Hemetsberger reaction

Although the Hemetsberger reaction is clearly a powerful synthesis of indole-2-carboxylates, some problems are encountered in addition to the occasional mixture of nitrene cyclization products. Indeed, often the aldoliza-tion route to the 2-azidocinnamates proceeds poorly. This can be obviated at lower temperatures (-30 °C) to stop the reaction at the azido alcohol stage. Subsequent dehydration with thionyl chloride in pyridine or triethylamine afforded the 2-azidocinnamates. This two-step process was superior to the conventional one-step aldolization/ dehydration reaction, as found by Murakami and coworkers [67]. Tercel s group also observed that a low temperature (-78 °C) aldol condensation, isolation of the azido... 

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

Aza-indoles can be prepared from 2,6-dichloropyridin-3-yl-epoxides by reaction with primary amines " and 5-, 6-, and 7-azaindole-2-esters can be made" via the Hemetsberger-Knittel route. Note that 4-aza-indoles cannot be made this way since cyclisation of the appropriate precursor takes place preferentially onto the ring nitrogen generating a pyrazolo[l,5-fl]-pyridine. 

Although the mechanism of Hemetsberger indole synthesis is not quite clear, the reaction is postulated to proceed via a highly electrophilic singlet nitrene species, which then inserts into an aromatic ring to form the indole derivatives. In addition, 2H-azirines are also proposed as the intermediates for this reaction, arising from the insertion of nitrene to the adjacent double bond. A tentative mechanism is given below. 

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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