Hemetsberger-Knittel synthesis

The preparation of an indole (nitrene generated from an azide - the Hemetsberger-Knittel synthesis) and of carbazole ° (nitrene generated by deoxygenation of a nitro group) illustrate the power of the method. 

In a complementary sense, thermolysis of P-azido-styrenes also gives indoles, but here the intermediate may be an azirine ° this method, the Hemetsberger-Knittel synthesis, is particularly useful for the fusion of a pyrrole ring onto rings other than a benzene ring, as illustrated. ... 

According to Hemetsberger-Knittel and others, AAE is widely used for the synthesis of heterocycles such as aziridines, pyrroles and indoles Due to its explosive properties, AAE may only be transported in special containers as a solution in various solvents. To reduce the safety risks and yield losses, an immediate conversion (possibly at the production facility) without transport is reconunended. The production scale might be in the range of lOOkg/a. 

Scheme 5.12 Synthesis of vinyl azides from aldehydes and azidoacetates by Hemetsberger-Knittel reaction ...

Hemetsberger and coworkers published in 1969 the special condensation reaction of benzaldehydes 76 with ethyl azidoacetate (77a) in the presence of sodium ethoxide to get moderate to good yields of the a-azidocinnamic esters 79a (Scheme 5.12). The temperature and the reaction time had to be controlled careMly, because the strongly alkaline reaction conditions induced the danger of decomposition of the base-sensitive azides 77 and other unwanted side reactions. Thus, Knittel reported some years later that usage of methyl azidoacetate (77b) and sodium methoxide offers several advantages in the synthesis of vinyl azides 79b. Nevertheless, the Hemetsberger-Knittel reaction can only be... 

R =aryl) in aprotic solvents, for example, xylene at 140 °C, is more important and has been applied very frequently to prepare indoles of type 176 via intermediate 172. This method is connected with the names of Hemetsberger and Knittel and can be transferred to the synthesis of azaindoles, fused indoles, and fused pyrrol derivatives. Quite recently, reactions like 171 (R =Ph) —> 176 have been conducted in a rhodium(II)-catalyzed way, which allows to decrease the necessary temperature into a range of 25-60 C. The transformation of 171 into isoquinolines is also possible if one or both ortho positions of the aryl group R are substituted appropriately. ... 

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