[KemistTheFrog]

    I've been told to determine the conditions for the synthesis of phenylbutazone from diethyl butylmalonate and hydrazobenzene. Every publication I've read on the synth of phenylbutazone uses a strong base (NaOEt or pyridine) at like 0 degrees C. Our instructor recommend trying a couple drops of a weak acid (to protonate the diethyl butylmalonate) and possibly refluxing. I'm having some trouble with specifics.
    How do I prevent the hydrazobenzene from being protonated? I've determined I should add the acid to the malonate, and then add the hyrazobenzene to the mix. Is there more I can do?
   Knowing that I'll have ethanol as a side product should I use that as my solvent or something else? how long should I reflux? And then can I just roto-evap my product out or will it be more complicated than that?
Any thoughts or help would be appreciated.
Thanks

[Doc Oc]

It is possible for the amine to get protonated, but if it does then those protons are acidic so it won't change anything really.  The thermodynamic well is formation of the amide so once that happens that's pretty much the end of the reaction.  You have the order correct though, I'd definitely add the acid to the ester and reflux.

I would read up on an experimental procedure to determine solvent selection and reflux time.  Ultimately, you can just take TLCs every 30-60 minutes to monitor disappearance of your starting material.

[OC pro]

Just reflux a 1:1-mixture in EtOH. Should be straight forward.

[KemistTheFrog]

Thanks guys. I added some dilute HCl acid, used ethanol as a solvent, refluxed for an hour, and then precipitated out some crystals by cooling in an ice bath. I got a 23% yield of orange crystals. I'm thinking maybe if I refluxed longer the yield would be better but that's just an idea. Is there anything I could do to help precipitate crystals out better besides just sticking it in an ice bath?

[anuradha]

Is there anybody who can help me in synthesizing phenylbutazone? Im trying in small scale and havung issues. However when I tried in larger scale with sodium ethoxide reaction works but repeating same procedure in small scale is not working.Any suggestion will be appreciated. Thanks

[AWK]

Search patents. Use anhydrous conditions.

[anuradha]

Search patents. Use anhydrous conditions.

I repeated many times in anhydrous condition but was not very successful, thanks

[kriggy]

Thanks guys. I added some dilute HCl acid, used ethanol as a solvent, refluxed for an hour, and then precipitated out some crystals by cooling in an ice bath. I got a 23% yield of orange crystals. I'm thinking maybe if I refluxed longer the yield would be better but that's just an idea. Is there anything I could do to help precipitate crystals out better besides just sticking it in an ice bath?

Was all of the starting material converted into product? If yes then you need to work on isolation. If the rection is not finished, you need to improve the reaction (longer time, higher temperature..)

[anuradha]

Thanks guys. I added some dilute HCl acid, used ethanol as a solvent, refluxed for an hour, and then precipitated out some crystals by cooling in an ice bath. I got a 23% yield of orange crystals. I'm thinking maybe if I refluxed longer the yield would be better but that's just an idea. Is there anything I could do to help precipitate crystals out better besides just sticking it in an ice bath?

Was all of the starting material converted into product? If yes then you need to work on isolation. If the rection is not finished, you need to improve the reaction (longer time, higher temperature..)

After two hour I checked by GCMS and showed only starting materials that is malonate, azobenzene and hydrazobenzene. Could u please let me know what exactly you did? I do see orange solid while refuxing in ethanol but no product by GCMS

[orthoformate]

Thanks guys. I added some dilute HCl acid, used ethanol as a solvent, refluxed for an hour, and then precipitated out some crystals by cooling in an ice bath. I got a 23% yield of orange crystals. I'm thinking maybe if I refluxed longer the yield would be better but that's just an idea. Is there anything I could do to help precipitate crystals out better besides just sticking it in an ice bath?

Was all of the starting material converted into product? If yes then you need to work on isolation. If the rection is not finished, you need to improve the reaction (longer time, higher temperature..)

After two hour I checked by GCMS and showed only starting materials that is malonate, azobenzene and hydrazobenzene. Could u please let me know what exactly you did? I do see orange solid while refuxing in ethanol but no product by GCMS

just to clarify:
You are adding hydrazobenzene, diethylmalonate (1:1) in ethanol with anhydrous HCl (6N in IPA, or Gaseous HCl) and heating?

And just confirm: you are using anhydrous HCl, not conc. HCl (37%)

Also, you said you are seeing azobenzene? this means you are seeing oxidized hydrazobenzene?

[anuradha]

Thanks guys. I added some dilute HCl acid, used ethanol as a solvent, refluxed for an hour, and then precipitated out some crystals by cooling in an ice bath. I got a 23% yield of orange crystals. I'm thinking maybe if I refluxed longer the yield would be better but that's just an idea. Is there anything I could do to help precipitate crystals out better besides just sticking it in an ice bath?

Was all of the starting material converted into product? If yes then you need to work on isolation. If the rection is not finished, you need to improve the reaction (longer time, higher temperature..)

After two hour I checked by GCMS and showed only starting materials that is malonate, azobenzene and hydrazobenzene. Could u please let me know what exactly you did? I do see orange solid while refuxing in ethanol but no product by GCMS

just to clarify:
You are adding hydrazobenzene, diethylmalonate (1:1) in ethanol with anhydrous HCl (6N in IPA, or Gaseous HCl) and heating?

