preparation of isocyanates

[freakJoe]

I have found patent (WO 2014/100417), in which they descibe preparation of isocyanate from amine. They use amine, triphosgene, THF, N,N-diisopropylethylamine (DIPEA). Is it possible to use DMAP or pyridine instead of DIPEA and oxalyl chloride instead of triphosgene? i am not sure about the mechanism of this reaction... what is more, on the reaction scheme they write piridine (no DIPEA) and now i am not sure if they made mistake... i havent found the same reaction with different substitutes

 

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=WO&NR=2014100417A1&KC=A1&FT=D&ND=&date=20140626&DB=&&locale=en_EP

Edited March 13, 2016 by freak90

[hypervalent_iodine]

I believe that you can use oxalyl chloride, but phosgene is your best bet. Why don't you want to use DiPEA? If you don't have any, I would go to TEA or straight pyridine before DMAP.

What are you making the isocyanate for? They are not the easiest compounds in the world to work with if you have to isolate them as they are notoriously unstable. The last time I made some, they had decomposed in the time it took me to carry a small sample down to the IR.

[freakJoe]

Thank you. I have found some publication, but there is no real procedure, they just mentioned that isocyanate was prepared in reaction of amine with oxalyl chloride... nothing more, and in cited literature i can´t find the real procedure as well...

Once i prepared some isocyanate starting from acid (so several steps), and measurement of IR was succesful... so, i hope, this time it will be OK as well... Then I plan to use it immediately in next reaction step.

I am not experienced in such a type of syntheses, but i was probably lucky

By the way, they carry out the 1 step of the reaction (triphosgene in THF + DIPEA) in 0^o C, so the reaction mixture before addition of amine should be cool, so i guess ït is very exothermic? After all amine was added, i can remove ice-water bath? And i should probably carry it out in an inert atmosphere of argon, and be careful and avoid the moisture, right?

 

I am not sure about the mechanism of the reaction... What is the role of DIPEA? does it has to remove some chlorides?

[hypervalent_iodine]

Presumably, the base is there to deprotonate the amine and mop up HCl.

 

Yes, the reaction would be exothermic. Having it cooled helps to control the excess heat and prevent side reactions. You also want to add the amine drop wise as a solution in THF. It should be okay to remove the ice bath after complete addition of the amine.

 

Definitely do it under inert atmosphere. Make sure everything is super dry and that your reagents are dry and of good quality. You may have to do some distillations for this part. My lab has a THF still set up in one of the fume hoods, which makes life easier.

 

Have you looked through SciFinder? I recall finding some protocols using oxalyl chloride there when I was attempting to make isocyanatses. I believe I found it through the reaction search tab using a generic pyrimidinyl amine as my reagent. I also found another method using Boc anhydride, which I thought was pretty neat but could not get to work with my jerk of an amine. What kind of amines are you working with? What's the step after the isocyanate?

 

Edit: here is a decent mechanism

 

 

From http://drugsynthesisint.blogspot.com.au/2014/02/a-review-and-methods-to-handle-phosgene.html

[freakJoe]

Thank you so much! You are so helpful!

 

By the way, about Boc-... I have some idea, but i am not sure, if i can prepare isocyanate from this compound:

http://www.sigmaaldrich.com/catalog/search?term=4-%28Boc-aminomethyl%29benzoic+acid&interface=All&N=0&mode=match%20partialmax〈=en&region=CZ&focus=product

 

Is Boc- protecting group stable enough to survive this reactions?

I would have to remove Boc- group later, after reaction of isocyanate with the the compound that contain hydroxyl group), as the final compound is much more stable...

[hypervalent_iodine]

Perhaps. The idea is that the O-tBu is eliminated after formation of the carbamate following a second deprotonation step with base (DMAP in this case, IIRC), giving the isocyanate. I believe the paper I got it from just did a liquid liquid extraction for work up and purification. It was an odd reaction and I was skeptical of it working even though I thought it sounded like a nice alternative. Like I said, I couldn't get it to work. My amine was particularly low on the nucleophilicity scale however, which may have contributed. I'll see if I can find the paper I got it from tomorrow when I'm back in the office.

 

Is your final product after the isocyanate a carbamate? There are other ways to make carbamates that avoid things like triphosgene. Is there any reason you're going this route and not another?

[freakJoe]

Yes carbamates... What ways do you mean? my starting material is oxidized complex with one/two -OH groups... that is why i use isocyanates.

Thank you very much for help!

[freakJoe]

I tried to prepare it, but: 1) it was unsuccesful, or 2) this small portion was decomposed before i measured IR. Is there any test to check, if it is isocyanate? some reaction in which i could obtain: 1) some colorful substance what could confirm it is the right compound, or 2) just something i could confirm its structure by e.g.NMR spectroscopy. I mean if some characteristic reaction with something will be succesful, it means that was isocyanate. I can´t risk and try it in my reaction, because i work with quite expensive complexes... By the way, why oxalyl chloride is worse?

Sorry for my english, and if my text is a bit chaotic, but i work and learn for 10-13h every day and i am exhausted zzzz..

[hypervalent_iodine]

I tried to prepare it, but: 1) it was unsuccesful, or 2) this small portion was decomposed before i measured IR. Is there any test to check, if it is isocyanate? some reaction in which i could obtain: 1) some colorful substance what could confirm it is the right compound, or 2) just something i could confirm its structure by e.g.NMR spectroscopy. I mean if some characteristic reaction with something will be succesful, it means that was isocyanate. I can´t risk and try it in my reaction, because i work with quite expensive complexes... By the way, why oxalyl chloride is worse?

Sorry for my english, and if my text is a bit chaotic, but i work and learn for 10-13h every day and i am exhausted zzzz..

IR is your best bet. It's quicker than NMR, and solvents like CDCl3 can cause problems if you have very unstable ones. The isocyanate peaks are pretty obvious as well. Colourful substance can often mean it decomposed. For reference, my ones would go bright red when they broke down. Unless you mean a chemical test? I suppose a ninhydrin test would tell you if you still had amine in there, but that doesn't say much about if you actually made an isocyanate. One way would be to try and do the next step one pot and see if you made that.

 

I'll respond to your last post later on. I've been pretty sick the last few days and am in need of more rest.