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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: Bertrand on January 04, 2020, 04:26:46 AM

Title: Synthesis of N-Acyl-N,O-alcohol
Post by: Bertrand on January 04, 2020, 04:26:46 AM
 :) 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 
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: rolnor on January 04, 2020, 01:14:32 PM
Can you post the reaction scheme? It sounds as if you are trying to make something unstable.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: Bertrand on January 06, 2020, 04:13:46 PM
Hello! Thank you so much for your feedback.

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

C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1C(N)=O +
O=CCCc1ccccc1 going to
C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1C(=O)NC(O)CCc2ccccc2

(mod edit convert structures to SMILES for inline representation)
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: kriggy on January 07, 2020, 07:01:52 AM
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.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: Bertrand on January 07, 2020, 10:38:49 AM
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.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: rolnor on January 07, 2020, 02:51:05 PM
Yes, it does not like something you can isolate.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: Bertrand on January 07, 2020, 03:29:20 PM
Could someone suggest another synthetic route until the target compound, please?
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: rolnor on January 07, 2020, 06:30:16 PM
If the target compound is unstable you can not make it by any route.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: rolnor on January 08, 2020, 03:57:17 PM
If you have a reference where they make this type of compound can you post this? It would be interesting to read.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: Bertrand on January 08, 2020, 05:55:43 PM
Hello!
The compound has not been synthesized before. It has been isolated from a plant
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: Bertrand on January 08, 2020, 06:02:51 PM
 https://doi.org/10.1002/ejoc.201500655

Here is a paper in which the N, O-alcohol bond is made.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: hypervalent_iodine on January 08, 2020, 07:14:43 PM
Quote from: Bertrand on January 08, 2020, 05:55:43 PM
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.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: rolnor on January 08, 2020, 11:34:25 PM
I am wrong Betrand, it seems stable. In your case you have multiple amide groups in your molecule, can this be a problem perhaps?
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: kriggy on January 09, 2020, 01:15:13 AM
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
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: Bertrand on January 09, 2020, 02:09:41 AM
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.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: Bertrand on January 09, 2020, 02:48:17 AM
My target compound is a modified structure of the isolated compound 4 of this paper https://doi.org/10.1016/j.bbrc.2016.09.041.
Please, I need your help to find out a good synthetic route of compound 4 of this paper https://doi.org/10.1016/j.bbrc.2016.09.041

Thanks in advance
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: rolnor on January 09, 2020, 02:41:53 PM
I think its not easy to make it, the molecule has more than one nitrogen that is more or less nucleophilic that can react with the aldehyde. The hemiaminal will probably be sensitive. Do you have any thoughts?
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: Bertrand on January 09, 2020, 03:04:15 PM
I have the same thoughts. The major issue will probably be making the hemiaminal and attach the thiol group (starting from carbon 7 to the thiol group)

I am still searching for how to make it. Please, all your suggestions will, of course, be welcome.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: rolnor on January 09, 2020, 05:20:54 PM
Quote from: Bertrand on January 09, 2020, 03:04:15 PM
I have the same thoughts. The major issue will probably be making the hemiaminal and attach the thiol group (starting from carbon 7 to the thiol group)

I am still searching for how to make it. Please, all your suggestions will, of course, be welcome.

I think a good start would be to use 2-azidobenzamide and try to add it to the thiolaldehyde. The azido group can be reduced with PPh3 to amine after this. I dont think you can have a Boc-protected amino acid, the deprotection will cleave the hemiaminal. Maybe a Fmoc is better, the hemiaminal should be stable to base like piperidine wich is used for Fmoc-deprotection. The first step with the azidobenzamide reacting with thiolaldehyde would be great to study directly with NMR, the aldehyde should dissapear and you get something close ta a acetal-peak. If you run TLC then use a system with base like triethylamine or use aluminunoxide instead if silica wich is acidic to avoid hydrolysis of the hemiaminal. One bad thing is the thiol wich smells veeeery bad i guess.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: Bertrand on January 10, 2020, 02:13:05 AM
Thank you very much.
 
I think instead of using the smelling thiol group, maybe I should protect it with trityl to also avoid any reactivity.
I am going to try your suggestion
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: rolnor on January 10, 2020, 02:02:38 PM
I would try the SEM-group for protection of the thiol, this group can be removed with fluoride (like TBAF) and you avoid acid. When you react the SEM-chloride with the thiolaldehyde you probably need only very mild base like pyridine since the thiol is such a strong nucleophile. With stronger base you get aldol with the aldehyde.
Title: Re: Synthesis of N-Acyl-N,O-alcohol
Post by: Bertrand on January 10, 2020, 04:25:28 PM
hello!

you are right... to avoid any acid SEM-group is better than trityl