[hypervalent_iodine]

Has anyone here made these before? I’m trying to make a couple using aromatic sulfonamides and some pretty unreactive 2-aminopyrimidines. I’ve tried a couple of one pot methods based on literature, one through the sulfonyl isocyanate and another the sulfonyl carbamate, with little to no success. I didn’t have any luck with the carbamate for whatever reason (dry reactions in sub tropical summers and barely functional, leaky air con don’t go well together), although I did manage to isolate the sulfonyl carbamate as a stable solid at one point. Unfortunately, I couldn’t push it to react with my amine. It’s been a month or so since I’ve looked at it, but I had considered remaking the carbamate and hitting the amine with a stronger base in the hopes that might work.

Anyway, I’m curious to know if anyone else here has made these and if they have a go-to method they use that has worked.

[clarkstill]

I've had some issues in the past reacting substituted 2-aminopyridines with some electrophiles. For example, in trying to form a 2,3-diketopiperizine by reacting the following with oxalyl chloride:



The reaction turned BRIGHT blue, but on work-up only the starting material was isolated. Eventually we worked out we were forming the following pyridinium species in situ, and it was promptly hydrolyzing on silica/work-up/the second we looked at it. I presume this happens because the sp2 pyridine nitrogen was actually the most nucleophilic, and the by-product was stable enough under the reaction conditions not to further react to the product through a DMAP-like pathway.



In the end we had to redesign our route, so unfortunately I can't offer you any insightful words of wisdom.

[wildfyr]

I am a fan of your pathway with sulfonyl isocyanates. If the amine is the unreactive one, then it better have a really hot partner.

Would making the sulfonyl chloride in order to get to the sulfonyl isocyanate (via potassium cyanate) be too difficult?

If you want to stick with the carbamate route, perhaps some of the transamidation procedures in the literature would help. Unless you have a strong enough base to deprotonate the amine, I dont think a stronger base is going to get you there. Its a matter of the electrophile/nucleophile pair in my mind. Carbamate is a crappy electrophile, so you need a powerful nucleophile, or some unique conditions, to get it to convert to the urea. I would also worry in general with this pathway that the amine would transamidate the wrong way and give you the urea of the pyrimidine instead of the coupling reaction, since the sulfonamide is probably a better leaving group than ammonia.

[wildfyr]

It looks like some pharmaceuticals are made with this connections (I assume thats your research area). For the synthesis of Tolazamide it looks like they just heated the amine with the sulfonyl carbamate neat (with excess? I didnt do the math).

https://en.wikipedia.org/wiki/Tolazamide https://patents.google.com/patent/US3063903

"C. N '4-CHLOROBENZENESULFONYL)-N -HEXA- METHYLENEIMINOUREA FREE BASE 1 A mixture of 11.41 g. of 1-aminohexamethyleneimine and 26.0 g. of 4-chlorobenzenesulfonylurethane (Marshall et al., supra) was heated at 130 C. (oil-bath temperature) for 2 hours. The resulting ethanol and unreacted amine were removed at 100 mm. pressure for 1 hour and at 20 mm. for 2 hours While keeping the oil bath at 130 C. The residue was cooled and recrystallized from methyl ethyl ketone, giving 20.53 g. (66%) of N-(4-chl0robenzenesulfonyl)-N'-hexamethyleneiminourea free base in the form of colorless prisms melting at 196-199 C."

[hypervalent_iodine]

I am a fan of your pathway with sulfonyl isocyanates. If the amine is the unreactive one, then it better have a really hot partner.

Would making the sulfonyl chloride in order to get to the sulfonyl isocyanate (via potassium cyanate) be too difficult?

If you want to stick with the carbamate route, perhaps some of the transamidation procedures in the literature would help. Unless you have a strong enough base to deprotonate the amine, I dont think a stronger base is going to get you there. Its a matter of the electrophile/nucleophile pair in my mind. Carbamate is a crappy electrophile, so you need a powerful nucleophile, or some unique conditions, to get it to convert to the urea. I would also worry in general with this pathway that the amine would transamidate the wrong way and give you the urea of the pyrimidine instead of the coupling reaction, since the sulfonamide is probably a better leaving group than ammonia.

Very helpful, thank you. I can make the sulfonyl chloride easily (I make the sulfonamide through the chloride in one pot starting with the corresponding thiol), so your suggestion for making the isocyanate should be doable. Looking back at my lab book, I had been using a few different procedures, one which I am fairly confident worked as far as the isocyanate, as I could see it by LRMS after work up of what should have been the sulfonylurea (https://pubs.acs.org/doi/full/10.1021/jm301501k?src=recsys). I couldn't convince my aminopyrimidine to go through to the sulfonylurea using their conditions (all I got back was starting material), but I also didn't have time to play around with them more.

I had considered using NaH with the carbamate pathway to try and deprotonate the amine, although I am not convinced it is a good option. Your transamidation suggestion is something I hadn't considered, so I may look at that also if I can't get the isocyanate to work for whatever reason.

