Safe azide or oxymoron?

The Huisgen cycloaddition or ‘click chemistry’ could certainly take part of the blame for the resurgence of one of the bad boys of organic chemistry: azide. Coming from a large – Risk averse – pharma, I have always tried to avoid such fragments, possibly due to the implications and paperwork if (or more likely when) it goes wrong. So when an article with ‘Azide’, ‘Facile’ and ‘Safe’ is published it’s certainly worth reading.

The article from Wang’s group is looking at the diazotransfer reaction converting a primary amine to the corresponding azide.

The pre-Goddard-Borger and Stick era was using triflate azides as diazotransfer reagents which proved to be prone to explosion (Figure 1).

azide1Figure 1

The Wang article here is looking at a safe protocol to the imidazole-1-sulfonyl azide (compound 4, Figure 2) reagents developed and optimised over the last 6 years.

azide2Figure 2

Key requirements to the described ‘safe’ route were to avoid the presence of NaN3 with strong acids, minimise the excess of NaN3 and avoid the formation of explosive intermediates.  Previously reported procedures to prepare diazotransfer reagents such as those depicted in Figure 2 all seem to engage sulfonyl chloride, leading to the generation of (N3)2SO2 as a highly explosive byproduct. Wang starts from sulfuryl diimidazole which after mono methylation is treated with NaN3 to give the  imidazole sulfuryl azide reagent (Figure 3).


Figure 3

Worth noting that dimethylation of the sulfuryl diimidazole is not observed, so no highly explosive (N3)2SO2 species were observed and that sulfuryl diimidazole itself proved unreactive with NaN3 (Figure 4).

azide4Figure 4

Furthermore, Wang report that the aqueous conditions the reaction is performed in prevent the formation of the explosive (N3)2SO2 intermediate from the diazotransfer reagent itself (Figure 5).


Figure 5

Does that make the whole process safe? What about stability and storage? Wang et al. prepared the  imidazole-1-sulfonyl azide (compound 4, Figure 2) in over 100g scale but seems to have used it in-situ….

Imidazole-1-sulfonyl azide (the preferred diazotransfer reagent from the Figure 2 bunch) is usually prepared as a HCl salt. The ‘safety update’ from Goddard-Borger and Stick, published in 2011 as a follow up to their original 2007 ‘shelf-stable’ imidazole-1-sulfonyl azide, reports that ‘imidazole-1-sulfonyl azide hydrochloride is hygroscopic and reacts slowly with water to produce hydrazoic acid. Concentration of the mother liquors from which imidazole-1-sulfonyl azide hydrochloride crystallised has resulted in an explosion. This solution may contain sulfonyl diazides and/or hydrazoic acid byproducts which are both extremely sensitive, explosive substances’.


The Sejer group seems to work regularly with such diazotransfer reagents and reports that ‘rigorous drying of the HCl salt of imidazole-1-sulfonyl azide followed by storage at -20⁰C makes it stable for >1 year’ and that tetrafluoroborate and hydrogensulfate salts of imidazole-1-sulfonyl azide were found to be much better with respect to shelf life.


Back to Wang et al.’s conclusion that the protocol can be applied to large scale preparation in both academia and industry…. I will ensure it’s on my day off!


Decarboxylative Esterification of Carboxylic Acids with Dialkyl Dicarbonates

To continue on from the esterification theme of our recent blog (Palladium catalyzed oxidative esterifications of aldehydes and benzylic alcohols) I would like to highlight 2 papers on the subject of decarboxylative esterification of carboxylic acids from professor Gooßen’s group at the Max-Planck-Institut für Kohlenforschung.

Gooßen’s first paper (Adv. Synth. Catal., 2005, 345, 943-947) describes the exploration of conditions for the optimisation of Lewis acid catalysed decarboxylative esterification of carboxylic acids with dialkyl dicarbonates (Scheme 1).

