[Bertrand]

  Hello everyone

I have some problems with making a connection in order to reach the final product of my synthesis.

I want to connect and amide an aldehyde thought a nucleophilic addition in order to get an N, O-alcohol product (Hemiaminal).

could you please give some advice? I have been trying to make that connection for a month using several papers but none of them lead me to the product.

Thank you very much in advance for your propositions 

[rolnor]

Can you post the reaction scheme? It sounds as if you are trying to make something unstable.

[Bertrand]

Hello! Thank you so much for your feedback.

Yes, the target compound is pretty unstable.  You will find attached the reaction scheme.

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going to


(mod edit convert structures to SMILES for inline representation)

[kriggy]

Tried this one?

https://pubs.acs.org/doi/10.1021/ol4031155

TBH, I dont think you can isolate your compound. There are cases of stable hemiaminals with free OH groups but thats AFAIK only in ring systems.

[Bertrand]

Thank you very much for your message, your help and for the paper.

I tried the synthetic mentioned in the paper but the synthesis did not work.

[rolnor]

Yes, it does not like something you can isolate.

[Bertrand]

Could someone suggest another synthetic route until the target compound, please?

[rolnor]

If the target compound is unstable you can not make it by any route.

[rolnor]

If you have a reference where they make this type of compound can you post this? It would be interesting to read.

[Bertrand]

Hello!
The compound has not been synthesized before. It has been isolated from a plant

[Bertrand]

 https://doi.org/10.1002/ejoc.201500655

Here is a paper in which the N, O-alcohol bond is made.

[hypervalent_iodine]

Hello!
The compound has not been synthesized before. It has been isolated from a plant

This seems...questionable. The compound you've shown looks to be quite unstable. If the isolation has been published, I would be very curious to look at the paper. I have seen examples of terpene derived hemiaminals, but those were able to be synthesised and shown to be stabilised through intramolecular H bonding (https://pubs.acs.org/doi/abs/10.1021/ol025558l). I'm not sure your target would be able to benefit from the same level of interactions.

[rolnor]

I am wrong Betrand, it seems stable. In your case you have multiple amide groups in your molecule, can this be a problem perhaps?

[kriggy]

Maybe the same method as in the zampanolide side chain synthesis could be used (decarboxylation of aminoacid derivative) but that would require little bit of re-doing the synthesis.

Based on all those publications shown in the thread I think it could be made because the aminals they prepare also dont have much hydrogen bonding to stabilize the aminal. They mostly do alcoholysis afterwards so maybe protecting the OH could work to make it more stable. There is a important note in one of the papers:

"The crude hemiaminals are unstable towards prolonged contact with water; therefore, a rapid workup is recommended!" however, they do aq. extractions...

OP: are you sure you have dry glassware and solvents? Maybe thats the problem.¨Also, could be nice to see what conditions did you try

[Bertrand]

Hello everyone!

I tried the conditions mentioned in this paper https://doi.org/10.1002/ejoc.201500655.
I even tried the synthetic route mentioned in this one (https://pubs.acs.org/doi/10.1021/ol4031155) basing on the synthesis of compound 7 which is quite similar to my target compound in terms of steric hindrance.