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).

azide3

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).

azide5

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!

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One-Pot Synthesis of Substituted Ureas Directly from Primary Alcohols


Publications that describe novel and unusual transformations or interesting one-pot procedures always grab my attention and the latest paper by Chi Zang et al. in Synthesis eFirst is a prime example of this.

Zang set out to develop a phosgene and transition metal free, easily handled, and mild method to synthesise substituted ureas. In this paper Zang describes a one-pot transformation of primary alcohols and amines into unsymmetrical ureas (scheme 1). This work builds on and optimises some previous work from Zang’s group where they use iodobenzenedichloride and sodium azide in acetonitrile to convert primary alcohols into carbamoyl azides, albeit in low yields.

After screening a selection of solvents, hypervalent iodine reagents and the number of equivalents of reagents required Zang’s best conditions used 5 equivalents of iodobenzenedichloride and 10 equivalents of sodium azide in ethyl acetate.

To test the generality of these conditions a variety of primary alcohols were converted to their respective carbamoyl azides (table 1). It was found that, regardless of the electronic or steric properties of the alcohols, all of the reactions proceeded smoothly. It is also noteworthy that no racemisation was observed with chiral alkyl alcohol 1h (table 1, entry 8).

With the synthesis of the first stage of the reaction optimised Zang proceeded to test his hypothesis that both symmetrical and unsymmetrical ureas could be synthesised from alcohols. Zang chose 4-methylbenzyl alcohol (1b) and aniline as the model substrates and as expected, 1-phenyl-3-p-tolylurea (3a) was isolated in high yields (table 2). It was also shown that by increasing the number of equivalents of aniline a small improvement in the yield could be achieved as well as a reduction in the reaction time.

Utilising these reaction conditions Zang explored the range of anilines to gage the generality for this new one-pot procedure (table 3). Satisfyingly all of the anilines examined, which included electron poor, electron rich and sterically hindered molecules, produced the desired products in good to excellent yields. Alkyl amines (table 3, entries 11-13) also gave the desired ureas in good yields. Zang acknowledges that 8 equivalents of the amine coupling partner is not ideal but he does explain that a majority of this excess can be recovered by a simple workup and gave the example that 4-bromo-aniline was recovered in a 78% yield (table 3, entry 4).

On the basis of the above experimental results and his previous related work, a stagewise reaction mechanism for the present one-pot transformation of primary alcohols to substituted ureas is proposed: i) oxidation of the primary alcohols to the corresponding aldehydes, ii) conversion of the aldehydes into acyl azides, iii) formation of carbamoyl azides from the acyl azides via Curtius rearrangement and subsequent addition of hydrazoic acid, and iv) transformation of the carbamoyl azides with amines to the corresponding ureas (scheme 2).

 

With this proposed mechanism Zang wanted to understand why the reaction gave higher yields when run in ethyl acetate compared to acetonitrile. He used benzyl alcohol to investigate the kinetic formation of benzaldehyde and benzoyl azide. The studies showed that the benzyl alcohol was completely oxidised to benzaldehyde within 30 minutes at 0 °C in both acetonitrile and ethyl acetate with only trace amounts of benzoyl azide observed. After stirring for a further 4 hours all of the benzaldehyde in ethyl acetate was converted to benzoyl azide but even after stirring for 5 hours only a small proportion of the benzaldehyde in acetonitrile was converted to benzoyl azide. [Bis(azido)iodo]benzene, the active intermediate generated when sodium azide is added iodobenzenedichloride, has been shown to be unstable at 0 °C and to decompose to iodobenzene and nitrogen gas. It was seen that in contrast to the reaction in ethyl acetate when the reaction was run in acetonitrile a large amount of gas was generated from the reaction mixture. A ligand-exchange experiment was undertaken to attempt to understand these differences. These results showed that the speed of the ligand-exchange reaction between iodobenzenedichloride and sodium azide is faster in acetonitrile than that in ethyl acetate; consequently, the concentration of the reactive intermediate [bis(azido)iodo]benzene would be higher in acetonitrile and thus kinetically result in the faster decomposition of [bis(azido)iodo]benzene.

 

In conclusion this paper demonstrates a phosgene and transition metal free, easily handled, and mild one-pot method to synthesise substituted ureas. It also includes a good explanation for the differences in yields that were observed when the reaction was run in different solvents. I believe that this methodology could be modified to synthesise carbamates in one-pot by the addition of an excess of an alcohol (instead of the amine) to the carbamoyl azide intermediate.