Hemetsberger Indole Synthesis

Indole Ring Synthesis From Natural Products to Drug Discovery, First Edition. Gordon W. Gribble. 2016 John Wiley Sons, Ltd. Published 2016 by John Wiley Sons, Ltd. 

26 (A575C) (Angiotensin converting enyme inhibitor and beta-adrenoceptor blocker) [38] 

28 (Neural stem cell derived neurosphere differentiation inducer) [40] 

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 

An important review of the synthesis and utility of azides is that of Scriven and Turnbull [73]. 

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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. 

Other references related to the Hemetsberger indole synthesis are cited in the literature. 

Scheme 3 Applications of the Hemetsberger Indole Synthesis to Drug Synthesis...

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]. 

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. 

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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