It’s not often I get an opportunity to talk about the formation of a urea, where I haven’t actually performed the reaction…see if you have. After spending the better part of 3 years making ureas as raf kinase and p38 target analogs, I never once ran this reaction — bummer. Don’t feel too bad for me — our team was able to make 2generations of drugs for cancer on the motif — so things didn’t end too badly.

So why make another isocyanate or the final urea for that matter. Well, the impact from these two materials is a high percent of chemical output per year so there is clearly an interest. So since I didn’t perform a Staudinger reaction you can bet that I used plenty of phosgene in my day….now you see why we need people to continue to develop alternatives to older ideas. Other alternatives including Curtius and Hoffmann rearrangements or an activation of an amine with CDI followed by a second amine are all excellent methods to get there….but the Staudinger, sign me up.First things first — Staudinger — azide to an amine –and Wikipedia’s pinwheel example shows us how:

Screen Shot 2014-01-22 at 4.36.39 PM

Staudinger: Azide to amine

We know of course that to be an aza-wittig variant we have to through the in situ formation of a phospazide and iminophosporane (perhaps this where the next part will come into play). To form an isocyanate at this point would involve reaction with CO2 at the iminophosphorane stage plus triphenylphosphene oxide. And voila, out goes the isocyanate — with total functional group compatibility. So the “crux” is the CO2 — although common enough in balloon and cyclinder form, there are so few examples of microwave technology being used to describe gaseous reagents in closed-vessels. Now that I have laid the trail — a very recent paper (Beilstein JOC 2013) does just this — a microwave method for the Staudinger reaction for the production of RNCO and ureas.

Screen Shot 2014-01-22 at 4.48.34 PM

MW Staudinger with azide, polymer resin phospine under CO2

Two things of note in the approach — moving away from PPh3 to a resin bound phosphine (of course everyone who is reading this will understand that polymer swelling will come into play– which could be regenerated and how much CO2 and pressure would be to get this to work in a mw– what solvent will end up the best.

Screen Shot 2014-01-22 at 4.48.45 PM

Optimizing Conditions

OK — this group used the SRC mw approach so that they could control the amount of CO2 pressure needed and they could test a few solvents simultaneously — comparing solvent and pressure — 14.5 bar did the trick for conversion and yield — and MeCN produced good yield and good conversion THF was a bit of an outsider here.

Screen Shot 2014-01-22 at 4.49.47 PM

MW RNCO formation then amine addition under mw

The next step was to form the RNCO under mw conditions, stop then add amine and react under mw conditions. Well I must have been a bit ahead of myself because my thinking was that you should be able to do this in one pot — because the azide should be tied up in the iminophosphorane/RNCO formation with the CO2 — should be fast….so doing this in the presence of an amine should work just fine. First thing is first — several different azides were used in a single chamber (forming multiple RNCOs then reacting with one amine following the first mw step with second one — nice, library library library — just kidding!

Screen Shot 2014-01-22 at 4.49.56 PM

cu de gras — mw to make azide – then phosphine, CO2 and second amine in one pot

And now they got where I wanted — a bit more in fact — RBr with NaN3 in mw to give multiple RN3s — then each of these reacted with resin, CO2 and amine in one pot to give a set of ureas with varying groups on either side. Don’t you just love it when a plan comes together. It is interesting that a few modifications in the microwave produced a nice method for an under-used reaction. Last thing to note — it comes up a bunch is that they scaled the reaction up in a Parr to show that the technology could be transferred back to conventional systems — I like that: hope the naysayers are watching and reading. For me personally, I would have scaled this up in the SRC as well to show the side by side ( a 1L pot would have produced even more material) For those interested — there is a 4L version of this technology — method development and scale are not that out of reach.

Hope you enjoy reading this one!

Advertisements