immediately upon formation even at lowered temps, or require outside heating.

It is a pretty dangerous beast to play with. Spontaneous can mean REALLY spontaneous. It is typically done in dilute solution under controlled (cold!) conditions, to yield the isocyanate from the acid chloride in one pot, and purified by fractional distillation.
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karlos³
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[*] posted on 29-6-2018 at 09:48


Thank you, I was really not sure about this.
This is already a really helpful reply!

It is a bit larger, my molecule, so I do not fear a spontaneous curtius rearrangement.
I will then simply keep it cold during the NaN3 addition to the reaction mixture, and extract the azide carefully in a solvent, wash it in while dissolved, and will keep it cold.
This would be the same as when the same acyl azide was made from the acid chloride using the long and way more work-intensive route.
And then I will simply proceed with it.
Which would be, by the way, to carry out the curtius rearrangement on the azide, coincidentally :)

Distillation is really not intendend on the raw azide, only intended afterwards when the rearrangement is completed.

I wanted to skip the very annoying steps that would normally be needed, i.e. oxidation of aldehyde to acid, preparation of the acid chloride and then finally formation of the acyl azide.

Doing it via formation of the bisulfite adduct, followed by the albright-goldman oxidation, and without a purification step directly addition of the NaN3 solution in the cold.... that would be, of course, a really useful short-cut in comparison!

Also eliminated would be the most annoying step so far, the time intensive distillation of the acid chloride in vacuo, its preparation, while reducing the overall expenses too!
Because I don't need to use my expensive chlorination agents up for this, and can save the precious (cocl)2 otherwise being needed.

Again, thank you! :)

Of course, if someone else has to object, or helpful advice, I am all ears.
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CuReUS
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[*] posted on 29-6-2018 at 19:34


preparation of alkyl azides -https://erowid.org/archive/rhodium/chemistry/azide.rxns.html
another way to directly get the isocyanate -https://www.organic-chemistry.org/abstracts/literature/653.s...
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karlos³
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[*] posted on 30-6-2018 at 02:15


Oh no, for real?

Just typed a lengthy reply, uploaded six references and then that!

I'll keep it short:
CuReUS, I don't see the revelance for my problem?
I already made the acyl azides using the "old" method, via aldehyde->acid->acid chloride->acyl azide, but I would like to avoid that?

But anyway.
I did some research, maybe a little bit more even, and dived deeper into the topic of one-pot azidations of aldehyde and acids.
Found several very interesting things(and please do not tell me from tert-butylhypochlorit, please no!), and think I might have one or three real winner amongst them.
Especially the DMP(=dess-martin periodinane) analogue azidobenziodoxolone, which is as it seems easier to prepare, as the former mentioned preparation looks both longer, more costly and more elaborate.
But the routes via mixed anhydrides, using peptide coupling catalysts look nice too, use mild reaction conditions and thus are suitable for almost any sensible functional group, et cetera.
The real winner is probably the method that is using PCC together with NaN3, aldehyde->acyl azide... hopefully it is also versatile?

Hope this time it works...

Attachment: Azidation of Aldehydes with azidobenziodoxolone.pdf (1.3MB)
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Attachment: TBAI azidobenziodoxolone azidation aldehyde.pdf (449kB)
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Attachment: php8QriLl (134kB)
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Attachment: BOP acyl azide.pdf (108kB)
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Attachment: acid azides from acid using peptide coupling reagent HBTU.pdf (154kB)
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Attachment: Modified PCC oxidation aldehyde to acyl azide.pdf (202kB)
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clearly_not_atara
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[*] posted on 30-6-2018 at 16:10


Azidobenziodoxolone is made by rxn of the corresponding hydroxybenziodoxolone with trimethylsilyl azide. Unfortunately the requisite silane seems like a nonnegotiable component.

1-chloro-3,3-dimethyl-1,2-benziodoxole has been described, but it is made using tert-butylhypochlorite... the direct reaction of this with sodium azide has not been described afaict, but it seems obvious. 1-chloro-1,2-benziodoxolone does not seem to exist, possibly it reacts with itself.

Unfortunately replacing the dreaded TMSCl does not seem to be possible using reactions that have been documented here. Azidation is already easy if you have that.

But maybe you can replace tBuOCl in the synthesis of 1-chloro-3,3-dimethylbenzodioxole. Still have to get that precursor, though...