It looks like some pharmaceuticals are made with this connections (I assume thats your research area). For the synthesis of Tolazamide it looks like they just heated the amine with the sulfonyl carbamate neat (with excess? I didnt do the math).

https://en.wikipedia.org/wiki/Tolazamide https://patents.google.com/patent/US3063903

"C. N '4-CHLOROBENZENESULFONYL)-N -HEXA- METHYLENEIMINOUREA FREE BASE 1 A mixture of 11.41 g. of 1-aminohexamethyleneimine and 26.0 g. of 4-chlorobenzenesulfonylurethane (Marshall et al., supra) was heated at 130 C. (oil-bath temperature) for 2 hours. The resulting ethanol and unreacted amine were removed at 100 mm. pressure for 1 hour and at 20 mm. for 2 hours While keeping the oil bath at 130 C. The residue was cooled and recrystallized from methyl ethyl ketone, giving 20.53 g. (66%) of N-(4-chl0robenzenesulfonyl)-N'-hexamethyleneiminourea free base in the form of colorless prisms melting at 196-199 C."

Yeah, there is a good amount of literature on molecules even closer in structure to mine that Tolazamide. The issue seems to be that the particular 2-aminopyrimidine I am using is especially non-nucleophilic (even for pyrimidines, which are already not very reactive) and just does not like to react in the ways others describe. Reacting the carbamate (or isocyanate) neat with the amine and heating the crap out of it in a pressure vessel is something I have scrawled in my notebook from last year when I was doing this as a point for further investigation. Thanks for bringing the patent to my attention.

I've had some issues in the past reacting substituted 2-aminopyridines with some electrophiles. For example, in trying to form a 2,3-diketopiperizine by reacting the following with oxalyl chloride:



The reaction turned BRIGHT blue, but on work-up only the starting material was isolated. Eventually we worked out we were forming the following pyridinium species in situ, and it was promptly hydrolyzing on silica/work-up/the second we looked at it. I presume this happens because the sp2 pyridine nitrogen was actually the most nucleophilic, and the by-product was stable enough under the reaction conditions not to further react to the product through a DMAP-like pathway.



In the end we had to redesign our route, so unfortunately I can't offer you any insightful words of wisdom.

In my experience, these pyrimidines are (thankfully) not overly prone to reaction on the ring nitrogens. The amine nitrogen *should* be the most reactive in the molecule, but it is something to watch out for. You have given me something to think about for another reaction that was giving me some odd results though, so thank you for that.

[wildfyr]

reacting X neat with Y and heating the crap out of it in a pressure vessel

Usually a procedure reserved for when you are at the end of your rope

It occurs to me that if the reactivity is at all like a sulfonamide, then the proton on the nitrogen next to the sulfonyl is going to be rather acidic, which could explain your base catalyzed failures, and torpedo deprotonating your pyrimidine with a strong base.

[wherescarmin]

Has anyone here made these before? I’m trying to make a couple using aromatic sulfonamides and some pretty unreactive 2-aminopyrimidines. I’ve tried a couple of one pot methods based on literature, one through the sulfonyl isocyanate and another the sulfonyl carbamate, with little to no success. I didn’t have any luck with the carbamate for whatever reason (dry reactions in sub tropical summers and barely functional, leaky air con don’t go well together), although I did manage to isolate the sulfonyl carbamate as a stable solid at one point. Unfortunately, I couldn’t push it to react with my amine. It’s been a month or so since I’ve looked at it, but I had considered remaking the carbamate and hitting the amine with a stronger base in the hopes that might work.

Anyway, I’m curious to know if anyone else here has made these and if they have a go-to method they use that has worked.

I've made some diaryl sulfonylureas, although none containing pyrimidine.
The following two methods may or may not be relevant:
- The in situ isocyanate method, using DMAP/Boc2O/sulfonamide/aniline. When I started in the lab I'm in we used this method or carbamates (either side), but I now rarely use this method.
https://onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.201700270
- I much prefer converting the electron rich aniline to an isocyanate and reacting with the sulfonamide (deprotonated with NaH). The reaction is just so much cleaner and you can just throw it down a c18 cartridge without clogging it with crud. Sometimes the reaction goes in 30 min @ RT, but usually 4 h. https://www.sciencedirect.com/science/article/pii/S0960894X17312283?via%3Dihub

[hypervalent_iodine]

Thank you, I will look these over. I haven't been able to return to this synthesis yet as I am very busy tying up some biological assays in another building. I have thought about making isocyanates out of my amine, though I had tried it once for another reaction and didn't have much luck. That being said, it was some time ago (at the start of my PhD) and using a bit of an odd procedure. I might look into it again if all of my other options do not work.

Another person in my lab who is working on a related project has successfully made some sulfonylureas using an aminotriazine and reacting it with a sulfonyl carbamate. His amine is more reactive than mine, and the yield was not good, but it gives me some hope regarding a previous thought I mentioned in this thread wherein I deprotonate the amine with NaH and react that with the carbamate.

[wherescarmin]

Yeah I'd defs give isocyanates a bash. From memory ysing Boc2O and TEA has worked well for me. Or you can use phosgene

Coincidentally, the other week I tried to make a hypervalent iodine. It didn't work though.

[hypervalent_iodine]

Yeah I'd defs give isocyanates a bash. From memory ysing Boc2O and TEA has worked well for me. Or you can use phosgene

Coincidentally, the other week I tried to make a hypervalent iodine. It didn't work though.

I have used triphosgene before, and I'm not opposed to trying again. It's the same as anything really - fine if you use it properly (i.e. safely).

My username actually comes from a past project when I was in honours, but I was using one in particular (PIFA) rather than making it. It failed spectacularly. A learning experience is the best way I can describe it (and not one I recommend).