And just confirm: you are using anhydrous HCl, not conc. HCl (37%)

Also, you said you are seeing azobenzene? this means you are seeing oxidized hydrazobenzene?

I'm using 1:1 hydrazobenzene and diethylmalonate in anhydrous ethanol. I added 2 M aq HCl. How much gaseous HCl should I add? I do see azobenzene on GCMS, I'm not sure whether it is oxidizing in reaction or on GCMS. However I always do see azobenzene as well as hydrazobenzene on GCMS when I ran GCMS of reaction. Could you please let me know in detail, how you made phenylbutazone? I would like to run this reaction in lower scale probably with 20 mg of starting material. Thank you very much for your help and suggestion. Any suggestion or help would be heartly appreciated. Thanks

[orthoformate]

Hi again,

to clarify, I have never made this molecule, but I think I can give you some good advice, as I have made very similar molecules using the acid catalysis you are describing. When synthesizing amide bonds from esters and amines with acid catalyst a long reaction time and high heat are required. If you are seeing no change in the rxn (just starting materials) I would increase the heat (>100 °C) and let it run overnight.

Are you certain you are not seeing any formation of the diacid? The 2M HCl you are adding could catalyze ester hydrolysis.

Do you simply need to prepare this compound quickly? Or are you more interested in getting the HCl catalyzed reaction to work?

I looked up a paper where they made this exact molecule you are trying to make (Open Source):

Chemistry of pyrazolidine. I. Synthesis and study of some mono- and disubstituted 1,2-diphenyl-3,5-dioxopyrazolidines
Zhurnal Obshchei Khimii (1958), 28, 2355-9.

To 30 g. Na in 1 l. abs. EtOH was added 250 g. BuCH(CO2Et)​2 and 212.2 g. (PhNH)​2; after refluxing until a homogenous soln. formed, the mixt. was freed of EtOH and heated 12 hrs. at 130-​50° yielding after diln. with H2O and extn. with Et2O 60​% 4-​butyl-​1,​2-​diphenyl-​3,​5-​dioxopyrazolidine (I)​, m. 105° (EtOH)​.

If you want to skip all the acid catalyst investigation, this procedure has been proven to work. I've looked up many references where they use this method to make similar molecules.

[AWK]

I'm using 1:1 hydrazobenzene and diethylmalonate in anhydrous ethanol. I added 2 M aq HCl. How much gaseous HCl should I add? I do see azobenzene on GCMS, I'm not sure whether it is oxidizing in reaction or on GCMS. However I always do see azobenzene as well as hydrazobenzene on GCMS when I ran GCMS of reaction. Could you please let me know in detail, how you made phenylbutazone? I would like to run this reaction in lower scale probably with 20 mg of starting material. Thank you very much for your help and suggestion. Any suggestion or help would be heartly appreciated. Thanks

Anhydrous HCl is rather unpleasant in use. Try solid p-toluenesulfonic acid.

[anuradha]

Hi again,

to clarify, I have never made this molecule, but I think I can give you some good advice, as I have made very similar molecules using the acid catalysis you are describing. When synthesizing amide bonds from esters and amines with acid catalyst a long reaction time and high heat are required. If you are seeing no change in the rxn (just starting materials) I would increase the heat (>100 °C) and let it run overnight.

Are you certain you are not seeing any formation of the diacid? The 2M HCl you are adding could catalyze ester hydrolysis.

Do you simply need to prepare this compound quickly? Or are you more interested in getting the HCl catalyzed reaction to work?

I looked up a paper where they made this exact molecule you are trying to make (Open Source):

Chemistry of pyrazolidine. I. Synthesis and study of some mono- and disubstituted 1,2-diphenyl-3,5-dioxopyrazolidines
Zhurnal Obshchei Khimii (1958), 28, 2355-9.

To 30 g. Na in 1 l. abs. EtOH was added 250 g. BuCH(CO2Et)​2 and 212.2 g. (PhNH)​2; after refluxing until a homogenous soln. formed, the mixt. was freed of EtOH and heated 12 hrs. at 130-​50° yielding after diln. with H2O and extn. with Et2O 60​% 4-​butyl-​1,​2-​diphenyl-​3,​5-​dioxopyrazolidine (I)​, m. 105° (EtOH)​.

If you want to skip all the acid catalyst investigation, this procedure has been proven to work. I've looked up many references where they use this method to make similar molecules.

I have tried this method already but did not see any products thats why I was trying with acid. I wanted to make this compound quickly. I will try this procedure again. Thank you for your advice.

[anuradha]

I'm using 1:1 hydrazobenzene and diethylmalonate in anhydrous ethanol. I added 2 M aq HCl. How much gaseous HCl should I add? I do see azobenzene on GCMS, I'm not sure whether it is oxidizing in reaction or on GCMS. However I always do see azobenzene as well as hydrazobenzene on GCMS when I ran GCMS of reaction. Could you please let me know in detail, how you made phenylbutazone? I would like to run this reaction in lower scale probably with 20 mg of starting material. Thank you very much for your help and suggestion. Any suggestion or help would be heartly appreciated. Thanks

Anhydrous HCl is rather unpleasant in use. Try solid p-toluenesulfonic acid.

I tried with p-toluenesulfonic acid in xylene but did not observe any product