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.