[Dan]

We are having some difficulty with a family of barbituric acid derivatives of the general structure:


R² = Ph, aryl

They do not behave very well at all on silica (very polar and streaky) - probably a result of C-H acidity and high crystallinity. The result of this is that unless further transformations are quite clean, purification (precipitation or recryst) is very difficult.

We are also having problems trying to perform S_EAr functionisation of the R² aryl ring due to reactivity at C5 (the CH) of the barbituric acid ring.

Two questions:

1. Has anyone worked with these compounds before and got any tips on handling/purification? I have tried AcOH doped silica and eluents, but TLC profiles are still awful.

2. Is there a convenient protecting group for C5 (to knock out the enolisation) that will survive some fairly harsh classical aromatic chemistry and can be readily removed later? I was considering Br or maybe allyl as dummy groups.

Cheers,

Dan

[Dan]

Update: For future reference, we recently published our solutions to these problems here (open access).

[pgk]

1). Try alumina TLC plates and columns that work at pH = 4-10 , instead of silica. However, Rf might be different.
2a).C5 hydrogen is very labile, as being between two amide groups. So:
Ar-C-H (1. EtONa, 2. ClCO2Me) → Ar-C-CO2Me (hydrolysis) → Ar-C-CO2H → (1. FC reaction, 2. Heat) → Ar’-C-H
The so prepared tertiary carboxylic acid must be stable up to 50 – 60 oC. After the FC, the carboxylic group is eliminated by heating. Note that amides are rather stable to hydrolysis.
2b). Additionally, you need one equivalent of EtONa/ ClCO2Me per equivalent of non-substituted amide nitrogen (if any). Under the reaction conditions, the corresponding urea groups when hydrolyzed, they will form the instable urea-carbamic acid that will immediately form the corresponding free amide group:
-CON-H → -CONCO2Me → [-CONHCO2H] → -CONH
2c). If you need further heating higher than 50- 60 oC, during FC reaction:
Firstly, esterify the tertiary carboxylic acid and hope that the corresponding ester will not be be a good a FC reagent, due to the steric hindrance:
Ar-C-CO2H → Ar-C-CO2Me (FC reaction, hydrolysis, heat) → Ar'-C-H
(I have never worked with barbiturates. This is paper chemistry but it might work, in practice.)
 

[Dan]

1). Try alumina TLC plates and columns that work at pH = 4-10 , instead of silica. However, Rf might be different.

AcOH-doped silica works well.

Edit: I just realized I said in the original post that AcOH-doping in ineffective - it took a while, but after a bit of tinkering I found that a combination of AcOH/acetone/toluene/hexanes gives nice tight spots on TLC and allows the compounds to be chromatographed on silica.

2a).C5 hydrogen is very labile, as being between two amide groups. So:
Ar-C-H (1. EtONa, 2. ClCO2Me) → Ar-C-CO2Me (hydrolysis) → Ar-C-CO2H → (1. FC reaction, 2. Heat) → Ar’-C-H
The so prepared tertiary carboxylic acid must be stable up to 50 – 60 oC. After the FC, the carboxylic group is eliminated by heating. Note that amides are rather stable to hydrolysis.
2b). Additionally, you need one equivalent of EtONa/ ClCO2Me per equivalent of non-substituted amide nitrogen (if any). Under the reaction conditions, the corresponding urea groups when hydrolyzed, they will form the instable urea-carbamic acid that will immediately form the corresponding free amide group:
-CON-H → -CONCO2Me → [-CONHCO2H] → -CONH
2c). If you need further heating higher than 50- 60 oC, during FC reaction:
Firstly, esterify the tertiary carboxylic acid and hope that the corresponding ester will not be be a good a FC reagent, due to the steric hindrance:
Ar-C-CO2H → Ar-C-CO2Me (FC reaction, hydrolysis, heat) → Ar'-C-H

Yes, carboxylate as a masking group at C5 was something I thought of too. We could not get any productive reaction with chloroformates, but we didn't try very hard because it was around this time that I figured out how to do the Ru(II)-catalysed diazo-arene coupling reaction.

[pgk]

I wish you the best.