Diazotransfer - Synthesising Azides from Amines

In our group we work a lot with diazotransfer reagents and diazomethane so I thought it might be a good idea to share some of our knowledge. These reaction involve reagents that are very dangerous and azide products can also be explosive so you shouldn't do any of this chemistry without being 100% sure you know what you are doing. However, if experiments are performed thoughtfully and with care the chemistry is predictable and well behaved. We are doing diazotransfer all the time these days to convert amino acids into azide derivatives. There are many reagents available for the diazotransfer reaction with the most common depicted in the figure below.

We recently, published a review that gives a detailed description of the various diazotransfer reagents when used on amino acids but I believe it would be of interest to anyone attempting the conversion of an amine to an azide. Check it out here for the full story. The conclusion is that we favour reagents 4 that was developed by Goddard-Borger and Stick and first reported here. Later a safety update was published here followed by a comprehensive stability study that was published here. The problem is that the HCl salt of 4 is hygroscopic and when it becomes wet is starts to decompose forming hydrazoic acid (HN3) which is very nasty and totally unpredictable. Fortunately, it is easy to see when the decomposition has kicked in because the product turns into a black tar. The tetrafluoroborate and hydrogensulfate salts of 4 were found to be much better with respect to shelf life. In the future we will use the hydrogensulfate salt of 4, however, we have a big pile of the HCl salt we have to get through first. Fortunately, we discovered that rigorous drying of the HCl salt of 4 followed by storage at -20 oC makes it stable for >1 year. Anyway, if you are new to this stuff you should definitely go for the hydrogensulfate salt. Using the HCl salt of 4 we regularly synthesise amino acids with terminal azides in the side chain (see below). 

This is easily achieved from the corresponding amine (in this example lysine). The pH of the reaction has to be adjusted to approx. 8 to get it going. We normally insert a pH meter to keep an eye on things and simply adjust pH by adding sat. aq. NaHCO3 when required. The fantastic thing about this reaction is that the crude product is of such high purity that we never perform any chromatography but simply dry it and use it as it is. The synthesis of this particular azide has been reported many times in the literature. For a recent detailed procedure check out our SYNLETT paper on the synthesis of Fmoc-L-Lys(N3)-OH and a number of other azide and alkyne derivatised amino acids.

Note that we are synthesising high molecular weight azides so these guys are not explosive. However, if you consider synthesising smaller azides please be aware that it isn't considered safe to handle azides with less than 6 heavy atoms per azido group (see our recent review for details).

Some of you are probably thinking what is the mechanism for this reaction? Well I'll leave that to someone else to have a go at. I don't think the actual mechanism has been conclusively established and the suggested arrow pushing is rather exotic. Suffice to say that it works and that nitrogen gets transferred from reagent to product without too much fuss. Have fun diazotransferring. D!

If you don't have access to our papers reprints can be requested from curlyarrow@gmail.com

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On a non-chemistry note I have started the blog Molt Bé, No? about Barcelona (and Catalonia). I spend a lot of time in Barcelona since my better half lives there and now I have started writing about our favourite spots. I find that guide books, news papers etc. are a disaster regarding their recommended restaurants, bars etc. so I thought I would do my bit to help visitors to Barcelona have a nice and authentic experience when visiting the Catalan capital (and the surrounding area). Check it out here if you are heading in that direction. D!