Scheme 1

Gooßen showed that in the presence of Bronsted acids almost no ester formation was observed and that DMAP only yielded a modest catalytic activity using the conditions previously described by Takeda. In contrast to these results it was shown that the all the Lewis acids investigated gave the desired ester with a catalyst loading of only 1 mol % (Table 1).

Table 1

Gooßen’s selected nitromethane as the solvent to further explore the generality of the chemistry, due to the carboxylic acids being readily soluble in it, but the reaction works equally well in methanol, dichloromethane or acetonitrile.

Both magnesium perchlorate and copper triflate are mild enough Lewis acids that transesterification of the sensitive phenol ester did not occur (table 1, entries 25 and 26) but they were both still able to convert the carboxylic acid into a methyl ester in a quantitative yield. Based on these results coupled with both environmental and economical considerations it was decided that magnesium perchlorate was the superior choice of Lewis acids for this reaction.

With these variables fixed the scope of this reaction was further explored with a range of carboxylic acid and dialkyl dicarbonates (table 2). All of the reactions produced the desired esters in high yield except for amino ester 8c. Both the methyl ester 8a and benzyl ester 8b were produced as expected but the t-butyl ester was unstable under the reaction conditions, producing isobutene and the carboxylic acid starting material.

Table 2

Gooßen believes that the reaction proceeds via an intramolecular decarboxylation due to methyl ester 18a (table 2) being formed in a high yield (92%). If only an intermolecular reaction of the mixed anhydride occurred then a statistical mixture of the methyl ester, lactone and oligomeric esters should be formed.  In an attempt to confirm this hypothesis Gooßen reacted phenylpropionic acid with dimethyl dicarbonate and Mg(ClO4)2 in the presence of 1 equivalent of n-butanol. The desired methyl ester formed (81%) but also a quantity of the n-butyl ester (19%).  Gooßen is investigating the mechanism of this reaction and will report his finding in due course.

In Gooßen’s second paper (Synlett 2004, 263–266) he describes a convenient protocol for the esterification of carboxylic acids with alcohols in the presence of di-t-butyl dicarbonate (Boc2O). By using a stoichiometric amount of a carboxylic acid, a primary or secondary alkyl alcohol and Boc2O, in the presence of a catalytic amount of N,N-dimethylaminopyridine (DMAP), gave high yields of the corresponding esters (Scheme 2).

Scheme 2

Gooßen investigated a range of catalysts (Hf(OTf)4, Mg(ClO4)2, Sc(OTf)3, Yb(OTf)3 and DMAP) as well as a selection of solvents (nitromethane, THF, toluene, DMF and MeCN) before arriving at his standard conditions (1.0 mmol 3-phenylpropionic acid, 1.3 mmol Boc2O, 1.3 mmol benzyl alcohol, 5 % DMAP, 4 mL nitromethane, 50°C, 16 h). It was observed that the reaction gave the same yield regardless of the solvent used to run the reaction in.

Scheme 3

Gooßen exemplified this procedure by using a selection of alcohols that he coupled with 3-phenylpropionates (Scheme3, Table 3). The reaction produced the desired products in high yields with both primary and secondary alcohols. Groups including cyano, keto, ester and less reactive alcohols were tolerated.

Table 3

Gooßen then chose a selection of carboxylic acids that he then coupled to benzyl alcohol (Table 4). The reaction was able to be performed on aryl, alkyl, vinyl and heterocyclic carboxylic acids which contain ester, ketone, amide, ether and nitrile functional groups. Unfortunately the reaction failed to yield the desired product and resulted in decomposition of the starting material for o-fluorobenzoic acid and m-NO2-benzoic acid.

This procedure presents an advantage over the use of alkylating reagents such as alkyl halides for esterifications due to the relative costs of reagents and the larger range of alcohols that are available.

Table 4

In summary both papers offer alternative approaches for synthesising esters from carboxylic acids. The reactions are mild enough to tolerate a large range of functional groups and use cheap, readily available starting materials. The work up of these reactions is also simplified by the fact that most of the by-products are either volatile or water-soluble and this make these methods very practical for a synthetic chemist to use.