[clemi2310]

Hello everyone,

I am trying to run the conversion of a diketo ester into a diketo hydroxamic acid (never described I think).
To avoid, hydrolysis product or degradation of the starting material, I chose a procedure that does not involve strong basic conditions (see scheme below).



The thing is, I don't know which product is formed.

In LCMS, I have one peak only with the mass 434

- The starting material is entirely consumed (comparison of retention times and mass)
- The corresponding methyl ketone is not regenerated (not the same retention time and mass)
- The diketo acid is not formed
- When I test the product with FeCl3, the test is positive I get a red complex

The mass missing from the product I want is 15, like a CH3 but I don't have any methanol, I wanted to avoid transesterification so I used ethanol.

Since I don't see hydrogens of OH et NH in NMR, I don't know which experiment I could use to understand the structure I formed !

Thank you for your help,

Clémence

[rolnor]

Can the ketone-carbonyl have formed a oxime?

[wildfyr]

Check it on FTIR. amide peak at about 1650 cm^-1

[clemi2310]

Thank you both for your answers !

Rolnor, it seems that the oxime formation is a good option, it correlates with the mass (see picture) but also with the formation of hydroxamic acid, do you think it is possible, that hydroxylamine attacks in such a way?

Which carbonyl preferentially? I would say the B. Thank you

Wildfyr, unfortunately I don't have FTIR facilities in my lab, I have to figure it out by other means.

[clemi2310]

Another question, do you think I can avoid this oxime formation and only keep the hydroxamic acid at the end of the chain ? Thank you

[kriggy]

Probably not. I would suggest to protect the carbonyls somehow. It might be enough to protect just one of them. You  might want to hydrolyze the ester into acid and then run the reaction with EDC and HOBt and you might get the hydroxamic acid. The aminogroup should be more reactive thatn the OH so you might not need to protect the hydroxylamine

[clemi2310]

Hello everyone,

I have been trying few things to manage to get only the hydroxamic acid at the end of the chain without success.

1- Peptide coupling between Diketo acid and EDCI, Hydroxylamine, DMAP : I see the complex between the diketo acid and EDCI in LCMS but I end up with a mixture of secondary products difficult to identify.

2- Then I wanted to protect the carbonyl at the diketo ester step which is predominantly in the enol form, so I wanted to silylate it

I tried with HMDS, TMSOTf, and TBMS (with imidazole) but nothing happens appart from a color change from yellow to dark purple for TBMS, I only get starting material.

I found a protocole that involves potassium hydride, TBDMS-Cl in THF at -78°C but it is for a ketone not a diketo ester.

I am not sure this is the right way to go but I am starting to run out of ideas

Any suggestions ?

Thank you !

[rolnor]

The first thing I can think of is to treat compound A or B with hydrochloric acid, I think the oxime would cleave but the hydroxamic acid should be more stable? More complicated would be to protect the ketones as dithioacetals with propanedithiol and acid then make the hydroxamic acid and then deprotect with mercury salt or NBS/2,6-lutidine. One bad thing with the later strategy is the terrible stench from propanedithiol, its really nasty.

[clemi2310]

Hello everyone,

I update this topic because I have a new question about the same reaction.

I managed to find a condition to get what I think is the diketo hydroxamic acid but I would like to have your opinion about the formation of a possible isomer.

As you can see in the scheme I perform the reaction like a peptide coupling starting from the diketo acid, with DCI, NMM, NH2OH.HCl

I get a product with a mass of 419 in LCMS. I want product A, but do you think it is possible to have formed product B, the oxime without the hydroxamic acid?

I performed a test with FeCl3 I get a red complex but I am not sure this staining reagent is selective to hydroxamic and maybe would react also with oxime.

Thank you for your help !!

Clémence

[wildfyr]

Perhaps try dissolving it in methanol with a catalytic amount of sulfuric acid and stirring overnight to see if the methyl ester forms. Your product should not give the methyl ester.

Hydroxamic acid should be stable to these conditions right?

I'll say again though, FTIR could be really useful the C=N double bond is characteristic at about 1640 cm^-1, same as trying to catch the amide earlier in this thread.

[kriggy]

Im wondering if you could just kick it with excess of hydroxylamine and then hydrolyze the oxime byproducts?