EDIT: look in to N-chlorosaccharin as an alternative to tBuOCl for these reactions, i think there's a good chance

https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/p...

[Edited on 1-7-2018 by clearly_not_atara]




[Edited on 04-20-1969 by clearly_not_atara]
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CuReUS
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[*] posted on 30-6-2018 at 19:34


Quote: Originally posted by karlos³  
CuReUS, I don't see the revelance for my problem?
my first link describes a way to make alkyl azides.You could apply that procedure here by replacing the alkyl halide with the bisulfite adduct.
the 2nd link shows another way to make isocyanates directly from aldehydes(via the acyl azide intermediate) without needing to convert it to the bisulfite adduct first.

[Edited on 1-7-2018 by CuReUS]
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wildfyr
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[*] posted on 1-7-2018 at 06:06


The direct from aldehyde one involves using IN3 which has to be prepared on site. Godspeed working with that sensitive compound.

Please report back with your bisulfite approach, it seems like a clever and reasonably safe idea.

[Edited on 1-7-2018 by wildfyr]
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karlos³
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[*] posted on 3-7-2018 at 08:41


Wouldn't it be problematic to add the sodium azide to the reaction mixture?

Because of the acetic anhydride...

@CuReUS, did you mean directly to the bisulfite adduct before the oxidation?
That would actually be very neat!
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CuReUS
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[*] posted on 13-7-2018 at 23:16


Quote: Originally posted by wildfyr  
The direct from aldehyde one involves using IN3 which has to be prepared on site. Godspeed working with that sensitive compound.

azides are already sensitive enough :P
Quote: Originally posted by karlos³  
@CuReUS, did you mean directly to the bisulfite adduct before the oxidation?
according to the erowid method,the azide is mixed with DMSO and the alkyl halide is added to the mixture.What I proposed was following the same procedure in the quenching step by using the oxidised bisulfite adduct in place of the alkyl halide

[Edited on 14-7-2018 by CuReUS]
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karlos³
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[*] posted on 24-7-2018 at 07:08


Ok thank you for clarifying CuReUS.

I have the bisulfite adduct ready and could directly try that synthesis.

But I still am not so sure about a possible reaction of sodium azide and acetic anhydride.
While the pka's are relatively safe as I see it(HN3 has 4,76 and AcOH has 4,72), what if it is not as safe as I think?
Of course, an anhydride reacts more like an ester and not acidic, but a tiny contamination of the acid could be in there.

The isolation of the oxidised bisulfite adduct looks somewhat problematic too, only method I can think of so far would be to distill everything volatile, the anhydride and DMSO, off with the use of reduced pressure.
It is after all, seemingly a bit sensible as obtained there, does react readily with base and alcohols.
And I would expect it to be also of limited solubility in most solvents, as bisulfite adducts usually are.

I probably would add a solution of the azide(in DMSO) directly to the cooled post reaction to quench it with this, if that is an option.
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clearly_not_atara
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[*] posted on 24-7-2018 at 09:02


According to:

https://pubs.acs.org/doi/abs/10.1021/jo00152a043

Acetyl azide decomposes at 40 C.

If you can oxidize the bisulfite adduct effectively, maybe rxn with acetate will give a mixed anhydride. IIRC mixed acetic-carboxylic anhydrides usually transfer the other group (this is true of acetic-formic at least).

EDIT: 1,2,3-triazole could be another alternative nucleophile. Somewhat conveniently, this can be produced by the reaction between hydrazoic acid and copper (I) acetylide, which should both be produced in situ for obvious reasons.

[Edited on 24-7-2018 by clearly_not_atara]

[Edited on 24-7-2018 by clearly_not_atara]




[Edited on 04-20-1969 by clearly_not_atara]
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CuReUS
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[*] posted on 25-7-2018 at 03:56


Quote: Originally posted by karlos³  
But I still am not so sure about a possible reaction of sodium azide and acetic anhydride.
your fear is justified.Azides do react with anhydrides-https://pubs.acs.org/doi/abs/10.1021/jo01067a604
Quote:
I probably would add a solution of the azide(in DMSO) directly to the cooled post reaction to quench it with this, if that is an option.
this is one of those reactions where nothing can be said without trying it first.
I suggest you use a very small amount of azide dissolved in DMSO,put this in an addition funnel,set it up over the flask containing the oxidised bisulphite mixture,start dripping slowly and get the hell out of there :D
seriously,use a good fume hood or do it outside.HN3 is poisonous :(
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